Articles
Roﬂumilast—an oral anti-inﬂammatory treatment for
chronic obstructive pulmonary disease: a randomised
controlled trial
Klaus F Rabe, Eric D Bateman, Denis O’Donnell, Stephan Witte, Dirk Bredenbröker, Thomas D Bethke
Summary
Background Chronic obstructive pulmonary disease (COPD) is characterised by progressive airﬂow limitation
associated with chronic inﬂammation. There are few treatment options for the disease. This study assessed the
efﬁcacy and safety of roﬂumilast, a phosphodiesterase-4 inhibitor, in patients with moderate to severe COPD.
Methods This phase III, multicentre, double-blind, randomised, placebo-controlled study was undertaken in an
outpatient setting. 1411 patients with COPD were randomly assigned roﬂumilast 250 g (n=576), roﬂumilast 500 g
(n=555), or placebo (n=280) given orally once daily for 24 weeks. Primary outcomes were postbronchodilator FEV1
and health-related quality of life. Secondary outcomes included other lung function parameters and COPD
exacerbations. Analyses were by intention to treat.
Findings 1157 (82%) patients completed the study; 32 (11%) withdrew from the placebo group, 100 (17%) from the
roﬂumilast 250 g group, and 124 (22%) from the roﬂumilast 500 g group. Postbronchodilator FEV1 at the end of
treatment signiﬁcantly improved with roﬂumilast 250 g (by 74 mL [SD 18]) and roﬂumilast 500 g (by 97 mL [18])
compared with placebo (p0·0001). Improvement in health-related quality of life was greater with roﬂumilast
250 g (–3·4 units [0·6]) and roﬂumilast 500 g (–3·5 units [0·6]) than with placebo (–1·8 units [0·8]), although the
differences between treatment groups were not signiﬁcant. The mean numbers of exacerbations per patient were
1·13 (2·37), 1·03 (2·33), and 0·75 (1·89) with placebo, roﬂumilast 250 g, and roﬂumilast 500 g, respectively.
Most adverse events were mild to moderate in intensity and resolved during the study.
Lancet 2005; 366: 563–71
Leiden University Medical
Centre, Leiden, Netherlands
(Prof K F Rabe MD); University
of Cape Town, Cape Town,
South Africa
(Prof E D Bateman MD);
Kingston General Hospital,
Kingston, Canada
(Prof D O’Donnell MD); and
ALTANA Pharma AG, Konstanz,
Germany (S Witte PhD,
D Bredenbröker MD,
TD Bethke MD)
Correspondence to:
Prof Klaus F Rabe, Leiden
University Medical Centre,
Department of Pulmonology
C3P, Albinusdreef 2, 2333 ZA,
Leiden, Netherlands
[email protected]
Interpretation Roﬂumilast is a promising candidate for anti-inﬂammatory COPD treatment because it improved lung
function and reduced exacerbations compared with placebo. Long-term studies are needed to fully assess the effect
on health-related quality of life.
Introduction
Chronic obstructive pulmonary disease (COPD) is a
leading cause of morbidity and mortality in adults
worldwide. A meta-analysis showed that the overall
prevalence is between 4% and 10%.1 COPD is the ﬁfth
leading cause of death worldwide, and its increasing
prevalence and limited treatment options suggest that it
will become the third leading cause of death by the
year 2020.2,3 As deﬁned by the Global Initiative for
Chronic Obstructive Lung Disease (GOLD) scientiﬁc
committee, COPD is a disease characterised by airﬂow
restriction that is not fully reversible. The airﬂow
limitation is usually progressive and associated with an
abnormal inﬂammatory response of the lungs to
noxious particles or gases.4 The disease is usually related
to cigarette smoking, but other causative factors, such as
exposure to air pollution, exist.5,6
Airﬂow obstruction in COPD arises as a result of
chronic inﬂammation and structural changes in small
airways and lung parenchyma.7 The inﬂammation is
characterised by increased numbers of neutrophils,
macrophages, and cytotoxic T cells, as well as by the
presence of multiple inﬂammatory mediators such as
cytokines, chemokines, and growth factors. The
recognition that chronic inﬂammation is a key
www.thelancet.com Vol 366 August 13, 2005
pathophysiological mechanism in COPD provided the
rationale for the use of inhaled corticosteroids as a
treatment option. However, corticosteroids have little
effect on inﬂammatory processes associated with COPD,
and even high doses of these drugs do not reduce the
progression of the disease.8 Bronchodilators, such as
2-agonists or anticholinergics, provide some
symptomatic relief, but there is a deﬁnite unmet medical
need to develop agents that speciﬁcally target chronic
inﬂammation associated with COPD.4
The search for an anti-inﬂammatory treatment for
COPD is now focusing on inhibitors of phosphodiesterase 4, the major hydrolase of cyclic adenosine
monophosphate (cAMP) in inﬂammatory cells.9
Inhibition
of
phosphodiesterase
4
increases
intracellular cAMP concentrations. The rise in
concentrations of cAMP can lead to activation of protein
kinase A, resulting in phosphorylation and inactivation
of target transcription factors, which ultimately result in
reduction of cellular inﬂammatory activity. Targeted
inhibition of phosphodiesterase 4 is thought to elicit
anti-inﬂammatory effects in patients with asthma or
COPD.9,10 Phosphodiesterase-4 inhibitors could
potentially provide better anti-inﬂammatory activity
than corticosteroids because corticosteroids do not
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Articles
suppress neutrophil activation or production of
cytokines and chemokines.8
Roﬂumilast is a targeted inhibitor of phosphodiesterase 4 and is given once daily via the oral route. The
anti-inﬂammatory potential of roﬂumilast has been
proven in vitro and in animal models and includes
inhibition of the synthesis of leukotriene B4 and reactive
oxygen species in neutrophils as well as inhibition of
TNF- release by mononuclear cells.11,12 Roﬂumilast also
inhibits T-cell proliferation, cytokine production, and
cell inﬁltration of the lungs.11,12 Preliminary clinical data
suggest that roﬂumilast could improve lung function in
patients with COPD while being well tolerated.13 We
undertook a large clinical phase III, randomised,
multicentre, multinational, double-blind, placebocontrolled study to assess whether once-daily roﬂumilast
(250 g or 500 g) given orally for 24 weeks has a
clinically meaningful effect on lung function and healthrelated quality of life when compared with placebo in
patients with moderate to severe COPD.
expiratory volume in 1 s) of 30–80% of predicted value;
postbronchodilator FEV1/FVC (forced vital capacity) ratio
70%; reversibility of FEV1 of 12% and/or 200 mL
after 400 g inhaled salbutamol; and stable clinical
disease status with no change in COPD treatment during
the 4 weeks before the run-in period (described later).
Patients were excluded from study enrolment if they
were diagnosed with asthma or other relevant lung
diseases (eg, lung cancer, bronchiectasis); if they were on
long-term oxygen treatment; or if they had a recent
exacerbation that required a course of systemic
corticosteroids, emergency room treatment, or hospital
admission (within 4 weeks before the run-in period).
Patients were also excluded from study enrolment if they
had a respiratory tract infection within 4 weeks before the
run-in period, known alpha-1-antitrypsin deﬁciency, or
regularly used more than eight puffs of rescue
medication per day. Study approval was obtained from
governing ethics committees for each study centre, and
all patients provided written informed consent.
Methods
Procedures
Patients
This parallel-group study was undertaken from April,
2002, to June, 2003 in 159 centres in Australia, Austria,
Belgium, Canada, France, Germany, Hungary, Ireland,
South Africa, Spain, and the UK. After a 4-week, singleblind run-in period, during which patients received
placebo and salbutamol as rescue medication, patients
were randomly assigned a study treatment if they had a
All patients were recruited from an outpatient setting.
Inclusion criteria for patients were: history of COPD
12 months, as deﬁned by GOLD guidelines;14 age
40 years or older; current smoker or ex-smoker (1 year
of smoking cessation) with a smoking history of
10 pack-years; postbronchodilator FEV1 (forced
1792 patients screened
379 not randomised
1413 randomised
280 assigned placebo
32 (11%) withdrew:
23 (72%) adverse events
3 (9%) other medical reasons
6 (19%) non-medical reasons
578 assigned
roflumilast 250 g
once daily
100 (17%) withdrew:
54 (54%) adverse events
8 (8%) other medical reasons
38 (38%) non-medical reasons
555 assigned
roflumilast 500 g
once daily
124 (22%) withdrew:
84 (68%) adverse events
11 (9%) other medical reasons
29 (23%) non-medical reasons
248 completed
478 completed
431 completed
257 assessed for FEV1*
267 assessed for QoL†
528 assessed for FEV1*
522 assessed for QoL†
501 assessed for FEV1*
496 assessed for QoL†
Figure 1: Trial proﬁle
Two patients randomised to roﬂumilast 250 mg did not take any study medication and were therefore excluded from the intention-to-treat analysis. QoL=healthrelated quality of life. *Remaining patients had no valid ﬁnal FEV1 measurement. †Two questionnaires were required for QoL assessment. Patients with an incomplete
or missing questionnaire at either baseline or at ﬁnal follow up were excluded from the ﬁnal analysis.
564
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Articles
postbronchodilator FEV1 between 30% and 80% of
predicted and if their medication compliance during this
period was 80% and 125% (as assessed by tablet
count). Treatment was assigned by the investigators with
sequential study numbers according to a block
randomisation list in ratios of 2: 2: 1 (roﬂumilast 500 g:
roﬂumilast 250 g: placebo). The randomisation
sequence was generated by ALTANA Pharma AG in a
blinded manner; no person involved in data analysis had
knowledge of the randomisation sequence. Treatment
was given once daily in the morning for 24 weeks.
Placebo tablets and packaging were identical to that of
roﬂumilast. Medication boxes were labelled with the
study protocol number, randomisation number, and visit
code; coding prevented the investigator and people at the
study centre from knowing which medication was given.
Concomitant respiratory medications allowed
throughout the study were salbutamol, as rescue
medication, and short-acting anticholinergics at a
constant daily dose. Patients could receive a course of
oral corticosteroids for treatment of exacerbations
during the active treatment phase. All other respiratory
medications (eg, inhaled corticosteroids) were
withdrawn 4 weeks before randomisation.
The primary outcome variables were postbronchodilator FEV1 and St. George’s respiratory questionnaire
(SGRQ) total score and were calculated as the change
from baseline to the endpoint (last observation carried
forward). Secondary outcome measures were change
from baseline in prebronchodilator FEV1, postbronchodilator FVC, postbronchodilator forced expiratory
volume in the ﬁrst 6 s (FEV6), postbronchodilator forced
expiratory ﬂow between 25% and 75% of the vital
capacity (FEF25–75), and number of COPD exacerbations.
We recorded adverse events as part of the safety
assessment using standard International Conference on
Harmonisation guidelines for Good Clinical Practice
(ICH-GCP).
Pulmonary function tests were done at the ﬁrst run-in
visit, at week 2 of run-in, at randomisation (ie, baseline),
and at weeks 4, 8, 12, 16, 20, and 24 of the treatment
period according to American Thoracic Society
recommendations.15 A centralised spirometer (Masterscope CT, VIASYS Healthcare GmbH, Hoechberg,
Germany) was used at each study site, and
measurements were undertaken both before and
30–45 min after inhalation of a 400 g dose of
salbutamol. Measurements were taken at the same time
of day within a 4-h window, based on the time of the
measurement at baseline visit. Patients were asked to
withhold salbutamol for at least 4 h and short-acting
anticholinergics for at least 6 h before each
measurement. For FEV1 and FVC, the highest value
from three technically acceptable attempts was chosen
for analysis. The ratio of FEV1 to FVC was calculated
from the highest value for FEV1 and FVC. FEV6 and
FEF25–75 values were taken from the best-test curve,
www.thelancet.com Vol 366 August 13, 2005
deﬁned as the value with the largest sum of FEV1 and
FVC.15 We calculated percent-of-predicted values
according to the recommendations for spirometry of the
European Respiratory Society.16 Throughout the study,
an independent expert at VIASYS assessed the quality of
blinded spirometry data, and only technically acceptable
ﬂow-volume loops were investigated.
We assessed health-related quality of life at week 2 of
run-in, at baseline, and at weeks 12 and 24 of the
treatment period using the validated SGRQ
questionnaire.17 The SGRQ is a disease-speciﬁc
instrument composed of 76 items that are weighted to
produce three subcomponent scores: symptoms,
activity, and impacts. The total score is calculated from
mathematical addition of these subcomponents and
provides a global assessment of a patient’s respiratory
health. The total score ranges from 0 to 100, with a score
of 100 indicating maximum disability. A difference of
–4 units versus a control (eg, placebo) is regarded as a
clinically relevant improvement in health-related quality
of life.
Exacerbations were classiﬁed according to severity
grades. Our deﬁnition of mild exacerbations was
modiﬁed from that of Szafranski and colleagues18 as an
increase in bronchodilator use on 2 or more consecutive
Characteristics
Median age, years (range)
Sex, n (%)
Male
Female
Race, n (%)
White
Height, cm (SD)
Weight, kg
Body-mass index
Smoking status
Current smokers, n (%)
Ex-smokers n (%)
Pack-years
Prebronchodilator FEV1, L
Postbronchodilator FEV1, L
Prebronchodilator FEV1, % predicted
Postbronchodilator FEV1, % predicted
Reversibility: change in FEV1, %
Postbronchodilator FVC, L
FEV1/FVC, %
Postbronchodilator FEV6, L
Postbronchodilator FEF25–75, L/s
Prestudy medication for COPD, n (%)
Inhaled short-acting 2 agonists
Inhaled short-acting anticholinergics
Xanthines
Inhaled corticosteroids
Inhaled long-acting 2 agonists
Concomitant short-acting anticholinergics, n (%)
Placebo n=280
63 (40–82)
Roﬂumilast
250 g n=576
500 g n=555
65 (40–86)
64 (42–87)
207 (74%)
73 (26%)
419 (73%)
157 (27%)
410 (74%)
145 (26%)
279 (100%)
169 (8·4)
76 (16·5)
26 (5·0)
573 (100%)
169 (8·5)
75 (15·7)
26 (4·7)
550 (99%)
168 (8·2)
75 (16·2)
26 (5·0)
125 (45%)
155 (55%)
43 (22·0)
1·45 (0·48)
1·57 (0·48)
51 (13·8)
55 (13·1)
9·6 (13·1)
3·17 (0·86)
50 (11)
2·86 (0·75)
0·62 (0·30)
267 (46%)
309 (54%)
43 (24·1)
1·40 (0·47)
1·52 (0·47)
50 (13·4)
54 (13·0)
9·6 (12·0)
3·08 (0·83)
50 (12)
2·77 (0·71)
0·60 (0·33)
254 (46%)
301 (54%)
41 (20·6)
1·41 (0·49)
1·50 (0·48)
51 (13·7)
54 (13·2)
9·1 (13·1)
3·08 (0·85)
50 (12)
2·76 (0·70)
0·59 (0·30)
142 (51%)
94 (34%)
72 (26%)
47 (17%)
37 (13%)
100 (36%)
301 (52%)
211 (37%)
157 (27%)
130 (23%)
76 (13%)
229 (40%)
267 (48%)
208 (38%)
143 (26%)
124 (22%)
92 (17%)
228 (41%)
Data are expressed as mean and SD, unless otherwise stated. FEV1=forced expiratory volume in 1 s; FVC=forced vital capacity;
FEV6=forced expiratory volume in 6 s; FEF25–75=forced expiratory ﬂow between 25% and 75% of the vital capacity; COPD=chronic
obstructive pulmonary disease.
Table 1: Demographics and baseline characteristics
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A
125
*
Mean change from basline
in postbronchodilator FEV1 mL
100
*
*
75
*
50
*
*
*
*
Roflumilast 500 g
Roflumilast 250 g
*
25
*
*
*
0
*
–25
Placebo
–50
–75
B
125
Mean change from basline
in prebronchodilator FEV1 mL
100
*
*
*
75
*
*
*
50
*
Roflumilast 500 g
*
25
*
*
0
*
*
Roflumilast 250 g
*
*
–25
Placebo
–50
–75
0
4
8
12
16
20
24
Figure 2: Change from baseline in postbronchodilator (A) and prebronchodilator (B) FEV1 over time
Data are least squares means ± standard errors. FEV1=forced expiratory volume in 1 s. *p0·05 versus baseline.
days (4 puffs of salbutamol per day, recorded in daily
diary cards, above the mean bronchodilator use recorded
during the week before randomisation) without
additional health-care contact. A moderate exacerbation
was deﬁned as home management with administration
of oral glucocorticosteroid treatment or unscheduled
health-care contact, or both. A severe exacerbation was
one that required hospital admission (or emergency
room treatment). Patients with a COPD exacerbation
that could be treated with 40 mg per day prednisolone
for 7–10 days could remain in the study unless the
investigator thought that continuing the study would be
a signiﬁcant health risk.
Statistical analysis
All efﬁcacy data were assessed in the intention-to-treat
population, deﬁned as the group of randomised patients
who received at least one dose of study medication and
566
who had at least one post-baseline efﬁcacy assessment
available. The primary comparison in the study was
to detect a signiﬁcant difference between roﬂumilast
500 g versus placebo for FEV1 and SGRQ.
If roﬂumilast 500 g was shown to be better than
placebo, roﬂumilast 250 g was compared with placebo
and roﬂumilast 500 g was compared with the 250 g
group. At a one-sided level of 0·025, a sample size of
400 patients in each roﬂumilast dose group and
200 patients in the placebo group was needed to
establish 90% power, based on a two-sample t test, to
provide a difference between group means of about
70 mL, assuming a SD of 250 mL in all treatment
groups. We undertook all statistical analyses using SAS
Windows NT version 8.2 (SAS Institute, Cary, NC,
USA). The within-treatment and between-treatment
differences for the primary and secondary lung function
variables as well as SGRQ were assessed with an
analysis of covariance (ANCOVA) with the factors and
covariates of treatment, sex, (pooled) centre, value at
randomisation, smoking status at study entry, and age
included in the model. In case of missing values the last
observation carried forward imputation technique was
applied. Based on the differences between the values
from endpoint (ie, to the last value analysis), we did
randomisation tests using pair-wise contrasts. Adjusted
means and 95% CI were given for treatment differences.
For within-group and between-group comparisons, the
two-sided tests were done at a level of =0·05
(corresponding to 0·025 one-sided). The number of
COPD exacerbations was analysed with the JonckheereTerpstra test for trend, and the number of patients with
COPD exacerbations was analysed with the CochraneArmitage test for trend. Descriptive statistics were used
for adverse events.
Role of the funding source
This study was supported by ALTANA Pharma AG,
Konstanz, Germany. The sponsor managed the data and
undertook all ﬁnal analyses. Authors had full access to all
data and were involved in data interpretation and
preparation of the manuscript in collaboration with the
sponsor. K F Rabe had ﬁnal responsibility for the
decision to submit for publication.
Results
Figure 1 shows the trial proﬁle. Two patients randomly
assigned roﬂumilast 250 g did not take any study
medication and were therefore excluded from the
intention-to-treat population. 1157 patients completed
the trial. Table 1 shows the baseline characteristics for the
three treatment groups.
Treatment with roﬂumilast 250 g and roﬂumilast
500 g increased postbronchodilator FEV1 from baseline,
whereas a decline was recorded with placebo (ﬁgure 2A).
Patients treated with placebo had a signiﬁcant decline in
FEV1 at week 24 compared with baseline (p=0·0041).
www.thelancet.com Vol 366 August 13, 2005
Articles
Improvement with roﬂumilast was noted within the ﬁrst
4 weeks; deterioration with placebo began at 8 weeks.
Roﬂumilast 250 g and 500 g signiﬁcantly increased
FEV1 from baseline at all visits during the 24-week
treatment period (p0·05 at each visit); this
improvement was also signiﬁcantly greater when
compared with placebo (p0·03) for both roﬂumilast
groups. At 24 weeks, the improvement in FEV1 from
baseline compared with placebo was 74 mL (SD 18) for
roﬂumilast 250 g and 97 mL (18) for roﬂumilast 500 g
(table 2). There were no differences between current
smokers and ex-smokers in the roﬂumilast treatment
groups (data not shown). A post-hoc subanalysis showed
that postbronchodilator FEV1 in patients with moderate
COPD (FEV1 50% of predicted) signiﬁcantly increased
in both roﬂumilast groups compared with placebo, with
differences of 87 mL (23) with 250 g (p=0·0001) and
103 mL (23) with 500 g (p0·0001). In patients with
severe COPD (FEV1 50% of predicted), postbronchodilator FEV1 signiﬁcantly increased with roﬂumilast
500 g compared with placebo, with a difference of
85 mL (28; p=0·0010). Roﬂumilast 250 g increased
A
Placebo
Roflumilast
250 g
Mean change in SGRQ score
from baseline
0
Roflumilast
500 g
–1
Placebo n=280
Roﬂumilast
250 g n=576
Prebronchodilator FEV1, L
Change from baseline
p value vs baseline
Change vs placebo
p value vs placebo
Postbronchodilator FEV1, L
Change from baseline
p value vs baseline
Change vs placebo
p value vs placebo
Postbronchodilator FVC, L
Change from baseline
p value vs baseline
Change vs placebo
p value vs placebo
Postbronchodilator FEV6, L
Change from baseline
p value vs baseline
Change vs placebo
p value vs placebo
Postbronchodilator FEF25–75, L/s
Change from baseline
p value vs baseline
Change vs placebo
p value vs placebo
500 g n=555
–0·039 (0·016)
0·0160
0·024 (0·012)
0·0454
0·064 (0·018)
0·0006
0·049 (0·012)
0·0001
0·088 (0·019)
0·0001
–0·045 (0·016)
0·0041
0·029 (0·012)
0·0134
0·074 (0·018)
0·0001
0·051 (0·012)
0·0001
0·097 (0·018)
0·0001
–0·075 (0·027)
0·0062
–0·004 (0·020)
0·8620
0·071 (0·031)
0·0193
0·039 (0·021)
0·0645
0·114 (0·031)
0·0002
–0·089 (0·022)
0·0001
0·007 (0·016)
0·6883
0·095 (0·024)
0·0001
0·047 (0·017)
0·0051
0·135 (0·025)
0·0001
–0·013 (0·014)
0·3550
0·019 (0·010)
0·0666
0·032 (0·016)
0·0435
0·026 (0·011)
0·0129
0·039 (0·016)
0·0139
Data are least squares means and SD. FEV1=forced expiratory volume in 1 s; FVC=forced vital capacity; FEV6=forced expiratory
volume in 6 s; FEF25–75=forced expiratory ﬂow between 25% and 75% of the vital capacity. *Data are presented as least squares
means and SD.
Table 2: Change in lung function parameters after treatment with roﬂumilast
–2
*
–3
–4
**
***
–5
B
Activity
Impacts
Symptoms
0
–1
Mean change in SGRQ subcomponent
scores from baseline
Parameter
–2
ns
ns
–3
–4
**
***
***
*
–5
–6
***
Placebo
Roflumilast 250 g
Roflumilast 500 g
–7
***
***
Figure 3: Change from baseline in St. George’s respiratory questionnaire total
score (A) and component scores (B) at week 24
Data are least squares means ± standard errors. *p0·05; **p0·01,
***p0·001 versus baseline; ns=not signiﬁcant.
www.thelancet.com Vol 366 August 13, 2005
postbronchodilator FEV1 by 52 mL (27) compared with
placebo (p=0·11).
Improvements from baseline in prebronchodilator
FEV1 were also noted with both doses of roﬂumilast,
whereas a decline was recorded with placebo (ﬁgure 2B).
At 24 weeks, roﬂumilast signiﬁcantly improved
prebronchodilator FEV1 versus placebo, with a difference
of 64 mL (18) with 250 g and 88 mL (19) with 500 g
(table 2). Improvements in FEV1 were maintained when
patients who withdrew from the study were excluded
from the analysis (data not shown). Additionally, a
dose–dependent association was recorded for both
prebronchodilator and postbronchodilator FEV1,
although the difference between the roﬂumilast doses
was not signiﬁcant.
For the other secondary lung function parameters a
similar pattern of results was recorded; postbronchodilator FVC, FEV6, and FEF25–75 improved in the
roﬂumilast treatment groups versus the placebo group
at the last visit (p0·05). Postbronchodilator FVC
signiﬁcantly increased in both roﬂumilast groups
compared with placebo, with differences of 71 mL (31)
with 250 g and 114 mL (31) with 500 g. Signiﬁcant
improvements from baseline with roﬂumilast 250 g
and 500 g compared with placebo were also noted for
postbronchodilator FEV6 and FEF25–75 (table 2).
Health-related quality of life assessed by SGRQ, a
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Placebo n=280
Total number of exacerbations
Total number of patients with exacerbations
Mean number of exacerbations per patient (SD)
Overall
Mild
Moderate
Severe
Number of patients with exacerbations
Mild
Moderate
Severe
Number of patients who received
concomitant oral corticosteroids
Roﬂumilast
250 g n=576
500 g n=555
317
97 (35%)
593
207 (36%)
418
157 (28%)
1·13 (2·37)
0·83 (2·25)
0·28 (0·64)
0·02 (0·13)
1·03 (2·33)
0·71 (2·13)
0·30 (0·66)
0·02 (0·14)
0·75 (1·89)
0·48 (1·74)
0·25 (0·62)
0·03 (0·19)
56 (20%)
58 (21%)
5 (2%)
115 (20%)
123 (21%)
12 (2%)
75 (14%)
99 (18%)
14 (3%)
51 (18%)
111 (19%)
97 (18%)
Table 3: Chronic obstructive pulmonary disease exacerbations
Placebo n=280
Patients experiencing 1 adverse event
COPD exacerbation*
Nasopharyngitis
Diarrhoea NOS
Upper respiratory tract infection
Nausea
174 (62%)
65 (23%)
19 (7%)
6 (2%)
14 (5%)
2 (1%)
Roﬂumilast
250 g n=576
500 g n=555
382 (66%)
135 (23%)
42 (7%)
28 (5%)
27 (5%)
16 (3%)
370 (67%)
113 (20%)
46 (8%)
50 (9%)
23 (4%)
27 (5%)
Data are number of patients (%). *Only moderate and severe exacerbations were reported as adverse events. COPD=chronic
obstructive pulmonary disease; NOS=not otherwise speciﬁed.
Table 4: Adverse events occurring in at least 5% of patients in any treatment group
coprimary variable, showed improvements (ie,
decreased score) with both placebo and roﬂumilast
treatment (ﬁgure 3A). The changes from baseline in
SGRQ total score were –3·4 units (SD 0·6; p0·0001)
for roﬂumilast 250 g, –3·5 units (0·6; p0·0001) for
roﬂumilast 500 g, and –1·8 units (0·8; p=0·0271) for
placebo. The improvement in SGRQ total score,
compared with placebo, was –1·7 units (0·8) with
roﬂumilast 500 g and –1·6 units (0·9) with
6
Patients with diarrhoea (%)
5
Placebo
Roflumilast 250 g
Roflumilast 500 g
4
3
2
1
0
Weeks 1
Weeks 2–4
Figure 4: Onset of diarrhoea
The percentage of patients with diarrhoea during each time period
568
Weeks 5–12
Weeks 13–24
roﬂumilast 250 g; however, these differences were not
statistically signiﬁcant (p=0·053 and p=0·077,
respectively). Scores in the subcomponents of activity,
impacts, and symptoms also improved with roﬂumilast
treatment compared with baseline (all p values 0·01),
with the symptoms scores showing the largest
improvement of –3·6 units (1·1) with placebo,
–6·0 units (0·9) with roﬂumilast 250 g, and
–4·6 units (0·9) with roﬂumilast 500 g (ﬁgure 3B).
Subcomponent scores did not differ between the
roﬂumilast groups compared with placebo.
The percentage of patients who had any exacerbation
was lower in the roﬂumilast 500 g group than in the
250 g or placebo groups during the 24 weeks of
treatment (p value for trend test=0·0114, one-sided;
table 3). Roﬂumilast treatment also reduced the overall
mean number of exacerbations per patient when
compared with placebo, which were 1·13, 1·03, and
0·75 in the placebo group, roﬂumilast 250 g group,
and roﬂumilast 500 g group, respectively (p=0·0029,
one-sided). Comparison of these mean exacerbation
rates showed that the rate of total exacerbations was
34% lower in the roﬂumilast 500 g group than in the
placebo group. This difference in the overall mean
exacerbation rate was primarily due to the difference in
mild exacerbations (p=0·004, one-sided), with a 42%
difference in the mean number of mild exacerbations
per patient observed with roﬂumilast 500 g compared
with placebo. The mean number of moderate and
severe exacerbations per patient was low and closely
similar between groups.
The most common adverse events reported by the
investigator during the study were moderate or severe
exacerbations of COPD and nasopharyngitis (table 4).
The frequency of headache was low and was much the
same across all treatment groups, with 4% of patients in
each treatment group reporting headache. Diarrhoea,
which occurred more often in the roﬂumilast treatment
groups, arose most commonly within the ﬁrst 4 weeks
of treatment and was generally mild to moderate in
intensity (ﬁgure 4). Adverse events regarded as likely to
be related to study medication by the investigator were
reported in 12 (4%) patients treated with placebo, 46
(8%) patients treated with roﬂumilast 250 g, and 92
(17%) patients treated with roﬂumilast 500 g.
Diarrhoea was the most common adverse event deemed
likely to be related to study medication, occurring in
none, 13 (2%), and 34 (6%) patients treated with
placebo, roﬂumilast 250 g, and roﬂumilast 500 g,
respectively. The next most common adverse event was
nausea, reported in none, six (1%), and 18 (3%) patients
treated with placebo, roﬂumilast 250 g, and
roﬂumilast 500 g, respectively. Headaches were
thought to be at least likely related to study medication
in one (1%), four (1%), and ten (2%) patients,
respectively. Vomiting was rare, occurring in only one
patient treated with roﬂumilast 250 g and one patient
www.thelancet.com Vol 366 August 13, 2005
Articles
treated with roﬂumilast 500 g. There were no apparent
clinically meaningful changes in vital signs,
electrocardiogram measurements, or clinical laboratory
parameters during treatment with roﬂumilast.
Most adverse events resolved during the course of the
study (90%). Discontinuations due to adverse events
were higher in the roﬂumilast 500 g group (15% of
patients) than in the roﬂumilast 250 g group (10%) or
in the placebo group (8%). COPD exacerbation was the
most common adverse event leading to withdrawal,
occurring in eight (3%), 25 (4%), and 18 (3%) patients in
the placebo, roﬂumilast 250 g, and roﬂumilast 500 g
treatment groups, respectively. Serious adverse events
were reported by 21 (8%), 41 (7%), and 53 (10%)
patients. The most frequent serious adverse event was
COPD exacerbation in each treatment group. The
percentage of patients who withdrew because of serious
adverse events was much the same between treatment
groups (4%, 5%, and 6% of patients in the placebo,
roﬂumilast 250 g, and roﬂumilast 500 g treatment
groups, respectively). There was no pattern or trend
relating the incidence or cause of serious adverse events
to roﬂumilast.
Discussion
Chronic inﬂammation is generally regarded as a central
mechanism in the pathogenesis of COPD.5 The
signiﬁcant morbidity and mortality associated with the
disease, combined with the lack of effective treatments,
warrant the development of drugs that target the
underlying chronic inﬂammation rather than solely the
clinical symptoms of COPD. Inhibition of phosphodiesterase 4 has been shown to inhibit the inﬂammatory
processes associated with COPD, and thus represents a
promising new treatment approach.
Roﬂumilast, at doses of 250 g or 500 g, given once
daily, was effective in patients with moderate to severe
COPD. The phosphodiesterase-4 inhibitor signiﬁcantly
improved postbronchodilator FEV1 throughout the
24-week treatment period, while a decline was recorded
with placebo. When assessed at each study visit,
roﬂumilast 500 g consistently provided an improvement versus placebo. At the end of the treatment period,
the 500 g dose improved FEV1 by 97 mL when
compared with placebo. These data are encouraging
given that in another study,19 treatment with inhaled
ﬂuticasone propionate 500 g twice daily in a similar
patient population (prebronchodilator FEV1 of about
45% of predicted versus about 51% in our study)
resulted in a 50 mL improvement in postbronchodilator
FEV1 over 6 months compared with placebo. Since FEV1
is thought to predict prognosis and overall mortality in
patients with COPD,20 the improvements in lung
function recorded in our study are encouraging.
Consistent with the results seen for postbronchodilator FEV1, prebronchodilator FEV1 and postbronchodilator FVC improved with roﬂumilast but deteriorated
www.thelancet.com Vol 366 August 13, 2005
with placebo. Roﬂumilast has been shown to have no
direct bronchodilating properties in animal models.11 In
patients with COPD, the phosphodiesterase-4 inhibitor
cilomilast has been shown to have no acute
bronchodilatory activity.21 Additionally, in a doubleblind, randomised, three-period study (n=15), FEV1
measured periodically for up to 6 h did not improve with
roﬂumilast 500 g or 1000 g compared with placebo.22
This information, together with the consistent
improvements in postbronchodilator lung function
parameters in patients with COPD, suggests that the
treatment effect of roﬂumilast is the result of the antiinﬂammatory activity of the drug11,12,23–25 and not due to
bronchodilation provided through airway smoothmuscle relaxation. However, we acknowledge that this
study was not designed to speciﬁcally assess the antiinﬂammatory activity of roﬂumilast.
We reduced observer bias for FEV1 by use of
independent and blinded review of all spirometric
measurements. Accidental bias is expected to be low
because of the size, global enrolment, and inclusion
criteria of the study. Furthermore, consistent with
EMEA recommendations,26 we stratiﬁed randomisation
according to smoking status. Therapeutic effectiveness
in COPD should be based not only on lung function
parameters but also on the overall assessment of the
patients’ well-being.5 Besides improving lung function,
roﬂumilast treatment improved health-related quality of
life, as assessed by the SGRQ total score. Roﬂumilast
250 g and 500 g improved SGRQ total score from
baseline by 3·4 units and 3·5 units, respectively, similar
to the improvements in health-related quality of life
reported in studies of the efﬁcacy of inhaled
corticosteroids in patients with COPD. Calverley and coworkers19 reported improvements of less than 3 units at
6 months in patients treated with inhaled corticosteroids. Additionally, improvements of 3–4 units were
reported in studies of the efﬁcacy of combination
treatment (eg, inhaled corticosteroids in combination
with a long-acting 2 agonist) in patients with
COPD.18,19,27 Previously reported COPD studies of
6 months’ duration showed short-term placebo-induced
improvements in quality of life, but these did not reach
clinical signiﬁcance.28,29 Over longer periods of follow-up,
progressive deterioration in health status in patients
treated with placebo is seen.30 Thus, long-term studies
(1 year or more) are needed to show the full beneﬁt of
roﬂumilast compared with placebo in improving healthrelated quality of life.
The mechanisms leading to COPD exacerbations are
unclear, but a further ampliﬁcation of the
inﬂammatory process could be implicated.8 This theory
implies that the ability of roﬂumilast to target the
underlying pulmonary inﬂammation could translate
into a reduction of COPD exacerbations. Indeed,
patients treated with roﬂumilast 500 g had a 34%
reduction in the mean number of total exacerbations
569
Articles
per patient, which was primarily driven by a reduction
in mild exacerbations. The inclusion criteria were
designed to target a study population with clinically
stable COPD (GOLD stages II and III). Patients,
therefore, might have a low incidence of moderate and
severe exacerbations and a drug effect could primarily
inﬂuence the occurrence of mild exacerbations. Not
unexpectedly, the reduction in exacerbations was
primarily due to a decrease in the number of mild
exacerbations per patient by 42% versus placebo.
Importantly, the occurrence of moderate and severe
exacerbations did not increase in the presence of
decreasing mild exacerbations. Another major feature
of most COPD exacerbations is an increase in
dyspnoea, which is often a consequence of worsening
of hyperinﬂation, characteristic of advanced COPD.31
Roﬂumilast-induced improvements in FEV1 as well as
in FVC and FEV6 might reduce the degree of
hyperinﬂation and, consequently, reduce dyspnoea and
exacerbations.32,33 Further studies that speciﬁcally
investigate the effect of roﬂumilast on small airway
calibre are warranted.
Historically,
archetypical
phosphodiesterase-4
inhibitors, such as rolipram, led to dose-limiting gastrointestinal adverse events that hindered clinical
development. Moreover, non-targeted, broad-spectrum
phosphodiesterase inhibitors, such as theophylline, are
associated with cardiac arrhythmias. No cardiac rhythm
disorders related to study medication were reported in
this study. Roﬂumilast might provide an acceptable
therapeutic ratio with a favourable side-effect proﬁle.
Roﬂumilast was well tolerated in this study.
Gastrointestinal side-effects occurred early during
treatment and were generally mild to moderate and selflimited. The incidence of gastrointestinal side-effects
was of a frequency that was similar to or lower than the
numbers reported for cilomilast.10 Furthermore, only 1%
of patients treated with roﬂumilast 250 g and 4% of
patients treated with roﬂumilast 500 g discontinued
treatment because of diarrhoea or nausea (data not
shown). Additionally, the percentage of patients
remaining in the study who experienced diarrhoea
decreased over time. Overall, the lack of cardiac effects
and the low incidence of drug-related adverse events
help to differentiate roﬂumilast from other phosphodiesterase-4 inhibitors.
In conclusion, roﬂumilast was effective in improving
lung function and reducing exacerbations in a
population of patients with moderate to severe COPD.
The phosphodiesterase-4 inhibitor class shows promise
as a new therapeutic strategy for patients with COPD.
Contributors
E D Bateman was principal investigator at the University of Cape Town
Lung Institute site, read and commented on the full study report, had
full access to all data, assisted with the preparation of abstracts and
presentations of data for investigators and academic meetings, and
contributed to the writing of each draft (including ﬁnal) of the
manuscript. D O’Donnell participated in the study, had full access to
570
all data, and contributed to the manuscript. S Witte was the sponsor’s
study manager, was responsible for study design and coordination of all
study-related activities, contributed to the evaluation and interpretation
of study data, and provided signiﬁcant input to the manuscript.
K F Rabe contributed sustantially to analysis of the data, assisted with
preparation of abstracts and presentation of data for investigators and
acedemic meetings, contributed to writing of the manuscript at all
stages, and had ﬁnal responsbibilty for the decision to submit for
publication. The sponsor’s responsible medical ofﬁcers for ALTANA
Pharma were D Bredenbröker and T Bethke, who contributed to the
preparation, conduct, analysis, and interpretation of the study for the
manuscript. All authors reviewed and approved the ﬁnal version.
RECORD Study investigators
Australia: Peter Frith, Peter Holmes, Mark Holmes, Christine Jenkins,
Christine McDonald, Matthew Peters, Abraham Rubinfeld,
Anne Marie Southcott, Philip Thompson. Austria: Harald Artner,
Richard Holzer, Wolfgang Pohl, Kurt Puganigg, Mahmud Sweilem,
Ingrid Thomüller, Norbert Vetter, Robert Voves, Michael Zeiner.
Belgium: Pierre Bartsch, Luc Croonenborghs, Roger Devogelaere,
Eduard Janssens, Jean-Benoît Martinot, Ingrid Monsieur,
Paul Ortmanns, Philippe Pinson, Daniel Rozen, Luc Siemons.
Canada: R Abboud, Martha Ainslie, Emad Amer, Meyer Balter,
Jean Bourbeau, Zoheir Bshouty, Kenneth Chapman, Brian Craig,
Anthony D’Urzo, Tharwat Fera, Stephen K Field, Michel Gagnon,
Roger Goldstein, Frederick Hargreave, Richard Hodder, Allan Kelly,
Pierre Larivée, Jacques Lenis, Robert Luton, François Maltais,
Irvin Mayers, Robert Mclvor, Jean-Pascal Ouellet, Bruno Paradis,
Michel Rouleau. France: Lucien Bernabeu, Jean-Marc Boivin,
Gur René Boyer, Pierre Dugue, Roger Escamilla, François Fortin,
Laurent Fouquert, Hervé Jullian, Henri Kafe, Dominique Lejay,
Edith Maetz, Jean-François Muir, Bernard Pigearias, Benoît Wallaert.
Germany: Rainer Bamberg, Ekkehard Beck, Karl-Heinz Franz,
Umberto Gehling, Thomas Ginko, Vera Grimm-Sachs, Ulf Harnest,
Peter Hofbauer, Axel Kroker, Ronitta Malek, Ingomar Naudts,
Klaus-Dieter Rost, Heiner Steffen, Hermann A. Trauth,
Wolf-Uwe Venske, Hans Henning Weber, Peter van Bodegom.
Hungary: Lászlò Hajdu, Gábor Juhász, Lászlò Kovács, Gyula Pánczél,
Magdolna Póczi, Zsuzsanna Szalai, Mihály Timár, Eua Valyon,
Ilona Vinkler, Maria Vigh. Ireland: Alan Martin Byrne, Derek Forde,
Michael A. O’Doherty, Eamonn Shanahan, Joseph Sweeney,
Niall Walsh. South Africa: Adél Aletta Gertruida De Klerk,
Leonard Gerhardus Herbst, Pierre Jordaan, James Rattray Joubert,
Michelle Vivienne Middle, Gideon Eduard Naudè,
Anna Maria (Annalène) Nei, Michael Plit, Gerhard Ras,
Susanna S Visser. Spain: Jose L. Alvarez-Sala, Juan Broquetas Doñate,
Jorge Castelao , Jose Castillo, Eusebi Chiner Vives, Jose Cifrian,
Jesus Fernandes Frances, Josep Luis Heredia, Pedro Martin Escribano,
Juan Ortiz-de-Saracho, Jose Maria Peñas Herrero, J Miguel Rodriguez,
Roberto Rodriguez Roisin, Rafael Vidal, Miguel Zabaleta.
United Kingdom: Malcolm B Addlestone, Lawrence Adler,
Dennis Martin Allin, Jonathan G Ayers, D J R Baird,
Mark David Blagden, Robert Brownlie, Michael J Callander,
William Duncan Carr, Paul Corrie, James Ronald Courtney,
Frederick Roger Cranﬁeld, Alun Michael George, Gerald John Gibson,
Stephen Hall, Peter Jeremy Horn, J Stephen Hutchison,
Chandra P Khatri, Teck Keong Khong, Alan John Knox, C Kyle,
Peter Francis Lane, John J Langan, Roderick Allan Lawson,
Graham David Ross Martin, Carol McKinnon, George Ian McLaren,
David Brendan Price, Narendra Savani, Rosemarie Webb,
Robert D Weir, J Zachariah.
Conﬂict of interest statement
K F Rabe has been consulting for, participated in advisory board
meetings, and received lecture fees from AstraZeneca, Boehringer,
Pﬁzer, Novartis, AltanaPharma, MSD, and GSK. The Department of
Pulmonology, and thereby K F Rabe as head of the department, has
received grants from AltanaPharma, Novartis, Bayer, AstraZeneca,
Pﬁzer, MSD, Exhale Therapeutics, and GSK in the years 2001 until 2004.
E D Bateman has served as principal investigator and national and
international coordinating investigator for clinical studies sponsored by
ALTANA Pharma and for other pharmaceutical companies for which his
www.thelancet.com Vol 366 August 13, 2005
Articles
institution has received payment. He has served or serves on advisory
boards for the following companies: AstraZeneca, Boehringer
Ingelheim, GlaxoSmithKline, Kyowa Hakko, Hoffmann-La Roche,
Aventis, and MSD. He has received honoraria for lectures delivered at
meetings organised by AstraZeneca, Boehringer Ingelheim,
GlaxoSmithKline, Kyowa Hakko, and MSD. D O’Donnell did not report
any conﬂict of interest. S Witte, D Bredenbröker, and T Bethke are
employees of ALTANA Pharma and own a limited amount of ALTANA
stock.
Acknowledgments
This study was supported ﬁnancially by ALTANA Pharma AG,
Konstanz, Germany.
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