A Study to Evaluate the Safety and Efficacy of Long Term Treatment With VX-661 in Combination With Ivacaftor in Participants With Cystic Fibrosis Who Have an F508del-CFTR Mutation

Vertex Pharmaceuticals Incorporated1,131 enrolled

Overview

This is a Phase 3, multicenter, open-label, 3-part rollover study in subjects with CF who are homozygous or heterozygous for the F508del-CFTR mutation and who participated in studies VX13-661-103 (Study 103, NCT02070744), VX14-661-106 (Study 106, NCT02347657), VX14-661-107 (Study 107, NCT02516410), VX14-661-108 (Study 108, NCT02392234), VX14-661-109 (Study 109, NCT02412111), VX14-661-111 (Study 111, NCT02508207), VX15-661-112 (NCT02730208), and VX16-661-114 (NCT03150719). The study is designed to evaluate the safety and efficacy of long-term treatment of VX-661 in combination with ivacaftor.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

1,131

Conditions

Cystic Fibrosis

Interventions

TEZ/IVA

Eligibility

Sex: ALLMin age: 12 Years

Medical Language ↔ Plain English

Inclusion Criteria: Part A: * Participants entering the Treatment Cohort must meet all of the following criteria: * Elect to enroll in the Treatment Cohort * Completed study drug Treatment Period in a parent study (NCT02070744, NCT02347657, NCT02516410, NCT02392234, NCT02412111) or study drug treatment and the Safety Follow up Visit for participants from NCT02508207. * Willing to remain on a stable CF regimen through the Safety Follow-up Visit. * Participants re-enrolling in the Part A Treatment Cohort must meet all of the following criteria: * Previously received at least 4 weeks of study drug before discontinuing in Part A of Study NCT02565914 to participate in another qualified Vertex study. * Completed the last required visit of another qualified Vertex study before or during the Returning Visit in Part A Study NCT02565914. * Participants entering the Part A Observational Cohort must meet the following criteria: * \<18 years of age (age on the date of informed consent/assent in the parent study) * Completed study drug Treatment Period in a parent study or study drug treatment and the Safety Follow up Visit for subjects from NCT02508207, but do not elect to enroll in the NCT02565914 Treatment Cohort; or * Received at least 4 weeks of study drug treatment and completed visits up to the last scheduled visit of the Treatment Period of a parent study (and the Safety Follow up Visit for participants from NCT02508207), but do not meet eligibility criteria for enrollment into the Treatment Cohort Part B: Participants who meet all of the following inclusion criteria will be eligible for Part B. * Did not withdraw consent from the parent study or Part A of Study NCT02565914. * Completed study drug treatment during the Treatment Period in Part A of - Willing to remain on a stable CF medication (and supplement) regimen through the 96 week visit of Study NCT02565914. Participants re enrolling in Part B must meet all of the following criteria: * Previously received at least 4 weeks of study drug before discontinuing Study NCT02565914 to participate in another qualified Vertex study, which is defined as a Vertex study of investigational CFTR modulators that allows participation of participants in Study NCT02565914. * Completed the last required visit of another qualified Vertex study before or during the Returning Visit in Part B. * Willing to remain on a stable CF medication (and supplement) regimen through the 96 week visit in Part B. Part C: * Participants who meet all of the following inclusion criteria will be eligible for Part C. * Did not withdraw consent from Part B of Study NCT02565914. * Completed study drug treatment during Part B of NCT02565914. * Willing to remain on a stable CF medication (and supplement) regimen through the 96 week visit of Part C. 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 to the subject. * Pregnant and nursing females. * Sexually active subjects of reproductive potential who are not willing to follow the contraception requirements. * History of drug intolerance in the parent study that would pose an additional risk to the subject. * Participation in an investigational drug trial (including studies investigating VX-661/ivacaftor or lumacaftor/ivacaftor) other than the parent studies of NCT02565914 or other eligible Vertex studies investigating VX-661 in combination with ivacaftor, or use of a commercially available CFTR modulator. Other protocol defined Inclusion/Exclusion criteria may apply.

Locations (154)

Unnamed facility

Birmingham, Alabama, United States

Unnamed facility

Tucson, Arizona, United States

Unnamed facility

Little Rock, Arkansas, United States

Unnamed facility

Long Beach, California, United States

Unnamed facility

Los Angeles, California, United States

Unnamed facility

Outcomes

Primary Outcomes

Part A: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time frame: Day 1 up to Week 100

Part B: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs

Time frame: Day 1 up to Week 100

Part C: Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

Time frame: Day 1 up to Week 196

Secondary Outcomes

Part A: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 106/110 Efficacy Set

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 106 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 106 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline except for Placebo-TEZ/IVA category, for which baseline was study 110 baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 108/110 Efficacy Set

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 103/110 Efficacy Set

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Data are reported for TEZ/IVA-TEZ/IVA group (participants who received TEZ/IVA in both parent study 103 and in current study 110). Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 111/110 Efficacy Set

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 111 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 111 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 106/110 Efficacy Set

Time frame: From Baseline at Study 110 Week 96

Part A: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 108/110 Efficacy Set

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 103/110 Efficacy Set

Time frame: From Baseline at Study 110 Week 96

Part A: Relative Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for 111/110 Efficacy Set

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 111 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 111 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Number of Pulmonary Exacerbation (PEx) Events for 106/110 PEx Analysis Set

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. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 106 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 106 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline except for Placebo-TEZ/IVA category, for which baseline was study 110 baseline.

Time frame: From Baseline up to Study 110 Week 96

Part A: Number of Pulmonary Exacerbation (PEx) Events for 108/110 PEx Analysis Set

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. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Time frame: From Baseline up to Week 96

Part A: Absolute Change in Body Mass Index (BMI) for 106/110 Efficacy Set

BMI was defined as weight in kilogram (kg) divided by height in square meter (m\^2). Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 106 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 106 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline except for Placebo-TEZ/IVA category, for which baseline was study 110 baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Body Mass Index (BMI) for 108/110 Efficacy Set

BMI was defined as weight in kg divided by height in square meter (m\^2). Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Body Mass Index (BMI) for 103/110 Efficacy Set

BMI was defined as weight in kg divided by height in square meter (m\^2). Data are reported for TEZ/IVA-TEZ/IVA group (participants who received TEZ/IVA in both parent study 103 and in current study 110). Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Body Mass Index (BMI) for Study 111/110 Efficacy Set

BMI was defined as weight in kg divided by height in square meter (m\^2). Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 111 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 111 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in BMI Z-score for 106/110 Efficacy Set

The z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 106 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 106 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline except for Placebo-TEZ/IVA category, for which baseline was study 110 baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in BMI Z-score for 108/110 Efficacy Set

The z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for 106/110 Efficacy Set

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, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 106 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 106 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline except for Placebo-TEZ/IVA category, for which baseline was study 110 baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for 108/110 Efficacy Set

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, score range: 0-100; higher scores indicating fewer symptoms and better health-related quality of life. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for 103/110 Efficacy Set

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Body Weight for Study 106/110 Efficacy Set

Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 106 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 106 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline except for Placebo-TEZ/IVA category, for which baseline was study 110 baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Body Weight for 108/110 Efficacy Set

Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Body Weight for 103/110 Efficacy Set

Data are reported for TEZ/IVA-TEZ/IVA group (participants who received TEZ/IVA in both parent study 103 and in current study 110). Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Body Weight for 111/110 Efficacy Set

Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 111 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 111 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Body Weight Z-score for 106/110 Efficacy Set

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Body Weight Z-score for 108/110 Efficacy Set

The z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Height Z-score for 106/110 Efficacy Set

Time frame: From Baseline at Study 110 Week 96

Part A: Absolute Change in Height Z-score for 108/110 Efficacy Set

The z-score is a statistical measure to describe whether a mean was above or below the standard. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan. Baseline was defined as the parent study baseline.

Time frame: From Baseline at Study 110 Week 96

Part A: Time-to-first Pulmonary Exacerbation (PEx) for 106/110 PEx Analysis Set

Time-to-first pulmonary exacerbation was analyzed using Kaplan-Meier estimates and expressed in terms of event-free probability. PEx 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. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 106 and TEZ/IVA in current study 110) and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 106 and in current study 110) as per pre-specified analysis plan.

Time frame: 96 weeks

Part A: Time-to-first Pulmonary Exacerbation (PEx) for 108/110 PEx Analysis Set

Time-to-first pulmonary exacerbation was analyzed using Kaplan-Meier estimates and expressed in terms of event-free probability. PEx 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. Data are reported separately for Placebo-TEZ/IVA category (participants who received placebo in parent study 108 and TEZ/IVA in current study 110); IVA-TEZ/IVA category (participants who received IVA monotherapy in parent study 108 and TEZ/IVA in current study 110); and TEZ/IVA-TEZ/IVA category (participants who received TEZ/IVA in both parent study 108 and in current study 110) as per pre-specified analysis plan.

Time frame: 96 weeks

Part A: Plasma Concentrations of TEZ, TEZ Metabolite (M1-TEZ), Ivacaftor (IVA) and Ivacaftor Metabolite (M1-IVA)

Time frame: Week 24

Part B: Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1)

FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.

Time frame: From Baseline at Study 110 Week 96

Part B: Absolute Change in Body Mass Index (BMI)

BMI was defined as weight in kilogram (kg) divided by height in square meter (m\^2).

Time frame: From Baseline at Week 96

Part B: Absolute Change in BMI Z-score

Time frame: From Baseline at Week 96

Part B: Number of Pulmonary Exacerbation (PEx) 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.

Time frame: From Baseline up to Week 96