Roflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Fixed Combinations of Long-acting β2-agonists (LABA) and Inhaled Glucocorticosteroid (ICS) (REACT)

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Obstructive Pulmonary Disease
• Intervention / Treatment: Drug: Placebo; Drug: Roflumilast

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.

• Study Type: Interventional
• Enrollment (Actual): 1945
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • Box Hill, Australia, 3128
    • Nycomed Investigational Site
  • Clayton, Australia, 3168
    • Nycomed Investigational Site
  • Concord, Australia, 2139
    • Nycomed Investigational Site
  • Daws Park, Australia, 5041
    • Nycomed Investigational Site
  • Frankston, Australia, 3199
    • Nycomed Investigational Site
  • Heidelberg, Australia, 3084
    • Nycomed Investigational Site
  • Parkville, Australia, 3050
    • Nycomed Investigational Site
  • Toorak Gardens, Australia, 5065
    • Nycomed Investigational Site
• Austria
  • Feldbach, Austria, 8330
    • Nycomed Investigational Site
  • Graz, Austria, 8036
    • Nycomed Investigational Site
  • Salzburg, Austria, 5020
    • Nycomed Investigational Site
  • Wien, Austria, 1140
    • Nycomed Investigational Site
• Belgium
  • Bruxelles, Belgium, 1000
    • Nycomed Investigational Site
  • Bruxelles, Belgium, 1200
    • Nycomed Investigational Site
  • Halen, Belgium, 3545
    • Nycomed Investigational Site
  • Liege, Belgium, 4000
    • Nycomed Investigational Site
  • Malmedy, Belgium, 4960
    • Nycomed Investigational Site
• Brazil
  • Belo Horizonte, Brazil
    • Nycomed Investigational Site
  • Botucatu, Brazil
    • Nycomed Investigational Site
  • Florianópolis, Brazil
    • Nycomed Investigational Site
  • Goiânia, Brazil
    • Nycomed Investigational Site
  • Porto Alegre, Brazil
    • Nycomed Investigational Site
  • Rio de Janeiro, Brazil
    • Nycomed Investigational Site
  • Sao Paolo, Brazil
    • Nycomed Investigational Site
  • Vitória, Brazil
    • Nycomed Investigational Site
• Canada
  • Hamilton, Canada, L8N 4A6
    • Nycomed Investigational Site
  • Kingston, Canada, K7L 2V7
    • Nycomed Investigational Site
  • Lachine, Canada, H8S 2E4
    • Nycomed Investigational Site
  • Niagara Falls, Canada, L2G 1J4
    • Nycomed Investigational Site
  • Richmond Hill, Canada, L4C 2N9
    • Nycomed Investigational Site
  • Toronto, Canada, M5T 3A9
    • Nycomed Investigational Site
  • Toronto, Canada, M6H 3M2
    • Nycomed Investigational Site
  • Winnepeg, Canada, R2K 3S8
    • Nycomed Investigational Site
• Denmark
  • Hellerup, Denmark, 2900
    • Nycomed Investigational Site
  • Hillerød, Denmark, 3400
    • Nycomed Investigational Site
  • Hvidovre, Denmark, 2650
    • Nycomed Investigational Site
  • København NV, Denmark, 2400
    • Nycomed Investigational Site
• France
  • Férolles Attilly, France, 77150
    • Nycomed Investigational Site
  • Nîmes, France, 30900
    • Nycomed Investigational Site
  • Poitiers, France, 86021
    • Nycomed Investigational Site
  • Saint-Laurent du Var, France, 06700
    • Nycomed Investigational Site
  • Strasbourg, France, 67091
    • Nycomed Investigational Site
• Germany
  • Berlin, Germany, 10367
    • Nycomed Investigational Site
  • Berlin, Germany, 10969
    • Nycomed Investigational Site
  • Berlin, Germany, 12203
    • Nycomed Investigational Site
  • Fürth, Germany, 90766
    • Nycomed Investigational Site
  • Großhansdorf, Germany, 22927
    • Nycomed Investigational Site
  • Hannover, Germany, 30167
    • Nycomed Investigational Site
  • Homburg, Germany, 66421
    • Nycomed Investigational Site
  • Koblenz, Germany, 56068
    • Nycomed Investigational Site
  • Marburg, Germany, 35043
    • Nycomed Investigational Site
  • Rüdersdorf, Germany, 15562
    • Nycomed Investigational Site
• Greece
  • Alexandroupolis, Greece, 68100
    • Nycomed Investigational Site
  • Athens, Greece, 10676
    • Nycomed Investigational Site
  • Athens, Greece, 11527
    • Nycomed Investigational Site
  • Heraklion, Crete, Greece, 71110
    • Nycomed Investigational Site
  • Kavala, Greece, 65201
    • Nycomed Investigational Site
  • Larissa, Greece, 41100
    • Nycomed Investigational Site
  • Marousi, Greece, 15126
    • Nycomed Investigational Site
  • Thessaloniki, Greece, 57010
    • Nycomed Investigational Site
• Hungary
  • Balassagyarmat, Hungary, 2660
    • Nycomed Investigational Site
  • Budapest, Hungary, 1125
    • Nycomed Investigational Site
  • Cegléd, Hungary, 2700
    • Nycomed Investigational Site
  • Csorna, Hungary, 9300
    • Nycomed Investigational Site
  • Deszk, Hungary, 6772
    • Nycomed Investigational Site
  • Erd, Hungary
    • Nycomed Investigational Site
  • Miskolc, Hungary, 3526
    • Nycomed Investigational Site
  • Nyíregyháza, Hungary, 4400
    • Nycomed Investigational Site
  • Pécs, Hungary, 7623
    • Nycomed Investigational Site
  • Siófok, Hungary, 8600
    • Nycomed Investigational Site
  • Sopron, Hungary, 9400
    • Nycomed Investigational Site
  • Szombathely, Hungary, 9700
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  • Törökbálint, Hungary, 2045
    • Nycomed Investigational Site
• Israel
  • Ashkelon, Israel, 78278
    • Nycomed Investigational Site
  • Beer Sheva, Israel, 84101
    • Nycomed Investigational Site
  • Haifa, Israel, 31096
    • Nycomed Investigational Site
  • Haifa, Israel, 34362
    • Nycomed Investigational Site
  • Holon, Israel, 58100
    • Nycomed Investigational Site
  • Jerusalem, Israel, 91031
    • Nycomed Investigational Site
  • Jerusalm, Israel, 91120
    • Nycomed Investigational Site
  • Kfar Saba, Israel, 44281
    • Nycomed Investigational Site
  • Petach Tikva, Israel, 49100
    • Nycomed Investigational Site
  • Rehovot, Israel, 76100
    • Nycomed Investigational Site
  • Tel Aviv, Israel, 67891
    • Nycomed Investigational Site
  • Tel Hashomer, Israel, 52621
    • Nycomed Investigational Site
  • Tel-Aviv, Israel, 64239
    • Nycomed Investigational Site
• Italy
  • Ferrara, Italy, 44011
    • Nycomed Investigational Site
  • Genova, Italy, 16132
    • Nycomed Investigational Site
  • Milano, Italy, 20122
    • Nycomed Investigational Site
  • Milano, Italy, 20138
    • Nycomed Investigational Site
  • Modena, Italy, 41100
    • Nycomed Investigational Site
  • Monza, Italy, 20052
    • Nycomed Investigational Site
  • Pordenone, Italy, 33170
    • Nycomed Investigational Site
  • Roma, Italy, 00133
    • Nycomed Investigational Site
• Korea, Republic of
  • Anyang, Korea, Republic of, 431-070
    • Nycomed Investigational Site
  • Cheongju, Korea, Republic of, 361-711
    • Nycomed Investigational Site
  • Daegu, Korea, Republic of
    • Nycomed Investigational Site
  • Seoul, Korea, Republic of, 110-744
    • Nycomed Investigational Site
  • Seoul, Korea, Republic of, 120-752
    • Nycomed Investigational Site
  • Seoul, Korea, Republic of, 152-703
    • Nycomed Investigational Site
  • Wonju, Korea, Republic of, 220-701
    • Nycomed Investigational Site
• Netherlands
  • 's Hertogenbosch, Netherlands, 5200 ME
    • Nycomed Investigational Site
  • Amersfoort, Netherlands, 3800 BM
    • Nycomed Investigational Site
  • Arnhem, Netherlands, 6815 AD
    • Nycomed Investigational Site
  • Enschede, Netherlands, 7500 KA
    • Nycomed Investigational Site
  • Heerlen, Netherlands, 6419 PC
    • Nycomed Investigational Site
  • Hoorn, Netherlands, 1624 NP
    • Nycomed Investigational Site
• Poland
  • Bialystok, Poland, 15-540
    • Nycomed Investigational Site
  • Bydgoszcz, Poland, 85-681
    • Nycomed Investigational Site
  • Gliwice, Poland
    • Nycomed Investigational Site
  • Katowice, Poland, 40-753
    • Nycomed Investigational Site
  • Lodz, Poland, 90-153
    • Nycomed Investigational Site
  • Lodz, Poland, 91-849
    • Nycomed Investigational Site
  • Lodz, Poland, 94-010
    • Nycomed Investigational Site
  • Lublin, Poland, 20-718
    • Nycomed Investigational Site
  • Olesnica, Poland
    • Nycomed Investigational Site
  • Ostrow Wielkopolski, Poland, 63-400
    • Nycomed Investigational Site
  • Tarnow, Poland, 33-100
    • Nycomed Investigational Site
  • Warszawa, Poland
    • Nycomed Investigational Site
  • Wroclaw, Poland, 50-127
    • Nycomed Investigational Site
  • Wroclaw, Poland, 53-301
    • Nycomed Investigational Site
  • Zawadzkie, Poland, 47-120
    • Nycomed Investigational Site
• Russian Federation
  • Chelyabinsk, Russian Federation, 454021
    • Nycomed Investigational Site
  • Kazan, Russian Federation, 420029
    • Nycomed Investigational Site
  • Kemerovo, Russian Federation, 650002
    • Nycomed Investigational Site
  • Moscow, Russian Federation, 105077
    • Nycomed Investigational Site
  • Moscow, Russian Federation, 117485
    • Nycomed Investigational Site
  • Moscow, Russian Federation, 117574
    • Nycomed Investigational Site
  • Moscow, Russian Federation, 125206
    • Nycomed Investigational Site
  • Nizhniy Novgorod, Russian Federation, 603011
    • Nycomed Investigational Site
  • Novosibirsk, Russian Federation, 630087
    • Nycomed Investigational Site
  • Novosibirsk, Russian Federation, 630091
    • Nycomed Investigational Site
  • Samara, Russian Federation
    • Nycomed Investigational Site
  • Saratov, Russian Federation, 410012
    • Nycomed Investigational Site
  • Smolensk, Russian Federation, 214006
    • Nycomed Investigational Site
  • St Petersburg, Russian Federation, 197706
    • Nycomed Investigational Site
  • St. Petersburg, Russian Federation, 196084
    • Nycomed Investigational Site
  • St. Petersburg, Russian Federation, 197089
    • Nycomed Investigational Site
  • Volgograd, Russian Federation, 400001
    • Nycomed Investigational Site
  • Vsevolozhsk, Russian Federation, 188640
    • Nycomed Investigational Site
  • Yaroslavl, Russian Federation, 150010
    • Nycomed Investigational Site
• Slovakia
  • Banska Bystrica, Slovakia, 975 17
    • Nycomed Investigational Site
  • Bardejov, Slovakia, 085 01
    • Nycomed Investigational Site
  • Bratislava, Slovakia, 821 06
    • Nycomed Investigational Site
  • Bratislava, Slovakia, 826 06
    • Nycomed Investigational Site
  • Kosice, Slovakia, 040 01
    • Nycomed Investigational Site
  • Martin, Slovakia, 036 01
    • Nycomed Investigational Site
  • Nitra, Slovakia, 950 01
    • Nycomed Investigational Site
  • Nove Zamky, Slovakia, 940 34
    • Nycomed Investigational Site
  • Spisska Nova Ves, Slovakia, 052 01
    • Nycomed Investigational Site
• South Africa
  • Auckland Park, Johannesburg Gauteng, South Africa, 2006
    • Nycomed Investigational Site
  • Benoni Gauteng, South Africa, 1500
    • Nycomed Investigational Site
  • Bloemfontein Free State, South Africa, 9300
    • Nycomed Investigational Site
  • Cape Town Western Cape, South Africa, 7764
    • Nycomed Investigational Site
  • Durban Kwazulu-Natal, South Africa, 4092
    • Nycomed Investigational Site
  • Johannesburg, South Africa, 2193
    • Nycomed Investigational Site
  • Morningside, Johannesburg Gauteng, South Africa, 2057
    • Nycomed Investigational Site
  • Thabazimbi Limpopo, South Africa, 0380
    • Nycomed Investigational Site
  • Umkomaas Kwazulu-Natal, South Africa, 4170
    • Nycomed Investigational Site
  • Witbank Mpumalanga, South Africa, 1035
    • Nycomed Investigational Site
• Spain
  • Barcelona, Spain, 08022
    • Nycomed Investigational Site
  • Guadalajara, Spain, 19002
    • Nycomed Investigational Site
  • Madrid, Spain, 28007
    • Nycomed Investigational Site
  • Pozuelo de Alarcon, Spain, 28223
    • Nycomed Investigational Site
  • Santander, Spain, 39008
    • Nycomed Investigational Site
  • Terrassa, Spain, 08221
    • Nycomed Investigational Site
  • Valencia, Spain, 46015
    • Nycomed Investigational Site
• Turkey
  • Ankara, Turkey, 06590
    • Nycomed Investigational Site
  • Canakkale, Turkey, 17020
    • Nycomed Investigational Site
  • Istanbul, Turkey, 34098
    • Nycomed Investigational Site
  • Izmir, Turkey, 35100
    • Nycomed Investigational Site
  • Kocaeli, Turkey, 41380
    • Nycomed Investigational Site
  • Konya, Turkey, 42075
    • Nycomed Investigational Site
  • Mersin, Turkey, 33079
    • Nycomed Investigational Site
• United Kingdom
  • Edinburgh, United Kingdom, EH16 4TJ
    • Nycomed Investigational Site
  • Glasgow, United Kingdom
    • Nycomed Investigational Site
  • Liverpool, United Kingdom, L9 7AL
    • Nycomed Investigational Site
  • London, United Kingdom, E2 9JX
    • Nycomed Investigational Site
  • London, United Kingdom, NW3 2PF
    • Nycomed Investigational Site
  • Norwich, United Kingdom, NR4 7UY
    • Nycomed Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Roflumilast; concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid	Drug: Roflumilast; 500 µg, once daily
Placebo Comparator: Placebo; concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid	Drug: Placebo; once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as follows: Severe=Requiring hospitalization and/or leading to death; Moderate=Requiring oral or parenteral glucocorticosteroid therapy. The defined number of days a patient was in the trial was divided by 365.25, in order to express the duration as a fraction of 1 year.	52 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1)	Pulmonary function testing was performed using centralised spirometry. FEV1 is the maximum amount of air that can be forcefully exhaled in one second. Least-squares means is from Analysis of Covariance (ANCOVA) including treatment by time interaction. A positive change from Baseline indicates improvement.	Baseline and Week 52
Rate of Severe COPD Exacerbations Per Patient Per Year	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. Severe COPD exacerbations were categorized as requiring hospitalization and/or leading to death. The defined number of days a patient was in the trial was divided by 365.25, in order to express the duration as a fraction of 1 year.	52 weeks
Rate of COPD Exacerbations Per Patient Per Year All Categories	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as follows: Severe=Requiring hospitalization and/or leading to death; Moderate=Requiring oral or parenteral glucocorticosteroid therapy. The defined number of days a patient was in the trial was divided by 365.25, in order to express the duration as a fraction of 1 year.	52 weeks
Percentage of Participants Experiencing at Least 1 COPD Exacerbation	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management.	52 weeks
Time to First COPD Exacerbation All Categories	Time to event was calculated as date of onset of event - date of first intake of double-blind study drug + 1 day for all events: mild, moderate or severe. A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management.	52 Weeks
Time to Second Moderate or Severe COPD Exacerbation	Time to event was calculated as date of onset of event - date of first intake of double-blind study drug + 1 day for events: moderate or severe. A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as Severe: Requiring hospitalization and/or leading to death; Moderate: Requiring oral or parenteral glucocorticosteroid therapy.	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
Time to Third Moderate or Severe COPD Exacerbation	Time to event was calculated as date of onset of event - date of first intake of double-blind study drug + 1 day for events: moderate or severe. A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as Severe: Requiring hospitalization and/or leading to death; Moderate: Requiring oral or parenteral glucocorticosteroid therapy.	52 Weeks
Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation Derived From Exacerbation Per Patient Per Year	The number needed to treat (NNT) analysis is a simple, concise method to quantify directly the benefits that alternative treatment options have on disease outcomes in terms of the number of patients who need to be treated before a benefit is observed. Risk reduction: Rate(Placebo)- Rate (Roflumilast 500 μg), Number needed to treat for benefit (NNTB): 1/(Risk reduction). A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. COPD exacerbations were categorized as Severe: Requiring hospitalization and/or leading to death; Moderate: Requiring oral or parenteral glucocorticosteroid therapy.	52 Weeks
Number of Moderate or Severe COPD Exacerbation Days	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management. The number of exacerbation days per patient is the sum of durations (stop date of exacerbation - start date of exacerbation + 1) of all exacerbations within the category.	52 Weeks
Duration of Moderate or Severe COPD Exacerbations Per Participant	A COPD exacerbation is an event in the natural course of the disease characterized by a worsening in the patient's baseline dyspnoea, cough, and/or sputum production beyond day to day variability sufficient to warrant a change in management.	52 Weeks
Change From Baseline in Post-Bronchodilator Forced Vital Capacity (FVC)	Forced vital capacity is the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Least-squares means was from ANCOVA including treatment by time interaction. A positive change from Baseline indicates improvement.	52 weeks
Change From Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%)	Forced expiratory flow 25-75% (FEF25-75%) is the flow (or speed) of air coming out of the lung during the middle half of a forced expiration. Pulmonary function testing was performed using centralized spirometry. Least-squares means was from ANCOVA including treatment by time interaction. A positive change from Baseline indicates improvement.	52 weeks
Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6)	FEV6 is the amount of air which can be forcibly exhaled from the lungs in the first six seconds of a forced exhalation. Pulmonary function testing was performed using centralized spirometry. A positive change from Baseline indicates improvement.	52 weeks
Change From Baseline in Post-Bronchodilator FEV1/FVC	The FEV1/FVC ratio represents the percentage of vital capacity expelled from the lungs during the first second of a forced exhalation. Pulmonary function testing was performed using centralized spirometry. A positive change from Baseline indicates improvement.	52 weeks
Change From Baseline in Use of Rescue Medication From Daily Diary	Salbutamol metered dose inhaler was available as rescue medication during the study. The participant recorded the use of rescue medication in a daily diary. A negative change from Baseline indicates an improvement.	Baseline and Week 52
Change From Baseline in COPD Symptom Score From Daily Diary	Participants recorded COPD symptoms cough and sputum production in a daily diary. Cough was assessed using a 4-point scale where 0=No cough to 3=severe cough and sputum was assessed using a 4-point scale where 0=no sputum production to 3=severe sputum production. Least-squares means from ANCOVA including treatment by time interaction. A negative change from Baseline indicates improvement. Total symptom score is the sum of cough and sputum scores, ranging from 0 (best possible outcome) to 6 (worst possible outcome).	52 weeks
Percentage of Symptom-Free Days	Symptoms of COPD (cough, sputum) were recorded in a daily diary. The percentage of days without symptoms is reported.	52 Weeks
Percentage of Rescue Medication-Free Days	Participants recorded their use of rescue medication in a daily diary. The percentage of days without rescue medication use.	52 Weeks
Change From Baseline in COPD Assessment Test (CAT) Total Score	Participants completed the CAT questionnaire at Baseline and after 52 Weeks of Treatment. The CAT questionnaire measures the impact of COPD on wellbeing and daily life. Participants answer 8 questions on a scale from 0 (best) to 5 (worst). The total score ranges from 0 to 40 with higher scores indicating more impact. A negative change from Baseline indicates improvement. Least-squares means from ANCOVA including treatment by time interaction.	Baseline and Week 52
Percentage of Participants With Improvement in CAT	Participants completed the CAT questionnaire at Baseline and after 52 Weeks of treatment. The CAT questionnaire measures the impact of COPD on wellbeing and daily life. Participants answer 8 questions on a scale from 0 (best) to 5 (worst). The total score ranges from 0 to 40 with higher scores indicating more impact. Improvement was defined as a CAT Total Score reduction from Baseline > 1.6.	Baseline and Week 52
Time to Mortality Due to Any Reason During the Treatment Period Score	Time to event will be calculated as date of onset of event - date of first intake of double-blind study drug + 1 day.	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
Time to Mortality Due to COPD Exacerbation During the Treatment Period	Time to event will be calculated as date of onset of event - date of first intake of double-blind study drug + 1 day.	52 Weeks
Time to Withdrawal During the Treatment Period	Time to event will be calculated as date of onset of event - date of first intake of double-blind study drug + 1 day.	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
Time to Withdrawal Due to COPD Exacerbation During the Treatment Period	Time to event will be calculated as date of onset of event - date of first intake of double-blind study drug + 1 day.	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
Percentage of Participants With Major Adverse Cardiovascular Event (MACE) During the Treatment Period	Composite MACE is a combined endpoint (cardiovascular death [including death due to undetermined cause], nonfatal myocardial infarction, and nonfatal stroke).	52 Weeks
Time to First Major Adverse Cardiovascular Event (MACE) During the Treatment Period	Composite MACE is a combined endpoint(cardiovascular death [including death due to undetermined cause], nonfatal myocardial infarction, and nonfatal stroke). Time to event was calculated as date of onset of event - date of first intake of double-blind study drug + 1 day.	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
Percentage of Participant With All-Cause Hospitalisation During the Treatment Period	Percentage of patients with at least one hospital admission due to any cause.	52 Weeks
Time to First Hospitalisation Due to Any Cause During the Treatment Period	Time to event will be calculated as date of onset of event - date of first intake of double-blind study drug + 1 day.	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
Time to Trial Withdrawal Due to an Adverse Event	Time to event will be calculated as date of onset of event - date of first intake of double-blind study drug + 1 day.	52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis)
Percentage of Participants Who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE)	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.	52 Weeks
Change From Baseline in Body Weight	Least Square Means was from an ANCOVA model including Last Observation Carried Forward (LOCF).	Baseline and Week 52
Change From Baseline in Body Mass Index (BMI)	Body mass index (BMI) is a measure of body fat based on height and weight. Least Square Means was from an ANCOVA model including LOCF.	Baseline and Week 52

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: March 30, 2011
• First Submitted That Met QC Criteria: April 4, 2011
• First Posted (Estimate): April 5, 2011

Study Record Updates

• Last Update Posted (Estimate): December 13, 2016
• Last Update Submitted That Met QC Criteria: October 31, 2016
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: COPD; Roflumilast; Daxas
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive
• Other Study ID Numbers: RO-2455-404-RD; 2010-019685-87 (EudraCT Number); U1111-1141-7422 (Registry Identifier: WHO)