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ARD Online First, published on December 25, 2012 as 10.1136/annrheumdis-2012-201536
Clinical and epidemiological research
EXTENDED REPORT
A multi-centre, blinded, randomised,
placebo-controlled, laboratory-based study of
MQX-503, a novel topical gel formulation of
nitroglycerine, in patients with Raynaud
phenomenon
Laura K Hummers,1 Carin E Dugowson,2 Frederick J Dechow,3 Robert A Wise,1
Jeffrey Gregory,4 Joel Michalek,5 Gayane Yenokyan,6 John McGready,6
Fredrick M Wigley1
▸ Additional supplementary
files are published online only.
To view these files please visit
the journal online (http://dx.
doi.org/10.1136/annrheumdis2012-201536).
1
Department of Medicine,
Division of Rheumatology,
Johns Hopkins University
School of Medicine, Baltimore,
Maryland, USA
2
Department of Medicine,
Division of Rheumatology,
University of Washington,
Seattle, Washington, USA
3
MediQuest Therapeutics, Inc.,
Bothell, Washington, USA
4
Acucela Inc, Seattle
Washington, USA
5
Department of Epidemiology
and Biostatistics, The University
of Texas Health Science Center
at San Antonio, San Antonio,
Texas, USA
6
Department of Biostatistics,
Johns Hopkins School of Public
Health, Baltimore, Maryland,
USA
Correspondence to
Dr Laura Kathleen Hummers,
Division of Rheumatology,
Johns Hopkins University,
5501 Hopkins Bayview Circle,
Baltimore, MD 21224, USA;
[email protected]
Received 16 February 2012
Revised 1 November 2012
Accepted 18 November 2012
ABSTRACT
Objective MQX-503 is a novel nitroglycerine
preparation designed to absorb quickly and allow local
vasodilatation in the skin. We examined the efficacy and
tolerability of this medication in Raynaud phenomenon
(RP) in a laboratory-based study.
Methods In this multi-centre, double-blind,
randomised, placebo-controlled, cross-over study,
subjects were treated with 0.5% or 1.25% nitroglycerine
or placebo gel. Subjects received each dose twice in a
randomised order. Each study session consisted of
baseline laser Doppler measurements, study gel
application and 5 min of cold chamber exposure
(−20°C). Blood flow (BF) was measured at the end of
exposure and for the next 120 min at set intervals.
Other outcome measures included achievement of
baseline BF; the time to achieve 50% and 70% baseline
skin temperature (ST); and pain, tingling and numbness
scores.
Results 37 subjects completed 214 treatment periods.
Time to achieve baseline BF was significantly shorter in
the two treated groups (HR=1.77 and 2.02 for 0.5%
and 1.25% vs placebo, respectively). The proportion of
subjects achieving baseline BF was 45.8% for placebo,
66.2% for 0.5% and 69% for 1.25% ( p=0.01 and
p=0.002 for 0.5% and 1.25% vs placebo, respectively).
No meaningful differences were seen in ST or pain/
numbness/tingling scores. Treatment was well tolerated
with no serious adverse events.
Conclusions Treatment with MQX-503 caused a
significant improvement in skin BF compared with
placebo. Data from this proof of concept study suggest
benefit of MQX-503 in subjects with RP.
INTRODUCTION
To cite: Hummers LK,
Dugowson CE, Dechow FJ,
et al. Ann Rheum Dis
Published Online First:
24 December 2012
doi:10.1136/annrheumdis2012-201536
Raynaud phenomenon (RP) is a cold or stress
induced vasospasm of thermoregulatory vessels in
the skin and tissues of the digits. Nitrates have long
been used as a therapy for both primary and secondary RP. Organic nitrates interact with their
receptors located on smooth muscle cells of blood
vessels and are converted to nitric oxide which
increases cyclic guanosine monophosphate (cGMP)
causing vasodilatation of venous and arterial
vessels. Various formulations of nitroglycerine exist
including ointment, transdermal patches, sublingual
tablets and tape.1–12 There has been evidence of
improvement in Raynaud attack severity and frequency,8 12 skin temperature (ST)3 13 14 and blood
flow (BF)1 4 9 11 with the use of nitrates. Topical
nitroglycerine is often prescribed to patients, but its
use has been limited by side effects including headache, flushing and nitrate tolerance. In some
studies, the dropout rate due to adverse events has
been as high as 20%, with headaches in as many as
80% of those treated.12 The object of this study
was to examine the tolerability and efficacy of a
novel preparation of nitroglycerine gel that has
little or no systemic absorption in the treatment of
RP. MQX-503 is a microemulsion formulation of
nitroglycerine, approximately half water and half
organic, with a surfactant system designed for
rapid, non-irritating local delivery of the active
agent topically on the skin.
METHODS
Design
This study is a laboratory-based, randomised,
double-blind, placebo-controlled, cross-over, dose
evaluation protocol with digital BF as the main
outcome measure. Upon study enrolment subjects
were randomly assigned to one of six sequences,
with sequence assignment determining the order in
which the different treatments (placebo gel, 0.5%
nitroglycerine, 1.25% nitroglycerine) were applied.
Each subject received each drug preparation twice,
completing six study periods during three visits
with two assessments per visit. This study was
approved by the Institutional Review Boards of
both participating institutions and all subjects
signed written consent forms prior to study entry.
Subjects
Subjects with primary or secondary RP were
recruited from two academic rheumatology centres
( Johns Hopkins University and University of
Washington). Subjects had a clinical diagnosis of RP
as determined by a history of cold sensitivity with
pallor and/or cyanosis of the digits or an observed
Hummers LK,
et al. Ann
Rheum Dis
2012;0:1–6.
doi:10.1136/annrheumdis-2012-201536
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2012. Produced by BMJ Publishing Group Ltd (& EULAR) under licence.
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Clinical and epidemiological research
event by the study physician. Subjects were required to discontinue other vasodilator therapies 2 weeks prior to the start of
the study. Subjects were excluded if they were currently using
any nitrate medication or medication known to interact with
nitroglycerine or were unable to discontinue their vasodilator
therapy safely (such as ongoing digital ischaemia) or had open
skin ulcerations. Subjects with migraine or cluster headaches and
those with medical conditions where the administration of
nitrate medications may be contraindicated were excluded.
Outcome assessment
The primary outcome measure was time to achieve baseline BF
as measured by laser Doppler and defined as the first time after
cold challenge when the subject had a BF value greater or equal
to the baseline value. BF was averaged over the second through
fourth digits for each assessment point. Secondary outcome
measures were: proportion achieving baseline BF, time to
achieve 50% and 70% baseline ST and pain, numbness and tingling scores measured on a 0–10 visual analogue scale.
Safety assessment
Tolerability of the study medication was assessed at the end of
each study period. The subject was also asked to report intervening adverse events between study visits. The subject was specifically asked about headache, lightheadedness and skin
irritation. Intensity of adverse reactions was rated as mild, moderate or severe and the likelihood of drug-relatedness was
judged by the investigator. Systemic blood pressure was monitored at all assessment points. Physical examinations and routine
laboratory studies were performed prior to study entry and following completion of all study visits.
Study medication
MQX-503, a topical gel formulation of nitroglycerine, was supplied in individual dose Del Pouch applicators containing 0.5 g
of gel each or identical applicators containing the placebo gel.
Study protocol
Subjects were placed in a quiet limited-access room with controlled temperature (20–25°C) and humidity for 30 min prior to
baseline measurements. The baseline BF was measured three
times in the fingers of the subject’s non-dominant hand (second
through fourth digits), using a Moor Instruments moorLDI
scanning laser Doppler instrument and reported in perfusion
units (PU). Baseline digital ST was defined using the average of
three prechallenge temperature measurements using a thermistor. The treatment gel was applied to the four fingers of the subject’s non-dominant hand and rubbed into the fingers for 1 min.
The cold challenge procedure was then performed by placing
the subject’s hand into the cold exposure chamber (−20°C) up
to the mid-forearm. The cold challenge was continued for a
maximum of 5 min, until the ST fell to 12°C, or until the
subject could no longer tolerate the cold. The hand was then
removed from the chamber and passively rewarmed in the room
environment. The digital temperature at the end of the cold
challenge was defined as the minimum ST. The recovery to 50%
and 70% of prechallenge digital ST was defined as: Minimum
ST+(( prechallenge temperature− minimum ST)×0.5 and 0.7)
respectively. The systemic blood pressure, ST and finger BF were
determined immediately after exposure and at 5, 15, 25, 35, 45,
55 and 120 min following the cold challenge. During this BF
monitoring period, the subject completed pain, numbness and
tingling scores.
2
At the end of the BF monitoring period, there was at least a
1 h interval before the next study period, which proceeded in
the same manner as described above. Two challenges and gel
applications occurred at each of three study visits (at least 15 h
but no more than 4 days apart) for a total of six sessions.
STATISTICAL ANALYSIS
Efficacy and safety analyses were based on the intent-to-treat
population defined as all subjects who received at least one dose
study medication. Summary statistics, including the mean and
SD as well as medians and ranges, are presented for the three
groups. Data for each treatment were pooled across sequences
and assessments for analysis. We used marginal generalised
linear model with binomial distribution and exchangeable correlation structure using generalised estimating equations to
account for non-independence of multiple observations per
patient and to compare the proportion of subjects achieving
baseline BF by dose. Differences in continuous variables
between groups were compared via the Kruskall–Wallis test for
equality. Contrasts between treatment groups with regard to
Raynaud symptoms (tingling, numbness, pain) were made using
the Wilcoxon Rank-Sum test.
Time to achieve baseline BF
Survival times were estimated using Kaplan–Meier method and
were compared using log-rank test. To estimate the relative efficiency of the treatment groups, Cox proportional hazards
models were used. Subjects who did not achieve baseline BF
were censored at the last measurement of BF. Proportionality of
hazards was assessed based on the analysis of Schoenfeld residuals.15 The HRs were adjusted for type of RP (secondary vs
primary) and the baseline BF level (continuous, per 50 PU).
Due to the discrete nature of the times, tied failure times were
accounted for using marginal calculation assuming that they
occurred due to inability to measure precise time of failure, not
due to true discreteness of the times.16 In order to account for
the fact that each patient contributed multiple observations,
Cox survival model with shared frailty was used and assumes
that each patient possesses underlying proneness to achieve the
baseline BF modelled as a random effect.17
For observations that achieved baseline BF at the end of cold
challenge (time 0) the distributions are presented by treatment
groups and were dropped from the Cox regression models. To
assess for carryover effect, a Cox regression was run for second
assessment at each visit using time to achieve baseline BF at the
first assessment as the predictor.
Missing data
Missing data patterns were assessed using PROC MI in SAS.
Two approaches of handling missing data were used. First, complete case analyses were conducted. Cases were called ‘nondisputable’ if patients achieved baseline BF at earlier times and
had missing values at later times. However, if earlier measurements were missing, even if patients achieved baseline BF at
later times, the time of that event is ‘disputable’. In the complete
case analyses, all disputable failures as well as all observations
with missing data and without achieving baseline BF were
excluded. All main results are based on complete case analyses.
Second, assuming that values are missing at random, multiple
imputation of missing data using Markov chain Monte Carlo
(MCMC) data augmentation method (using other available measures, such as non-missing BF values, to impute the missing
values) was performed.18
Hummers LK, et al. Ann Rheum Dis 2012;0:1–6. doi:10.1136/annrheumdis-2012-201536
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Clinical and epidemiological research
Table 1
Subject demographics/characteristics
Subject characteristics
Age, years±SD
Range, years
Gender, % female/male
Race, N (%)
White
Black
Asian
Prior use of calcium channel blockers, N (%)
Prior use of prostacyclin, endothelial receptor antagonists,
phosphodiesterase inhibitors, N (%)
Smoker, N (%)
Disease category, N (%)
Primary Raynaud
Secondary Raynaud
Scleroderma
Diffuse
Limited
Systemic lupus erythematosus
Baseline blood flow, PU, mean±SD, total
Primary
Secondary
Symptom scores, median (range)
Pain
Numbness
Tingling
Study subjects,
N=37
45.4±14.2
19–75
83.8/16.2
25 (67.6)
11 (29.7)
1 (2.7)
20 (54.1)
0 (0)
4 (10.8)
11 (29.7)
26 (70.3)
24 (64.9)
7 (18.9)
17 (45.9)
2 (5.4)
139.8±105.3
168.4±135.7
127.4±87.2
0 (0–6)
0 (0–5)
0 (0–4)
PU, perfusion units.
Skin temperature
The actual time of each measurement of ST was used in the analysis of recovery of 50% and 70% ST. Subjects who did not
achieve 50% or 70% recovery of ST were censored at the time
of their last recorded measurement. Survival times were estimated using Kaplan–Meier method and were compared using
log-rank test.
Stata 11 (StataCorp. 2009. Stata Statistical Software: Release
11. College Station, Texas, USA: StataCorp LP) was used for the
analyses and SAS V.9.2 for Windows (SAS Institute, Cary, North
Carolina, USA) was used for multiple imputations of missing
values and for combining the parameter estimates.
RESULTS
Subject characteristics
Overall, 37 subjects were entered into the study, 25 subjects
from Johns Hopkins Hosptial (JHH) and 12 from University of
Washington (UW). Two subjects withdrew from the study after
the first treatment period. A total of 35 subjects completed the
study protocol (214 treatment periods, 72 for placebo, 71 for
0.5% gel and 71 for 1.25% gel) and all 37 subjects were
included in the intent-to-treat analysis. Subject demographics
and baseline data are presented in table 1.
Blood flow
The mean±SD baseline BF for the entire study population was
139.8±105.3 PU and there were no differences between groups
(p=0.18, df=2). Subjects with primary RP had higher mean baseline BF compared with those with secondary RP (168.4±135.7 vs
127.4±87.2) but this difference was not statistically significant
(p=0.25). There was a significant drop in mean BF after cold
Hummers LK, et al. Ann Rheum Dis 2012;0:1–6. doi:10.1136/annrheumdis-2012-201536
challenge in all three groups (mean change from baseline −46.4
±75.3 PU).
The distribution of patients that achieved baseline BF is represented in table 2. The proportion of subjects who achieved baseline
BF was significantly higher in each of the two active arms relative
to placebo (placebo: 45.8%, 0.5%: 66.2%, 1.25%: 69%), but the
two active arms did not differ significantly from each other
(p=0.53). There were no overall differences in the proportion who
achieved baseline BF comparing those with primary versus secondary RP (p=0.48) (table 2B). However, the treatment effect was
only significant in the primary RP group and significantly attenuated in the secondary RP group (table 2C).
The proportion, rate and median time of achieving baseline
BF in each treatment group is represented in table 3. The proportion of visits where the subject had already achieved baseline
BF at the end of cold challenge were five for placebo 15 for
0.5 mg and 13 for 1.25 mg groups. There was a more rapid
recovery of BF in the two treatment arms compared with
placebo (figure 1). As it can be seen in figure 1, at each point in
time, the probability of not achieving baseline BF is greater in
the placebo group compared with the treatment groups. The
log-rank test yields statistically significant difference among the
three groups (χ2=6.90 df=2, p=0.032).
Table 4 presents the results of the standard Cox regression
models. According to the table, active treatment appears superior in achieving baseline BF compared with the placebo with
HR=2.02 (95%CI 1.17 to 3.49) for the 1.25% group and
HR=1.77 (95%CI 1.03 to 3.07) for the 0.5% groups compared
with placebo. The results were not significantly different in the
random effect analyses. Furthermore, likelihood ratio test suggests that there is little evidence of high underlying heterogeneity in achieving baseline BF among the patients (adjusted
shared frailty model: χ2=1.02, p value=0.156). After multiple
imputation of missing BF variables, the results appear to be consistent with the main conclusions.
Skin temperature
Almost all subjects achieved 50% and 70% recovery of ST but the
proportions of subjects did not differ by treatment group (table 5A
and B). There were no significant differences between treatment
groups with regard to time to achieve either 50% or 70% of baseline ST. The results of log-rank test comparing three doses suggest
that the doses are not significantly different from each other in
achieving 50% (p value=0.358) or 70% (p value=0.354) of baseline temperature. After adjusting for the baseline ST using Cox
regression with shared frailty, the results were consistent with no
difference among three groups (χ2 Wald test with 2 degrees of
freedom=0.4, p value=0.820 and 0.803, respectively).
Symptoms
Overall the median baseline symptom scores were all zero (see
table 1) and the within-treatment group means were similarly
near zero (data not shown), indicating a lack of symptoms at
baseline. There was an overall increase in each of the three
mean symptom scores after the cold challenge procedure (data
not shown), but median symptom score values remained zero
for all symptoms at all time points. There was a significant
increase in the mean % change (±SD) tingling score in the
0.5% treatment group at end of cold challenge ( placebo: 66.4
±146.5; 0.5%: 143.3±236.5 ( p=0.04), 1.25%: 107.6±222.8
(p=0.27)); all other comparisons with placebo for pain, tingling
and numbness scores were not significant.
3
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Clinical and epidemiological research
Table 2
Proportion of cases achieving baseline blood flow by treatment arm (A) and by Raynaud type (B) and by both treatment arm and Raynaud type (C)
Proportion of achieving baseline blood flow, n (%)
Number of observations
A
Dose
Placebo
72
0.5
71
1.25
71
Total
214
B
Type of Raynaud phenomenon
Primary
66
Secondary
148
Total
214
Disputable cases
Non-disputable cases
Total
p Value*
4
0
4
8
29
47
45
121
33 (45.8)
47 (66.2)
49 (69.0)
129 (60.3)
0.0044
5
3
8
31
90
121
36 (54.5)
93 (62.8)
129 (60.3)
0.488
Primary Raynaud
–
–
Secondary Raynaud
Number of
observations
Proportion of achieving baseline
blood flow, n (%)
22
22
22
66
6 (27.3)
15 (68.2)
15 (68.2)
36 (54.5)
p Value
Number of
observations
Proportion of achieving baseline
blood flow, n (%)
p Value
–
0.017‡
0.003§
0.008†
50
49
49
148
27
32
34
93
–
0.194‡
0.112§
0.231†
C
Placebo
0.5
1.25
Total
(54.0)
(65.3)
(69.4)
(62.8)
*chi-squared test from the generalised linear marginal model with generalised estimating equations (five observations with missing times are excluded).
†Group 1.25 versus 0.5 in primary, p value=0.435, in secondary, p value=0.774.
‡Comparing 0.5 dose with placebo.
§Comparing 1.25 dose with placebo.
Safety
There were no serious adverse events that occurred during this
study. The most common adverse events included headache (three
subjects), lightheadedness (two subjects) and dizziness (two subjects). Overall, adverse events were no more common in either of
the treatment groups compared with placebo. However, both
occurrences of lightheadedness occurred in subjects receiving
active treatment (either 0.5% or 1.25%). Two of the subjects’
headaches and one episode of lightheadedness were thought to be
possibly related to the treatment by the physician. The baseline
blood pressure for the whole group was 127/76. No group at any
time point had >5% mean change in systolic or diastolic blood
pressures. Although there were some statistical differences
between the groups in per cent change in systolic blood pressure
(−3.86% change in systolic blood pressure in the 0.5% group and
−2.55% in the 1.25% group at 15 min and −4.25% in the 0.5%
group at 55 min), this was not a consistent difference and the differences were not thought to be clinically relevant. There were no
differences in percentage change in blood pressure between treatment groups at either time point (15 and 55 min).
Two subjects discontinued the study due to adverse events.
One patient developed hypertension after stopping calcium
channel blocker therapy (although therapy had been instituted
for RP and not a known history of hypertension). The second
subject developed some paresthesias of the arm after the second
visit and withdrew from the study; this subject received 1.25%
gel during that visit.
Table 3 Proportion, rate and median time of achieving baseline blood flow in
each treatment arm among non-disputable cases
Dose
Achieved
baseline blood
flow
Estimated rate of
achieving baseline
blood flow
Estimated median time
of achieving baseline
blood flow (min)
Placebo
0.5
1.25
Total
29
47
45
121
0.34/h
0.67/h
0.74/h
0.55/h
*
35
35
55
*Median time for placebo dose was beyond 120 min of observation.
4
Figure 1 Kaplan–Meier curves of estimated probabilities of not
achieving baseline blood flow by treatment groups (assuming no
correlation in study periods within each patient, N=179).
Hummers LK, et al. Ann Rheum Dis 2012;0:1–6. doi:10.1136/annrheumdis-2012-201536
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Clinical and epidemiological research
Table 4 Results of Cox proportional hazards model estimating the effect of treatment on achieving baseline blood flow and random effects analysis (unadjusted and
adjusted). Presented as HR (95% CI)
Uncorrelated analyses
Variables
Dose
0.5%
1.25%
Placebo
Type of Raynaud
Secondary
Primary
Baseline blood flow (per 50 perfusion units)
Table 5
Random effects analyses
Unadjusted
Adjusted
Unadjusted
Adjusted
1.80 (1.05, 3.11)
1.94 (1.13, 3.35)
1.0
1.77 (1.03, 3.07)
2.02 (1.17, 3.49)
1.0
1.74 (1.01, 3.00)
1.87 (1.09, 3.23)
1.0
1.74 (1.00, 3.02)
2.05 (1.18, 3.57)
1.0
0.85 (0.46, 1.56)
1.0
0.79 (0.69, 0.92)
0.80 (0.43,1.49)
1.0
0.79 (0.68, 0.91)
–
0.82 (0.38, 1.76)
1.0
0.76 (0.65, 0.89)
0.78 (0.67, 0.91)
Distribution of achieving 50% (A) and 70% (B) of baseline temperature by the treatment group
Proportion of achieving 50% of skin temp., n (%)
Number of observations
Disputable cases
A
Dose
Placebo
0.5
1.25
Total
72
71
71
214
B
Dose
Placebo
0.5
1.25
Total
72
71
71
214
Non-disputable cases
Total
p Value*
0
67
0
69
1
65
1
201
Proportion of achieving 70% of skin temp., n (%)
67 (93.1)
69 (97.2)
66 (93.0)
202 (94.4)
0.237
2
1
1
4
64 (88.9)
66 (93.0)
63 (88.7)
193 (90.2)
0.432
62
65
62
189
–
–
*χ2 Test of association (four observations with missing reference skin temperature are excluded).
DISCUSSION
This study demonstrates an improvement in digital BF in those
subjects treated with MQX-503 compared with placebo in a
laboratory-based investigation. This difference was noted in
both the 0.5% and 1.25% preparation, with no dose–response
effect noted. The study medication was well tolerated with no
serious adverse events and no difference in frequency of mild to
moderate adverse events. There were a few instances of headache and lightheadedness that may have been related to the
active treatment. The rates of side effects seen in this study, if
related to the study drug, were remarkably lower than the rates
in other published studies of nitroglycerine preparations.
The first placebo-controlled trial with a clinical endpoint suggested benefit of topical nitroglycerine in Raynaud attack frequency, attack severity and digital ulcers.8 Anderson et al4 showed
improvement in vasodilatory response as measured by laser
Doppler in subjects treated with local topical nitroglycerine
therapy, although the placebo ointment also showed some benefit.
No other outcome assessments were performed and there was no
mention of tolerability or side effects. A preparation of nitroglycerine tape was examined in 25 subjects with scleroderma-associated
RP in an open label study using thermography as the main
outcome measure. This study showed an increase in finger temperature, but a significant fall in systolic blood pressure and 25%
of subjects experienced headache and flushing.3
Hummers LK, et al. Ann Rheum Dis 2012;0:1–6. doi:10.1136/annrheumdis-2012-201536
In the current study, since subjects receive two doses over two
assessments per treatment visit, there could be a concern that
the effects of the first dose could linger into the second assessment timeframe, or even into the next visit. This is unlikely
given the 1–4 min half-life of nitroglycerine and the high volatility of nitroglycerine, making what has not been absorbed by the
skin evaporate within 5 min. Human studies confirm that the
pharmacodynamic effects of MQX-503 last only 45 min. In
addition, no significant carry over effect was found in this analysis (data not shown).
This study also suggested that the effectiveness of this preparation may be more pronounced in those with primary compared
with secondary RP, although the study may have been underpowered to see smaller effect sizes in these subgroups. This
would be consistent with other therapies, where the effect is
seen primarily in milder disease states. Other than type of
Raynaud, we did not have any other baseline measures of
Raynaud severity to test this further, but since only half of the
subjects had received prior therapy for RP, this was likely a mild
group of subjects.
This study demonstrated an improvement in BF, but no differences in ST. This disparity has been noted in other studies. In
another study of subjects with primary and secondary RP and
healthy controls, there was a poor correlation between thermography and laser Doppler imaging.19 The authors suggested that
5
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Clinical and epidemiological research
BF measured by Laser Doppler may be more sensitive to change
compared with an indirect measure of BF such as ST.
We did not find any meaningful differences in mean
symptom scores between the groups and, in fact, most subjects were without symptoms throughout the study. Given
that this was a laboratory-based acute challenge study, it is
difficult to make any judgments about the effectiveness of
this therapy for symptomatic Raynaud attacks. In addition,
this study may have been biased towards a milder population
of RP patients, making any judgment of these clinical outcomes difficult to assess. This would need to be further evaluated in a longer ambulatory treatment trial with clinical
endpoints. These data do support, however, the hypothesis
that this novel preparation of nitroglycerine can improve
digital BF in those with RP and continued clinical studies of
this medication are warranted.
3
4
5
6
7
8
9
10
11
Acknowledgements The authors would like to acknowledge the contribution of
Lindsay Waite, MS, formerly of the Department of Epidemiology and Biostatistics,
The University of Texas Health Science Center at San Antonio, San Antonio, Texas,
for her statistical contribution to some of the analyses in this manuscript.
Funding Supported by MediQuest Therapeutics, Inc.
12
13
Competing interests None.
Ethics approval Johns Hopkins University and University of Washington
Institutional Review Boards.
14
Provenance and peer review Not commissioned; externally peer reviewed.
15
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Hummers LK, et al. Ann Rheum Dis 2012;0:1–6. doi:10.1136/annrheumdis-2012-201536
Downloaded from ard.bmj.com on January 17, 2013 - Published by group.bmj.com
A multi-centre, blinded, randomised,
placebo-controlled, laboratory-based study
of MQX-503, a novel topical gel formulation
of nitroglycerine, in patients with Raynaud
phenomenon
Laura K Hummers, Carin E Dugowson, Frederick J Dechow, et al.
Ann Rheum Dis published online December 25, 2012
doi: 10.1136/annrheumdis-2012-201536
Updated information and services can be found at:
http://ard.bmj.com/content/early/2012/12/24/annrheumdis-2012-201536.full.html
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Advance online articles have been peer reviewed, accepted for publication, edited and
typeset, but have not not yet appeared in the paper journal. Advance online articles are
citable and establish publication priority; they are indexed by PubMed from initial
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(DOIs) and date of initial publication.
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