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
Results First Received: March 10, 2015  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator);   Primary Purpose: Treatment
Condition: Chronic Obstructive Pulmonary Disease
Interventions: Drug: Roflumilast
Drug: Placebo

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Participants took part in the study at 203 investigative sites in Australia, Austria, Belgium, Brazil, Canada, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Korea (Republic of), Netherlands, Poland, Russia, Slovak Republic, South Africa, Spain, Turkey and United Kingdom from 28 May 2011 to 27 May 2014.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Participants with a diagnosis of Chronic Obstructive Pulmonary Disease (COPD) entered a 4 week baseline period during which all patients received placebo then were enrolled equally in 1 of 2 treatment groups, once a day placebo or roflumilast 500 µg.

Reporting Groups
  Description
Roflumilast 500 µg Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.

Participant Flow:   Overall Study
    Roflumilast 500 µg     Placebo  
STARTED     973     972  
Full Analysis Set (FAS)     969     966  
Safety Population     968     967  
COMPLETED     704     780  
NOT COMPLETED     269     192  
Withdrawal by Subject                 117                 87  
Adverse Event                 82                 29  
Death                 16                 19  
Other                 14                 20  
COPD Exacerbation                 11                 18  
Physician Decision                 16                 13  
Lost to Follow-up                 8                 5  
Met Pre-defined Discontinuation Criteria                 5                 1  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
Full Analysis Set (FAS) includes all randomised participants who took at least 1 dose of investigational medicinal product (IMP) after randomisation.

Reporting Groups
  Description
Roflumilast 500 µg Roflumilast 500 µg tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Placebo Placebo-matching roflumilast tablet, orally, once daily for 52 weeks. Background therapy concomitant medication: fixed combination of long-acting β2-agonist and inhaled glucocorticosteroid.
Total Total of all reporting groups

Baseline Measures
    Roflumilast 500 µg     Placebo     Total  
Number of Participants  
[units: participants]
  969     966     1935  
Age  
[units: years]
Mean (Standard Deviation)
  64.7  (8.38)     64.7  (8.37)     64.7  (8.37)  
Age, Customized  
[units: participants]
     
≤ 65 years     527     542     1069  
> 65 years     442     424     866  
Gender  
[units: participants]
     
Female     251     241     492  
Male     718     725     1443  
Race/Ethnicity, Customized  
[units: participants]
     
Asian     20     16     36  
Black or African American     6     5     11  
White     940     943     1883  
Other     3     2     5  
Region of Enrollment  
[units: participants]
     
Australia     9     16     25  
Austria     11     3     14  
Belgium     19     18     37  
Brazil     42     38     80  
Canada     14     12     26  
Denmark     15     19     34  
France     16     13     29  
Germany     70     63     133  
Greece     38     30     68  
Hungary     111     125     236  
Israel     114     126     240  
Italy     64     51     115  
Korea, Republic Of     11     7     18  
Netherlands     11     8     19  
Poland     88     88     176  
Russian Federation     177     181     358  
Slovakia     25     33     58  
South Africa     23     30     53  
Spain     37     33     70  
Turkey     52     44     96  
United Kingdom     22     28     50  
Height  
[units: cm]
Mean (Standard Deviation)
  168.20  (8.652)     168.33  (8.198)     168.26  (8.427)  
Weight  
[units: kg]
Mean (Standard Deviation)
  75.07  (17.275)     75.60  (17.238)     75.33  (17.254)  
Body Mass Index (BMI)  
[units: kg/m^2]
Mean (Standard Deviation)
  26.45  (5.474)     26.58  (5.359)     26.52  (5.416)  
Chronic Obstructive Pulmonary Disease (COPD) Severity [1]
[units: participants]
     
Mild     2     0     2  
Moderate     18     16     34  
Severe     658     677     1335  
Very Severe     291     273     564  
COPD Disease Characteristics  
[units: participants]
     
Pure emphysema     4     2     6  
Predominantly chronic bronchitis     338     330     668  
Combined emphysema and chronic bronchitis     626     634     1260  
Missing     1     0     1  
Global Initiative for Chronic Obstructive Lung Disease (GOLD) Patient Group  
[units: participants]
     
A : low risk, less symptoms     0     0     0  
B: low risk, more symptoms     0     0     0  
C: high risk, less symptoms     62     57     119  
D: high risk, more symptoms     905     907     1812  
Missing     2     2     4  
Smoking Status  
[units: participants]
     
Current smoker     411     432     843  
Former smoker     558     534     1092  
Nonsmoker     0     0     0  
Cigarette Pack Years [2]
[units: pack years]
Mean (Standard Deviation)
  47.6  (24.55)     47.6  (23.56)     47.6  (24.6)  
Pre-bronchodilator Forced Expiratory Volume in the First Second (FEV1) [3]
[units: Liters]
Mean (Standard Deviation)
  0.999  (0.3149)     1.016  (0.3209)     1.008  (0.3180)  
Post-bronchodilator FEV1  
[units: Liters]
Mean (Standard Deviation)
  1.066  (0.3317)     1.078  (0.3244)     1.072  (0.3280)  
Pre-bronchodilator FEV1 Predicted [4]
[units: percent of predicted]
Mean (Standard Deviation)
  33.259  (9.0781)     33.562  (9.0043)     33.411  (9.0402)  
Post-bronchodilator FEV1 Predicted  
[units: percent predicted]
Mean (Standard Deviation)
  35.392  (9.2484)     35.532  (8.7573)     35.462  (9.0045)  
FEV1 Reversibility % Increase [5]
[units: percent reversibility]
Mean (Standard Deviation)
  7.465  (11.2559)     7.383  (12.0752)     7.424  (11.6703)  
FEV1 Reversibility Increase [6]
[units: mL]
Mean (Standard Deviation)
  65.2  (108.72)     65.4  (121.55)     65.3  (115.29)  
Post-bronchodilator FEV1/Forced Vital Capacity (FVC) [7]
[units: FEV1/FVC percent]
Mean (Standard Deviation)
  40.2  (10.81)     40.1  (10.26)     40.1  (10.54)  
[1] COPD severity was classified according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Guideline (2009) as: - Very severe COPD: baseline post-bronchodilator FEV1 %predicted < 30% - Severe COPD: baseline post-bronchodilator FEV1 %predicted ≥ 30% to < 50% - Moderate COPD: baseline post-bronchodilator FEV1 %predicted ≥ 50% to < 80% - Mild COPD: baseline post-bronchodilator FEV1 %predicted ≥ 80%.
[2] Pack Years = (packs smoked per day) * (years as a smoker)
[3] Number of participants for whom pre-bronchodilator FEV1 data was available was 938 and 937 in each treatment arm, respectively.
[4] Number of participants for whom pre-bronchodilator FEV1 data was available was 938 and 933 in each treatment arm, respectively.
[5] FEV reversibility (%) = (post-bronchodilator FEV minus pre-bronchodilator FEV) / pre-bronchodilator FEV * 100. Number of participants for whom FEV1 reversibility % increase data was available was 912 and 915 in each treatment arm, respectively.
[6] Number of participants for whom FEV1 reversibility increase data was available was 912 and 915 in each treatment arm, respectively.
[7] Calculated as FEV1/FVC * 100



  Outcome Measures
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1.  Primary:   Rate of Moderate or Severe COPD Exacerbations Per Patient Per Year   [ Time Frame: 52 weeks ]

2.  Secondary:   Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First Second (FEV1)   [ Time Frame: Baseline and Week 52 ]

3.  Secondary:   Rate of Severe COPD Exacerbations Per Patient Per Year   [ Time Frame: 52 weeks ]

4.  Secondary:   Rate of COPD Exacerbations Per Patient Per Year All Categories   [ Time Frame: 52 weeks ]

5.  Secondary:   Percentage of Participants Experiencing at Least 1 COPD Exacerbation   [ Time Frame: 52 weeks ]

6.  Secondary:   Time to First COPD Exacerbation All Categories   [ Time Frame: 52 Weeks ]

7.  Secondary:   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) ]

8.  Secondary:   Time to Third Moderate or Severe COPD Exacerbation   [ Time Frame: 52 Weeks ]

9.  Secondary:   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 ]

10.  Secondary:   Number of Moderate or Severe COPD Exacerbation Days   [ Time Frame: 52 Weeks ]

11.  Secondary:   Duration of Moderate or Severe COPD Exacerbations Per Participant   [ Time Frame: 52 Weeks ]

12.  Secondary:   Change From Baseline in Post-Bronchodilator Forced Vital Capacity (FVC)   [ Time Frame: 52 weeks ]

13.  Secondary:   Change From Baseline in Post-Bronchodilator Forced Expiratory Flow at 25% to 75% of Vital Capacity (FEF25-75%)   [ Time Frame: 52 weeks ]

14.  Secondary:   Change From Baseline in Post-Bronchodilator Forced Expiratory Volume in the First 6 Seconds (FEV6)   [ Time Frame: 52 weeks ]

15.  Secondary:   Change From Baseline in Post-Bronchodilator FEV1/FVC   [ Time Frame: 52 weeks ]

16.  Secondary:   Change From Baseline in Use of Rescue Medication From Daily Diary   [ Time Frame: Baseline and Week 52 ]

17.  Secondary:   Change From Baseline in COPD Symptom Score From Daily Diary   [ Time Frame: 52 weeks ]

18.  Secondary:   Percentage of Symptom-Free Days   [ Time Frame: 52 Weeks ]

19.  Secondary:   Percentage of Rescue Medication-Free Days   [ Time Frame: 52 Weeks ]

20.  Secondary:   Change From Baseline in COPD Assessment Test (CAT) Total Score   [ Time Frame: Baseline and Week 52 ]

21.  Secondary:   Percentage of Participants With Improvement in CAT   [ Time Frame: Baseline and Week 52 ]

22.  Secondary:   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) ]

23.  Secondary:   Time to Mortality Due to COPD Exacerbation During the Treatment Period   [ Time Frame: 52 Weeks ]

24.  Secondary:   Time to Withdrawal During the Treatment Period   [ Time Frame: 52 Weeks (some participants extended treatment beyond 52 Weeks and are included in the analysis) ]

25.  Secondary:   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) ]

26.  Secondary:   Percentage of Participants With Major Adverse Cardiovascular Event (MACE) During the Treatment Period   [ Time Frame: 52 Weeks ]

27.  Secondary:   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) ]

28.  Secondary:   Percentage of Participant With All-Cause Hospitalisation During the Treatment Period   [ Time Frame: 52 Weeks ]

29.  Secondary:   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) ]

30.  Secondary:   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) ]

31.  Secondary:   Percentage of Participants Who Experienced at Least 1 Treatment Emergent Adverse Event (TEAE)   [ Time Frame: 52 Weeks ]

32.  Secondary:   Change From Baseline in Body Weight   [ Time Frame: Baseline and Week 52 ]

33.  Secondary:   Change From Baseline in Body Mass Index (BMI)   [ Time Frame: Baseline and Week 52 ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Medical Director, Clinical Science
Organization: Takeda
phone: +1-877-825-3327
e-mail: trialdisclosures@takeda.com


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 ( EudraCT Number )
U1111-1141-7422 ( Registry Identifier: WHO )
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