Clinical trial NCT01329029: Roflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Fixed Combinations of Long-acting β2-agonists (LABA) and Inhaled Glucocorticosteroid (ICS)
Official title: Effect of Roflumilast on Exacerbation Rate in Patients With COPD Treated With Fixed Combinations of LABA and ICS. A 52-week, Randomised Double-blind Trial With Roflumilast 500 µg Versus Placebo. The REACT Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: COPD
Roflumilast
Daxas
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2011-04-05
Enrollment: 1945
Sex: ALL
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The objective of the REACT trial is to investigate the effect of roflumilast 500 μg tablets once daily versus placebo on exacerbation rate and pulmonary function in COPD patients who are concomitantly treated with a fixed combination of long-acting β2-agonists (LABA) and inhaled glucocorticosteroids (ICS). In addition, data on safety and tolerability of roflumilast will be obtained. An additional objective is to further characterize the population pharmacokinetic profile of roflumilast and roflumilast N oxide and to further characterize their pharmacokinetics/pharmacodynamics (PK/PD) relationship in terms of efficacy and relevant safety aspects.

Patients to be included are required to have severe COPD associated with chronic bronchitis and a history of frequent exacerbations and must be concomitantly treated with a fixed combination of LABA and ICS. Two parallel treatment arms (roflumilast 500 μg once daily and placebo) are included.

Detailed description: The drug tested in this study is called Roflumilast. Roflumilast is being developed to treat people who have chronic obstructive pulmonary disease (COPD). This study investigated the effect of roflumilast 500 μg tablets once daily versus placebo on exacerbation rate, pulmonary function, and major adverse cardiovascular events (MACE) in COPD patients who were concomitantly treated with a fixed combination of long-acting beta-agonists (LABA) and inhaled glucocorticosteroids.

The study was targeted to enroll approximately 1934 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there was an urgent medical need):

* Roflumilast 500 μg once daily
* Placebo (dummy inactive pill) - this was a tablet that looked like the study drug but had no active ingredient

Trial treatment was taken in the morning by mouth after breakfast with some water.

The trial consisted of the following periods:

* Single-blind baseline period (4 weeks) during which all patients received placebo.
* Double-blind treatment period (52 weeks) during which patients received either roflumilast or matching placebo.
* Safety follow-up (30 days after end of treatment (Vend) or premature discontinuation date) in case of ongoing Adverse Events at Vend, if necessary.
* Follow-up visit 12 weeks after end of treatment, at Week 64 (VFU), only for patients who completed the trial as scheduled.

This multi-center trial was conducted worldwide. The overall time to participate in this study was up to 64 weeks. Participants made multiple visits to the clinic which included a follow-up visit at week 64.

Eligibility criteria: Inclusion Criteria:

* Giving written informed consent
* History of COPD (according to GOLD 2009) for at least 12 months prior to baseline Visit V0 associated with chronic productive cough for 3 months in each of the 2 years prior to baseline visit (with other causes of productive cough excluded)
* Age ≥ 40 years
* Forced expiratory volume after one second (FEV1)/forced vital capacity (FVC) ratio (post-bronchodilator) \< 70%
* FEV1 (post-bronchodilator) ≤ 50% of predicted
* At least two documented moderate or severe COPD exacerbations within one year prior to baseline visit
* Patients must be pre-treated with LABA and ICS for at least 12 months before baseline Visit V0. Up to 3 months before baseline Visit V0 free or fixed combinations of LABA and ICS are allowed, including changes in dose, active substances, and brands. In the last 3 months before baseline Visit V0 patients must be pre-treated with fixed combinations of LABA and ICS at a constant dose (maximum approved dosage strength of the combination).
* Former smoker (defined as smoking cessation at least one year ago) or current smoker both with a smoking history of at least 20 pack years

Main Exclusion Criteria:

* Exacerbations not resolved at first baseline visit
* Diagnosis of asthma and/or other relevant lung disease
* Known alpha-1-antitrypsin deficiency
* Other protocol-defined exclusion criteria may apply

Primary outcomes:
measure: Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year
timeFrame: 52 weeks
Secondary outcomes:
measure: Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1)
timeFrame: Baseline and Week 52
measure: Rate of Severe COPD Exacerbations Per Patient Per Year
timeFrame: 52 weeks
measure: Rate of COPD Exacerbations Per Patient Per Year All Categories
timeFrame: 52 weeks
measure: Percentage of Participants Experiencing at Least 1 COPD Exacerbation
timeFrame: 52 weeks
measure: Time to First COPD Exacerbation All Categories
timeFrame: 52 Weeks
measure: Time to Second Moderate or Severe COPD Exacerbation
timeFrame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
measure: Time to Third Moderate or Severe COPD Exacerbation
timeFrame: 52 Weeks
measure: Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation Derived From Exacerbation Per Patient Per Year
timeFrame: 52 Weeks
measure: Number of Moderate or Severe COPD Exacerbation Days
timeFrame: 52 Weeks
measure: Duration of Moderate or Severe COPD Exacerbations Per Participant
timeFrame: 52 Weeks
measure: Change From Baseline in Post-Bronchodilator Forced Vital Capacity (FVC)
timeFrame: 52 weeks
measure: Change From Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%)
timeFrame: 52 weeks
measure: Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6)
timeFrame: 52 weeks
measure: Change From Baseline in Post-Bronchodilator FEV1/FVC
timeFrame: 52 weeks
measure: Change From Baseline in Use of Rescue Medication From Daily Diary
timeFrame: Baseline and Week 52
measure: Change From Baseline in COPD Symptom Score From Daily Diary
timeFrame: 52 weeks
measure: Percentage of Symptom-Free Days
timeFrame: 52 Weeks
measure: Percentage of Rescue Medication-Free Days
timeFrame: 52 Weeks
measure: Change From Baseline in COPD Assessment Test (CAT) Total Score
timeFrame: Baseline and Week 52
measure: Percentage of Participants With Improvement in CAT
timeFrame: Baseline and Week 52
measure: Time to Mortality Due to Any Reason During the Treatment Period Score
timeFrame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
measure: Time to Mortality Due to COPD Exacerbation During the Treatment Period
timeFrame: 52 Weeks
measure: Time to Withdrawal During the Treatment Period
timeFrame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
measure: Time to Withdrawal Due to COPD Exacerbation During the Treatment Period
timeFrame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
measure: Percentage of Participants With Major Adverse Cardiovascular Event (MACE) During the Treatment Period
timeFrame: 52 Weeks
measure: Time to First Major Adverse Cardiovascular Event (MACE) During the Treatment Period
timeFrame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
measure: Percentage of Participant With All-Cause Hospitalisation During the Treatment Period
timeFrame: 52 Weeks
measure: Time to First Hospitalisation Due to Any Cause During the Treatment Period
timeFrame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
measure: Time to Trial Withdrawal Due to an Adverse Event
timeFrame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
measure: Percentage of Participants Who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE)
timeFrame: 52 Weeks
measure: Change From Baseline in Body Weight
timeFrame: Baseline and Week 52
measure: Change From Baseline in Body Mass Index (BMI)
timeFrame: Baseline and Week 52
Other outcomes:
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country: South Africa
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city: Benoni Gauteng
country: South Africa
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city: Bloemfontein Free State
country: South Africa
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country: South Africa
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city: Durban Kwazulu-Natal
country: South Africa
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city: Johannesburg
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city: Barcelona
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city: Guadalajara
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city: Pozuelo de Alarcon
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country: Spain
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city: Valencia
country: Spain
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city: Ankara
country: Turkey
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city: Canakkale
country: Turkey
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city: Istanbul
country: Turkey
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city: Izmir
country: Turkey
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city: Kocaeli
country: Turkey
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city: Konya
country: Turkey
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city: Mersin
country: Turkey
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city: Edinburgh
country: United Kingdom
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city: Glasgow
country: United Kingdom
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city: Liverpool
country: United Kingdom
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city: London
country: United Kingdom
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city: London
country: United Kingdom
facility: Nycomed Investigational Site
city: Norwich
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Study officials:
affiliation: AstraZeneca
name: AstraZeneca AstraZeneca
role: STUDY_DIRECTOR
References:
citation: Facius A, Marostica E, Gardiner P, Watz H, Lahu G. Pharmacokinetic and Pharmacodynamic Modelling to Characterize the Tolerability of Alternative Up-Titration Regimens of Roflumilast in Patients with Chronic Obstructive Pulmonary Disease. Clin Pharmacokinet. 2018 Aug;57(8):1029-1038. doi: 10.1007/s40262-018-0671-4.
citation: Martinez FJ, Rabe KF, Calverley PMA, Fabbri LM, Sethi S, Pizzichini E, McIvor A, Anzueto A, Alagappan VKT, Siddiqui S, Reisner C, Zetterstrand S, Roman J, Purkayastha D, Bagul N, Rennard SI. Determinants of Response to Roflumilast in Severe Chronic Obstructive Pulmonary Disease. Pooled Analysis of Two Randomized Trials. Am J Respir Crit Care Med. 2018 Nov 15;198(10):1268-1278. doi: 10.1164/rccm.201712-2493OC.
citation: Rabe KF, Calverley PMA, Martinez FJ, Fabbri LM. Effect of roflumilast in patients with severe COPD and a history of hospitalisation. Eur Respir J. 2017 Jul 5;50(1):1700158. doi: 10.1183/13993003.00158-2017. Print 2017 Jul. No abstract available.
citation: Martinez FJ, Calverley PM, Goehring UM, Brose M, Fabbri LM, Rabe KF. Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial. Lancet. 2015 Mar 7;385(9971):857-66. doi: 10.1016/S0140-6736(14)62410-7. Epub 2015 Feb 13.
citation: Calverley PM, Martinez FJ, Fabbri LM, Goehring UM, Rabe KF. Does roflumilast decrease exacerbations in severe COPD patients not controlled by inhaled combination therapy? The REACT study protocol. Int J Chron Obstruct Pulmon Dis. 2012;7:375-82. doi: 10.2147/COPD.S31100. Epub 2012 Jun 20.