Phosphodiesterase 4 inhibitors for chronic obstructive pulmonary disease

  • Review
  • Intervention

Authors


Abstract

Background

Chronic obstructive pulmonary disease (COPD) is associated with cough, sputum production or dyspnoea and a reduction in lung function, quality of life and life expectancy. Apart from smoking cessation, there are no other treatments that slow lung function decline. Roflumilast and cilomilast are oral phosphodiesterase 4 (PDE4) inhibitors proposed to reduce the airway inflammation and bronchoconstriction seen in COPD.

Objectives

To evaluate the efficacy and safety of oral PDE4 inhibitors in the management of stable COPD.

Search methods

We identified randomised controlled trials (RCTs) from the Cochrane Airways Group Specialised Register of trials (date of last search June 2013). We found other trials from web-based clinical trial registers.

Selection criteria

We included RCTs if they compared oral PDE4 inhibitors with placebo in people with COPD. We allowed co-administration of standard COPD therapy.

Data collection and analysis

One review author extracted data and a second review author checked the data, before entry into The Cochrane Collaboration software program (RevMan version 5.2). We reported pooled data as mean differences (MD), standardised mean differences (SMD) or odds ratios (OR).

Main results

Twenty-nine separate RCTs studying roflumilast (15 trials, 12,654 patients) or cilomilast (14 trials, 6457 patients) met the inclusion criteria, with a duration between six weeks and one year. These included people across international study centres with moderate to very severe COPD (GOLD grades II-IV), with a mean age of 64 years.

Treatment with a PDE4 inhibitor was associated with a significant improvement in forced expiratory volume in one second (FEV1) over the trial period compared with placebo (MD 45.60 mL; 95% confidence interval (CI) 39.45 to 51.75, 22 trials with 15,670 participants, moderate quality evidence due to moderate levels of heterogeneity and risk of reporting bias). There were small improvements in quality of life (St George's Respiratory Questionnaire MD -1.04; 95% CI -1.66 to -0.41, 10 trials with 7618 participants, moderate quality evidence due to moderate levels of heterogeneity and risk of reporting bias) and COPD-related symptoms, but no change in exercise tolerance. Treatment with a PDE4 inhibitor was associated with a reduced likelihood of COPD exacerbation (OR 0.77; 95% CI 0.71 to 0.83, high quality evidence). For every 100 people treated with PDE4 inhibitors, six more remained exacerbation-free during the study period compared with placebo (number needed to treat for an additional beneficial effect (NNTB) 20; 95% CI 16 to 27). More participants in the treatment groups experienced non-serious adverse events compared with controls, particularly gastrointestinal symptoms and headache. Roflumilast in particular was associated with weight loss during the trial period and an increase in insomnia and depressive mood symptoms. Participants treated with PDE4 inhibitors were also more likely to withdraw from the trials because of adverse effects; on average 24% in the treatment groups withdrew compared with 19% in the control groups.

Authors' conclusions

In people with COPD, PDE4 inhibitors offered benefit over placebo in improving lung function and reducing the likelihood of exacerbations; however, they had little impact on quality of life or symptoms. Gastrointestinal adverse effects and weight loss were common, and safety data submitted to the US Food and Drug Administration (FDA) have raised concerns over psychiatric adverse events with roflumilast. The optimum place of PDE4 inhibitors in COPD management therefore remains to be defined. Longer-term trials are needed to determine whether or not PDE4 inhibitors modify FEV1 decline, hospitalisation or mortality in COPD.

Plain language summary

In people with chronic obstructive pulmonary disease (COPD), what are the benefits and risks of phosphodiesterase 4 inhibitors?

Background of the review

Chronic obstructive pulmonary disease (COPD) is a progressive lung condition caused by damage from harmful chemicals that are breathed in. This condition is predominantly seen in people who smoke tobacco. Chemicals in cigarettes set up a cascade of inflammatory reactions, which on one hand damage the structures in the lung responsible for the exchange of oxygen into the bloodstream, but also increase mucus production in the airways. These two processes leads to intermittent symptoms of breathlessness and decreased capacity to perform day to day tasks. In addition, people with COPD are at greater risk of developing exacerbations ('flare ups') which become more frequent and severe over time. People vary in terms of how they are affected by COPD. This is in part related to the severity of the disease but also to differences in response to medicines, an individual's fitness and coexistent conditions. The only way to prevent further lung damage in most people is to stop smoking. General approaches such as exercise, nutrition and vaccinations against influenza and pneumococcal infections are important in maintaining health.

Medicines prescribed to manage COPD generally aim to improve symptoms, reduce exacerbations or both. In the early stages, bronchodilator medicines are helpful because these relax the small muscles in the airway allowing more air to move freely in and out of the lungs. Some long-acting agents may reduce exacerbations. Steroid-containing inhalers may be added specifically to target inflammation in the lungs and thus modestly reduce the number of exacerbations.

Phosphodiesterase 4 (PDE4) inhibitors are a relatively new class of medicines that have been marketed to improve COPD. They have both bronchodilator and anti-inflammatory effects. Moreover, the two currently available medicines, roflumilast and cilomilast, are taken as a tablet. Our review collated and analysed existing trials to define the benefits and risks of PDE4 inhibitors in COPD.

What did we look at?

We found 29 trials on 12,654 adults, completed up to June 2013. This consisted mainly of trials in people with moderate to severe disease who discontinued other regular COPD medications. However, there were three trials that allowed continuation of inhaled corticosteroids and two that continued long-acting bronchodilators. The trials ranged from 6 to 52 weeks duration and the average age of participants was 64 years. The trials were all sponsored by the manufacturers of PDE4 inhibitors.

What did we find out?

Compared with placebo, these medicines provide a small improvement in lung function measurements and reduce the likelihood of an exacerbation of COPD. Based on these results, we would expect that out of 100 people who took PDE4 inhibitors every day for a year, 24 would experience at least one exacerbation which is six fewer than others who did not receive these medicines.

However, people reported that these medicines only provided a small effect on levels of breathlessness and quality of life. On the other hand, around 5% to 10% of people in trials who received roflumilast or cilomilast reported side effects such as diarrhoea, nausea and vomiting. There was also a two- to three-fold increase in the risk of sleep or mood disturbance, although overall the total number of reported incidents was still small. There was no effect on rates of hospitalisation and deaths. Trial duration and COPD severity did not influence the size of the effects. Furthermore, there was a suggestion of an additive benefit on top of inhaled corticosteroids or bronchodilators, but the number of studies that reported this was small.

Quality of the evidence

The studies were generally well designed, as people did not know if they were receiving this new treatment or a placebo medicine. Overall we rated the evidence as being of moderate to high quality.

It is of concern that results seen in trials published in journals by pharmaceutical companies showed a greater benefit of these medicines than those which were unpublished. The psychiatric adverse effects data remain unpublished. Longer-term trials are necessary to get a more accurate estimate of the benefits and safety of these medicines over time, including whether they slow COPD disease progression.

Laički sažetak

Inhibitori fosfodiesteraze-4 za liječenje kronične opstruktivne plućne bolesti: prednosti i rizici

Dosadašnje spoznaje

Kronična opstruktivna plućna bolesti (KOPB) je progresivni poremećaj pluća uzrokovan štetnim kemikalijama koje se udišu. Poremećaj se uglavnom viđa u osoba koje puše duhan. Kemijski spojevi u cigaretama uzrokuju niz upalnih rekacija, koje s jedne strane mogu oštetiti tkivo pluća koje je odgovorno za izmjenu kisika s krvlju, a isto tako mogu povećati proizvodnju sluzi u dišnim putovima. Ta dva procesa uzrokuju povremene simptome nedostatka daha i smanjene mogućnosti izvođenja svakodnevnih aktivnosti. Osim toga, oboljeli od KOPB-a imaju veći rizik od razvoja egzacerbacija (pogoršanja), koje postaju sve češće i sve teže tijekom vremena. KOPB ne pogađa na jednak način sve pacijente. To se dijelom odnosi na težinu bolesti, ali isto tako i na odgovor na lijekove, tjelesnu kondiciju pojedinca i druge zdravstvene poremećaje koje osoba ima. Jedini način za sprječavanje daljnjeg oštećenja pluća je za većinu osoba prestanak pušenja. Opći pristupi kao što je tjelovježba, promjena prehrane i cijepljenje protiv gripe i pneumokoknih infekcija vrlo su važni za održavanje zdravlja.

Lijekovi koji se propisuju oboljelima od KOPB imaju cilj ublažiti simptome, smanjiti broj egzacerbacija, ili oboje. U ranim stadijima su korisni lijekovi bronhodilatatori jer opuštaju male mišiće u dišnim putovima, što dozvoljava veći protok zraka u pluća. Neki dugo-djelujući lijekovi mogu smanjti broj egzacerbacija. Inhalatori koji sadrže steroide mogu se dodati kako bi se ublažila upala u plućima i na taj način malo smanjio broj egzacerbacija.

Inhibitori fosfodiesteraze-4 (PDE4) inhibitori su relativno nova vrsta lijekova koji se reklamiraju za liječenje KOPB. Imaju bronhodilatacijsko i protu-upalno djelovanje. Dva trenutno dostupna lijeka iz te skupine, roflumilast i cilomilast, uzimaju se u obliku tableta. Ovaj Cochrane sustavni pregled prikupio je i analizirao sve postojeće kliničke pokuse koji su ispitali djelotvornost i sigurnost PDE4 inhibitora za liječenje KOPB.

Što je istraženo?

Pronađeno je 29 kliničkih pokusa u kojima je sudjelovalo ukupno 12.654 ispitanika, i koji su dovršeni do lipnja 2013. Uglavnom se radilo o studijama koje su uključile bolesnike s umjerenom ili ozbiljnom bolesti koji su za vrijeme trajanja istraživanja prestali uzimati druge redovne lijekove za KOPB. Međutim, tri studije su dopustile ispitanicima da i dalje uzimaju inhalacijske kortikosteroide, a dvije uzimanje dugodjelujućih bronhodilatatora. Istraživanja su trajala od 6 do 52 tjedna i prosječna dob ispitanika bila je 64 godine. Sve studije financirali su proizvođači PDE4 inhibitora.

Rezultati istraživanja

U usporedbi s placebom ti lijekovi omogućuju malo poboljšanje funkcije pluća i smanjuju vjerojatnost egzacerbacije KOPB-a. Temeljem tih rezultata, može se reći da se očekuje da od 100 osoba koje uzmu PDE4 inhibitore svaki dan tijekom jedne godine, 24 osobe bi doživjele najmanje jednu egzacerbaciju, što je 6 manje nego u drugih osoba koje nisu primile taj lijek.

Međutim, ispitanici su opisali da su ti lijekovi imali samo mali učinak na nedostatak daha i kvalitetu života. S druge strane, oko 5-10% ispitanika u studijama koji su primali roflumilast ili cilomilast opisali su nuspojave kao što su proljev, mučnina i povraćanje. Također je zabilježeno dvostruko do trostruko povećanje u riziku od poremećaja spavanja il raspoloženja, iako je ukupan broj opisanih incidenata bio i dalje malen. Nije bilo učinaka na broj primitaka u bolnicu (hospitalizacija) i smrti. Trajanje istraživanja i težina KOPB nisu utjecali na veličinu učinka. Nadalje, uočen je dodatni koristan učinak ako se lijek daje zajedno s inhalacijskim kortikosteroidima ili bronhodilatatorima, ali broj studija koji je to opisao bio je malen.

Kvaliteta dokaza

Studije su općenito bile dobro osmišljene i ispitanici nisu znali koju terapiju primaju - novi lijek ili placebo. Kvaliteta svih dokaza procijenjena je kao umjerena do visoka.

Svakako treba voditi računa da je poznato kako istraživanja koja u časopisima objavljuje farmaceutska industrija pokazuju veći učinak nego neobjavljene studije. Podatci o psihijatrijskim nuspojavama i dalje ostaju neobjavljeni. Nužna su dugoročna ispitivanja na ovu temu kako bismo dobili precizniju procjenu djelotvornosti i sigurnosti tih lijekova, uključujući pitanje da li usporavaju napredovanje KOPB.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Livia Puljak
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Summary of findings(Explanation)

Summary of findings for the main comparison. Phosphodiesterase 4 inhibitors compared to placebo for chronic obstructive pulmonary disease
  1. 1There was a greater proportion of participant withdrawals in the treatment (24%) compared with the control group (19%), but not sufficient to warrant downgrading the quality of evidence.
    2There was moderate heterogeneity between the studies (I2 = 30% to 50%).
    3There was a statistically significant difference between published and unpublished studies.
    4There were very few events, leading to wide confidence intervals.
    5There was high level of heterogeneity between study results (I2 > 50%).
    6Based on data from the combined COPD safety pool. Individual study data not obtained.

Phosphodiesterase 4 inhibitors compared to placebo for chronic obstructive pulmonary disease
Patient or population: patients with stable chronic obstructive pulmonary disease
Settings: community-based, randomised, parallel, double-blind, placebo-controlled trials
Intervention: phosphodiesterase 4 inhibitors
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)1
Comments
Assumed riskCorresponding risk
Placebo Phosphodiesterase IV inhibitors
Change in FEV1 lung function
(mL)
Follow-up: mean 17.5 weeks
The mean change in FEV1 lung function in the control groups was
a fall of 22.5 mL
The mean change in FEV1 lung function in the intervention groups was
45.6 mL better
(39.45 to 51.75 higher)
 15,670
(22 studies)
⊕⊕⊕⊝
moderate 2,3
 
Change in quality of life
St George's Respiratory Questionnaire
Follow-up: mean 27.8 weeks
The mean change in quality of life in the control groups was an improvement of
1.81 SGRQ units
The mean change in quality of life in the intervention groups was
1.04 units better
(1.66 to 0.41)
 7618
(10 studies)
⊕⊕⊕⊝
moderate 2,3
Lower scores on SGRQ represent improved quality of life
COPD exacerbations
No. of patients with exacerbations
Follow-up: 12 to 52 weeks
30 per 100 24 per 100
(23 to 26)
OR 0.77
(0.71 to 0.83)
15,035
(20 studies)
⊕⊕⊕⊕
high
 
Mortality (all-cause)
No. of participants
Follow-up: 6 to 52 weeks
1 per 100 1 per 100
(1 to 2)
OR 0.92
(0.69 to 1.22)
15,030
(20 studies)
⊕⊕⊕⊝
moderate 4
 
Adverse events
No. of participants experiencing any adverse event
Follow-up: 6 to 52 weeks
66 per 100 71 per 100
(70 to 73)
OR 1.27
(1.19 to 1.36)
16,048
(23 studies)
⊕⊕⊕⊝
moderate 5
This outcome includes participants who reported COPD exacerbations as an adverse event
Gastrointestinal side effects
No. of participants experiencing diarrhoea
Follow-up: 6 to 52 weeks
4 per 100 11 per 100
(10 to 13)
OR 3.07
(2.66 to 3.53)
15,241
(21 studies)
⊕⊕⊕⊕
high
Diarrhoea was the most commonly reported gastrointestinal side effect. Weight loss was more common, and may be a result of diarrhoea
Psychiatric adverse events (roflumilast)
No. of participants
Follow-up: 12 to 52 weeks
35 per 1000 71 per 1000
(60 to 83)
OR 2.13
(1.79 to 2.54)
11,168
(14 studies)
⊕⊕⊕⊝
moderate 6
Pooled data from FDA website, not individual trial reports
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; COPD: chronic obstructive pulmonary disease; FDA: Food and Drug Administration (US); FEV1: forced expiratory volume in one second; OR: odds ratio; SGRQ: St George's Respiratory Questionnaire
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of global morbidity and mortality, resulting in a growing social and economic burden (GOLD 2013). In 2002, it was estimated to be the fifth leading cause of death, responsible for approximately 4.8% of total deaths worldwide and it is projected to rise to fourth position by the year 2030 (Mathers 2005).

COPD is defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as a "common preventable and treatable disease, is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious particles or gases. Exacerbations and co-morbidities contribute to the overall severity in individual patients" (GOLD 2013). Diagnosis is based on a history of exposure to risk factors for this disease and symptoms of cough, sputum production or dyspnoea (shortness of breath). Spirometry is required for diagnosis, with airflow obstruction being confirmed by a post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ≤ 0.7 (Celli 2004). Life expectancy is reduced in people diagnosed with COPD and, although prognosis is variable, age and FEV1 are the strongest predictors of mortality.

The predominant risk factor for COPD is tobacco smoking, with other environmental pollutants also known to contribute. Cigarette smoke leads to the activation of macrophages and CD8 T lymphocytes that release inflammatory mediators and cytokines. The process also involves neutrophil attraction and cell apoptosis (Barnes 2000). To date, smoking cessation is the only intervention known to slow the decline in lung function associated with COPD (GOLD 2013).

Pharmacotherapy is commonly used to treat people with COPD, with effects on symptoms, quality of life, or frequency and severity of exacerbations (Celli 2004; GOLD 2013). Mainstays of treatment include short- and long-acting inhaled beta-2 agonists and anticholinergics, corticosteroids and methylxanthines. New approaches to treatment are needed, as no individual agent slows the decline in lung function or survival. In the TORCH study (Calverley 2007) a combination of salmeterol 50 μg and fluticasone 500 μg twice daily reduced the risk of death by 17% compared with placebo over the three-year trial period; however, this did not reach the pre-defined level of statistical significance for the study.

Description of the intervention

The intervention is an oral medicine which is a selective inhibitor of the isoenzyme phosphodiesterase 4 (PDE4). This isoenzyme has a role in airway inflammation and bronchoconstriction, both of which are pathological features of COPD (Boswell-Smith 2006).

How the intervention might work

Cyclic adenosine monophosphate (cAMP) is a secondary messenger that suppresses the activity of inflammatory cells and mediates the process of smooth muscle relaxation in the airways. Phosphodiesterases, in turn, hydrolyse and turn off the biological activity of cAMP (Boswell-Smith 2006). Therefore, inhibitors of phosphodiesterase action should theoretically provide improvements in the extent of airway narrowing and damage from inflammation.

Non-selective phosphodiesterase (PDE) inhibitors such as theophylline, a methylxanthine, have been used in the management of people with COPD for years. These are recommended by current international guidelines as part of adjunctive therapy to long-acting bronchodilators (GOLD 2013). Limitations to their use include a narrow therapeutic margin, and the frequency of adverse effects, which may occur even when the plasma level is within the therapeutic range (Boswell-Smith 2006). Common adverse effects associated with theophylline include headache, nausea, vomiting, diarrhoea, restlessness, nervousness, insomnia and gastrointestinal effects (Barnes 2003). Less common, but more serious, are the increased risks of cardiac arrhythmias and seizures (Barnes 2003). Some of the adverse effects associated with theophylline have been attributed to its non-selective PDE inhibition and concurrent adenosine receptor antagonism (Barnes 2005).

The isoenzyme PDE4 is the predominant isoenzyme involved with metabolising cAMP in immune and inflammatory immune cells, such as neutrophils, macrophages, T cells and endothelial cells in COPD, in airway smooth muscle and pulmonary nerves (Torphy 1998; Vignola 2004; Agusti 2005; Boswell-Smith 2006). Inhibition of PDE4 leads to elevation of cAMP in inflammatory and immunomodulatory cells, resulting in suppression of inflammatory cell function, relaxation of airways smooth muscle and modulation of pulmonary nerves (Torphy 1999; Essayan 2001; Boswell-Smith 2006). Thus, PDE4 is an attractive target for inhibition in COPD. Furthermore, the central nervous system (CNS) and cardiovascular adverse effects experienced in patients treated with the non-selective PDE inhibitor, theophylline, are a result of adenosine receptor antagonism. This feature is not present with PDE4 specific inhibitors (Vignola 2004).

Why it is important to do this review

The development of selective PDE4 inhibitors offers new hope for therapy offering both anti-inflammatory and bronchodilatory effects in COPD, with fewer of the adverse effects encountered with non-selective inhibitors. Additionally, PDE4 inhibitors may be easier to use because there is less pharmacokinetic variability and lower potential for drug interactions compared with theophylline (Barnes 2005). Several PDE4 inhibitors have been developed, with some progressing to phase III clinical trials. These include the second-generation PDE4 inhibitors roflumilast (Nycomed, formerly Altana) and cilomilast (GlaxoSmithKline). At the time of review publication, roflumilast was the only medication in this class approved for use in Europe, as an add-on bronchodilator in patients with severe COPD associated with chronic bronchitis and a history of frequent exacerbations.

This review focuses on the effect of PDE4 inhibitors in the management of people with stable COPD, using clinically important outcomes. Collating this evidence into a systematic review allows an assessment as to whether or not the theoretical benefits of PDE4 inhibitors translate into useful clinical effects, and may suggest the potential place of PDE4 inhibitors within the increasing pharmacopoeia of COPD treatments.

Objectives

To evaluate the efficacy and safety of oral PDE4 inhibitors in the management of stable COPD.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs) that compared orally administered PDE4 inhibitors with placebo. We included any chronic treatment trials, but excluded single-dose trials, as well as trials in acute exacerbations of COPD. We also excluded cross-over trials.

Types of participants

Adults (over 18 years of age) with COPD, as defined by the American Thoracic Society, European Respiratory Society or GOLD, with airflow obstruction evident by spirometry with post-bronchodilator FEV1/FVC ≤ 0.7 (GOLD 2013). We considered trials that included patients with both COPD and asthma only if data from patients with COPD could be extracted separately from the study report, or through correspondence with the authors. We excluded ex-vivo experiments and trials with patients requiring mechanical ventilation on presentation.

Types of interventions

We included trials if they compared outcomes for participants who received an orally administered PDE4 inhibitor with those of control participants who received placebo.

In this latest update of the review, although not mentioned in the initial protocol, we have excluded cross-over design studies as a way to minimise non-random sources of bias between studies.

Types of outcome measures

Primary outcomes
  • Changes in lung function from baseline including forced expiratory volume in one second (FEV1), forced vital capacity (FVC) or peak expiratory flow rate (PEF)

  • Quality of life (e.g. total score on St George's Respiratory Questionnaire (SGRQ))

Secondary outcomes
  • Incidence of COPD exacerbations

  • Symptoms (breathlessness on Borg and other scales and Shortness of Breath Questionnaire; composite measures (summary symptom score))

  • Exercise tolerance (six-minute walk test)

  • Adverse effects (number of participants experiencing one or more adverse event, e.g. gastrointestinal, central nervous system (CNS) and cardiovascular adverse events, change in weight, withdrawal rates)

  • Serious adverse events and mortality

Search methods for identification of studies

Electronic searches

We identified trials using the Cochrane Airways Group Specialised Register of trials, which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL, AMED and PsycINFO, and handsearching of respiratory journals and meeting abstracts (please see Appendix 1 for further details). There was no restriction on the basis of language. We searched all records in the Specialised Register coded as 'COPD' using the following terms:

"Phosphodiesterase 4*" OR "PDE4*" OR Rolipram OR Roflumilast OR Cilomilast OR Ariflo OR SB207499 OR Tetomilast or ORIC485 OR Oglemilast OR GRC-3886 OR QAK423 OR Arofylline OR AWD12-281.

We conducted the most recent search in June 2013. The original strategy for this review, which was more sensitive but less specific, is in Appendix 2.

Searching other resources

We reviewed the reference lists of all primary trials and review articles for additional references. We contacted investigators in this area and pharmaceutical companies manufacturing PDE4 inhibitors to ascertain if they could provide any potentially relevant trial data. We also searched the US Food and Drug Administration (FDA) website and US National Institutes of Health (NIH) clinical trials registry (last accessed 6 June 2013).

Data collection and analysis

Selection of studies

Two review authors (JC, PP) independently screened the search results to select citations to retrieve in full text. The same two review authors then screened the full-text articles to identify studies for inclusion.

Data extraction and management

One review author (JC) extracted data from the eligible studies and a second review author (BL) checked the data. We entered data into RevMan 5.2. In some cases, we had to estimate information regarding outcomes from graphs. Where standard errors (SE) were reported, we converted them to standard deviations (SD).

We extracted the following data.

  • Methods: trial design, duration of follow-up.

  • Participants: age, gender, smoking status, study setting, inclusion and exclusion criteria.

  • Intervention: drug name, dose, duration of treatment, control and/or standard therapy.

  • Outcome measures.

We categorised references according to the trial name (by drug name and number, or by author and year). We obtained data on additional outcomes from other references to the same trial, and more detailed descriptions of study populations from information submitted by the drug manufacturer to the FDA website.

Where there were data from more than one report of the same trial, we considered the data from the primary published reference with the most complete data on the primary outcome(s) to take priority. For primary outcomes, we used intention-to-treat analysis in preference to per-protocol analysis. On the other hand, the trial data on the company website for Cilomilast 076 provided more complete details of adverse events than Gamble 2003, and we used this preferentially.

Our initial plan had been to perform meta-analysis on the change from baseline in post-bronchodilator FEV1. Only pre-bronchodilator values were reported for the majority of cilomilast trials, with pre- and post-bronchodilator values available for most trials of roflumilast, with the exception of Roflumilast FK1 101, Roflumilast FK1 103 and Roflumilast IN-108 for which only post-bronchodilator measures were available.

In order to increase the number of trials in the meta-analysis, we decided to use the change in the pre-bronchodilator FEV1 for all trials, except for the three just mentioned where it was not available. Between them, these three trials contributed only 8% to the mean difference (MD), with the mean change seen from baseline in FEV1 similar to other trials.

Lung function is reported in millilitres (mL). Exercise tolerance is reported in metres (m).

The outcome 'total adverse events' included the participants in each group experiencing one or more adverse events, including an acute exacerbation of COPD. Similarly, serious adverse events included conditions requiring hospital level treatment and encompassed more serious COPD exacerbations.

Assessment of risk of bias in included studies

Trials were assessed using the 'Risk of bias' methods outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008) as low, unclear or high.

Measures of treatment effect

Where appropriate, we combined data from trials using RevMan 5.2. We expressed results for continuous variables using a fixed-effect MD, or standardised mean difference (SMD), with 95% confidence intervals (CI). We expressed results for pooled outcomes with dichotomous variables using a fixed-effect odds ratio (OR) with 95% CI. We considered a P value of less than 0.05 statistically significant. Rate ratios were combined on a natural logarithm scale and were weighted by the inverse of the variance of the log rate ratio.

Unit of analysis issues

The unit of analysis was the patient, with the exception of analysis of exacerbation rates

Dealing with missing data

We contacted the respective pharmaceutical companies for missing trial data. In particular, Nycomed and Forest Laboratories provided us with some study details and results extracted from published articles and abstracts that were not identified in our initial search.

Assessment of heterogeneity

We used the I² statistic to measure heterogeneity among the trials in each analysis. Where we identified substantial heterogeneity we planned to report it and explore possible causes by prespecified subgroup analysis

Assessment of reporting biases

We compared available published outcomes with prescribed methods and, where available, original study protocols.

Data synthesis

We presented the findings of our primary outcomes in a 'Summary of findings' table generated using GRADEpro software and based on the recommendations in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008).

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses a priori.

  • Severity of airflow obstruction at baseline (FEV1 % predicted GOLD Grade II 50% to 80%, Grade III 30% to 50%, Grade IV < 30%) (GOLD 2013).

  • Drug (e.g. roflumilast, cilomilast).

  • Dose (e.g. roflumilast 250 μg or 500 μg).

  • Duration of therapy (12 weeks or less; 24 to 26 weeks; 52 weeks).

  • Concomitant therapy (inhaled or oral corticosteroids, inhaled long-acting beta-2 agonists, or anticholinergics, or both).

Sensitivity analysis

We planned the following sensitivity analyses a priori.

  • Fixed-effect versus random-effects models for studies with unexplained heterogeneity.

  • Methodological quality.

We did not anticipate the large number of unpublished trials at the protocol stage. Consequently, we undertook a sensitivity analysis of the effect sizes of the primary outcomes seen in published and unpublished trials.

Results

Description of studies

Results of the search

See Figure 1 for study flow diagram.

Figure 1.

Study flow diagram.

From a search in October 2006, we identified 477 abstracts of potentially relevant trials, which was narrowed to 71 abstracts using a less sensitive search of the Airways Group Specialised Register. We searched again in December 2008 and located 79 abstracts, many of which had been identified in the original search. From these two searches, we sought the full text for 53 trials (Table 1). We conducted two searches in January and August 2010, during which we identified another 17 abstracts as being potentially eligible. This latest update of the review includes a further 20 abstracts identified from a search of the literature in June 2013. We decided whether or not to seek the full text based on a review of the abstract text, title and MeSH headings of all identified citations.

Table 1. Number of references for which we sought full text
Search date:No. of references for which we sought full text
December 200853
January 20105
August 201012
June 201320

Thus, we sought full papers for 90 abstracts; however, many of the abstracts referred to the same trials and some were published only in abstract format. Two review authors (JC and PP) assessed the full-text versions of the trials to determine whether or not they met the inclusion criteria. We resolved any differences by discussion. We then assessed trials that met the inclusion criteria for methodological quality.

In addition, we found 15 completed trials for roflumilast and one for cilomilast in patients with COPD in a search of the online clinical trials registry of the US National Institutes of Health (NIH). After attempting to correlate each unique NIH study number with trials already identified in the above searches of the Airways registry, there were seven studies of roflumilast on the NIH clinical trials registry that had not been published elsewhere in any form.

For cilomilast, we identified one trial(Compton 2001) from the literature search and obtained the full text. Further, we found a summary of the study design, along with a report of results, for 12 individual phase II or III trials on the GlaxoSmithKline (GSK) website.

We identified another two trials, both through the literature search and from the GSK website (Cilomilast 039; Cilomilast 076). Gamble 2003 is the primary published reference for the latter study.

Included studies

Twenty-nine separate RCTs studying roflumilast (15 trials with 12,654 patients) or cilomilast (14 trials with 6457 patients) met the inclusion criteria. Sixteen of these 29 studies have been published in full in a peer-reviewed journal.

Those for roflumilast included the following.

  • An early dose selection study comparing patients given roflumilast 250 μg and 500 μg (Roflumilast M2-107) for 24 weeks. Subsequent studies all used 500 µg of roflumilast in the intervention group and this is the dose that appears in the analyses except where otherwise stipulated.

  • The first published one-year study of PDE4 inhibitor treatment in COPD (Roflumilast M2-112). This was the only trial included in this review that allowed concomitant corticosteroid use during the treatment period. Since then, the results of a replicate study have been published (Roflumilast M2-111).

  • This was followed by two year-long studies (Roflumilast M2-124; Roflumilast M2-125) investigating the effect in a specific subgroup - severe to very severe COPD associated with chronic bronchitis in patients at risk of exacerbations.

  • We found two studies (Roflumilast M2-127; Roflumilast M2-128) that evaluated the add-on use of roflumilast with long-acting bronchodilator agents, the first with salmeterol and the second with tiotropium. Both studies ran for 24 weeks.

  • Roflumilast M2-118 was a 12-week study which focused on airway physiology during rest and exercise in patients with moderate to severe disease. In addition, Roflumilast M2-119 investigated pulmonary function and safety in a group of patients recruited in centres across the Asia-Pacific regions.

There were two trials reported only as conference posters: Roflumilast FK1 101 and Roflumilast FK1 103. The first compared roflumilast 500 µg, roflumilast 250 µg and placebo for 26 weeks; the second compared roflumilast 500 µg once daily for 24 weeks with roflumilast 500 µg once daily for 12 weeks, then placebo once daily for the following 12 weeks.

Unpublished results were identified for two further studies: Roflumilast IN-108 compared the safety and efficacy of roflumilast 250 μg and 500 μg in patients recruited from five centres across India; however, no inclusion criteria were stated, concomitant medications were poorly described and only 15 patients in the placebo group completed the protocol; Roflumilast JP-706 was a 24-week study sponsored by a different collaborator that, in addition to treatment effects, monitored pharmacokinetic levels of roflumilast and its metabolite roflumilast-N-oxide.

All of these were designed as randomised, double-blind, placebo-controlled studies and, apart from Roflumilast JP-706, are included in combined safety figures for roflumilast that have been made available through publications on the FDA website (www.accessdata.fda.gov). This also includes participants in two other 24-week studies (Roflumilast M2-110; Roflumilast M2-121) which have been completed recently, but not published at the time of this review update. The total number of participants including these two studies is roflumilast 500 µg: 5970, roflumilast 250 µg: 1002 and placebo: 5682.

For cilomilast, data were mainly from phase III clinical trials with one phase II/III trial. These included unpublished studies. All used a 15 mg dose twice daily except for Compton 2001.

The trials fell into four groups:

  • Other studies were Cilomilast 121 (phase II/III 24 weeks), Cilomilast 157 (52 weeks) and Cilomilast 103657 (24 weeks), which followed the pivotal efficacy studies and were smaller in sample size. Cilomilast 180 (18 weeks) had a primary lung function endpoint, functional residual capacity, and Cilomilast 181 (13 weeks) assessed the number of inflammatory cells in a bronchial biopsy.

Almost all studies used inclusion criteria of spirometry and a history of smoking. Only four of the 29 studies mandated a history of exacerbation in the previous year (Cilomilast 103657; Cilomilast 121; Roflumilast M2-124; Roflumilast M2-125).

Excluded studies

We excluded 24 studies with reasons which can be found in Characteristics of excluded studies.

Risk of bias in included studies

We considered that the methodological quality of the 29 published and unpublished trials was acceptable overall.

Allocation

In the roflumilast trials, there were adequate descriptions of allocation concealment and method of blinding in seven out of 15 trials. Information about allocation concealment and blinding was only provided for one of the 14 cilomilast trials, while further details for the remaining trials were unclear. The risk of bias for each parameter in the 29 studies is shown in Figure 2.

Figure 2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Blinding

All studies included in this review were double-blind randomised controlled trials.

Incomplete outcome data

The percentage of participant withdrawals varied among the 25 trials that reported this outcome. Withdrawals were significantly higher in the PDE4 inhibitor-treated groups compared with control groups. The mean withdrawal rate for roflumilast studies was 23% in the treatment group (range 3% to 37%) and 17% in the control group (range 3% to 27%). In the cilomilast studies a mean of 25% of the participants withdrew in the treatment group (range 13% to 34%) and 21% (range 9% to 40%) in the control group.

Since the participants who withdraw tend to have poorer outcome measures than those remaining, the higher withdrawal rates for the PDE4 inhibitor-treated groups may have inflated the apparent benefits of treatment.

Selective reporting

There were 16 published and 13 unpublished trials. We performed analyses of differences in treatment effect between published and unpublished treatment groups for primary outcomes and this is reported in the subgroup and sensitivity analysis below.

Effects of interventions

See: Summary of findings for the main comparison Phosphodiesterase 4 inhibitors compared to placebo for chronic obstructive pulmonary disease

Change in lung function from baseline

Based on the 22 trials that reported this outcome, there was a statistically significant improvement in FEV1 from baseline in the PDE4 inhibitor-treated participants compared with controls (MD 45.60 mL; 95% CI 39.45 to 51.75), over the study period (Analysis 1.1).

The effect on FEV1 was seen for roflumilast 500 µg (MD 52.58 mL; 95% CI 43.61 to 61.56), roflumilast 250 µg (MD 56.88 mL; 95% CI 24.38 to 89.38) and for cilomilast 15 mg twice daily (MD 38.15 mL; 95% CI 29.41 to 46.90). A moderate level of heterogeneity existed for this outcome (Chi² = 44, df = 24, P = 0.007; I² = 46%), which is only partially explained by investigating differences between roflumilast and cilomilast. This is discussed further in the sensitivity analysis below. Analysis of a dose effect was possible in three trials: Roflumilast FK1 101, Roflumilast M2-107 and Roflumilast IN-108. Roflumilast 500 μg was associated with a greater change in FEV1 than roflumilast 250 μg, but this was not statistically significant (MD 22.61; 95% CI -5.95 to 51.16).

With respect to PDE4 inhibitor use with concomitant therapies (Analysis 1.5), the largest increases in FEV1 were seen in the two trials where participants were taking regular long-acting bronchodilators: in one, salmeterol (Roflumilast M2-127) and in the other, tiotropium (Roflumilast M2-128) (overall MD 60.52 mL; 95% CI 40.57 to 80.46). The next largest improvements were seen in trials where all other medications apart from short-acting beta-2 agonists were stopped (MD 43.73 mL; 95% CI 36.56 to 50.90), with similar improvement seen in the three trials (Roflumilast M2-111+M2-112; Roflumilast M2-118) where both treatment and control groups continued on an inhaled corticosteroid (ICS) (MD 42.26 mL; 95% CI 25.46 to 59.05). However, based on the available data there were no statistically significant differences between treatment groups with and without concomitant use of long-acting beta-2 agonists (LABA) (P = 0.12), ICS (P = 0.87), nor PDE4 inhibitor treatment together with either LABA or ICS (P = 0.42).

Treatment with a PDE4 inhibitor was associated with a statistically greater change in FVC from baseline than placebo (MD 84.66 mL; 95% CI 68.33 to 100.99) with minimal heterogeneity among the 13 trials (Analysis 1.9). Change in PEF was measured in only five of the 29 trials, but was significantly higher with treatment than in controls (MD 6.54 L/min; 95% CI 3.95 to 9.13) (Analysis 1.10).

Quality of life

Note that with the SGRQ, a decrease in the total score represents an improvement in the quality of life. We noted a small but statistically significant decrease in total score on the SGRQ from baseline in participants treated with PDE4 inhibitors compared with those in the control groups (MD -1.04; 95% CI -1.66 to -0.41, P = 0.001; Analysis 1.11). There was heterogeneity in this observation (Chi² = 19.84, df = 10, P = 0.03, I² = 50%). Subgroup analysis showed COPD severity had no bearing on the size of the change in quality of life score (Analysis 1.12).

The greatest change was seen with 15 mg of cilomilast twice daily in the six-week Compton 2001 trial (MD -3.90; 95% CI -7.50 to -0.30), although this estimate had wide confidence intervals. In that trial, 5 mg and 10 mg doses of cilomilast were not different to placebo in terms of change in SGRQ from baseline. It was notable that in the two trials with a duration of one year that reported total SGRQ, there was no significant change in quality of life seen with treatment compared with control (MD 0.26; 95% CI -1.18 to 1.69). Outcome data for Roflumilast M2-111 were not included as data were provided in the form of a 'repeated measures analysis' and pooled data did not equal the sum of numbers in each of the individual studies.

Exacerbations

Use of PDE4 inhibitors was associated with a statistically significant reduction in the numbers of participants experiencing one or more COPD exacerbations. This is a relative reduction of more than 20% (OR 0.77; 95% CI 0.71 to 0.83; Analysis 1.15), from a representative risk of 30 per 100 on placebo to 24 per hundred on PDE4 inhibitors over 12 to 52 weeks (Summary of findings for the main comparison). There was little heterogeneity among trials (Chi² = 20, df = 19, P = 0.37, I² = 7%). Similar efficacy was seen for both roflumilast and cilomilast.

In terms of exacerbation rate and the number of exacerbations experienced on average per patient per year (Analysis 1.16), a small significant benefit with treatment was observed, representing a 13% reduction in the rate ratio (rate ratio 0.87; 95% CI 0.81 to 0.93, P < 0.0001).

Only one trial (Roflumilast M2-107) reported the mean number of exacerbations per patient for different doses of roflumilast. Overall, treatment with roflumilast was associated with significantly fewer exacerbations over a 24-week period than placebo (MD -0.25; 95% CI -0.48 to -0.02). This was statistically significant only for the 500 μg dose (Analysis 1.17). Furthermore, the 500 μg dose had a statistically significantly greater effect on exacerbations than the 250 μg dose when the exacerbation rate was compared directly in a single trial (Roflumilast M2-107; Analysis 1.18).

In the Roflumilast FK1 101 trial, it was reported that the probability of experiencing an exacerbation was reduced by 8% with 250 μg of roflumilast and 48% with 500 μg, although the absolute value was not reported, nor whether this was statistically significant.

Symptoms and exercise tolerance

Overall, the mean difference in change from baseline with PDE4 inhibitor treatment compared with controls on COPD-related symptoms was small, regardless of the scale used to measure it. The only statistically significant effect was seen in one trial of cilomilast, for breathlessness scored using a Borg scale (MD -0.19; 95% CI -0.33 to -0.05, P = 0.007; Analysis 1.21).

Exercise tolerance using the six-minute walk test was measured in four cilomilast trials. There was no significant difference in walk test distance between treatment and controls (MD 1.92 m; 95% CI -7.58 to 11.41; Analysis 1.24).

Adverse events

The likelihood of a participant experiencing an adverse event was higher with PDE4 inhibitor treatment than with placebo (OR 1.27; 95% CI 1.19 to 1.36; Analysis 1.25). This effect was seen for both roflumilast and cilomilast.

We noted a range of adverse effects that occurred more frequently in PDE4 inhibitor-treated participants. Diarrhoea was more common in PDE4 inhibitor-treated groups than in controls (OR 3.07; 95% CI 2.66 to 3.53; Analysis 1.27), as was nausea (OR 4.06; 95% CI 3.40 to 4.86; Analysis 1.28), headache (OR 1.67; 95% CI 1.42 to 1.96; Analysis 1.29), vomiting (OR 4.01; 95% CI 2.80 to 5.74; Analysis 1.30), dyspepsia (OR 3.13; 95% CI 2.30 to 4.27; Analysis 1.31) and abdominal pain (OR 1.97; 95% CI 1.55 to 2.49; Analysis 1.32). More than 10% of participants in the treatment group experienced gastrointestinal-related side effects, with the most frequently reported symptom being diarrhoea (number needed to treat for an additional harmful effect (NNTH): 14; 95% CI 12 to 17). Weight loss was more likely in the treatment groups in the four roflumilast trials (OR 3.94; 95% CI 3.11 to 5.00; Analysis 1.33), but has not been reported in the cilomilast trials. There were no significant differences in the incidence of either influenza-like symptoms (Analysis 1.34) or upper respiratory tract infections (Analysis 1.35) between treatment and control groups.

The lower dose of roflumilast (250 μg) was associated with fewer adverse effects than the 500 μg dose; however, this was based on only three trials and confidence intervals were wide (Analysis 1.26). In the trial of Compton 2001 that studied the effects of varying doses of cilomilast, adverse effects were seen in 52% of the placebo group, 48% of the cilomilast 5 mg group, 47% of the 10 mg group and 61% of the 15 mg group, with rates of serious adverse events similar across the groups.

An increase in withdrawals attributed to adverse effects was recorded for both roflumilast and cilomilast treatment groups (OR 1.84; 95% CI 1.66 to 2.03; Analysis 1.36). There was, however, no significant effect of treatment on non-fatal serious adverse events (OR 1.01; 95% CI 0.91 to 1.11; Analysis 1.37) or mortality (OR 0.92; 95% CI 0.69 to 1.22; Analysis 1.38), although mortality was a relatively rare event during the trials.

The number of psychiatric adverse events was recorded from pooled data from all parallel design, double-blind studies investigating roflumilast collated and presented to the FDA. This included data from the 15 fully published trials, but excluded Roflumilast JP-706 which was conducted by a different study collaborator. These results reported symptoms of depression separately from depressed mood, depressive symptoms or major depression. There was a higher risk in the roflumilast 500 μg treatment group, compared with placebo, of experiencing a psychiatric-related adverse event (OR 2.13; 95% CI 1.79 to 2.54; Analysis 1.39). This was reported in three people out of 100 in the placebo group, compared to seven (95% CI 6 to 8) out of 100 for the PDE4 inhibitor-treated group (NNTH 28; 95% CI 21 to 39). In particular, the numbers of participants experiencing insomnia or sleep disorders (OR 2.88; 95% CI 2.15 to 3.86; Analysis 1.40), symptoms of anxiety (OR 1.81; 95% CI 1.26 to 2.62; Analysis 1.41) or depression (OR 1.59; 95% CI 1.11 to 2.27; Analysis 1.42) were higher in the roflumilast group compared with the placebo. There was no statistically significant different in the rate of psychiatric adverse events in the roflumilast 250 μg treatment group compared with placebo as it was found that in each of the analyses, the 95% confidence intervals crossed the midline.

In the roflumilast COPD safety database (n = 12,054 patients), there were reports of three completed suicides and two suicide attempts in roflumilast-treated patients compared to none in patients treated with placebo.

In the same group of participants the rates of major adverse cardiovascular events (MACE) have been meta-analysed and reported in paper published by White 2013. This found that the risk of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke, when combined into a composite outcome (MACE), was reduced in the roflumilast group compared with placebo (hazard ratio 0.65; 95% CI 0.45 to 0.93; P = 0.019). On the other hand, hazard ratios for treatment effects for each of these types of event individually were statistically different. Cardiovascular events were higher in participants with baseline cardiovascular risk factors than in those without baseline cardiovascular risk (defined as the presence of hypertension, diabetes mellitus, hyperlipidaemia and/or a history of heart disease). In addition, it was found that the difference between treatment and placebo was only statistically significant in the group of patients without baseline risk factors. Event rates in a subgroup of trials that were one year in duration found no significant difference between treatment and placebo groups in the proportion of participants who reported a MACE, even when divided into those who did, or did not, experience a COPD exacerbation. Similarly, between patients with and without MACE events, the proportions of patients experiencing exacerbations were similar (43.2% and 42.1%, respectively).

Subgroup and sensitivity analyses

A moderate level of heterogeneity existed for the change in FEV1 outcome when all trials were pooled (Chi² = 44, df = 24, P = 0.007; I² = 46%). Using a random-effects model made no difference to the levels of statistical significance or degree of heterogeneity for the change in FEV1 (Analysis 1.7). There were too many 'Risk of bias' domains judged to be at 'unclear' risk of bias to do subgroup analysis according to study quality. Of note, some effect sizes were greater in the published trials; for example, the treatment effect on FEV1 was MD 53.92 mL (95% CI 45.50 to 62.34) in the 14 published trials, and MD 34.82 (95% CI 25.44 to 44.19) in the eight unpublished trials (Analysis 1.6), which was a statistically significant difference. This is illustrated in the funnel plot with more unpublished studies showing a smaller treatment effect (Figure 3). Similarly, there was a difference in the effect size of the total SGRQ score between published and unpublished trials (MD -1.93; 95% CI -3.02 to -0.83 versus MD -0.43; 95% CI -1.26 to 0.40) (Analysis 1.13). For both primary outcomes, the size of the treatment effect, i.e. the mean difference between PDE4 and placebo groups, was far greater in short studies of 6 to 12 weeks, compared with 24 and 52-week studies (Analysis 1.4; Analysis 1.14).

Figure 3.

Funnel plot of comparison: 1 PDE4 inhibitor versus placebo, outcome: 1.6 FEV1 (published versus unpublished).

By visual analysis of the forest plot and sequential elimination, the six-week Compton 2001 cilomilast trial was identified as a major contributor towards the heterogeneity of pooled FEV1 results. When it was removed, the overall I2 decreased from 46% to 17% and in the cilomilast subgroup from 62% to 0%. It is notable that this study had the shortest treatment duration of six weeks and showed the largest improvement in FEV1 lung function from baseline in the treatment group across all studies.

To see whether the size of the treatment effect varied with COPD severity, we conducted subgroup analyses of trials where the mean per cent predicted FEV1 at baseline was available (Analysis 1.2). The effects seen in both old GOLD grades I or II (FEV1 ≥ 50%) predicted and old GOLD grades III or IV (FEV1< 50%) were of similar magnitude, with both statistically significant.

Concomitant treatment with corticosteroids or long-acting beta agonists did not seem to affect the size of the beneficial effect of roflumilast on the number of people experiencing exacerbations in the study period (Analysis 1.19).

Discussion

Summary of main results

This systematic review evaluated randomised controlled trials (RCTs) that assessed the efficacy and safety of oral phosphodiesterase 4 (PDE4) inhibitors in people with chronic obstructive pulmonary disease (COPD). The first major finding, based on data from 29 trials, was that both roflumilast and cilomilast led to significantly greater improvements in lung function from baseline, as measured by forced expiratory volume in one second (FEV1), forced vital capacity (FVC) or peak expiratory flow rate (PEF), than placebo. Furthermore, the improvement in lung function was seen regardless of the severity of the disease. Significant improvement occurred even when treatment was given in addition to other standard COPD treatments such as beta-2 agonists, anticholinergics and inhaled corticosteroids (ICS).

The mean change in FEV1 was, however, below what is usually considered a minimum clinically important difference (100 mL, Donohue 2005), but comparable to those seen with other COPD treatments in recent large RCTs. For example, the mean improvement in FEV1 of 46 mL with treatment seen in moderate to severe COPD in this review is of similar magnitude to that seen with fluticasone (47 mL), salmeterol (42 mL), and fluticasone and salmeterol combined (92 mL) in the TORCH 2007 study in people with severe COPD.

A second major finding, based on data from 20 trials, was that participants were more likely to be exacerbation-free while being treated with PDE4 inhibitors compared with controls. Overall, participants were 23% less likely to have an exacerbation, translating to a number needed to treat(NNT) of around 20 (95% CI 16 to 27), for one person to be exacerbation-free in the study period. While the likelihood of an individual experiencing an exacerbation was lowered with PDE4 inhibitor treatment, the decrease in the overall rate of exacerbations was less marked, with a relative reduction of 13%.

Taken together, these two major findings suggest PDE4 inhibitors in patients with COPD are acting independently of other treatments, particularly bronchodilators. This is an encouraging finding that could be consistent with a broad anti-inflammatory effect (Fabbri 2009). On the other hand, short-duration studies showed more favourable results than the longer studies, but the reasons for this are unclear. Significant heterogeneity was noted among the trials, suggesting that unmeasured differences between the trials may be having an impact. Further studies are currently ongoing comparing the benefits of roflumilast with fixed-dose ICS + long-acting beta2-agonist (LABA) combinations (Calverley 2012; Ferguson 2012).

A third major finding of the review was that, despite significant improvements in lung function and a reduction in exacerbations in participants treated with PDE4 inhibitors, there was only a small improvement in quality of life as assessed by the St George's Respiratory Questionnaire (SGRQ) total score. Quality of life had been chosen as a primary outcome because of concerns as to whether or not the adverse effects of PDE4 inhibitors might outweigh any beneficial COPD-related effects. The average change in SGRQ total score was 1.04 units (over a duration of between six and 12 months), and was of similar magnitude among trials of participants with milder or more severe COPD. Although this improvement was statistically significant, a change of greater than four units is usually regarded as the minimum clinically important difference (Jones 2005). While symptom scores were marginally better in the treatment groups, there was no change seen in exercise tolerance, suggesting that improvements in respiratory symptoms may not necessarily translate into enhancement of physical functioning. There were, though, fewer trials assessable for these outcomes, raising the possibility of type 1 or type 2 errors.

This review found that adverse effects were greater in the roflumilast and cilomilast-treated participants than in those receiving placebo, particularly gastrointestinal-related effects such as diarrhoea, nausea, vomiting and dyspepsia. More recently, there has been greater awareness of the risk of psychiatric adverse events associated with roflumilast treatment, in particular the increased likelihood of experiencing sleep disturbances, anxiety and depressed mood. Participants in the treatment groups were also more likely to withdraw from the trials because of adverse effects; on average 24% in the treatment groups withdrew compared with 19% in the control groups. Nevertheless, there is only a slight excess in the total number of participants in the treatment groups experiencing any adverse effect, compared with controls (Analysis 1.25). As this analysis included symptoms as well as exacerbations, which were reduced in the treatment groups, this analysis will tend to under-estimate the excess of non COPD-related adverse effects occurring with PDE4 inhibitor treatment.

It was notable that treatment with roflumilast was associated with a significant chance of weight loss. Whether this was due to anorexia from gastrointestinal adverse effects, or another effect, is not yet clear. Also not clear is whether cilomilast has the same effect as it has not been studied. Weight loss may be a beneficial effect in patients who are obese. In contrast, low body mass in the later stages of COPD is associated with a worse prognosis and is notoriously difficult to reverse (GOLD 2013). This adverse effect warrants further investigation. Reassuringly, there was no increase in serious adverse effects or mortality, although trials were of relatively short duration, and analyses were underpowered to report on the latter outcome.

While a lower dose (250 μg) of roflumilast produced similar improvements in FEV1 and was associated with slightly fewer adverse effects than the larger dose (Analysis 1.8), this was associated with a smaller reduction in rate of exacerbations than the 500 μg dose, in the one trial that reported this (Analysis 1.18). Moreover, data on the lower dose were only available in a limited number of studies and it has not been studied as add-on therapy to other bronchodilators.

Overall completeness and applicability of evidence

We have reviewed all known published and unpublished trials, which we identified from standard Cochrane searches, as well as from the trial register for the NIH and from pharmaceutical websites.

We have not been able to verify the pooled endpoint data for psychiatric (treatment possibly harmful) and cardiovascular-related adverse events (treatment possibly beneficial) as they were obtained from reports on the US Food and Drug Administration (FDA) website and from White 2013, respectively.

To ensure our Cochrane systematic review accurately reflects all known outcomes of roflumilast therapy, we approached the manufacturer of roflumilast for study-level data on each of the cardiovascular outcomes (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) as well as the composite outcome (MACE). This would have allowed us to perform comparisons both within (i.e. between roflumilast and placebo groups) and among the studies. Unfortunately, our request for individual trial data was refused with the following reasons being cited:

  1. it is inappropriate from a statistical perspective to look into individual trials with too small a sample size for this kind of relatively rare endpoint;

  2. it was part of the retrospective analyses to evaluate the whole data set with a sufficiently broad database and not to go into subcuts per study that would comprise studies with numbers in each treatment arm that were too low for conclusive interpretation;

  3. in none of the studies was the blinded adjudication of the events implemented as a prospective analyses, which would have required a data release in terms of transparency in each individual study (which is the reason why it was not mentioned in the original publications of the individual trials).

In response to the statement by representatives of Takeda Pharmaceuticals Limited, we have urged that these issues be reconsidered for future studies and that study data be made more widely available. Finally, caution must be used when interpreting associations between COPD exacerbations and MACE, because although the treatment groups were matched at baseline, it cannot be assumed that these groups are equivalent when looking only at the group of participants who experienced exacerbations. These concerns could not be assessed in this review as further study data were not provided.

Quality of the evidence

For the key outcomes of changes in lung function and quality of life, there were greater beneficial effects of PDE4 inhibitors reported in the published studies than in the unpublished studies, raising concerns about publication bias. There was a moderate level of heterogeneity identified in both of the primary outcomes for this review which is not fully explained by subgroup or sensitivity analyses according to study duration or concomitant medication use. This suggests unknown factors that may impact on the effect size, and has led us to downgrade the quality of evidence and certainty of our findings (Summary of findings for the main comparison). In contrast, the blinded design of the studies comparing roflumilast or cilomilast with placebo protected against detection bias in our view. The quality of evidence for a reduction in exacerbation was therefore higher for this comparison. On balance, we believe the true beneficial effect of PDE4 inhibitors is likely to be no greater than we have reported, and probably less; equally the harms may have been understated (partly due to higher withdrawal rates in active treatment arms). On the other hand, as subgroup analyses for COPD severity are based on the mean predicted lung function for the study group and not individual participants, we cannot rule out that there is a benefit for individuals of a specific COPD phenotype.

Potential biases in the review process

Potential biases in the review process were minimised by double-checking of data extraction and input. The authors have no conflicts of interest to declare and have not been involved in prescribing these medicines as neither roflumilast nor cilomilast are available on the New Zealand pharmaceutical schedule.

Authors' conclusions

Implications for practice

Phosphodiesterase 4 inhibitors are oral medicines that may be taken in combination with other standard COPD treatments. Most evidence exists for roflumilast at a dose of 500 μg daily and cilomilast at 15 mg twice daily.

Phosphodiesterase 4 inhibitors join an increasing list of treatments for COPD that improve short-term lung function and reduce exacerbations, but have not been shown to increase life expectancy. Trials to date have been one year or less in duration. In contrast to long-acting bronchodilators, PDE4 inhibitors have minimal benefits on symptoms on a day-to-day basis, or quality of life, and are often associated with adverse effects, especially of the gastrointestinal system, and headaches. Roflumilast is associated with significant weight loss and more psychiatric symptoms than placebo treatment. Thus, their use may best be limited to add-on therapy in a subgroup of patients with persistent symptoms or exacerbations despite optimal COPD management. If they are not well-tolerated, consider discontinuation.

Implications for research

This review has highlighted several possible areas for further study:

  • longer-duration studies to look at the effect of PDE4 inhibitors on FEV1 decline and mortality;

  • subgroup analysis in patients with/without chronic bronchitis and with/without history of exacerbations;

  • effect of PDE4 inhibitors in patients with frequent exacerbations;

  • effect of PDE4 inhibitors on healthcare utilisation, including hospitalisation (incidence and bed days);

  • a direct comparison of PDE4 inhibitors and ICS, when used as add-on therapies to either tiotropium or long-acting beta-2 agonists, or both;

  • a direct comparison of either tiotropium or long-acting beta-2 agonists, or both, as add-on therapies to PDE4 inhibitors (+/- ICS);

  • effect of roflumilast on quality of life;

  • better characterisation of the weight loss seen with PDE4 inhibitors in COPD;

  • better description of the nature of the effect on the exacerbations that do occur;

  • use of PDE4 inhibitors in acute exacerbations;

  • cost-effectiveness of PDE4 inhibitors;

  • ascertaining exercise tolerance data for roflumilast;

  • determining if there is any benefit on cardiovascular outcomes with PDE4 inhibitors in COPD;

  • using the effects of PDE4 inhibitors to better understand the pathophysiology of COPD.

Acknowledgements

This review is dedicated to Professor Peter Black (deceased January 2010) who led the development of the protocol and the early part of the review. Peter made significant contributions through research, teaching and clinical practice to the furthering of evidence-based management of airways diseases.

We thank Claire Arandjus for her contribution to protocol development.

We thank Professor Milo Puhan for assistance in locating reports on the FDA website.

To Nycomed and Forest Laboratories for confirming some study details and results extracted from published articles and abstracts.

GlaxoSmithKline (GSK) for study summaries available via the GSK online clinical study register.

Data and analyses

Download statistical data

Comparison 1. PDE4 inhibitor versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 FEV1 (by drug)2215670Mean Difference (IV, Fixed, 95% CI)45.60 [39.45, 51.75]
1.1 Roflumilast 500 μg129315Mean Difference (IV, Fixed, 95% CI)52.58 [43.61, 61.56]
1.2 Roflumilast 250 μg31033Mean Difference (IV, Fixed, 95% CI)56.88 [24.38, 89.38]
1.3 Cilomilast 15 mg105322Mean Difference (IV, Fixed, 95% CI)38.15 [29.41, 46.90]
2 FEV1 (by mean COPD severity)1611744Mean Difference (IV, Fixed, 95% CI)49.18 [41.35, 57.01]
2.1 GOLD grade I + II (FEV1 ≥ 50% predicted)94647Mean Difference (IV, Fixed, 95% CI)51.79 [38.99, 64.59]
2.2 GOLD grade III + IV (FEV1 < 50% predicted)77097Mean Difference (IV, Fixed, 95% CI)47.62 [37.72, 57.52]
3 FEV1 (Roflumilast 500 μg by mean COPD severity)108827Mean Difference (IV, Fixed, 95% CI)53.08 [43.85, 62.32]
3.1 GOLD grade I + II (FEV1 ≥ 50% predicted)63187Mean Difference (IV, Fixed, 95% CI)69.86 [53.34, 86.38]
3.2 GOLD grade III + IV (FEV1 < 50% predicted)45640Mean Difference (IV, Fixed, 95% CI)45.46 [34.32, 56.60]
4 FEV1 (by study duration)2214870Mean Difference (IV, Fixed, 95% CI)45.19 [38.92, 51.45]
4.1 Duration ≤ 12 weeks61010Mean Difference (IV, Fixed, 95% CI)107.25 [75.44, 139.07]
4.2 Duration 24 to 26 weeks117419Mean Difference (IV, Fixed, 95% CI)42.03 [33.86, 50.20]
4.3 Duration 52 weeks56441Mean Difference (IV, Fixed, 95% CI)43.71 [33.46, 53.97]
5 FEV1 (additional medication)2214650Mean Difference (IV, Fixed, 95% CI)45.18 [38.92, 51.44]
5.1 Long-acting bronchodilator21645Mean Difference (IV, Fixed, 95% CI)60.52 [40.57, 80.46]
5.2 Corticosteroids32904Mean Difference (IV, Fixed, 95% CI)42.26 [25.46, 59.05]
5.3 PDE4i treatment only1710101Mean Difference (IV, Fixed, 95% CI)43.73 [36.56, 50.90]
6 FEV1 (published versus unpublished)2214870Mean Difference (IV, Fixed, 95% CI)45.39 [39.13, 51.66]
6.1 Published1410329Mean Difference (IV, Fixed, 95% CI)53.92 [45.50, 62.34]
6.2 Unpublished84541Mean Difference (IV, Fixed, 95% CI)34.82 [25.44, 44.19]
7 FEV1 (random-effects model)2214870Mean Difference (IV, Random, 95% CI)48.42 [38.22, 58.63]
8 FEV1 (roflumilast 500 μg versus 250 μg)31560Mean Difference (IV, Fixed, 95% CI)22.61 [-5.95, 51.16]
9 FVC1310861Mean Difference (IV, Fixed, 95% CI)84.66 [68.33, 100.99]
10 PEF54245Mean Difference (IV, Fixed, 95% CI)6.54 [3.95, 9.13]
10.1 Roflumilast 500 μg43685Mean Difference (IV, Fixed, 95% CI)5.46 [2.74, 8.17]
10.2 Roflumilast 250 μg1347Mean Difference (IV, Fixed, 95% CI)7.0 [-4.05, 18.05]
10.3 Cilomilast 15 mg1213Mean Difference (IV, Fixed, 95% CI)34.0 [20.14, 47.86]
11 SGRQ total score107618Mean Difference (IV, Fixed, 95% CI)-1.04 [-1.66, -0.41]
11.1 Roflumilast 500 μg22208Mean Difference (IV, Fixed, 95% CI)-0.69 [-2.07, 0.69]
11.2 Roflumilast 250 μg1716Mean Difference (IV, Fixed, 95% CI)-1.60 [-3.56, 0.36]
11.3 Cilomilast 15 mg84694Mean Difference (IV, Fixed, 95% CI)-1.06 [-1.81, -0.31]
12 SGRQ total score (by mean COPD severity)74824Mean Difference (IV, Fixed, 95% CI)-1.53 [-2.36, -0.70]
12.1 GOLD grade I and II32042Mean Difference (IV, Fixed, 95% CI)-1.62 [-2.80, -0.44]
12.2 GOLD grade III and IV42782Mean Difference (IV, Fixed, 95% CI)-1.44 [-2.61, -0.27]
13 SGRQ total score (by published versus unpublished)107042Mean Difference (IV, Fixed, 95% CI)-0.97 [-1.63, -0.31]
13.1 Published43052Mean Difference (IV, Fixed, 95% CI)-1.93 [-3.02, -0.83]
13.2 Unpublished63990Mean Difference (IV, Fixed, 95% CI)-0.43 [-1.26, 0.40]
14 SGRQ total score (by duration)107042Mean Difference (IV, Fixed, 95% CI)-0.97 [-1.63, -0.31]
14.1 Duration < 12 weeks1213Mean Difference (IV, Fixed, 95% CI)-3.90 [-7.50, -0.30]
14.2 Duration 24 to 26 weeks74600Mean Difference (IV, Fixed, 95% CI)-1.18 [-1.94, -0.42]
14.3 Duration 52 weeks22229Mean Difference (IV, Fixed, 95% CI)0.26 [-1.18, 1.69]
15 No. people with one or more exacerbations (by drug)2015035Odds Ratio (M-H, Fixed, 95% CI)0.77 [0.71, 0.83]
15.1 Roflumilast 500 μg109507Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.71, 0.87]
15.2 Cilomilast105528Odds Ratio (M-H, Fixed, 95% CI)0.76 [0.67, 0.85]
16 Exacerbation rate (inverse variance)7 Rate Ratio (Fixed, 95% CI)0.87 [0.81, 0.93]
16.1 Roflumilast6 Rate Ratio (Fixed, 95% CI)0.86 [0.80, 0.92]
16.2 Cilomilast1 Rate Ratio (Fixed, 95% CI)0.95 [0.78, 1.17]
17 Exacerbation rate11691Mean Difference (IV, Fixed, 95% CI)-0.25 [-0.48, -0.02]
17.1 Roflumilast 500 μg1835Mean Difference (IV, Fixed, 95% CI)-0.38 [-0.70, -0.06]
17.2 Roflumilast 250 μg1856Mean Difference (IV, Fixed, 95% CI)-0.10 [-0.44, 0.24]
18 Exacerbation rate (roflumilast 500 μg versus 250 μg)1 Mean Difference (IV, Fixed, 95% CI)Totals not selected
19 Number of people on roflumilast with one or more exacerbations (additional medication)109507Odds Ratio (M-H, Fixed, 95% CI)0.78 [0.71, 0.87]
19.1 Long-acting bronchodilators21676Odds Ratio (M-H, Fixed, 95% CI)0.69 [0.54, 0.88]
19.2 Corticosteroids12686Odds Ratio (M-H, Fixed, 95% CI)0.81 [0.70, 0.95]
19.3 Treatment only75145Odds Ratio (M-H, Fixed, 95% CI)0.79 [0.67, 0.93]
20 SGRQ symptom score21048Mean Difference (IV, Fixed, 95% CI)-1.53 [-4.11, 1.06]
20.1 Roflumilast1835Mean Difference (IV, Fixed, 95% CI)1.00 [-3.78, 1.78]
20.2 Cilomilast1213Mean Difference (IV, Fixed, 95% CI)-4.80 [-11.73, 2.13]
21 Borg Scale62860Mean Difference (IV, Fixed, 95% CI)-0.19 [-0.33, -0.05]
21.1 Cilomilast62860Mean Difference (IV, Fixed, 95% CI)-0.19 [-0.33, -0.05]
22 Summary symptom score31899Mean Difference (IV, Fixed, 95% CI)-0.06 [-0.25, 0.13]
22.1 Cilomilast31899Mean Difference (IV, Fixed, 95% CI)-0.06 [-0.25, 0.13]
23 Shortness of breath questionnaire21633Mean Difference (IV, Fixed, 95% CI)-1.09 [-2.47, 0.28]
24 6-minute walk test41948Mean Difference (IV, Fixed, 95% CI)1.92 [-7.58, 11.41]
24.1 Cilomilast41948Mean Difference (IV, Fixed, 95% CI)1.92 [-7.58, 11.41]
25 No. of patients experiencing an adverse effect2316048Odds Ratio (M-H, Fixed, 95% CI)1.27 [1.19, 1.36]
25.1 Roflumilast 500 μg99506Odds Ratio (M-H, Fixed, 95% CI)1.31 [1.20, 1.43]
25.2 Cilomilast 15 mg146542Odds Ratio (M-H, Fixed, 95% CI)1.21 [1.08, 1.36]
26 No of patients experiencing an adverse event (Roflumilast 500 μg versus 250 μg)41977Odds Ratio (M-H, Fixed, 95% CI)1.21 [1.01, 1.46]
27 Diarrhoea2115241Odds Ratio (M-H, Fixed, 95% CI)3.07 [2.66, 3.53]
27.1 Roflumilast78699Odds Ratio (M-H, Fixed, 95% CI)3.96 [3.20, 4.89]
27.2 Cilomilast146542Odds Ratio (M-H, Fixed, 95% CI)2.47 [2.05, 2.98]
28 Nausea2015687Odds Ratio (M-H, Fixed, 95% CI)4.06 [3.40, 4.86]
28.1 Roflumilast 500 μg68289Odds Ratio (M-H, Fixed, 95% CI)3.54 [2.63, 4.78]
28.2 Roflumilast 250 μg1856Odds Ratio (M-H, Fixed, 95% CI)3.97 [0.91, 17.39]
28.3 Cilomilast 15 mg146542Odds Ratio (M-H, Fixed, 95% CI)4.37 [3.49, 5.47]
29 Headache1914690Odds Ratio (M-H, Fixed, 95% CI)1.67 [1.42, 1.96]
29.1 Roflumilast 500 μg89040Odds Ratio (M-H, Fixed, 95% CI)2.48 [1.90, 3.25]
29.2 Roflumilast 250 μg1347Odds Ratio (M-H, Fixed, 95% CI)0.98 [0.24, 3.99]
29.3 Cilomilast 15 mg115303Odds Ratio (M-H, Fixed, 95% CI)1.32 [1.08, 1.62]
30 Vomiting115828Odds Ratio (M-H, Fixed, 95% CI)4.01 [2.80, 5.74]
30.1 Roflumilast1835Odds Ratio (M-H, Fixed, 95% CI)1.52 [0.06, 37.37]
30.2 Cilomilast104993Odds Ratio (M-H, Fixed, 95% CI)4.06 [2.83, 5.82]
31 Dyspepsia125621Odds Ratio (M-H, Fixed, 95% CI)3.13 [2.30, 4.27]
31.1 Cilomilast125621Odds Ratio (M-H, Fixed, 95% CI)3.13 [2.30, 4.27]
32 Abdominal pain115604Odds Ratio (M-H, Fixed, 95% CI)1.97 [1.55, 2.49]
32.1 Cilomilast115604Odds Ratio (M-H, Fixed, 95% CI)1.97 [1.55, 2.49]
33 Weight loss67864Odds Ratio (M-H, Fixed, 95% CI)3.94 [3.11, 5.00]
33.1 Roflumilast67864Odds Ratio (M-H, Fixed, 95% CI)3.94 [3.11, 5.00]
34 Influenza-like symptoms89108Odds Ratio (M-H, Fixed, 95% CI)1.10 [0.86, 1.41]
34.1 Roflumilast 500 μg67795Odds Ratio (M-H, Fixed, 95% CI)1.13 [0.87, 1.48]
34.2 Roflumilast 250 μg1347Odds Ratio (M-H, Fixed, 95% CI)1.98 [0.18, 22.00]
34.3 Cilomilast 15 mg2966Odds Ratio (M-H, Fixed, 95% CI)0.88 [0.44, 1.75]
35 Upper respiratory tract infection1814523Odds Ratio (M-H, Fixed, 95% CI)0.90 [0.79, 1.03]
35.1 Roflumilast 500 μg89040Odds Ratio (M-H, Fixed, 95% CI)0.89 [0.73, 1.09]
35.2 Roflumilast 250 μg21203Odds Ratio (M-H, Fixed, 95% CI)0.84 [0.54, 1.31]
35.3 Cilomilast 15 mg104280Odds Ratio (M-H, Fixed, 95% CI)0.92 [0.75, 1.13]
36 Withdrawals due to adverse events2416056Odds Ratio (M-H, Fixed, 95% CI)1.84 [1.66, 2.03]
36.1 Roflumilast 500 μg109511Odds Ratio (M-H, Fixed, 95% CI)1.80 [1.58, 2.04]
36.2 Cilomilast 15 mg146545Odds Ratio (M-H, Fixed, 95% CI)1.90 [1.61, 2.24]
37 Non-fatal serious adverse events2114375Odds Ratio (M-H, Fixed, 95% CI)1.01 [0.91, 1.11]
37.1 Roflumilast 500 μg77830Odds Ratio (M-H, Fixed, 95% CI)1.06 [0.94, 1.19]
37.2 Cilomilast 15 mg146545Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.72, 1.06]
38 Mortality2015030Odds Ratio (M-H, Fixed, 95% CI)0.92 [0.69, 1.22]
38.1 Roflumilast78698Odds Ratio (M-H, Fixed, 95% CI)0.96 [0.70, 1.32]
38.2 Cilomilast136332Odds Ratio (M-H, Fixed, 95% CI)0.70 [0.34, 1.45]
39 All psychiatric disorders (roflumilast)1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
39.1 Roflumilast 500 μg111168Odds Ratio (M-H, Fixed, 95% CI)2.13 [1.79, 2.54]
39.2 Roflumilast 250 μg16288Odds Ratio (M-H, Fixed, 95% CI)0.87 [0.56, 1.33]
40 Insomnia and sleep disorders (roflumilast)1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
40.1 Roflumilast 500 μg111168Odds Ratio (M-H, Fixed, 95% CI)2.88 [2.15, 3.86]
40.2 Roflumilast 250 μg16288Odds Ratio (M-H, Fixed, 95% CI)1.48 [0.81, 2.70]
41 Anxiety or anxiety disorder (roflumilast)1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
41.1 Roflumilast 500 μg111168Odds Ratio (M-H, Fixed, 95% CI)1.81 [1.26, 2.62]
41.2 Roflumilast 250 μg16288Odds Ratio (M-H, Fixed, 95% CI)0.94 [0.40, 2.21]
42 Depression (roflumilast)1 Odds Ratio (M-H, Fixed, 95% CI)Subtotals only
42.1 Roflumilast 500 μg111168Odds Ratio (M-H, Fixed, 95% CI)1.59 [1.11, 2.27]
42.2 Roflumilast 250 μg16288Odds Ratio (M-H, Fixed, 95% CI)0.56 [0.20, 1.56]
Analysis 1.1.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 1 FEV1 (by drug).

Analysis 1.2.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 2 FEV1 (by mean COPD severity).

Analysis 1.3.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 3 FEV1 (Roflumilast 500 μg by mean COPD severity).

Analysis 1.4.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 4 FEV1 (by study duration).

Analysis 1.5.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 5 FEV1 (additional medication).

Analysis 1.6.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 6 FEV1 (published versus unpublished).

Analysis 1.7.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 7 FEV1 (random-effects model).

Analysis 1.8.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 8 FEV1 (roflumilast 500 μg versus 250 μg).

Analysis 1.9.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 9 FVC.

Analysis 1.10.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 10 PEF.

Analysis 1.11.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 11 SGRQ total score.

Analysis 1.12.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 12 SGRQ total score (by mean COPD severity).

Analysis 1.13.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 13 SGRQ total score (by published versus unpublished).

Analysis 1.14.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 14 SGRQ total score (by duration).

Analysis 1.15.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 15 No. people with one or more exacerbations (by drug).

Analysis 1.16.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 16 Exacerbation rate (inverse variance).

Analysis 1.17.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 17 Exacerbation rate.

Analysis 1.18.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 18 Exacerbation rate (roflumilast 500 μg versus 250 μg).

Analysis 1.19.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 19 Number of people on roflumilast with one or more exacerbations (additional medication).

Analysis 1.20.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 20 SGRQ symptom score.

Analysis 1.21.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 21 Borg Scale.

Analysis 1.22.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 22 Summary symptom score.

Analysis 1.23.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 23 Shortness of breath questionnaire.

Analysis 1.24.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 24 6-minute walk test.

Analysis 1.25.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 25 No. of patients experiencing an adverse effect.

Analysis 1.26.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 26 No of patients experiencing an adverse event (Roflumilast 500 μg versus 250 μg).

Analysis 1.27.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 27 Diarrhoea.

Analysis 1.28.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 28 Nausea.

Analysis 1.29.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 29 Headache.

Analysis 1.30.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 30 Vomiting.

Analysis 1.31.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 31 Dyspepsia.

Analysis 1.32.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 32 Abdominal pain.

Analysis 1.33.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 33 Weight loss.

Analysis 1.34.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 34 Influenza-like symptoms.

Analysis 1.35.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 35 Upper respiratory tract infection.

Analysis 1.36.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 36 Withdrawals due to adverse events.

Analysis 1.37.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 37 Non-fatal serious adverse events.

Analysis 1.38.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 38 Mortality.

Analysis 1.39.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 39 All psychiatric disorders (roflumilast).

Analysis 1.40.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 40 Insomnia and sleep disorders (roflumilast).

Analysis 1.41.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 41 Anxiety or anxiety disorder (roflumilast).

Analysis 1.42.

Comparison 1 PDE4 inhibitor versus placebo, Outcome 42 Depression (roflumilast).

Appendices

Appendix 1. Sources and search methods for the Cochrane Airways Group Specialised Register (CAGR)

Electronic searches: core databases

Database Frequency of search
CENTRAL (T he Cochrane Library)Monthly
MEDLINE (Ovid)Weekly
EMBASE (Ovid)Weekly
PsycINFO (Ovid)Monthly
CINAHL (EBSCO)Monthly
AMED (EBSCO)Monthly

 

Handsearches: core respiratory conference abstracts

Conference Years searched
American Academy of Allergy, Asthma and Immunology (AAAAI)2001 onwards
American Thoracic Society (ATS)2001 onwards
Asia Pacific Society of Respirology (APSR)2004 onwards
British Thoracic Society Winter Meeting (BTS)2000 onwards
Chest Meeting2003 onwards
European Respiratory Society (ERS)1992, 1994, 2000 onwards
International Primary Care Respiratory Group Congress (IPCRG)2002 onwards
Thoracic Society of Australia and New Zealand (TSANZ)1999 onwards

 

MEDLINE search strategy used to identify trials for the CAGR

COPD  search

1. Lung Diseases, Obstructive/

2. exp Pulmonary Disease, Chronic Obstructive/

3. emphysema$.mp.

4. (chronic$ adj3 bronchiti$).mp.

5. (obstruct$ adj3 (pulmonary or lung$ or airway$ or airflow$ or bronch$ or respirat$)).mp.

6. COPD.mp.

7. COAD.mp.

8. COBD.mp.

9. AECB.mp.

10. or/1-9

Filter to identify RCTs

1. exp "clinical trial [publication type]"/

2. (randomised or randomised).ab,ti.

3. placebo.ab,ti.

4. dt.fs.

5. randomly.ab,ti.

6. trial.ab,ti.

7. groups.ab,ti.

8. or/1-7

9. Animals/

10. Humans/

11. 9 not (9 and 10)

12. 8 not 11

The MEDLINE strategy and RCT filter are adapted to identify trials in other electronic databases

Appendix 2. Airways Group Trials Register search strategy (sensitive search)

PDE* or phosphodiesterase* or isoenzyme* or theophylline or rolipram or pentoxifylline or papaverine or milrinone or etazolate or etazolate or dyphylline or dipyridamole or caffeine or amrinone or aminophylline or isobutylxanthine or cilomilast or ariflo or cilostazol or enoximone or milrinone or olprinone or roflumilast or sb207499 or zardaverine or cilostamide or enoximone or trequinsin or Telomilast or IC485 or Oglemilast or QAK423 or GRC-3886 or Arofylline or AWD12-281

What's new

Last assessed as up-to-date: 6 June 2013.

DateEventDescription
17 December 2013AmendedTypo in plain language summary title amended

History

Protocol first published: Issue 4, 2000
Review first published: Issue 5, 2011

DateEventDescription
4 November 2013AmendedRisk of bias for Cilomilast 076 added.
6 June 2013New citation required and conclusions have changed

We included seven new studies in this update and excluded one cross-over trial. FDA report on psychiatric adverse events and suicides included.

Text revised to take account of Cochrane reporting standards.

'Summary of findings' table added.

6 June 2013New search has been performedNew literature search run.

Contributions of authors

Jimmy Chong: study selection, data extraction, review write up, leading update of review.

Phillippa Poole: protocol initiation and development, study selection, data extraction, review write up, all stages of update.

Bonnie Leung: study selection, data extraction, review write up.

Declarations of interest

Nil.

Differences between protocol and review

We added the comparison between published and unpublished results when we discovered the large number of unpublished studies, but before we extracted the data from the studies and carried out the analysis.

We have excluded cross-over trials.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Cilomilast 039

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 102 centres in Canada, Mexico and the US

2) Participants: 647 (15 mg cilomilast: 431, placebo: 216)

3) Baseline characteristics: mean age: 65 years, 62% male, mean FEV1% predicted of 49.7%, mean smoking history of 59.9 pack-years for cilomilast and 56.1 pack-years for placebo) or current smokers (44% and 47%, respectively)

4) Inclusion criteria: FEV1/FVC ≤ 0.7, FEV1 30% to 70% with smoking history > 10 pack-years or current smokers.

5) Exclusion criteria: active tuberculosis, lung cancer and bronchiectasis

6) Total number of participant withdrawals: 137 (32%) and 52 (24%) from treatment and control groups, respectively

Interventions

Run-in: 4 weeks, single-blind. Placebo tablets to assess suitability

1) Cilomilast 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: "The only other permitted medications for the treatment of airways disease were stable doses of Ipratropium, via a metered-dose inhaler, and mucolytic agents."

  • Short-acting β2 agonist: "...the short-acting ß2-agonist Albuterol, which was administered via a metered- dose inhaler, was supplied for the relief of acute respiratory symptoms."

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: none

Outcomes

Primary outcomes: lung function; ΔFEV1, SGRQ averaged over 24 weeks

Secondary outcomes: incidence rate of COPD exacerbations, adverse events, FVC at the trough, 6-min walk test, post-exercise dyspnoea

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available
Randomised?Low risk"Eligible subjects were randomised in a 2:1 ratio to receive oral cilomilast, 15 mg bid, or placebo for 24 weeks."
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low risk"The primary reasons for the withdrawal of subjects from the study prior to randomisation were the failure to meet inclusion/exclusion criteria (15.4%) and the presence of adverse effects, including COPD exacerbations (8.5%). More subjects receiving cilomilast than placebo withdrew from the double-blind phase of study (31.8% (n = 137) versus 24.1% (n = 52)."
Baseline profile: anticholingeric useLow risk54% in cilomilast; 58% placebo used ipratropium
Baseline profile: β2 agonist useLow risk99% in cilomilast; 100% placebo used albuterol. 9% in cilomilast; 12% placebo used salmeterol
Baseline profile: corticosteroid useLow risk7% in cilomilast; 8% placebo used triamcinolone. 6% in cilomilast; 7% placebo used beclomethasone

Cilomilast 042

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 98 centres in Australia and New Zealand, Germany, Spain, South Africa and the UK

2) Participants: 700 (15 mg cilomilast: 474, placebo: 226)

3) Baseline characteristics: mean age: 64.6 years, 80% male, mean FEV1% predicted of 49% with 5.1% reversibility, DLCO was 71% predicted, also with higher rates of chronic bronchitis 80.1%. 45% active smokers

4) Inclusion criteria: aged 40 to 80 years, FEV1/FVC ≤ 0.7, FEV1 30% to 70% with smoking history > 10 pack-years

5) Exclusion criteria: active tuberculosis, lung cancer and bronchiectasis

6) Total number of participant withdrawals: 122 (26%) and 51 (23%) from treatment and control groups, respectively

Interventions

Run-in: 4 weeks, single-blind with placebo

1) Cilomilast 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: 2% in cilomilast; 3% placebo used salbutamol. 3% in cilomilast; 1% placebo used ipratropium

  • Short-acting β2 agonist: "Albuterol MDI was used as rescue medication"

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: none

Outcomes

Primary outcomes: lung function; ΔFEV1, SGRQ averaged over 24 weeks

Secondary outcomes: incidence rate of COPD exacerbations, summary symptom score, FVC at the trough, 6-min walk test, post-exercise dyspnoea

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available
Randomised?Low riskPatients were randomised in a 2:1 ratio to receive oral cilomilast, 15 mg twice daily, or placebo for 24 weeks
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 51 (23%) placebo, 122 (26%) cilomilast, primarily due to adverse events, of which most were not from COPD exacerbations
Baseline profile: anticholingeric useUnclear riskNo information available
Baseline profile: β2 agonist useUnclear riskNo information available
Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 076

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Analysis was done per-protocol population

Participants

1) Setting: not stated

2) Participants: 59 (15 mg cilomilast: 29, placebo: 30)

3) Baseline characteristics: mean age: 61 to 62 years, 81% male, 53% active smokers, mean 46 pack-years, 53% to 58% FEV1 predicted

4) Inclusion criteria: aged 40 to 80 years, fixed airflow obstruction, smoking history > 10 pack-years

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 4 (14%) and 2 (7%) from treatment and control groups, respectively

Interventions

Run-in: 4 weeks, single-blind with placebo

1) Cilomilast 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: "14 of 59 used ipratropium bromide at a constant dosage (eight in the placebo group, six in the cilomilast group)."

  • Short-acting β2 agonist: "All patients were given albuterol for use as required"

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: none

Used alongside short-acting ß2 agonists (available to all) and anticholingeric drugs (offered to 24%)

Outcomes

Primary outcomes: change in neutrophil percentage in induced sputum

Secondary outcomes: FEV1, numbers of subepithelial CD8+ cells, CD 68+ cells, epithelial and subepithelial neutrophils

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available
Randomised?Low riskRandomised to a ratio of 1:1
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low risk"One patient was lost to follow-up 3 days after randomisation and another withdrawn for non-compliance 32 days after randomisation. Four patients were withdrawn after adverse events."
Baseline profile: anticholingeric useUnclear riskNo information available
Baseline profile: β2 agonist useUnclear riskNo information available
Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 091

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 110 centres in Belgium, Finland, France, Italy, the Netherlands, Norway, Portugal, Spain and the UK

2) Participants: 711 (15 mg cilomilast: 469, placebo: 242)

3) Baseline characteristics: mean age: 64.6 years, 86% male, mean FEV1 % predicted of 53% with 5.0% reversibility. 38% active smokers

4) Inclusion criteria: FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years

5) Exclusion criteria: active tuberculosis, lung cancer and bronchiectasis

6) Total number of participant withdrawals: 121 (26%) and 63 (26%) from treatment and control groups, respectively

Interventions

Run-in: 4 weeks, single-blind with placebo

1) Cilomilast 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: 0.9% in cilomilast; 4% placebo used salbutamol. 1% in cilomilast; 3% placebo used ipratropium

  • Short-acting β2 agonist: "Albuterol MDI was used as rescue medication"

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: none

Outcomes

Primary outcomes: lung function; ΔFEV1, SGRQ averaged over 24 weeks

Secondary outcomes: incidence rate of COPD exacerbations, summary symptom score, FVC at the trough, 6-min walk test, post-exercise dyspnoea

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available
Randomised?Low risk"Eligible patients were randomised to receive either SB 207499 or matching placebo ina ratio of 2:1 for 24 weeks."
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 63 (26%) placebo, 121 (26%) cilomilast, primarily due to adverse events, of which most were not from COPD exacerbations
Baseline profile: anticholingeric useUnclear riskNo information available
Baseline profile: β2 agonist useUnclear riskNo information available
Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 103657

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 103 centres in the US

2) Participants: 613 (15 mg cilomilast: 296, placebo: 317)

3) Baseline characteristics: mean age: 63.2 years: placebo and 63.1 years; cilomilast. 47% male: placebo and 46% male: cilomilast. Mean FEV1 % predicted not available

4) Inclusion criteria: aged ≥ 40 years of age. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. ≤70%, post-albuterol reversibility ≤ 15% or ≤ 200 mL (or both), post-albuterol FEV1 ≤ 70% of predicted normal and at least 1 COPD exacerbation within the 12 months prior to screening

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 105 (35%) and 76 (24%) from treatment and control groups, respectively

Interventions

Run-in: not stated

1) Cilomilast 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: no information available

  • Short-acting β2 agonist: no information available

  • Corticosteroid: no information available

  • Long-acting β2 bronchodilator: no information available

Outcomes

Primary outcomes: Change from baseline to endpoint in trough pre-bronchodilator FEV1. Change in total score of SGRQ averaged over 24 weeks

Secondary outcomes: changes from baseline in clinic trough FVC, time to first level 2 or level 3 COPD exacerbation

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskRandomised. No other information given
Randomised?Low riskParticipants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 76 (24%) placebo, 105 (35%) cilomilast
Baseline profile: anticholingeric useUnclear riskNo information available
Baseline profile: β2 agonist useUnclear riskNo information available
Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 110

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Analysis was done per-protocol population

Participants

1) Setting: 10 centres in the US

2) Participants: 65 (15 mg cilomilast: 31, placebo: 34)

3) Baseline characteristics: mean age: 64.4 years: placebo and 66.1 years: cilomilast. 67% male: placebo and 84% male: cilomilast. Mean FEV1 % predicted not available

4) Inclusion criteria: aged 40 to 80 years. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. Post-salbutamol reversibility ≤ 15% or 200 mL and a post-salbutamol FEV1 at least 1.0 L and between 30% and 70% of predicted

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 1 (3%) and 1 (3%) from treatment and control groups, respectively

Interventions

Run-in: not stated

1) Cilomilast 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: no information available

  • Short-acting β2 agonist: no information available

  • Corticosteroid: no information available

  • Long-acting β2 bronchodilator: no information available

Outcomes

Primary outcomes: change from baseline at endpoint in neutrophils as a percentage of total cells in induced sputum

Secondary outcomes: FVC at the trough, sputum macrophages, eosinophils and lymphocytes as a percentage of total cells in induced sputum. Total cell counts in induced sputum

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available
Randomised?Low riskAll participants were randomised to receive either cilomilast 15 mg or matching placebo
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 1 (3%) placebo, 1 (3%) cilomilast
Baseline profile: anticholingeric useUnclear riskNo information available
Baseline profile: β2 agonist useUnclear riskNo information available
Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 111

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 32 centres in the US, Canada and Australia

2) Participants: 156 (15 mg cilomilast: 79, placebo: 77)

3) Baseline characteristics: mean age: 64.2 years: placebo and 65 years; cilomilast. 66% male: placebo and 65% male: cilomilast. Mean FEV1 % predicted not available

4) Inclusion criteria: aged 40 to 80. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. Post-salbutamol reversibility less than or equal to 15% or 200 mL and a post-salbutamol FEV1 at least 1.0 L and between 30% and 70% of predicted. Baseline RV (from plethysmography) ≥ 120% of predicted RV

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 15 (19%) and 14 (18%) from treatment and control groups, respectively

Interventions

Run-in: not stated

1) Cilomilast 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: no information available

  • Short-acting β2 agonist: no information available

  • Corticosteroid: no information available

  • Long-acting β2 bronchodilator: no information available

Outcomes

Primary outcomes: change from baseline to endpoint in volume of trapped gas (D)

Secondary outcomes: lung volume measurements, including SVC and RV, 6-min walk test and exertional dyspnoea

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available
Randomised?Low riskParticipants were randomised to receive either 15 mg of cilomilast or matching placebo
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 14 (18%) placebo, 15 (19%) cilomilast
Baseline profile: anticholingeric useUnclear riskNo information available
Baseline profile: β2 agonist useUnclear riskNo information available
Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 121

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 22 centres in China

2) Participants: 1018 (15 mg cilomilast: 678, placebo: 340)

3) Baseline characteristics: mean age:63.9 years: placebo and 64.6 years; cilomilast. 91% male: placebo and 93% male: cilomilast. Mean FEV1 % predicted not available

4) Inclusion criteria: aged 40 to 75 years. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. Documented history of COPD exacerbations each year for 3 years prior to screening. At least 1 exacerbation in the last year that required oral corticosteroids or antibiotics. Post-salbutamol reversibility less than or equal to 15% or 200 mL and a post-salbutamol FEV1 at least 1.0 L and between 25% and 70% of predicted. % predicted FRC of ≥ 120% from plethysmography

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 124 (18%) and 35 (10%) from treatment and control groups, respectively

Interventions

Run-in: not stated

1) Cilomilast 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: no information available

  • Short-acting β2 agonist: no information available

  • Corticosteroid: no information available

  • Long-acting β2 bronchodilator: no information available

Outcomes

Primary outcomes: change from baseline to endpoint in trough pre-bronchodilator FEV1

Secondary outcomes: time to first level 2 or level 3 COPD exacerbation. Level 2 is defined as acute worsening of COPD that requires additional treatment or hospital outpatient visit. Level 3 is hospital admission for treatment. Change from baseline to endpoint RV and FRC. Change from baseline total score of SGRQ

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available
Randomised?Low riskParticipants were randomised to a 2:1 ratio for cilomilast 15 mg to placebo
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 35 (10%) placebo, 124 (18%) cilomilast
Baseline profile: anticholingeric useUnclear riskNo information available
Baseline profile: β2 agonist useUnclear riskNo information available
Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 156

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 132 centres in US and Canada

2) Participants: 825 (15 mg cilomilast: 418, placebo: 407)

3) Baseline characteristics: mean age: 64.4 years: placebo and 64.5 years; cilomilast. 62% male: placebo and 56% male: cilomilast > 50% predicted FEV1 for both groups

4) Inclusion criteria: aged 40 to 80 years. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. Post-salbutamol reversibility less than or equal to 15% or 200 mL and a post-salbutamol FEV1 at least 1.0 L and between 30% and 70% of predicted

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 143 (34%) and 96 (24%) from treatment and control groups, respectively

Interventions

Run-in: not stated

1) Cilomilast 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: 8.1% in cilomilast; 8.6% placebo used salbutamol. 1.7% in cilomilast; 2% placebo used ipratropium bromide

  • Short-acting β2 agonist: "Albuterol MDI was used as rescue medication"

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: none

Outcomes

Primary outcomes: change from baseline to endpoint in trough pre-bronchodilator FEV1. Change in total score of SGRQ averaged over 24 weeks

Secondary outcomes: post-exercise breathlessness, clinic trough FVC, time to first level 2 or level 3 COPD exacerbation

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available
Randomised?Low riskParticipants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 96 (24%) placebo, 143 (34%) cilomilast
Baseline profile: anticholingeric useUnclear riskNo information available
Baseline profile: β2 agonist useUnclear riskNo information available
Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 157

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 52 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 137 centres from 18 countries

2) Participants: 907 (15 mg cilomilast: 455, placebo: 452)

3) Baseline characteristics: mean age: 63.3 years: placebo and 64.6 years; cilomilast. 73% male: placebo and 78% male: cilomilast. 42% current smokers

4) Inclusion criteria: aged 40 to 80 years. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. Poor reversibility of airway obstruction, defined by ≤ 10% of predicted normal or ≤ 200 mL (or both) increase in FEV1 after administration of salbutamol 400 µg via MDI at screening; post-salbutamol FEV1 of between 30% to 70% predicted normal at screening

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 167 (37%) and 121 (27%) from treatment and control groups, respectively

Interventions

Run-in: not stated

1) Cilomilast 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: no information available

  • Short-acting β2 agonist: no information available

  • Corticosteroid: no information available

  • Long-acting β2 bronchodilator: no information available

Outcomes

Primary outcomes: mean change from baseline in trough pre-bronchodilator FEV1 averaged over 52 weeks. Incidence rate of level 2 (moderate) and level 3 (severe) COPD exacerbations during the treatment period

Secondary outcomes: time to first level 2 or level 3 COPD exacerbation. Quality of life determined by SGRQ

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available
Randomised?Low riskParticipants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily
Method of randomisation described?Unclear riskA randomisation criteria was used. No other information available
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 121 (27%) placebo, 167 (37%) cilomilast
Baseline profile: anticholingeric useUnclear riskNo information available
Baseline profile: β2 agonist useUnclear riskNo information available
Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 168

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Intention-to-treat analysis: not stated

Participants

1) Setting: 42 centres in the US

2) Participants: 306 (15 mg cilomilast: 203, placebo: 103)

3) Baseline characteristics: mean age: 64.3 years: placebo and 65.0 years; cilomilast. 64% male: placebo and 70% male: cilomilast.

4) Inclusion criteria: pre-albuterol FEV1/FVC ≤ 0.7. Post-albuterol FEV1 between 30% and 70% of predicted

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 61 (30%) and 14 (14%) from treatment and control groups, respectively

Interventions

Run-in: not stated

1) Cilomilast 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: no information available

  • Short-acting β2 agonist: no information available

  • Corticosteroid: no information available

  • Long-acting β2 bronchodilator: no information available

Outcomes

Primary outcomes: no primary efficacy or safety analyses were defined. Descriptive statistics of change from baseline in minimum and maximum heart rate via 24-hour Holter monitoring reported

Secondary outcomes: no secondary efficacy or safety analyses were defined

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available
Randomised?Low riskPatients were randomised at 2:1 ratio of cilomilast to placebo
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 14 (14%) placebo, 61 (30%) cilomilast
Baseline profile: anticholingeric useUnclear riskNo other information available
Baseline profile: β2 agonist useUnclear riskNo other information available
Baseline profile: corticosteroid useUnclear riskNo other information available

Cilomilast 180

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 18 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 34 centres in the US, Canada and South America

2) Participants: 199 (15 mg cilomilast: 97, placebo: 102)

3) Baseline characteristics: mean age: 64.7 years: placebo and 63.7 years; cilomilast. 76% male: placebo and 69% male: cilomilast.

4) Inclusion criteria: age at least 40 years. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. Baseline FEV1 < 70% predicted normal. Moderate to severe chronic dyspnoea defined by baseline Dyspnoea Index focal score 7 or less, evidence of hyperinflation defined by RFRC at least 140% of predicted. Exercise limitation, defined as peak symptom limited VO2 < 75%

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 24 (25%) and 13 (13%) from treatment and control groups, respectively

Interventions

Run-in: not stated

1) Cilomilast 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: no information available

  • Short-acting β2 agonist: no information available

  • Corticosteroid: no information available

  • Long-acting β2 bronchodilator: no information available

Outcomes

Primary outcomes: change from baseline at endpoint in RFRC

Secondary outcomes: change from baseline at endpoint in IC during exercise, exertional dyspnoea as measured by the modified Borg scale

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available
Randomised?Low riskParticipants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 13 (13%) placebo, 24 (25%) cilomilast
Baseline profile: anticholingeric useUnclear riskNo information available
Baseline profile: β2 agonist useUnclear riskNo information available
Baseline profile: corticosteroid useUnclear riskNo information available

Cilomilast 181

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 13 weeks

Analysis was done per-protocol population

Participants

1) Setting: 27 centres in Australia, Canada, Finland, Ireland, Lithuania, Norway, Romania, Slovakia, Slovenia, South Africa, Sweden and the UK

2) Participants: 127 (15 mg cilomilast: 65, placebo: 62)

3) Baseline characteristics: mean age: 63.4 years: placebo and 61.4 years; cilomilast. 76% male: placebo and 72% male: cilomilast

4) Inclusion criteria: aged 40 to 80 years. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. Post-bronchodilator FEV1 between 40% and 80% predicted normal. Poor reversibility of less than or equal to 10% or 200 mL increase in FEV1

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: 8 (12%) and 6 (10%) from treatment and control groups, respectively

Interventions

Run-in: not stated

1) Cilomilast 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: no information available

  • Short-acting β2 agonist: no information available

  • Corticosteroid: no information available

  • Long-acting β2 bronchodilator: no information available

Outcomes

Primary outcome: change from baseline at endpoint in CD68+ (macrophages) and CD8+ (cytotoxic T-lymphocytes) per unit area of tissue

Secondary outcome: change from baseline in numbers of sub-epithelial cells per unit area in biopsy for neutrophil elastase positive (ne+) cells, CD4+, IL-8 mRNA positive cells, TNF-alpha mRNA positive cells

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskRandomised. No other information available
Randomised?Low riskParticipants were randomised to receive either 15 mg of cilomilast or matching placebo twice daily
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinding
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low riskTotal number of participants withdrawn 6 (10%) placebo, 8 (12%) cilomilast
Baseline profile: anticholingeric useUnclear riskNo other information available
Baseline profile: β2 agonist useUnclear riskNo other information available
Baseline profile: corticosteroid useUnclear riskNo other information available

Compton 2001

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 6 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 60 centres in Austria, France, Germany, the Netherlands and the UK

2) Participants: 424 (5 mg cilomilast: 109, 10 mg cilomilast: 102, 15 mg cilomilast: 107, placebo: 106)

3) Baseline characteristics: mean age: 62 to 63 years, 75% to 78% male, mean FEV1% predicted of 46.8%, mean smoking history of 36 to 43 (SD 22.4) pack-years

4) Inclusion criteria: FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years

5) Exclusion criteria: asthma, poorly controlled COPD needing hospital visit 6 weeks before study, recent COPD exacerbations or recent corticosteroid use

6) Total number of participant withdrawals: 18 (17%) and 17 (16%) from treatment and control groups, respectively

Interventions

Run-in: 2 weeks, single-blind. Placebo tablets to assess compliance

1) Cilomilast 5 mg, 10 mg, 15 mg twice daily

2) Placebo twice daily

Concomitant medication

  • Short-acting anticholingeric: 382 (90%) patients were given concomitant treatment for COPD during the study; 267 (70%)salbutamol and 115 (30%) ipratropium bromide

  • Short-acting β2 agonist: salbutamol used in 70%

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: none

Outcomes

Primary outcomes: lung function: ΔFEV1, SGRQ

Secondary outcomes: peak expiratory flow and FVC, the first dose effect of active treatment on FEV1

NotesPost-bronchodilator results not given so pre-bronchodilator values used in analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskDescribed as randomised. No other information available
Randomised?Low risk"Eligible patients were randomly assigned to receive a 5, 10, or 15 mg tablet of cilomilast twice daily (morning and evening) or matching placebo for 6 weeks."
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low risk"14 patients (13%) taking cilomilast 15 mg had adverse events leading to patient withdrawal, as did 12 each in the 5 and 10 mg groups (11 and 12%, respectively) and eight (8%) in the placebo group."
Baseline profile: anticholingeric useUnclear riskInformation not available
Baseline profile: β2 agonist useLow risk102 (24%) patients had been taking long-acting ß2- agonists; e.g. salmeterol, formoterol
Baseline profile: corticosteroid useLow risk331 (78%) individuals had taken other medications for their COPD, the most common being inhaled steroids. 229 (54%) took beclomethasone, budesonide or fluticasone

COPD safety pool

Methods14 double-blind and placebo-controlled studies (Roflumilast FK1 101; Roflumilast FK1 103; Roflumilast IN-108; Roflumilast M2-107; Roflumilast M2-110; Roflumilast M2-111; Roflumilast M2-112; Roflumilast M2-118; Roflumilast M2-119; Roflumilast M2-121; Roflumilast M2-124; Roflumilast M2-125; Roflumilast M2-127; Roflumilast M2-128)
ParticipantsSee individual studies
Interventions

1) Roflumilast 500 µg once daily

2) Roflumilast 250 µg once daily

3) Placebo once daily

Outcomes 
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskSee individual studies
Randomised?Low riskRandomised
Method of randomisation described?Unclear riskSee individual studies
Blinding?Unclear riskDouble-blind
Method of blinding described?Unclear riskSee individual studies
Description of withdrawals and drop-outs?Unclear riskSee individuals studies
Baseline profile: anticholingeric useUnclear riskSee individuals studies
Baseline profile: β2 agonist useUnclear riskSee individuals studies
Baseline profile: corticosteroid useUnclear riskSee individuals studies

Roflumilast FK1 101

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 26 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: not stated

2) Participants: 516 (roflumilast 250 µg: 175, roflumilast 500 µg: 169, placebo: 172)

3) Baseline characteristics: median age: 61 to 62 years. 72% male. Mean 38 to 63 pack-years. 53% current smokers

4) Inclusion criteria: aged 40 to 75. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. Reversibility < 12% or 200 mL Post-bronchodilator FEV1 35% to 75% predicted

5) Exclusion criteria: not stated

6) Participant withdrawals: not stated

Interventions

Run-in: 2 weeks with placebo

1) Roflumilast 500 µg once daily

2) Roflumilast 250 µg once daily

3) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: allowed at a constant daily dose for those treated before with anticholinergics on a constant dosage

  • Short-acting β2 agonist: salbutamol was allowed as rescue medication

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: none

Outcomes

Primary outcomes: post-bronchodilator FEV1 and FEF between 25% to 75% of vital capacity

Secondary outcomes: number of moderate or severe COPD exacerbations which required treatment with oral steroids

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskRandomised. No other information available
Randomised?Low riskPatients randomised in either roflumilast 250 µg, roflumilast 500 µg or placebo groups
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?High riskNot stated
Baseline profile: anticholingeric useUnclear riskNo information available
Baseline profile: β2 agonist useUnclear riskNo information available
Baseline profile: corticosteroid useUnclear riskNo information available

Roflumilast FK1 103

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: not stated

2) Participants: 518 (roflumilast 500 µg: 200, placebo: 186)

3) Baseline characteristics: mean age: 60 years. 75% male. 62% current smokers. Average of 35 pack-years

4) Inclusion criteria: aged 40 to 75 years. FEV1/FVC ≤ 0.7. Post-bronchodilator FEV1 35% to 75% of predicted. FEV1 reversibility ≤ 12% and ≤ 200 mL. Pre-bronchodilator FEV1/FVC ≤ 70%

5) Exclusion criteria: not stated

6) Participant withdrawals not stated

Interventions

Run-in: 2 weeks with placebo

1) Roflumilast 500 µg once daily for 24 weeks

2) Roflumilast 500 µg once daily for 12 weeks. Placebo once daily for following 12 weeks

Concomitant medication

  • Short-acting anticholingeric: all medications were withdrawn except constant dose short-acting anticholinergics

  • Short-acting β2 agonist: as rescue medication

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: none

Used alongside short-acting ß2 agonists (available to all)

Outcomes Primary outcomes: results for 12/24 week post-bronchodilator FEV1
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskNo information available
Randomised?Low risk"After randomisation, patients received placebo or roflumilast 500 µg once daily for 24 weeks or roflumilast 500 µg for 12 weeks followed by placebo for 12 weeks
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?High riskNot stated
Baseline profile: anticholingeric useUnclear riskNo further information available
Baseline profile: β2 agonist useUnclear riskNo further information available
Baseline profile: corticosteroid useUnclear riskNo information available

Roflumilast IN-108

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Intention-to-treat analysis: not stated

Participants

1) Setting: 5 centres in India

2) Participants: 118 recruited (roflumilast 500 µg: 47; roflumilast 200 µg: 46, placebo: 25)

3) Baseline characteristics: mean age: 60 years. 98% male. 41% current smokers. Post-bronchodilator FEV1 of 57% to 61%. Average of 25 pack-years

4) Inclusion criteria: not stated

5) Exclusion criteria: not stated

6) Participant withdrawals: roflumilast 500 µg: 13 (28%); roflumilast 200 µg: 7 (15%) and 10 (40%) from control group

Interventions

1) Roflumilast 250 µg once daily

2) Roflumilast 500 µg once daily

3) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: not stated

  • Short-acting β2 agonist: not stated

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: not stated

Outcomes1) To study the safety and tolerability of roflumilast 250 μg versus roflumilast 500 μg versus placebo
2) To investigate the effect of roflumilast 250 μg versus roflumilast 500 μg versus placebo on pulmonary function, efficacy rating and exacerbation rate
3) To evaluate plasma levels of roflumilast and its major metabolite roflumilast N-oxide
Note: only the third objective is discussed here
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskNot stated
Randomised?Low riskRandomised
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blind
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low riskData as above
Baseline profile: anticholingeric useUnclear riskNo information available
Baseline profile: β2 agonist useUnclear riskNo information available
Baseline profile: corticosteroid useUnclear riskNo information available

Roflumilast JP-706

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: not stated

Participants

1) Setting: Japanese study

2) Participants: 600 (roflumilast 250 µg: 205, roflumilast 500 µg: 204, placebo: 191)

3) Baseline characteristics: mean age: 70 years. 96% male. Post-bronchodilator FEV1 not stated. Average of 56 pack-years. 37% current smokers

4) Inclusion criteria: not stated

5) Exclusion criteria: not stated

6) Total number of participant withdrawals: not stated

Interventions

Run-in: single-blind 4 weeks with placebo

1) Roflumilast 500 µg once daily

2) Roflumilast 250 µg once daily

3) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: used at a constant daily dose

  • Short-acting β2 agonist: not stated

  • Corticosteroid: not stated

  • Long-acting β2 bronchodilator: not stated

Outcomes

(1) To investigate the efficacy and safety after 24-week treatment of APTA-2217 (roflumilast) at doses of 500 µg and 250 µg in patients with COPD using placebo as a control

(2) To investigate the pharmacokinetics of roflumilast and roflumilast N-oxide after repeated administration of APTA-2217 at doses of 500 µg and 250 µg

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskNot stated
Randomised?Low riskRandomised
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blind
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?High riskNot described
Baseline profile: anticholingeric useLow riskConstant dose of short anticholinergics used in 35% (roflumilast 500 µg), 33% (roflumilast 200 µg) and 33% (placebo), respectively
Baseline profile: β2 agonist useUnclear riskNot described
Baseline profile: corticosteroid useUnclear riskNot described

Roflumilast M2-107

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 159 centres in Australia, Austria, Belgium, Canada, France, Germany, Hungary, Ireland, South Africa, Spain and the UK

2) Participants: 1411 (roflumilast 250 µg: 576, roflumilast 500 µg: 555, placebo: 280)

3) Baseline characteristics: median age: 64 years. 74% male. Post-bronchodilator FEV1 is 51% for both groups. Average of 42 pack-years. 45% current smokers

4) Inclusion criteria: aged ≥ 40 with history of COPD > 12 months. FEV1 < 50% predicted, FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. Reversibility < 12% or 200 mL. Mean post-bronchodilator FEV1 30% to 80% predicted

5) Exclusion criteria: asthma, lung cancer or bronchiectasis, long-term oxygen treatment, recent exacerbation that required a course of systemic corticosteroids, emergency room treatment or hospital admission within 4 weeks before the run-in period

6) Total number of participant withdrawals: 124 (22%) and 32 (11%) from treatment and control groups, respectively

Interventions

Run-in: 4 weeks with placebo

1) Roflumilast 500 µg once daily

2) Roflumilast 250 µg once daily

3) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: used at a constant daily dose

  • Short-acting β2 agonist: salbutamol as rescue medication

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: none

Outcomes

Primary outcomes: post-bronchodilator FEV1 and SGRQ total score

Secondary outcomes: change from baseline in pre-bronchodilator FEV1, post-bronchodilator FVC, post-bronchodilator FEV in 6 seconds and FVC, FEF rate between 25% to 75% of vital capacity and number of moderate or severe COPD exacerbations

NotesThere is inconsistency in the quoting of statistical errors. Within the text and Table 2, data are quoted as "least squares means and SD", however in Figures 2 and 3, SE bars are shown. It is more likely that the results represent SE and not SD
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low risk"No person involved in data analysis had knowledge of the randomisation sequence"
Randomised?Low risk"Treatment was assigned by the investigators with sequential study numbers according to a block randomisation list in ratios of 2:2:1 (Roflumilast 250 µg, Roflumilast 500 µg, Placebo)."
Method of randomisation described?Low risk"The randomisation sequence was generated by ALTANA Pharma AG in a blinded manner"
Blinding?Low riskDouble-blinded
Method of blinding described?Low risk"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."
Description of withdrawals and drop-outs?Low risk100 patients discontinued from study from the roflumilast 250 µg group, 124 from the roflumilast 500 µg group and 32 from the placebo group
Baseline profile: anticholingeric useUnclear riskNo information available
Baseline profile: β2 agonist useUnclear riskNo information available
Baseline profile: corticosteroid useUnclear riskNo information available

Roflumilast M2-110

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: not stated

Participants

1) Setting: 36 centres in Argentina, Canada, Columbia, Mexico, Peru and the USA

2) Participants: estimated enrolment of 1000 participants

3) Baseline characteristics: not stated

4) Inclusion criteria:

  • Clinical diagnosis of COPD

  • Currently stable COPD with no change in COPD treatment in the prior 4 weeks

5) Exclusion criteria:

  • Clinical diagnosis of asthma

  • Poorly controlled COPD

  • Regular need for daily oxygen therapy

6) Total number of participant withdrawals: not stated

InterventionsRoflumilast 500 µg daily versus placebo
Outcomes Primary outcomes: pulmonary function
Secondary outcomes: exacerbation rate, quality of life, symptoms, use of rescue medication, safety and tolerability
NotesClinicalTrials.gov Identifier: nCT00062582
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskNot stated
Randomised?Low riskRandomised
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blind
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Unclear riskNot stated
Baseline profile: anticholingeric useUnclear riskNot stated
Baseline profile: β2 agonist useUnclear riskNot stated
Baseline profile: corticosteroid useUnclear riskNot stated

Roflumilast M2-111

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 52 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: m2-111 was conducted in 188 centres in 6 countries, and M2-112 in 159 centre in 14 countries
2) Participants: data combined with M2-112 showing 2686 (roflumilast 500 µg: 1327, placebo: 1359)
3) Baseline characteristics: severe COPD according to GOLD criteria grades III and IV. Mean age: 64 to 65 years. 72% male

4) Inclusion criteria: aged ≥ 40 years. Post-bronchodilator FEV1 < 50% predicted. Reversibility < 15%. Mean post-bronchodilator FEV1 42%. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. 40% current smokers, 60% ex-smokers; average 46 to 48 pack-years

5) Exclusion criteria: history of asthma, lung cancer or bronchiectasis, need for long-term oxygen therapy, known α1antitrypsin deficiency or clinically significant cardiopulmonary co-morbidity

6) Total number of participant withdrawals: data combined with M2-112 showing 433 (33%) and 348 (26%) from treatment and control groups, respectively

Interventions

Run-in: 4 weeks with placebo

1) Roflumilast 500 µg once daily

2) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: 891 patients on short-acting anticholinergics

  • Short-acting β2 agonist: salbutamol as rescue medication

  • Corticosteroid: 943 patients continued corticosteroid use

  • Long-acting β2 bronchodilator: none

Used alongside corticosteroids, anticholinergics and rescue short-acting ß2 agonists 54% overall (available to all)

Outcomes

Primary outcomes: change from baseline to endpoint in post-bronchodilator FEV1 and the number of moderate or severe exacerbations per patient per year

Secondary outcomes: change from baseline in SGRQ total score, change from baseline in prebronchial FEV1, post-bronchodilator FEV in 6 seconds and FVC, FEF rate between 25% to 75% of vital capacity and number of moderate or severe COPD exacerbations requiring systemic corticosteroid treatment per patient per year

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low risk"Each study participant who qualified was assigned a number in sequential order. Code labelling prevented the investigator and the patient from knowing which drug was administered."
Randomised?Low risk"randomised (1:1)"
Method of randomisation described?Low risk"The randomisation list was generated using a multiplicative congruential pseudorandom number generator (program RANDOM, based on Fishman and Moore)."
Blinding?Low riskDouble-blinded
Method of blinding described?Low risk"There was a stratification of patients according to smoking status (current smokers/ex-smokers) and treatment with inhaled corticosteroids (yes/no)."
Description of withdrawals and drop-outs?Low riskData combined with M2-112
Baseline profile: anticholingeric useLow riskData combined with M2-112 showing 1604 (60%) patients used anticholinergics
Baseline profile: β2 agonist useLow risk1463 (55%) patients on short-acting β2-agonists
Baseline profile: corticosteroid useLow risk1622 (61%) on concomitant inhaled corticosteroids

Roflumilast M2-111+M2-112

MethodsAs described in separate studies above and below
Participants 
Interventions 
Outcomes 
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskSee individual trials
Randomised?Low riskSee individual trials
Method of randomisation described?Low riskSee individual trials
Blinding?Low riskSee individual trials
Method of blinding described?Low riskSee individual trials
Description of withdrawals and drop-outs?Low riskSee individual trials
Baseline profile: anticholingeric useLow riskSee individual trials
Baseline profile: β2 agonist useLow riskSee individual trials
Baseline profile: corticosteroid useLow riskSee individual trials

Roflumilast M2-112

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 52 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 159 centres in 14 countries

2) Participants: 1513 (roflumilast 500 µg: 760, placebo: 753)

3) Baseline characteristics: severe COPD according to GOLD criteria grades III and IV. Mean age: 65 years. 75% male

4) Inclusion criteria: aged ≥ 40 years. Post-bronchodilator FEV1 < 50% predicted. Reversibility < 15%. Mean post-bronchodilator FEV1 41%. FEV1/FVC ≤ 0.7 with smoking history > 10 pack-years. 37% current smokers, 63% ex-smokers; average 44 pack-years

5) Exclusion criteria: history of asthma, lung cancer or bronchiectasis, need for long-term oxygen therapy, known α1antitrypsin deficiency or clinically significant cardiopulmonary co-morbidity

6) Total number of participant withdrawals: 217 (29%) and 163 (22%) from treatment and control groups, respectively

Interventions

Run-in: 4 weeks with placebo

1) Roflumilast 500 µg once daily

2) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: 891 patients on short-acting anticholinergics

  • Short-acting β2 agonist: salbutamol as rescue medication

  • Corticosteroid: 943 patients continued corticosteroid use

  • Long-acting β2 bronchodilator: none

Used alongside corticosteroids, anticholinergics and rescue short-acting ß2 agonists 54% overall (available to all)

Outcomes

Primary outcomes: change from baseline to endpoint in post-bronchodilator FEV1 and the number of moderate or severe exacerbations per patient per year

Secondary outcomes: change from baseline in SGRQ total score, change from baseline in prebronchial FEV1, post-bronchodilator FEV in 6 seconds and FVC, FEF rate between 25% to 75% of vital capacity and number of moderate or severe COPD exacerbations requiring systemic corticosteroid treatment per patient per year

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low risk"Each study participant who qualified was assigned a number in sequential order. Code labelling prevented the investigator and the patient from knowing which drug was administered."
Randomised?Low risk"randomised (1:1)"
Method of randomisation described?Low risk"The randomisation list was generated using a multiplicative congruential pseudorandom number generator (program RANDOM, based on Fishman and Moore)."
Blinding?Low riskDouble-blinded
Method of blinding described?Low risk"There was a stratification of patients according to smoking status (current smokers/ex-smokers) and treatment with inhaled corticosteroids (yes/no)."
Description of withdrawals and drop-outs?Low risk

"Over 70% of patients completed the study. The reasons for withdrawal were similar between groups except for adverse events, which occurred more frequently with roflumilast."

"Withdrawal due to COPD exacerbations was reported in 3.5 and 3.2% of patients in roflumilast and placebo groups, respectively."

Baseline profile: anticholingeric useLow risk739 patients used anticholinergics
Baseline profile: β2 agonist useLow risk820 patients on short-acting β2-agonists
Baseline profile: corticosteroid useLow risk727 on beclomethasone dipropionate 2000 µg or less

Roflumilast M2-118

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 22 centres in 4 countries

2) Participants: 250 (roflumilast 500 µg: 127, placebo: 123)

3) Baseline characteristics: mean age: 60 years. 73% (roflumilast) versus 84% (placebo) male. Post-bronchodilator FEV1 55% predicted. Average of 41 pack-years. 53% current smokers

4) Inclusion criteria: participants were clinically stable patients 40 years of age and above with a smoking history of greater than 10 pack-years and a 12-month history of COPD. Other inclusion criteria included: post-bronchodilator FEV1 30% to 80% predicted, FEV1/forced vital capacity (FVC) < 0.7 and set plethysmographic functional residual capacity (FRC) and peak oxygen uptake requirements

5) Exclusion criteria: asthma or a lung disease other than COPD; a1-antitrypsin deficiency; participation in a pulmonary rehabilitation programme within 2 months; supplemental oxygen therapy; a significant medical comorbidity that may influence exercise tolerance

6) Total number of participant withdrawals: 16 (13%) and 12 (10%) from treatment and control groups, respectively

Interventions

1) Roflumilast 500 µg once daily

2) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: patients could use ipratropium bromide in regular stable doses as needed

  • Short-acting β2 agonist: patients could use short-acting β2-agonists as needed

  • Corticosteroid: inhaled corticosteroids (ICS) were permitted throughout the study if taken at a constant dosage for greater than 3 months prior to the study

  • Long-acting β2 bronchodilator: none

OutcomesActivity-related dyspnoea (TDI). Spirometry and body plethysmography. Symptom-limited exercise tests
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskNot stated
Randomised?Low riskA 1:1 randomisation ratio was used
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low riskOf the 250 randomised participants, 16 from the roflumilast group and 12 from the placebo group discontinued prematurely
Baseline profile: anticholingeric useUnclear riskNot stated
Baseline profile: β2 agonist useUnclear riskNot stated
Baseline profile: corticosteroid useUnclear riskNot stated

Roflumilast M2-119

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 32 centres in 5 countries

2) Participants: 410 (roflumilast 500 µg: 203, placebo: 207)

3) Baseline characteristics: mean age: 68 years. 93% male. Post-bronchodilator FEV1 50.5% predicted. Average of 44 pack-years. 69% current smokers

4) Inclusion criteria: former or current smokers with at least a 10 pack-year history. Aged ≥ 40 years. Post-bronchodilator FEV1/FVC ≤ 0.7 and FEV1 of 30% to 80%. Clinically stable COPD within 4 weeks prior to baseline

5) Exclusion criteria: history of asthma or other relevant lung disease, COPD exacerbation with the 4 weeks prior to baseline, need for long-term oxygen therapy, known α1antitrypsin deficiency or clinically significant cardiopulmonary co-morbidity

6) Total number of participant withdrawals: 40 (20%) and 18 (9%) from treatment and control groups, respectively

Interventions

Run-in: 4 weeks with placebo

1) Roflumilast 500 µg once daily

2) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: "Short-acting anticholinergics at a constant daily dosage as concomitant medication if already taken on a regular basis at a constant dosage for at least 4 weeks prior to the study."

  • Short-acting β2 agonist: patients could use short-acting β2 agonists as needed

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: none

Outcomes

Primary outcome: mean change in post-bronchodilator FEV1 from baseline

Secondary outcomes: mean change in pre-bronchodilator FEV1 from baseline, change in other lung function measures, time to COPD exacerbation, proportion of patients experiencing exacerbations, time to study withdrawal and adverse effects

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskNot stated
Randomised?Low riskRandomised
Method of randomisation described?Low riskComputer-generated randomisation list used
Blinding?Low riskDouble-blinded
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Low riskPatient numbers at different stages of the study described in figure
Baseline profile: anticholingeric useUnclear riskNot stated
Baseline profile: β2 agonist useUnclear riskNot stated
Baseline profile: corticosteroid useUnclear riskNot stated

Roflumilast M2-121

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 12 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 16 centres in 6 countries

2) Participants: estimated enrolment 550 participants

3) Baseline characteristics: not stated

4) Inclusion criteria: patients with a history of chronic obstructive pulmonary disease for at least 12 months as defined by the GOLD criteria, age ≥ 40 years, FEV1/FVC ratio (post-bronchodilator) ≤ 70%, FEV1 (post-bronchodilator) ≤ 65% of predicted, FRC (post-bronchodilator) ≤ 120% of predicted

5) Exclusion criteria: COPD exacerbation indicated by a treatment with systemic glucocorticosteroids not stopped at least 4 weeks prior to the baseline visit, non-smoker, current smoker or ex-smoker (smoking cessation at least 1 year ago) with a smoking history of < 10 pack-years, or suffering from any concomitant disease that might interfere with study procedures or evaluation

6) Total number of participant withdrawals: not stated

Interventions500 µg roflumilast tablets once daily versus placebo
Outcomes

Primary outcome: lung function parameters indicative of hyperinflation in patients with COPD

Secondary outcomes:

  • Mean change from randomisation to endpoint in additional pre- and post-bronchodilator spirometric and lung volume parameters

  • Measurement of quality of life parameters and dyspnoea

NotesClinicalTrials.gov Identifier: nCT00108823
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Unclear riskNot stated
Randomised?Low riskRandomised
Method of randomisation described?Unclear riskNot stated
Blinding?Low riskDouble-blind
Method of blinding described?Unclear riskNot stated
Description of withdrawals and drop-outs?Unclear riskNot stated
Baseline profile: anticholingeric useUnclear riskNot stated
Baseline profile: β2 agonist useUnclear riskNot stated
Baseline profile: corticosteroid useUnclear riskNot stated

Roflumilast M2-124

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 52 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 246 centres in 10 countries

2) Participants: 1513 (roflumilast 500 µg: 760, placebo: 753)

3) Baseline characteristics: mean age: 64 years. 71% male. Post-bronchodilator FEV1 37.6% predicted. Average of 47 pack-years. 48% current smokers

4) Inclusion criteria: former or current smokers with at least a 20 pack-year history. Aged ≥ 40 years. Post-bronchodilator FEV1/FVC ≤ 0.7. Chronic cough and sputum production. Post-bronchodilator FEV1 < 50% predicted. At least 1 recorded COPD exacerbation requiring systemic glucocorticosteroids or treatment in hospital in previous year

5) Exclusion criteria: available in the online web appendix (pg 11)

6) Total number of participant withdrawals: 264 (34%) and 234 (31%) from treatment and control groups, respectively

Interventions

Run-in: 4 weeks with placebo

1) Roflumilast 500 µg once daily

2) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: 31% of those in the roflumilast group and 32% on placebo

  • Short-acting β2 agonist: "Patients could use short acting β2 agonists as needed"

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: "Eligible patients were stratified according to their use of long acting β2 agonists and smoking status." Roflumilast 49%, placebo 51%

Outcomes

Primary outcomes: mean change in pre-bronchodilator FEV1 from baseline to each post-randomisation visit during the treatment period. Mean rate of COPD exacerbations requiring oral or parenteral glucocorticosteroids or requiring hospitalisation or leading to death, per patient per year

Secondary outcomes: mean change in post-bronchodilator FEV1 from baseline to each post-randomisation visit during the treatment period. Time to mortality due to any reason. Natural log-transformed CRP (mg/L), Mean TDI focal score during the treatment period

NotesAdverse event data are pooled with numbers from study M2-125 that followed an identical study design
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskAll individuals involved in the studies were unaware of treatment assignment
Randomised?Low risk"Randomly assigned to oral roflumilast 500 µg once daily or placebo."
Method of randomisation described?Low risk"The sponsor generated a randomisation list of patient random numbers using a pseudorandom number generator. The investigator used an automated, interactive voice response system to randomly assign patients."
Blinding?Low riskDouble-blinded
Method of blinding described?Low risk"All individuals involved in the studies were unaware of treatment assignment. Tablets were identical in appearance. The investigator or anyone at the study site was prevented from knowing the allocation sequence with code labelling."
Description of withdrawals and drop-outs?Low risk264 patients discontinued from study in the roflumilast group and 234 discontinued from the placebo group
Baseline profile: anticholingeric useUnclear riskNo other information available
Baseline profile: β2 agonist useUnclear riskNo other information available
Baseline profile: corticosteroid useHigh riskPretreatment of 44% in both roflumilast and placebo groups

Roflumilast M2-124+M2-125

MethodsAs described in separate studies above and below
Participants 
Interventions 
Outcomes 
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskSee individual studies
Randomised?Low riskSee individual studies
Method of randomisation described?Low riskSee individual studies
Blinding?Low riskSee individual studies
Method of blinding described?Low riskSee individual studies
Description of withdrawals and drop-outs?Low riskSee individual studies
Baseline profile: anticholingeric useLow riskSee individual studies
Baseline profile: β2 agonist useLow riskSee individual studies
Baseline profile: corticosteroid useHigh riskSee individual studies

Roflumilast M2-125

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 52 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 221 centres in 8 countries

2) Participants: 1571 (roflumilast 500 µg: 773, placebo: 798)

3) Baseline characteristics: mean age: 64 years. 80% male. Average of 48 pack-years. 35% current smokers

4) Inclusion criteria: former or current smokers with at least a 20 pack-year history. Aged ≥ 40 years. Post-bronchodilator FEV1/FVC ≤ 0.7. Chronic cough and sputum production. Post-bronchodilator FEV1 < 50% predicted. At least 1 recorded COPD exacerbation requiring systemic glucocorticosteroids or treatment in hospital in previous year

5) Exclusion criteria: available in the online web appendix (pg 11)

6) Total number of participant withdrawals: 246 (32%) and 248 (31%) from treatment and control groups, respectively

Interventions

Run-in: 4 weeks with placebo

1) Roflumilast 500 µg once daily

2) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: 38% of those in the roflumilast group and 41% on placebo

  • Short-acting β2 agonist: "Patients could use short acting β2 agonists as needed"

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: "Eligible patients were stratified according to their use of long acting β2 agonists and smoking status." Roflumilast 48%, placebo 51%

Outcomes

Primary outcomes: mean change in pre-bronchodilator FEV1 from baseline to each post-randomisation visit during the treatment period. Mean rate of COPD exacerbations requiring oral or parenteral glucocorticosteroids or requiring hospitalisation or leading to death, per patient per year

Secondary outcomes: mean change in post-bronchodilator FEV1 from baseline to each post-randomisation visit during the treatment period. Time to mortality due to any reason. Natural log-transformed CRP (mg/L), Mean TDI focal score during the treatment period

NotesAdverse event data are pooled with numbers from study M2-124 that followed an identical study design
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskAll individuals involved in the studies were unaware of treatment assignment
Randomised?Low risk"Randomly assigned to oral roflumilast 500 µg once daily or placebo."
Method of randomisation described?Low risk"The sponsor generated a randomisation list of patient random numbers using a pseudorandom number generator. The investigator used an automated, interactive voice response system to randomly assign patients."
Blinding?Low riskDouble-blinded
Method of blinding described?Low risk"All individuals involved in the studies were unaware of treatment assignment. Tablets were identical in appearance. The investigator or anyone at the study site was prevented from knowing the allocation sequence with code labelling."
Description of withdrawals and drop-outs?Low risk246 patients discontinued from study in the roflumilast group and 248 discontinued from the placebo group
Baseline profile: anticholingeric useLow riskNo other information available
Baseline profile: β2 agonist useLow riskNo other information available
Baseline profile: corticosteroid useHigh riskPretreatment of 40% in both roflumilast and placebo groups

Roflumilast M2-127

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 135 centres in 10 countries

2) Participants: 1221 (roflumilast 500 µg: 467, placebo: 468)

3) Baseline characteristics: mean age: 65 years. 71% male. Post-bronchodilator FEV1 54.7% and 55.3% predicted (roflumilast and placebo). Average of 43 pack-years. 39% current smokers

4) Inclusion criteria: former or current smokers with (≥ 1 year smoking cessation) and at least a 10 pack-year history. Aged ≥ 40 years. Post-bronchodilator FEV1/FVC ≤ 0.7. Post-bronchodilator FEV1 40% to 70% predicted. Partial reversibility to albuterol with increase from baseline FEV1 of ≤ 12% or 200 mL

5) Exclusion criteria: available in the online web appendix (pg 10)

6) Total number of participant withdrawals: 107 (23%) and 82 (18%) from treatment and control groups, respectively

Interventions

Run-in: 4 weeks with placebo once a day

1) Roflumilast 500 µg and salmeterol once daily

2) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: none

  • Short-acting β2 agonist: patients used short-acting β2 as rescue medication

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: none

Outcomes Primary outcomes: change in mean pre-bronchodilator FEV1 from baseline to each post-randomisation visit
Secondary outcomes: post-bronchodilator FEV1 and FVC, TDI score, SOBQ, rate of COPD exacerbations, and use of rescue medication
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskAll individuals involved in the studies were unaware of treatment assignment
Randomised?Low risk"Randomly assigned to oral roflumilast 500 µg once daily or placebo."
Method of randomisation described?Low risk"The sponsor generated a randomisation list of patient random numbers using a pseudorandom number generator. The investigator used an automated, interactive voice response system to randomly assign patients."
Blinding?Low riskDouble-blinded
Method of blinding described?Low risk"All individuals involved in the studies were unaware of treatment assignment. The investigator or anyone at the study site was prevented from knowing the allocation sequence with code labelling. Tablets were identical in appearance."
Description of withdrawals and drop-outs?Low risk107 patients discontinued from study in the roflumilast group and 82 discontinued from the placebo group
Baseline profile: anticholingeric useUnclear riskNo other information available
Baseline profile: β2 agonist useUnclear riskNo other information available
Baseline profile: corticosteroid useUnclear riskNo other information available

Roflumilast M2-128

  1. a

    COPD: chronic obstructive pulmonary disease
    DLCO: diffusing capacity of the lung for carbon monoxide
    FEF: forced expiratory flow
    FEV1: forced expiratory volume in one second
    FRC: functional residual capacity
    FVC: forced vital capacity
    GOLD: Global Initiative for Chronic Obstructive Lung Disease
    IC: inspiratory capacity
    L: litre
    MDI: metered dose inhaler
    mL: millilitre
    RFRC: resting functional residue capacity
    RV: residual volume
    SD: standard deviation
    SE: standard error
    SGRQ: St George's Respiratory Questionnaire
    SOBQ: Shortness of Breath Questionnaire
    SVC: slow vital capacity
    TDI: transition dyspnoea index
    ≤: less than or equal to
    ≥: more than or equal to

Methods

Parallel-group study

Randomisation: randomised, double-blind, placebo-controlled trial

Trial duration: 24 weeks

Intention-to-treat analysis: stated

Participants

1) Setting: 85 centres in 7 countries

2) Participants: 910 (roflumilast 500 µg: 372, placebo: 372)

3) Baseline characteristics: mean age: 64 years. 71% male. Post-bronchodilator FEV1 56.0% and 56.2% predicted (roflumilast and placebo). Average of 44 pack-years. 40% current smokers

4) Inclusion criteria: former or current smokers with (≥ 1 year smoking cessation) and at least a 10 pack-year history. Aged ≥ 40 years. Post-bronchodilator FEV1/FVC ≤ 0.7. Post-bronchodilator FEV1 40% to 70% predicted. Partial reversibility to albuterol with increase from baseline FEV1 of ≤ 12% or 200 mL

5) Exclusion criteria: available in the online web appendix (pg 10)

6) Total number of participant withdrawals: 62 (17%) and 39 (11%) from treatment and control groups, respectively

Interventions

Run-in: 4 weeks with placebo once a day

1) Roflumilast 500 µg and tiotropium once daily

2) Placebo once daily

Concomitant medication

  • Short-acting anticholingeric: none

  • Short-acting β2 agonist: patients used short-acting β2 as rescue medication

  • Corticosteroid: none

  • Long-acting β2 bronchodilator: none

Outcomes Primary outcomes: change in mean pre-bronchodilator FEV1 from baseline to each post-randomisation visit
Secondary outcomes: post-bronchodilator FEV1 and FVC, TDI score, SOBQ, rate of COPD exacerbations and use of rescue medication
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low riskAll individuals involved in the studies were unaware of treatment assignment
Randomised?Low risk"Randomly assigned to oral roflumilast 500 µg once daily or placebo."
Method of randomisation described?Low risk"The sponsor generated a randomisation list of patient random numbers using a pseudorandom number generator. The investigator used an automated, interactive voice response system to randomly assign patients."
Blinding?Low riskDouble-blinded
Method of blinding described?Low risk"All individuals involved in the studies were unaware of treatment assignment. The investigator or anyone at the study site was prevented from knowing the allocation sequence with code labelling. Tablets were identical in appearance."
Description of withdrawals and drop-outs?Low risk62 patients discontinued from study in the roflumilast group and 39 discontinued from the placebo group
Baseline profile: anticholingeric useUnclear riskNo information available
Baseline profile: β2 agonist useUnclear riskNo information available
Baseline profile: corticosteroid useUnclear riskNo information available

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    COPD: chronic obstructive pulmonary disease
    RR: risk ratio
    QOL: quality of life
    SD: standard deviation
    SE: standard error
    ≥: more than or equal to

Borker 2003Insufficient data. Only RR of QOL improvement provided
Ferguson 2003Integrated results from four 24-week cilomilast trials
Fischer 2003Analysis focused on patients with a baseline SGRQ score of ≥ the median SGRQ score only
Grootendorst 2001Endpoint: first dose-bronchodilator effects only
Grootendorst 2002Treatment Bayer BAY 19-8004; 11 patients only 1 week in duration
Grootendorst 2003Endpoint: first-dose bronchodilator effects only
Grootendorst 2007Cross-over design
GSK256066Phase II trial. No primary outcome measure investigating lung function. Only one trial to date
Kelsen 2002No study ID or group numbers identified
Knobil 2003No SD or SE given
Lim 2004Combining results from 2 pivotal European phase III cilomilast trials
Nieman 1999Study 038. Insufficient data available for changes in lung function and exacerbation rates
Pascoe 2007Treatment QAK423 (Novartis), discontinued. Only 1 trial available
Reisner 2003Combined results. Individual studies already included in review
Rennard 2008SE not provided for exacerbation rates
Roflumilast JP708JP108 is an extension study of APTA-2217-06 study. After the key-open of APTA-2217-06 study, administration to placebo group would be terminated. Not all patients enrolled in JP106 continued onto the JP108 study
SB207499/040Open-label study. Males or females with COPD who successfully completed study 042 or 091 where participants received cilomilast 15 mg twice daily or placebo for 24 weeks in study 042 and 26 weeks in study 091 without tolerability problems. Concomitant COPD medication use allowed, given placebo or placebo/Ariflo during study period
SB207499/041Open-label study. Males or females with COPD who successfully completed study 039 where participants received cilomilast 15 mg twice daily or placebo for 24 weeks without tolerability problems. Concomitant COPD medication use allowed, given placebo or placebo/Ariflo during study period
Song 2005Although quoted as significant, mean and SD figures not provided
Spencer 2002No study ID or group numbers identified
Vestbo 2007Treatment UK-500,001 (Pfizer). Discontinued
Vestbo 2009Treatment UK-500,001 (Pfizer). Discontinued
Wang 2005Although quoted as significant, mean and SD figures not provided

Characteristics of ongoing studies [ordered by study ID]

Calverley 2012

Trial name or titleRoflumilast in the Prevention of COPD Exacerbations While Taking Appropriate Combination Treatment
Methods1-year, randomised, double-blind, multicentre, phase III/IV study
ParticipantsCOPD patients with severe to very severe airflow limitation, symptoms of chronic bronchitis and at least 2 exacerbations in the previous year will be recruited
InterventionsRoflumilast 500 µg once daily or placebo on top of a fixed long-acting β2 agonist/inhaled corticosteroid combination
OutcomesThe primary outcome is the rate of moderate or severe COPD exacerbations
Starting dateMay 2011
Contact information 
NotesIdentification number RO-2455-404-RD, clinicaltrials.gov identifier NCT01329029

Ferguson 2012

  1. a

    COPD: chronic obstructive pulmonary disease

Trial name or titleRoflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Fixed Dose Combinations of Long-acting β2-agonist (LABA) and Inhaled Corticosteroid (ICS)
MethodsA 52-week, double-blind, randomised, placebo-controlled, parallel-group study
ParticipantsMale or female patients at least 40 years of age, history of COPD (according to GOLD 2010) for at least 12 months prior to screening (Visit 1) associated with chronic productive cough for 3 months in each of 2 consecutive years (with other causes of productive cough excluded). Only patients with chronic bronchitis will be included (concomitant emphysema is permitted). FEV1 (post-bronchodilator) ≤ 50% of predicted at screening with at least 2 documented moderate or severe COPD exacerbations within 12 months prior. Patients must be on FDC LABA/ICS treatment ≥ 3 months prior
Interventions

Roflumilast 500 µg, oral administration, once per day. Other name: Daliresp

Dose-matched placebo, oral administration, once per day

OutcomesPrimary outcome measures: rate of moderate or severe COPD exacerbations per participant per year
Secondary outcome measures: pre-bronchodilator forced expiratory volume in 1 second (FEV1) in litres
Starting dateSeptember 2011
Contact information 
NotesClinicalTrials.gov Identifier: nCT01443845

Ancillary