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Evidence Tables: Injection- Hyaluronic Acid (Knee)
Hyaluronic Acid Injection for Osteoarthritic Knee Pain
Evidence of effectiveness
5 systematic reviews (5 included)
−/~ (1)
~ (1)
~/+ (3)
43 experimental studies (41 included)
- (2)
+ (7)
−/~ (7)
~ (10)
12 observational studies (9 included)
0
0.5
1
1.5 (4)
~/+ (13)
2 (2)
~/+ to NR (1)
~/+ to + (3)
2.5 (3)
Evidence of safety and harm
2 other reports
5 studies appraised as low quality (excluded above)
Generic legend:
n/a - not applicable
n/s - not stated
n/r - not relevant
? - unsure or unclear
1
Evidence Tables: Injection- Hyaluronic Acid (Knee)
Systematic Reviews
study
authors and
year
study
inclusion &
exclusion criteria
exposure /
comparison
treatment
(number of
studies
included)
common outcomes
among studies
results
validity / applicability
yes
no
n/a
n/s
conclusions, comments
and quality scores
Objective
To determine if IA hyaluronic
acid (HA) injections improve pain
and function in patients with
osteoarthritis (OA) in their knees.
Exposure
IA injections course of
HA
Reported products (no. of trials)
Hyalgan (N=5)
Artza (N=1)
Synvisc (N=6)
Orthovisc (N=)
Suplasyn, (N=2)
BioHy (N=1)
Hyalart (N=1)
Low MW unspecified (N=1)
Case series N=5 (main details tabulated for each trial,
text synthesis)
Patients population: Middle aged, more females than
males
Molecular weight(MW) of HA: 3/5 used high MW
HA (Synvisc)
focussed question
thorough search strategy
search terms defined
yes
yes?
yes
Validity: -/~
Precision: −
Applicability: ?
appropriate inclusion / exclusion criteria
yes
Overall quality: -/~
two reviewers – selection
study validity rated
two reviewers – validity
valid combination of studies
appropriate analysis
n/s
yes
n/s
n/a
no
all important outcomes considered
balance between benefits and harms
fair conclusions from evidence
yes
yes
?yes
Authors’ conclusions:
High molecular weight HA is an
effective treatment for patients with
knee OA or who have ongoing pain or
are unable to tolerate conservative
treatment or joint replacement. HA has
a slower onset of action than IA steroids
but the effect seems to last longer.
study design
Aggarwal, A., &
Sempowski, I. P.
(2004).
Hyaluronic acid
injections for knee
osteoarthritis.
Systematic review of
the literature.
Canadian Family
Physician, 50(FEB),
249-256.
Systematic review
Participants
Tabulated for each of the 18
studies
Inclusion
Primary research trials with
clinical outcome measures related
to treatment with HA.
Exclusion
Primary outcome measure
histologic, biologic or
arthroscopic.
Overall population sizes
Patients, N=NR
Knees, N=NR
Injections, N=NR
Overall drop-out
N=NR
Included studies
Screened
N=NR
Eligible
N=NR
Evaluable
N=31?
Included
N=18
Comparison
None, saline placebo,
NSAIDs, local
anaesthetic
Studies
Case series
Lussier et al., 1996
Frizziero et al., 1998
Kotz & Kolarz 1999
Goorman et al., 2000
Evanich et al., 2001
RCTs
Adams et al., 1995
Lohmander et al., 1996
Wu et al., 1997
Wobig et al., 1998
Altman & Moskowitz
1998
Huskisson & Donnelly
1999
Payne & Petrella 2000
Brandt et al., 2001
Tamir et al., 2001
Bunyaratavej et al 2001
Petrella et al., 2002
Miltner et al., 2002
Raynauld et al., 2002
Duration
6 wks –2.5 years
Endpoints
All outcome measures
reported/tabulated
Results summary: data from 3 HMW studies
demonstrated significant improvement in pain, activity
levels and function. Authors reported that lack of
blinding and controls, recall bias, unclear ITT analysis
and poorly documented co-intervention made results
difficult to interpret.
RCTs N=13 (main details tabulated for each trial, text
only synthesis)
MW of HA: 3/13 used high MA HA (Synvisc)
Results summary; the three HMW studies
demonstrated significant improvements in pain,
activity levels and function. Studies of LMW HA had
conflicting results.
Reviewer’s comments:
Weak systematic review, no statistical
analysis.
Problems: lack of blinding of injector, possibly conflict
of interest, heterogeneity of study design, patient
population, study design, FU and outcomes made data
unsuitable for meta-analysis.
Safety and side effects; injection site pain and swelling
were the most common adverse effects (AEs).
Systemic reactions were rare.
2
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study
authors and
year
study
inclusion &
exclusion criteria
exposure /
comparison
treatment
(number of
studies included)
common
outcomes
among
studies
results
Objective
To review the scientific evidence
on the efficacy, effectiveness, and
safety of intra-articular injections
of Hylan G-F 20 for the treatment
of knee osteoarthritis.
Exposure
IA injection of hyaluronic
acid
Reported products,
Hyalgan
Artzal
Synvisc
Orthovisc
BioHy
Overall population sizes
Patients, N= NR
Knees, N=2252 (safety), N=1647
(effectiveness)
Injections, N=NR
Drop-out, N=NR
Studies (all RCTs)
Altman & Moskowitz, 1998
Bragantini et al., 1987;
Brandt et al., 2001;
Carrabba et al., 1995;
Cohen et al., 1994;
Corrado et al., 1995;
Creamer et al., 1994;
Dickson et al., 1998;
Dixon et al., 1988;
Dougados et al., 1993;
Grecomoro et al., 1987;
Henderson et al., 1994;
Huskisson & Donnelly,
1999;
Lohmander et al., 1996;
Puhl et al., 1993;
Sala & de Miguel, 1995;
Scale et al., 1994;
Tamir et al., 2001;
Wobig et al., 1998;
Wu et al., 1997.
Pain with activities
SPID% (overall efficacy)
ASPID% (adjusted efficacy)
Peak PID% (max efficacy)
SPID% Cross linked HA
SPID% Non-cross linked HA
ASPID% Cross linked HA
ASPID% Non-cross linked HA
Peak PID% Cross linked HA
Peak PID% Non-cross linked HA
study design
Wang, C. T., Lin, J.,
Chang, C. J., Lin, Y.
T., & Hou, S. M.
(2004). Therapeutic
Effects of Hyaluronic
Acid on
Osteoarthritis of the
Knee: A MetaAnalysis of
Randomised
Controlled Trials.
Journal of Bone &
Joint Surgery
American, 86(3),
538-545.
Systematic review
Meta-analysis
Inclusion
Single or double blind randomised
placebo controlled trials of
therapeutic effect.
Studies with outcome end points
for pain or function and
quantitative data on therapeutic
effects.
Exclusion
NR
Included studies
Screened
N=647
Retrieved N=61
Eligible
N=25
Evaluable
N=20
Included in MA
N=20
Comparison
IA injection of placebo
Endpoints
Pain with activity
Pain without
activity
Function
Duration
not reported
Pooled mean difference
7.9% (4.1-11.7%CI)
13.4% (5.5-21.3%CI)
9.9% (4.8-15.0%CI)
23.6%
5.4%
34.8%
8.7%
27.1%
7.4%
Note: SPID%= an integrated overall efficacy score with time as a dimension
ASPID% = adjusted SPID for baseline pain intensity
Peak PID% = maximum efficacy during trial
Heterogeneity: no significant heterogeneity (p>0.1) between non-cross-linked (low
molecular weight) studies for pain with activity and pain without activity scores.
Function
SFID% Cross linked HA
SFID% Non-cross linked HA
ASFID% Cross linked HA
ASFID% Non-cross linked HA
Peak PID% Cross linked HA
Peak PID% Non-cross linked HA
21.9%
5.3%
38.3%
11.7%
26.8%
8.2%
Note:
SFID%= an integrated overall efficacy score with time as a dimension
AFPID% = adjusted SPID for baseline pain intensity.
Peak FID% = maximum efficacy during trial
Notes
Heterogeneity: there was significant between study heterogeneity for the non-linked
studies (p<=0.01).
Publication Bias – funnel plots were symmetric suggested that publication bias was
unlikely.
Sub-group analysis
Study type differences: single blind trials and single centre trials had higher estimates
of efficacy than double-blind and multicentre trials.
Escape analgesic: trials with escape analgesic (Paracetamol) had smaller pooled mean
differences than those without.
Patient age: trials with a patient mean age of 65 years or less had significantly positive
mean differences while those with a mean patients age greater than 65 years did not.
Radiographic stage: trials with patients with the most advanced radiographic stage had
smaller mean pooled differences than those with no advanced stage patients.
Trial size: trials with a sample size of 100 or more (N=2) had significantly positive
pooled mean differences however, those with 100 or fewer had greater pooled
differences.
Sponsorship: industry funded trials had greater pooled differences for pain without
activity than non-industry funded trials, but smaller pooled mean differences for pain
with activity and function.
Safety
Major adverse events 3/1002 (knees) non- crossed linked HA (0.003)
Major adverse events 1/139 (knees) crossed linked HA (0.007)
Minor adverse events pooled relative risk for all included trails = 1.19(95%
CI=1.01=1.41). there was no significant between study heterogeneity in the RR of
minor adverse events (p=0.585).
validity /
applicability
yes
no
n/a
n/s
conclusions,
comments and
quality scores
focussed question
thorough search strategy
search terms defined
yes
yes
yes
Validity: ~/+
Precision: ~/+
Applicability: ~
appropriate inclusion /
exclusion criteria
yes
Overall quality: ~/+
two reviewers – selection
study validity rated
two reviewers – validity
valid combination of studies
appropriate analysis
yes
yes
yes
yes
yes*
all important outcomes
considered
balance between benefits and
harms
fair conclusions from evidence
some
*studies weighted for size in
sub-group analysis
There was significant
heterogeneity for some trials
yes
yes
Authors’ conclusions:
The MA confirmed the
therapeutic efficacy and safety
of IA HA injection for the
treatment of OA of the knee.
Additional well designed
RCTs of high methodological
quality are needed to resolve
uncertainty around the
therapeutic efficacy of
different types of HA in
various clinical situations and
patient populations.
Reviewer’s comments:
Drop out and follow –up time
not reported and patient
populations not described.
Unpublished trials not
included but no publication
bias was apparent in the funnel
plots. There was significant
heterogeneity between the
trials, however sub-group
analysis allowed homogenous
trials groups to be established
for analysis.
Sub-group analyses were
generated from study level not
patient level data - but results
considered as hypothesis
generating not hypothesis
testing.
3
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study
authors and
year
study
inclusion &
exclusion criteria
exposure /
comparison
treatment
(number of
studies
included)
common outcomes
among studies
results
validity /
applicability
yes
no
n/a
n/s
conclusions, comments and
quality scores
Objective
To review the scientific evidence
on the efficacy, effectiveness and
safety of intra-articular injections
of Hylan G-F 20 for the treatment
of knee OA.
Exposure
IA injection of Hylan
G-F 20 (Synvisc®)
Reported products
Hylan G-F 20.
Placebo-controlled studies assessing one course of HA (no
data analysis given).
The evidence from 4 RCTs suggests that IA HA produces a
statistically significant and clinically relevant decrease of
painful symptoms and a short-term improvement in joint
function (3-6 months). Improvement is also found in the
control group which may be due a high placebo effect and/or
the benefit of fluid removal from the joint. The incremental
benefit was reported to be small. High study heterogeneity
precluded determination of effect magnitude.
focussed question
thorough search strategy
search terms defined
yes
yes
yes
Validity: +
Precision: ~/+
Applicability: ~/+
appropriate inclusion /
exclusion criteria
yes
Overall quality: ~/+
two reviewers – selection
study validity rated
two reviewers – validity
valid combination of studies
appropriate analysis
yes
yes
yes
n/a
?yes
all important outcomes
considered
balance between benefits
and harms
fair conclusions from
evidence
yes
study design
Espallargues, M., &
Pons, J. M. (2003).
Efficacy and safety
of viscosupplementation with
Hylan G-F 20 for the
treatment of knee
osteoarthritis: a
systematic review.
International Journal
of Technology
Assessment in Health
Care.,19(1), 41-56.
Systematic review
Partial meta-analysis
Participants
Main details tabulated
Inclusion
Experimental and observational
studies, published and
unpublished, human studies using
health outcomes IA injection of
Hylan G-F20 for the treatment of
OA of the knee compared with
placebo or other conventional
active treatment, English, French,
Italian or Spanish.
Exclusion
Studies including only surrogate
endpoints such as synovial fluid
analysis.
Abstract only publications
were included
Databases searched
MEDLINE, EMBASE,
HealthSTAR, Current Contents,
Cochrane Library
Included studies
Screened
N=NR
Eligible
N=NR
Evaluable
N=14
Included in MA
N=4
Number of participants
1724 patients + 298 additional
knees
Comparison
Placebo, conventional
active treatment, other
types of hyaluronic acid
(HA), different HA
treatment schedules.
Studies
RCTs
Adams 1995;
Bach 1997,
Wobig 1999;
*Dickson 1998, 1999;
Moreland 1993;
*Scale 1994;
Torrance 1999,
Raynaud 1999,2000;
*Wobig 1998,
Beks 1996;
Clinical series
Becks 1997;
Lussier 1996;
Marshall 1999;
Miller 1999;
Puttick 1995,
O’Hanlon 1995;
Weiss 1999.
Cross-sectional study
Sripada 1999.
* Also in Wang et al.,
2004
Endpoints
Weight bearing pain, WMOC
pain scale, % symptom free,
Need for TKA, overall response
to treatment, % improved
patients
Duration
FU 12-135 weeks
No of studies
N=14??
(10 experimental
Conventional therapy controlled studies
Meta- analysis of 3 RCTs suggest a RR of approximately 1.7
(graph only, small incremental effect). The RCT results
suggest that HA has comparable efficacy to that of oral
NSAIDs. HA seems to provide additional benefits over
conventional therapy but further data are required. There is
some evidence that cost-effectiveness and cost utility ratios
favour Hylan G-F 20 over appropriate care without HA.
Parallel group (with other IA) controlled studies
Two RCTs and a descriptive study by postal survey compared
Hylan G-F 20 with a low molecular weight sodium HA. The
results suggested that Hylan G-F 20 was more effective in the
reduction of acute symptoms than the LMW products BUT
small sample numbers and self reporting limit the validity of
the results.
yes
yes
Authors’ conclusions:
There is good quality scientific evidence that
Hylan G-F 20 is safe, well tolerated and provides
short term decrease in pain and improved joint
function. A delay in the need for knee
replacement and long term durability of effect
has only been demonstrated in uncontrolled
clinical series. The evidence is not sufficient to
reach firm conclusions on the effect of multiple
courses of Hylan G-F 20 on health outcomes.
Reviewer’s comments:
Only one product assessed
Limited data analysis
Cumbersome tabulation of summary results of
each trial most result reporting and analysis
textual.
The study was solely financed by Biomatrix UK
the manufacturers of Synvisc®
Uncontrolled studies (n=6)
Two before and after studies and 4 post intervention studies.
Reporting quality was variable. Overall 40% or more of the
patients showed an improvement in their symptoms and 70%
or more did not need a total knee arthroplasty. One study only
considered safety.
Multiple courses of Hylan G-F 20
5 longitudinal descriptive studies of limited scientific merit.
They describe similar results after multiple courses of Hylan
G-F-20 compared with the baseline treatment course. Self
selected study populations with high potential for selection
bias.
Safety
Available data suggests that local adverse events with Hylan
G-F 20 are generally infrequent of mild severity and transient
and appearing in 0%-8.3% of the patients/knees and 0%-2.7%
of all injections administered. No differences were found
between groups. Controlled studies reported the lowest rates
of local AEs. Generally there were no systemic reactions and
little evidence of the potential long-term adverse effects of
repeated exposure.
4
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study
authors and
year
study
inclusion &
exclusion criteria
exposure /
comparison
treatment
(number of
studies
included)
common
outcomes among
studies
results
validity /
applicability
yes
no
n/a
n/s
conclusions, comments and
quality scores
Objective
To evaluate whether IA hyaluronic acid
is efficacious in treating knee OA.
Exposure
IA hyaluronic acid at
least once a week for
3 weeks for treatment
of OA of the knee
Endpoints
Pain (1 outcome measure)
Effect size and precision
Forest plot: Most trials had 95% CI that included an
effect size of zero. Trials with the highest MW
products had large effect sizes.
focussed question
thorough search strategy
search terms defined
yes
yes
yes
Validity: ~/+
Precision: ~
Applicability: -/~
appropriate inclusion / exclusion
criteria
yes
Overall quality: ~
two reviewers – selection
study validity rated
two reviewers – validity
valid combination of studies
appropriate analysis
n/s
yes
yes
?yes
no
Authors’ conclusions:
IA HA has a small effect when compared to IA
placebo and the presence of publication bias
suggests that this may have been overestimated.
Lower molecular weight HA may be less
efficacious than the highest MW products.
Heterogeneity of studies limits conclusions.
all important outcomes considered
balance between benefits and harms
fair conclusions from evidence
no
no
yes
study design
Lo, G. H., LaValley,
M., McAlindon, T.,
& Felson, D. T.
(2003). Intraarticular hyaluronic
acid in treatment of
knee osteoarthritis: a
meta-analysis. Jama.,
290(23), 3115-3121.
Systematic review
Meta-analysis
Inclusion
English and non-English studies,
human, RCTs single or double blind
placebo controlled. Pain reported by
one of the outcome measures
recommended by the ORS, minimum
follow-up- of 2 months and drop-out
rate of less than 50%.
Exclusion
NR
Studies
Screened
N=57
Eligible
N=21
Evaluable
N=22*
Included in MA
N=22*
*one study had two separate
comparisons.
Comparison
IA placebo in the
treatment of OA of
the knee.
Duration
Min FU =2 months
ITT analyses used
Studies (all RCTs)
Dixon et al., 1988
Russell et al., 1992
Dougados et al.,
1993
Puhl et al., 1993
Dahlberg et al., 1994
Creamer et al., 1994
Henderson et al.,
1994
Cohen et al., 1994
Scale et al., 1994
Corrado et al., 1995
Sala & de Miguel
1995
Carrabba et al., 1995
Lohmander et al.,
1996
Wobig et al., 1998
Altman &
Moskowitz 1998
Huskisson &
Donnelly 1999
Brandt et al., 2001
Tamir et al., 2001
Petrella et al., 2002
Karlsson et al., 2002
Pham et al., 2003
Jubb et al., 2003
Measure of effect
Standardised mean
difference of change from
baseline pain at 2-3 months.
Patients=2927
Knees=2949
Injections=NR
Drop-out=12.4%
Reported products, no of
studies
Hyalgan,,N=11
Artzal,,N=4
Synvisc,N=3
Orthovisc, N=1
Hyalart, N=1
BioHy, N=1
Suplasyn, N=1
Heterogeneity all trials: p<0.001
Heterogeneity LMW: p=0.58
Heterogeneity HMWS: p<0.001
Measure
Pooled effect size (all): ES 0.32; 0.17-0.47 95%CI;
p<0.001
Pooled effect size (LMW): ES 0.19; 0.10-0.27 95%CI;
p<0.001
Publication bias: Asymmetrical funnel plot—p=0,07a
Pooled effect size unpublished studies: ES 0.07; -0.15
to 0.28 95%CI
Adverse events not reported
ES=effect size
IA= intra-articular
LMW= low molecular weight
HMW = high molecular weight
OA= osteoarthritis
HA=hyaluronic acid
MA=meta-analysis
ITT=intention to treat
Reviewer’s comments:
Pain from baseline at 2-3 months does not
allow time for placebo effect, (which is know
to occur and is known to be short lived) to be
distinguished from longer term treatment
effects.
Quality of studies not assessed and patient
populations not reported.
Adverse events not reported
5
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study
authors
and year
study
inclusion &
exclusion criteria
exposure /
comparison
treatment
(number of
studies
included)
common
outcomes
among
studies
results
validity /
applicability
yes
no
n/a
n/s
conclusions, comments and quality scores
Objective
To examine the strength of the
eveidence and the cost
effectivenss of intra-articular
viscosupplementation for the
treatment of OA of the knee to
assist the Minister to determine if
there should be pubic funding
support for this procedure.
Studies N=10
Exposure
IA hyaluronic acid
Endpoints: Pain
physical function
patient global
assessment. Joint
imaging, to evaluate
the extent of joint
space
narrowing(long-term
(≥ 1 year trial) quality
of life, utility
measures and a
global assessment
performed by a
medical practitioner
optional assessment
outcome variables
can include extent of
inflammation,
stiffness, biologic
markers and others
(eg analgesic use).
Where possible,
length of time
until total knee
replacement surgery
was also evaluated
No difference at 26 weeks
focussed question
thorough search strategy
search terms defined
yes
yes
yes
Validity: ~/+
Precision: ~
Applicability: ~/+
appropriate inclusion /
exclusion criteria
?no
Overall quality: ~/+
two reviewers – selection
study validity rated
two reviewers – validity
valid combination of
studies
appropriate analysis
?
yes
no
?
all important outcomes
considered
balance between benefits
and harms
fair conclusions from
evidence
yes
study
design
Medical Services
Advisory
Committee. Intraarticular
viscosupplementat
ion for treatment
of osteoarthritis of
the knee.
Canberra: Medical
Services Advisory
Committee,
2003:1-88.
Systematic
review
Inclusion
(not reported separately)
Identified citations were selected
based on strict inclusion and
exclusion criteria that described
the study patient compositions,
intervention evaluated, study
design, outcomes measured, the
comparator and language of the
publication.
RCTs or non-randomised
comparative studies for
effectiveness. RCTs and cohort
studies for safety.
Exclusion
Placebo controlled trials. No
other criteria mentioned.
Included studies:
Screened
N=1687
Potentially eligible
N=152
Evaluable
N=10
Note: only 9 of these studies
were eligible for the ACC review
Comparison
IA corticosteroid
NSAIDs
COX-2 inhibitors
Appropriate care
Other
viscosupplementation
products
Duration
No reported
Pain outcomes
Pietrogrande(1991)
Leardini (1991)*
Leardini(1987)**
Dickson(2001)
Raynauld(2000)
Altman (1998)***
Adams 1995***
Wobig 1999
Petrella 2002*
No pain outcome
Tekeoglu 1998*
* also assessed on the
ACC review
** considered to be an
earlier report of Leardini
1991
*** reported in an
assessed SR
Pain
HA vs NSAIDs:
Altman 1998
Hylan G-F 20 vs
NSAIDs
Dickson 2001
Hylan G-F 20 +
NSAIDs
vs NSAIDs: Adams
1995
Hylan G-F 20 vs low
MW HA: Wobig:
1999
HA vs IA steroids :
Pietrogrande 1991
Hylan G-F 20 +
appropriate care vs
appropriate care :
Raynauld 2000
Greater improvement in scores for pain at night,
walking on a flat surface, pain sitting or lying at 12
weeks
Reduced mean pain score at 26 weeks, greater
number of patients symptom free of pain with
motion, at rest and at night at 26 weeks.
Data unavailable fro conclusion
Trend for reduced risk under load at 60 days, no
difference for night, touch or pain at rest at 60
days.
Lower mean pain score at one year.
Safety and Adverse Events
Studies included in this review are limited in their
assessment of adverse events.
Viscosupplementation with HA compounds has
similar incidence of local adverse events (ie at the
level of the knee) as intra-articular (IA)
corticosteroid injections but greater incidence than
non-steroidal anti-inflammatory drugs (NSAIDs).
Conversely, IA injection of HA produces fewer
systemic adverse events (specifically
gastrointestinal upset) than NSAID treatment.
Studies showed that viscosupplementation with
hylan G-F 20 produces a similar incidence of local
adverse events as injection with lower MW
hyaluronic acid viscosupplement and with
NSAIDs.
Hylan G-F 20 combined with appropriate care
showed a higher incidence of local adverse events
when compared with appropriate careonly.
Conversely, hylan G-F 20 was found to have a
lower incidence of systemic adverse events than
NSAIDs.
There was no difference in systemic adverse events
when hylan GF20 combined with appropriate care
was compared with appropriate care only.
However, hylan G-F 20 plus appropriate care was
found to be associated with a lowerrisk of side
effects and gastrointestinal adverse events when
compared with appropriatecare only.
No studies were found that compared safety,
effectiveness or cost-effectiveness of HA or hylans
with COX-2 inhibitors.
?
?no
yes
Authors’ conclusions:
From the limited evidence available, HA was found to be as effective as, but no more
effective than, NSAIDs at improving patient perceived pain scores, physical function,
patient global assessment or stiffness scores. HA was found to be as effective as, but
no more effective than, IA corticosteroids for alleviating night, rest and touch pain, but
found to show a trend for reduced risk of pain under load. HA improved physical
functioning and patient global assessment scores in comparison to IA corticosteroids.
Results of stiffness scores and analgesic use when comparing HA to IA corticosteroids
were inconclusive and contradictory.Comparison with a lower MW HA was
inconclusive due to poor data reporting.
The combination of hylan G-F 20 with appropriate care produced significant
improvements in pain, global assessment, physical function and stiffness compared to
appropriate care alone. However, these results were questionable due to potential bias
inherent in the study design.
Overall, hylan G-F 20 was associated with some level of improvement in measures
suchas mean pain scores at 26 weeks when blinding was instituted, particularly in
combination. with NSAID therapy. However, these results were found in a single
study of relatively small size.
Authors’ comments:
The majority of RCTs uncovered in the search for viscosupplements for osteoarthritis
(OA) of the knee have been performed using a placebo treated group as the control.
Studies comparing the effectiveness of HA or hylan to IA corticosteroids or NSAIDs
were few. No studies comparing COX-2 inhibitors were found. The design and
heterogeneity of the studies included in this review provided for few strong
conclusions of the effectiveness ofviscosupplementation with HA or hylan.
Reviewer’s comments:
The use of a placebo control was not considered to be a legitimate comparator –only
comparator treatments that were part of the Australian clinical pathway were
considered. This eliminated a large number of placebo controlled trials from this
evidence review. The search cut-off date was August 2002; there have been at least
four SRs published since then.
Inclusion and exclusion criteria for studies were not clearly documented.
Only one evaluator was used to assess the studies – this is not usual MSAC procedure.
Also, studies used mixed high and low weight HA, few high molecular weight studies.
Conclusions are based on all outcomes not just pain and rely heavily upon an assertion
that most of the studies were underpowered. It is not clear how the power calculations
were made to support this assertion and what clinical criteria were used to set the level
of improvement.
The purpose of this HTA was to assess effectiveness and cost effectiveness with a
view to funding. In this setting the intervention has to be better than the comparators
and/or more cost effective.
6
Evidence Tables: Injection- Hyaluronic Acid (Knee)
Experimental Studies
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
To compare the
efficacy and
tolerability of a
course of hylan G-F
20 (HA) therapy to a
typical course of
triamicinolone
hexacetonide (TH)
therapy.
Inclusion
Ambulatory males and
females, 40 years of
older, general good
health, diagnosed with
OA of the knee by the
criteria of the ACR at
least 3 months prior to
study entry. Patients
were required to have
been taking analgesics or
NSAIDs for at least 3
days a week for 2
months and have a score
of > 2 on QA1 of the
WOMC at screening, 14
days prior to starting
therapy and 50-90 mm
on a VAS for both
patients and investigator
overall assessment of
the target knee at
baseline. Women of
child bearing potential
were required to be using
adequate means of
contraception.
Exposure (HA)
Synvisc®
Hylan G-F20 3 X 2ml IA
injections given at one week
intervals
Mean
improvement
from baseline for
WOMAC scores,
patient and
blinded
investigator VAS
scores
HA (N=113) TH (N=102) p-value
Primary efficacy variables, Week 12
WOMAC A1 (0-4)
0.9±0.1
0.5±0.1
0.0071
Patient VAS (mm)
31.3±2.3
17.4±2.41 <0.0001
a
Blinded investigator VAS (mm) 32.0±2.2
25.3±2.3
0.0300
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
Exclusion
Patients having any
unstable medical
condition or actute
synovitis, allergy to
avian products/
hyaluronan-based
injection components
/cortico-steroid
injections Paracetamol,
inflammatory arthopathy
or infection in the area of
the injection site,
primary patellofemoral
knee pain, effusion
>10ml, venous or
lymphatic stasis in the
leg, claudation or
peripheral vascular
disease, malignancy
within 5 years, diabetic
neuropathy or related
infections and laboratory
abnormalities.
Target joint arthroplasty
Medication for pre-existing
medical conditions was allowed
and Paracetamol ( up to 4000
mg/day), analgesics or short
acting NSAIDs were allowed for
specific and limited time
periods.
study design
Caborn, D., Rush, J.,
Lanzer, W., Parenti, D.,
& Murray, C. (2004). A
Randomised, SingleBlind Comparison of the
Efficacy and Tolerability
of Hylan G-F 20 and
Triamcinolone
Hexacetonide in Patients
with Osteoarthritis of the
Knee. Journal of
Rheumatology, 31(2),
333-343.
RCT
Prospective
Multicentre
Single blind (evaluating
physician))
Parallel group
Screened
N=NR
Randomised
N=218
ITT=215
Evaluable
N=177
Completed
N=153
Comparison (TH)
Aristospan®
Triamcinolone hexacetonide
given as one IA injection of 40
mg (2 ml of a 20 mg/ml
suspension).
Concomitant medication
The use of glucosamine and/or
chondroitin sulphate, and prior
viscosupplementation in the
target knee or oral
corticosteroids or IA injection in
the target knee within 3 months
or non-target knee within 4weeks were not allowed. Longer
acting NSAIDS had to be
finished 7 days before study
start and NSAIDS with oncedaily dose regimens were not
allowed.
Study duration
26 weeks
Primary efficacy variables, Wk 26
WOMAC A1 (0-4)
0.7±0.1
Patient VAS (mm)
28.0±2.5
Blinded investigator VAS (mm) 30.0±2.3
0.4±0.1
0.0129
12.4±2.6 <0.0001
18.2±2.5 a 0.0004
Secondary efficacy variables, Wk 12
Full WOMAC (0-96)
20.7±1.6
WOMAC domain C score (0-68) 14.6±1.1
12.7±1.7
9.1±1.2
0.0004
0.0006
Secondary efficacy variables, Wk 26
Full WOMAC (0-96)
18.4±1.7
WOMAC domain C score (0-68) 13.0±1.2
10.4±1.8
7.5±1.2
0.0008
0.0010
Safety and adverse events
At least one AE
Overall incidence of AEs
Discontinuation due to AEs
SAEs
77%
DNR
10%
0
70%
DNR
10%
9b
ns
ns
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
n/s
yes
n/s
yes
no
yes
no
yes
yes
st*
yes
yes
y/n/s
yes
yes
conclusions,
comments, and
quality scores
Validity: +
Precision: +
Applicability: +
Overall quality: +
Authors’ conclusions:
Hyaluronic acid injections
results in a longer duration of
effect than steroid injections
with a comparable tolerability
profile. These data support the
preferential use of Hylan-F20
over triamcinolone hexacetonide
for the treatment of chronic OA
of the knee.
Reviewer’s comments:
27-28% of patient had severe
OA judged by radiology.
*st=short-medium term
FU
Recorded adverse events in ≥5% of all patients having at least 1
injection
Arthralgia
36
32
ns
Headache NOS
13
7
ns
Swelling NOS
9 (90?)
5
ns
Joint swelling
7
6
ns
Injection site pain
7
8
ns
Joint stiffness
6
3
ns
Injection site swelling
6
1
ns
Injection site oedema
5
7
ns
Back pain
3
6
ns
Joint stiffness
6
3
ns
a
n=101, b not considered to be treatment related
7
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
yes
no
n/a
n/s
conclusions, comments, and
quality scores
Objective
To compare
symptomatic relief
in terms of pain
and function
produced by
hyalgan and
arthroscopic
washout for OA of
the knee.
Inclusion
Symptomatic
OA of the knee
with
radiographic
evidence of
some remaining
joint space on
weight bearing
films, fit for
regional or
general
anaesthesia.
Exposure (HA)
Hyalgan
20 mg IA injection once
a week for 5 weeks +
joint effusion aspiration.
Knee society
rating score
(FS) and
VAS score
(10cm),
Lequesne
Index
function
score
Knee society rating score
(FS) and VAS score (10cm)
outcomes at 6wks, 3months,
6months, and 1year were not
significantly different from
baseline.
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
yes
yes
no
yes
no
yes
n/s
n/s
n/s
n/s
yes
yes
Validity: −/~
Precision: −/~
Applicability: ~
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
no
yes/n/s
yes
study design
Forster, M. C., &
Straw, R. (2003).
A prospective
randomised trial
comparing intraarticular Hyalgan
injection and
arthroscopic
washout for knee
osteoarthritis.
Knee, 10(3), 291293.
RCT
Prospective
Participants
Mean age 60 yrs
and 63 years
Study size
N=38
Waiting list for
arthroscopic
washout for OA of
knee
Exclusion
Mechanical
symptoms, IA
injection with
last 6 months,
previous
arthroscopic
surgery,
hypersensitivity
to avian
proteins.
Control (AR)
Joint effusion aspiration
(arthroscopic washout)
with general or spinal
anesthesia as
appropriate. Repair or
excision of tears or flaps
was carried out as
necessary.
FU
1 year
For the Lequesne Index (LI),
the function score was better
in the HA group compared to
the AR group, but unclear if
difference was significant.
Adverse events
Pain at injection site n=2
Potential for allergic reaction
to avian protein
FS= Knee Society Rating
System
IA= intra-articular
OA= osteoarthritis
HA=hyaluronic acid
yes
Overall quality: −/~
Authors’ conclusions:
The authors concluded that IA
injection with HA may be
considered as an alternative to
arthoscopic washout.
Reviewer’s comments:
4/38 lost to FU, 2/34 declined
surgery
Concealment by sealed envelop
Knee Society rating system worse
in control group.
Contamination with 2 of the HA
group having arthroscopy
Interventions 7/17 in HA and 3/15
in AR.
No costs given but AR intervention
reported to be expensive.
8
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To investigate structural
change as measured by
joint narrowing in
patients with OA of the
knee.
Inclusion
Primary OAS of the knee
(ARA/ACR) and
radiographic grade II or III
(Kellgren-Lawrence).
Exposure (HA)
Hyalgan 20mg/2ml IA
injection once a week
for 3 weeks and
repeated twice more at
four monthly intervals
i.e. 9 injections
Clinical
findings (e.g.
joint space
width) and pain
on walking
HA (N=136) PL(N=137)
Primary endpoints - all patients
Joint space width at baseline (mm) 4.9(1.6)
4.5 (1.6)
Joint space width wk 52 (mm)
4.8(1.7)
4.4(1.4)
Primary endpoints—Joint pace width ≥4.6mma
Joint space narrowing (mm)
0.55 (1.04) 0.13 (1.05)
Primary endpoints—Joint space width <4.6mm
Joint space narrowing (mm)
-0.20(1.12) 0.06(1.0)
Secondary endpoints (ITT)
st
DNR
DNR
Pain on walking wk 11 (1 cycle)
Pain on walking wk 35 (2nd cycle)
DNR
DNR
Pain on walking wk 52 (3rd cycle)
DNR
DNR
Assessors assessment 1st cycle
79.6
71.1
%response
nd
Assessors assessment 2 cycle
78.5
64.1
%response
Assessors assessment 3rd cycle
85.1
72.3
%response
Patient’s judgment cycles 1-3
DNR
DNR
Drop-outs
48
41
validity /
applicability
study design
Jubb, R. W., Piva, S.,
Beinat, L., Dacre, J., &
Gishen, P. (2003). A
one-year, randomised,
placebo (saline)
controlled clinical trial of
500-730 KDA sodium
hyaluronate (hyalgan) on
the radiological change
in osteoarthritis of the
knee. International
Journal of Clinical
Practice, 57(6), 467-474.
RCT
Placebo-controlled
Double-blind
Masked observer
Parallel group
Multi-centre (17)
Participants
Female: 63% (PL)and
73% (HA)
Mean age: 65yrs and 64
yrs
BMI: 30 and 30
Duration of OA: 8.5 and
7.9 yrs
Bilateral disease=90%
and 88%
Randomised
N=408
Completers
N=319
Primary analysis
N=273
Exclusion
OA of hip or any other joint,
psoriasis, sacroiliitis, other
joint disease, known or
suspected joint infection,
disease of the skin overlying
the treated knee, other
painful knee conditions or
severe concurrent illness. IA
corticosteroid or radiocolloid
in previous 3 months or
surgical procedures on the
legs, clinically important
axial deviation of the legs.
History of allergic reactions
to avian proteins, pregnant
or breast feeding.
Bilateral disease: the most
painful knee was treated.
Placebo (PL)
Saline 2 ml IA
injection once a week
for 3 weeks and
repeated twice more at
four monthly intervals
i.e. 9 injections
Concomitant
medication
Free use of analgesics
and NSAIDs except
indomethacin was
allowed, regimens
were required to be
stable for at least one
month before study.
Corticosteroids,
glucosamine and
chondroitin sulphate
not permitted.
Adverse events
At least one adverse event (% pts)
Flu syndrome
Injection site reaction
Pain
No drug-related SAEs
a
90
21
24
34
84
18
13
31
p-value
ns
ns
0.02
ns
0.018
0.007
0.048
0.010
0.033
0.018
ns
0.079
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
yes
yes
yes
yes/nob
yes
yes
yes
?
yes
yes
no
n/s
no
?
conclusions,
comments, and
quality scores
Validity: ~/+
Precision: +
Applicability: ~
Overall quality: ~
Authors’ conclusions:
Although in this one year study
no overall treatment effect was
seen, those with radiologically
milder disease at baseline had
less progression of joint space
narrowing when treated with
hyaluronic acid.
Reviewer’s comments:
Most patients had bilateral long
standing disease grade II or III.
Drop-out 33%
b
Primary endpoints =
completers, secondary
endpoints ITT.
cut –off was the median population JWS at baseline.
Trial duration
1 year
9
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
A comparison of the
medico-economic
benefits over 9 months in
506 patients given Hylan
GF-20 or conventional
treatment for knee
osteoarthritis
Inclusion
Age greater than 18
years predominantly
femorotibial
osteoarthritis meeting
the ACR criteria,
pain on walking
40mm or higher on
100mm VAS. At
least 2 courses of
NSAIDs of at least
10d each in the last 3
months (international
guidelines for HA)
and/or symptomatic
slow acting drug
taken continuously
during the last 2
months.
Exposure (HA)
Synvisc® 3 IA
injections in target
knee one week apart.
Effectiveness of
intervention as
measured by
Lequesne index,
WOMAC pain
scores, and costs
Mean effectivenessa
Lequesne index (points)
Difference (completion-baseline)
WOMAC Total score (mm)
WOMAC (A) pain (mm)
WOMAC (B) stiffness (mm)
WOMAC (C) function (mm)
validity /
applicability
yes
no
n/a
n/s
conclusions,
comments, and
quality scores
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
yes
yes
yes
yes
yes
no
no
no
n/s
n/s
yes
yes
Validity: +
Precision: +
Applicability: ~/+
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
yes
yes
study design
Kahan, A., Lleu, P. L., &
Salin, L. (2003).
Prospective randomized
study comparing the
medicoeconomic
benefits of Hylan GF-20
vs. conventional
treatment in knee
osteoarthritis. Joint Bone
Spine, 70(4), 276-281.
RCT
Prospective
Multicentre
Participants
Mean age: 66 years
Female: 68%
BMI:28 kg/m2
Stage IV disease:16%
Screened
N=NR
Randomised
N=518
Evaluable
N=506
Completed
N=450
Exclusion
Inflammatory flare in
the target knee,
viscosupplementatio
n in the target knee in
the last year,
glucocorticoid
injection into the
target knee within the
last 3 months, IA
procedure within the
last year, history of
synovectomy, tibial
osteotomy or knee
replacement surgery,
or surgery scheduled
in the next 9 months.
Comparison (CT)
Conventional
treatments
Duration
9 months
HA (N=253) CT (N=253)
7.9±3.6
9.9±3.5
-19.8±18.9
-8.1±20.0
-24.6±20.0
12.2±21.6
-20.7±25.9
-7.7±26.1
-18.4±19.6
-7.0±20.6
-37.4±22.3
-24.4±24.0
p-value
0.0001
0.0001
0.0001
0.0001
0.0001
0.0001
Mean cost per patient of management of knee OA for 9 months
HA
CT
HA-CT (%)
Physician visits
€136.80
€102.60
+33.4
Investigations
€20.70
€21.10
-1.7
Medications
€164.00
€271.10
-39.5
Non-pharmacological Rx
€46.40
€57.50
-19.4
Hospitalisations
€300.70
€325.60
-7.6
Cost of Synvisc
€116.70
€0
NA
Total medical costs
€785.30
€777.90
+1
Sick leave
€43.80
€51.60
-15.1
Total medical and sick leave
829.10
829.40
-0.04
Cost effectiveness ratio: based on a bootstrap analysis of 2500 simulations
Of the CER based on the area under the curve of the Lequesne index showed
that the ratio was negative or zero for 91.4% of the cases and that the mean
was - €1.78 (±105.22)
yes
Overall quality: +
Authors’ conclusions:
Viscosupplementation is more
effective than conventional
treatment at no additional cost.
Reviewer’s comments:
Conventional treatment not
detailed. Long term safety and
treatment (repeat courses) not
considered. Limited detail about
the sampling.
Large study, large numbers of
centres.
Recent study.
Comparative costing.
Adverse events, patients (%) 114 (44%) 83(32%)
The most common AE in the HA group was pain and/ or swelling at the
injection site. One of the most common AE in the CT group was
gastrointestinal symptoms.
a
mean effectiveness of treatment was estimated by calculating the area under
the curve over the 9 month study period.
IA= intra-articular
10
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To test the
hypothesis that
there was no
significant
difference between
Hylan G-F 20
(Synvisc®) and the
corticosteroid
betamethasone.
Inclusion
>18 years, radiographic
evidence of symptomatic
OA of the knee,
dissatistfaction with nonoperative management and
would have been offered
some sort of IA injection
to try to avoid knee
surgery.
Exposure
Hyalan G_F 20
(Synvisc) 2ml IA
injections once a week
for 3 weeks + knee
aspiration
N=50
Mean outcome
scores for
WOMAC, Knee
Society Rating,
and VAS pain
score
Median outcomes scores:
Participants
Age: medians 64,
66yrs
Female: 56%, 52%
Exclusion
Pregnant or lactating, bone
on bone arthritis on any
radiograph, radiographic
evidence of
chondrocalcinosis,
insufficiency of the
collateral ligament,
insufficiency of the
anterior or posterior
cruciate ligament with
symptomatic giving way
of the affected extremity,
or a current infection of
the affected extremity.
History of crystalline
arthropathy or
inflammatory arthritis,
neuropathic arthropathy,
and intra-articular knee
injection within the
previous 3 months and
allergy or hypersensitivity
to any of the study
medication or to avian
proteins.
validity /
applicability
yes
no
n/a
n/s
conclusions,
comments, and
quality scores
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
yes
yes
no
yes
no
no
yes
no
yes
yes
medium
term
no
Validity: ~/+
Precision: ~/+
Applicability: ~/+
study design
Leopold, S. S., Redd, B.
B., Warme, W. J.,
Wehrle, P. A., Pettis, P.
D., & Shott, S. (2003).
Corticosteroid compared
with hyaluronic acid
injections for the
treatment of
osteoarthritis of the knee.
A prospective,
randomized trial. Journal
of Bone & Joint Surgery
- American Volume., 85A(7), 1197-1203.
RCT
Single blind
Prospective
Screened
N=NR
Randomised
N=100
Evaluable
N=80?
Completed
N=77
Comparison
Corticosteroid
injection 2ml of
betamethasone sodium
phosphatebetamethasone acetate
mixed in 4 ml of
Marcaine and 4 ml of
lignocaine. 1 injection.
Note: no aspiration of
effusion and second
injection upon request.
N=50
Duration
6 months
Baseline
N=42/38
3 mos.
6 mos. Within-gp
N=40/37 N=41/36 p-value
WOMAC (points)
Corticosteroid
55
42
40
Hylan G-F 20
54
41
44
Between group p-value
-ns
0.98
Knee Society Rating (points)
Corticosteroid
58
72
70
Hylan G-F 20
58
69
68
Between group p-value
-ns
0.69
VAS (mm)
Corticosteroid
64
52
52
Hylan G-F 20
70
45
52
Between group p-value
-ns
0.94
Gender sub-analysis—WOMAC (points)
Corticosteroid Male
54
30
38
Hylan G-F 20 Male
54
28
54
Corticosteroid Female
60
48
48
Hylan G-F 20 Female
54
46
36
Gender sub-analysis—Knee Society rating (points)
Corticosteroid Male
66
85
86
Hylan G-F 20 Male
62
74
67
Corticosteroid Female
56
62
59
Hylan G-F 20 Female
53
68
70
Gender sub-analysis—VAS (mm)
Corticosteroid Male
67
46
36
Hylan G-F 20 Male
70
37
64
Corticosteroid Female
59
57
68
Hylan G-F 20 Female
69
46
45
<0.01
<0.01
-0.06
0.15
-0.28
<0.01
--
Drop outs<20%
<0.01
<0.01
0.16
<0.01
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
0.02
0.17
0.72
0.39
<0.01
0.02
0.73
0.08
Adverse events
No acute local reactions in the corticosteroid group and one in the Hylan
group. No further details given.
IA=intra-articular
?
yes/no
yes
Overall quality: ~/+
Authors’ conclusions:
The study demonstrated only
modest treatment effects from
baseline for both treatments
with no significant between
group differences in outcome
despite an 80% power to detect
clinically relevant differences.
Women demonstrated
significantly less response to
treatment than men.
?
Given the additional pain and
potential risk associated with 3
HA injections and the
approximately 100 fold
difference in pharmacy cost,
HA was not considered to be a
first line treatment for patients
considering IA injections for
palliation.
Reviewer’s comments:
The numbers in the hylan
treatment group fulfilled the
minimum of N=36 at 6 months.
The numbers in sub-group
analyses fell below the
minimum number required for
80% power.
There was limited information
about adverse events and safety.
Almost half of the corticosteroid
group (48%) opted for a second
injection during the study, this
was not incorporated in the subgroup analysis or its effects or
timing discussed.
Earlier case series
Leopold, S. S., Warme, W. J.,
Pettis, P. D., & Shott, S. (2002).
Increased frequency of acute
local reaction to intra-articular
hylan GF-20 (synvisc) in
patients receiving more than one
course of treatment. Journal of
Bone & Joint Surgery American Volume, 84-A(9),
1619-1623. is earlier report of
the same group and has not been
appraised separately
11
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To assess the efficacy of
intra-articular hyaluronic
acid in patients with OA
of the knee.
Inclusion
Female, ambulant,
idiopathic OA of the
knee (ACR criteria),
K-L radiological
grade II-III, pain
under weight bearing
>40mm on a VAS
scale.
Exposure
Orthovisc® MW=1.0-2.9
million Da, 2 ml IA injection
once a week for 3 weeks.
VAS pain score,
Lequesne
function index,
range of motion
Results (mean, ±s.d.)
Pain VAS
Baseline
Week 4
Month 3
Month 6
validity /
applicability
study design
Tascioglu, F., & Oner, C.
(2003). Efficacy of intraarticular sodium
hyaluronate in the
treatment of knee
osteoarthritis. Clinical
Rheumatology, 22(2),
112-117.
RCT
Open-label
Prospective
Parallel group
Participants
Mean age:57 and 60yrs
Female: 100%
BMI=33
Disease duration 67years.
Screened
N=NR
Randomised
N=69?
Evaluable
N=60
Completed
N=55
Exclusion
K-L grade IV, knee
joint disease other
than OA, hip or foot
OA, serious
concomitant systemic
disease, IA injection
within 3 months of
the study, skin
infections overlying
the joint, IA fluid
effusion, history of
allergy of
hypersensitivity to
drugs, treatment with
anticoagulants,
previous knee
surgery.
Comparison
6-MPA
1 ml of 6-methylprednisolone
IA injection once a week for 3
weeks.
Concomitant medication
Paracetamol allowed to a
maximum of 3 gr daily but not
for 48 hours before each
injection and clinical
assessment.
Duration
6 months
HA (N=28)
30.43(9.78)
11.83(11.47)
12.00(10.15)
23.56(10.11)
Weight bearing Pain VAS
Baseline
54.26(22.65)
Week 4
31.83(21.57)
Month 3
22.86(17.05)
Month 6
40.96(23.15)
6-MPA (N=27) p-value
29.90(10.15)
8.30(9.76)
19.70(11.72)
26.46(14.30)
53.10(18.30)
26.80(15.83)
38.50(16.53)
56.36(16.10)
ns
ns
0.030
ns
ns
ns
0.033
ns
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
Pain on walking VAS
Baseline
67.60(21.03)
Week 4
37.60(25.00)
Month 3
32.03(22.15)
Month 6
51.16(20.81)
Lequesne functional index
Baseline
10.23(1.88)
Week 4
7.86(1.47)
Month 3
7.66(1.60)
Month 6
8.46(2.04)
69.00(21.96)
38.00(16.01)
50.46(18.46)
66.06(20.83)
9.86(1.88)
7.96(1.58)
9.06(1.13)
9.60(1.83)
Active range of knee flexion (degrees)
Baseline
108.70(10.79) 108.06(10.27)
Week 4
116.36(7.79) 114.20(9.98)
Month 3
115.76(7.72) 113.40(8.10)
Month 6
114.60(8.19) 109.60(9.91)
ns
ns
0.015
ns
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes
n/s
n/s
no
no
no
no
n/s
medium
term
no
no
n/s
yes
yes
conclusions,
comments, and
quality scores
Validity: ~
Precision: +
Applicability: ~
Overall quality: ~/+
Authors’ conclusions:
Both IA HA and 6-MPA
provide clinically significant
improvement and that HA has
long-term beneficial clinical
effects in patients with knee
OA.
Reviewer’s comments:
Small study groups, probably
underpowered. Females only
recruited, 69 were recruited but
only 60 randomisations
reported.
ns
ns
0.042
ns
ns
ns
ns
ns
Bold = significant difference from baseline for that group
Paracetamol consumption: no significant difference between the
groups
Adverse events and safety: no treatment related serious adverse
event was reported. 6 (21%) NA and 5 (18%) 6-MPA patients
reported knee pain and swelling after injection. Overall 16 AEs
were reported by HA patients and 13 AEs by 6-MPA patients (ns)
including, musculoskeletal
(n=12), skin (n=3), GI (n=5), general (n=9).
12
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
Objective
To examine the
clinical efficacy and
structural effects of
of IA sodium
hyaluronate versus
methylprednisolone
actetate in the
treatment of OA of
the knee.
Inclusion
Primary or
secondary OA,KL
grades I-II,
fulfilling the
radiological criteria
of the American
College of
Rheumatology.
Exposure
(HA)
20mg (in 2ml)
hyaluronic acid, 500730 kDa) IA
injection once a week
for 5 weeks.
Overall function as
measured by flexion,
extension, duration
of morning stiffness,
overall improvement,
arthroscopic findings
results
validity /
applicability
yes
no
n/a
n/s
conclusions,
comments, and quality
scores
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
yes
yes
yes
no
yes
no*
yes
no
yes
yes
yes
no
Validity: +
Precision: ~
Applicability: ~/+
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
yes/n/s
yes
study design
Frizziero, L., & Pasquali
Ronchetti, I. (2002).
Intra-articular treatment
of osteoarthritis of the
knee: An arthroscopic
and clinical comparison
between sodium
hyaluronate (500-730
kDa) and
methylprednisolone
acetate. Journal of
Orthopaedics &
Traumatology., 3(2), 8996.
RCT
Single centre
Parallel group
Observer blinded
Participants
Age: 49 years
Male:46%
Female:54%
Primary OA=51%
Secondary OA=49%
KL-grade I =26%
KL-grade II=48%
KL-grade III=25%
Screened
N=NR
Randomised
N=99
Evaluable
N=NR
Completed
N=70
Note 55/99 had
second arthroscopy
Exclusion
Patients judged
uncontrollable,
unreliable or with
severe concomitant
disease, joint
infection,
concomitant
treatment with
NSAIDs, IA
steroids in previous
3 months, pregnant
or breast feeding
were excluded.
Comparison
(MP)
Methylprednisolone
acetate IA once a
week for 3 weeks
Note: MP dose not
reported.
Different treatment
amounts (5 vs. 3)
would affect the
likely success of any
attempt at patient
blinding.
Duration
180 days
HA
MP
Overall clinical efficacy day 35
Nocturnal pain
NR
NR
Pain at rest
NR
NR
Pain on spontaneous or forced movement
NR
Overall clinical efficacy day 180
(parameters as above)
NR
p-value
<0.05 in
favour of MP
<0.05 in
favour of MP
NR
<0.05 in
favour of MP
NR
ns
Function: Average increase from baseline
Maximal flexion d35 (degrees)
Maximal flexion d180 (degrees)
Maximal extension d35 (degrees)
Maximal extension d180 (degrees)
Duration of morning stiffness d35 (min)
Duration of morning stiffness d180 (min)
1.96
3.90
ns
3.29
4.38
ns
0.22
1.49
ns
0.79
1.43
ns
Present in some patients
Absent in all patients
Overall improvement
Physician opinion day 35
Patient opinion day 35
Physician opinion day 180
Patient opinion day 180
DNR
DNR
DNR
DNR
Arthroscopy findings n=55 (56%)
Total arthroscopy score (AS)reductions
reflecting changes d180
Reduction in (AS) for lesion extent
d180 medial tibial plateau
Reduction in (AS) for lesion grade
d180 in patellar compartment
DNR
DNR
DNR
DNR
34.7±6.0 35.6±6.5
<0.005a
<0.001 a
ns
ns
ns
8
1
<0.03
17
5
<0.02
* blinding not possible for
patients because of
different treatment
regimens
yes
Overall quality: ~/+
Authors’ conclusions:
The study suggests that IA HA
injections exerts a beneficial effect
leading to a reduction of synovial
inflammation and a slowing of
cartilage damage progression
confirming its validity as an
alternative to IA steroids and NSAIDs
in the treatment of OA of the knee
Reviewer’s comments:
Not tested against NSAIDs
Figures suggest that the effect of HA
appears more gradually but lasted
longer than MP.
MP also has lower scores for VAS for
pain to day 60 – but s.d.s for HA and
MP appear to overlap
Not all of the claims made by the
authors are substantiated by the data.
Note: for all other (AS) values a tendency for improvement in HA group
reported, but no p values given.
Sub-group analysis: primary OA group d 180 selectively reported
extent Medial tibial plateau p=<0.03, extent patella p<0.03, grade patella
p=<0.01 Note: not made clear which group is favoured
Adverse events and safety
MP group: 1 patient withdrew with AEs which included malaise,
tachycardia and hypotension, 1 other in MP group had gastric malaise.
HA group: No adverse events reported
Overall – no significant change in lab parameters in either group.
a
in favour of MP, DNR= data not reported
a ITT analysis was also performed but there were no significant
difference from the PP analysis – summary only given.
IA= intra-articular
HA= hyaluronic acid
13
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To compare the efficacy
and safety of two
different HA
preparations and placebo
in patients with OA of
the knee.
Inclusion
Age ∃60 years
Lequesne index of at
least 10 points,
weight bearing pain
of at least 40mm on a
VAS of 100mm ,
normal physical
examination,
dominant pain in one
knee, radiologically
verified Grade I or II
i.e. no bone erosion.
Artzal
(mw=900 kDa)
3 IA injections 1% HA in
2.5ml 7 days apart.
Change from
baseline mean
VAS rated on
100 mm scale
Artzal
N=76 (s.d.)
Per protocol analysis at 26 weeks
Weight bearing knee pain
-16(31)
Lequesne Index (LOCF)
-3.9(4.6)
validity /
applicability
yes
no
n/a
n/s
conclusions,
comments, and
quality scores
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
yes
yes
yes
yes
*
yes
yes
yes
yes
n/s
yes
yes
Validity: ~/+
Precision: +
Applicability: ~/+
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
no
n/s
yes
study design
Karlsson, J., Sjogren, L.
S., & Lohmander, L. S.
(2002). Comparison of
two hyaluronan drugs
and placebo in patients
with knee osteoarthritis.
A controlled,
randomized, doubleblind, parallel-design
multicentre study.
Rheumatology., 41(11),
1240-1248.
RCT
Placebo-controlled
Double-blind
Multi-centre (19)
Parallel group
Age
70-72 yrs
Female
65% ITT pop
68% PP pop
Ahlback Grade IOA
=60%% (ITT and PP)
All patients had
significant knee pain and
impairment.
Randomised
N=246
Treated
N=242
Per p[protocol analysis
N=210
Completed 26 weeks
N=184
Completed FU to 52
weeks
N=99
Exclusion
Bone attrition,
previous knee
fracture,
inflammatory joint
disease, IA injections
or other invasive
procedure of the knee
in previous 6 months,
known alcohol or
drug abuse.
Known allergies to
any substance used in
the study,
Haematological or
clinical chemistry
values out side
normal range.
Any disabling
problem that could
interfere with the
assessment of
efficacy.
Synvisc (mw=7000 kDa)
3 IA injections 0.8% HA
in 2ml.
Placebo
3 IA injections of 3ml of
saline.
Concomitant medicine
Only paracetamol allowed.
Doses above
8x500 mg/day for pain in
the treated knee was
regarded as clinical failure.
Analgesics used for other
reasons were considered to
be study withdrawals.
Study length/FU
52 weeks
Treatment
2 weeks
Power calculation
To detect a difference of
15mm (VAS) in the
decrease from baseline
with a power of 80% and
s.d. of 30mm, 50 placebo
and 75 active treatment
patients were required in
each group.
a
Synvisc
Placebo
N=77 (s.d.) N=57 (s.d.)
-20(31)
-4.4(4.1)
-21(31)
-4.7(4.4)
Bold = significant diff from baseline
No significant difference between treatment and placebo
Per protocol analysisa at 26 weeks
WOMAC score (LOCF) v
-11.3
Pain (LOCF)
-3.1
Physical function (LOCF)
-7.3
Stiffness (LOCF)
-0.9
-16.8
-3.6
-11.7
-1.4
-16.8
-3.8
-11.1
-1.6
Resting pain, maximum pain and WOMAC score showed no
significant difference between groups. Pain improved from baseline
but p value was not reported.
VAS pain and Lequesne Index at 52 weeks showed no significant
differences between groups – drop out = 45 %. ( data not conclusive)
Adverse events (ITT)
AEs 314 reported in 132 patients.
Because of the elderly population many co-morbidity events were
recorded that were unrelated to treatment.
So significant differences were found between the study groups.
SAEs 30 were reported.
Proportion of patients reporting AEs 61%
No. serious adverse events
12
No. possible treatment related AEs
2a
a
51%
8
1a
yes
Overall quality: ~/+
Authors’ conclusions:
All groups showed clinical
improvement in the first 26 weeks
with no significant between group
variation. The pooled HA data for
weeks 27-52 showed a significantly
longer clinical benefit than the data
from the placebo group.
Reviewer’s comments:
17% drop out.
Elderly population
* only for safety, per
protocol for efficacy
because of anticipated high
drop-out rate.
50%
11
2a
Safety committee eventually classified these as disease related.
IA= intra-articular
MW=molecular weight
14
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
Objective
To determine if IA
injection of HA can
improve knee function
and clinical test results in
patients with OA of the
knee.
Inclusion
At least 50 years old, OA
of both knees.
Kellgren stage II-III bilaterally, symptomatic
gonarthritis for at least 12
months, weight bearing
pain level minimum 4cm
bilaterally on VAS.
Lequesne score for both
joints at baseline not
differing by more than ±2
points in the total value.
Hyalart®
20mg HA IA
injections weekly up
to a total of 5
injections.
Measurements
of torque
(extensor and
flexor),
Lequesne and
VAS pain
scores
results
validity /
applicability
study design
Miltner, O., Schneider,
U., Siebert, C. H.,
Niedhart, C., & Uwe
Niethard, F. (2002).
Efficacy of intraarticular
hyaluronic acid in
patients with
osteoarthritis - A
prospective clinical trial.
Osteoarthritis &
Cartilage., 10(9), 680686.
RCT
Prospective
Controlled
(contralateral knee).
Stratified by knee
impairment
Participants
Male=20,Female=23
Average age= 67yrs
(range 55-78).
Average weight = 79
±17kg.
Average height =170±8
cm
Study size
N=43
Completers
N=43
Exclusion
Patients who do not meet
all of the inclusion criteria,
neurological deficits in the
lower extremities.
Inflammatory joint disease
or joint infections or
previous fracture,
crystalline arthritis, IA
tumours, varus or valgus
deviations, ligamentous
instability.
Knee surgery or IA
injections in prior 3
months.
Control
No treatment
Concomitant
medicine
No analgesics or
NSAIDs, only
paracetamol 500 mg
was allowed. No
paracetamol 8 hours
before assessment.
No physical therapy.
Note
Randomization of
treatment to right or
left knee.
Stratification carried
out
Baseline
Follow-up p-value
Treated knee
Max peak torque Nm (extensor) 60os
Max peak torque Nm (extensor) 180os
Max peak torque Nm (flexor) 60os
Max peak torque Nm (flexor) 180os
Lequesne score treated knee
Pain at rest (VAS)
Pain on weight bearing
57.0
32.33
40.44
22.89
13.57
3.83
7.57
77.17
47.83
53.33
34.05
7.94
1.36
3.75
Untreated knee
Max peak torque (extensor) 60os
Max peak torque Nm (extensor) 180os
Max peak torque Nm (flexor) 60os
Max peak torque Nm (flexor) 180os
Lequesne score treated knee
Pain at rest (VAS)
Pain on weight bearing
73.38
48.83
51.06
29.33
DNR
3.67
7.43
71.55
42.05
46.58
27.11
DNR
DNR
DNR
Safety data not reported
DNR = data not reported
HA = hyaluronic acid
IA = intra-articular
OA= osteoarthrtis
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
ns
ns
ns
ns
ns
ns
ns
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
no
n/s
yes
yes
n/s
n/s
n/s
no
no
no
n/s
yes
n/s
conclusions,
comments, and
quality scores
Validity: ~/+
Precision: +
Applicability: −/~
Overall quality: ~
Authors’ conclusions:
The authors concluded that 5
weekly IA injections of HA in
patients with OA of the knee
provided pain relief and functional
improvement.
Reviewer’s comments:
The more impaired knee was
randomised to treatment more
frequently than to control and there
were more grade III knees in the
treatment group. No statistical test
was reported.
Short FU
Study length
6 weeks
Treatment
5 weeks
15
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
yes
no
n/a
n/s
conclusions, comments,
and quality scores
Objective
To determine the impact
of hyaluronic acid (HA)
vs conventional therapy
on pain, stiffness and
disability at rest and
following functionally
relevant walking and
stepping activities.
Inclusion
Radiographic grades
1-3 medial
compartment
unilateral knee OA,
at least 3cm current
rest pain on VAS.
Exposure- 4 groups
Group 1 (HAPLt)
IA HA (Suplasyn) 2 ml of 10
mg/mL+ 100 mg lactose placebo
tablets
Group 2 (HANS)
IA HA (Suplasyn ) 2 ml of 10
mg/mL.+ 75 mg oral diclofenac
and 200:g misoprostol
Group 3 (NSPLi)
75 mg oral diclofenac and
200:g misoprostol and placebo 2
ml saline injection.
Control Group 4 (PltPLi)
Placebo tab+ placebo injection.
WOMAC pain,
disability, and
stiffness
Week 4 comparison with baseline score
Within group comparisons of mean WOMAC Pain,
disability and stiffness scores were significant
(p<0.05) for all groups except the Control group.
WOMAC Pain and WOMAC stiffness scores for
the Control group were not significant although the
WOMAC disability score was significant at
p<0.05.
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
yes
yes
yes
yes
yes
*
*
yes
yes
yes
st
yes
Validity: +
Precision: +
Applicability: ~
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits and
harms
?
yes/n/s
yes
Reviewer’s comments:
Only within group analysis reported,
between group mean differences?
Adverse events not well reported.
A simple 10 min home-based resistance
exercise program was included to be
performed on at least 3 days but preferably
every day of the week. Compliance was
reported to be good and an analysis of the
effect of % compliance on outcomes was
not significant.
study design
Petrella, R. J.,
DiSilvestro, M. D., &
Hildebrand, C. (2002).
Effects of hyaluronate
sodium on pain and
physical functioning in
osteoarthritis of the knee:
a randomised, doubleblind, placebo-controlled
clinical trial.[see
comment]. Archives of
Internal Medicine.,
162(3), 292-298.
RCT
Double-blind
Placebo-controlled
Participants
Male: 49 (41%)
Female: 71 (59%)
Screened
N=NR
Randomised
N=120
Evaluable
N=
Completed
N=108
Exclusion
Non-OA arthritis,
previous NSAID
intolerance, GI
haemorrhage, peptic
ulcer, regular
consumption of
herbal OA products,
IA with HA in
previous 6 months.
Note:
HA injection = once a week for
3 weeks
Placebo injection =2ml of
isotonic sodium chloride
injection once a week for 3
weeks
Placebo NSAIDs =100 mg
lactose twice daily for weeks 012.
NSAIDs =75 mg oral dicofenac,
+ 200 :g microprostol twice
daily, weeks 0-12.
Rescue medication
325 mg Paracetamol to be taken
as needed up to 650 mg 4 times
a day.
Duration
12 weeks
Rest pain
Self-paced walk
test (SPW) pain
Self –paced
stepping test
(SPS) pain
Maximum
oxygen uptake
(V02 max)
Physical functioning week 4 comparison with
baseline score
Within group comparisons of mean Rest pain,
SPW pain and SPS pain scores were significant
(p<0.05) for all groups except the Control group.
Only the Rest pain score was significant for the
Control group.
Within group comparisons were significant
(p<0.05) for SPW times (HANS group), SPS times
(HAPLt group), VO2 max, ml/kg/min SPW
(HAPLt and HANS groups) and Vo2 max,
ml/kg/min SPS (HAPLt group). SPW times, SPS
times, VO2 max, ml/kg/min SPW and VO2 max,
ml/kg/min SPS were not significant for all other
groups.
Week 12
Pain scores: the difference in pain scores was
unchanged from week 4 in terms of significance.
Disability scores: groups 1 and 2 showed further
significant improvement in physical disability from
weeks 4-12.
Vo2 max, SPW pain, exercise times: there was no
significant difference amongst the 4 groups
between weeks 4 and 12.
* it is not clear if patients were
blinded though the use of
placebos should have
permitted patient blinding.
n/s
Overall quality: ~/+
Authors’ conclusions:
For resting pain relief hyaluronate sodium
seems to be as effective as NSAIDs. For
pain with physical activity and functional
performance hyaluronate sodium may be
superior to placebo alone or NSAIDs alone.
Note: the significant improvement of the
control group from baseline was attributed
to the exercise program.
A group without exercise was not included.
Adverse events
No serious adverse events were reported, most
adverse events occurred in group 3 but the
difference was not significant.
IA= intra-articular
OA= osteoarthritis
HA=hyaluronic acid
HA = hyaluornic acid,
PLt = placebo tablets (lactose)
PLi = placebo injection (saline)
16
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
yes
no
n/a
n/s
conclusions,
comments, and
quality scores
Objective
To assess the clinical
effectiveness of hylan GF 20 in an appropriate
care treatment regimen
(as defined by the ACRa,
1995 guidelines) as
measured by validated
disease specific
outcomes and health
related quality of life
endpoints for patients
with OA of the knee.
Inclusion
Age >40 years, primary
Dx of radiologically
verified OA in the study
knee (most symptomatic or
predominant
musculoskeletal problem),
symptomatic (VAS score
>175mm of 500mm on
WMOC pain scale despite
prior treatment with
Paracetamol or NSAIDs at
any point prior to the
study, ambulatory and
willing to participate and
sign informed consent.
Exposure
Appropriate care + hylan
G-F 20 1 IA injection
weekly for 3 weeks
(AC+H)
Note: the contra-lateral
knee could also be treated
with HA and patients
could receive subsequent
treatment to either or both
knees as required.
WOMAC pain
score, global
assessment
Primary outcome ( up to termination)
WOMAC pain (mean diff)
-2.6 (p=0.0001)
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
yes
yes
n/s
yes
yes
no
no
no
no
yes
yes
yes
Validity: ~/+
Precision: +
Applicability: +
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
yes
yes
study design
Raynauld, J. P.,
Torrance, G. W., Band,
P. A., Goldsmith, C. H.,
Tugwell, P., Walker, V.,
et al. (2002). A
prospective, randomized,
pragmatic, health
outcomes trial evaluating
the incorporation of
hylan G-F 20 into the
treatment paradigm for
patients with knee
osteoarthritis (Part 1 of
2): clinical results.[see
comment]. Osteoarthritis
& Cartilage., 10(7), 506517.
RCT
Open label
Prospective
Multicentre (14)
Participants
Mean age: 63years
Female: 70%
BMI=32-33 kg/m2
Grade IVb= 20-30%
Enrollment:
April-December 1997
Screened
N=287
Randomised
N=255
Evaluable
N=
Completed
N=231
a
American College of
Rheumatology
b
grade IV radiologic
change according to the
clinical investigator
Exclusion
Grade IV radiologic
changes according to the
clinical investigators,
inflammatory
arthropathies, a tense
effusion in the study knee
at baseline,
chondrocalcinosis, severe
varus or valgus deformity
in the study knee or steroid
injection in the study knee
during the previous 3
months, prior
viscosupplemenation
therapy, isolated
patellofemoral OA or any
uncontrolled morbidity,
particularly morbidity in
any joint which could
impede measurements in
the study knee.
Comparison
Appropriate care (AC)
Note: appropriate care was
the preferred management
strategy of the treating
physician who was
encouraged to follow the
guidelines for the medical
management of OA of the
knee proposed by the
ACR. Appropriate care
could include;
Analgesics, NSAIDs,
corticosteroid injections,
education and counselling,
weight loss, joint rest,
application of heat or ice,
physical therapy,
arthroscopy, total joint
replacement.
Duration
1 year
Secondary outcome (% of n)
WOMAC pain (% diff)
29% (p=0.0001)
WOMAC pain + either
27% (p=0.0001)
stiffness or physical functioning
Patients global assessment of change since baseline
OA in study knee
46% (p<0.0001)
OA in all joints
21% (p=0.0011)
Overall health
22% (p=0.0010)
Patients global assessment month12 over the past 4 weeks
OA in study knee
33% (p<0.0001)
OA in all joints
29% (p<0.0001)
Overall health
10% (p=0.0115)
WOMAC sub scales
Pain
-4.41/-1.83 (p<0.0001)
(mean change HA+AC/AC)
Stiffness
-1.83/-0.71 (p<0.0001)
(mean change HA+AC/AC)
Physical function
-15.04/-5.85 (p<0.0001)
(mean change HA+AC/AC)
Health related quality of life (SF-36 short form)
Aggregate physical comp
4.88/-0.40 (p<0.0001)
(mean change HA+AC/AC)
Aggregate mental comp
3.32/1.55 (p=0.0939)
(mean change HA+AC/AC)
Health Utilities index 3
HUI3
(mean change HA+AC/AC)
0.13/0.03 (p<0.0001)
Safety/adverse events
Adverse events reporting (% pts)
Serious AEs (no.)
All local adverse events (no/pts)
Possibly related to HA (AEs/no. injections)
GI adverse events
GI events attributed to AC
Severe GI events attributed to AC
Global assessment (pts with no side effects)
HA+AC
96%
0
82/38
15/700
109
25
5
62%
AC
90%
1
140
62
22
41%
Safety/adverse events:
Patients in the HA+AC group experienced some discomfort
associated with the IA procedure but a clinically meaningful decrease
in both the number and severity of GI side effects related to
appropriate care and the need for medication to treat GI side effects.
Overall rate of AEs possibly or probably related to HA =2%
yes
Overall quality: +
Authors’ conclusions:
HA G-F 20 provision within
an appropriate care treatment
regimen provides benefits to
the knee, overall health and
health related quality of life at
reduced levels of co-therapy
and systemic adverse
reactions.
Reviewer’s comments:
This is a very well thought out
and carefully conducted study.
Pragmatic design to mimic
real world therefore no
blinding and no placebo.
Incremental effectiveness
assessed.
Thorough adverse event
assessment reporting with pros
and cons reported.
Note: a second publication
utilizes the measures of
effectiveness and costs in an
economic evaluation.
Torrance GW. Raynauld JP.
Walker V. Goldsmith CH.
Bellamy N. Band PA. Schultz
M. Tugwell P. Canadian Knee
OA Study Group. A
prospective, randomized,
pragmatic, health outcomes
trial evaluating the
incorporation of hylan G-F 20
into the treatment paradigm
for patients with knee
osteoarthritis (Part 2 of 2):
economic results.
Osteoarthritis & Cartilage.
10(7):518-27, 2002 Jul.
Not appraised as part of this
review
17
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
To evaluate safety and
effectiveness of
orthovisc formulation in
the treatment of joint
pain in patients with
mild-moderate knee OA
in whom pain in the
contralateral knee is
relatively modest.
Investigational device
exemption cert.
Inclusion
>50 years old
Diagnosis idiopathic OA
(American College of
Rheumatology criteria)
Kellgren-Lawrence Grade II
or III radiographic evidence of
knee OA and a summed
WOMU osteoarthritis pain
score of 13 in the treated knee
and less than 13 in the
contralateral knee.
Willing to discontinue all
analgesics and NSAIDs.
Mobile (walk 50 feet
unassisted).
Not pregnant or planning a
pregnancy.
Exposure
Sodium hyaluronate
ORTOVISC (high
molecular weight)
3 injections separated
by 1-week intervals, IA
injections of 30 mg HA
+ observation for
additional 25 weeks
WOMAC
stiffness and
function scores,
walking time
ITT population
For all endpoints both HA and saline injected
resulted in significant improvement from baseline
scores.
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
Exclusion
Quadracepts exercise program
within 4 months.
Oral or intramuscular steroids.
IA injection of HA in last
year.
K-L grade IV radiographic
changes.
Treatment with anticoagulants,
immunosuppressives or
muscle relaxants.
Inability to tolerate
Paracetamol.
Clinically significant comorbidity or abnormality in
routine lab tests. Allergy to
lignocaine.
In both groups IA
injections were done
after skin and subcutaneous tissue had
been anaesthetised
with 3-5ml of a 1%
lignocaine HCL
solution
study design
Brandt, K. D., Block, J.
A., Michalski, J. P.,
Moreland, L. W.,
Caldwell, J. R., & Lavin,
P. T. (2001). Efficacy
and safety of intraarticular sodium
hyaluronate in knee
osteoarthritis. Clinical
Orthopaedics & Related
Research. Issue, 385(pp
130-143).
RCT
Prospective
Salinecontrolled/parallel-group
Double-blind
Multi-centre (10)
Participants
Mean age 65-67 years
Male= 37-39%
Female =61-63%
BMI=30-32 kg/m2
ITT pop
N =226
Effectiveness pop
(completing at least 15
weeks of treatment)
N=135
Comparison
Saline group
3 weekly injections of
saline + observation
for additional 25 weeks
Co-medication
Paracetamol
Randomisation 1:1
Total study duration
=27 weeks
Note: the efficacy of HA in the index knee increased
as the level of pain in the contralateral knee
decreased.
Change from baseline:
HA saline
Effectiveness population
(completing 15 weeks)
Week 3
WOMAC Stiffness Score
-1.5 -1.5
WOMAC Function score
-11.4 -10.0
Time to walk 50 feet (secs) -1.8 -1.7
Week 27
WOMAC Stiffness Score
-1.7
WOMAC Function score
-14.7
Time to walk 50 feet (secs) -2.0
-1.1
-9.8
-0.6
p-value
ns
ns
ns
ns
ns
ns
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits and
harms
yes
no
n/a
n/s
no
no
yes
yes
yes
yes
yes
yes
no
yes
yes
yes
n/s
yes
yes
conclusions, comments,
and quality scores
Validity: ~/+
Precision: +
Applicability: ~/−
Overall quality: ~
Authors’ conclusions:
HA may provide a well tolerated alternative
to NSAIDs and IA injection s of
corticosteroids. It may provide sustained
benefit for patients with moderate pain
from OA of the knee in whom pain in the
contra lateral knee is relatively modest.
Reviewer’s comments:
HA population obese at baseline. Placebo
group not obese (BMI<30 kg/m2 )
Detailed data from ITT analysis not given
Bold = significant improvement from baseline
Adverse events in ≥5% ITT population (Fisher’s
exact test)
Musculoskeletal (%)
30
27
ns
Respirator (%)
23
16
ns
General body (%)
18
21
ns
CNS (%)
13
14
ns
GI (%)
10
14
ns
Urinary (%)
5
8
ns
Skin (%)
4
5
ns
Serious adverse events (%) 5
4
NR
None were thought to be treatment related
18
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity / applicability
Objective
To evaluate the
efficacy of HA in
Asian populations
Inclusion
Male and female
Age 50-70 years
Mono or bilateral
disease
Congenital or locally
acquired
Pain on movement >40
mma
Diagnosis of OA within
6 previous mob
Hylagan® (HA)
20 mg/2 ml
One IA
injection
weekly for 4
weeks.
Pain on
movement,
day pain,
morning
stiffness, pain
on touch,
night pain,
joint
circumference
Day 180 outcome
HA and PL groups did not have
significantly different outcomes
for Pain on movement (p=0.07),
had borderline significant
differences in Day pain (p=0.05)
and had significantly different
Morning stiffness (p=0.03).
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
study design
Bunyaratavej, N.,
Chan, K. M., &
Subramanian, N.
(2001). Treatment
of painful
osteoarthritis of
the knee with
hyaluronic acid.
Results of a
multicenter Asian
study. Journal of
the Medical
Association of
Thailand.,
84(Suppl 2), S576581.
RCT
Multi-centre
Participants
Mean age =59yrs
M=13, F=46
Study size
N=49
(59 screened)
Exclusion
Rapid destructive
arthritis
Arthritis needing
surgery
Treatment with IA
injections in previous 3
months, NSAID
treatment in previous
week.
Painful knee conditions
not caused by OA, knee
conditions caused by
trauma.
Pregnant females and
females of childbearing
age.
Placebo (PL)
2 ml saline
One IA
injection
weekly for 4
weeks.
Concomitant
therapy
Paracetamol up
to 6X500mg
tablets daily.
4 weeks
treatment
+
20 weeks FU
Both groups were reported to
show similar trends for Pain on
touch, Joint circumference
(mm), and Night pain (no
supporting data given).
Adverse events
Both treatments were well
tolerated and no local or
systemic effects related to
treatment were observed.
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes
n/s
n/s
n/s
n/s
n/s
n/s
n/s
yes
n/s
yes
n/s
no
yes
conclusions, comments,
and quality scores
Validity: −/~
Precision: −/~
Applicability: ~/+
Overall quality: −/~
Authors’ conclusions:
The study was reported to have
confirmed the beneficial effects
of treatment with Hyalgan® in
Asian populations suffering
from OA of the knee.
Reviewer’s comments:
Severe OA and X-ray stage IV
included.
Limited reporting.
IA= intra-articular
OA = osteoarthritis
DNR= data not reported
19
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
To compare safety and
efficacy of hylan G-F 20
with NSAID and a
control in an RCT of
patients with
symptomatic OA of the
knee.
Inclusion
Age 35-80 yrs
Radiologically
confirmed OA of the
knee predominant in the
tibio-femoral
compartment and no
other OA joint likely to
need escape analgesia.
Knee most painful joint,
X-ray report indicating
OA in the last 2 years.
3 Treatment groups:
Pain, Lequesne
index, WOMAC
score (aggregate)
Mean difference p-values:
HA vs PL DI vs PL HA vs DI
12 weeks, ITT population
WOMAC aggregate
0.02
0.44
0.10
Walking on flat surface
0.01
0.88
0.008
Up-down stairs
0.30
0.93
0.35
Pain at night
0.09
0.32
0.01
Pain sitting or lying
0.05
0.32
0.004
Pain standing
0.15
0.93
0.14
Lequesne index
0.17
0.99
0.18
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
study design
Dickson, D. J., Hosie,
G., & English, J. R.
(2001). A double-blind,
placebo-controlled
comparison of hylan G-F
20 against diclofenac in
knee osteoarthritis.
Journal of Drug
Assessment, 4(3), 179190.
RCT
Double-blind
Parallel group
Multi-center (18)
Participants were
recruited by GPs.
Recruited
N = 189
Eligible
N=165 (ITT)
Evaluable
N=134
Completers
N=117
Power calculation
Sample size of 50 per
group was shown to
provide 80% power to
detect 25% difference in
the proportion of patients
improving with active
treatment compared to
placebo at a one sided
significance of 5%.
Exclusion
Bed ridden or unable to
walk 50 steps without
help.
Other joint diseases,
clinically significant
renal, hepatic or
haematological disorders
at baseline or any
contraindications to
study treatment.
Hylan G-F-20
2ml IA injections weekly
for 3 weeks + oral placebo
capsules once daily for 12
weeks
Diclofenac
retard 100 mg (NSAID)
capsules once daily for 12
weeks and athrocentesis
once a week fro 3 weeks
Control group
Placebo capsules +
arthrocentesis on same
schedule as above
Concomitant medication
Only paracetamol (500 mg,
up to six tablets daily) was
allowed.
Study duration
12 weeks
12 weeks evaluable populations
WOMAC aggregate
0.02
Walking on flat surface
0.007
Up-down stairs
0.05
Pain at night
0.05
Pain sitting or lying
0.07
Pain standing
0.21
Lequesne Index
0.03
0.17
0.70
0.26
0.51
0.52
0.70
1.0
0.35
0.03
0.44
0.01
0.02
0.40
0.03
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes
yes
yes
yes
yes
yes
?yes
n/s
yes
yes
yes
n/s
yes
conclusions, comments,
and quality scores
Validity: +
Precision: +
Applicability: ~/+
Overall quality: +
Authors’ conclusions:
Treatment with Hylan G-F 20 offered
significant advantages over diclofenec in
terms of efficacy and safety in the
treatment of patients with OA of the knee.
Reviewer’s comments:
HMW HA
Short FU
Well done trial
yes
Bold = significant
Adverse Events
Seven HA , 4 DI and 4 control patients experienced local
pain and or swelling in the injected knee (ns), in 2 HA
patients the reaction was severe. Systemic events that were
possibly related to treatment were reported in 22% of the
HA group, 48% of the diclofenac group and 11% of the
control group.
Serious adverse events
SEA’s were reported in 4 patients. Only 1 event, a
suspected GI bleed in a diclofenac patients, was attributed
to treatment.
20
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
A feasibility study
to assess the
tolerability and
efficacy of
BioHyTM in a small
placebocontrolled group
of patients with
OA of the knee.
Inclusion
Males or females age 6085 with evidence of
idiopathic symptomatic
clinical OA of the knee
(Altman criteria) and
radiologically verified
stages 2-4 ( K and L
system). Good health, no
previous history of
surgical treatment to the
joint or of arthroscopy or
injections to the knee in
the previous 6 months.
Exposure
BioHyTM
High molecular
weight (3.0
MDa) HA 20 mg
(10mg/ml) in 2
ml phosphate
buffered saline.
Administered
once a week for
five weeks.
Pain at rest,
during
motion, knee
joint
tenderness
Week 20 assessment (no data
reported results shown in
graphs)
There was no significant
difference between HA and PL
groups for:
Pain walking on flat surface
Pain walking on steps or
standing
Pain at night
Pain sitting or lying
Muscle strength
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
study design
Tamir, E.,
Robinson, D.,
Koren, R., Agar,
G., & Halperin, N.
(2001). Intraarticular
hyaluronan
injections for the
treatment of
osteoarthritis of
the knee: A
randomized,
double blind,
placebo controlled
study. Clinical &
Experimental
Rheumatology.,
19(3), 265-270.
RCT
Open-label
Single-blind
Placebo-controlled
Participants
Age: 71 years
Male: 27%,
Female: 73%
Grade 3 :HA 64%
vs PL 44%.
Grade 4:HA 12%
vs PL 28%
Screened
N=NR
Randomised
N=49
Evaluable
N=42?
Completed
N=36
Exclusion
Traumatic OA of the
knee, rheumatoid
arthristis, joint infection,
other inflammatory and
metabolic arthritis or OA
of the hip joint, patients
with significant systemic
disease allergy or atrophy
or skin conditions
overlying the joint,
copious joint exudates
(>15ml).
Comparison
Placebo of 2 ml
same buffered
saline.
Administered
once a week for
five weeks.
Concomitant
medication
Analgesics or
NSAIDs
medication were
not deprived
during the trial.
Only 5 patients
had synovial
fluid aspiration.
Duration
20 weeks
Drop outs<20%
Knee joint tenderness on
palpation: both groups found
maximum relief at week 12.
Overall 64% of the HA group
vs 46 % of the placebo reported
some relief.
Stiffness of the knee joint:
indicated a trend suggesting
that HA may decrease stiffness.
Adverse events
No systemic adverse events
were reported that could be
related to treatment. 18 HA and
11 PL patients had knee pain
immediately post injection.
One HA patient had pain and
swelling 2 weeks after injection
no 5.
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes
n/s
n/s
conclusions, comments,
and quality scores
Validity: ~/+
Precision: −/~
Applicability: −/~
Overall quality: −/~
yes
no
?
yes
medium
term
yes
Authors’ conclusions:
HA provides some relief for
OA patients without causing
adverse effects, although the
study was not sufficiently
powered to obtain statistically
significant differences.
no
?/n/s
?
Reviewer’s comments:
This was a small study group
with less than 20 patients in
each group completing the
study. The patient group were
elderly and a significant
proportion had radiologically
severe disease.
The study was likely to be
significantly underpowered.
?
Result reporting was poor and
the study design weak.
5 patients were aspirated, it is
not clear which group the
patients belonged to.
21
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
yes
no
n/a
n/s
conclusions,
comments, and
quality scores
Objective
To compare the
effect of a new
IA
viscosupplement
Fermathron®
manufactured by
bacterial
fermentation.
To study a
sufficient number
of patients to
provide reliable
information on
the performance
and safety of the
study device.
Inclusion
Radiologically
confirmed
(Ahlback I-III)
diagnosis of OA
of the knee (ACR
criteria), clinical
confirmation that
it was
appropriate for
the patients to
withdraw all
analgesic
medication and
rely on
paracetamol as
escape
medication for
the duration of
the study.
Exposure (HA)
Hyalart® 2ml IA
injection once a
week for 5
weeks.
Lequesne
and VAS
scores
Mean (s.d.):
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
yes
yes
n/s
yes
yes
yes
yes
no
yes
yes
medium
term
yes
Validity: +
Precision: +
Applicability: ~
study design
McDonald, C.,
Hantel, S., &
Strohmeier, M.
(2000). A
randomised,
controlled study to
compare the
performance and
safety of two
sources of sodium
hyaluronate given
as a
viscosupplement
by intra-articular
injection to
patients with
osteoarthritis of
the knee. Journal
of Clinical
Research, 3(4150), 41-50.
RCT
Observer –blind
Multi-centre(12)
Demographics
NR
Screened,
N=NR
Randomised,
N=256
Evaluable,
N=233
Completed,
N=233
Exclusion
IA injection for
arthroplasty to
the affected knee
within the
previous 3
months,
concomitant
medical
conditions that
may interfere
with the study
assessments.
Comparison
(FER)
Fermathron®
2ml IA injection
once a week for
5 weeks.
Note:
Hyalart® = 1%
(w/v)) sodium
hyaluronate
obtained from
roster combs.
Fermathron®
=1% (w/v))
sodium
hyaluronate
obtained by
continuous
fermentation
from
Streptococcus
equi.
Duration
6 months
FER(n=114) HA(n=119) p-value
Primary outcome variable – Lequesne Index
score
Baseline score* 11.09 (2.75) 10.89 (3.74) ns
6-month assess.* 6.91 (4.22) 6.36 (3.74) ns
Secondary outcome variables—VAS score
Baseline score
56.4 (16.5) 56.4 (16.8) ns
6-month assess. 25.4 (19.3) 24.6 (22.0) ns
Safety/adverse events (SAEs)
24
Number of events a
17
a
most frequent symptom =knee joint pain.
There were 4 SAEs not related to the
administration of the study drugs.
No clinically significant abnormal laboratory
parameters were reported during the study.
*There was an effect of baseline value (p<0.001)
and centre (p<0.001) on the final Lequesne score.
IA= intra-articular
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
no/n/s
yes/n/s
yes
yes
Overall quality: +
Authors’
conclusions:
The two HA products
are similar in
performance as
assessed by the
Lequesne index and
VAS pain in the
affected knee.
Clinically important
benefits were
maintained for up to 6
months after the last
injection. Both are
well tolerated.
Reviewer’s
comments:
Two novel low
molecular weight
compounds were
compared.
Allergic reaction
potential not reported
for avian product
(hyalart®).
22
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Participants
Mean Age= 66 and 65
years
Male=33
Female=67
Inclusion
Fully ambulant
Diagnosis of OA of knee
according to the ARA criteria.
Radiographic changes Grade
II or III (Kellgren and
Lawrence) within previous 6
months. Constant pain for 3
months. Moderate to severe
pain on walking.
Exposure
Hyalgan®
HA 20mg/2ml IA
injections once a week
for five weeks +
aspiration of any fluid
present.
100mm VAS
and Lequesne
functional
index
Mean and s.d.:
validity /
applicability
study design
Huskisson, E. C., &
Donnelly, S. (1999).
Hyaluronic acid in the
treatment of
osteoarthritis of the knee.
Rheumatology., 38(7),
602-607.
RCT
Placebocontrolled/parallel group
Blind observer
Study size
N=100
Treatment completers
N=94
Available for FU
N=81
Setting
Hospital outpatients
clinic
Power calculation
Using a VAS s.d.=24mm
and a power of 90% to
detect mean treatment
change of 15.4mm, a 2tailed test and a 5%
significance level 50
samples for each group
were required.
Exclusion
Grade IV radiographic
changes. Serious functional
impairment of the knee. OA of
hip or any other joint of
sufficient severity to interfere
with assessment of the knee,
psoriasis, sacroiltiitis any other
joint disease or infection. Skin
conditions overlaying the
injection site, other painful
knee conditions, intercurrent
hepatic of renal disease or
major general medical
conditions. Use of intraarticular steroid or
radiocolloid in previous 3
months.
Placebo
Saline
2ml IA injections once
a week for five weeks
+ aspiration of any
fluid present.
Treatment
5 weeks
Follow-up
Six months
HA(n=39)
PL(n=41)
p-value
Week 5 (end of treatment)
Pain on walking
Lequesne Functional Index
27.5(22.7)
10.0(4.6)
40.6(29.4) 0.0087
12.1(3.8) 0.030
6-month follow-up
Pain on walking
Lequesne Functional Index
Global impression (exc-fair)
Patient satisfaction wk 5
Patient satisfaction 6-mo.
39.4 (27.8)
11.2(4.4)
75%
DNR
DNR
53.7 (29.9) 0.0049
12.6(4.8)
ns
47.5%
0.012
DNR
ns
DNR
0.006
Note:
Pain at rest, joint tenderness, morning stiffness and inactivity
stiffness were not significantly different between HA and placebo.
Adverse events
Total reported: HA Group=17, PL Group=14
Mostly local reactions at the site of injection
Not local: HA Group=11, PL Group=5
Serious adverse events: HA Group= 2, PL Group = 0
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes*
n/s
yes
yes
yes
yes
yes
n/s
yes
yes
conclusions,
comments, and
quality scores
Validity: +
Precision: +
Applicability: ~
Overall quality: +
Authors’ conclusions:
The authors concluded that 5
weekly IA injections with HA
were superior to placebo and well
tolerated. HA had a symptomatic
benefit which persisted for 6
months.
yes
n/s
yes
yes
* HA had fewer males
(p=0.056)
23
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To compare Hylan G-F
20 with a lower
molecular weight HA
product.
Inclusion
Male or female, >18
years with a Dx of
primary osteoarthritis
deformans of the
knee confirmed
radiographically
(Larsen grades 1-III).
ESR<40mm/h and a
rheumatoid factor
<1:160. Daily
persistent pain
despite medication.
Procedure
Knees were randomised, both
knees could be randomised in
patients with bilateral disease.
Each knee was independently
evaluated. For safety assessment
patients only were considered.
Patient and
evaluator
evaluations of
pain
Improvement from baseline, mean scores
GF20 LMW HA
(n=38) (n=35)
Patient evaluations (VAS 100mm) ITT week 12
Weight bearing pain (mean change) 38
25
Most painful knee movement
62
46
(mean scores)
Overall pain (mean scores)
67
51
validity /
applicability
study design
Wobig, M., Bach, G.,
Beks, P., Dickhut, A.,
Runzheimer, J.,
Schwieger, G., et al.
(1999). The role of
elastoviscosity in the
efficacy of
viscosupplementation for
osteoarthritis of the knee:
a comparison of hylan
G-F 20 and a lowermolecular-weight
hyaluronan. Clinical
Therapeutics., 21(9),
1549-1562.
RCT
prospective
Double? triple-blind (
patients, administrating
physicians and
evaluators masked)
Comparative
Multicentre (4)
Participants
Mean age: 60 yrs
Male: 49%
Female:51%
Larsen grade:
I =12%,II=47%
IIi=30%, IV=10%
V=1%
Screened
N=NR
Randomised
N=70 (73 knees)
Evaluable
N=70?
Completed
N=69pts
Exclusion
No pain in the
osteoarthritic knee,
detectable effusion in
the knee at the time
of first treatmentb or
considered by the
investigator to be
unreliable.
their consent.
Exposure
Atherocentesis + 3 IA injections
of Hylan G-F 20 + optional sc
local anesthetic
Study evaluators (VAS 100mm) ITT week 12
Weight bearing pain (mean change) 39
Overall assessment (mean score)
63
27
49
p-value
<0.05
<0.05
<0.05
<0.05
<0.05
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
Comparison
Atherocentesis + 3 IA injections
of LMW HA + optional sc local
anesthetic
Concomitant medication for other
conditions permitted and recorded
during study.
Rescue therapy
Any medication, surgery or
physical therapy for OA of the
knee.
Withdrawal – patients could be
withdrawn from the study if
compliance with treatment or
follow-up was inadequate or if
they withdrew
Note 4 knees in each group
violated protocol requirements.
Duration
12 weeks
Per-protocol analysis: between group differences were significant
for all outcome measures (p<0.05) except improvement in the most
painful knee movement (data not reported)
% Symptom free knees at 12 weeks ITT
The GF20 HA and LMW HA groups were significantly different
(p<0.05) in terms of:
Weight bearing pain (patients)
Weight bearing pain (evaluator)
Overall response (patient)
Overall response (evaluator)
Knee movement (patient)
Per-protocol analysis: between group differences were significant
for all outcome measures except patient evaluations of weight
bearing and overall pain (data not reported)
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes
n/s
yes
yes
yes
yes
yes
yes
short
term
yes
yes
yes/n/s
yes
conclusions,
comments, and
quality scores
Validity: ~/+
Precision: +
Applicability: ~
Overall quality: ~/+
Authors’ conclusions:
The pain-relieving effect of
viscosupplementation of the
osteoarthritic joint is directly
related to the elastoviscocity
of the material used in the
treatment.
Reviewer’s comments:
Short FU
yes
Note: There is no direct
evidence that the same HA
GF20 group is used in this as
well as the Wobig et al 1998
study (also reviewed here),
but the possibility of partial
duplication cannot be ruled
out
Rescue therapy: one HA GF20 and two LMW HA patients received
rescue therapy which consisted of analgesics and anti-inflammatory
medication.
Adverse events
38 knees received a total of 114 injections of HA GF-20, 35 knees
received a total of 105 injections of LMW HA - no general
systemic adverse event was reported in either group. Three local
AEs were reported 2 in HA GF20 and 1 in LMW HA (1.8% and
0.9% respectively)
24
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
Assess the longterm efficacy and
safety of HA
compared to
placebo and
naproxen in OA of
the knee.
Inclusion
Male or female
≥ 40 yrs
Diagnosis OA of kneea
Knee pain ≥1yr
Pain ≥ 20mm on ≥ 1 items
of the WOMACb pain subscale. Moderate or marked
pain of a 6-point
categorical scale (none,
mild, moderate, marked,
severe).
Knee radiograph showing
≥1 osteophyte and a
Kellgren-Lawrence grade
2 or 3.
No prior IA of HA within
1 year.
No other IA injections n
the preceding 3 months.
Treatment groups
Pain
assessments
Mean and s.d. VAS for pain:
validity /
applicability
study design
Altman, R. D., &
Moskowitz, R. (1998).
Intraarticular sodium
hyaluronate (Hyalgan) in
the treatment of patients
with osteoarthritis of the
knee: a randomized
clinical trial. Hyalgan
Study Group. [see
comments.] [erratum
appears in J Rheumatol
1999 May;26(5):1216.].
Journal of
Rheumatology, 25(11),
2203-2212.
RCT
Double blind
Blind assessor
Multi-centre
Placebo and naproxen
(NASAID) –controlled
Consecutive screening
pop
Screened
N=607
Eligible
N=495
Completers
N=333
Exclusion criteria
None reported
Hyalgan
5 once weekly, 2 ml (20 mg) IA
injections + subcutaneous
lignocaine local anesthesia and
aspiration of any fluid + oral
placebo identical to naproxen
for 26 weeks.
Oral naproxen
500 mg orally twice daily for 26
weeks +sham lignocaine (no
planned joint penetration) +
aspiration if fluid obvious.
Placebo,
subcutaneous lignocaine,
aspiration of any fluid +2ml
saline, once a week for 5 weeks
+ oral placebo identical to
naproxen for 26 weeks.
Concomitant medication
Paracetamol for escape
analgesia, pts allowed up to
4000 mg/day.
a
American College of
Rheumatology criteria.
b
Western Ontario and
McMaster Universities
Osteoarthritis Index 5 item
(VAS).
HA
Assessment at 26 weeks
Pain on 50ft walk ITT
Pain on 50ft walk LOCF ITT
Adjusted means
≥20 mm VAS improvement (%)
18(21)
27(27)
17.9
36
Secondary outcomes, 26 weeks
Categorical assessment
No pain (%)
Slight pain (%)
Mild pain (%)
Moderate pain (%)
Marked pain (%)
Total
22
26
18
25
10
100
Adverse events in >5% pts
Pain at injection site
Gastrointestinal events
Headache
Local skin reaction
Joint swelling and pain
Local pruritis
Severe knee swelling
23
29
18
14
13
7
2
d
NSAID
21(25)
25(28)
12
27
23
27
11
100
∀=0.10d
9
41
10
18
6
4
1
Placebo p-value
24(27)
28(30)
26.7
28
12
21
21
35
11
100
13
36
17
10
13
4
1
Significance for safety set at ∀=0.10, bold = highest effects.
0.004
0.127
ns
ns
ns
ns
ns
<0.001
0.087
ns
ns
ns
ns
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
b
Not powered for ITT
When performed ITT used
LOCF
yes
no
n/a
n/s
no
yes
yes
yes*
yes
yes
yes
yes
yes
yes
yes
no
n/s
no
yes
conclusions,
comments, and
quality scores
Validity: +
Precision: +
Applicability: ~/+
Overall quality: +
Authors’ conclusions:
IA HA was considered to be
an effective and safe therapy
for patient with OA of the
knee. Treatment benefits
persisted after treatment and
HA was more efficacious
than placebo and as effective
as oral naporoxen with fewer
adverse reactions.
Reviewer’s comments:
Main analysis completers
only
Compliance assessment =
tablet count+ periodic
salicylate and ibuprofen
serum determinations
High drop-out (30-36%)
Blinding was enforced
Completers analysis
Stratified by pain
severity
Parallel group
Double dummyc
Note
In the case of bilateral disease,
the most severely affected knee
was treated.
Duration
26 weeks
c
post hoc ITT with last
observation carried forward,
main analysis of completers
only to assess long-term
benefits.
25
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To compare the efficacy
and tolerability of intraarticular injections of 20
mg of sodium
hyaluronate and 3mgbetamethasone in an
open randomised trial.
Inclusion
Kellgran grade IIIII+ presence of pain
Exposure
Orthovisc (HA) IA injection of
20mg sodium hyaluronate in
phosphate buffer once a week
for 3 weeks.
WOMAC score,
flexion, overall
satisfaction,
analgesic
consumption
Mean (s.d.)
validity /
applicability
study design
Tekeoglu, I., Adak, B.,
Goksoy, T., & Tosun, N.
(1998). Effects of intraarticular injections of
sodium hyaluronate
(orthovisc) and
betamethasone on
osteoarthritis of the knee.
Journal of Rheumatology
& Medical
Rehabilitation., 9(4),
220-224.
RCT
Open label
Parallel group
Participants
Mean age: 58 years
Male: 0%
Female:100%
Screened
N=NR
Randomised
N=40
Evaluable
N=40
Completed
N=40
Exclusion
Knee joint disease
other than OA,
history of allergy,
skin infections, other
IA treatment in 3
months prior.
Comparison
Betamethasone (BT) 3mg/m1 IA
injection once a week for 3
weeks.
Note:
All patients were kept in rest for
one day after the injection.
When present, effusions were
aspirated
Concomitant medication:
Patients were asked to
discontinue NSAIDs and were
only allowed to use paracetamol
during the study.
Duration
15 weeks
Major outcome measures
WOMAC score baseline
WOMAC score week 15
Max flexion baseline (degrees)
Max flexion week 15 (degrees)
HA(n=20)
BT(n=20) p-value
45.5 (8.2)
30.9 (8.7)
110.5 (22.7)
121.2 (16.3)
45.6 (10.3) 0.002
29.9 (7.9)
116 (14.4)
ns
128.25 (102?) ns
Overall judgment end of study (15 weeks)
Good—very good—investigator
16
Good—very good—patient
15
Analgesic consumption at baseline
Occasional
4
Continuous low doses
5
Continuous high doses
11
8
8
?
0.05
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
2
7
11
Analgesic consumption at end of study (week 15)
Occasional
6
1
Continuous low doses
14
9
Continuous high doses
10?
0?
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes
n/s
n/a
no
no
no
no
n/s
short
term
yes
no
yes/n/s
no
?
conclusions,
comments, and
quality scores
Validity: ~/+
Precision: ~/+
Applicability: ~
Overall quality: ~/+
Authors’s conclusions:
Results in the 3rd week
favoured the BT group but
there were clinically
significant differences in
favour of HA in the 15th
week.
Reviewer’s comments:
Only females
No blind assessment
Some reporting errors?
Weak reporting of AEs or
cultural differences/
reluctance in reporting side
effects.
Safety and adverse events
None of the 40 patients presented any local or systemic reactions or
any clinically significant modifications in BP or lab tests.
IA = intra-articular
OA=osteparthritus
26
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
Evaluation of safety and
efficacy of HA-G-F 20
Inclusion
Male or female, >18 years
with a Diagnosis of
chronic primary
osteoarthritis of the knee
confirmed
radiographically (Larsen
grades 1-III).
ESR<40mm/h and a
rheumatoid factor <1:160.
Daily pain on activity
Exposure n=57 knees (HA)
Athrocentesis + 3 IA injections
of Hylan G-F 20 + optional
subcutaneous local anaesthetic
given at one week intervals
(total of 3 IA injections)
Pain (VAS score)
The differences between the HA and PL groups for Pain during
weight bearing, Overall efficacy and Loss of activity were
statistically significant (p=0.0001) at the:
Patients’ week 12 evaluation (VAS 100mm) ITT
Evaluators’ week 12 assessment (VAS 100mm) ITT
Evaluators’ week 26 assessment (VAS 100mm) ITT
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
study design
Wobig, M., Dickhut, A.,
Maier, R., & Vetter, G.
(1998).
Viscosupplementation
with hylan G-F 20: a 26week controlled trial of
efficacy and safety in the
osteoarthritic knee.
Clinical Therapeutics.,
20(3), 410-423.
RCT
Prospective
Double/triple?-blind
Multicentre (4)
Participants
Mean age: 62 yrs
Female:65% (p<0.0001)
Screened
N=NR
Randomised
N=110 pts (117 knees)
Evaluable
N=117 knees
Completed
N=108pts 115? knees
Exclusion
Effusion of the knee
Comparison n=60 knees (PL)
Atherocentesis +Physiologic
buffered saline placebo (the
hydration fluid of hylan G-F 20)
3 2ml IA injection + optional sc
local anaesthetic (total of 3 IA
injections)
Procedure
Knees were randomised, both
knees could be randomised in
patients with bilateral disease.
Each knee was independently
evaluated. For safety assessment
patients only were considered.
Concomitant medication for
other conditions permitted and
recorded during study.
Rescue therapy
Any medication, surgery or
physical therapy for OA of the
knee during the study was
recorded.
Duration
26 weeks telephone FU
At one centre 12 HAG-F20
patients underwent further
evaluations between 17-27
months after treatment.
The HA and PL groups (n=57 and n=60 respectively) were
significantly different (p<0.001, unless otherwise noted) for the
following:
HA
PL
% of patients who were symptom freea at 12 weeks (Patient
assessment)
Weight bearing pain:
56
12
Night pain:
82
53
Most painful knee movement: 60
13
Overall treatment success:
70
18
% of patients who were symptom free at 12 weeks (evaluator)
Weight bearing pain:
47
8
Night pain:
77
42
Loss of activity:
60
17
Overall treatment success:
51
15
% of patients who were symptom free at 26 weeks (evaluator)
Weight bearing pain:
39
13
Night pain:
71
45 (p=0.004)
Loss of activity:
59
27
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
no
n/s
yes
yes
yes
yes
yes
yes
medium
term
yes
?
yes/n/s
yes
yes
conclusions,
comments, and
quality scores
Validity: ~/+
Precision: ~/+
Applicability: ~
Overall quality: ~/+
Authors’ conclusions:
Hylan G-F 20 is well
tolerated and effective in
the management of
chronic idiopathic OA of
the knee.
Reviewer’s comments:
8 patients with grade IV
disease were enrolled
despite being excluded by
the protocol, 6/8 were
randomised to placebo.
Treatment group had
significantly lower Larsen
grades and significantly
more patients with < 1
year OA duration.
Baseline efficacy
assessments were not
significantly different
despite these differences.
Note: one centre followed up 12 patients for 17-27 months,
10/12 required no further medication, had no night pain, very
little pain on weight bearing and no restriction of activity at their
final FU
Rescue medication/therapy:
6pts 32pts (p<0.005)
Safety/adverse events:
There were no reports of local adverse reactions to HA.
Systemic reactions – itching, calf cramps and haemorrhoids
were reported in 3 HA patients. Two knees in the saline group
had pain at the injection site.
a
pain scores of 0-20 or improvement scores or 80-100% on
respective VAS scales.
Note: There is no direct
evidence that the same
HA GF20 group is used in
this as well as the Wobig
et al 1999 study (also
reviewed here), but the
possibility of partial
duplication cannot be
ruled out.
27
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To evaluate the
potential structure
modifying effects of
Hyalgan.
Inclusion
Patients with knee OA (ACR
criteria), clinical
involvement of the medial
compartment, active disease
justifying lavage, absence of
contraindication of
arthroscopy, absence of
advanced disease (K-L grade
IV), presence of
chondropathy of the medial
compartment at least grade
II (Begiun & Locker) and
observed on at least 10% of
the evaluated surface.
Exposure (HA)
Hyalgan MW=500-730 kDa
20mg/2ml IA injection once
a week for 2 weeks (3
injections) every three
months for a total of nine
injections.
The first injection was
performed 1 month after
arthroscopy and the last
injection 3 months before
the final visit. Before each
injection any synovial fluid
was aspirated.
Pain, functional
impairment,
quality of life;
Radiological
findings (e.g.
joint space
narrowing)
Difference from baseline
Clinical variables
Pain, VAS mm
Functional impairment a
Quality of life b
validity /
applicability
study design
Listrat, V., Ayral, X.,
Patarnello, F., Bonvarlet,
J. P., Simonnet, J.,
Amor, B., et al. (1997).
Arthroscopic evaluation
of potential structure
modifying activity of
hyaluronan
(Hyalgan(TM)) in
osteoarthritis of the knee.
Osteoarthritis &
Cartilage., 5(3), 153-160.
RCT
prospective
Participants
Mean age: 60 & 64
yrs
Male:13
Female:26
BMI=26.6 & 27.5.
Screened
N=NR
Randomised
N=39
Evaluable
N=NR
Completed
N=36
Exclusion
IA surgery in the past 5
years, IA treatment in the
last 3 months, concurrent
symptomatic treatment.
Comparison (CT)
No IA injections during the
year
Conventional therapy?
Note:
All patients underwent knee
arthroscopy during which
lavage using 2l saline serum
was performed
Duration
1 year
Radiological variables
Joint space narrowing:
Worse
Stable
Improved
Joint space width mm
HA(n=19)
CT(n=17) p-value
-16.8±23.9 -5.2±36.6 0.13
-1.7±2.9
-1.4±5.9
0.66
-0.42±0.67 +0.18±0.88 0.047
7
11
1
-0.4±0.8
10
5
2
-0.7±1.2
Arthroscopy
Overall assessment VAS mm 5.1±12.7 16.7±18.3
SFA Score
3.7±7.3 9.0±11.5
SFA grade
Worsened
1
5
Stable
15
12
Improved
3
0
NSAID use (% pts)
30%
68%
NSAID daily intake (mean)
0.65±2.17 2.77±3.56
0.222
0.39
0.016
0.05
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
no
n/s
n/s
no
n/s
?
yes
n/s
yes
yes
?
no
yes
yes
conclusions,
comments, and
quality scores
Validity: ~
Precision: ~/+
Applicability: ~
Overall quality: ~
Authors’ conclusions:
The study supports existing data
concerning the favourable
symptomatic effect of IA
injections of HA for OA in the
knee and suggests that repeated
IA injections of HA might delay
the structural progression of the
disease.
Reviewer’s comments:
Small study
Not clear how the control group
were treated
0.016
0.044
Safety and adverse events: 8/20 (40%) reported pain during or
immediately after their HA injection for at least 1 of 9 injections for
17 events out of 180 injections (9%). No acute hydarthroidal flare
occurred during the study.
a
Lequesne’s Index,
AIMS
* differences between treatment groups at discrete time points are not
reported unless a significant difference was also found for the variable
by the AUC technique of data analysis. No significant differences
were found for VAS range of motion and VAS knee function.
b
DNR =data not reported
IA= intra-articular
MW=molecular weight
OA= osteoarthritis
HA=hyaluronic acid
28
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
To assess the effects of
intra-articular
injections of HA on
symptoms of knee OA.
Inclusion
Age 40-75 years,
symptomatic,
radiologically verified
knee OA stage I-II
(Ahlback), knee pain
on the day of
examination scoring
more than 10mm on a
100mm VAS at
baseline, an
algofunctional score of
4 or greater at baseline.
Exposure
Artzal MW=900
Hyaluronan 25 mg
1% in 2.5 ml phosphate buffered
saline one IA injection a week
for 5 weeks.
Pain activity,
Lequesne
index, global
assessments by
patients and
evaluators
Week 20. Analysis of treatment efficacy of the unstratified groups
showed no significant difference between groups (p=0.538).
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
study design
Lohmander, L. S., Dalen,
N., Englund, G.,
Hamalainen, M., Jensen,
E. M., Karlsson, K., et
al. (1996). Intra-articular
hyaluronan injections in
the treatment of
osteoarthritis of the knee:
A randomised, double
blind, placebo controlled
multicentre trial. Annals
of the Rheumatic
Diseases, 55(7), 424431.
RCT
Double-blind
Placebo-controlled
Participants
Age:58yrs
Male:53/67 each
group.
Screened
N=NR
Randomised
N=240
Evaluable
N=189
Completed
N=189
Exclusion
Significant symptoms
of osteoarthritis of both
knees, previous IA
fracture of the knee,
rheumatoid arthritis or
other inflammatory
arthritis as diagnosed
by the ACR including
C reactive protein and
serum rheumatoid
factor concentrations,
IA injections of
steroids or any other
invasive procedure
within the previous six
months, any other
condition that might
interfere with the
efficacy assessment or
completion of the trial.
Comparison
Placebo 2.5 ml phosphate
buffered saline one IA injection
per week for 5 weeks.
Note:
Patients were stratified into four
groups on variable with
potential value – age,
algofunctional index. No
significant interactions were
found for two other potential
prognostic variable gender and
centre
Stratified groups* 60-75 years/baseline Lequesne index>10
Pain at 13 and 20 weeks:
AUC differencea p=0.008 for both HA and PL groups;
p-value between groups at 13 weeks p=0.014 and at 20 weeks
p=0.004.
Activity at 4, 5, 13 and 20 weeks:
AUC differencea p=0.008 for both HA and PL groups;
p-value between groups at 4 weeks p=0.001, at 5 weeks p=0.037, at
13 weeks p=0.030 and at 20 weeks p=0.028.
Lequesne index at 4 and 13 weeks:
AUC differencea p=0.028 for both HA and PL groups;
p-value between groups at 4 weeks p=0.043 and at 13 weeks p=0.032.
All differences above were in favour of the HA group.
Activity: the younger group with a baseline l score of 10 or less
exhibited a difference in favour of placebo for AUC (p=0.038) and at
weeks 5 (p=0.023) and 13 (p=0.018).
No differences between HA and placebo were found for the other
sub-groups for these variables.
Duration
20 weeks
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
no
n/s
yes
yes
yes
yes
yes
n/s
short
term
yes
?
?
yes
yes
conclusions,
comments, and quality
scores
Validity: ~/+
Precision: +
Applicability: ~/+
Overall quality: ~/+
Authors’ conclusions:
Patients older than 60 years with OA
of the knee and significant symptoms
corresponding to and index of severity
of knee disease of 10 or more,
comprise the group most likely to
benefit from treatment with IA HA
injections.
Reviewer’s comments:
Rather a lot of analyses by different
techniques, AUC, ITT, per protocol,
and for different groups – stratified,
unstratified and 8 time periods. This
increases the likelihood of significant
results.
Global assessments by patients and investigator
Sub groups >60 years , 20 weeks
Both Patients’ Global Assessments and Investigators’ Global
Assessments demonstrated significant changes from baseline between
HA and PL groups (p=0.019 for Patients and p=0.024 for
Investigators).
Sub groups >60 years and Lequesne index >10, 20 weeks
Both Patients’ Global Assessments and Investigators’ Global
Assessments demonstrated significant changes from baseline between
HA and PL groups (p=0.037 for Patients and p=0.027 for
Investigators).
No differences between HA and placebo were found for the other
sub-groups.
Adverse events/safety
Severity of injection site swelling was significantly less in the placebo
group as compared to the HA group (p=0.041).
2 patients in the HA group and 5 in the placebo group discontinued
the injections due to adverse effects.
No SAEs and no differences between the groups in terms of the
frequency of adverse events were found. There were no differences
between the groups in the consumption of analgesics or NSAIDs.
* differences between treatment groups at discrete time points are not
reported unless a significant difference was also found for the variable
by the AUC technique of data analysis. No significant differences
were found for VAS range of motion and VAS knee function.
DNR =data not reported
29
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
yes
no
n/a
n/s
conclusions, comments,
and quality scores
Participants
Enrolled
N=102
Completed
N=93
Inclusion
Diagnosis of chronic
idiopathic OA of the knee on
radiographic examination,1875 years, 4 of the following 6
criteria;
ESR<30mm/h,RH
factor<1:160, morning
stiffness no longer than 30
min, 4.crepitus on active
motion, tenderness of the bony
margins, physician
determination of absence of
rheumatoid disease.
NSAID tolerant for at least 30day period pre-trial, actively
using the joint, score >50mm
on a VAS of 100mm for pain
on motion with weight
bearing.
3 treatment groups;
NSAID only, n=34, usual dose +
3 wkly arthrocenteses
Physical findings
(e.g. medial and
lateral joint
tenderness),
activity (e.g.
walk time,
activity
restriction), and
reported pain
(e.g. pain with
motion, at rest,
severity of pain,
overall pain)
All treatments had significant (<0.01)
improvements from baseline at 12 weeks
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
no
yes
yes
yes
yes
yes
yes
yes
n/s
yes
yes
yes
Validity: ~/+
Precision: +
Applicability: ~/+
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
?
n/s
yes
study design
Adams, M. E., Atkinson,
M. H., Lussier, A. J.,
Schulz, J. I.,
Siminovitch, K. A.,
Wade, J. P., et al. (1995).
The role of
viscosupplementation
with hylan G-F 20
(Synvisc) in the
treatment of
osteoarthritis of the knee:
a Canadian multicenter
trial comparing hylan GF 20 alone, hylan G-F 20
with non-steroidal antiinflammatory drugs
(NSAIDs) and NSAIDs
alone. Osteoarthritis &
Cartilage., 3(4), 213-225.
RCT
Double blind
Follow-up
26 weeks
Excluded:
other serious systemic disease,
depression, neuroses, acute
synovitis or excessive
effusion, obese ,varus or
valgus deformity >15°,
pregnant or no effective
contraception, surgery or joint
infection in last 3 months
HylanG-F 20 only, n=31
3 weekly injections of 2.0 ml
hylan G-F 20
NSAID + Hylan G-F 20, n=37
Usual NSAID + 3 weekly
injections of
2.0 ml hylan G-F 20
12 week FU
Medical assessors evaluated the improvement in
all groups. No group was found to show
significant improvement over any other group as
regards to:
Medial joint tenderness
Lateral joint tenderness
Pain while walking
Overall assessment
50-foot walk time
No placebo group
Patients were told that they
could take Paracetamol as a
rescue if the pain became
unbearable.
Control group= NSAID only
group
Patients did a self-evaluation of improvement at
12 weeks. The NSAID group reported
significant improvement over the Hylan GF20
group for Support used (p=0.022); the NSAID
group reported significant improvement over the
Hyland GF20 + NSAID group for Pain at night
(p=0.048) and the Hylan GF20 group reported
significant improvement over the Hylan GF20 +
NSAID group for Pain at night (p=0.041). All
other comparisons (Pain with motion, Pain at
rest, Severity of pain, Activity restriction, Overall
pain and Support used) were not significant.
Assessment of equivalency
q-statistical analysis of improvement at 12 weeks
indicated that the Hylan G-F20 only group wase
considered to be equivalent or better than the
NSAID only group for all outcomes except
activity restriction.
yes
Overall quality: ~/+ to +
Authors’ conclusions:
Hylan G-F20 is a safe and effective treatment
for OA of the knee and can be used either as
a replacement for or an adjunct to NSAID
therapy.
Reviewer’s comments:
44% improvement, HA and NSAIDS better
than NSAID alone
Treatment of the pain of OA of the knee with
hylan G-F 20 is at least effective as treatment
with NSAIDs
Pain at rest was the only outcome measure to
improve significantly with hylan G-F20
Placebo group considered unethical
Some patients may not have had OA.
13 patients had bilateral treatment but only
one knee was assessed.
26 week FU
Both hylan G-F 20 groups were significantly
better than the NSAID only group.
Adverse Events
N=3 local transient reactions with 1 withdrawal
30
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
To evaluate safety
and efficacy of
different dose
schedules of HA in
comparison with
placebo and knee
arthrocentesis.
Inclusion
Male or female aged at
least 40 years.
Diagnosis of OA of the
knee according to
American College of
Rheumatology.
Clinical history of OA
knee pain for at least 6
months.
Presence of knee effusion
>3ml,
Pain on movement greater
than 40 mm (100mm
VAS).
Five treatment groups
7 pain parameters
Results (s.d.)—n=20 for all groups
PL
AR
HA-1
HA-3
HA-5
Day 60 (end of treatment)
Pain on movement 59.8(14.5) 63.2(13.7) 53.4(20.4) 47.8(17.7) 42.1(12.5)
Pain at rest
39.9(14.6) 43.2(14.8) 34.1(15.2) 33.0(15.8) 29.3(9.3)
Lequesne index
13.9(3.5) 14.4(3.2) 12.7(5.1) 12.0(4.3) 11.6(2.6)
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
study design
Carrabba, M., Paresce,
E., Angelini, M., Re, K.
A., Torchiana, E. E. M.,
& Perbellini, A. (1995).
The safety and efficacy
of different dose
schedules of hyaluronic
acid in the treatment of
painful osteoarthritis of
the knee with joint
effusion. European
Journal of Rheumatology
& Inflammation., 15(1),
25-31.
RCT
Prospective
Single-centre
Double-blind
Placebo and
arthrocentesis controlled
Participants
N=100
Exclusion
Generalized arthritis or
secondary OA of the knee.
Joint infection,
Specific conditions or poor
health that could interfere
with functional
assessment.
IA or arthrocentesis in
previous 3 months.
Very severe OA of the
knee.
Other concomitant
treatment for OA of the
knee except paracetamol.
HA-1
Hyalgan (mw=615)
20mg/2ml, IA injection
once at
baseline.
HA--3
Hyalgan (mw=615)
20mg/2ml, IA
injections at baseline
then once a week for 2
weeks
HA-5
Hyalgan (mw=615)
20mg/2ml, IA injection
at baseline and then
once a week for 4
weeks
Placebo
2ml saline IA
injections once a week
for 4 weeks
Arthrocentesis
IA injections once a
week for 4 week
In 2x2 comparisons of different combinations of the 5 treatment groups:
HA-5 vs HA-3: No significant difference for any pain parameter
HA-5 vs HA-1: Significant difference for all 7 pain parameters
HA-5 vs AR:
Significant difference for all 7 pain parameters
HA-5 vs PL:
Significant difference for all 7 pain parameters
HA-3 vs HA-1: Significant diff for pain on movement, ISOAK score and
joint effusion (3/7).
HA-3 vs AR:
Significant difference for all pain parameters
HA-3 vs PL:
Significant difference for all pain parameters except pain
at rest
HA-1 vs AR:
Significant difference for 2/7 pain parameters
HA-1 vs PL:
No significant difference for any pain parameter
AR vs PL:
No significant difference for any pain parameter
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes
yes
yes
yes
yes
yes
yes
yes
yes
no
yes
n/s
yes
conclusions,
comments, and
quality scores
Validity: +
Precision: +
Applicability: ~
Overall quality: ~/+ to +
(60days)
Authors’ conclusions:
Five and three injections of
HA were significantly better
than one injection of HA,
placebo or arthrocentesis. The
effects of placebo and
arthrocentesis were short
lived. For HA the duration of
the therapeutic effect appeared
to be dose-dependent.
yes
Reviewer’s comments:
Small sample – each group
n=20
Adverse events
No severe adverse events were reported during the study. Doses of HA of 3-5
injections are well tolerated. The maximum therapeutic dose was found after
the third injection. The effect persisted for the second month and relapsed only
at the 3-4th month of FU.
Few local adverse reactions which were transitory and equally distributed
amongst the groups.
Study duration=6
months
Treatment duration = 1
month
31
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
yes
no
n/a
n/s
conclusions,
comments, and
quality scores
Objective
To evaluate the safety
and efficacy of HA in the
treatment of post
immobilisation pain and
stiffness after knee injury
or surgical intervention
to reduce a fracture.
Inclusion
Males and female 1865 years, knee pain
and functional
disability resulting
from immobilisation
in a plaster cast for
>=20 days following
treatment of an intra
or extra articular
fracture or following
and acute knee injury
or after intra or extraarticular surgical
intervention.
Exposure (HA)
Active treatment comprising 20
mg/2ml IA injection of
hyalgan® (HA) on removal of
the plaster cast and once a week
for a further 4 injections + a
course of standard
physiotherapy.
Pain symptoms,
joint mobility
HA(n=15) C(n=15) p-value
Pain symptoms (mean VAS) day 21
Spontaneous pain
35.0±14.8 44.6±14.0 <0.001
Pain under load
47.0±14.4 54.0±13.6 <0.001
Pain on touch
39.3±14.1
46.0±12.1
<0.001
Night pain
30.4±12.4
41.3±14.8
<0.001
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
yes
yes
yes
n/s
n/a
?
yes
no
yes
n/s
short
term
yes
Validity: ~/+
Precision: +
Applicability: ~/+
study design
Di Marco, C., & Letizia,
G. A. (1995). Hyaluronic
acid in the treatment of
pain due to knee joint
immobilisation. A
controlled clinical study.
Clinical Drug
Investigation., 10(4),
191-197.
RCT
Open label
Single blind
Participants
Mean age: 37 and 39
years
Male: 19
Female:11
N=30
Screened
N=NR
Randomised
N=30
Evaluable
N=30
Completed
N=30
Exclusion
Pregnancy or breast
feeding, allergy or
hypersensitivity to
drugs, severe
concomitant disease
or diseases that could
interfer with the
evaluation of the
affected knee, drugs
that would interfere
with study
evaluations. IA
injection 3 months
previously, infection
from which an
arthritic condition
could ensue, noncompliant or
unreliable patients.
Comparison (C)
No IA drug treatment, a course
of standard physiotherapy.
Pain symptoms (mean VAS) Day 45
Spontaneous pain
2.0±4.1
Pain under load
11.0±12.3
Pain on touch
2.3±4.5
Night pain
0.3±1.2
28.3±10.9
38.0±10.4
29.6±10.2
25.0±12.5
<0.001
<0.001
<0.001
<0.001
Drop outs<20%
Duration
45 days
Joint mobility (mean degrees) Day 21
Maximum flexion
107.7±16.2 105.3±12.0 <0.001
Maximum extension
162.3±8.6 156.0±7.4
ns
Joint mobility (mean degrees) Day 45
Maximum flexion
142.7±5.0 123.7±9.2
Maximum extension
174.0±2.1 168.3±5.6
<0.001
ns
Overall judgements: the differences between the two groups
were significant (in favour of HA) from day7 to day 45
(p<0.001), patients and doctors judgements were very similar.
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
yes/n/s
yes
Overall quality: ~/+ to +
Authors’ conclusions:
A significant difference between
groups for all parameters of
efficacy was seen from the 21st
day up to the end of the 45th day.
No adverse events were observed.
Reviewer’s comments:
Small group size
Young age group
Short follow-up
yes
Note: This study is very similar
to the Zattoni et al 1995 study also
reviewed here but there is no
evidence that any of the same
patients are involved.
Concomitant medication: No patients in the HA group took
analgesics, in the control group 6 patients took analgesics to day
7. After day 7 no patients in the study took analgesics.
Adverse events and safety: no adverse events or clinically
relevant changes in blood chemistry were seen in any of the
patients. In particular, local and general tolerability were very
good in all patients treated with HA.
IA = intra-articular
32
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
yes
no
n/a
n/s
conclusions,
comments, and
quality scores
Objective
To evaluate the effects of
a 1% HA solution in
comparison with
physiological saline in
patients with monolateral or bilateral OA of
the knee and painful
limitation of movement.
Inclusion
Adults with mono or
bilateral OA of the
knee, painful
limitation of
movement,
narrowing of the
femoro-tibial space
and osteophytes, subchondral sclerosis or
cysts.
Exposure (HA)
Hyalgan®
One IA injection of
20mg/2ml of a 1% HA
solution per week for
five weeks.
Pain, subjective
evaluation of
effectiveness of
intervention
There was a significant decrease (p<0.001) compared to baseline for both HA
and PL groups for the following outcomes. However, there were no
significant differences between the 2 groups:
Evolution of pain (reported primarily in graphs) one week after end of Rx:
Spontaneous pain
Pain on load
Pain on movement
Pain on pressure
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
yes
yes
yes
yes
n/a
yes
yes
yes
yes
yes
yes
yes
Validity: ~/+
Precision: ~
Applicability: ~
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
RCT
yes/n/s
yes
study design
Formiguera Sala, S., &
Esteve de Miguel, R.
(1995). Intra-articular
hyaluronic acid in the
treatment osteoarthritis
of the knee: A short term
study. European Journal
of Rheumatology &
Inflammation., 15(1), 3338.
RCT
Double blind
Placebo controlled
Participants
Age: mean 61-63 yrs
Male: 11 (knees?)
Female: 29 (knees?)
Screened
N=not reported
Randomised
N=40 knees (36 pts)
Evaluable
N= 40 knees
Completed
N=40 knees
Exclusion
Secondary OA of the
knee, non-arthritic
arthropathies, large
volume joint
effusion, severe
systemic disease,
pregnancy or
lactation and
inexplicable
haematological or
biochemical
abnormalities.
Comparison (PL)
One IA injection of 2
ml of physiological
saline per week for 5
weeks.
Duration
90 days
P-values for the differences between the HA and PL groups for the following
outcomes (all differences were in favour of the HA group; data not reported)
were:
Evolution of pain Day 90 end of study
Spontaneous pain p<0.05
Pain on load p<0.05
Pain on movement p<0.005
Pain on pressure p=0.06
MANOVA for pain and joint mobility (day0-28, treatment period)
Variable group:
Active and passive flexion, active and passive extension, heart rate, SBP,
DBPÆno significant treatment differences
Pain on pressure, spontaneous pain, pain on load, pain on
movementÆsignificant time difference (p<0.001), no significant treatment
differences
yes
Overall quality: ~
Authors’ conclusions:
That IA HA is safe and more
effective than placebo in the
treatment of patients with
unilateral or bilateral OA of
the knee. HA also provided
pain relief and improved joint
function without accelerating
joint damage
Reviewer’s comments:
small group size
data not given only p values.
Post treatment follow-up (day 28-90) 3 groups recognised
Group 1. Heart rate, BP active and passive flexion were not modified by the
treatments.
Group 2. Active and passive extension and evolution of severity scale
improved with time in both groups but between group differences were not
significant
Group 3. Pain variable which improved with time and dependent upon
treatment with improvements always in favour of HA. P values <0.05 to
<0.01.
Subjective judgments of the effectiveness of the intervention (HA group) are
as follows:
Excellent-good vs average-poor p-value diff
Doctor—day 35
10/10
0.401
Doctor—day 90
13/7
0.086
Patient—day 35
12/8
0.126
Patient—day 90
14/6
0.004
Safety/adverse events: no clinically important changes in blood were
reported, no treatment related adverse events were reported. Local painful
reactions were reported by 3 patients from each group and a subcutaeous
haematoma appeared in 2/3 of the placebo cases attributed to the route of
administration.
IA= intra-articular
OA= osteoarthritis
HA=hyaluronic acid
Pl=placebo
33
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
To determine the
comparative efficacy
and safety of IA
triamcinolone
hexacetonide (TH) and
IA hyaluronic acid
(HA) in inflammatory
osteoarthritis
Inclusion
Bilateral OA of the knee
Exposure (HA)
Hyalgan 20 mg IA
injection once a week
for 5 weeks into the
worst knee.
VAS pain
scores for pain
on activity, at
rest, at night
Mean scores±s.d.
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
study design
Jones, A. C., Pattrick,
M., Doherty, S., &
Doherty, M. (1995).
Intra-articular hyaluronic
acid compared to intraarticular triamcinolone
hexacetonide in
inflammatory knee
osteoarthritis.
Osteoarthritis &
Cartilage., 3(4), 269-273.
RCT
Double blind
Single centre
Participants
Age:
Male:
Female:
Screened
N=NR
Randomised
N=63
Evaluable
N=56
Completed
N=20/21
Exclusion
Co-existent
rheumatological or
serious medical disease
Comparison (TA)
Triamcinolone
hexacetonide 20 ml IA
injection in worst knee
followed by 4 placebo
doses.
Placebo (PL)
1 ml 0.9% saline
contralateral knee
received placebo
injections in both
groups.
Concomitant
medication
Patients were asked to
discontinue taking
NSAIDs and take only
Paracetamol for
analgesia.
Duration
Treatment 4 weeks
FU=6 months
HA(Rx knee) HA(PL knee) TA(Rx knee) TA(PL knee)
VAS Week 0 (baseline) N=32, N=31
Pain on activity (mm)
77.2±3.3
68.6±3.9
75.8±3.0
66.2±4.5
Pain at rest (mm)
53.2±5.6
43.1±5.4
55.3±5.3
41.3±5.2
Pain at night (mm)
57.8±6.2
45.5±6.0
62.2±5.3
48.7±5.3
VAS Week 4 ( end of treatment) N=29, N=27
Pain on activity (mm)
56.6±6.3
47.0±6.5
Pain at rest (mm)
39.9±6.4
27.9±5.4
Pain at night (mm)
35.9±5.9
27.9±5.2
56.7±6.1
40.6±6.2
43.0±6.5
51.7±5.9
34.9±5.4
35.7±6.0
VAS Week 29 ( end of study) N=12, N=8
Pain on activity (mm)
44.3±
38.3±7.5
Pain at rest (mm)
28.2±
17.9±7.1
Pain at night (mm)
15.4±
18.5±6.9
54.3±8.5
48.6±9.6
36.1±7.5
53.4±7.6
30.5±7.5
39.8±9.5
Drop outs<20%
Note: p-values not reported
No significant differences between the groups developed at any time during the
treatment period.
Safety and adverse events
Not reported but high drop-out rate was mainly because patients developed
symptoms for which they wanted to resume their NSAID medication.
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes
n/s
yes
?
yes
yes
yes
n/s
medium
term
no
?
?
No
?
conclusions,
comments,
and quality
scores
Validity: ~/+
Precision: ~/+
Applicability: −
Overall quality: ~
Authors’ conclusions:
In patients completing
the study significantly
less pain was
experienced by the HA
group during the 6th
month of FU. We
could not, however,
demonstrate significant
differences between the
active and placebo
knee. HA may
therefore be a useful
additional therapy for
symptomatic OA of the
knee and may have a
long duration of action.
Reviewer’s
comments:
Very high number of
IA injections.
Both knees injected.
Rescue pain
medication allowed
was inadequate leading
to high drop out.
Statistical significance
not well reported.
Very small number
completed study.
High drop rate (6274%)
No adverse events data
reported.
34
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
To assess the efficacy
and tolerability of HA
administered by IA
injection in patients with
acute knee injury.
Inclusion
Male or female, age 1865 years, with injury
within 24 hours prior to
admission and who
practiced sport at
different levels, mainly
soccer and skiing,
affected by acute knee
injury with mild or
moderate ligament tears
(I,II degree) and
instability.
Exposure – active treatment
comprising hyalgan® (HA) one
IA 20mg/2ml injection
administered within 24 hours of
the trauma and after
arthrocentesis if effusion was
present. After injection a
bandage was applied and
removed the following day and
replaced by a plaster knee cast.
The cast was removed on day 21
and the patients received three
consecutive IA injections of HA
at a rate of one injection per
week + 10 sessions of standard
physiokinesiotherapy.
Pain symptoms,
joint mobility,
overall efficacy
Mean ± s.d.
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
study design
Zattoni, G., Cabrioli,
A., Brunelli, G., &
Perbellini, A. (1995).
Efficacy and tolerabilty
of hyaluronic acid in
acute knee injury: A
controlled clinical
study. European
Journal of
Rheumatology &
Inflammation., 15(1),
63-69.
Participants
Mean age: 32 years
Male: 34
Female:16
Typical sports injury pop
Male predominance
Young patients.
RCT
Single blind
Screened
N=NR
Randomised
N=50
Evaluable
N=48
Completed
N=48
Exclusion
Concomitant meniscal
lesions, clinical or
radiological evidence of
other joint pathologies,
severe concomitant
disease, treatment with
IA in the previous 6
months, pregnant or
lactating females.
Comparison- No IA drug
treatment. After arthrocentesis if
effusion was present. After
injection a bandage was applied
and removed the following day
and replaced by a plaster knee
cast. The cast was removed on
day 21 and the patients
underwent 10 sessions of
standard physiokinesiotherapy.
Duration
58 days
HA(n=24) C(n=26)
p-value diff
Pain symptoms (mean VAS) day 28
Pain at rest
2.2±4.2
9.2±9.2
ns
Pain on movement
13.0±9.0
24.6±16.1
<0.01
Pain on touch
5.7±7.3
17.4±15.2
<0.01
Night pain
0.4±2.1
6.8±10.0
ns
Pain symptoms (mean VAS) Day 58
Pain at rest
0.0±0.0
2.2±4.1
Pain on movement
1.1±3.0
10.2±12.4
Pain on touch
0.0±0.0
7.4±10.1
Night pain
0.0±0.0
0.8±2.8
ns
<0.01
ns
2.8
Joint mobility (mean degrees) day 28
Maximum extension
0.2±1.0
2.6±4.1
Maximum flexion
122.4±13.2 106±25.1
ns
<0.01
Joint mobility (mean degrees) day 58
Maximum extension
0.4±1.4
2.8±3.8
Maximum flexion
135.0±8.8 127.4±16.4
ns
ns
Overall efficacy judgment rating good-excellent
Patient day 1
16
9
Patient day 21
20
14
Patient day 58
23
19
Doctor day 1
18
12
Doctor day 21
21
13
Doctor day 58
23
20
0.025
0.027
NR
0.016
0.004
NR
Note: day 58 comparison of no. of excellent vs rest was
significantly higher for HA by both doctor and patient
evaluations.
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
yes
yes
n/s
no
yes
yes
no
yes
n/s
short
term
yes
yes
yes/n/s
yes
yes
conclusions,
comments, and
quality scores
Validity: ~/+
Precision: +
Applicability: ~/+ to +
Overall quality: ~/+
Authors’ conclusions:
The results suggest that IA
injection of HA can be
considered a useful therapeutic
measure in the treatment o not
only for acute knee injuries but
also for all those pathological
conditions such as fracture,
which require long periods of
joint immobilisation.
Reviewer’s comments:
Randomisation list not a very
good method of randomisation
as it may be subject to abuse
and therefore bias – no
precautions were reported to
ensure concealment.
Note: This study is very
similar to the Di Marco et al
1995 study also reviewed here,
but there is no evidence that
any of the same patients are
involved.
Consumption of analgesics: there were no significant differences
between the groups for the consumption of analgesics. However,
five patients in the control group were taking between 500-1,500
mg/d of paracetamol from day 21 onwards.
Safety and adverse events:
No adverse events of clinically relevant modifications of the
laboratory parameters of vital signs were observed.
I patient in each group withdrew to have a meniscectomy (days 28
and 42)
IA= intra articular
35
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
To investigate the
mechanism of
action of IA
hyaluronic acid in
OA of the knee.
Participants
Inclusion
Use related pain in both
knees, no steroid
injection for at least
three months prior to the
trial, X Ray evidence of
OA, presence of bilateral
Synovial effusions.
Exposure (HA)
Hyalgan 20 mg in
2 ml saline.
VAS pain scores,
clinical
measurement of
night pain and rest
pain
VAS pain scores for
use fell in both knees
but there was no
difference between the
HA and placebo knee.
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
study design
Creamer, P., Sharif,
M., George, E.,
Meadows, K.,
Cushnaghan, J.,
Shinmei, M., et al.
(1994). Intra-articular
hyaluronic acid in
osteoarthritis of the
knee: an
investigation into
mechanisms of
action. Osteoarthritis
& Cartilage, 2(2),
133-140.
RCT
Single blind
Observer blinded
Age: mean = 72.2
years (52-83 years)
Female: 100%
Mean disease
durations 21.5 years
Advanced disease
N=12
Screened
N=NR
Randomised
N=12
Evaluable
N=12
Completed
N=12
Exclusion
Non reported
Comparison (PL)
2 ml saline
Schedule
One injection
once a week for 5
weeks.
Note: all patients
had aspiration of
synovial fluid
before each
injection.
Note: knees
randomised not
patients.
Duration
9 weeks
Clinical measurements
of night pain and rest
pain were not
significant.
Adverse events:
7 patients reported 12
AEs, 5 in the HA and
3 in the PL knee, 4 in
both knees. 5 events
were graded as severe
and included swelling
of the knee (3 in
treated knee 2 in
placebo knee)
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
n/a
n/s
n/a
yes
yes
no
yes
yes
short
term
yes
no
?
yes
?
conclusions, comments,
and quality scores
Validity: ~/+
Precision: Applicability: ~
Overall quality: -/~
Authors’ conclusions:
Intra-articular injection of
hyaluronic acid did not result
in any improvement in the
clinical indices compared to
placebo.
Reviewer’s comments:
Very small study using
patients as their own control.
Not designed as a study of
clinical efficacy; primary
outcomes related to
mechanism of action.
Knee randomised not patients
– not clear how similar the
knees were.
All patients had long standing
advanced disease. All female.
All patients had knee
aspiration before injections
which may have accounted
for the improvement reported
regardless of type of
treatment received.
36
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
yes
no
n/a
n/s
conclusions, comments,
and quality scores
Objective
To compare the
effect of IA
hyaluronic acid and
placebo in patients
with knee pain on
exertion and with
joint cartilage
abnormalities.
Inclusion
Knee pain on exertion or
cartilage abnormalities.
Artzal (HA) (mw=900)
2.5ml (10mg/ml), IA once
weekly IA injection for 5
weeks + knee aspiration
Lysholm knee function
score, assessments of
pain, mobility, function
,activity
Median of individual differences compared with
baseline:
HA
PL
Wk 0-13 =significant improvement in all primary
outcome parameters for HA and PL (see c)
End of treatment (5 weeks)
-3.0
0.5
Lysholm score a
Pain b
-8.0
-15.0
Mobility b
-6.0
1.0
Function b
-6.0
-10.0
b
Activity
-10.0
-29.0
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
yes
yes
yes
yes
yes
yes
yes
yes
yes
n/s
yes
yes
Validity: ~/+
Precision: +
Applicability: ~/+
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
no
n/s
yes
study design
Dahlberg, L.,
Lohmander, L. S., &
Ryd, L. (1994).
Intraarticular injections
of hyaluronan in patients
with cartilage
abnormalities and knee
pain. A one-year doubleblind, placebo-controlled
study. Arthritis &
Rheumatism., 37(4),
521-528.
RCT
Randomised
Placebo-controlled
Triple blind
Participants
N=52
Screened
N=NR
Randomised
N=52
Completed
N=48
Exclusion
Any condition that would
interfere with the study
protocol or interpretation
of the results e.g.
previous IA fracture
serious liver or kidney
disease, blood disease,
allergy to any substance
used in the study, alcohol
or drug abuse, rheumatoid
arthritis or other
inflammatory joint disease,
elevated C-reaction protein
or RF level, steroid
injection, arthroscopy or
other invasive procedure
administered in the
previous 6 months.
Placebo (PL)
2.5 ml saline IA once weekly
IA injection for 5 weeks +
knee aspiration
Patients were not required to
discontinue their pain
medications prior to study.
Power analysis
For patients with the type of
abnormality under
investigation a study size of 50
was calculated. This was
based on the following
assumptions
• Baseline mean score on a
100mm VAS=45mm (s.d.
=22).
• Response of approx 9mm
i.e. 20% with placebo.
• Expected minimum
clinically relevant
treatment response of 18
mm i.e. twice the estimated
placebo response
Treatment =5 wks
Study=52 wks
Follow-up at 26 weeks
Lysholm score a
6.0
Pain b
-17.0
Mobility b
-11.0
Function b
-20.0
Activity b
-4.0
8.0
-10.0
-3.0
-14.0
-9.0
Overall quality: ~/+
Authors’ conclusions:
The study had shown a significant
effect of IA injections in the knee in
patients with knee pain and arthroscopic
cartilage degeneration without any
severe side effects. The study was
unable to demonstrate any difference
between HA and saline placebo.
Reviewer’s comments:
N=4 drop out (2 excluded for fractures)
Follow-up at 52 weeks (n=26,22)
Lysholm score a
3.0
13.0
Pain b
-10.0
-11.0
Mobility b
-15.0
-13.0
Function b
-17.0
-16.0
Activity b
-10.0
-11.0
None of the differences between the HA and PL
groups was statistically significant.
Secondary outcomes
There were no significant differences between the
median or mean values for the treatment groups at
any time point.
Adverse events
No severe side effects reported for HA, one placebo
treated patient acquired Candid arthritis and another
had intolerable pain at injection site, both withdrew
from the study. A few patients in each group had a
transient swelling and rash after injections.
MW=molecular weight
a
Higher value = better condition,
b
rated by patients on a 100mm visual analogue scale
(VAS), a lower value represents a better condition.
c
except for PL activity score week 13, and PL
activity and motion scores week 26.
37
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
yes
no
n/a
n/s
conclusions,
comments, and
quality scores
Participants
Male=28
Female=63
Inclusion
Clinical history
and radiological
evidence of OA
of the knee.
Pain≥30mm on
100mm VAS
for pain evoked
by at least one
of 5 specified
activities.
Hyalgan (mw=615)
20mg in 2 ml
buffered saline IA
injection
administered once a
week for 5 weeks (5
injections)
+ aspiration to
dryness of any fluid
present in the knee.
Differences
in mean pain
scores for
various
activities as
reported by
patient and at
clinic visit
assessment
Difference in mean scores week 0 and week 5:
HA
PL
Stratification groups
1
2
1
2
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
yes
yes
yes
yes
?
yes
yes
yes
yes
n/s
yes
yes*
Validity: ~/+
Precision: ~/+
Applicability: ~
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
no**
n/s
yes
study design
Henderson, E. B.,
Smith, E. C.,
Pegley, F., &
Blake, D. R.
(1994). Intraarticular injections
of 750 kD
hyaluronan in the
treatment of
osteoarthritis: A
randomised single
centre doubleblind placebocontrolled trial of
91 patients
demonstrating lack
of efficacy. Annals
of the Rheumatic
Diseases, 53(8),
529-534.
Randomised
N=91
Analysed
N=84
Power
calculations
Sample size of
100 ( 50 in each
group) required
for
90% power to
detect a
13.1 mm mean
treatment
difference in
VAS scores
Exclusion
Inflammatory
joint disease,
metabolic bone
disease,
anserine
bursitis or pain
referred from
other structures.
Placebo
2 ml buffered saline
IA injection
administered once a
week for 5 weeks (5
injections)
+ aspiration to
dryness of any fluid
present in the knee.
Pre-trial=2 weeks
FU=5 months
Treatment =4 weeks.
RCT
Placebo-controlled
Double-blind
Bilateral disease
Most severely
affected knee treated
Stratification
Patients were
stratified on disease
severity based on
radiological changes.
Kellgren and
Lawrence
1 =I & II
2=III & IV
Diary VAS assessments (figures = reduction in
pain score)
Pain in the morning 17.7
9.1
12.3 6.9
Pain in the evening 24.1 8.1
13.8 12.5
Pain climbing stairs 10.9 8.5
19.4 6.9
Pain rising from chair 22.7 3.2
11.2 13.3
Pain on nominated
22.4 10.7
13.3 11.3
activity
Clinic visit assessment
Pain at rest
3.1 -0.01 -1.0
Pain on active
15.6 8.7
14.2
movement
Pain on passive
17.5
3.4
8.4
movement
Pain on horizontal 25.7
9.2
3.7
pressure
Pain on vertical
19.8 11.9
7.0
pressure
14.9
18.0
9.9
15.0
18.5
The differences between the HA and PL groups
for all values above were not statistically
significant.
yes
Overall quality: ~/+
Authors’ conclusions:
All patients improved
their VAS scores over
the period, there was
however no significant
different in scores
between the HA and
placebo groups.
Reviewer’s
comments:
Follow-up phase drop
out =33% (28/84)
Did not recruit
required number.
The significance of the
changes from baseline
for IA HA not
reported.
*Treatment drop-out 8%
** 90/91 had bilateral
disease
Adverse events (Proportion of patients)
Transient increase in pain and/or swelling:
HL=47%, PL=22%
Pain reported to be severe: HL=9%, PL=10%
Concomitant
medication/therapy
Only Paracetamol
allowed.
38
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To compare the efficacy
and safety of 2 injections
of hylan vs 3 injections
of hylan vs physiologic
saline administered intraarticularly.
Inclusion
Male and females
older than 18 yrs, Dx
of degenerative OA
of the knee and
radiologic grade IIIV (Larsen scale).
Free of rheumatoid
arthritis.
Study one
Exposure N=25
Hylan G-F 20 (Synvisc®)
2ml, 2 injections
Patient and
evaluator
assessments of
pain, joint
mobility, global
evaluation
Results: p values for diff between mean vas or % scores:
Hax2
Hax3
vs PL
vs PL
Patient pain evaluation ( mean VAS)
Weight bearing 4 weeks (VAS)
<0.05
<0.05
Weight bearing 8 weeks (VAS)
<0.05
<0.05
Weight bearing 12 weeks (VAS)
<0.05
<0.05
ns
<0.05
<0.05
Categorical a analysis of same data
Weight bearing 4 weeks (VAS)
Weight bearing 8 weeks (VAS)
Weight bearing 12 weeks (VAS)
ns
<0.05
<0.05
validity /
applicability
study design
Scale, D., Wobig, L. M.,
& Wolpert, W. (1994).
Viscosupplementation of
osteoarthritic knees with
hylan: A treatment
schedule study. Current
Therapeutic Research,
Clinical &
Experimental., 55(3),
220-232.
RCT
Double- blind
(patients and assessor
blinding, physician
administrator not
blinded)
Multicentre (2)
Participants
N=80 pts
Screened
N=NR
Randomised
N=80
Evaluable
N=80
Completed
N=80
Exclusion
Unreliability, pain on
weight bearing less
than 40mm on a
100mm VAS, joint
effusion.
Comparison N=25
Buffered saline 2ml, 2
injections
Study two
Exposure N=15
Hylan G-F 20 (Synvisc®)
2ml, 3 injections
Comparison N=15
Buffered saline 2ml, 3
injections
Concomitant medication
Non permitted for OA,
medication for concurrent
disease was allowed
providing that it was not
steroidal or NSAIDs. All
medication use was
reported.
Duration
6 months (telephone FU)
ns
<0.05
<0.05
<0.05
<0.05
<0.05
Hax2
vs Hax3
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
Evaluator assessment (Mean VAS)
Joint mobility at 4 weeks (VAS)
ns
<0.05
Joint mobility at 8 weeks (VAS)
ns
<0.05
Joint mobility at 12 weeks (VAS)
<0.05
<0.05
Categorical analysis of same data showed the same pattern
Patient assessment (Mean VAS)
Most painful movement 4 weeks
Most painful movement 8 weeks
Most painful movement 12 weeks
ns
<0.05
<0.05
<0.05
<0.05
<0.05
<0.05
<0.05
<0.05
ns
<0.05
<0.05
Patient assessment (Categoricala, % success)
Most painful movement 4 weeks
<0.05
Most painful movement 8 weeks
ns
Most painful movement 12 weeks
<0.05
ns
<0.05
<0.05
ns
<0.05
<0.05
Investigator (Mean VAS)
Global evaluation 4 weeks
Global evaluation 8 weeks
Global evaluation 12 weeks
<0.05
ns
ns
<0.05
<0.05
<0.05
<0.05
<0.05
<0.05
Investigator ( Categorical a % success)
Global evaluation 4 weeks
Global evaluation 8 weeks
Global evaluation 12 weeks
ns
ns
<0.05
ns
<0.05
<0.05
ns
<0.05
<0.05
6 month FU
Results in both hylan groups were significantly superior to those in the
control group in terms of reducing weight bearing pain, night pain and
restoring joint function.
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
no
n/s
yes
yes
yes
yes
yes
yes
medium
term
yes
?
yes/n/s
yes
yes
conclusions,
comments, and
quality scores
Validity: ~/+
Precision: ~/+
Applicability: ~
Overall quality: ~/+
Authors’ conclusions:
Hylan is an effective and
safe viscosupplementation
therapy for the
management of
degenerative OA of the
knee.
Beneficial results can be
maximised with a
treatment schedule of 3
hylan injections
administered at 1-week
intervals.
Reviewer’s comments:
There were significant
differences between
groups at baseline in a
number of factors duration of disease,
weight. The placebo
group had significantly
more patients (p=0.01)
grade IV disease.
In the Hax3 group
male=11, female= 4.
(reversal of usual ratio)
Disparate sizes 40 in
control, 15 in Hax3, 25
Hax2. Very small group in
favoured arm may have
been influenced by
random fluctuations,
however the pattern of
result was consistent.
Adverse events no generalised AEs were observed and only one local
transient adverse event – muscle pain.
39
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
To assess the
efficacy and
tolerability of
hyalectin by
conducting a
prospective
randomised
controlled trial
conducted over
one year.
Inclusion
Outpatients
fulfilling ACR
criteria for OA
knee, femorotibial
localization of
the disease, the
presence of
knee effusion, a
painful knee
(40mm or more
on VAS.
Exposure (HA)
Hyalgan (LMW)
20mg in 2 ml saline
Primary outcome
= disappearance
of knee effusion
at 7 weeks
HA p-value
PL
Disappearance of knee effusion at 7 weeks:
-6.0
-12.4 0.007
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
study design
Dougados, M., M.
Nguyen, et al.
(1993). High
molecular weight
sodium
hyaluronate
(hyalectin) in
osteoarthritis of
the knee: a 1 year
placebo-controlled
trial. Osteoarthritis
& Cartilage. 1(2):
97-103.
RCT
Multi-centre
Participants
Age: 67-69
(mean)
Male: 32
Female: 78
Screened
N=NR
Randomised
N=110
Evaluable
N=95
Completed
N=88
Exclusion
Serious
concomitant
illness,
secondary
arthritis of the
knee, knee with
prosthesis, any
IA of the knee
surgery in last
10 years, any
extra-articular
surgery of the
knee in last 2
years,
arthrocenthesis
in previous 3
months.
Comparison (PL)
2 ml saline
4 injections over 3
weeks
Aspiration of
synovial fluid
before injectiuons.
Concomitant
medication – basic
therapy for OA
stable during the
previous 3 months,
any physiotherapy
or NSAIDs and/or
analgesics had to be
stable during the
previous month.
These therapies had
to be maintained at
a stable dosage
during the first 7
weeks of the study.
Duration
1 year
Differences from baseline:
Week 7 (one month after the end of treatment)
VAS pain at rest
-15.1 -20.0 0.16
VAS pain after exercise -25.8 -35.5 0.03
Week 52
VAS pain at rest
-16.9
VAS pain after exercise -32.7
-17.9
-38.9
0.43
0.15
Adverse events
No serious adverse events were reported. IA
injections were considered to be painful by
36/110 patients. AEs were minor and transient
and probably not due to the drug. 4AEs in the
HA group, headache, fever aphtosis (2). 1 AE
in placebo group – pruritus. There were no
clinically significant changes in laboratory
parameters.
Note: during the 1 year of FU the need to
perform supplementary local therapies was
more frequent in the pacebo group (44%) than
the HA group (30%) p=0.03.
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes/no
n/s
yes
?
n/s
n/s
n/s
n/s
yes
yes/no
?
yes/n/s
yes
conclusions,
comments, and
quality scores
Validity: +
Precision: +
Applicability: ~/+
Overall quality:
~/+ to +&NR
Authors’
conclusions:
This study suggests
that IA injections of
hyalectin may
improve clinical
condition and have a
long term beneficial
effect in patients
with OA of the knee.
yes
Reviewer’s
comments:
The primary
outcome of this trial
was not pain.
Blinding was not
reported.
The HA used was
not really a HMW
preparation.
No interim
assessment at 2-4
months.
40
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
To compare the
efficacy and safety of
hyaluronic acid (HA)
and
mucopolysaccharide
polysulfuric acid
ester (MPA)
Inclusion
Clinic outpatients
With clinical and
radiological signs of OA
of the knee, at least 18
years old.
Exposure (HA)
Hyaluronic acid
20mg/ml IA injection
once a week (seven
injections over 6 weeks)
Knee function
(Larsen scale),
global assessment
Results: absolute change from baseline at end of period (s.d.)
HA
MPA p-value
(n=33)
(n=27)
Knee function (Larsen scale, subtotals and total) end of
treatment
Function
1.1 (5.8) 0.5(4.2) 0.66
(raw value 0-30)
Range of motion 0.3(0.9) 0.0(0.5) 0.12
Anatomy
0.80(1.3) 0.5(0.9) 0.34
Pain
5.5(6.2) 1.5(5.6) 0.01
Total Larson
8.4(10.3) 2.5(7.7) 0.02
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Global assessment at end of study ( proportion of pts)
investigator rating
Symptom free/marked 76%
46%
0.02
Improvement
Drop outs<20%
study design
Graf, J., Neusel, E.,
Schneider, E., &
Niethard, F. U. (1993).
Intra-articular treatment
with hyaluronic acid in
osteoarthritis of the knee
joint: a controlled
clinical trial versus
mucopolysaccharide
polysulfuric acid ester.
Clinical & Experimental
Rheumatology., 11(4),
367-372.
RCT
Single-blind
Participants
Mean age:
51 (HA) 59 (MPA)
yrs
Male:45%
Female:55%
Recurrent knee
effusion: 45%(HA)
15%(MPA)
Previous arthroscopy
45%(HA)
11%(MPA)
Screened
N=NR
Randomised
N=60
Evaluable
N=
Completed
N=57
Exclusion
No radiographic
cartilage lesions,
arthropathy other than
OA, tubercular
osteopathy, peripheral;
neuropathy accompanied
by pain or severe
decompensated
concomitant disease.
Pregnant and nursing
females, patients who
had received IA
corticosteroids within the
previous 3 months or
NSAIDs within 14 days
of study start.
Comparison
(MPA) 50mg/ml IA
injection twice a week
(13 injections over 6
weeks).
Note:
Additional
physiotherapy, analgesic
or antiinflammatory
agents were not
employed.
Duration
Rx=6 weeks
FU=6 months
1986-1987
Knee function (Larsen scale, subtotals and total) end of study
Function
1.9(5.6) 1.4(3.0)
(raw value 0-30)
Range of motion 0.1(0.5) 0.1(0.5)
Anatomy
0.2(1.1) 0.0(0.5)
Pain
2.2(5.5) 2.5(6.0)
Total Larson
3.7(8.0) 3.2(6.6)
Adverse events
Patients
Events
6
9(18%)
6
6(22%)
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
no
n/s
n/s
yes
yes
no
?
n/s
medium
term
yes
?
?
yes
conclusions,
comments, and
quality scores
Validity: ~
Precision: ~/+
Applicability: ~/?
Overall quality: ~
Authors’ conclusions:
HA was superior to MPA even
though the number of injections
was less. It is a clear advantage of
HA that with a lower number of
injections a more favourable effect
can be achieved.
Reviewer’s comments:
It was not clear who was blinded
the treating physician or the
evaluator.
yes
The number of HA injections was
higher than many other studies.
The treatment was given 17 years
ago which may limit the relevance
of the study.
Limited inclusion criteria
Other: effusion, a feeling of warmth in the knee, sensation of heat,
tingling and pain were reported following the HA injection.
Burning sensation in the calf, cramp like pain in the calf, pulling
pain in the calf, swelling and tightness in the knee and tightness
and feeling of warmth in the knee following the MPA injection.
41
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
To compare the efficacy
of HA and orgotein
following IA
administration to patients
with OA of the knee.
Inclusion
Painful primary and
post traumatic OA of
the knee, assessed by
the ARA criteria and
a radiological
examination
according to the
Kellgren
classification.
Clinical severity
assessed on a 3 point
scale.
Exposure (HA)
Hyalgan MW= 500-730 kDa
20mg sodium hyaluronate in 2
ml phosphate buffer IA injection
once a week for five weeks.
Intensity of pain,
joint motion,
morning
stiffness, effusion
volume, overall
judgment
Results: mean (s.d.)
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
study design
Carrabba, M., Paresce,
E., Angelini, M.,
Zamboni, A. M.,
Bragantini, A., Paissan,
A., et al. (1992). The
intra-articular treatment
of osteoarthritis of the
knee. A comparative
study between
hyaluronic acid (Hyalgan
(TM)) and orgotein.
European Journal of
Rheumatology &
Inflammation, 12(3), 4757.
RCT
Open label
Multi centre
Participants
Mean age: 58 years
Male: 38
Female:80
Grade IV severity =8%
Clinically severe
disease=15%
Screened
N=NR
Randomised
N=118
Evaluable
N=NR
Completed
N=116
Exclusion
Pregnant or breast
feeding women,
severe associated
disease that could
interfere with
evaluation, allergy or
hypersensitivity to
drugs, IA therapy in
the target knee within
three months,
infective conditions
from which an
arthritic complication
could arise, noncompliant or
unreliable patients.
Comparison (OR)
Orgotein 8mg/2ml IA injection
once a week for 5 weeks.
Duration
60 days
HA
OR
p-value
Primary outcome variable-Intensity of spontaneous paina
Day 35 (1 wk after end of Rx)
0.025
Day 60 (end of study)
0.022
Secondary outcome variables day 35
Night pain (no. asymptomatic)
43
Pain at rest (no. asymptomatic)
39
Pain under load (no. asymptomatic) 29
Pain on touch (no. asymptomatic) 35
Secondary outcome variables day 60
Night pain (no. asymptomatic)
46
Pain at rest (no. asymptomatic)
44
Pain under load (no. asymptomatic) 30
Pain on touch (no. asymptomatic) 39
Joint motion (degrees)
Morning stiffness (min)
Effusion volume (ml)
35
30
21
27
ns
ns
ns
ns
38
30
23
33
ns
0.012
ns
ns
0.046
0.040
0.031
Drop outs<20%
Overall Judgment day 35
Investigators (good-v. good)
Patients (good-v. good)
71.2
78.0
40.7
52.5
<0.001
<0.001
Overall Judgment day 60
Investigators (good-v. good)
Patients (good-v. good)
72.9
78.0
44.1
52.5
<0.001
<0.001
Safety and adverse events
Local side effects (no. pts)
Systemic side effects
Clinically signif. lab test results
4
0
0
4
0
0
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes
n/s
n/s*
?
no
no
no
n/s
short
term
yes
low
?/n/s
yes
conclusions,
comments, and
quality scores
Validity: ~
Precision: ~/+
Applicability: ~
Overall quality: ~
Authors’ conclusions:
Overall judgements of efficacy
expressed by patients and
clinicians confirmed the greater
efficacy of the HA treatment.
Reviewer’s comments:
Follow up too short (1 month
after final injections)
Two novel drugs
Little information about the
comparator orgotein.
yes
* all patients were included
in the analysis totals
Local side effects included pain, swelling and minor skin rash.
a
Scott-Huskisson VAS
IA= intra-articular
MW=molecular weight
OA= osteoarthritis
HA=hyaluronic acid
42
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To investigate
the use of low
doses of
dexamethasone
associated with
HA in patients
with OA of the
knee and to
evaluate any
increase in
therapeutic
activity without
the undesirable
effects of
steroids used in
large doses.
Inclusion
Male or female
experiencing
joint pain and
objective
clinical signs –
limitation of
joint function
and unaided
walking.
Exposure (HA)
Hyalgan
MW=500-750
kDa
20mg sodium
hyalanurate in
2ml phosphate
buffer, IA
injection once a
week for 5
weeks.
Spontaneous
pain,
improvement
in joint
mobility
Results: mean ± s.e.m.
validity /
applicability
study design
Grecomoro, G.,
Piccione, F., &
Letizia, G.
(1992).
Therapeutic
synergism
between
hyaluronic acid
and
dexamethasone
in the intraarticular
treatment of
osteoarthritis of
the knee: a
preliminary open
study. Current
Medical
Research &
Opinion., 13(1),
49-55.
RCT
Open-label
Parallel group
Participants
Mean-age =42.30
(41-79 years)
Male: 13
Female:17
Screened
N=nr
Randomised
N=40
Evaluable
N=40
Completed
N=40
Exclusion
Not reported
Comparison
(HA+DM)
Hyalgan
MW=500-750
kDa
20mg sodium
hyalanurate in
2ml phosphate
buffer,
+ 0.4mg
dexamethazone
phosphate in IA
injection once a
week for 5
weeks.
Duration
60 days
HA(n=20) HA+DM(n=20)
Spontaneous pain Scott-Huskisson VAS
Data not given – graph = similar decrease in both
groups but with lower pain levels in the HA+DM
group, the beneficial effects lasted until day 60
when the scores were at a statistically lower level
in HA+DM group.
Severity of daytime pain (mean rating scores)
arbitrary 5-point scale
Baseline
2.1
2.7
End of treatment (day 35) 0.3
0.2
End of study (day 60)
0.3
0.0
Severity of nigh time pain (mean rating scores)
arbitrary 5-point scale
Baseline
1.7
2.6
End of treatment (day 35) 0.3
0.2
End of study (day 60)
0.3
0.1
Severity of weight-bearing
on arbitrary 5-point scale
Baseline
End of treatment (day 35)
End of study (day 60)
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
n/s
n/s
yes
yes
no
no
no
n/s
short
term
yes
n/s
yes/n/s
yes
yes
conclusions,
comments, and
quality scores
Validity: ~
Precision: −/~
Applicability: ~
Overall quality: −/~
Authors’ conclusions:
These data suggest a
very effective
therapeutic synergism
between HA and the
steroid but further
studies are needed to
confirm the preliminary
findings.
Reviewer’s comments:
Young patient group
Preliminary study
Highly selected pop?
Poor result reporting.
pain (mean rating
2.6
0.6
0.7
3.4
0.9
0.8
P-values were not reported, scale 1=none 5=very
severe
Improvement in joint mobility: data values not
reported, data graph indicates a more rapid
improvement in the HA+DM group, with a %
increase at day 60 of 26% and 19% for HA+DM
and HA respectively
Adverse events and safety: local tolerance was
good in both treatment groups with no untoward
signs or symptoms at any time.
IA=intra-articular
MW= molecular weight
43
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
To compare the efficacy
and tolerability of HA
and 6-MPA
Administered by IA
injection.
Inclusion
Painful idiopathic
osteoarthritis of the
knee diagnosed
according to the
ARA criteria and
radiologically
assessed according to
Kellgren’s
classification.
Previous NSAID
treatment with poor
results.
Exposure (HA)
Hyalgan®
3 IA injections of
sodium hyaluronate
(HA) 20 mg in 2ml
phosphate buffer at 7
day intervals + 2 days
post injection rest.
Pain scores,
morning
stiffness, joint
flexion, overall
patient and
investigator
judgment
Difference in pain score from baseline:
HA(n=20) 6-MPA(n=20)
Day 21 (end of treatment)
Night pain (score scale 0-4)
<0.05
ns
Rest pain (score scale 0-4)
ns
ns
Pain under load (score scale 0-4)
ns
ns
Touch pain (score scale 0-4)
ns
ns
Analgesic consumption (yes/no)
19/1
17/3
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
study design
Leardini, G., Mattara, L.,
Franceschini, M., &
Perbellini, A. (1991).
Intra-articular treatment
of knee osteoarthritis. A
comparative study
between hyaluronic acid
and 6-methyl
prednisolone acetate.
Clinical & Experimental
Rheumatology., 9(4),
375-381.
RCT
Open-label
Participants
Mean age: 65 years (3477yrs)
Male:5
Female:35
Radiologic grade:
II=9 (22%)
III=29 (73%)
IV=2(5%)
Screened
N=NR
Randomised
N=40
Evaluable
N=40
Completed
N=40
Exclusion
IA treatment in
previous 3 months,,
serious concomitant
disorders, ongoing
infections,
pregnancy, history of
allergy or sensitivity
to drugs.
Comparison (6-MPA)
6-MPA
3 IA injections of
methylprednisolone
acetate , 40 mg in 1 ml
of an aqueous vehicle
+ 2 days post injection
rest.
Duration
60 Days
Day 60 (end of study)
Night pain (score scale 0-4)
Rest pain (score scale 0-4)
Pain under load (score scale 0-4)
Touch pain (score scale 0-4)
Analgesic consumption (yes/no)
<0.05
<0.01
<0.01
<0.01
13/?
ns
ns
ns
ns
15/5
Between group differences in spontaneous pain intensity (VAS
100mm)
By day 35, and continuing to day 60, there was a significant
difference between the groups (p<0.05)
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes
n/s
yes
no
n/s
n/s
n/s
yes
short
term
yes
?
yes/n/s
yes
yes
conclusions, comments,
and quality scores
Validity: ~/+
Precision: ~/+
Applicability: ~
Overall quality: ~
Authors’ conclusions:
For up to one week after the end of
treatment HA’s analgesic activity was
comparable with that of the steroid, while
at the end of the study (45 days after the
end of treatment) all main monitoring
parameters presented significant
differences in favour of the HA group.
Reviewer’s comments:
No blinding reported for study staff, small
group numbers. Females =87.5%. Short
acting steroid (7 days), 40 mg =low
dose?
Between group differences in morning stiffness (mins)
No significant between group difference from baseline to day
60.
Between group differences in joint flexion (degrees)
No significant between group difference from baseline to day 60
Overall judgement day 14
Investigator (good to v. good)
Patient (good to v good)
HA (%pts) 6-MPA(%pts)
40%
55%
35%
60%
Overall judgement day 35
Investigator (good to v. good)
Patient (good to v good)
55%
55%
40%
45%
Overall judgement day 60
Investigator (good to v. good)
Patient (good to v good)
50%
50%
35%
35%
Note: Earlier report (not reviewed here):
Leardini G., Franceschini M., Mattara L.,
Bruno R., Perbellini A. Intra-articluarlr
sodium hyaluronate (Hyalgan®) in
gonarthrosis. A controlled study
comparing methylprednisolone acetate.
Clinical Trials Journal 1987, 24(4) 341350.
Adverse events/ safety : no patients presented any adverse local
or systemic reactions or any clinically significant modifications
in blood pressure, heartbeat or lab test results.
IA= intra-articular
44
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To compare the
efficacy and
tolerability of a
course of IA
injections of 20
mg HA with
similar treatment
with placebo.
Inclusion
Male or female
Hospital
outpatients
Symptomatic
OA of one or
both knees.
Hyalgan (mw=615)
2 ml (20mg) HA
Up to 11 IA
injections over a 23
week period.
Pain,
activities of
daily living
Mean score from baseline:
HA
validity /
applicability
study design
Dixon, A. S.,
Jacoby, R. K.,
Berry, H., &
Hamilton, E. B.
(1988). Clinical
trial of intraarticular injection
of sodium
hyaluronate in
patients with
osteoarthritis of
the knee. Current
Medical Research
& Opinion., 11(4),
205-213.
RCT
Double-blind
Placebo-controlled
Multicentre (n=3)
Participants
Male=29,
Female=34
Mean age
68.5 (range 4385yrs)
Mean weight =
75.3kg (range 42105 kg)
Randomised
N=63
Analysed
N=53
Trial duration = 48
weeks
Treatment = 23
weeks
Exclusion
OA of hip
Primary
inflammatory
conditions
Poor general
health
Skin conditions
overlying the
joint.
Regular
analgesic
therapy for
reasons other
than painful OA
of the knee.
Placebo
0.2mg HA i.e. 1%
of treatment HA
dose. Up to 11 IA
injections over a 23
week period.
Concomitant
therapy
Treatment with
cortico steroids,
NSAIDs and strong
analgesics was not
permitted during the
trails period but
other medicines
were not restricted.
Paracetamol up to a
dose of 1g 3-times
per day for pain was
allowed.
PL
p-value
HA-PL diff
Assessment at end of study
Severity of pain at rest -17.1 +3.6
Severity of pain on
-21.9
-7.7
movementa
Activities of daily living DNR DNR
<0.05
<0.05b
ns
Figures in bold = significant improvement from
baseline values
Adverse events
3 adverse events reported in the treatment group.
HA was reported to be well tolerated
a
at 9 weeks, b at the 5 week assessment
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes
yes
n/s
yes
yes
yes
yes
n/s
yes
yes
?
n/s
no
yes
conclusions,
comments, and
quality scores
Validity: ~/+
Precision: ~
Applicability: ~
Overall quality: ~
Authors’ conclusions:
A course of HA
injections (20mg)
results in significant
reduction in knee pain
and is well tolerated in
patients with OA of
the knee.
Reviewer’s
comments:
Drop out 15.9%
Limited reporting
45
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity / applicability
Objective
To confirm the
therapeutic
usefulness of HA
By comparing the
effects of two dose
levels and placebo
in patients with
OA of the knee.
Inclusion
Diagnosis of
OA of the knee
based on
clinical and
radiographic
changes
Treatment groups
Hyaluronic acid (HA)
20 mg/week
Spontaneous
pain intensity,
walking and
loading pain
Spontaneous pain intensity
P-values for the following outcomes
were:
Each treatment baseline to 21st day:
p<0.05
Between treatment baseline to 21st
day: p<0.01
Between treatment dose: p=ns
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
study design
Bragantini, A.,
Cassini, M. D. B.,
& Perbellini, A.
(1987). Controlled
single-blind trial
of intra-articularly
injected
hyaluronic acid
(Hyalgan(Reg.trad
emark)) in osteoarthritis of the
knee. Clinical
Trials Journal,
24(4), 333-340.
RCT
Study participants
N=55
M=14, females=41
2-4th degree
Kellgren’s scale
Mean age =57
Monolateral
disease=50
Bilalateral
disease=5
Disease duration
1->10yrs
Exclusion
None reported
Hyaluronic acid (HA)
40 mg/week
Placebo
2ml saline
Study time=60 days
HA (both doses combined) vs
Placebo
Walking pain 21st day: p<0.05
Walking pain 60th day: p<0.01
Loading pain 21st day: p<0.01
Loading pain 60th day: p<0.01
Adverse reactions
Local pain and burning post injection:
2 patients receiving HA 20mg,
2 patients receiving HA 40 mg
Well tolerated with no systemic or
serious reactions, 4 mild adverse
events.
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes
n/s
n/s
yes
yes
no
n/s
n/s
yes
yes
n/s
n/s
no
yes
conclusions,
comments, and
quality scores
Validity: ~/+
Precision: −/~
Applicability: ~
Overall quality: −/~
Authors’ conclusions:
Low dose HA (20
mg/week) is an active
agent which could have a
useful role in the treatment
of OA of the knee.
Reviewer’s comments:
Limited reporting of
results, methodological
limitations.
Note- benefits of HA were reported to
have lasted for >1 month post
treatment.
46
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
A RCT to confirm
assumptions.
Inclusion
Patients with
gonarthrosis.
Pain and
clinical signs
such as
limitation of
joint function
and of unaided
walking.
Hyalgan (mw500750)
Sodium hyaluronate
20 mg in 2ml
phosphate buffer
injection once a week
for three weeks.
N=20 knees
Spontaneous
pain
intensity,
pain on
touch, under
loading and
while
walking
Differences in mean values for the
following outcomes were significant
(data not reported):
Spontaneous pain intensityd <0.01a
Pain on touche
<0.05b
Pain under loadinge
<0.01b
e
Pain while walking
<0.01b
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
Drop outs<20%
study design
Grecomoro, G.,
Martorana, U., &
Di Marco, C.
(1987). Intraarticular treatment
with sodium
hyaluronate in
gonarthrosis: a
controlled clinical
trial versus
placebo.
Pharmatherapeutic
a., 5(2), 137-141.
Participants
Age:65 (s.d. 11,
range 43-92yrs)
Male:15
Female:19
Trial size
N=34pts
N=40 knees
Both knees
N=6pts
RCT
Placebo-controlled
Double-blind
Placebo
2ml phosphate buffer
injection once a week
for three weeks.
N=18 knees
(2 knees dropped out
after the 2nd injection
for reasons unrelated
to the study).
Treatment
2 weeks
FU=60 days
At FU – 60 days
Spontaneous pain intensity <0.005b
Comparison of number that
improved in each category
Pain on touch
<0.025
Pain under loading
<0.005
Pain while walking
<0.001
Adverse reactions
Local tolerance was reported to be
very good for treatment and placebo
with no untoward signs or symptoms
at any time.
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
n/s
n/s
no
yes
yes
yes
n/s
n/s
yes
no
conclusions, comments,
and quality scores
Validity: ~/+
Precision: ~
Applicability: −/~
Overall quality: ~
Authors’ conclusions:
The authors concluded that
treatment with HA was effective
and long lasting with the effect
lasting after treatment had
stopped.
yes
n/s
yes
Not clear if patients with severe
OA were included.
yes
Note all of the scoring scales
used had been validated
Raw data/means not reported.
a
ANOVA,
t-test of means,
c
Π2 test,
d
measured using a VAS of the
Scott-Huskisson pain self-rating
system,
e
scored on an arbitrary 5-point scale.
b
47
Evidence Tables: Injection- Hyaluronic Acid (Knee)
Observational Studies
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To assess the longterm efficacy and
tolerability of
sodium
hyaluronate
(Hyalgan) after 1
cycle of 5 IA
injections in
patients with OA
of the knee. The
benefits of a
second treatment
cycle in patients
with renewed need
for therapy was
also examined.
Inclusion
OA of the knee,
radiologic severity IIII (Kellgren and
Lawrence), subjective
complaints for the last
1 year, knee pain for at
least 20 days in the last
month before study
start. A minimum
score for pain on
movement of at least
3.3 cm on a 10 cm
VAS.
Exposure
Hyalgan®
MW=500-730
kDa.
20mg/2ml IA
injection once a
week for 5
weeks
Pain on movement
and at rest,
walking time
Results: mean value ±s.d.
conclusions, comments, and
quality scores
study design
Kolarz, G., Kotz,
R., & Hochmayer, I.
(2003). Long-term
benefits and
repeated treatment
cycles of intraarticular sodium
hyaluronate
(Hyalgan) in
patients with
osteoarthritis of the
knee. Seminars in
Arthritis &
Rheumatism, 32(5),
310-319.
Case series
No. studies
Screened
N=NR
Randomised
N=108
Completed
N=59
Exclusion
NR
Duration
1 year
ITT pop.
N=108
Day 35 assessment (n=101)
Pain on movement (VAS cm) 3.1±2.4
Pain at rest (VAS cm)
1.0±1.6
Function: Larson total score
8.2±9.5
Maximum walk time
88.2±64.2
Completers
N=59
2.8±2.2
0.5±0.9
39.3±7.5
85.8±57.4
Case series score: ?2/3
Authors’ conclusions:
Hyalgan administered either as a single or
repeat course is an effective and well
tolerated therapy for the long term
treatment of the pain of OA.
12 month assessment (n=59)
Pain on movement (VAS cm) 1.9±1.9
1.9±1.9
Pain at rest (VAS cm)
0.5±1.1
0.5±1.1
Function: Larson total score 42.7±6.2
42.7±6.2
Maximum walk time (min) 102.0±54.0 102.0±54.2
Reviwer’s comments:
High drop out
Low molecular weight product.
Pain on movement day 35 (ordinal scale)
Improved
89(82%)
54(92%)
Unchanged
16(15%)
3(5%)
Worse
3 (3%)
0
Note: This study was originally designed
as an RCT but was changed to an
observational study when comparator drug
was withdrawn from the market.
Preliminary results from the RCT were
published in Kolarz G., Kotz, R., Broll,
H., Dunky, A., Landsiedl, F., et al. (1995).
Hyaluronic acid in the treatment of
osteoarthrtitis of the knee joint: interim
results of a comparative clinical study.
European J. Rheumatology and
Inflammation., 15(1); 39-45.
Pain on movement 12 month assessment (ordinal scale)
Improved
80(74%)
57(97%)
Unchanged
20(18%)
1(2%)
Worse
8(7%)
1(2%)
Second course of therapy (N=15)
1 year
Day 35
Pain on movement (VAS cm) 4.6±2.4
3.2±2.6
Pain at rest (VAS cm)
2.2±2.2
2.5±2.5
Function: Larson total score 35.6±9.4 39.8±7.2
Maximum walk time
69.6±40.6 100.0±77.5
Bold = significant (p<0.01) difference from baseline
Safety and adverse events
50/108 (46%) of patients experienced 119 adverse events.
Most frequently reported adverse events were back
pain(17%), injection site reaction (12%), injection site
pain(7%), 102/119 were reported as slight to moderate and
63% of adverse events were not thought to be related to the
study drug. 17 adverse events were rated as severe, 6 of
these were judged as possibly related and 2 related to the
study drug (knee joint effusion and skin eruption with
puritis),4 patients withdrew because of AEs
48
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
conclusions, comments, and quality
scores
Neustadt, D. H.
(2003). Long-term
efficacy and safety
of intra-articular
sodium hyaluronate
(Hyalgan) in
patients with
osteoarthritis of the
knee. Clinical &
Experimental
Rheumatology.,
21(3), 307-311.
Objective
To evaluate the
long-term efficacy
and safety of a
course of 5 IA
injections of
sodium
hyaluronate
administered in a
clinical office
setting in patients
with moderate to
severe OA of the
knee.
Inclusion
All patients who
received sodium
hyaluronate for OA of
the knee during the
study period .
Exposure
Hyalgan® (HA)
5 IA injections
of sodium
hyaluronate
administered at
one week
intervals.
VAS pain
score,
duration of
clinical
response
Results: number (proportion of knees with score)
Baseline 6 months 2 years
N=58
N=24
N=92
Overall assessment of pain VAS score
None (0)
0
6
4
Slight (0)
0
32(35%) 12(13%)
Moderate (4-6)
28(31%) 16(18%)
7
Severe (7-9)
54(59%)
4
1
Extreme (≥9)
10(11%)
0
0
Lost to FU or TKR
0
34(37%) 68(74%)
Case series score: ?2.5/3
Case Series
Prospective
Consecutive?
Participants
Mean age:64 years
Male:79%
study design
Enrolled
N=76pt 92 knees
Completed
N= 22-24 knees
Exclusion
No patients were
excluded because of
age or any other
reason.
Note: all patients who
received the treatment
were included in the
data analysis.
Duration
24 months
Duration of response/clinical benefit (n=92 knees)
None
0
5
3
Slight 1+
0
29(32%) 11(12%)
Moderate 2+
13(14%) 20(22%)
7
Severe 3+
73(80%)
3
1
Extreme 4+
6
0
0
Lost to FU or TKR
0
35(38%) 70(76%)
Authors’ conclusions:
Intra-articular sodium hyaluronate is an effective
and safe treatment for pain in difficult to treat
patients with moderate to severe OA of the knee.
Reviewer’s comments:
Moderate and severe grades treated.
Not clear if there was informed consent which one
would expect for a prospective study.
Not clear if any patients refused treatment, i.e. how
representative the study population was of the
eligible for treatment population.
Low molecular weight product.
High loss to follow-up.
Adverse events during the 1-2 year follow –up period
Injection site pain: 20%
Injection site pain 1-2 hrs post injection: 12%
Injection site pain 24 hours after injection: 2%
Injection site bruising: 9%
Injection site bruising 24 hrs: 4.7%
Headache 24 hrs post injection: 7.5%
Nausea: 3%
IA = intra-articular
OA= osteoarthritis
49
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
conclusions, comments, and quality
scores
Objective
To assess the
difference in
efficacy between
knee lavage +
standard hylan GF20 and hylan GF 20 alone for the
treatment of OA of
the knee.
Inclusion
Documented
evidence of OA of
the knee on MRI
and failure of
conservative
treatment including
IA corticosteroid
injections.
Exposure
Patients were divided by
patient choice into two
groups
Pain
reduction
Successful outcome (pain reduction>50% + pt
satisfaction good-excellent)
Group 1
Group 2
HA+LV
HA
N=37
N=44
Overall
79.5%
54%
Grade IV OA
58%
36%
Patellofemoral OA 50%
33%
Case series score: 1.5/3
study design
Vad, V. B., Bhat, A.
L., Sculco, T. P., &
Wickiewicz, T. L.
(2003).
Management of
knee osteoarthritis:
knee lavage
combined with
hylan versus hylan
alone. Archives of
Physical Medicine
& Rehabilitation.,
84(5), 634-637.
Case Series
Prospective
Comparative
Open-label
Single centre
Blind assessor?
Participants
Mean age: 63 and
64 years
Female: 57%
K-L Grade
I=8
II=12
III=38
IV=23
Screened
N=NR
Enrolled
N=81
Evaluable
N=NR
Completed
N=NR?81
Exclusion
History of knee
replacement in the
other knee.
Group 1 (HA+LV)
Closed single-needle
lavage with local
aesthetic followed by
500 ml of normal saline
+ hylan G-F 20 IA
injections at weeks 2,3
and 4.
Group 2 (HA)
hylan G-F 20 IA
injections at weeks 1,2
and 3 without prior knee
lavage.
Note:
Both groups participated
in a programme of home
rehabilitation.
NSAIDs and analgesic
medications were
discontinued upon study
entry.
Duration
Average FU 1.1 years
(range 12-19 months)
p-value
0.001
0.003
0.007
Changes comparing group 1 / group 2 p<0.05:
Lysholm-II score 42.4 ±1.3 43.1 ±1.2
pre-Rx*
Lysholm-II score 81.1±1.6 71.2 ±1.5
post-Rx*
VS pre-Rx
8.6±1.2
8.8 ±1.3
VS post-Rx
2.1±1.4
3.2±1.2
Authors’ conclusions:
The results of HA treatment were better
when knee lavage was performed at the start
of the treatment protocol
The presence of radiological grade IV OA or
moderate to severe patellofemoral arthritis
were negative prognostic factors.
Reviewer’s comments:
Non-randomised study but groups were very
similar at baseline.
Loss to FU not reported
AEs – no detail
High proportion of severe OA.
Note: changes for each group pre and post Rx were also
significant (p<0.05).
*administered by a nurse practitioner who was blinded
to the treatment protocol.
Adverse events: a total of 8 patients from both groups
experienced transient reactions such as local erythema
and pain, the majority (6) of the AEs still had a good
outcome.
IA= intra-articular
OA= osteoarthritis
HA=hyaluronic acid
50
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
conclusions, comments, and
quality scores
Objective
To evaluate the
efficacy and
tolerability of a
second course of
hylan G-F20 for
the treatment of
OA knee pain in
patients who
experienced
clinical benefit
with an initial
course of therapy.
Inclusion
Consecutive patients who returned for
a second course of HA between
October 2000- January 2001.
Healthy, ambulatory males or females
at least 40 years old, with OA
diagnosis of at least 3 months standing
based on ACR criteria. Knee pain
scores of at least 2 (moderate) on Q1A
WOMAC at screening and a score of
50-90mm on a VAS scale for patients
and investigator overall assessment at
baseline. Clinical benefit (>= 20mm
improvement from baseline in
physician VAS from an initial course
of hylan given at least 3 months prior)
and return to request an additional
course of therapy.
Exposure
Synvisc® 2ml
hylan G-F 20 IA
injection once a
week for 3 weeks.
WOMAC pain
score, overall
patient and
investigator
assessment
Results: mean change from baseline
p-value
N=85
Primary efficacy parameter week 26 ITT
population
WOMAC Qa1
-1.40±0.10 <0.001
Case series score: 2.5/3
study design
Waddell, D. D.,
Cefalu, C. A., &
Bricker, D. C.
(2003). An openlabel study of a
second course of
hylan G-F 20 for
the treatment of
pain associated with
knee osteoarthritis.
Current Medical
Research &
Opinion., 19(6),
499-507.
Case Series
Prospective
Open label
Single site
Informed consent
Participants
Mean age=65
years
Female=65%
K-L Grade
III=25%
IV=73%
Mean time since
1st course of
injections 19.59
months
No studies
Screened
N=NR
Enrolled
N=85 pts
Evaluable
N=71 pts
Exclusion
Any serious systemic disease or
significant psychiatric or neurological
disorder, pregnant or nursing women
or women of childbearing age not
using reliable birth control; known
allergy to avian products or
corticosteroid injections, Paracetamol
hypersensitivity or use of an
investigational drug or device within
90 days of study start. Inflammatory
arthropody or other joint disease or
conditions, patella/femoral knee pain,
acute synovitis, local adverse event
with the first course of hylan G-F20,
palpable effusion (>10ml), history of
joint sepsis, major surgery or
arthroscopy in either knee 6 months
prior to screening, arthroplasty at the
target joint, oral or IA corticosteriod
or any other IA at the target joint
within 3 months or non-target joint
within 4 weeks of screening. Use of
glucosamine and/or chondroitin
sulphate within 30 days prior to study
entry.
No IA anaesthetics
were injected
concomitantly.
Patients were
instructed to ice
the joint for 4
hours and rest
knee for 24 hours.
Concomitant
medications
recorded by
patients in a daily
diary. Systemic or
injected
corticosterioids
were not allowed.
Duration
26 weeks
Secondary efficacy parameters week 26 ITT
pop
Full WOMAC score
-26.99±2.11 <0.001
WOMAC domain C
-18.63±1.50 <0.001
scores
Patient overall
-48.73±2.53 <0.001
assessment wk 26 (VAS score)
Investigator overall
-51.94±2.14 <0.001
assessment wk 26 (VAS score)
Safety, tolerability and adverse events
Pts (%) % inj.
At least one AE
54 (76.1)
Possibly related to treatment 3 ( 4.2) 1.4%
Probably related to treatment 3 ( 4.2) 1.4%
Definitely related to treatment 7 ( 9.9) 3.2%
Authors’ conclusions:
A second course of hylan G-F 20 is
appropriate therapy for the
treatment of OA pain in patients
who have had a previous
favourable response.
Reviewer’s comments:
Well designed large study. Main
sources of bias likely to arise from
lack of a control group and
blinding. Highly selected
population, 73% with grade IV
disease.
ITT pop =70/85.
High molecular weight product.
Main Adverse Events (AEs):
Arthralgia, n=2
Arthritis, n=1
Arthrosis, n=10
Note: no patients withdrew because of AEs
IA=intra-articular
OA= osteoarthritis
51
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
Safety evaluation
Inclusion
Male or female
>= 50 years
Radiologically/
arthroscopically
verified
OA. Fully ambulant
Initial study
N=103 (128
knees)
One injection of
non-animal
stabilized
hyaluronic acid
(NASHA)
(Durolane®)
(60mg/3ml)
Pain at rest,
while in
motion,
night pain
Results: change from baseline VAS 0-100
Mean S.D.
First Injection N=103 pts (128 knees)
Pain at rest
-4.6
16.5
Pain at weight bearing motion
-9.1 20.2
Pain at non-weight bearing motion -20.7 26.0
Night pain
-8.2 23.4
conclusions, comments, and
quality scores
study design
Akermark, C., Berg,
P., Bjorkman, A., &
Malm, P. (2002).
Non-animal
stabilised
hyaluronic acid in
the treatment of
osteoarthritis of the
knee: A tolerability
study. Clinical Drug
Investigation.,
22(3), 157-166.
Case series
Non-blind
Prospective
Multi-centre (5)
All patients
recruited in
primary care
setting.
FU=3 months for
initial study, I
month for
extension.
Excluded
Systemic
inflammatory
conditions
Planned joint surgery
within study period
Other conditions likely
to effect efficacy of
NASHA
Extension study
N=53
Second
injection 7
months later
(average)
of non-animal
stabilized
hyaluronic acid
(Durolane®)
(60mg/3ml)
Second Injection N=53 (72 knees)
Pain at rest
-5.8
Pain at weight bearing motion
-8.2
Pain at non-weight bearing motion -13.2
Night pain
-9.9
Adverse events
All = 74% of patients
SAEs=4 (none due to treatment)
Treatment related AEs =49% of all AE’s
Local reaction (90%)
Unanticipated AEs – 5%
Case series score: 1.5/3
p-value
<0.0001
<0.0001
<0.0001
0.0005
14.0
0.0001
16.6 <0.0001
19.9 <0.0001
17.8 <0.0001
Authors’ conclusions:
Patients satisfaction was very good to
fair in 80% of those treated. Further
investigation into long-term efficacy of
NASHA was warranted.
No safety concerns were raised during
the study and treatment was well
tolerated. No increased risk of AEs was
found after 2nd injection.
Reviewer’s comments:
Uncontrolled study not powered to
evaluate efficacy.
Confounding by use of NSAIDS
throughout the study.
Severity of pain and movement
restriction not reported.
Reporting inconsistencies – per knee, per
patient.
52
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To assess functional
change and well being
in patients with OA of
the knee after treatment
with Hylan G-F 20.
Inclusion
Diagnosis of OA in
one or both knees
confirmed by x-ray.
No reported benefit
from NSAIDs or
unable to tolerate side
effects.
Exposure
Synvisc®
3, weekly injections
of 2 cc IA Hylan GF 20
SF-36 health
survey results
Mean results:
conclusions, comments, and
quality scores
study design
Goorman, S. D.,
Watanabe, T. K.,
Miller, E. H., &
Perry, C. (2000).
Functional outcome
in knee
osteoarthritis after
treatment with
hylan G-F 20: A
prospective study.
Archives of
Physical Medicine
& Rehabilitation,
81(4), 479-483.
Case series
Prospective
Consecutive
Setting
Outpatient community
private orthopaedic
practice.
Participants
Average age
67 years
Male:26
Female:36
Study size
N=84
Completers
N=61
No knees
N=110
Follow-up
6 months
Exclusion
Metal implants
History of joint
Infection
Chicken or egg
allergy
Knee instability
or marked deformity.
Pre-study
SF-36
Note: 26 patients of
initial 84 were
treated bilaterally.
NSAIDS permitted
after treatment
during the followup.
Pre-test
N=61
SF-36 Health Survey categories
Physical functioning
38.8
Role-physical
29.1
Bodily pain
42.4
General health
66.1
Vitality
49.8
Social functioning
70.5
Role-emotional
52.5
Mental health
47.1
Case series score: 2.5/3
Post-test p-value
N=61
60.1
64.3
55.2
65.9
50.6
79.2
94.0
42.7
<0.001
<0.001
<0.001
0.92
0.60
0.01
<0.001
0.01
Authors’ conclusions:
The authors concluded that the efficacy
of IA HA was demonstrated 6 months
after treatment and that age and %
above ideal body weight were not
significant predictors of functional
change.
Reviewer’s comments:
Outcomes not specific for OA of knee.
Wilks’ Lambda statistic indicated a significant change
(p<0.001) in the combined set of scores.
No severity grade of OA given in
patients description.
Null hypothesis (Ho)= pre and post treatment mean
scores are equal.
Not controlled for use of physical
therapy, assistive devices or use of
NSAIDs during follow-up period.
Safety/adverse events
No safety data reported.
IA= intra-articular
OA= osteoarthritis
HA=hyaluronic acid
53
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To evaluate
patients treated
with HA in terms
of time interval
from first
improvement,
duration of
improvement after
first cycle and
effect of a second
cycle if a renewed
need for therapy
occurred between
the 4th and 12
month after the
last injection
Inclusion
Diagnosis of OA of
knee grade 1-3
(Kellgren and
Lawrence).
Symptoms for >1year
>3.3 on a 10mm VAS
for pain on movement.
Age 18-74 years.
Pain for at least 20
days in the prior
month.
Hyalgan
HA 20 mg 5
weekly
injections
(low molecular
weight)
Therapeutic
effects as
measured by
VAS pain score,
Larson score
Results: mean values
conclusions, comments, and quality
scores
study design
Kotz, R., & Kolarz,
G. (1999). Intraarticular hyaluronic
acid: duration of
effect and results of
repeated treatment
cycles. American
Journal of
Orthopedics
(Chatham, Nj).
28(11 Suppl), 5-7.
Case series
Open label
Prospective
Multicentre
(14 Austrian
orthopaedic and
rheumatological
centres October
1991-October 1994)
Participants
Average
age=57yrs
Male=31
Females=77
Enrolled
N=108
Completed 1st
treatment cycle
N=73
Follow-up
1 year after last
injection
Exclusion
NR?
Case series score: 1.5/3
N=108
N =59
1 year
Day 0
Therapeutic effect day 35, cycle one
VAS
88%
NR
Rating scale
93%
NR
p-value
NR
NR
Therapeutic effect during treatment (wks1-5)
Pain after exercise decrease NR
3.91
in VAS score
Pain at rest decrease in VAS NR
2.64
Score
Walking increase in mins
70
from baseline
Therapeutic effect at 1 year FU
Larson score (max=50 pts)
Larson score diff from baseline
Changes from baseline wk1-52 <0.01
Author’s conclusions:
Relief of symptoms seen after 4 weeks of
treatment in 68% of patients, in 55% relief
was maintained to the end of FU at 1 year.
Half of the patients that required a second
cycle of treatment after 4-8 months obtained
improvement for a further 12 months.
Reviewer’s comments:
Limited data for second cycle group, limited
reporting of results, limited analysis.
High drop-out.
42.8
11.1
<0.01a
Adverse events (total=119)b
Back pain
16.8%
Injection site reaction
11.8%
Injection site pain
6.7%
4 instances of joint effusion were observed
14 patients who required a second treatment cycle showed
further amelioration, only 6 completed FU to 1 year
a
number completing one year
total enrolled population was reported for safety and
global assessment
b
OA=osteoarthritis
HA= hyaluronic acid
Study drop-out
Discontinued the study before 1 year n=35
Adverse events=7
Non-compliance n=2
Patient refusal n=10
Loss to FU n=10
Protocol violation n=6
54
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
conclusions, comments, and quality
scores
Objective
To evaluate
viscosupplementation with intraarticular hylan GF 20 in current
clinical practice.
Inclusion
All patients receiving
hylan to treat OA of
the knee in the course
of the clinical practice
of 5 Canadian
clinicians from the
time that hylan became
available in Canada
(Sept 1992) to the time
the study was
conducted study (Jan
1995)
Exposure
Synvisc®
3 IA injections of
2ml
Hylan G-F20 over a
three week period.
Change in
activity
levels, use of
medication,
duration of
clinical
benefit
2nd course
1st course
(N=22)
(n=157)
Overall patient response to HA treatment.
Better/much better
77%
87%
Case series scores: 1.5/3
Exclusion
Patients with know
avian allergy were
never treated with
hylan
Number of treatment
courses (knees)
1 course ,N= 458*
2 courses, N=56**
3 courses, N=4
4 courses, N=4
study design
Lussier, A.,
Cividino, A. A.,
McFarlane, C. A.,
Olszynski, W. P.,
Potasner, W. J., &
De Medicis, R.
(1996).
Viscosupplementati
on with hylan for
the treatment of
osteoarthritis:
Findings from
clinical practice in
Canada. Journal of
Rheumatology.,
23(9), 1579-1585.
Case Series
Retrospecive review
of medical records.
Multi-centre(5)
Participants
Mean age: 65
years
Female:63%
Grade IV=19%
Screened
N=
Enrolled
N=336 (pts) 458
(knees)
Evaluable
N=
Completed
N=
The three injection
course was repeated
in some patients with
a minimum time
between 2 courses of
2 months.
*122 patients treated
bilaterally.
** 15 patients treated
bilaterally.
Duration
2.5 years
Change in activity level after treatment
Better/much better
76%
84%
Use of medication (patient report)
Less analgesic (% pts)
56%
Les NSAIDS (% pts)
45%
Less steroids (% pts)
47%
49%
52%
38%
Authors’ conclusions:
Hylan G-F20 provided good clinical benefits
and an acceptable safety profile.
Reviewer’s comments:
Weak scoring system?
Retrospective medical record review
But all patients included?
detailed reporting of safety
Duration of clinical benefit (investigator evaluated)
3-6 months (% pts)
22%
32%
6-12 months (% pts)
31%
30%
No answer (no. pts)
42
9
Mean (sd) time between 1st and 2nds courses (months)
all pts: 8.2 (3.6) min=2.4, max=18.6
Rate of local adverse events
By injection (%)
2.7%
By joint (%)
6.3%
By patient (%)
7.4%
3.4%
5.3%
7.3%
Type of local AE
Pain 83%
Swelling 69%
Heat 29%
Redness 26%
Others 14%
Severity
Mild 26%
Moderate 40%
Severe 33%
79% of AEs resolved with sequelae, the incidence of
AEs was significantly affected by injection technique.
Medial approach partially bent knee = 5.2% AE’s
Straight medial =2.4%
Straight lateral=1.5%
55
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To evaluate the
long-term (30
months) safety and
efficacy of
repeated treatment
cycles of IA
injections of HA
in patients with
painful OA of the
knee.
Inclusion
Painful clinically
diagnosed OA of the
knee (ARA criteria)
confirmed by X-ray
assessment ( Altman
criteria).
Exposure
Hyalart®
20 mg/2 ml IA
injection once
weekly for 5
weeks, repeated
every 6 months
over a period of
2 years. Total
no of
injections=25.
VAS pain
score and
clinical
findings, e.g.
degree of
extension,
flexion
Results (mean, s.d.)
conclusions, comments,
and quality scores
study design
Scali, J. J. (1995).
Intra-articular
hyaluronic acid in
the treatment of
osteoarthritis of the
knee: A long term
study. European
Journal of
Rheumatology &
Inflammation.,
15(1), 57-62.
Case series
Open label
Participants
Male: 35
Female:40
Note: the study
males were
significantly
younger, heavier
and with shorter
OA duration.
No Studies
Screened
N=NR
Enrolled
N=75
Evaluable
N=75
Completed
N=75
Exclusion
Degenerative arthritis
or other disease not
related to arthritis,
other severe disease,
pregnancy, lactation,
history of allergy or
hypersensitivity to
drugs, IA in the joint
to be treated during
previous 6 month,
diabetes.
Escape
medication –
only
paracetamol
allowed
Duration
30 months
Baseline
N=75
Evolution of pain
Male (mean VAS mm) N=35
63 (2.8)
Female (mean VAS mm) N=40
65 (2.8)
Evolution of joint movement – Extension
Male (mean degrees) N=35
165
Female (mean degrees) N=40
163
Evolution of joint movement – Flexion
Male (mean degrees) N=35
69 (26.6)
Female (mean degrees) N=40
72 (26.8)
Suprapatellar circumference
Male (mean cm) N=35
42.9 (3.()
Female (mean cm) N=40
42.5 (3.1)
After
1st Rx
42 (2.5)
39 (3.9)
End of trial
N=75
28(2.8)
29(3.6)
170
169
179
179
66 (29.4)
67 (26.6)
61 (25.3)
62 (6.4)
42.6(2.7)
41.6(2.6)
42.0 (2.6)
41.0 (2.3)
Pain Symptoms at End of Trial* (0=no joint pain, Severe effusion)
0
1
2
3
Pain at night (no. pts)
22
38
13
2
Pain at rest (no. pts)
16
46
14
2
Pain on touch (no. pts)
14
49
11
1
Pain on movement (no. pts)
6
21
46
2
Bold = significant improvement from base
* not clear if 1st treatment was included in the test.
Case series score: 2/3
Authors’ conclusions:
After the first course of
injections 60% of patients were
judged to have a very good/good
improvement. By the end of the
study 88% achieved very
good/good improvement.
Given the interesting results
obtained it would be appropriate
to carry out controlled studies to
confirm these promising
findings.
Reviewer’s comments:
25 injections unlikely to be
feasible or affordable in most
circumstances.
Not controlled, not blinded,
selection process not reported.
Low molecular weight product.
Intake of escape medication decreased throughout the study (40-5%)
Efficacy of treatment ( patients and investigator (% of patients)
Good-very good improvement
60%
88%
No evidence of improvement
12%
Adverse events
No serious local or systemic effects were observed following repeated
cycles of IA injection with HA. Five patients complained of local pain
after the injection. The effect lasted less than 72 hours and treatment was
not interrupted.
IA= intra-articular
OA= osteoarthritis
HA=hyaluronic acid
56
Evidence Tables: Injection- Hyaluronic Acid (Knee)
Other Reports (safety and harm)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
conclusions, comments, and quality
scores
Objective
Evaluation of
safety and
efficacy of Hylan
G-F 20
Inclusion mostly as
Wobig 1998-1999
Exposure
Hylan G-F 20
(HA)
Local and
general
reactions to
Hylan G-F
20 injection
Safety outcomes
General reactions:
4 HA patients (events), none treatment related, 2 withdrawals
Authors’ conclusions for safety:
HA-G-F 20 is well tolerated with a low rate
of adverse events no systemic side effects
attributed to treatment.
study design
Wobig, M., Beks, P.,
Dickhut, A., Maier,
R., & Vetter, G.
(1999). Open-label
multicenter trial of
the safety and
efficacy of
viscosupplementation
with Hylan G-F 20
(Synvisc) in primary
osteoarthritis of the
knee. JCR: Journal of
Clinical
Rheumatology., 5(6
SUPPL.), S24-S31.
Note: Symposium
presentation of
published data?
Protocol amended to
include additional
patients evaluated for
safety in an
uncontrolled open
study.
Case series
Multi centre
(5)
Participants
Female:N=222
Male or female, >18
years with a diagnosis
of chronic primary
osteoarthritis of the
knee confirmed
radiographically
(Larsen grades 1-IV).
ESR<40mm/h and a
rheumatoid factor
<1:160. Daily pain on
activity
Exclusion
No pain
Unreliable
Patients who were
unco-operative or
withdrew consent were
withdrawn from the
study.
Both knees
could be treated
in patients with
bilateral
disease. Each
knee was
independently
evaluated. For
safety
assessment
patients only
were
considered.
Local reactionsa
16 HA patients (19 events), 18 treatment related, 2 withdrawals
Pain and swelling in joint, swelling alone or pain alone.
13/16 patients did not require treatment other than analgesics,
the other 3 had 4 relatively severe local reactions
Summary: the rate per injection of local adverse events in the
injected knee, regardless of their relationship to treatment was
2.5%, the rate per patient was 8.5% and the rate per knee was
7.4%.
Serious Adverse events: those involving acute or severe effects
on vital signs or potentially life-threatening or irreversible or
requiring immediate remedial therapy.
Arthocentesis for pain and swelling (knees): 4
Note:
34 patients
treated
bilaterally, 2
had previously
received HA
injections.
Consideration in relation to the safety profile of IA
corticosteroid injections
Systemic effects have been reported, local AEs of post injection
flare in<=10% of patients which may occur more frequently
with microcrystalline steroid preparations.
Duration
12 weeks
a
Local adverse events = signs and symptoms that emerged up
to 1 week after treatment. Physicians assessed severity and
likely relationship to treatment.
IA= intra-articular
Safety and harm
57
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors, year, study
design
reviewer summary
Kroesen, S., Schmid, W., &
Theiler, R. (2000). Induction of
an acute attack of calcium
pyrophosphate dihydrate arthritis
by intra-articular injection of
hylan G-F 20 (Synvisc). Clinical
Rheumatology, 19(2), 147-149.
Objective
To report an acute attack of Calcium pyrophosphate dihydrate (CPPD) after 2 IA hylan injections.
Case Report
Participants
60 year old male
Exposure
Hyaluronan injected under aseptic conditions.
Two courses administered 1 week apart.
Authors’ conclusions:
There have been four reported cases of CPPD. Each attack occurred a few
hours or days after the second injection suggesting that an allergic reaction
may be necessary to produce the symptoms. It is not known if the type of HA
could play a role. All patients had a meniscectomy or some other surgery in
the affected knee.
There may be more unreported cases of CPPD as the symptoms are very
similar to septic arthritis.
Outcomes:
Serious adverse event report
Safety and harm
The first injection was well tolerated. Two days after the second injection a very painful swelling
developed without fever or systemic signs of inflammation.
Arthrocenesis was performed – there was no bacterial contamination of the synovial fluid. Calcium
pyrophosphate dihydrate (CPPD) crystals were identified in the synovial fluid and CPPD arthritis
diagnosed.
After treatment with NSAIDs and an IA steroid injection symptoms disappeared.
58
Evidence Tables: Injection- Hyaluronic Acid (Knee)
Studies appraised as low quality
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Bagis, S., Sahin, G.,
Oztuna, V., Milcan,
A., Erdogan, C., &
Camdeviren, H.
(2002). The longterm effect of intraarticular hyaluronic
acid on pain and
functional status in
knee osteoarthritis
(one year followup). Pain Clinic,
14(4), 331-337.
Objective
To investigate the
effect of sodium
hyaluronate on
pain and
functional status
and to determine
the exact duration
of its effect.
Inclusion
Inflammatory knee OA
diagnosed clinically on
the basis of the ACR
criteria.
Exposure
Orthovisc
(HMW_
2ml IA
injections once
a week for three
weeks.
Pain as measured
by Lequesne Index
score
Lequesne Index (mean scores) 3 months
N=80
Night pain
2.40
Morning stiffness
2.60
Pain on standing
2.58
Pain on walking
2.72
Pain on rising from seat
2.72
Max walking distance
2.44
Difficulties in daily activites
2.43
Case Series
Screened
N=NR
Enrolled
N=81
Evaluable
N=?
Completed
N=38
conclusions, comments, and quality
scores
study design
Participants
Mean age:59.76
years (45-76
years)
Male:23
Female:58
Exclusion
Systemic disease,
suspected joint
infections, increased
effusion of the knee
and previous treatment
with IA drugs. Grade 4
OA (K-L)
Lateral
approach,
flexed knee.
Patients with
bilateral disease
were treated
bilaterally but
only the most
severe knee
appraised.
Concomitant
medication
Paracetamol
allowed
Stratification
Duration of OA
and BMI
Duration
1 year
1 year
N=38
3.35
2.94
3.28
3.06
3.49
2.97
3.04
Case series score: 0.5/3
Authors’ conclusions:
HA is an effective therapy in knee OA.
The best results were obtained on nocturnal
pain, morning stiffness minimum walking
distance and daily activities.
Patients with medial compartment OA and
with grade I and 2 OA responded
significantly better to therapy.
Bold = significant improvement from baseline p<0.05
Change in VAS score and total Lequesne score at one
year
Reported as a figure, text summary reported that VAS
and total LI score decreased significantly after treatment
(p<0.01), the most relevant decreases seen after 1-3
months.
At one year the scores were still lower than the preinjection score.
Reviewer’s comments:
High drop out (53%)
Little info on sampling
Not clear if stratification was post hoc.
Safety reporting limited
Limited results reporting and analysis.
Stratification
No significant effect on the results
Duration of disease, p =0.086
BMI, p=0.851
.
Age, p=0.534
Gender, p=0.089
Significant effect
Compartment involvement, p<0.001
Radiological stage, p<0.001
Adverse events
Local reaction at the injection site was reported in one
patients (1.2%)
HMW= high molecular weight
OA=osteoarthritis
IA= intra-articular
HA=hyaluronic acid
59
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
Objective
To compare patient
responses regarding the
efficacy and incidence of
side effects with sodium
hyaluronate and hylan GF 20 as treatment
regimens for pain from
OA of the knee.
Inclusion
All patients seen by a
rheumatology group in
suburban Philadelphia
and reviewed for the use
of sodium hyaluronate or
hylan to relieve pain due
to OA of the knee in the
16 months preceding the
study.
Group 1
Hyalgan® (HA)
Sodium hyaluronate
WM=500-730 kDa
5 IA injection regimen over
4 weeks.
Clinical
symptoms (pain),
usefulness, side
effects, use of
medication
HA
HA G-F20
N=42
N=57
Comparison of improvement in clinical symptoms after injection
Pain at rest (mean reduction)
-1.81
-2.81
Pain with weight bearing (mean reduction) -2.40
-3.97
Awakening (mean reduction in nights/wk) -0.54
-2.51
Mobility (mean improvement)
+1.35
+2.41
Initially consecutive i.e.
all patients in period but
only 50% responded to
questionnaire
Group 2
Synvisc® (HAG-F20)
MW=6,000kDa
Hylan G-F 20
3 IA injection regimen over
two weeks.
conclusions, comments, and quality
scores
study design
Pritchard, C. H., Sripada,
P., Bankes, P. F., Smith,
D. G., & Schneider, D.
(2002). A retrospective
comparison of the efficacy
and tolerability of sodium
hyaluronate and hylan G-F
20 in the treatment of
osteoarthritis of the knee.
Journal of Musculoskeletal
Research, 6(3-4), 197-205.
Comparative case Series
Retrospective-chart
review, pilot study
Participants
Mean age: 69, 72 years
Male: 22
Female: 75
Exclusion
NR?
Screened
N=?
Potential cases
N=200
Eligible
N=199
Evaluable (i.e. returned
questionnaire)
N=100
Note: from purified natural
hyaluronan extracted from
chicken combs.
Note: this is a crosslinked
derivative of purified natural
hyaluronan formulated as a
fluid phase hylanA and a gel
phase hylan B in an 80:20
volume ratio.
Method
Mailed self-reported
questionnaire. No follow-up
or additional questionnaire.
Therapy usefulness (% of cases)
Helpful
No helpful
No answer
Side effects
Overall side effect (n%)
Pain
Rash
Flare
Serious Adverse events
Use of medication / therapy (n-=42)
% responding to question
Use of Paracetamol or ibuprofen after
injection therapy
Use of oral glucosamine, chondroitin
after injection therapy
Avoidance of knee replacement
willingness to repeat treatment
Undecided/ did not respond to Q on
willingness to repeat treatment
52.4%
42.8%
4.8%
63.2%
36.8%
0
Case series score: 0/3
p-value
0.080
0.017
0.002
0.052
ns
ns
ns
Authors’ conclusions:
While both therapies benefited patients with similar
tolerability, patients reported greater efficacy with hylan G-F
20 than sodium hyalurnate in relieving pain with weight
bearing, reducing night-time awakenings and improving
mobility in OA of the knee.
Reviewer’s comments:
Mailed questionnaire with low response rate.
Unblinded treatment, allocation not randomised.
Up to 16 months after the treatment and self reported.
Very limited study reporting and design.
10(23.8%) 13(22.8%)
9(21.4%) 10(17.5%)
2( 4.8%) 4( 7.0%)
1( 2.4%) 1( 1.8%)
0
0
52%
DNR
35%
DNR
ns
38%
28%
ns
48%
48%
17%
54%
51%
19%
ns
ns
There was a significant decrease in the use of ibuprofen in the hylan group after
therapy.
60
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
conclusions, comments, and quality
scores
Objective
To define the
efficacy of IA HA
in a review of the
author’s own
initial clinical
experience with
HA.
Inclusion
The first 100 knees to
be treated with IA
hyaluronic acid in the
author’s clinic from
the time it became
available in August
1997 were reviewed
retrospectively.
Exposure
Hyalan G-F 20
(Synvisc)
2ml IA given in
3 consecutive
weeks.
Pain relief
No pain relief: 31% of knees
Some pain relief: 69% of knees
Average relief: 65%
Average onset (wks): 2.3
Average duration (mos): 4.8
Increased activity: 35% of knees
Satisfactory results: 49% of knees
Case series score: 1 /3
study design
Evanich, J.,
Evanich, C.,
Wright, M., &
Rydlewicz, J.
(2001). Efficacy of
intraarticular
hyaluronic acid
injections in knee
osteoarthritis.
Clinical
Orthopaedics &
Related Research,
390, 173-181.
Case series
Retrospective
Consecutive?
Participants:
Average age =66
years (+/- 14
years)
Male=39%
Female=61%
Study size
N=84
Completers
N=70
Number of knees
N=100
Note:
70 patients (80
knees) were
available for
FU
10 patients
received
treatment in
both knees
Study length
10 months
Average FU=10
months +/- 4
months
Radiographic grade
Knee score pre and post
injection difference
Mean pain relief (%)
Some pain relief (%)
Mean degree of pain
relief (%)
Increased activitiy (%)
Satisfactory results (%)
I
3
II
2
III
1
IV
0
p-value
<0.05
53
82
64
51
69
73
33
57
59
10
33
30
<0.05
<0,05
ns
39
61
38
46
30
43
0
0
<0,15
<0.10
Authors’ conclusions:
Less than 50 % of the treated knees achieved
satisfactory results and only 35% reported
increased activity. HA was recommended
only for symptomatic patients with
significant surgical risk factors and mild
radiographic disease in whom conservative
treatment has failed.
Reviewer’s comments:
Elderly, advanced disease included.
Limited reporting.
Average degree of pain relief
Age <40 yrs
58% ---Age 40-60 yrs
38% 47% 31% -Age 65-79 yrs
73% 54% 28% 0%
Age 80+ yrs
73% 52% 65% 15%
Adverse events
15% of knees had adverse reactions most commonly transient
pain and swelling. One case of septic arthritis.
IA=intra-articular
HA=hyaluronic acid
61
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
To assess the efficacy
and safety of intraarticular therapy in
patients suffering from
gonarthrosis as a whole
and to identify variables
resulting from the type
of HA.
Inclusion
Diagnosis of
gonarthritis
following clinical
and radiological
criteria (grade II-III
K-L)
Two parallel groups
Efficacy,
improvement in
symnptoms
HA
AD
No. (%)
No. (%)
N=19
N=30
Efficacy assessment at 5 weeks (N=49)
Excellent
2(10.5)
2(6.7)
Good
5(26.3)
11(36.7)
Fair
9(47.4)
8(26.7)
No response
3 (15.8)
9(30)
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
study design
Roman, J. A., Chismol,
J., Morales, M., &
Donderis, J. L. (2000).
Intra-articular treatment
with hyaluronic acid.
Comparative study of
Hyalgan and Adant.
Clinical Rheumatology.,
19(3), 204-206.
RCT
Parallel group
Blinding but not clear
who
Participants
Age:65 years s.d. 9.77
years.
Male:8
Female:41
Screened
N=NR
Randomised
N=49
Evaluable
N=49
Completed
N=49
Exclusion
None reported
Hyalgan (HA)
(MW=800 kDa), 5 injections of
20 mg (2ml). Source cock’s
crest.
Comparison (AD)
Adnant (MW = 900kDa)
5 injections of 25 mf (2.5 ml)
Biotechni-cally obtained.
Duration
6 months
p-value
ns
ns
ns
ns
Efficacy assessment at 3 months (N=49)
Excellent
1(5.3)
1(3.3)
Good
3(15.8)
14(46.7)
Fair
2(10.5)
3(10)
No response
13(68.4)
12 (40)
ns
0.026
ns
<0.05
Efficacy assessment at 6 months (N=49)
Excellent
1(5.3)
1(3.3)
Good
2(10.5)
9(30)
Fair
1(5.3)
3(10%)
No response
15(78.9)
17(56.7)
ns
ns
ns
ns
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes
n/s
n/s
?
?
?
?
yes
medium
term
yes
conclusions,
comments, and
quality scores
Validity: ~/−
Precision: −
Applicability: ~/−
Overall quality: −
Authors’ conclusions:
The efficacy with Adnant at 3
months (50%) after treatment was
greater than with Hyalgan (21.1%),
probably because its greater
viscosity increases its half-life in
the joint.
no
?/n/s
no
Reviewer’s comments:
Blinding reported but it was not
made clear who was blinded.
yes
Disparity in the numbers given each
drug 30:19.
Improvement within treatment groups over the study time
Poor AE reporting
HA = no significant change in excellent, good or fair, significant
change over 6 months in no response (p<0.0001) which increased
from 3 to 15 over the period.
Efficacy assessment very limited.
AD= no significant change in excellent, good or fair, significant
change over 6 months in no response (p<0.05) which increased
from 9 to 17 over the period.
Maximum improvement
All patients:
P<0.0001
5 wks
75.4%
3 mos.
22.4%
6 mos.
2%
Adverse events: 16.3 of patients had painful infiltration with
Adnant compared to 10.5% with Hyalgan (RR=1.9). Patients did
not modify their analgesic or NSAID consumption during the
period.
a
categorical analysis performed ( chi-square) successful treatment
vs not successful where success = 0.20mm VAS for pain and
activity reduction and 80-100mm for improvement of the most
painful knee movement, the data comprised % of patients
reporting successful treatment.
MW=molecular weight
62
Evidence Tables: Injection- Hyaluronic Acid (Knee)
study authors
and year
participants
study
inclusion/
exclusion
exposure/
comparison
outcomes
results
validity /
applicability
Objective
To apply HA to
patients in china
with OA of the
knee and
investigate its
clinical value and
any side effects.
Inclusion
Adults with a
diagnosis of early
osteoarthritis (mild
to moderate) by 4
senior surgeons
were selected to
join the test.
Clinical symptoms
with exercise pain,
limitation of joint
function and
radiological
findings of bone
spur, space
narrowing or
osteosclerosis.
Exposure
1% sodium
hyaluronate solution
(ARTZ), 2.5 ml IA
injection once a
week for 5
injections.
Clinical
symptoms
results were
reported
graphically,
no tabular
results given.
Text
summary
reports given
All of the following showed a
significant improvement with
time in favour of ARTZ
(p≤0,05 to p<0.001):
Knee motions (mean values)
Static conditions (mean
values)
Daily activities (mean values)
Randomised
Method described
Similar at baseline
Concealment
Intention to treat
Blinding appropriate
Single blind
Double blind
Blind outcome assessment
Compliance OK
Follow-up OK
study design
Wu, J. J., Shih, L.
Y., Hsu, H. C., &
Chen, T. H.
(1997). The
double-blind test
of sodium
hyaluronate
(ARTZ) on
osteoarthritis knee.
Chinese Medical
Journal (Taipei).
59(2), 99-106.
RCT
Double blind
Participants N=90
Mean age: 69
years
Male: 72%
Exclusion
Steroid intraarticular-injection,
functional
disturbance of the
liver and kidney,
pregnancy and
server degeneration
of the knee joints
with marked
narrowing, marked
varus or valgus
deformity or a large
amount of synovial
effusion.
Comparison
2.5 ml of the ARTZ
solvent (sodium
chloride phosphate
solution).
Note:
No local
anaesthesia was
used and during the
test period no
concomitant therapy
was allowed (inc.
NSAIDS)
Duration
4weeks treatment
6 months FU
The following had
significantly better results in
the ARTZ group:
Subjective measurements
Objective measurements
Usefulness measurements
Effectiveness measurements
Note: most differences
between the two groups
appeared to peak at 5 weeks
with differences still apparent
at 13 weeks for some
variables and few significant
differences remaining at 26
weeks. There were difficulties
in discerning results detail
from the small crowded
graphs.
Drop outs<20%
Generalisability
Feasible/Affordable
All important outcomes
considered
Balance between benefits
and harms
yes
no
n/a
n/s
no
yes
n/s
n/s
yes
yes
yes
n/s
n/s
medium
term
yes
no
n/s
yes
?
conclusions, comments, and
quality scores
Validity: ~/−
Precision: ~/−
Applicability: −
Overall quality: −
Authors’ conclusions:
HA is a safe drug for
administration as an alternative
approach to treat the OA knee.
Reviewer’s comments:
No pain relief at injection or
through the study was allowed.
A high drop out (50%) mostly
because of protocol violation (no
pain relief or anaesthetic was
allowed)
No side effects were reported
which is unusual, this may be due
to cultural and gender differences.
Population largely elderly males
The results were poorly reported
and the population was such that
results would be unlikely to be
generalisable.
Radiological study at 6
months was viewed to be too
early to develop significant
change, some PL subjects
showed worsened lesion.
There were no significant
differences between the
groups.
Adverse events/safety
No side effects developed
No abnormal lab tests
observed
63