Study of Ivacaftor in Subjects With Cystic Fibrosis (CF) Who Have a Non-G551D CF Transmembrane Conductance Regulator (CFTR) Gating Mutation - Clinical Trial for Cystic Fibrosis | NCT01614470

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Primary Purpose

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Ivacaftor

Placebo

About this trial

This is an interventional treatment trial for Cystic Fibrosis

Eligibility Criteria

6 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Part 1: Ivacaftor First, Then Placebo

Part 1: Placebo First, Then Ivacaftor

Part 2: Ivacaftor

Arm 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.

Outcomes

Primary Outcome Measures

Part 1: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through 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.

Part 2: Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through 24 Weeks of Treatment (Week 36 Visit)

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

Part 1: Change From Baseline in Body Mass Index (BMI) at 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.

Part 2: Change From Baseline in Body Mass Index (BMI) at 24 Weeks of Treatment (Week 36 Visit)

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.

Part 1: Change From Baseline in Sweat Chloride Through 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.

Part 2: Change From Baseline in Sweat Chloride Through 24 Weeks of Treatment (Week 36 Visit)

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.

Part 1: Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through 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.

Part 2: Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through 24 Weeks of Treatment (Week 36 Visit)

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.

Part 1: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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.

Part 2: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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.

Full Information

NCT ID

NCT01614470

First Posted

June 5, 2012

Last Updated

October 23, 2014

Sponsor

Vertex Pharmaceuticals Incorporated

Collaborators

Cystic Fibrosis Foundation

1. Study Identification

Unique Protocol Identification Number

NCT01614470

Brief Title

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

Acronym

KONNECTION

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 Type

Interventional

2. Study Status

Record Verification Date

October 2014

Overall Recruitment Status

Completed

Study Start Date

July 2012 (undefined)

Primary Completion Date

October 2013 (Actual)

Study Completion Date

October 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Vertex Pharmaceuticals Incorporated

Collaborators

Cystic Fibrosis Foundation

4. Oversight

Data Monitoring Committee

Yes

5. 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).

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Cystic Fibrosis

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Crossover Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

39 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Part 1: Ivacaftor First, Then Placebo

Arm Type

Experimental

Arm 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.

Arm Title

Part 1: Placebo First, Then Ivacaftor

Arm Type

Experimental

Arm Description

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.

Arm Title

Part 2: Ivacaftor

Arm Type

Experimental

Arm Description

Ivacaftor 150 mg tablet orally twice daily for 16 weeks.

Intervention Type

Drug

Intervention Name(s)

Ivacaftor

Other Intervention Name(s)

Kalydeco, VX-770

Intervention Description

150 mg tablet, oral use, administered twice a day (q12h)

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

oral use, administered twice a day (q12h)

Primary Outcome Measure Information:

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

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

Secondary Outcome Measure Information:

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

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

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

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

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

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

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

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

10. Eligibility

Sex

All

Minimum Age & Unit of Time

6 Years

Accepts Healthy Volunteers

No

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Christine De Boeck, MD, PhD

Organizational Affiliation

University of Leuven

Official's Role

Principal Investigator

Facility Information:

City

Tampa

State/Province

Florida

Country

United States

City

Atlanta

State/Province

Georgia

Country

United States

City

Chicago

State/Province

Illinois

Country

United States

City

Boston

State/Province

Massachusetts

Country

United States

City

Ann Arbor

State/Province

Michigan

Country

United States

City

Minneapolis

State/Province

Minnesota

Country

United States

City

St. Louis

State/Province

Missouri

Country

United States

City

Houston

State/Province

Texas

Country

United States

City

Leuven

Country

Belgium

City

Lyon

Country

France

City

Montpellier

Country

France

City

Paris

Country

France

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

Cystic Fibrosis

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial