STRIVE: Study of Ivacaftor in Cystic Fibrosis Subjects Aged 12 Years and Older With the G551D Mutation

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00909532
• Collaborator: Cystic Fibrosis Foundation (Other)
• Enrollment: 167
• Locations: 65
• Arms: 2
• Duration (Months): 41
• Patients Per Site: 2.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis aged 12 years and older who have the G551D mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Ivacaftor is a potent and selective CFTR potentiator of wild-type, G551D, F508del, and R117H forms of human CFTR protein. Potentiators are pharmacological agents that increase the chloride ion transport properties of the channel in the presence of cyclic AMP-dependent protein kinase A (PKA) activation.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis	Drug: Ivacaftor; Drug: Placebo	Phase 3

Detailed Description

This was a phase 3 study in subjects with cystic fibrosis (CF) age 12 years and older who have a G551D-CFTR mutation and percent predicted forced expiratory volumn in 1 second (FEV1) between 40% and 90%.

Based on in vitro studies and pharmacologic, pharmacokinetic (PK), and safety profiles, ivacaftor was selected for clinical development as a possible treatment for patients with CF. Patients with the G551D mutation were the targeted population for this study because ivacaftor is a potentiator of the gating function of the CFTR protein, and the most prevalent mutation with a gating defect in CF is the G551D mutation.

This study was designed to further evaluate the efficacy of ivacaftor in subjects with CF who have a G551D-CFTR gene mutation and to evaluate safety in this population over a longer period than previously studied.

Study Design

• Study Type: Interventional
• Actual Enrollment: 167 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of VX-770 in Subjects With Cystic Fibrosis and the G551D Mutation
• Study Start Date: Jun 1, 2009
• Actual Primary Completion Date: Jul 1, 2010
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Subjects who received placebo every 12 hours (q12h) for up to 48 weeks.	Drug: Placebo; Tablet given orally q12h for up to 48 weeks
Experimental: 150 mg Ivacaftor q12h Subjects who received 150 mg of ivacaftor q12h for up to 48 weeks.	Drug: Ivacaftor; 150-mg tablets given orally q12h for up to 48 weeks; Other Names: VX-770

Outcome Measures

Primary Outcome Measures

1. Absolute Mean Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24 [baseline through 24 weeks]

   Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.

Secondary Outcome Measures

1. Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48 [baseline through 48 weeks]

   Spirometry (as measured by FEV1) is a standardized assessment to evaluate lung function that is the most widely used endpoint in cystic fibrosis studies.

2. Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled) [baseline through 24 weeks and 48 weeks]

   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).

3. Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48 [baseline through 24 weeks and 48 weeks]

   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.

4. Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48 [baseline through 24 weeks and 48 weeks]

   Pulmonary exacerbation was defined as a change in antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of signs/symptoms such as change in sputum; new or increased hemoptysis; increased cough or dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees C; anorexia or weight loss; sinus pain/tenderness and discharge; change in physical examination of the chest; decreased pulmonary function by 10%; and radiographic changes indicative of pulmonary infection.

5. Absolute Change From Baseline in Weight at Week 24 and Week 48 [baseline to 24 weeks and 48 weeks]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Confirmed diagnosis of cystic fibrosis (CF) and G551D mutation in at least 1 allele

• Forced expiratory volume in 1 second (FEV1) of 40% to 90% (inclusive) of predicted normal for age, gender, and height at Screening.

• No clinically significant abnormalities that would have interfered with the study assessments, as judged by the investigator

• Willing to use highly effective birth control methods during the study

Exclusion Criteria:

• History of any illness or condition that might confound the results of the study or pose an additional risk in administering study drug to the subject

• Acute respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 4 weeks of Day 1 of the study

• History of alcohol, medication or illicit drug abuse within one year prior to Day 1

• Abnormal liver function ≥ 3x the upper limit of normal

• Abnormal renal function at Screening

• History of solid organ or hematological transplantation

• Pregnant, planning a pregnancy, breast-feeding, or unwilling to follow contraception requirements

• Ongoing participation in another therapeutic clinical study or prior participation in an investigational drug study within 30 days prior to Screening

• Use of inhaled hypertonic saline treatment

• Concomitant use of any inhibitors or inducers of cytochrome P450 3A4 (CYP 3A4)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama	Birmingham	Alabama	United States	35233-1711
2	Kaiser Permanente Medical Care Program	Oakland	California	United States	94611
3	Cystic Fibrosis Research Office, Stanford University	Palo Alto	California	United States	94304
4	Rady Children's Hospital	San Diego	California	United States	92123-5070
5	National Jewish Medical and Research Center	Denver	Colorado	United States	80206
6	Emory Cystic Fibrosis Center	Atlanta	Georgia	United States	30322
7	St. Luke's CF Clinic	Boise	Idaho	United States	83712
8	Children's Memorial Hospital	Chicago	Illinois	United States	60614
9	Indiana University	Indianapolis	Indiana	United States	46202
10	University of Iowa	Iowa City	Iowa	United States	52242
11	Johns Hopkins University	Baltimore	Maryland	United States	21205
12	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
13	Children's Hospital Boston	Boston	Massachusetts	United States	02115
14	University of Michigan	Ann Arbor	Michigan	United States	48109
15	Pulmonary, Allergy & Critical Care Medicine, University of Minnesota	Minneapolis	Minnesota	United States	55455
16	The Children's Mercy Hospital	Kansas City	Missouri	United States	64108
17	Washington University	St. Louis	Missouri	United States	63110
18	Adult Pulmonary/ CF, University of Nebraska Medical Center	Omaha	Nebraska	United States	68198-5300
19	Monmouth Medical Center	Long Branch	New Jersey	United States	07740
20	Women and Children's Hospital of Buffalo	Buffalo	New York	United States	14222
21	Long Island Jewish Medical Center	New Hyde Park	New York	United States	11042
22	SUNY Upstate Medical University	Syracuse	New York	United States	13210
23	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina	United States	27599
24	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
25	Pediatric & Pulmonary Division, Rainbow Babies/Case Western	Cleveland	Ohio	United States	44106
26	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
27	Toledo Children's Hospital	Toledo	Ohio	United States	43606
28	Oregon Health & Sciences University	Portland	Oregon	United States	97239-3098
29	Hershey Medical Center	Hershey	Pennsylvania	United States	17033
30	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
31	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania	United States	15224
32	East Tennessee Children's Hospital	Knoxville	Tennessee	United States	37916
33	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232-5735
34	University of Utah	Salt Lake City	Utah	United States	84132
35	University of Virginia	Charlottesville	Virginia	United States	22908
36	Seattle Children's Hospital	Seattle	Washington	United States	98105
37	Division of Pulmonary and CCM, University of Washington	Seattle	Washington	United States	98195-6522
38	West Virginia University	Morgantown	West Virginia	United States	26506
39	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
40	The Children's Hospital Westmead	Westmead	New South Wales	Australia	2145
41	The Prince Charles Hospital	Chermside	Queensland	Australia	4032
42	Royal Children's Hospital Brisbane	Herston	Queensland	Australia	4026
43	Mater Adult Hospital	South Brisbane	Queensland	Australia	4101
44	Royal Children's Hospital Melbourne	Parkville	Victoria	Australia	3052
45	Lung Institute of Western Australia	Nedlands	Western Australia	Australia	6009
46	Princess Margaret Hospital for Children	Subiaco	Western Australia	Australia	6008
47	Queen Elizabeth II Health Sciences Centre	Halifax	Nova Scotia	Canada	B3H 3A7
48	St. Michael's Hospital	Toronto	Ontario	Canada	M5B 1W8
49	CF Center, Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
50	Montreal Children's Hospital - MUHC	Montreal	Quebec	Canada	H3H 1P3
51	FN Motol	Prague		Czech Republic	15006
52	Hopital Cochin	Paris		France	75014
53	Hopital Necker	Paris		France	75015
54	Centre de Perharidy	Roscoff		France	29684
55	Kinder- und Jugendklinik Universitätsklinikum Erlangen	Erlangen		Germany	91054
56	Mukoviszidose-Zentrum am Klinikum der Friedrich-Schiller-Universität Jena, Klinik für Kinder- und Jugendmedizin	Jena		Germany	07740
57	Klinikum der LMU München, Dr. von Haunersches Kinderspital (CHA)	Munich		Germany	80337
58	Universitäts-Kinderklinik Würzburg	Wurzburg		Germany	97080
59	Cork University Hospital	Cork		Ireland
60	Our Lady's Children's Hospital	Dublin		Ireland	12
61	The National Children's Hospital	Dublin		Ireland	24
62	St. Vincent's University Hospital	Dublin		Ireland	4
63	Beaumont Hospital	Dublin		Ireland	9
64	Belfast City Hospital	Belfast	Northern Ireland	United Kingdom	BT9 7AB
65	Imperial College London	London		United Kingdom	SW3 6LR

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated
• Cystic Fibrosis Foundation

Investigators

• Principal Investigator: Bonnie W. Ramsey, MD, Children's Hospital and Regional Medical Center, Seattle, Washington, USA
• Principal Investigator: Stuart Elborn, MD, Respiratory Medicine Group, Queen's University of Belfast, Belfast, Northern Ireland, UK

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Genetics Home Reference
• Medline Plus
• U.S. FDA Resources

Publications

• Ramsey BW, Davies J, McElvaney NG, Tullis E, Bell SC, Dřevínek P, Griese M, McKone EF, Wainwright CE, Konstan MW, Moss R, Ratjen F, Sermet-Gaudelus I, Rowe SM, Dong Q, Rodriguez S, Yen K, Ordoñez C, Elborn JS; VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011 Nov 3;365(18):1663-72. doi: 10.1056/NEJMoa1105185.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT00909532
• Other Study ID Numbers: VX08-770-102
• First Posted: May 28, 2009
• Last Update Posted: Jan 18, 2013
• Last Verified: Jan 1, 2013

• Keywords provided by Vertex Pharmaceuticals Incorporated: Fibrosis; Pancreatic Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Pathologic Processes
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Ivacaftor

Study Results

Participant Flow

Recruitment Details	The study started on 10 June 2009 (signing 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 Detail	A total of 167 subjects were randomized; 161 subjects 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 taking their cystic fibrosis (CF) medication regimens.

Arm/Group Title	Placebo	150 mg Ivacaftor q12h
Arm/Group Description	Oral tablet every 12 hours (q12h) for up to 48 weeks.	Oral tablet of 150 mg of ivacaftor q12h for up to 48 weeks.
Period Title: Overall Study
STARTED	78	83
Completed Treatment Period, Week 24	71	80
COMPLETED	68	77
NOT COMPLETED	10	6

Baseline Characteristics

Arm/Group Title	Placebo	150 mg Ivacaftor q12h	Total
Arm/Group Description	Oral tablet every 12 hours (q12h) for up to 48 weeks.	Oral tablet of 150 mg of ivacaftor q12h for up to 48 weeks.	Total of all reporting groups
Overall Participants	78	83	161
Age (Count of Participants)
<=18 years	17 21.8%	19 22.9%	36 22.4%
Between 18 and 65 years	61 78.2%	64 77.1%	125 77.6%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	24.7 (9.21)	26.2 (9.85)	25.5 (9.54)
Sex: Female, Male (Count of Participants)
Female	40 51.3%	44 53%	84 52.2%
Male	38 48.7%	39 47%	77 47.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	77 98.7%	81 97.6%	158 98.1%
Unknown or Not Reported	1 1.3%	2 2.4%	3 1.9%
Race/Ethnicity, Customized (participants) [Number]
White	77 98.7%	81 97.6%	158 98.1%
Not Allowed to Ask Per Local Regulations	1 1.3%	2 2.4%	3 1.9%
Region of Enrollment (participants) [Number]
North America	50 64.1%	50 60.2%	100 62.1%
Europe	19 24.4%	23 27.7%	42 26.1%
Australia	9 11.5%	10 12%	19 11.8%
Percent Predicted Forced Expiratory Volume in 1 Second (FEV1), Continuous (percentage) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage]	63.7 (16.83)	63.5 (16.14)	63.6 (16.43)
Percent Predicted FEV1, Categorical (participants) [Number]
< 70% predicted FEV1	45 57.7%	49 59%	94 58.4%
≥ 70% predicted FEV1	33 42.3%	34 41%	67 41.6%
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	61.2 (13.93)	61.7 (14.26)	61.5 (14.06)
Body Mass Index (kilograms per square meter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms per square meter]	21.9 (3.49)	21.7 (3.65)	21.8 (3.56)
Sweat Chloride (millimoles per liter) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [millimoles per liter]	100.1 (10.63)	100.4 (10.00)	100.2 (10.28)

Outcome Measures

1. Primary Outcome

Title	Absolute Mean Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24
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 24 weeks

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.

Arm/Group Title	Placebo	150 mg Ivacaftor q12h
Arm/Group Description	Oral tablet every 12 hours (q12h) for up to 48 weeks.	Oral tablet of 150 mg of ivacaftor q12h for up to 48 weeks.
Measure Participants	78	83
Least Squares Mean (Standard Error) [percent of predicted volume (L)]	-0.2 (0.7)	10.4 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 150 mg Ivacaftor q12h
	Comments	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 (Day 15, Week 8, Week 16, and Week 24) as fixed effects, and subject as a random effect, with adjustment for the continuous baseline values of age and percent predicted FEV1.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The primary and key secondary endpoints were analyzed using Hochberg's step-up procedure: test 1, primary (α=0.05); test 2, CFQ-R resp domain (Wk24) and sweat chloride (Wk24)(α=0.05).
	Method	Mixed Models Analysis
	Comments	Denominator degrees of freedom were estimated using the Kenward-Roger approximation.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.6
	Confidence Interval	(2-Sided) 95%; 8.6 to 12.6
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.0
	Estimation Comments

2. Secondary Outcome

Title	Absolute Mean Change From Baseline in Percent Predicted FEV1 Through Week 48
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 48 weeks

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame..

Arm/Group Title	Placebo	150 mg Ivacaftor q12h
Arm/Group Description	Oral tablet every 12 hours (q12h) for up to 48 weeks.	Oral tablets of 150 mg of ivacaftor q12h for up to 48 weeks.
Measure Participants	78	83
Least Squares Mean (Standard Error) [percent of predicted volume (L)]	-0.4 (0.7)	10.1 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 150 mg Ivacaftor q12h
	Comments	Analysis of this variable was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were obtained from Mixed-Effects Model for Repeated Measures (MMRM) with dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for the continuous baseline values of age and percent predicted forced expiratory volume in 1 second (FEV1),using unstructured covariance matrix.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	There was no adjustment for multiple comparisons.
	Method	Mixed Models Analysis
	Comments	Denominator degrees of freedom were estimated using the Kenward-Roger approximation. No imputation of missing data was done.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	10.5
	Confidence Interval	(2-Sided) 95%; 8.5 to 12.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.0
	Estimation Comments

3. Secondary Outcome

Title	Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Score Through Week 24 and Week 48 (Respiratory Domain Score, Pooled)
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 24 weeks and 48 weeks

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.

Arm/Group Title	Placebo	150 mg Ivacaftor q12h
Arm/Group Description	Oral tablet every 12 hours (q12h) for up to 48 weeks.	Oral tablet of 150 mg of ivacaftor q12h for up to 48 weeks.
Measure Participants	71	80
Change from Baseline Through Week 24	-2.1 (1.3)	6.0 (1.2)
Change from Baseline Through Week 48	-2.7 (1.2)	6.0 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 150 mg Ivacaftor q12h
	Comments	Through Week 24: 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 dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age, domain score, and percent predicted FEV1, using unstructured covariance matrix.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Analyzed in sequence: test 1, primary (α=0.05); test 2, using Hochberg's step-up procedure on CFQ-R resp domain(Wk 24) and sweat chloride (Wk 24) (α=0.05).
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.1
	Confidence Interval	(2-Sided) 95%; 4.7 to 11.4
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.7
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, 150 mg Ivacaftor q12h
	Comments	Through Week 48: Analysis for the CFQ-R respiratory domain score endpoint was similar to that of the primary analysis of the primary efficacy endpoint. Estimates were from MMRM with dependent variable absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age,sweat chloride, and percent predicted FEV1,using unstructured covariance matrix.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	There was no adjustment for multiple comparisons.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.6
	Confidence Interval	(2-Sided) 95%; 5.3 to 11.9
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.7
	Estimation Comments

4. Secondary Outcome

Title	Absolute Change From Baseline in Sweat Chloride Concentration Through Week 24 and Week 48
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 24 weeks and 48 weeks

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame..

Arm/Group Title	Placebo	150 mg Ivacaftor q12h
Arm/Group Description	Oral tablet every 12 hours (q12h) for up to 48 weeks.	Oral tablet of 150 mg of ivacaftor q12h for up to 48 weeks.
Measure Participants	74	78
Change from Baseline Through Week 24	-0.8 (1.3)	-48.7 (1.2)
Change from Baseline Through Week 48	-0.6 (1.3)	-48.7 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 150 mg Ivacaftor q12h
	Comments	Through Week 24: 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 absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age, sweat chloride, and percent predicted FEV1, using unstructured covariance matrix.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Analyzed in sequence: test 1, primary (α=0.05); test 2, using Hochberg's step-up procedure on CFQ-R resp domain(Wk 24) and sweat chloride (Wk 24) (α=0.05); test 3 using Hochberg's on time to pulmonary exacerbation (Wk 48) and weight (Wk 48).
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-47.9
	Confidence Interval	(2-Sided) 95%; -51.3 to -44.5
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.7
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, 150 mg Ivacaftor q12h
	Comments	Through Week 48: 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 absolute change from baseline, fixed effects for categorical visit and treatment group, and adjustment for continuous baseline value for age, sweat chloride, and percent predicted FEV1, using unstructured covariance matrix.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	There was no adjustment for multiple comparisons.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-48.1
	Confidence Interval	(2-Sided) 95%; -51.5 to -44.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.7
	Estimation Comments

5. Secondary Outcome

Title	Time-to-first Pulmonary Exacerbation Through Week 24 and Week 48
Description	Pulmonary exacerbation was defined as a change in antibiotic therapy (intravenous, inhaled, or oral) for any 4 or more of signs/symptoms such as change in sputum; new or increased hemoptysis; increased cough or dyspnea; malaise, fatigue, or lethargy; temperature above 38 degrees C; anorexia or weight loss; sinus pain/tenderness and discharge; change in physical examination of the chest; decreased pulmonary function by 10%; and radiographic changes indicative of pulmonary infection.
Time Frame	baseline through 24 weeks and 48 weeks

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.

Arm/Group Title	Placebo	150 mg Ivacaftor q12h
Arm/Group Description	Oral tablet every 12 hours (q12h) for up to 48 weeks.	Oral tablet of 150 mg of ivacaftor q12h for up to 48 weeks.
Measure Participants	78	83
0 to 15 Days	0.97 1.2%	0.98 1.2%
16 to 56 Days	0.87 1.1%	0.89 1.1%
57 to 112 Days	0.72 0.9%	0.83 1%
113 to 168 Days	0.53 0.7%	0.78 0.9%
169 to 224 Days	0.51 0.7%	0.75 0.9%
225 to 280 Days	0.44 0.6%	0.70 0.8%
281 to 336 Days	0.41 0.5%	0.67 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 150 mg Ivacaftor q12h
	Comments	Time to first pulmonary exacerbation through Week 24 was analyzed using Cox regression. The model included a covariate for treatment and adjustments for the age group and percent predicted forced expiratory volume in 1 second (FEV1) severity at baseline.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0016
	Comments	There was no adjustment for multiple comparisons.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard at Week 24
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; 0.23 to 0.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, 150 mg Ivacaftor q12h
	Comments	Time to first pulmonary exacerbation through Week 48 was analyzed using Cox regression. The model included a covariate for treatment and adjustments for the age group and percent predicted forced expiratory volume in 1 second (FEV1) severity at baseline.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0012
	Comments	Analyzed in sequence: test 1, primary (α=0.05); test 2, using Hochberg's step-up procedure on CFQ-R resp domain(Wk 24) and sweat chloride (Wk 24) (α=0.05); test 3 using Hochberg's on time to pulmonary exacerbation (Wk 48) and weight (Wk 48).
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard at 48 Weeks
	Estimated Value	0.46
	Confidence Interval	(2-Sided) 95%; 0.28 to 0.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Absolute Change From Baseline in Weight at Week 24 and Week 48
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 24 weeks and 48 weeks

Outcome Measure Data

Analysis Population Description

All randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo) and had available assessments during the time frame.

Arm/Group Title	Placebo	150 mg Ivacaftor q12h
Arm/Group Description	Oral tablet every 12 hours (q12h) for up to 48 weeks.	Oral tablet of 150 mg of ivacaftor q12h for up to 48 weeks.
Measure Participants	78	83
At Week 24	0.2 (0.4)	3.0 (0.4)
At Week 48	0.4 (0.5)	3.1 (0.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, 150 mg Ivacaftor q12h
	Comments	At Week 24: Analysis for this variable was based on a linear mixed effects (LME) model with treatment as a fixed effect, and intercept, visit (days on study) and treatment by visit interaction as random effects, with adjustment for age group and baseline percent predicted forced expiratory volume in 1 second (FEV1) severity.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	There was no adjustment for multiple comparisons.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.8
	Confidence Interval	(2-Sided) 95%; 1.8 to 3.7
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.5
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, 150 mg Ivacaftor q12h
	Comments	At Week 48: Analysis for this variable was based on a linear mixed effects (LME) model with treatment as a fixed effect and visit (days on study) and treatment by visit interaction as random effects, with adjustment for age group and baseline percent predicted forced expiratory volume in 1 second (FEV1) severity.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	Analyzed in sequence: test 1, primary (α=0.05); test 2, using Hochberg's step-up procedure on CFQ-R resp domain(Wk 24) and sweat chloride (Wk 24) (α=0.05).
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.7
	Confidence Interval	(2-Sided) 95%; 1.3 to 4.1
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.7
	Estimation Comments

Adverse Events

Time Frame	For enrolled subjects, adverse events were collected through the Follow-up Visit (4 weeks [± 7 days] after the last dose of study drug).
Adverse Event Reporting Description	For subjects who were screened but were not subsequently enrolled in the study, non-serious AEs were not collected, but SAEs were reported. For subjects who completed 48 weeks of study drug treatment and enrolled in the open-label extension study, adverse events were only collected through the Week 48 Visit.
Arm/Group Title	Placebo		150 mg Ivacaftor q12h
Arm/Group Description	Oral tablet every 12 hours (q12h) for up to 48 weeks.		Oral tablet of 150 mg of ivacaftor q12h for up to 48 weeks.
All Cause Mortality
	Placebo		150 mg Ivacaftor q12h
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		150 mg Ivacaftor q12h
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/78 (42.3%)		20/83 (24.1%)
Cardiac disorders
Atrioventricular block complete	1/78 (1.3%)	1	0/83 (0%)	0
Congenital, familial and genetic disorders
Cystic fibrosis lung	26/78 (33.3%)	37	11/83 (13.3%)	22
Gastrointestinal disorders
Gastrooesophageal reflux disease	1/78 (1.3%)	1	0/83 (0%)	0
Pancreatic pseudocyst	0/78 (0%)	0	1/83 (1.2%)	1
Pancreatitis	0/78 (0%)	0	1/83 (1.2%)	1
Vomiting	1/78 (1.3%)	1	0/83 (0%)	0
General disorders
Catheter related complication	1/78 (1.3%)	1	0/83 (0%)	0
Immune system disorders
Anaphylactic shock	0/78 (0%)	0	1/83 (1.2%)	1
Infections and infestations
Implant site infection	1/78 (1.3%)	1	0/83 (0%)	0
Influenza	0/78 (0%)	0	1/83 (1.2%)	1
Lung infection pseudomonal	1/78 (1.3%)	1	0/83 (0%)	0
Myringitis bullous	0/78 (0%)	0	1/83 (1.2%)	1
Pneumonia	0/78 (0%)	0	1/83 (1.2%)	1
Sinusitis	0/78 (0%)	0	1/83 (1.2%)	1
Investigations
Hepatic enzyme increased	0/78 (0%)	0	1/83 (1.2%)	1
Weight decreased	0/78 (0%)	0	1/83 (1.2%)	1
Metabolism and nutrition disorders
Hypoglycaemia	0/78 (0%)	0	2/83 (2.4%)	2
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	0/78 (0%)	0	1/83 (1.2%)	1
Pain in extremity	1/78 (1.3%)	1	0/83 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cervix carcinoma	0/78 (0%)	0	1/83 (1.2%)	1
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	0/78 (0%)	0	1/83 (1.2%)	1
Renal and urinary disorders
Haematuria	0/78 (0%)	0	1/83 (1.2%)	1
IgA nephropathy	0/78 (0%)	0	1/83 (1.2%)	1
Nephrolithiasis	1/78 (1.3%)	1	0/83 (0%)	0
Renal colic	1/78 (1.3%)	1	0/83 (0%)	0
Reproductive system and breast disorders
Testicular torsion	1/78 (1.3%)	1	0/83 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	0/78 (0%)	0	1/83 (1.2%)	1
Hemoptysis	4/78 (5.1%)	4	1/83 (1.2%)	1
Pleuritic pain	0/78 (0%)	0	1/83 (1.2%)	1
Pulmonary embolism	1/78 (1.3%)	1	0/83 (0%)	0
Respiratory distress	1/78 (1.3%)	1	0/83 (0%)	0
Respiratory failure	1/78 (1.3%)	1	0/83 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		150 mg Ivacaftor q12h
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	78/78 (100%)		82/83 (98.8%)
Congenital, familial and genetic disorders
Cystic fibrosis lung	39/78 (50%)	77	29/83 (34.9%)	47
Gastrointestinal disorders
Abdominal pain	10/78 (12.8%)	13	13/83 (15.7%)	14
Nausea	9/78 (11.5%)	12	13/83 (15.7%)	22
Diarrhoea	10/78 (12.8%)	12	11/83 (13.3%)	12
Vomiting	10/78 (12.8%)	10	9/83 (10.8%)	13
Abdominal pain upper	6/78 (7.7%)	7	4/83 (4.8%)	5
Constipation	5/78 (6.4%)	5	1/83 (1.2%)	1
General disorders
Pyrexia	9/78 (11.5%)	11	10/83 (12%)	13
Fatigue	7/78 (9%)	9	7/83 (8.4%)	8
Infections and infestations
Upper respiratory tract infection	12/78 (15.4%)	16	19/83 (22.9%)	26
Nasopharyngitis	10/78 (12.8%)	14	10/83 (12%)	13
Sinusitis	7/78 (9%)	12	6/83 (7.2%)	8
Rhinitis	4/78 (5.1%)	4	6/83 (7.2%)	6
Viral infection	5/78 (6.4%)	5	2/83 (2.4%)	2
Injury, poisoning and procedural complications
Joint sprain	4/78 (5.1%)	5	0/83 (0%)	0
Investigations
Pulmonary function test decreased	11/78 (14.1%)	14	3/83 (3.6%)	3
Alanine aminotransferase increased	5/78 (6.4%)	6	5/83 (6%)	9
C-reactive protein increased	5/78 (6.4%)	6	4/83 (4.8%)	4
Blood glucose increased	3/78 (3.8%)	3	5/83 (6%)	6
Aspartate aminotransferase increased	2/78 (2.6%)	2	5/83 (6%)	7
Bacteria sputum identified	1/78 (1.3%)	1	6/83 (7.2%)	7
Breath sounds abnormal	4/78 (5.1%)	5	2/83 (2.4%)	2
Weight decreased	4/78 (5.1%)	4	2/83 (2.4%)	2
Metabolism and nutrition disorders
Hypoglycaemia	4/78 (5.1%)	4	3/83 (3.6%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	5/78 (6.4%)	5	7/83 (8.4%)	11
Back pain	5/78 (6.4%)	7	5/83 (6%)	5
Nervous system disorders
Headache	13/78 (16.7%)	31	19/83 (22.9%)	39
Dizziness	1/78 (1.3%)	1	10/83 (12%)	11
Sinus headache	4/78 (5.1%)	4	6/83 (7.2%)	6
Respiratory, thoracic and mediastinal disorders
Cough	33/78 (42.3%)	59	27/83 (32.5%)	38
Oropharyngeal pain	15/78 (19.2%)	23	17/83 (20.5%)	25
Nasal congestion	12/78 (15.4%)	17	17/83 (20.5%)	22
Haemoptysis	15/78 (19.2%)	21	9/83 (10.8%)	17
Productive cough	11/78 (14.1%)	19	12/83 (14.5%)	15
Rales	8/78 (10.3%)	14	9/83 (10.8%)	17
Respiratory tract congestion	6/78 (7.7%)	9	6/83 (7.2%)	7
Sinus congestion	4/78 (5.1%)	4	8/83 (9.6%)	9
Rhinorrhoea	6/78 (7.7%)	6	4/83 (4.8%)	4
Paranasal sinus hypersecretion	6/78 (7.7%)	7	3/83 (3.6%)	3
Wheezing	3/78 (3.8%)	3	5/83 (6%)	8
Dyspnoea	5/78 (6.4%)	5	2/83 (2.4%)	2
Pleuritic pain	2/78 (2.6%)	2	5/83 (6%)	7
Respiration abnormal	4/78 (5.1%)	5	2/83 (2.4%)	2
Skin and subcutaneous tissue disorders
Rash	4/78 (5.1%)	4	12/83 (14.5%)	22
Acne	3/78 (3.8%)	3	6/83 (7.2%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.