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

This study has been terminated.
(Following review of results obtained from a pre-specified 6-month analysis of Part B data the study was terminated on the basis of futility.)
Sponsor:
Collaborator:
Cystic Fibrosis Foundation Therapeutics
Information provided by (Responsible Party):
Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier:
NCT00953706
First received: August 4, 2009
Last updated: July 29, 2015
Last verified: July 2015
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
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
Placebo – Part A Placebo matched to ivacaftor tablet orally every 12 hours (q12h) for 16 weeks during Part A (double-blind treatment period).
Ivacaftor – Part A Ivacaftor 150 milligram (mg) tablet orally q12h for 16 weeks during Part A (double-blind treatment period).
Placebo/Ivacaftor – Part B Participants who received placebo during Part A, received ivacaftor 150 mg tablet orally q12h for 96 weeks during Part B (open-label extension period).
Ivacaftor/Ivacaftor – Part B Participants who received ivacaftor during Part A, received ivacaftor 150 mg tablet orally q12h for 96 weeks during Part B (open-label extension period).

Participant Flow for 2 periods

Period 1:   Part A (16-Week Double-Blind Treatment)
    Placebo – Part A     Ivacaftor – Part A     Placebo/Ivacaftor – Part B     Ivacaftor/Ivacaftor – Part B  
STARTED     28 [1]   112 [2]   0     0  
COMPLETED     26 [3]   104 [4]   0     0  
NOT COMPLETED     2     8     0     0  
Adverse Event                 2                 3                 0                 0  
Lost to Follow-up                 0                 1                 0                 0  
Noncompliance with Study Requirements                 0                 2                 0                 0  
Required Prohibited Medication                 0                 1                 0                 0  
Sponsor Decision                 0                 1                 0                 0  
[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] Only 5 participants continued in Part B.
[4] Only 33 participants continued in Part B.

Period 2:   Part B (96-Week Open-Label Extension)
    Placebo – Part A     Ivacaftor – Part A     Placebo/Ivacaftor – Part B     Ivacaftor/Ivacaftor – Part B  
STARTED     0     0     5     33  
COMPLETED     0     0     0     0  
NOT COMPLETED     0     0     5     33  
Adverse Event                 0                 0                 0                 2  
Noncompliance with Study Requirements                 0                 0                 0                 1  
Required Prohibited Medication                 0                 0                 0                 1  
Study Termination by Sponsor                 0                 0                 4                 25  
Withdrawal by Subject                 0                 0                 1                 2  
Unspecified                 0                 0                 0                 2  



  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 – Part A Placebo matched to ivacaftor tablet orally every 12 hours (q12h) for 16 weeks during Part A (double-blind treatment period).
Ivacaftor – Part A Ivacaftor 150 milligram (mg) tablet orally q12h for 16 weeks during Part A (double-blind treatment period).
Total Total of all reporting groups

Baseline Measures
    Placebo – Part A     Ivacaftor – Part A     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 (ppFEV1), Continuous [1]
[units: percent predicted of FEV1]
Mean (Standard Deviation)
  74.8  (24.06)     79.7  (22.67)     78.7  (22.95)  
ppFEV1, 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:   Part A : Absolute Change From Part A Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 16   [ Time Frame: Part A baseline through Week 16 ]
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Measure Type Primary
Measure Title Part A : Absolute Change From Part A Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 16
Measure Description Spirometry (as measured by ppFEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, and height) was calculated using the Knudson method.
Time Frame Part A baseline through Week 16  
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.
Part A Full Analysis Set (FAS) included all randomized participants who received at least 1 dose of study drug during Part A. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.

Reporting Groups
  Description
Placebo – Part A Placebo matched to ivacaftor tablet orally q12h for 16 weeks during Part A (double-blind treatment period).
Ivacaftor – Part A Ivacaftor 150 mg tablet orally q12h for 16 weeks during Part A (double-blind treatment period).

Measured Values
    Placebo – Part A     Ivacaftor – Part A  
Number of Participants Analyzed  
[units: participants]
  28     111  
Part A : Absolute Change From Part A Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 16  
[units: percent predicted of FEV1]
Least Squares Mean (Standard Error)
  -0.2  (1.1)     1.5  (0.5)  


Statistical Analysis 1 for Part A : Absolute Change From Part A Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 16
Groups [1] All groups
Method [2] Mixed Models Analysis
P Value [3] 0.1509
Mean Difference (Final Values) [4] 1.7
Standard Error of the mean (1.2)
95% Confidence Interval -0.6 to 4.1
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  The primary analysis for the primary efficacy variable was based on a Mixed-Effects Model for Repeated Measures (MMRM). The model included absolute change from baseline in percent predicted forced expiratory volume in 1 second (FEV1) as the dependent variable, treatment (ivacaftor versus placebo) and visit as fixed effects, and participant as a random effect, with adjustment for age and continuous baseline value of percent predicted FEV1.
[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.



2.  Secondary:   Part A : Absolute Change From Part A Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 16   [ Time Frame: Part A baseline through Week 16 ]

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

4.  Secondary:   Part A : Rate of Change From Baseline in Weight Through Week 16   [ Time Frame: Part A baseline through Week 16 ]

5.  Secondary:   Part B : Absolute Change From Part A and Part B Baseline in ppFEV1 Through Week 64   [ Time Frame: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64 ]

6.  Secondary:   Part B : Rate of Decline From Part A Baseline in ppFEV1 Through Week 64   [ Time Frame: Part A baseline through Week 64 ]

7.  Secondary:   Part B : Rate of Decline From Part B Baseline in ppFEV1 Through Week 64   [ Time Frame: Part B baseline through Week 64 ]

8.  Secondary:   Part B : Absolute Change From Part A and Part B Baseline in CFQ-R Respiratory Domain Score Through Week 64   [ Time Frame: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64 ]

9.  Secondary:   Part B : Absolute Change From Part A and Part B Baseline in Sweat Chloride Concentration Through Week 64   [ Time Frame: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64 ]

10.  Secondary:   Part B : Absolute Change From Part A and Part B Baseline in Weight Through Week 64   [ Time Frame: Change from Part A baseline: Part A Baseline, Week 64; Change from Part B baseline: Part B Baseline (Week 16), Week 64 ]

11.  Secondary:   Part B : Number of Participants With Pulmonary Exacerbations   [ Time Frame: Part B baseline through Week 64 ]

12.  Secondary:   Part B : Number of Pulmonary Exacerbation Events   [ Time Frame: Part B baseline through Week 64 ]

13.  Secondary:   Part B : Number of Pulmonary Exacerbation Events Per Participant Per Year   [ Time Frame: Part B baseline through Week 64 ]


  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
In Part B, the treatment duration was 96 weeks; however, due to early study termination all analysis were performed up to Week 64, as planned.


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