Study of Ivacaftor in Cystic Fibrosis Subjects Aged 12 Years and Older Homozygous for the F508del-CFTR Mutation (DISCOVER)

This study has been completed.
Sponsor:
Collaborator:
Cystic Fibrosis Foundation
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier:
NCT00953706
First received: August 4, 2009
Last updated: April 22, 2014
Last verified: April 2014
Results First Received: February 27, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Cystic Fibrosis
Interventions: Drug: Ivacaftor
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
Part A started on 21 September 2009 (date of first informed consent). After obtaining consent and assent (where applicable), screening evaluations were completed during a period of 2 to 5 weeks (Day -35 to Day -15) before the first dose of study drug.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
In Part A, a total of 140 subjects were enrolled. All received at least 1 dose of the study drug. A 2-week run-in period was included to establish the baseline assessments on Day 1 after ensuring that subjects were properly adhering to their cystic fibrosis (CF) medication regimens.

Reporting Groups
  Description
Placebo Oral tablet every 12 hours (q12h) for 16 weeks
150 mg Ivacaftor q12h Oral tablet of 150 mg of ivacaftor q12h for 16 weeks

Participant Flow:   Overall Study
    Placebo     150 mg Ivacaftor q12h  
STARTED     28 [1]   112 [2]
COMPLETED     26 [3]   104 [3]
NOT COMPLETED     2     8  
Adverse Event                 2                 3  
Lost to Follow-up                 0                 1  
Noncompliance with Study Requirements                 0                 2  
Prohibited Medication                 0                 1  
Early Termination Per Sponsor Decision                 0                 1  
[1] All subjects who received at least 1 dose of study drug (placebo)
[2] All subjects who received at least 1 dose of study drug (ivacaftor)
[3] Completed Part A Treatment Period (Through Week 16)



  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
Placebo Oral tablet every 12 hours (q12h) for 16 weeks
150 mg Ivacaftor q12h Oral tablet of 150 mg of ivacaftor q12h for 16 weeks
Total Total of all reporting groups

Baseline Measures
    Placebo     150 mg Ivacaftor q12h     Total  
Number of Participants  
[units: participants]
  28     112     140  
Age  
[units: years]
Mean ± Standard Deviation
  25.0  ± 8.35     22.8  ± 10.26     23.2  ± 9.91  
Age, Customized  
[units: participants]
     
12 to 17 Years     6     44     50  
18 to 24 Years     10     32     42  
25 to 39 Years     12     26     38  
40 to 45 Years     0     5     5  
> 45 Years     0     5     5  
Gender  
[units: participants]
     
Female     12     54     66  
Male     16     58     74  
Race/Ethnicity, Customized  
[units: participants]
     
Hispanic or Latino     1     2     3  
Not Hispanic or Latino     27     110     137  
Race/Ethnicity, Customized  
[units: participants]
     
Black or African American     0     1     1  
White     28     111     139  
Percent Predicted Forced Expiratory Volume in 1 Second (FEV1), Continuous [1]
[units: percentage]
Mean ± Standard Deviation
  74.8  ± 24.06     79.7  ± 22.67     78.7  ± 22.95  
Percent Predicted FEV1, Categorical [1]
[units: participants]
     
< 70%     15     38     53  
≥ 70% to ≤ 90%     5     35     40  
> 90%     8     39     47  
Weight  
[units: kilograms]
Mean ± Standard Deviation
  63.2  ± 14.96     58.2  ± 13.49     59.2  ± 13.89  
Body Mass Index  
[units: kilogram per square meter]
Mean ± Standard Deviation
  22.2  ± 4.48     21.2  ± 3.25     21.4  ± 3.54  
Sweat Chloride  
[units: millimoles per liter]
Mean ± Standard Deviation
  102.4  ± 7.91     101.4  ± 10.28     101.6  ± 9.83  
[1] Percent predicted for age, gender, and height.



  Outcome Measures
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1.  Primary:   Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 16   [ Time Frame: baseline through 16 weeks ]

2.  Secondary:   Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 16 (Respiratory Domain Score, Pooled)   [ Time Frame: baseline through 16 weeks ]
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Measure Type Secondary
Measure Title Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 16 (Respiratory Domain Score, Pooled)
Measure Description The CFQ-R is a health-related quality of life measure for subjects with cystic fibrosis. Each domain is scored from 0 (worst) to 100 (best). A difference of at least 4 points in the respiratory domain score of the CFQ-R is considered a minimal clinically important difference (MCID).
Time Frame baseline through 16 weeks  
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.
All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.

Reporting Groups
  Description
Placebo Oral tablet every 12 hours (q12h) for 16 weeks
150 mg Ivacaftor q12h Oral tablet of 150 mg of ivacaftor q12h for 16 weeks

Measured Values
    Placebo     150 mg Ivacaftor q12h  
Number of Participants Analyzed  
[units: participants]
  28     111  
Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 16 (Respiratory Domain Score, Pooled)  
[units: score on a scale]
Least Squares Mean ± Standard Error
  -1.4  ± 1.9     -0.1  ± 1.0  


Statistical Analysis 1 for Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 16 (Respiratory Domain Score, Pooled)
Groups [1] All groups
Method [2] Mixed Models Analysis
P Value [3] 0.5408
Mean Difference (Final Values) [4] 1.3
Standard Error of the mean ± 2.1
95% Confidence Interval ( -2.9 to 5.6 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis for the respiratory domain score endpoint was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from Mixed-Effects Model for Repeated Measures (MMRM) with the dependent variable being absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for for age and baseline value for CFQ-R score, using unstructured covariance matrix
[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 text entered.
[4] Other relevant estimation information:
  No text entered.

Statistical Analysis 2 for Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 16 (Respiratory Domain Score, Pooled)
Groups [1] All groups
Method [2] Mixed Models Analysis
P Value [3] 0.5408
Mean Difference (Final Values) [4] 1.3
Standard Error of the mean ± 2.1
95% Confidence Interval ( -2.9 to 5.6 )
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  Analysis for the respiratory domain score endpoint was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from Mixed-Effects Model for Repeated Measures (MMRM) with the dependent variable being absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for age and baseline value for CFQ-R score, using unstructured covariance matrix.
[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 text entered.
[4] Other relevant estimation information:
  No text entered.



3.  Secondary:   Absolute Change From Baseline in Sweat Chloride Concentration Through Week 16   [ Time Frame: baseline through 16 weeks ]

4.  Secondary:   Rate of Change From Baseline in Weight Through Week 16   [ Time Frame: baseline to 16 weeks ]


  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
This study was primarily designed to collect safety information for subjects treated with ivacaftor and was not powered to detect a statistically significant treatment effect in any efficacy endpoints.


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