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

This study is ongoing, but not recruiting participants.

Sponsor:

Collaborator:

Cystic Fibrosis Foundation

Information provided by (Responsible Party):

Vertex Pharmaceuticals Incorporated

ClinicalTrials.gov Identifier:

NCT00953706

First received: August 4, 2009

Last updated: October 25, 2012

Last verified: October 2012

History of Changes

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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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 ]

Measure Type	Primary
Measure Title	Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 16
Measure Description	Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.
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 Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 16 [units: percent of predicted volume (L)] Least Squares Mean ± Standard Error	-0.2 ± 1.1	1.5 ± 0.5

Statistical Analysis 1 for Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) 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 subject as a random effect, with adjustment for age and continuous baseline value of percent predicted FEV1.
[2]	Other relevant 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:

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 ]

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 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 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 ]

Measure Type	Secondary
Measure Title	Absolute Change From Baseline in Sweat Chloride Concentration Through Week 16
Measure Description	The sweat chloride (quantitative pilocarpine iontophoresis) test is a standard diagnostic tool for cystic fibrosis (CF), serving as an indicator of cystic fibrosis transmembrane conductance regulator (CFTR) activity.
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 Sweat Chloride Concentration Through Week 16 [units: millimoles per liter] Least Squares Mean ± Standard Error	0.1 ± 1.2	-2.7 ± 0.6

Statistical Analysis 1 for Absolute Change From Baseline in Sweat Chloride Concentration Through Week 16

Groups ^[1]	All groups
Method ^[2]	Mixed Models Analysis
P Value ^[3]	0.0384
Mean Difference (Final Values) ^[4]	-2.9
Standard Error of the mean	± 1.4
95% Confidence Interval	( -5.6 to -0.2 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	Analysis for this variable was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from Mixed-Effects Model for Repeated Measures (MMRM) with dependent variable being absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous age and baseline value for age, sweat chloride, using unstructured covariance matrix.
[2]	Other relevant 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.

4. Secondary:

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

Measure Type	Secondary
Measure Title	Rate of Change From Baseline in Weight Through Week 16
Measure Description	As malnutrition is common in patients with cystic fibrosis (CF) because of increased energy expenditures due to lung disease and fat malabsorption, body weight is an important clinical measure of nutritional status.
Time Frame	baseline to 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	112
Rate of Change From Baseline in Weight Through Week 16 [units: kilograms per 112 days] Least Squares Mean ± Standard Error	0.9 ± 0.4	0.8 ± 0.2

Statistical Analysis 1 for Rate of Change From Baseline in Weight Through Week 16

Groups ^[1]	All groups
Method ^[2]	Mixed Models Analysis
P Value ^[3]	0.7265
Mean Difference (Final Values) ^[4]	-0.2
Standard Error of the mean	± 0.5
95% Confidence Interval	( -1.1 to 0.7 )

[1]	Additional details about the analysis, such as null hypothesis and power calculation:
	The analysis used the linear mixed model with treatment as fixed effects, visit (days on study) and treatment by visit interaction as random effects, with adjustment for age group (< 18 years and ≥ 18 years) and percent predicted forced expiratory volume (FEV1) severity (< 70%, ≥ 70% to ≤ 90%, > 90%) at screening, with random intercept and random slope. Rate of change in the study period is the slope of weight versus time (days) multiplied by the number of days in the study period (112 days).
[2]	Other relevant 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.

Serious Adverse Events

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Other Adverse Events

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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:

	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.
	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.
	Other disclosure agreement that restricts the right of the PI to discuss or publish trial results after the trial is completed.

Limitations and Caveats

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.

Results Point of Contact:

Name/Title: Medical Monitor
Organization: Vertex
phone: 617-444-6777
e-mail: medicalinfo@vrtx.com

No publications provided by Vertex Pharmaceuticals Incorporated

Publications automatically indexed to this study:

Flume PA, Liou TG, Borowitz DS, Li H, Yen K, Ordoñez CL, Geller DE; VX 08-770-104 Study Group. Ivacaftor in subjects with cystic fibrosis who are homozygous for the F508del-CFTR mutation. Chest. 2012 Sep;142(3):718-24.

Responsible Party:	Vertex Pharmaceuticals Incorporated
ClinicalTrials.gov Identifier:	NCT00953706 History of Changes
Other Study ID Numbers:	VX08-770-104
Study First Received:	August 4, 2009
Results First Received:	February 27, 2012
Last Updated:	October 25, 2012
Health Authority:	United States: Food and Drug Administration

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