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

Study Overview
=================
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.

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

Conditions
-----------------
Chronic Obstructive Pulmonary Disease

Intervention / Treatment
-----------------
* Drug: Roflumilast
* Drug: Placebo


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 40 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COPD, Roflumilast, Daxas