A Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-CFTR Mutation
Primary Purpose
Cystic Fibrosis
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
VX-661 plus ivacaftor combination
Ivacaftor
Placebo (matched to VX-661 plus ivacaftor combination)
Placebo (matched to ivacaftor)
Sponsored by
About this trial
This is an interventional treatment trial for Cystic Fibrosis
Eligibility Criteria
Inclusion Criteria:
- Confirmed diagnosis of CF defined as a sweat chloride value greater than or equal to (>=)60 millimole per liter (mmol/L) by quantitative pilocarpine iontophoresis.
- Heterozygous for the F508del-CFTR mutation and with a second CFTR mutation that is not likely to respond to VX-661 and/or ivacaftor therapy, genotype to be confirmed via assessment at the Screening Visit.
- Forced Expiratory Volume in 1 Second (FEV1) >=40 percent (%) and less than or equal to (<=)90% of predicted normal for age, sex, and height at Screening Visit.
Exclusion Criteria:
- History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the participant.
- An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug).
- History of solid organ or hematological transplantation.
- Ongoing or prior participation in an investigational drug study or use of commercially available CFTR modulator within 30 days of screening.
- Pregnant or nursing females.
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
VX-661/IVA
Placebo
Arm Description
VX-661 100 milligram (mg) plus IVA 150 mg fixed dose combination (FDC) tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA film-coated tablet administered orally in the evening up to Week 12.
Outcomes
Primary Outcome Measures
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 12
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 participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years.
Secondary Outcome Measures
Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 12
The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants 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.
Number of Pulmonary Exacerbation Events
Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. The number of events were reported.
Number of Pulmonary Exacerbation Events Per Year
Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Total number of days on study is equal to the Week 12 date or the last dose date (whichever occurs last) minus first dose date plus 1. The total number of years (48 weeks) on study is equal to the total number of days on study divided by 336. Pulmonary exacerbation events per year (48 weeks) are reported.
Absolute Change From Baseline in Body Mass Index (BMI) at Week 12
BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2).
Relative Change From Baseline in Percent Predicted FEV1 Through Week 12
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 participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years.
Absolute Change From Baseline in Sweat Chloride Through Week 12
Sweat samples were collected using an approved collection device.
Number of Participants With at Least One Pulmonary Exacerbation Through Week 12
Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Time-to-first pulmonary exacerbation was planned to be estimated using Kaplan-Meier (KM) estimates. However, due to less than 50% of events, time-to-first event data was not estimated. Instead, number of participants with at least one pulmonary exacerbation event were collected and are reported.
Absolute Change From Baseline in BMI Z-score at Week 12 (in Participants Less Than [<] 20 Years Old at the Time of Screening)
Z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is, with range from infinity to +infinity; where 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age Z-score (BMI z-score). BMI-for-age z-score was calculated by using centers for disease control and prevention (CDC) growth charts for the paediatric population.
Absolute Change From Baseline in Body Weight at Week 12
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, inpatient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Any AE that increased in severity or newly developed at or after initial dosing of study drug to Week 16 was considered treatment-emergent.
Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA)
This outcome was not planned to be assessed in Placebo arm.
Full Information
NCT ID
NCT02516410
First Posted
July 28, 2015
Last Updated
May 8, 2018
Sponsor
Vertex Pharmaceuticals Incorporated
1. Study Identification
Unique Protocol Identification Number
NCT02516410
Brief Title
A Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-CFTR Mutation
Official Title
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-CFTR Mutation and With a Second CFTR Mutation That Is Not Likely to Respond to VX-661 and/or Ivacaftor Therapy (F508del/NR)
Study Type
Interventional
2. Study Status
Record Verification Date
May 2018
Overall Recruitment Status
Completed
Study Start Date
August 2015 (undefined)
Primary Completion Date
June 7, 2016 (Actual)
Study Completion Date
June 7, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Vertex Pharmaceuticals Incorporated
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
Study to evaluate the efficacy of VX-661 in combination with ivacaftor (IVA, VX-770) through Week 12 in participants with cystic fibrosis (CF) who are heterozygous for the F508del mutation on the CF transmembrane conductance regulator (CFTR) gene and with a second CFTR mutation that is not likely to respond to VX-661 and/or IVA therapy (F508del/not responsive [NR]).
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
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
168 (Actual)
8. Arms, Groups, and Interventions
Arm Title
VX-661/IVA
Arm Type
Experimental
Arm Description
VX-661 100 milligram (mg) plus IVA 150 mg fixed dose combination (FDC) tablet administered orally in the morning and IVA 150 mg film-coated tablet administered orally in the evening up to Week 12.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA film-coated tablet administered orally in the evening up to Week 12.
Intervention Type
Drug
Intervention Name(s)
VX-661 plus ivacaftor combination
Intervention Type
Drug
Intervention Name(s)
Ivacaftor
Other Intervention Name(s)
IVA, VX-770
Intervention Type
Drug
Intervention Name(s)
Placebo (matched to VX-661 plus ivacaftor combination)
Intervention Type
Drug
Intervention Name(s)
Placebo (matched to ivacaftor)
Primary Outcome Measure Information:
Title
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 12
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 participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years.
Time Frame
Baseline, Through Week 12
Secondary Outcome Measure Information:
Title
Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 12
Description
The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants 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.
Time Frame
Baseline, Through Week 12
Title
Number of Pulmonary Exacerbation Events
Description
Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. The number of events were reported.
Time Frame
Baseline through Week 12
Title
Number of Pulmonary Exacerbation Events Per Year
Description
Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Total number of days on study is equal to the Week 12 date or the last dose date (whichever occurs last) minus first dose date plus 1. The total number of years (48 weeks) on study is equal to the total number of days on study divided by 336. Pulmonary exacerbation events per year (48 weeks) are reported.
Time Frame
Baseline through Week 12
Title
Absolute Change From Baseline in Body Mass Index (BMI) at Week 12
Description
BMI was defined as weight in kilogram (kg) divided by height*height in square meter (m^2).
Time Frame
Baseline, Week 12
Title
Relative Change From Baseline in Percent Predicted FEV1 Through Week 12
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 participants 18 years and older and female participants 16 years and older. The Wang standard was used for male participants aged 12 to 17 years and for female participants aged 12 to 15 years.
Time Frame
Baseline, Through Week 12
Title
Absolute Change From Baseline in Sweat Chloride Through Week 12
Description
Sweat samples were collected using an approved collection device.
Time Frame
Baseline, Through Week 12
Title
Number of Participants With at Least One Pulmonary Exacerbation Through Week 12
Description
Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. Time-to-first pulmonary exacerbation was planned to be estimated using Kaplan-Meier (KM) estimates. However, due to less than 50% of events, time-to-first event data was not estimated. Instead, number of participants with at least one pulmonary exacerbation event were collected and are reported.
Time Frame
Baseline through Week 12
Title
Absolute Change From Baseline in BMI Z-score at Week 12 (in Participants Less Than [<] 20 Years Old at the Time of Screening)
Description
Z-score is a statistical measure to evaluate how a single data point compares to a standard. It describes whether a mean was above or below the standard and how unusual the measurement is, with range from infinity to +infinity; where 0: same mean, >0: a greater mean, and <0: a lesser mean than the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age Z-score (BMI z-score). BMI-for-age z-score was calculated by using centers for disease control and prevention (CDC) growth charts for the paediatric population.
Time Frame
Baseline, Week 12
Title
Absolute Change From Baseline in Body Weight at Week 12
Time Frame
Baseline, Week 12
Title
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description
AE: any untoward medical occurrence in a participant during the study; the event does not necessarily have a causal relationship with the treatment. This includes any newly occurring event or previous condition that has increased in severity or frequency after the informed consent form is signed. AE includes serious as well as non-serious AEs. SAE (subset of AE): medical event or condition, which falls into any of the following categories, regardless of its relationship to the study drug: death, life threatening adverse experience, inpatient hospitalization/prolongation of hospitalization, persistent/significant disability or incapacity, congenital anomaly/birth defect, important medical event. Any AE that increased in severity or newly developed at or after initial dosing of study drug to Week 16 was considered treatment-emergent.
Time Frame
Baseline up to Week 16
Title
Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolite (M1 VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA)
Description
This outcome was not planned to be assessed in Placebo arm.
Time Frame
Pre-morning dose on Week 2, Week 4, Week 8 and Week 12
10. Eligibility
Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Confirmed diagnosis of CF defined as a sweat chloride value greater than or equal to (>=)60 millimole per liter (mmol/L) by quantitative pilocarpine iontophoresis.
Heterozygous for the F508del-CFTR mutation and with a second CFTR mutation that is not likely to respond to VX-661 and/or ivacaftor therapy, genotype to be confirmed via assessment at the Screening Visit.
Forced Expiratory Volume in 1 Second (FEV1) >=40 percent (%) and less than or equal to (<=)90% of predicted normal for age, sex, and height at Screening Visit.
Exclusion Criteria:
History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the participant.
An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy (including antibiotics) for pulmonary disease within 28 days before Day 1 (first dose of study drug).
History of solid organ or hematological transplantation.
Ongoing or prior participation in an investigational drug study or use of commercially available CFTR modulator within 30 days of screening.
Pregnant or nursing females.
Facility Information:
City
Birmingham
State/Province
Alabama
Country
United States
City
La Jolla
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California
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United States
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Los Angeles
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Denver
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Colorado
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Miami
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Florida
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Atlanta
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Chicago
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Illinois
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Indianapolis
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Indiana
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New Orleans
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Ann Arbor
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Detroit
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New York
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New York
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Cincinnati
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Ohio
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Memphis
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Austin
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Dallas
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Richmond
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Virginia
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Seattle
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Spokane
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Washington
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United States
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Brisban
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Queensland
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Australia
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Chermside
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Australia
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Herston
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Australia
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Innsbruck
Country
Australia
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Westmead
Country
Australia
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Graz
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Austria
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Innsbruck
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Austria
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Salzburg
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Austria
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Vancouver
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British Columbia
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Canada
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Montreal
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Canada
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Bron Cedex
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France
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Montpellier Cedex 5
Country
France
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Paris Cedex 14
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France
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Paris Cedex 19
Country
France
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Paris
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France
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Haifa
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Israel
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Hashomer
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Israel
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Jerusalem
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Israel
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Petah Tikva
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Israel
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Barcelona
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Spain
City
Valencia
Country
Spain
12. IPD Sharing Statement
Citations:
PubMed Identifier
32546431
Citation
Munck A, Kerem E, Ellemunter H, Campbell D, Wang LT, Ahluwalia N, Owen CA, Wainwright C. Tezacaftor/ivacaftor in people with cystic fibrosis heterozygous for minimal function CFTR mutations. J Cyst Fibros. 2020 Nov;19(6):962-968. doi: 10.1016/j.jcf.2020.04.015. Epub 2020 Jun 13.
Results Reference
derived
Learn more about this trial
A Study to Evaluate the Efficacy and Safety of VX-661 in Combination With Ivacaftor in Subjects Aged 12 Years and Older With Cystic Fibrosis, Heterozygous for the F508del-CFTR Mutation
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