Cystic Fibrosis
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy and safety of ivacaftor in subjects with cystic fibrosis (CF) who have the R117H-CFTR mutation.
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.
Interventions
DRUGIvacaftor
Ivacaftor 150 milligram (mg) tablet orally twice daily for 24 weeks.
DRUGPlacebo
Placebo matched to Ivacaftor tablet orally twice daily for 24 weeks.
Sponsors
Vertex Pharmaceuticals Incorporated
Cystic Fibrosis Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female with confirmed diagnosis of CF * Must have at least 1 allele of the R117H CFTR mutation * Percent predicted forced expiratory volume in 1 second (FEV1) 40 percent (%) to 90% (for subjects aged 12 years or older) or 40% to 105% (for subjects aged 6 to 11 years) 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
* CFTR gene mutation leading to CFTR channel with gating defect (that is, any 1 of the following mutations: G551D, G178R, G551S, S549N, S549R, G970R, G1244E, S1251N, S1255P, or G1349D) * 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 * Abnormal liver function, at screening, defined as greater than or equal to (\>=) 3 time upper limit of normal (ULN), of any 3 or more of the following: serum aspartate transaminase (AST), serum alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), serum alkaline phosphatase (ALP), total bilirubin * Colonization with organisms associated with a more rapid decline in pulmonary status (for example, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus) at screening * 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 * Any non-CF-related illness within 2 weeks before Day 1 (first dose of study drug). Illness was defined as an acute (serious or non-serious) condition (for example, gastroenteritis) * Use of any inhibitors or inducers of cytochrome (CYP) P450 3A
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24 | Baseline, Week 24 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Body Mass Index (BMI) at Week 24 | Baseline, Week 24 | BMI was defined as weight in kilogram (kg) divided by height in square meter (m\^2). |
| Change From Baseline in Sweat Chloride Through Week 24 | Baseline, Week 24 | 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 From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24 | Baseline, Week 24 | The CFQ-R is a validated subject-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 |
| Time to First Pulmonary Exacerbation | Day 0 to 15, Day 16 to 56, Day 57 to 112, Day 113 to 168 | Number of events (pulmonary exacerbation) during the pre-specified time intervals were reported. A subject without an exacerbation before withdrawal from the study was considered censored at the time of withdrawal, and a subject without an exacerbation who completes the study period was considered censored at the end of the analysis period. |
| Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to follow-up (3 to 4 weeks after last dose [last dose = Week 24]) | AE: any untoward medical occurrence, including clinically significant clinical laboratory assessments 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. |
Countries
United Kingdom, United States
Participant flow
Pre-assignment details
A total of 70 subjects were randomized, of which 1 subject discontinued the study prior to study drug administration. A total of 69 subjects started treatment.
Participants by arm
| Arm | Count |
|---|---|
| Ivacaftor Ivacaftor 150 milligram (mg) tablet orally twice daily for 24 weeks. | 34 |
| Placebo Placebo matched to ivacaftor tablet orally twice daily for 24 weeks. | 35 |
| Total | 69 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Non-Compliance | 1 | 0 |
| Overall Study | Pregnancy (Self or Partner) | 1 | 0 |
Baseline characteristics
| Characteristic | Ivacaftor | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 29.2 years STANDARD_DEVIATION 16.57 | 32.7 years STANDARD_DEVIATION 17.43 | 31.0 years STANDARD_DEVIATION 16.98 |
| Sex: Female, Male Female | 19 Participants | 20 Participants | 39 Participants |
| Sex: Female, Male Male | 15 Participants | 15 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 34 | 35 / 35 |
| serious Total, serious adverse events | 4 / 34 | 6 / 35 |
Outcome results
Primary
Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24
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.
Time frame: Baseline, Week 24
Population: Full Analysis Set (FAS) included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ivacaftor | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24 | 2.5724 percent predicted of FEV1 | Standard Error 1.1532 |
| Placebo | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 24 | 0.4611 percent predicted of FEV1 | Standard Error 1.1313 |
Comparison: Analysis was based on mixed effects model for repeated measures (MMRM) with dependent variable absolute change from baseline, with treatment group, visit and treatment by visit interaction as fixed effects, subject as random effect, and with adjustment for the continuous baseline value of age and percent predicted FEV1, using compound symmetry covariance matrix.p-value: 0.197995% CI: [-1.1305, 5.3532]Mixed Model Repeated Measures
Secondary
Change From Baseline in Body Mass Index (BMI) at Week 24
BMI was defined as weight in kilogram (kg) divided by height in square meter (m\^2).
Time frame: Baseline, Week 24
Population: FAS included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ivacaftor | Change From Baseline in Body Mass Index (BMI) at Week 24 | 0.4910 kg/m^2 | Standard Error 0.6653 |
| Placebo | Change From Baseline in Body Mass Index (BMI) at Week 24 | 0.2284 kg/m^2 | Standard Error 0.6504 |
Comparison: Analysis was based on linear mixed model with dependent variable BMI and treatment as a fixed effect, adjustment for baseline percent predicted FEV1, age and visit by treatment interaction was included as covariates and intercept, visit were included as random effects.p-value: 0.77895% CI: [-1.5698, 2.095]Linear Mixed model
Secondary
Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24
The CFQ-R is a validated subject-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
Time frame: Baseline, Week 24
Population: FAS included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo). Here, Number of participants analyzed signifies those subjects who were evaluable for this measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ivacaftor | Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24 | 7.5585 units on a scale | Standard Error 2.2073 |
| Placebo | Change From Baseline in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24 | -0.8289 units on a scale | Standard Error 2.1569 |
Comparison: Analysis was based on MMRM with dependent variable absolute change from baseline, with treatment group, visit and treatment by visit interaction as fixed effects, subject as random effect, and with adjustment for the continuous baseline value of age and percent predicted FEV1, and CFQ-R respiratory domain score, using compound symmetry covariance matrix.p-value: 0.009195% CI: [2.1658, 14.609]Mixed Model Repeated Measures
Secondary
Change From Baseline in Sweat Chloride Through Week 24
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.
Time frame: Baseline, Week 24
Population: FAS included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo). Here, Number of participants analyzed signifies those subjects who were evaluable for this measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Ivacaftor | Change From Baseline in Sweat Chloride Through Week 24 | -26.2771 millimole per liter (mmol/L) | Standard Error 1.4584 |
| Placebo | Change From Baseline in Sweat Chloride Through Week 24 | -2.3078 millimole per liter (mmol/L) | Standard Error 1.3716 |
Comparison: Analysis was based on MMRM with dependent variable absolute change from baseline, with treatment group, visit and treatment by visit interaction as fixed effects, subject as random effect, and with adjustment for the continuous baseline value of age and percent predicted FEV1, and sweat chloride, using a compound symmetry covariance matrix.p-value: <0.000195% CI: [-28.0094, -19.9293]Mixed Model Repeated Measures
Secondary
Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
AE: any untoward medical occurrence, including clinically significant clinical laboratory assessments 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: Baseline up to follow-up (3 to 4 weeks after last dose [last dose = Week 24])
Population: Safety Set included all subjects who received at least 1 dose of study drug (ivacaftor or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ivacaftor | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Subjects with any AEs | 32 participants |
| Ivacaftor | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Subjects with SAEs | 4 participants |
| Placebo | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Subjects with any AEs | 35 participants |
| Placebo | Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Subjects with SAEs | 6 participants |
Secondary
Time to First Pulmonary Exacerbation
Number of events (pulmonary exacerbation) during the pre-specified time intervals were reported. A subject without an exacerbation before withdrawal from the study was considered censored at the time of withdrawal, and a subject without an exacerbation who completes the study period was considered censored at the end of the analysis period.
Time frame: Day 0 to 15, Day 16 to 56, Day 57 to 112, Day 113 to 168
Population: FAS included all randomized subjects who received at least 1 dose of study drug (ivacaftor or placebo).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ivacaftor | Time to First Pulmonary Exacerbation | Day 0 to 15 | 3 events |
| Ivacaftor | Time to First Pulmonary Exacerbation | Day 16 to 56 | 4 events |
| Ivacaftor | Time to First Pulmonary Exacerbation | Day 57 to 112 | 2 events |
| Ivacaftor | Time to First Pulmonary Exacerbation | Day 113 to 168 | 1 events |
| Placebo | Time to First Pulmonary Exacerbation | Day 113 to 168 | 4 events |
| Placebo | Time to First Pulmonary Exacerbation | Day 0 to 15 | 1 events |
| Placebo | Time to First Pulmonary Exacerbation | Day 57 to 112 | 6 events |
| Placebo | Time to First Pulmonary Exacerbation | Day 16 to 56 | 2 events |
p-value: 0.8556Cox Proportional Hazard Regression