Now Available: Final Rule for FDAAA 801 and NIH Policy on Clinical Trial Reporting

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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT01329029
First received: March 30, 2011
Last updated: September 25, 2015
Last verified: September 2015
  Purpose

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.


Condition Intervention Phase
Chronic Obstructive Pulmonary Disease
Drug: Roflumilast
Drug: Placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Takeda:

Primary Outcome Measures:
  • Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1) [ Time Frame: Baseline and Week 52 ] [ Designated as safety issue: No ]
    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.

  • Rate of Severe COPD Exacerbations Per Patient Per Year [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Rate of COPD Exacerbations Per Patient Per Year All Categories [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Experiencing at Least 1 COPD Exacerbation [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Time to First COPD Exacerbation All Categories [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
    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.

  • Time to Second Moderate or Severe COPD Exacerbation [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ] [ Designated as safety issue: No ]
    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.

  • Time to Third Moderate or Severe COPD Exacerbation [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
    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.

  • Number of Patients Needed to Treat to Avoid 1 Moderate or Severe COPD Exacerbation Derived From Exacerbation Per Patient Per Year [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
    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.

  • Number of Moderate or Severe COPD Exacerbation Days [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
    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.

  • Duration of Moderate or Severe COPD Exacerbations Per Participant [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Post-Bronchodilator Forced Vital Capacity (FVC) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6) [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Post-Bronchodilator FEV1/FVC [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in Use of Rescue Medication From Daily Diary [ Time Frame: Baseline and Week 52 ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline in COPD Symptom Score From Daily Diary [ Time Frame: 52 weeks ] [ Designated as safety issue: No ]
    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).

  • Percentage of Symptom-Free Days [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
    Symptoms of COPD (cough, sputum) were recorded in a daily diary. The percentage of days without symptoms is reported.

  • Percentage of Rescue Medication-Free Days [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
    Participants recorded their use of rescue medication in a daily diary. The percentage of days without rescue medication use.

  • Change From Baseline in COPD Assessment Test (CAT) Total Score [ Time Frame: Baseline and Week 52 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants With Improvement in CAT [ Time Frame: Baseline and Week 52 ] [ Designated as safety issue: No ]
    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.

  • Time to Mortality Due to Any Reason During the Treatment Period Score [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ] [ Designated as safety issue: No ]
    Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.

  • Time to Mortality Due to COPD Exacerbation During the Treatment Period [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
    Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.

  • Time to Withdrawal During the Treatment Period [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ] [ Designated as safety issue: No ]
    Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.

  • Time to Withdrawal Due to COPD Exacerbation During the Treatment Period [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ] [ Designated as safety issue: No ]
    Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.

  • Percentage of Participants With Major Adverse Cardiovascular Event (MACE) During the Treatment Period [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
    Composite MACE is a combined endpoint (cardiovascular death [including death due to undetermined cause], nonfatal myocardial infarction, and nonfatal stroke).

  • Time to First Major Adverse Cardiovascular Event (MACE) During the Treatment Period [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participant With All-Cause Hospitalisation During the Treatment Period [ Time Frame: 52 Weeks ] [ Designated as safety issue: No ]
    Percentage of patients with at least one hospital admission due to any cause.

  • Time to First Hospitalisation Due to Any Cause During the Treatment Period [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ] [ Designated as safety issue: No ]
    Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.

  • Time to Trial Withdrawal Due to an Adverse Event [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ] [ Designated as safety issue: No ]
    Time to event will be calculated as date of onset of event — date of first intake of double-blind study drug + 1 day.

  • Percentage of Participants Who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE) [ Time Frame: 52 Weeks ] [ Designated as safety issue: Yes ]
    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.

  • Change From Baseline in Body Weight [ Time Frame: Baseline and Week 52 ] [ Designated as safety issue: Yes ]
    Least Square Means was from an ANCOVA model including Last Observation Carried Forward (LOCF).

  • Change From Baseline in Body Mass Index (BMI) [ Time Frame: Baseline and Week 52 ] [ Designated as safety issue: Yes ]
    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.


Enrollment: 1945
Study Start Date: May 2011
Study Completion Date: May 2014
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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

Ages Eligible for Study:   40 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01329029

  Show 180 Study Locations
Sponsors and Collaborators
Takeda
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01329029     History of Changes
Other Study ID Numbers: RO-2455-404-RD  2010-019685-87  U1111-1141-7422 
Study First Received: March 30, 2011
Results First Received: March 10, 2015
Last Updated: September 25, 2015
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
Austria: Federal Office for Safety in Health Care
Belgium: Federal Agency for Medicinal Products and Health Products
Brazil: National Health Surveillance Agency
Canada: Health Canada
Denmark: Danish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Greece: National Organization of Medicines
Hungary: National Institute of Pharmacy
Israel: Israeli Health Ministry Pharmaceutical Administration
Italy: The Italian Medicines Agency
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Russia: Ministry of Health of the Russian Federation
Slovakia: State Institute for Drug Control
South Africa: Medicines Control Council
South Korea: Korea Food and Drug Administration (KFDA)
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Turkey: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Takeda:
COPD
Roflumilast
Daxas

Additional relevant MeSH terms:
Lung Diseases
Lung Diseases, Obstructive
Pulmonary Disease, Chronic Obstructive
Respiratory Tract Diseases

ClinicalTrials.gov processed this record on September 30, 2016