KONNECTION: Study of Ivacaftor in Subjects With Cystic Fibrosis (CF) Who Have a Non-G551D CF Transmembrane Conductance Regulator (CFTR) Gating Mutation

• Sponsor: Vertex Pharmaceuticals Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01614470
• Collaborator: Cystic Fibrosis Foundation (Other)
• Enrollment: 39
• Locations: 12
• Arms: 3
• Duration (Months): 15
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis (CF) who have a non-G551D cystic fibrosis transmembrane regulator (CFTR) gating mutation (any one of the following CFTR mutations: G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, or G1349D).

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

Detailed Description

Ivacaftor is the first CFTR modulator to show an improvement in CFTR function and clinical benefit in subjects with CF. Results from Phase 3 studies (VX08-770-102 [Study 102] [NCT00909532] and VX08-770-103 [Study 103] [NCT00909727]) showed that ivacaftor is effective in the treatment of subjects with CF who have the G551D-CFTR mutation, as evidenced by sustained improvements in CFTR channel function (measured by reduction in sweat chloride concentration) and corresponding substantial, durable improvements in lung function, pulmonary exacerbations, respiratory symptoms, and weight gain. Ivacaftor was also well tolerated, as evidenced by the rates and reasons for premature discontinuation and results of safety assessments.

Ivacaftor (Trade Name Kalydeco; 150 mg tablets) was initially approved in the United States for the treatment of CF in subjects 6 years of age and older who have a G551D mutation in the CFTR gene.

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Two-Part, Randomized, Double-Blind, Placebo-Controlled, Crossover Study With an Open-Label Period to Evaluate the Efficacy and Safety of Ivacaftor in Subjects With Cystic Fibrosis Who Have a Non-G551D CFTR Gating Mutation
• Study Start Date: Jul 1, 2012
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1: Ivacaftor First, Then Placebo Ivacaftor 150 milligram (mg) tablet orally twice daily for 8 weeks in treatment period 1 followed by placebo matched to ivacaftor tablet orally twice daily for 8 weeks in treatment period 2. Washout out period of 4 to 8 weeks was maintained between each treatment period.	Drug: Ivacaftor; 150 mg tablet, oral use, administered twice a day (q12h); Other Names: Kalydeco VX-770 ; Drug: Placebo; oral use, administered twice a day (q12h)
Experimental: Part 1: Placebo First, Then Ivacaftor Placebo matched to ivacaftor tablet orally twice daily for 8 weeks in treatment period 1 followed by ivacaftor 150 mg tablet orally twice daily for 8 weeks in treatment period 2. Washout out period of 4 to 8 weeks was maintained between each treatment period.	Drug: Ivacaftor; 150 mg tablet, oral use, administered twice a day (q12h); Other Names: Kalydeco VX-770 ; Drug: Placebo; oral use, administered twice a day (q12h)
Experimental: Part 2: Ivacaftor Ivacaftor 150 mg tablet orally twice daily for 16 weeks.	Drug: Ivacaftor; 150 mg tablet, oral use, administered twice a day (q12h); Other Names: Kalydeco VX-770

Outcome Measures

Primary Outcome Measures

1. Part 1: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8 [Part 1: Baseline (pre-dose Day 1), Week 8]

   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 6 to 17 years and for female subjects aged 6 to 15 years. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during study Part 1.

2. Part 2: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through 24 Weeks of Treatment (Week 36 Visit) [Baseline (pre-dose Week 12), Week 36]

   FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 6 to 17 years and for female subjects aged 6 to 15 years. Absolute change in percent predicted FEV1 over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2, as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.

Secondary Outcome Measures

1. Part 1: Change From Baseline in Body Mass Index (BMI) at Week 8 [Part 1: Baseline (pre-dose Day 1), Week 8]

   BMI was defined as weight in kilogram (kg) divided by height in meters^2 (m^2). Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during study Part 1.

2. Part 2: Change From Baseline in Body Mass Index (BMI) at 24 Weeks of Treatment (Week 36 Visit) [Baseline (pre-dose Week 12), Week 36]

   BMI was defined as weight in kg divided by height in m^2. Change in BMI over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2 as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.

3. Part 1: Change From Baseline in Sweat Chloride Through Week 8 [Part 1: Baseline (pre-dose Day 1), Week 8]

   Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during study Part 1.

4. Part 2: Change From Baseline in Sweat Chloride Through 24 Weeks of Treatment (Week 36 Visit) [Baseline (pre-dose Week 12), Week 36]

   Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Change in sweat chloride over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2 as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.

5. Part 1: Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 8 [Part 1: Baseline (pre-dose Day 1), Week 8]

   The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during study Part 1.

6. Part 2: Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through 24 Weeks of Treatment (Week 36 Visit) [Baseline (pre-dose Week 12), Week 36]

   The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Change in CFQ-R respiratory domain score over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2 as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.

7. Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Part 1: From signing of informed consent up to Week 20]

   AE: any adverse change from subject's baseline (pre-treatment) condition, including any adverse experience, abnormal recording/clinical laboratory assessment which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event.

8. Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [Part 2: Week 20 up to Week 40]

   AE: any adverse change from subject's baseline (pre-treatment) condition, including any adverse experience, abnormal recording/clinical laboratory assessment which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female with confirmed diagnosis of CF

• At least 1 allele of the following CFTR gating mutations: G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, G1349D

• Percent predicted forced expiratory volume in 1 second (FEV1) greater than or equal to (>=) 40 percent (%) predicted normal for age, sex, and height

• 6 years of age or older

• Minimum weight of 15 kilogram (kg) at screening

• Females of childbearing potential must not be pregnant

• Willing to comply with contraception requirements

Exclusion Criteria:

• G551D-CFTR mutation on at least 1 allele

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

• An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 4 weeks before the first dose of study drug

• History of solid organ or hematological transplantation

• History of alcohol, medication or illicit drug abuse within 1 year before the first dose of study drug

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

• Use of inhaled hypertonic saline treatment

• Use of any inhibitors or inducers of cytochrome (CYP) P450 3A

• Evidence of cataract or lens opacity at screening

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Tampa	Florida	United States
2		Atlanta	Georgia	United States
3		Chicago	Illinois	United States
4		Boston	Massachusetts	United States
5		Ann Arbor	Michigan	United States
6		Minneapolis	Minnesota	United States
7		St. Louis	Missouri	United States
8		Houston	Texas	United States
9		Leuven		Belgium
10		Lyon		France
11		Montpellier		France
12		Paris		France

Sponsors and Collaborators

• Vertex Pharmaceuticals Incorporated
• Cystic Fibrosis Foundation

Investigators

• Principal Investigator: Christine De Boeck, MD, PhD, University of Leuven

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Vertex Pharmaceuticals Incorporated
• ClinicalTrials.gov Identifier: NCT01614470
• Other Study ID Numbers: VX12-770-111
• First Posted: Jun 8, 2012
• Last Update Posted: Oct 29, 2014
• Last Verified: Oct 1, 2014

• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis; Ivacaftor

Study Results

Participant Flow

Arm/Group Title	Part 1: Ivacaftor First, Then Placebo	Part 1: Placebo First, Then Ivacaftor	Part 2: Ivacaftor
Arm/Group Description	Ivacaftor 150 milligram (mg) tablet orally twice daily for 8 weeks in treatment period 1 followed by placebo matched to ivacaftor tablet orally twice daily for 8 weeks in treatment period 2. Washout out period of 4 to 8 weeks was maintained between each treatment period.	Placebo matched to ivacaftor tablet orally twice daily for 8 weeks in treatment period 1 followed by ivacaftor 150 mg tablet orally twice daily for 8 weeks in treatment period 2. Washout out period of 4 to 8 weeks was maintained between each treatment period.	Ivacaftor 150 mg tablet orally twice daily for 16 weeks.
Period Title: Part 1: Treatment Period 1 (8 Weeks)
STARTED	20	19	0
COMPLETED	18	18	0
NOT COMPLETED	2	1	0
Period Title: Part 1: Treatment Period 1 (8 Weeks)
STARTED	18	18	0
COMPLETED	18	18	0
NOT COMPLETED	0	0	0
Period Title: Part 1: Treatment Period 1 (8 Weeks)
STARTED	18	18	0
COMPLETED	18	18	0
NOT COMPLETED	0	0	0
Period Title: Part 1: Treatment Period 1 (8 Weeks)
STARTED	0	0	36
COMPLETED	0	0	36
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Part 1: Ivacaftor First, Then Placebo	Part 1: Placebo First, Then Ivacaftor	Total
Arm/Group Description	Ivacaftor 150 milligram (mg) tablet orally twice daily for 8 weeks in treatment period 1 followed by placebo matched to ivacaftor tablet orally twice daily for 8 weeks in treatment period 2. Washout out period of 4 to 8 weeks was maintained between each treatment period.	Placebo matched to ivacaftor tablet orally twice daily for 8 weeks in treatment period 1 followed by ivacaftor 150 mg tablet orally twice daily for 8 weeks in treatment period 2. Washout out period of 4 to 8 weeks was maintained between each treatment period.	Total of all reporting groups
Overall Participants	20	19	39
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	23.8 (13.25)	21.7 (12.92)	22.8 (12.96)
Sex: Female, Male (Count of Participants)
Female	7 35%	10 52.6%	17 43.6%
Male	13 65%	9 47.4%	22 56.4%

Outcome Measures

1. Primary Outcome

Title	Part 1: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 6 to 17 years and for female subjects aged 6 to 15 years. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during study Part 1.
Time Frame	Part 1: Baseline (pre-dose Day 1), Week 8

Outcome Measure Data

Analysis Population Description

FAS for Part 1: all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo). Here, "n" signifies those subjects who were evaluable for this measure at given time point for each group, respectively.

Arm/Group Title	Part 1: Ivacaftor	Part 1: Placebo
Arm/Group Description	Ivacaftor 150 mg tablet orally twice daily for 8 weeks in either treatment period 1 or treatment period 2.	Placebo matched to ivacaftor tablet orally twice daily for 8 weeks in either treatment period 1 or treatment period 2.
Measure Participants	38	37
Baseline (n=38, 37)	76.3659 (20.33450)	79.3361 (20.83991)
Change Through Week 8 (n=37, 37)	8.1308 (9.94676)	-5.8738 (7.23722)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Ivacaftor, Part 1: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Least squares (LS) mean difference
	Estimated Value	10.6780
	Confidence Interval	(2-Sided) 95%; 7.2559 to 14.1000
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Part 1: Change From Baseline in Body Mass Index (BMI) at Week 8
Description	BMI was defined as weight in kilogram (kg) divided by height in meters^2 (m^2). Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during study Part 1.
Time Frame	Part 1: Baseline (pre-dose Day 1), Week 8

Outcome Measure Data

Analysis Population Description

FAS for Part 1: all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo). Here, "n" signifies those subjects who were evaluable for this measure at given time point for each group, respectively.

Arm/Group Title	Part 1: Ivacaftor	Part 1: Placebo
Arm/Group Description	Ivacaftor 150 mg tablet orally twice daily for 8 weeks in either treatment period 1 or treatment period 2.	Placebo matched to ivacaftor tablet orally twice daily for 8 weeks in either treatment period 1 or treatment period 2.
Measure Participants	38	37
Baseline (n=38, 37)	22.241 (5.1880)	22.527 (4.9956)
Change at Week 8 (n=37, 37)	0.748 (0.5793)	0.043 (0.6980)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Ivacaftor, Part 1: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	0.6624
	Confidence Interval	(2-Sided) 95%; 0.3366 to 0.9881
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Part 2: Change From Baseline in Body Mass Index (BMI) at 24 Weeks of Treatment (Week 36 Visit)
Description	BMI was defined as weight in kg divided by height in m^2. Change in BMI over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2 as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.
Time Frame	Baseline (pre-dose Week 12), Week 36

Outcome Measure Data

Analysis Population Description

FAS for Part 2: all randomized subjects who received at least 1 dose of study drug (ivacaftor). Only subjects who were randomized to receive ivacaftor during Part 1: Treatment Period 2 were to be analyzed for this measure.

Arm/Group Title	Part 1 Treatment Period 2: Ivacaftor, Part 2: Ivacaftor
Arm/Group Description	Ivacaftor 150 mg tablet orally twice daily for 24 weeks (8 weeks in Part 1: Treatment Period 2 and 16 weeks in Part 2).
Measure Participants	18
Baseline	22.222 (6.2919)
Change at Week 36	1.263 (0.7588)

4. Secondary Outcome

Title	Part 1: Change From Baseline in Sweat Chloride Through Week 8
Description	Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during study Part 1.
Time Frame	Part 1: Baseline (pre-dose Day 1), Week 8

Outcome Measure Data

Analysis Population Description

FAS for Part 1: all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo). Here, "n" signifies those subjects who were evaluable for this measure at given time point for each group, respectively.

Arm/Group Title	Part 1: Ivacaftor	Part 1: Placebo
Arm/Group Description	Ivacaftor 150 mg tablet orally twice daily for 8 weeks in either treatment period 1 or treatment period 2.	Placebo matched to ivacaftor tablet orally twice daily for 8 weeks in either treatment period 1 or treatment period 2.
Measure Participants	38	37
Baseline (n=38, 37)	93.37 (18.099)	94.23 (20.581)
Change Through Week 8 (n=36, 36)	-55.82 (24.890)	-5.63 (9.833)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Ivacaftor, Part 1: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	-49.1667
	Confidence Interval	(2-Sided) 95%; -56.9527 to -41.3807
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Primary Outcome

Title	Part 2: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through 24 Weeks of Treatment (Week 36 Visit)
Description	FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson and Wang standards were used to calculate percent predicted FEV1 (for age, gender, and height). The Hankinson standard was used for male subjects 18 years and older and female subjects 16 years and older. The Wang standard was used for male subjects aged 6 to 17 years and for female subjects aged 6 to 15 years. Absolute change in percent predicted FEV1 over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2, as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.
Time Frame	Baseline (pre-dose Week 12), Week 36

Outcome Measure Data

Analysis Population Description

FAS for Part 2: all randomized subjects who received at least 1 dose of study drug (ivacaftor). Only subjects who were randomized to receive ivacaftor during Part 1: Treatment Period 2 were to be analyzed for this measure.

Arm/Group Title	Part 1 Treatment Period 2: Ivacaftor, Part 2: Ivacaftor
Arm/Group Description	Ivacaftor 150 mg tablet orally twice daily for 24 weeks (8 weeks in Part 1: Treatment Period 2 and 16 weeks in Part 2).
Measure Participants	18
Baseline	74.8375 (19.36754)
Change Through Week 36	13.5307 (10.18174)

6. Secondary Outcome

Title	Part 2: Change From Baseline in Sweat Chloride Through 24 Weeks of Treatment (Week 36 Visit)
Description	Sweat samples were collected using an approved Macroduct (Wescor, Logan, Utah) collection device. A volume of greater than or equal to (>=) 15 microliter was required for determination of sweat chloride. Change in sweat chloride over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2 as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.
Time Frame	Baseline (pre-dose Week 12), Week 36

Outcome Measure Data

Analysis Population Description

FAS for Part 2: all randomized subjects who received at least 1 dose of study drug (ivacaftor). Only subjects who were randomized to receive ivacaftor during Part 1: Treatment Period 2 were to be analyzed for this measure. Here "n" signifies those subjects who were evaluable for this measure at given time point.

Arm/Group Title	Part 1 Treatment Period 2: Ivacaftor, Part 2: Ivacaftor
Arm/Group Description	Ivacaftor 150 mg tablet orally twice daily for 24 weeks (8 weeks in Part 1: Treatment Period 2 and 16 weeks in Part 2).
Measure Participants	18
Baseline (n=18)	92.03 (11.468)
Change Through Week 36 (n=17)	-59.24 (32.566)

7. Secondary Outcome

Title	Part 1: Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 8
Description	The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during study Part 1.
Time Frame	Part 1: Baseline (pre-dose Day 1), Week 8

Outcome Measure Data

Analysis Population Description

FAS for Part 1: all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo). Here, "n" signifies those subjects who were evaluable for this measure at given time point for each group, respectively.

Arm/Group Title	Part 1: Ivacaftor	Part 1: Placebo
Arm/Group Description	Ivacaftor 150 mg tablet orally twice daily for 8 weeks in either treatment period 1 or treatment period 2.	Placebo matched to ivacaftor tablet orally twice daily for 8 weeks in either treatment period 1 or treatment period 2.
Measure Participants	38	37
Baseline (n=38, 37)	70.61 (17.409)	74.55 (20.616)
Change Through Week 8 (n=37, 37)	12.31 (16.891)	-2.33 (20.648)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part 1: Ivacaftor, Part 1: Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS mean difference
	Estimated Value	9.6105
	Confidence Interval	(2-Sided) 95%; 4.4874 to 14.7336
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Part 2: Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through 24 Weeks of Treatment (Week 36 Visit)
Description	The CFQ-R is a validated patient-reported outcome measuring health-related quality of life for subjects with cystic fibrosis. Respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Change in CFQ-R respiratory domain score over 24 weeks of ivacaftor treatment (from Week 12 [Part 1: Treatment Period 2] through Week 36 [Part 2]) was reported for subjects who received ivacaftor in Part 1: Treatment Period 2 as per planned analysis. Baseline was defined as the most recent non-missing measurement collected before initial administration of study drug during Part 1: Treatment Period 2.
Time Frame	Baseline (pre-dose Week 12), Week 36

Outcome Measure Data

Analysis Population Description

FAS for Part 2: all randomized subjects who received at least 1 dose of study drug (ivacaftor). Only subjects who were randomized to receive ivacaftor during Part 1: Treatment Period 2 were to be analyzed for this measure.

Arm/Group Title	Part 1 Treatment Period 2: Ivacaftor, Part 2: Ivacaftor
Arm/Group Description	Ivacaftor 150 mg tablet orally twice daily for 24 weeks (8 weeks in Part 1: Treatment Period 2 and 16 weeks in Part 2).
Measure Participants	18
Baseline	71.30 (19.526)
Change Through Week 36	11.42 (13.604)

9. Secondary Outcome

Title	Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	AE: any adverse change from subject's baseline (pre-treatment) condition, including any adverse experience, abnormal recording/clinical laboratory assessment which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event.
Time Frame	Part 1: From signing of informed consent up to Week 20

Outcome Measure Data

Analysis Population Description

Safety Set for Part 1 included all subjects who received at least 1 dose of study drug (ivacaftor or placebo).

Arm/Group Title	Part 1: Ivacaftor	Part 1: Placebo
Arm/Group Description	Ivacaftor 150 mg tablet orally twice daily for 8 weeks in either treatment period 1 or treatment period 2.	Placebo matched to ivacaftor tablet orally twice daily for 8 weeks in either treatment period 1 or treatment period 2.
Measure Participants	38	37
AEs	28 140%	31 163.2%
SAEs	4 20%	7 36.8%

10. Secondary Outcome

Title	Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	AE: any adverse change from subject's baseline (pre-treatment) condition, including any adverse experience, abnormal recording/clinical laboratory assessment which occurs during course of study, whether it is considered related to study drug or not. SAE: medical event or condition, which falls into any of following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, in-patient hospitalization/prolonged hospitalization, persistent/significant disability/incapacity, congenital anomaly/birth defect, important medical event.
Time Frame	Part 2: Week 20 up to Week 40

Outcome Measure Data

Analysis Population Description

Safety Set for Part 2 included all subjects who received at least 1 dose of study drug (ivacaftor).

Arm/Group Title	Part 2: Ivacaftor
Arm/Group Description	Ivacaftor 150 mg tablet orally twice daily for 16 weeks.
Measure Participants	36
AEs	30 150%
SAEs	3 15%

Adverse Events

Time Frame	Part 1: From signing of informed consent up to Week 20; Part 2: Week 20 up to Week 40
Arm/Group Title	Part 1: Ivacaftor		Part 1: Placebo		Part 2: Ivacaftor
Arm/Group Description	Ivacaftor 150 mg tablet orally twice daily for 8 weeks in either treatment period 1 or treatment period 2.		Placebo matched to ivacaftor tablet orally twice daily for 8 weeks in either treatment period 1 or treatment period 2.		Ivacaftor 150 mg tablet orally twice daily for 16 weeks.
All Cause Mortality
	Part 1: Ivacaftor		Part 1: Placebo		Part 2: Ivacaftor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Part 1: Ivacaftor		Part 1: Placebo		Part 2: Ivacaftor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/38 (10.5%)		7/37 (18.9%)		3/36 (8.3%)
Gastrointestinal disorders
Distal Ileal Obstruction Syndrome	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Appendiceal Mucocoele	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Intussusception	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Distal intestinal obstruction syndrome	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	2/38 (5.3%)		6/37 (16.2%)		2/36 (5.6%)
Metabolism and nutrition disorders
Dehydration	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Musculoskeletal and connective tissue disorders
Intervertebral Disc Protrusion	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Nervous system disorders
Convulsion	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Dizziness	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Respiratory, thoracic and mediastinal disorders
Paranasal Cyst	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Pneumothorax	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Other (Not Including Serious) Adverse Events
	Part 1: Ivacaftor		Part 1: Placebo		Part 2: Ivacaftor
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/38 (71.1%)		30/37 (81.1%)		30/36 (83.3%)
Blood and lymphatic system disorders
Anaemia	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Ear and labyrinth disorders
Hyperacusis	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Cerumen impaction	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Hypoacusis	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Endocrine disorders
Thyroid disorder	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Eye disorders
Conjunctivitis allergic	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Gastrointestinal disorders
Constipation	2/38 (5.3%)		1/37 (2.7%)		2/36 (5.6%)
Abdominal pain	1/38 (2.6%)		4/37 (10.8%)		3/36 (8.3%)
Abdominal pain upper	1/38 (2.6%)		0/37 (0%)		2/36 (5.6%)
Distal ileal obstruction syndrome	1/38 (2.6%)		1/37 (2.7%)		0/36 (0%)
Nausea	1/38 (2.6%)		4/37 (10.8%)		1/36 (2.8%)
Toothache	1/38 (2.6%)		0/37 (0%)		1/36 (2.8%)
Vomiting	1/38 (2.6%)		1/37 (2.7%)		0/36 (0%)
Cheilitis	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Diarrhoea	0/38 (0%)		1/37 (2.7%)		1/36 (2.8%)
Distal intestinal obstruction syndrome	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Flatulence	0/38 (0%)		2/37 (5.4%)		0/36 (0%)
Gastrooesophageal reflux disease	0/38 (0%)		2/37 (5.4%)		1/36 (2.8%)
Abdominal distension	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Anal fissure	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Food poisoning	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Gastritis	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Haemorrhoids	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Pancreatitis	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
General disorders
Pyrexia	3/38 (7.9%)		1/37 (2.7%)		2/36 (5.6%)
Fatigue	2/38 (5.3%)		0/37 (0%)		1/36 (2.8%)
Chest pain	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Exercise tolerance decreased	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Malaise	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Medical device site reaction	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Oedema peripheral	0/38 (0%)		1/37 (2.7%)		1/36 (2.8%)
Infusion site thrombosis	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Injection site pain	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Non-cardiac chest pain	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Hepatobiliary disorders
Biliary colic	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Immune system disorders
Hypersensitivity	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Seasonal allergy	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Infections and infestations
Infective pulmonary exacerbation of cystic fibrosis	7/38 (18.4%)		6/37 (16.2%)		4/36 (11.1%)
Rhinitis	3/38 (7.9%)		2/37 (5.4%)		0/36 (0%)
Influenza	2/38 (5.3%)		2/37 (5.4%)		0/36 (0%)
Conjunctivitis infective	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Respiratory tract infection viral	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Sinusitis	1/38 (2.6%)		2/37 (5.4%)		2/36 (5.6%)
Upper respiratory tract infection	1/38 (2.6%)		2/37 (5.4%)		3/36 (8.3%)
Urinary tract infection	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Bacterial disease carrier	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Bronchitis	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Gastroenteritis	0/38 (0%)		1/37 (2.7%)		1/36 (2.8%)
Tonsillitis	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Vulvovaginal mycotic infection	0/38 (0%)		1/37 (2.7%)		1/36 (2.8%)
Gastrointestinal viral infection	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Impetigo	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Lower respiratory tract infection	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Pharyngitis streptococcal	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Injury, poisoning and procedural complications
Contusion	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Ligament sprain	0/38 (0%)		1/37 (2.7%)		1/36 (2.8%)
Arthropod bite	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Sunburn	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Vaccination complication	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Investigations
Alanine aminotransferase increased	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Blood creatinine increased	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
C-reactive protein increased	1/38 (2.6%)		1/37 (2.7%)		0/36 (0%)
Gamma-glutamyltransferase increased	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Neutrophil count increased	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Respiratory rate increased	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
White blood cell count increased	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Hepatic enzyme increased	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Pulmonary function test decreased	0/38 (0%)		1/37 (2.7%)		1/36 (2.8%)
Breath sounds abnormal	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Weight decreased	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Metabolism and nutrition disorders
Hypoglycaemia	0/38 (0%)		1/37 (2.7%)		1/36 (2.8%)
Decreased appetite	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/38 (5.3%)		0/37 (0%)		1/36 (2.8%)
Back pain	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Torticollis	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Osteochondrosis	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Musculoskeletal pain	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Pain in jaw	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Tendonitis	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Oral papilloma	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Malignant melanoma	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Nervous system disorders
Headache	3/38 (7.9%)		5/37 (13.5%)		4/36 (11.1%)
Dysgeusia	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Sinus headache	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Lethargy	0/38 (0%)		1/37 (2.7%)		1/36 (2.8%)
Benign intracranial hypertension	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Psychiatric disorders
Anxiety	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Reproductive system and breast disorders
Metrorrhagia	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Vulvovaginal discomfort	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	6/38 (15.8%)		7/37 (18.9%)		5/36 (13.9%)
Sputum increased	3/38 (7.9%)		3/37 (8.1%)		2/36 (5.6%)
Dysphonia	1/38 (2.6%)		0/37 (0%)		1/36 (2.8%)
Epistaxis	1/38 (2.6%)		0/37 (0%)		1/36 (2.8%)
Haemoptysis	1/38 (2.6%)		2/37 (5.4%)		1/36 (2.8%)
Lung hyperinflation	1/38 (2.6%)		1/37 (2.7%)		1/36 (2.8%)
Nasal congestion	1/38 (2.6%)		1/37 (2.7%)		0/36 (0%)
Oropharyngeal pain	1/38 (2.6%)		3/37 (8.1%)		3/36 (8.3%)
Rales	1/38 (2.6%)		3/37 (8.1%)		1/36 (2.8%)
Respiration abnormal	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Rhinorrhoea	1/38 (2.6%)		2/37 (5.4%)		0/36 (0%)
Wheezing	1/38 (2.6%)		0/37 (0%)		2/36 (5.6%)
Asthma	0/38 (0%)		1/37 (2.7%)		3/36 (8.3%)
Bronchospasm	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Nasal mucosal disorder	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Paranasal sinus hypersecretion	0/38 (0%)		1/37 (2.7%)		1/36 (2.8%)
Productive cough	0/38 (0%)		2/37 (5.4%)		0/36 (0%)
Pulmonary congestion	0/38 (0%)		1/37 (2.7%)		1/36 (2.8%)
Respiratory tract congestion	0/38 (0%)		2/37 (5.4%)		0/36 (0%)
Sinus congestion	0/38 (0%)		2/37 (5.4%)		2/36 (5.6%)
Sputum discoloured	0/38 (0%)		1/37 (2.7%)		2/36 (5.6%)
Nasal polyps	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Nasal turbinate hypertrophy	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Pneumonitis	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Vocal cord inflammation	0/38 (0%)		0/37 (0%)		1/36 (2.8%)
Skin and subcutaneous tissue disorders
Dermatitis contact	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Dry skin	1/38 (2.6%)		1/37 (2.7%)		0/36 (0%)
Pruritus	1/38 (2.6%)		1/37 (2.7%)		0/36 (0%)
Rash	1/38 (2.6%)		2/37 (5.4%)		1/36 (2.8%)
Rash papular	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Acne	0/38 (0%)		1/37 (2.7%)		1/36 (2.8%)
Urticaria	0/38 (0%)		1/37 (2.7%)		0/36 (0%)
Vascular disorders
Orthostatic hypotension	1/38 (2.6%)		0/37 (0%)		0/36 (0%)
Hypertension	0/38 (0%)		0/37 (0%)		1/36 (2.8%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

PI is free to publish results of the study after (1) the first multi-center publication, (2) if the sponsor elects not to publish the results, or (3) 18 months after close of the study, whichever occurs first. Proposed publications are to be submitted to the sponsor for review and comment for a period of at least 45 days (which may be extended under certain circumstances related to protection of intellectual property); the sponsor cannot require changes to the proposed publications.