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Eur Respir J
1993, 6, 35-41
The clinical efficacy of inhaled nedocromil sodium (Tilade®)
in the treatment of asthma
A.M. Edwards*, M.T. Stevens**
The clinical efficacy of inhaled nedocromil sodium (Ti/ade"') in the treatment of
asthma. A.M. Edwards, M.T. Stevens.
ABSTRACT: Inhaled nedocromil sodium, an anti-inflammatory agent for the
maintenance treatment of asthma, has been the subject of many clinical trials
but only a proportion have been published .
This paper provides an overview analysis of all known placebo-controlled,
double-blind, randomized therapeutic trials. Both single centre and multicentre
trials are included. A comparison has been made between the treatment effects
of nedocromil sodium and placebo, using six efficacy variables (day and night
asthma, cough, mean daily peak expiratory flow rate, inhaled bronchodilator
use, clinic lung function (forced expiratory volume in one second) and global
opinion of treatment efficacy. One hundred and twenty seven trial centres,
involving 4,723 patients, have been included.
The results demonstrate the efficacy of inhaled nedocromil sodium in a
variety of patients with asthma. Optimal effects are evident in patients with
moderate asthma, currently r eceiving treatment with inhaled and oral
bronchodilators.
Eur Respir J., 1993, 6, 35-41.
The evaluation of therapeutic agents is a difficult
task, not only for the research scientist involved in
drug development, but also for the physician who has
to make a clinical decision on the basis of published
data. Journals tend to favour "positive" findings, and
this selective publication, combined with the multiple
testing which is carried out in most studies, can produce bias, which may mislead the medical profession.
In pa1ticular, the evaluation of new drugs in the treatment of bronchial asthma is well recognized as being
a difficult task [1, 2]. This is due, in part, to the
inherent variability of the disease state, the lack of any
objective measure of success and the complications
introduced into the interpretation by the use of
concomitant medications.
Typically, the size of trial required to detect the
clinically meaningful effects of a maintenance therapy
for asthma as statistically significant tends to be large.
Even when the trial is well designed in advance, the
required number of patients is often not achieved.
Evaluation from a number of trials or multicentre trials
is, therefore, often needed.
The most realistic assessment of the value of a new
therapy is likely to come from an initial phase of
double-blind studies. The larger this programme of
work, the more likely it is that some trials will produce statistically significant results, even if no real
treatment effect exists. These "false positives" will
*
Medical Dept. Asia-Pacific Region,
Fisons plc (Pharmaceutical Division).
** S ta ti stics Dept. Research and
Development Laboratories, Fisons plc
(Phannaccutical Division).
Correspondence: A.M. Edwards
Medical Department
Asia-Pacific Region
Fisons plc (Phannaceutical Division)
12 Derby Road
Loughborough
Leics
LEII OBB, UK
Keywords: Asthma
nedocromil sodium
overview analysis
Received: January 13, 1992
Accepted after revision July 25, 1992
tend to be those published in the scientific literature
and may overstate the effectiveness of the new drug.
The proper assessment of therapeutic efficacy should
involve a compilation of all the evidence [3]. The
pharmaceutical company concerned is well-placed to
do a complete overview of all available data, both
published and unpublished.
An overview of this type should have a statistical
basis. Statistical analyses carried out on individual
trials do not encompass all of the available information
or address the complete question. Indeed, there is a
paradox in using decision making techniques, such as
statistical hypotheses tests, within individual clinical
trials, when decisions on efficacy and drug development are based on a package of trials. However, there
are difficulties in this approach and it has been suggested [4] that several criteria be met before proceeding: l) all patients should have been treated for the
same disease; 2) the clinical severity of disease should
be known; 3) all patients should have received similar
test therapy; and 4) the end-points measured should be
similar.
We have adopted this approach in the evaluation of
an inhaled maintenance therapy for asthma, nedocromil
sodium (Tilade® registered trade mark of Fisons plc).
Individual studies have indicated statistical evidence
of efficacy but, as is common in asthma studies, these
indications have not always been in the same
36
A.M. EDWARDS, M.T. STEVENS
variables. Many individual studies have been reported.
Here, we bring together the data from all known
placebo-controlled studies in the programme, in order
to demonstrate the value of a complete review, as
suggested by PocoCK [3 J.
Methods
The programme of clinical trials consisted of both
single centre and multicentre trials. The principle
behind the analyses presented in this paper is that each
trial centre provides an unbiased estimate of the difference between nedocromil sodium and placebo.
Under the null hypothesis that the test treatment has
no effect compared to placebo, it would be expected
that there would be no statistical differences between
the two treatments taken over all trial centres .
Conclusions from this analysis have real practical
advantages, in that they indicate the efficacy of a
treatment as it is likely to be applied in a range of
different therapeutic settings.
All double-blind, placebo-controlled studies supplied
and analysed by Fisons R & D Laboratories in
Loughborough, to date, have been considered. We
believe that, up to the time of this analysis, it is unlikely that any other source of inhaled nedocromil
sodium and matching placebo was available, so that
all completed and analysed, placebo-controlled trials
have been included. All were randomized and the
majority of these have been of a group comparative
design. A small number used a cross-over design and
for these, the first treatment period of each order group
has been utilized.
The outcome variables have been similar across the
range of trials. The scales used, though differing in
minor respects, have essentially been similar.
Four classes of variable have been used in the
analyses:
l . Global opinion
At the end of treatment, each patient was asked to
state their opinion of the effectiveness of the test
treatment, using a scale of very effective, moderately
effective, slightly effective, no effect, made condition
worse. Patients withdrawn owing to treatment failure
were assigned the option "made condition worse". For
each centre, the percentage of patients demonstrating
a good effect (i.e. very or moderately effective) was
calculated and the difference between the two treatments compared.
each trial had a baseline period and the change from
this period to the period between the last two clinic
visits has been used for comparative purposes. For
four week trials this was the last week of treatment,
for six week studies this was the last two weeks, and
for 12 week trials the last three weeks.
For the purposes of presentation, day and night
asthma scores are added together as a single Day and
Night Asthma (scale 0- 8).
3. Inhaled bronchodilator treatment
The use of inhaled bronchodilators was recorded
night and day on the diary cards. The total 24 h
usage was used in the analyses; the data have been
handled in a similar fashion to symptom scores.
4. Pulmonary function tests
Morning and evening peak expiratory flow rates
(PEFR). These were recorded daily on the diary cards
and the data handled in the same way as symptom
scores and inhaled bronchodilator usage.
For presentation purposes the mean of the two daily
readings is calculated and presented as a mean daily
PEFR with mean changes from baseline.
Forced expiratory volume in one second (FEV 1).
Pulmonary function tests were carried out at each
clinic visit; FEV 1 has been used as the representative
measurement and the change from the baseline visit
to the final visit at the end of treatment in the two
groups used in the comparison.
Trial design
The trials were of different dose frequency and
different design. The two daily dose frequencies (x2
and x4) resulted in a total daily dose of nedocromil
sodium of either 8 or 16 mg.
The trials fall into five designs as follows:
Group I. Test treatment added to baseline treatment
consisting of bronchodilators alone. No change to
baseline treatment.
Group 2. Test treatment added to baseline treatment
consisting of bronchodilators alone. Oral bronchodilators reduced or withdrawn during test treatment.
2. Asthma symptoms
Group 3. Patients well-controlled on inhaled corticosteroid treatment. Dosage of inhaled corticosteroids
reduced prior to baseline period. In this Group, the
16 mg daily dose only was used.
Throughout the trials, patients were asked to record
the severity of their day and night asthma and cough.
The scale for each symptom was 0-4 (O=no symptoms,
4=very severe). In this analysis no scaling was used;
Group 4. Patients inadequately controlled on baseline
treatment, which consisted of inhaled corticosteroids.
Test treatment added to baseline treatment, which was
unchanged during the trial.
37
META-ANAL YSTS OF NEDOCROMrL SODIUM IN ASTHMA
Group 5. Test treatment added to baseline treatment
consisting of inhaled corticosteroids. Patients selected
as being adequately controlled on baseline treatment.
Inhaled corticosteroids withdrawn during the trial.
Results
Of the full data set of 196 trial centres (5 ,601
patients) 69 were excluded as they contributed less
than nine patients per treatment group. The remaining
127 centres provided 4,723 patients, of whom 2,385
were treated with nedocromil sodium and 2,338 with
placebo. The numbers in each group are shown in
table 1.
Mean baseline values for the five groups for symptoms, pulmonary function test and daily use of inhaled
bronchodilators are shown in table 2. Groups 1 and
2 have been combined as patient selection criteria
pretrial were the same.
Apart from use of inhaled bronchodilators, in comparison to Groups 1 and 2, patients in Group 5 had
less severe symptom scores and higher lung function
values than the other three Groups. Groups 1 and 2
were significantly different to Group 3 for PEFR,
FEV 1 and use of bronchodilators. Groups 1 and
2 were significantly different from Group 4 for day
and night asthma, cough, PEFR, FEV 1 and bronchodilator use. Group 3 did not differ significantly from
Group 4 in baseline severity, but Group 3 had been
made deliberately worse by halving the dosage of
inhaled corticosteroids prior to measurement of baseline values.
The results of the analysis of the differences of
the effects of nedocromil sodium and the effects of
placebo on changes f r om baseline values for
each group and at each dose level are shown in the
figures.
Centres used
The full data set consisted of 196 trial centres. In
order to provide an adequate within-centre estimate
of the treatment effect, only those centres contributing at least nine patients per treatment group were
included.
Statistical analysis
Statistical comparisons were carried out using paired
t-tests between treatments considering each centre as
a unit. The 5% level of significance (two-tailed) has
been used throughout.
Presentation of results
Results are presented as the mean differences across
all centres between the effects of nedocromil sodium
and placebo on changes from baseline values. As well
as the mean difference between treatments, the 95%
confidence limits of the mean are presented. Differences in favour of nedocromil sodium are presented
as positive values.
Table 1. -
Data set used for analysis
Dose regimen 16 mg·day·1
Dose regimen 8 mg·day·1
No. of
Centres
Group
Group
Group
Group
Group
I
2
3
4
5
Total
Table 2. Variable
Nedocromil
sodium
(no. of patjents)
Placebo
(no. of patients)
No. of
Centres
Nedocromil
sodjum
(no. of patients)
Placebo
(no. of patients)
31
20
498
439
500
424
184
102
22
13
7
16
5
350
196
149
377
83
341
191
153
357
86
7
6
185
108
64
1230
1210
63
1155
1128
Baseline values
Scale/units
0-8
Day and night
asthma
Cough
0-4
Mean daily PEFR /·min· 1
I
FEVI
Bronchodilator use puffs·24 h·1
Data are presented as mean±so.
second.
Groups 1 and 2
Group 3
Group 4
Group 5
2.47±0.83
2.31±0.44
2.14±0.58
1.06±0.39
1.11±0.45
359±56
2.27±0.41
4.78±2.2
1.00±0.27
301±47
1.93±0.23
7.91±1.96
0.88±0.23
327±48
2.02±0.41
7..95±2.42
0.47±0.19
399±45
2.49±0.32
5.96±2.71
PEFR: peak expiratory flow rate; FEVI: forced expiratory volume in one
A.M. EDWARDS, M.T. STEVENS
38
Day and night asthma
Cough
Significant differences are shown (fig. l) for all
groups at both dose levels, apart from Group 4 at 8
mg·day·'. Combining the results of all trials at 8
mg·day·' and those at 16 mg·day·' shows both doses to
be significantly better than placebo (p<O.OOl).
The effects on cough (fig. 2) are significantly in
favour of nedocromil sodium in Groups l, 2 and 3 at
both dose levels but not in Group 4 and 5. Combining all trials according to dose shows significant effects overall at both dose levels (p<O.OO I).
1-*-1
16mg
1-*---1
16 mg
8mg
1-*-l
8 mg
Group 3
X
16 mg
)(
)(
)(
16 mg
/ Smg
Group 4-......._
16 mg
Bmg
Group4(
f---X--1
8 mg
H
16 mg
)(
8mg
1-*-1
/ 8mg
Group 5-......._
16 mg
Groups(
/
)(
16 mg
)(
16 mg
/
Bmg
All-......._
All......_
16 mg
-1
16 mg
1-X-l
0.5
0
0.5
1.5
-0.5
2
Fig. L - Day and night asthma. Difference between change
from baseline with nedocromil sodium and change from baseline
with placebo. Positive differences are in favo!Jr of nedocromil
sodium. X: mean difference; 1- - 1 : 95% confidence limits.
·0.25
0
0.5
0.75
Fig. 2. - Cough. Difference between change from baseline with
nedocromil sodium and change from baseline with placebo.
Positive differences are in favour of nedocromil sodium. X: mean
difference; 1----4 : 95% confidence limits.
16mg
-'-
8mg
X
X
8mg
Group 1(
16mg
I
X
I
8mg
Group 2(
X
16 mg
Group2(
16 mg
16 mg
Group 3
/ 8mg
Group 4-......._
16 mg
Group4(
X
I
16 mg
amg
/ Smg
Group 5-......._
16 mg
8mg
1--*--1
8mg
All-......._
All/
X
16mg
-20
I
16mg
/ Smg
Groups......._
16 mg
/
0.25
)(
8mg
Group 1(
Group 3
I
Group2(
Group2(
Group 3
)(
Group 1(
Group 1(
16 mg
I
8mg
Bmg
-10
0
10
........_16 mg
20
30
40
50
Fig. 3. - Mean peak expiratory flow rate. Difference between
change from baseline with nedocromil sodium and change from
baseline with placebo. Positive differences are in favour of
nedocromil sodium. X: mean difference; 1----4 : 95% confidence
limits.
1--*-i
-0.4
-0.2
0
0.2
0.4
Fig. 4. - FEV 1• Difference between change from baseline with
nedocromil sodium and change from baseline with placebo. Positive differences are in favou r of nedocromil sodium. X: mean
difference; 1 - -1: 95% confidence limits.
39
META-ANAL YSIS OF NEDOCROMlL SODlUM IN ASTHMA
Mean daily peak expiratory flow rate
8mg
X
16 mg
X
Group 1(
Significant effects in favour of nedocromil
sodium are shown (fig. 3) at both dose levels when
all centres are combined (p<O.OOl). Significant effects
are also shown for Groups 2 and 3, and Group 4 at
16 mg·day·•. The optimal effects are seen in Group
2 at 16 mg·day· •, with the mean difference of
nedocromil sodium over placebo being 22±19 l·min·•
(mean±so).
FEV1 (clinic)
The changes in FEV 1 measured at VISitS to the
clinic (fig. 4) are more variable, with significant differences in favour of nedocromil sodium overall, at
both dose levels in Group 1, and in Group 2 at 16
mg·day·•.
Inhaled bronchodilator use
16 mg
Group3
Smg
Group 1(
16 mg
8mg
Group 2(
16mg
)(
16 mg
)(
/ 8mg
Group4.......,_
16 mg
)(
X
/ 8mg
GroupS.......,_
16 mg
)(
)(
/ 8mg
All.......,_
16mg
-10
There was a mean reduction in the use of rescue
bronchodilators across all centres (fig. 5) which was
significantly in favour of nedocromi1 sodium
(p<O.OO 1). This was also the case in Groups 1, 2 and
3, but not Groups 4 and 5.
The mean reduction overall in the nedocromil sodium group was 1.02 puffs·day·• at 8 mg·day- 1 and 1.07
puffs·day·• at 16 mg·day·•.
Group 3
8mg
Group2(
0
10
20
30
40
50
60
Fig. 6. - Patient opinion. Difference between percentage of
patients treated with nedocromil sodium and those treated with
placebo reporting treatment to be very or moderately effective.
Positive differences are in favour of nedocromil sodium. X: mean
difference; f - 1 : 95% confidence limits.
Patients opinion
In fig. 6, the percentage of patients who reported
the test treatment as very effective, or moderately
effective, is presented as a mean figure together with
95% confidence limits. The figures for nedocromil
sodium are significantly in favour (p<O.OOI) and consistently higher than those for placebo. The largest
percentage of patients finding nedocromil sodium very
or moderately effective is in Group 2 at 16 mg·day·•,
the figure being 60±18%.
)(
16 mg
Discussion
8 mg
Group4(
16 mg
/
Groups-........
8mg
16 mg
/
8mg
All-........
16 mg
-2
0
2
4
Fig. 5. - Inhaled bronchodilator use (puffs·24 h·'). Difference
between change from baseline with nedocromil sodium and change
from baseline with placebo. Positive differences are in favour of
nedocromil sodium. X: mean difference; 1--1 : 95% confidence
limits.
Assessing the efficacy of a new asthma therapy is
not an easy task and conflicting results and conclusions have been reached in different trials with new
therapies. This review attempts to assess, in an easily
understood format, the results of a complete programme of work on an asthma drug (nedocromil
sodium) and reduce the risk of decisions being influenced by a small number of "positive" or "negative"
studies. To do this, all available data on nedocromil
sodium as compared to a placebo treatment have been
used. The only criteria specified were that the studies should be double-blind, placebo-controlled and
that each centre should have entered at least nine
patients per treatment group. One hundred and twenty
seven centres were included and each provided an
independent estimate of the treatment difference between nedocromil sodium and placebo.
40
A.M. EDWARDS, M.T. STEVENS
Examples of each of the five groups have been published as individual trials Group 1 [5-11): Group 2
[12-17]: Group 3 [18-22]: Group 4 [23-27] : Group 5
[28, 29].
Examination of baseline values shows that existing
treatment is an important factor in determining the
level of asthma control. The use of inhaled corticosteroids in the treatment regimen provided, in many
patients, better asthma control as compared to bronchodilator treatment alone. There was, however, a
group of patients (Group 4) who did not have optimal control of asthma using inhaled corticosteroids, as
compared to Group 5 and also to patients maintained
on bronchodilator treatment alone. The difference
between Groups 4 and 5 did not appear to be
dependent upon dose of inhaled corticosteroids. Group
5 are the nearest to normal values, with respect to
pulmonary function and symptom scores, and the addition of nedocromil sodium or placebo during the first
two weeks of the trial did not produce any further
improvement (data on file). The rapid withdrawal of
inhaled corticosteroids during test treatment in these
patients resulted in a worsening of asthma symptoms
and a reduction of pulmonary function, which suggests
that nedocromil sodium is unable to replace inhaled
corticosteroids in these circumstances. In a more recent single centre trial [30], in which the doses of inhaled corticosteroid were reduced in small amounts
over a 16 week treatment period, there was no loss
of asthma control and it was possible over this time
scale to reduce the dose of inhaled corticosteroid by
80% in the nedocromil sodium treated group and by
65% in the placebo treated group.
In Group 3 patients, the reduction of the dose of
inhaled corticosteroids by between 50-75% of pretrial
levels before the baseline induced a worsening of
symptoms and pulmonary function. Nedocromil sodium was able to improve values back to those of the
presteroid reduction phase within a four week period.
Placebo treatment did not result in a similar improvement and the difference between treatments was significant. This indicates that nedocromil sodium has
an inhaled corticosteroid sparing effect, an attribute
that has not been demonstrated with inhaled sodium
cromoglycate in adult patients [31].
In the final group of patients, whose treatment
included inhaled corticosteroids (Group 4) and whose
control of asthma was poor, nedocromil sodium provided improvement in asthma severity and pulmonary
function at a dose of 16 mg·day·•. Also, in this group,
a significantly higher proportion of patients considered
nedocromil sodium to be very or moderately effective
(45%, p<O.Ol). This demonstrates that the addition of
nedocrornil sodium does have a potentia11y useful place
in the management of these difficult patients.
It is in patients whose current treatment regimen
consisted of inhaled and oral bronchodilator therapy
alone that the addition of nedocromil sodium
showed a consistent and clinically useful effect in the
treatment of asthma. In Group l, in which current
bronchodilator therapy remained unaltered during the
addition of test treatment, the dose of 8 mg·day·•
produced statistically significant additional effects both
in symptoms and pulmonary function. At the higher
dose of 16 mg·day·• all of the improvements in asthma
severity were significant or highly significant, apart
from mean daily PEFR. At the higher dose, 56%
considered nedocromil sodium to be very or moderately effective.
In Group 2, in which oral bronchodilator therapy
was reduced in dose or withdrawn during the test
treatment period, a rather different result emerged. In
the circumstances of this trial design, the placebotreated patients showed a worsening of asthma symptoms and reduction in pulmonary function . In contrast,
the nedocromil sodium treated patients showed an
improvement, the size of which was generally much
greater at 16 mg·day·• than at 8 mg·day·•. Both dose
regimens, however, were significantly beuer than
placebo for the majority of variables, with 51% of
patients at 8 mg·day·• and 60% at 16 mg·day·• considering nedocromil sodium to be very or moderately
effective. This latter group of trials indicates that
nedocromil sodium can replace all or part of oral ~2 agonist or oral theophylline therapy with a significantly
and clinically useful improvement in asthma control.
One of the purposes of overview analysis or metaanalysis is to make the available data relevant to
treatment decisions (14]. In the management of
asthma, changes in treatment usually occur when existing treatment fails to produce satisfactory symptom
control. In this series of trials it is Groups 1 and 4
that satisfy this criteria: removing existing treatment
before the addition of a new treatment (Group 3) or
after (Groups 2 and 5) may be of value in demonstrating the efficacy of a new treatment but is not of
value to the physician seeking optimal management of
asthma. The baseline values of symptoms, pulmonary
function and use of inhaled bronchodilators in Groups
1 and 4 are very similar and show less adequate
symptom control and pulmonary function below
predicted normal. The addition of nedocromil sodium
to both groups does result in improvement in all
parameters but improvement is greater and achieves
more statistical significance compared to placebo in
Group 1, those patients taking bronchodilator treatment
alone. This suggests that the drug is likely to be of
most benefit in patients in this category and of less
benefit in patients already taking corticosteroids.
Overall, these results demonstrate a statistically significant treatment effect of nedocromil sodium as
compared to placebo, resulting in improved clinical
benefit in patients in a wide range of circumstances.
Although some individual studies have failed to detect
a statistically significant difference between treatment,
useful conclusions can be drawn from this overall
evaluation.
In summary, the data clearly demonstrate in all
response variables that nedocromil sodium has a significant and therapeutically useful effect in bronchial
asthma, particularly when used as a first line maintenance treatment in disease of mild to moderate
META-ANALYSIS OF NEDOCROMIL SODIUM lN ASTHMA
severity. The overview presented here demonstrated
the benefits and value of an overall statistical evaluation of a co-ordinated programme of work. We
consider that this is a sound, unbiased and essential
approach to decision making in drug development.
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