Effect of Roflumilast in Chronic Obstructive Pulmonary Disease (COPD) Patients Treated With Tiotropium: The HELIOS Study (BY217/M2-128)

This study has been completed.
Sponsor:
Information provided by:
Takeda
ClinicalTrials.gov Identifier:
NCT00424268
First received: January 18, 2007
Last updated: May 4, 2012
Last verified: August 2011
Results First Received: March 17, 2011  
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
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Roflumilast Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled
Placebo Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled

Participant Flow:   Overall Study
    Roflumilast     Placebo  
STARTED     371 [1]   372 [1]
COMPLETED     309     333  
NOT COMPLETED     62     39  
[1] Includes all randomized patients who took at least one dose of the investigational drug.



  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.
No text entered.

Reporting Groups
  Description
Roflumilast Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled
Placebo Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled
Total Total of all reporting groups

Baseline Measures
    Roflumilast     Placebo     Total  
Number of Participants  
[units: participants]
  371     372     743  
Age  
[units: years]
Mean ± Standard Deviation
  64.2  ± 9.1     64.0  ± 9.3     64.1  ± 9.2  
Gender  
[units: participants]
     
Female     109     105     214  
Male     262     267     529  



  Outcome Measures
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1.  Primary:   Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1)   [ Time Frame: Change from baseline over 24 weeks of treatment ]

Measure Type Primary
Measure Title Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1)
Measure Description Mean change from baseline during the treatment period in pre-bronchodilator FEV1 [L]
Time Frame Change from baseline over 24 weeks of treatment  
Safety Issue No  

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.
ITT (Intention to Treat) analysis. Number of participants analyzed = number of participants with data available.

Reporting Groups
  Description
Roflumilast Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled
Placebo Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled

Measured Values
    Roflumilast     Placebo  
Number of Participants Analyzed  
[units: participants]
  365     364  
Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1)  
[units: mL]
Least Squares Mean ± Standard Error
  65  ± 12     -16  ± 12  


Statistical Analysis 1 for Pre-bronchodilator Forced Expiratory Volume in First Second (FEV1)
Groups [1] All groups
Method [2] ANCOVA
P Value [3] <0.0001
Mean Difference (Net) [4] 80
Standard Error of the mean ± 15
95% Confidence Interval ( 51 to 110 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Repeated measurements analysis (change from baseline over 24 weeks of treatment taking all post-randomization measurements into account).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No adjustment of the significance level (0.05) was done as a hierarchical approach for hypotheses testing was used.
[4] Other relevant estimation information:
  No text entered.



2.  Secondary:   Post-bronchodilator FEV1   [ Time Frame: Change from baseline over 24 weeks of treatment ]

Measure Type Secondary
Measure Title Post-bronchodilator FEV1
Measure Description Mean change from baseline during the treatment period in post-bronchodilator FEV1 [L]
Time Frame Change from baseline over 24 weeks of treatment  
Safety Issue No  

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.
ITT analysis. Number of participants analyzed = number of participants with data available.

Reporting Groups
  Description
Roflumilast Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled
Placebo Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled

Measured Values
    Roflumilast     Placebo  
Number of Participants Analyzed  
[units: participants]
  364     363  
Post-bronchodilator FEV1  
[units: mL]
Least Squares Mean ± Standard Error
  74  ± 12     -7  ± 11  


Statistical Analysis 1 for Post-bronchodilator FEV1
Groups [1] All groups
Method [2] ANCOVA
P Value [3] <0.0001
Mean Difference (Net) [4] 81
Standard Error of the mean ± 15
95% Confidence Interval ( 51 to 110 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Repeated measurements analysis (change from baseline over 24 weeks of treatment taking all post-randomization measurements into account).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No adjustment of the significance level (0.05) was done as a hierarchical approach for hypotheses testing was used.
[4] Other relevant estimation information:
  No text entered.



3.  Secondary:   COPD Exacerbation Rate (Moderate or Severe)   [ Time Frame: 24 weeks treatment period ]

Measure Type Secondary
Measure Title COPD Exacerbation Rate (Moderate or Severe)
Measure Description

Mean rate of COPD exacerbations requiring oral or parenteral glucocorticosteroids (=moderate COPD exacerbations), or requiring hospitalization, or leading to death (=severe COPD exacerbations), per patient per year.

A COPD exacerbation is an event in the natural course of the disease characterized by a change in the patient's baseline dyspnea, cough and/or sputum beyond day-to-day variability sufficient to warrant a change in management [American Thoracic Society (ATS) / European Respiratory Society (ERS) 2005].

Time Frame 24 weeks treatment period  
Safety Issue No  

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.
ITT analysis

Reporting Groups
  Description
Roflumilast Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled
Placebo Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled

Measured Values
    Roflumilast     Placebo  
Number of Participants Analyzed  
[units: participants]
  371     372  
COPD Exacerbation Rate (Moderate or Severe)  
[units: exacerbations per patient per year]
Mean ( 95% Confidence Interval )
  0.262  
  ( 0.184 to 0.375 )  
  0.342  
  ( 0.248 to 0.472 )  


Statistical Analysis 1 for COPD Exacerbation Rate (Moderate or Severe)
Groups [1] All groups
Method [2] Poisson regression
P Value [3] 0.1957
Rate ratio [4] 0.768
Standard Error of the mean ± 0.157
95% Confidence Interval ( 0.515 to 1.146 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  No adjustment of the significance level (0.05) was done as a hierarchical approach for hypotheses testing was used.
[4] Other relevant estimation information:
  No text entered.



4.  Secondary:   Transition Dyspnea Index (TDI) Focal Score   [ Time Frame: Change from baseline over 24 weeks of treatment ]

Measure Type Secondary
Measure Title Transition Dyspnea Index (TDI) Focal Score
Measure Description

The TDI is a recognized questionnaire to measure dyspnea in an out patient COPD population. At baseline, 3 components of dyspnea, each graded with 4 questions, were asked:

  • Functional Impairment
  • Magnitude of Task
  • Magnitude of Effort

At each of the post-randomization visits questions from the TDI were asked related to 3 components:

Change in

  • Functional Impairment
  • Magnitude of Task
  • Magnitude of Effort

Each question in the TDI is graded from –3 (major deterioration) to +3 (major improvement). This results in a TDI Focal Score ranging from –9 to +9.

Time Frame Change from baseline over 24 weeks of treatment  
Safety Issue No  

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.
ITT analysis. Number of participants analyzed = number of participants with data available.

Reporting Groups
  Description
Roflumilast Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled
Placebo Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled

Measured Values
    Roflumilast     Placebo  
Number of Participants Analyzed  
[units: participants]
  364     364  
Transition Dyspnea Index (TDI) Focal Score  
[units: scores on a scale]
Least Squares Mean ± Standard Error
  1.4  ± 0.1     0.9  ± 0.1  


Statistical Analysis 1 for Transition Dyspnea Index (TDI) Focal Score
Groups [1] All groups
Method [2] ANCOVA
P Value [3] 0.0032
Mean Difference (Final Values) [4] 0.4
Standard Error of the mean ± 0.1
95% Confidence Interval ( 0.1 to 0.7 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Repeated measurements analysis (change from baseline over 24 weeks of treatment taking all post-randomization measurements into account).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  This secondary endpoint was analyzed in an exploratory manner.
[4] Other relevant estimation information:
  No text entered.



5.  Secondary:   Shortness of Breath Questionnaire (SOBQ) Total Score   [ Time Frame: Change from baseline over 24 weeks of treatment ]

Measure Type Secondary
Measure Title Shortness of Breath Questionnaire (SOBQ) Total Score
Measure Description

Mean change from baseline during the treatment period in SOBQ. This is a 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living.

The questions were administered at visits V0, V2, V3, V4, V5, V6 and Vend to assess the perceived shortness of breath of the patient.

For each activity listed in the questionnaire the patient should rate his/her breathlessness on a scale between zero and five, where zero is "not at all breathless" and five is "maximally breathless or too breathless to do the activity".

Time Frame Change from baseline over 24 weeks of treatment  
Safety Issue No  

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.
ITT analysis. Number of participants analyzed = number of participants with data available.

Reporting Groups
  Description
Roflumilast Roflumilast 500 µg, once daily, oral and tiotropium 18 µg, once daily, inhaled
Placebo Placebo, once daily, oral and tiotropium 18 µg, once daily, inhaled

Measured Values
    Roflumilast     Placebo  
Number of Participants Analyzed  
[units: participants]
  359     359  
Shortness of Breath Questionnaire (SOBQ) Total Score  
[units: scores on a scale]
Least Squares Mean ± Standard Error
  -3.4  ± 0.7     -0.7  ± 0.7  


Statistical Analysis 1 for Shortness of Breath Questionnaire (SOBQ) Total Score
Groups [1] All groups
Method [2] ANCOVA
P Value [3] 0.0051
Mean Difference (Net) [4] -2.6
Standard Error of the mean ± 0.9
95% Confidence Interval ( -4.5 to -0.8 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Other relevant method information, such as adjustments or degrees of freedom:
  Repeated measurements analysis (change from baseline over 24 weeks of treatment taking all post-randomization measurements into account).
[3] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  This secondary endpoint was analyzed in an exploratory manner.
[4] Other relevant estimation information:
  No text entered.




  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