Cystic Fibrosis
Conditions
Keywords
Homozygous for the F508del CFTR Mutation
Brief summary
This is a Phase 3, randomized, double blind, placebo controlled, parallel group, multicenter study in people with cystic fibrosis (CF) who are homozygous for the F508del CF transmembrane conductance regulator (CFTR) gene mutation.
Detailed description
This is a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study in people with CF who are homozygous for the F508del-CFTR mutation. This study is designed to evaluate the efficacy and safety of VX-661 in combination with Ivacaftor (IVA, VX-770). The active treatment regimen comprised of a morning dose of a fixed-dose combination (FDC) tablet of 100 milligram (mg) VX-661/150 mg IVA once daily (qd) and an evening dose of IVA 150 mg to be taken approximately 12 hours after the morning dose. The placebo regimen was visually matched tablets to be taken with the same schedule as the active treatment.
Interventions
FDC tablet, oral use
DRUGIvacaftor
Tablet, oral use
DRUGVX-661 Plus Ivacaftor Combination Placebo
FDC tablet, oral use
Tablet, oral use
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Homozygous for the F508del CFTR mutation, genotype to be confirmed at the Screening Visit * Confirmed diagnosis of CF defined as a sweat chloride value ≥60 mmol/L by quantitative pilocarpine iontophoresis * Forced expiratory volume at one second (FEV1) ≥40% and ≤90% of predicted normal for age, sex, and height during screening * Stable CF disease as judged by the investigator * Willing to remain on a stable CF medication regimen through Week 24 or, if applicable, the Safety Follow up 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) * Pregnant or nursing females (females of childbearing potential must have a negative pregnancy test at Screening and Day 1) * Sexually active participants of reproductive potential who are not willing to follow the contraception requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline (Day 1) in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 24 | Day 1, Through Week 24 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Pulmonary Exacerbations Per Year | Day 1 through Week 24 | Pulmonary exacerbation was defined as a new event or change in antibiotic therapy for greater than or equal to 4 sinopulmonary signs/symptoms. Pulmonary exacerbation events per year (48 weeks) were reported. |
| Absolute Change From Baseline (Day 1) Body Mass Index (BMI) at Week 24 | Day 1, Week 24 | BMI was defined as weight in kilograms (kg) divided by height in square meter (m\^2). |
| Absolute Change From Baseline (Day 1) in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24 | Day 1, Through Week 24 | 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. |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Day 1 up to Week 28 | 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 28 was considered treatment-emergent. |
| Relative Change From Baseline (Day 1) in ppFEV1 Through Week 24 | Day 1, Through Week 24 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
| Absolute Change From Baseline (Day 1) in Sweat Chloride Through Week 24 | Day 1, Through Week 24 | Sweat samples were collected using an approved collection device. |
| Absolute Change From Baseline (Day 1) in BMI Z-score at Week 24 in Participants Less Than (<) 20 Years Old at the Time of Screening) | Day 1, Week 24 | BMI was defined as weight in kg divided by height in m\^2. z-score is a statistical measure to describe whether a mean was above or below the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score (BMI z-score). |
| Absolute Change From Baseline (Day 1) in Body Weight at Week 24 | Day 1, Week 24 | — |
| Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661 and M2-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Pre-morning dose on Week 16 | This outcome was not planned to be assessed in Placebo arm. |
| Number of Participants With at Least One Pulmonary Exacerbation Pulmonary Exacerbation Through Week 24 | Day 1 through Week 24 | Pulmonary exacerbation was defined as a new event or change in antibiotic therapy for greater than or equal to 4 sinopulmonary signs/symptoms. Time to event data was not collected and instead, Number of Subjects with first event were collected and are reported. 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. |
Countries
Canada, Denmark, France, Germany, Ireland, Italy, Netherlands, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted across 91 sites in 12 countries.
Pre-assignment details
A total of 510 participants were randomized and 509 participants were treated in the study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo matched to VX-661 plus IVA FDC tablet administered orally in the morning and placebo matched to IVA tablet administered orally in the evening up to Week 24. | 256 |
| VX-661/IVA VX-661 100 mg plus IVA 150 mg FDC tablet administered orally in the morning and IVA 150 mg tablet administered orally in the evening up to Week 24. | 248 |
| Total | 504 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 8 | 4 |
| Overall Study | Other | 3 | 3 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Randomized but not treated | 1 | 0 |
| Overall Study | Withdrawal by Subject | 6 | 7 |
Baseline characteristics
| Characteristic | VX-661/IVA | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 26.9 years STANDARD_DEVIATION 11.2 | 26.3 years STANDARD_DEVIATION 10.4 | 25.7 years STANDARD_DEVIATION 9.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 12 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 234 Participants | 484 Participants | 250 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 5 Participants | 8 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) White | 245 Participants | 499 Participants | 254 Participants |
| Sex: Female, Male Female | 121 Participants | 246 Participants | 125 Participants |
| Sex: Female, Male Male | 127 Participants | 258 Participants | 131 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 258 | 0 / 251 |
| other Total, other adverse events | 243 / 258 | 227 / 251 |
| serious Total, serious adverse events | 47 / 258 | 31 / 251 |
Outcome results
Primary
Absolute Change From Baseline (Day 1) in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 24
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time frame: Day 1, Through Week 24
Population: FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline (Day 1) in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 24 | -0.6 Percentage of predicted FEV1 |
| VX-661/IVA | Absolute Change From Baseline (Day 1) in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) Through Week 24 | 3.4 Percentage of predicted FEV1 |
Comparison: Testing was performed according to the hierarchical testing procedure to control the overall type I error for tested at α = 0.05.p-value: <0.000195% CI: [3.1, 4.8]Mixed model for repeated measures (MMRM)
Secondary
Absolute Change From Baseline (Day 1) Body Mass Index (BMI) at Week 24
BMI was defined as weight in kilograms (kg) divided by height in square meter (m\^2).
Time frame: Day 1, Week 24
Population: FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline (Day 1) Body Mass Index (BMI) at Week 24 | 0.12 kilogram per square meter (kg/m^2) |
| VX-661/IVA | Absolute Change From Baseline (Day 1) Body Mass Index (BMI) at Week 24 | 0.18 kilogram per square meter (kg/m^2) |
Comparison: Testing was performed according to the hierarchical testing procedure to control the overall type I error for tested at α = 0.05.p-value: 0.412795% CI: [-0.08, 0.19]MMRM
Secondary
Absolute Change From Baseline (Day 1) in BMI Z-score at Week 24 in Participants Less Than (<) 20 Years Old at the Time of Screening)
BMI was defined as weight in kg divided by height in m\^2. z-score is a statistical measure to describe whether a mean was above or below the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score (BMI z-score).
Time frame: Day 1, Week 24
Population: Analysis population included all randomized participants who received at least 1 dose of study drug and were \<20 years of age at the time of screening. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline (Day 1) in BMI Z-score at Week 24 in Participants Less Than (<) 20 Years Old at the Time of Screening) | -0.02 z-score |
| VX-661/IVA | Absolute Change From Baseline (Day 1) in BMI Z-score at Week 24 in Participants Less Than (<) 20 Years Old at the Time of Screening) | -0.06 z-score |
Secondary
Absolute Change From Baseline (Day 1) in Body Weight at Week 24
Time frame: Day 1, Week 24
Population: FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline (Day 1) in Body Weight at Week 24 | 0.6 kg |
| VX-661/IVA | Absolute Change From Baseline (Day 1) in Body Weight at Week 24 | 0.7 kg |
Secondary
Absolute Change From Baseline (Day 1) in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24
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.
Time frame: Day 1, Through Week 24
Population: FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline (Day 1) in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24 | -0.1 units on a scale |
| VX-661/IVA | Absolute Change From Baseline (Day 1) in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score Through Week 24 | 5.0 units on a scale |
Secondary
Absolute Change From Baseline (Day 1) in Sweat Chloride Through Week 24
Sweat samples were collected using an approved collection device.
Time frame: Day 1, Through Week 24
Population: FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Absolute Change From Baseline (Day 1) in Sweat Chloride Through Week 24 | 0.2 millimole per liter (mmol/L) |
| VX-661/IVA | Absolute Change From Baseline (Day 1) in Sweat Chloride Through Week 24 | -9.9 millimole per liter (mmol/L) |
Secondary
Number of Participants With at Least One Pulmonary Exacerbation Pulmonary Exacerbation Through Week 24
Pulmonary exacerbation was defined as a new event or change in antibiotic therapy for greater than or equal to 4 sinopulmonary signs/symptoms. Time to event data was not collected and instead, Number of Subjects with first event were collected and are reported. 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: Day 1 through Week 24
Population: FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With at Least One Pulmonary Exacerbation Pulmonary Exacerbation Through Week 24 | 88 Participants |
| VX-661/IVA | Number of Participants With at Least One Pulmonary Exacerbation Pulmonary Exacerbation Through Week 24 | 62 Participants |
Secondary
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 28 was considered treatment-emergent.
Time frame: Day 1 up to Week 28
Population: Safety Set included all participants who received at least 1 dose of the study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 245 Participants |
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 47 Participants |
| VX-661/IVA | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 227 Participants |
| VX-661/IVA | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 31 Participants |
Secondary
Number of Pulmonary Exacerbations Per Year
Pulmonary exacerbation was defined as a new event or change in antibiotic therapy for greater than or equal to 4 sinopulmonary signs/symptoms. Pulmonary exacerbation events per year (48 weeks) were reported.
Time frame: Day 1 through Week 24
Population: FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Pulmonary Exacerbations Per Year | 0.99 pulmonary exacerbation events per year |
| VX-661/IVA | Number of Pulmonary Exacerbations Per Year | 0.64 pulmonary exacerbation events per year |
Comparison: Testing was performed according to the hierarchical testing procedure to control the overall type I error for tested at α = 0.05.p-value: 0.005495% CI: [0.48, 0.88]Negative Binomial Regression
Secondary
Relative Change From Baseline (Day 1) in ppFEV1 Through Week 24
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time frame: Day 1, Through Week 24
Population: FAS included all randomized participants who carry the intended CFTR allele mutation and have received at least 1 dose of study drug. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Relative Change From Baseline (Day 1) in ppFEV1 Through Week 24 | -0.5 percent change |
| VX-661/IVA | Relative Change From Baseline (Day 1) in ppFEV1 Through Week 24 | 6.3 percent change |
Comparison: Testing was performed according to the hierarchical testing procedure to control the overall type I error for tested at α = 0.05.p-value: <0.000195% CI: [5.3, 8.3]MMRM
Secondary
Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661 and M2-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA)
This outcome was not planned to be assessed in Placebo arm.
Time frame: Pre-morning dose on Week 16
Population: Pharmacokinetic (PK) set included all randomized participants who received any amount of study drug and had a PK assessment. Here 'Number of participants analyzed' signifies those participants who were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661 and M2-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | VX-661 | 1890 nanogram per milliliter (ng/mL) | Standard Deviation 1150 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661 and M2-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | M1 VX-661 | 4730 nanogram per milliliter (ng/mL) | Standard Deviation 1730 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661 and M2-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | M2 VX-661 | 4830 nanogram per milliliter (ng/mL) | Standard Deviation 2750 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661 and M2-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | IVA | 815 nanogram per milliliter (ng/mL) | Standard Deviation 572 |
| Placebo | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1 VX-661 and M2-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | M1 IVA | 1590 nanogram per milliliter (ng/mL) | Standard Deviation 961 |