Cystic Fibrosis
Conditions
Brief summary
This is a Phase 3, randomized, double-blind, ivacaftor-controlled, parallel-group, multicenter study of tezacaftor in combination with ivacaftor in subjects aged 12 years and older with CF who are heterozygous for the F508del-CFTR mutation and a second CFTR allele with a gating defect that is clinically demonstrated to be ivacaftor responsive.
Interventions
DRUGIvacaftor
Sponsors
Vertex Pharmaceuticals Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Heterozygous for F508del-CFTR mutation and a second CFTR allele with a gating defect that is clinically demonstrated to be ivacaftor responsive * FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height during screening * Stable CF disease as judged by the investigator.
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 subject. * Pregnant and nursing females (females of childbearing potential must have a negative pregnancy test at Screening and Week -4 Visits). * Sexually active subjects of reproductive potential who are not willing to follow the contraception requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8 | Baseline, Through Week 8 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relative Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8 | Baseline, Through Week 8 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
| Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline Through Week 8 | Baseline, Through Week 8 | 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. |
| Absolute Change From Baseline in Sweat Chloride Through Week 8 | Baseline, Through Week 8 | Sweat samples were collected using an approved collection device. |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Baseline up to Week 16 | — |
| Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | Predose on Week -2 for Run-in period; Pre-dose on Week 2 for Active comparator period | — |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Ireland, Italy, United Kingdom, United States
Participant flow
Pre-assignment details
The study consisted of 2 periods: an Ivacaftor Run-in Period and an Active Comparator Treatment Period. Participants were randomized in a ratio of 1:1 to receive either VX-661/ivacaftor combination therapy or ivacaftor monotherapy for 8 weeks during the Active Comparator Treatment Period after completion of 4 weeks Ivacaftor Run-in Period.
Participants by arm
| Arm | Count |
|---|---|
| VX-661 + Ivacaftor (Active Comparator Period) VX-661 100 mg and ivacaftor 150 mg fixed-dose combination tablet orally once daily in the morning and ivacaftor 150 mg tablet orally once daily in the evening for 8 weeks. | 76 |
| Ivacaftor Monotherapy (Active Comparator Period) Ivacaftor 150 mg tablet orally every 12 hours as monotherapy for 8 weeks. | 74 |
| Total | 150 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Active Comparator Period (8 Weeks) | Adverse Event | 0 | 0 | 2 |
| Active Comparator Period (8 Weeks) | Lost to Follow-up | 0 | 0 | 1 |
| Active Comparator Period (8 Weeks) | Other | 0 | 0 | 2 |
| Active Comparator Period (8 Weeks) | Other non-compliance | 0 | 1 | 0 |
| Active Comparator Period (8 Weeks) | Participants refused further dosing | 0 | 0 | 1 |
| Ivacaftor Run-in Period (4 Weeks) | Did not meet eligibility criteria | 1 | 0 | 0 |
| Ivacaftor Run-in Period (4 Weeks) | Participants refused further dosing | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Ivacaftor Monotherapy (Active Comparator Period) | Total | VX-661 + Ivacaftor (Active Comparator Period) |
|---|---|---|---|
| Age, Continuous | 31.8 years STANDARD_DEVIATION 11.1 | 32.4 years STANDARD_DEVIATION 12.2 | 33.0 years STANDARD_DEVIATION 13.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 72 Participants | 148 Participants | 76 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 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 | 3 Participants | 1 Participants |
| Race (NIH/OMB) White | 72 Participants | 145 Participants | 73 Participants |
| Sex: Female, Male Female | 34 Participants | 66 Participants | 32 Participants |
| Sex: Female, Male Male | 40 Participants | 84 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 156 | 0 / 76 | 0 / 75 |
| other Total, other adverse events | 24 / 156 | 25 / 76 | 32 / 75 |
| serious Total, serious adverse events | 2 / 156 | 4 / 76 | 7 / 75 |
Outcome results
Primary
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.
Time frame: Baseline, Through Week 8
Population: Full Analysis Set was defined as all randomized participants who have received at least 1 dose of blinded study drug during the active comparator treatment period. Here Overall number of participants analyzed signifies those participants who were evaluable for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| VX-661 + Ivacaftor (Active Comparator Period) | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8 | 0.5 Percent predicted of FEV1 | Standard Error 0.4 |
| Ivacaftor Monotherapy (Active Comparator Period) | Absolute Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8 | 0.2 Percent predicted of FEV1 | Standard Error 0.4 |
p-value: =0.584695% CI: [-0.8, 1.4]Mixed Model for Repeated Measures (MMRM)
Secondary
Absolute Change From Baseline in Sweat Chloride Through Week 8
Sweat samples were collected using an approved collection device.
Time frame: Baseline, Through Week 8
Population: Full Analysis Set was defined as all randomized participants who have received at least 1 dose of blinded study drug during the active comparator treatment period. Here Overall number of participants analyzed signifies those participants who were evaluable for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| VX-661 + Ivacaftor (Active Comparator Period) | Absolute Change From Baseline in Sweat Chloride Through Week 8 | -7.9 Millimoles per liter | Standard Error 1.7 |
| Ivacaftor Monotherapy (Active Comparator Period) | Absolute Change From Baseline in Sweat Chloride Through Week 8 | -2.1 Millimoles per liter | Standard Error 1.8 |
p-value: =0.021695% CI: [-10.7, -0.9]Mixed models Repeated Measures (MMRM)
Secondary
Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline Through Week 8
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: Baseline, Through Week 8
Population: Full Analysis Set was defined as all randomized participants who have received at least 1 dose of blinded study drug during the active comparator treatment period. Here Overall number of participants analyzed signifies those participants who were evaluable for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| VX-661 + Ivacaftor (Active Comparator Period) | Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline Through Week 8 | 0.7 units on a scale | Standard Error 1.3 |
| Ivacaftor Monotherapy (Active Comparator Period) | Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score From Baseline Through Week 8 | -2.1 units on a scale | Standard Error 1.3 |
p-value: =0.123695% CI: [-0.8, 6.4]Mixed models Repeated Measures (MMRM)
Secondary
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: Baseline up to Week 16
Population: The Safety Set included all participants who received at least 1 dose of study drug during Ivacaftor (Run-in period) and active comparator treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VX-661 + Ivacaftor (Active Comparator Period) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 66 Participants |
| VX-661 + Ivacaftor (Active Comparator Period) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 2 Participants |
| Ivacaftor Monotherapy (Active Comparator Period) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 50 Participants |
| Ivacaftor Monotherapy (Active Comparator Period) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 4 Participants |
| Ivacaftor Monotherapy (Active Comparator Period) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 54 Participants |
| Ivacaftor Monotherapy (Active Comparator Period) | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 7 Participants |
Secondary
Relative 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.
Time frame: Baseline, Through Week 8
Population: Full Analysis Set was defined as all randomized participants who have received at least 1 dose of blinded study drug during the active comparator treatment period. Here Overall number of participants analyzed signifies those participants who were evaluable for this outcome.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| VX-661 + Ivacaftor (Active Comparator Period) | Relative Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8 | 1.3 Percent change | Standard Error 0.6 |
| Ivacaftor Monotherapy (Active Comparator Period) | Relative Change From Baseline in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) Through Week 8 | 0.5 Percent change | Standard Error 0.6 |
p-value: =0.38695% CI: [-1, 2.6]Mixed models Repeated Measures (MMRM)
Secondary
Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA)
Time frame: Predose on Week -2 for Run-in period; Pre-dose on Week 2 for Active comparator period
Population: Pharmacokinetic (PK) set included participants who received study drug and had PK assessment. Here 'Overall number of participants analyzed' signifies participants who were evaluable for this outcome. Number Analyzed=0 indicates no participants were analyzed for specified categories because VX-661 was not administered in the specified arms.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| VX-661 + Ivacaftor (Active Comparator Period) | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | M1-IVA | 1590 nanogram per milliliter (ng/mL) | Standard Deviation 956 |
| VX-661 + Ivacaftor (Active Comparator Period) | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | IVA | 812 nanogram per milliliter (ng/mL) | Standard Deviation 615 |
| Ivacaftor Monotherapy (Active Comparator Period) | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | M1-IVA | 1830 nanogram per milliliter (ng/mL) | Standard Deviation 1010 |
| Ivacaftor Monotherapy (Active Comparator Period) | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | M1-VX-661 | 4870 nanogram per milliliter (ng/mL) | Standard Deviation 1750 |
| Ivacaftor Monotherapy (Active Comparator Period) | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | IVA | 1000 nanogram per milliliter (ng/mL) | Standard Deviation 742 |
| Ivacaftor Monotherapy (Active Comparator Period) | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | VX-661 | 2520 nanogram per milliliter (ng/mL) | Standard Deviation 1490 |
| Ivacaftor Monotherapy (Active Comparator Period) | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | IVA | 740 nanogram per milliliter (ng/mL) | Standard Deviation 464 |
| Ivacaftor Monotherapy (Active Comparator Period) | Trough Plasma Concentrations (Ctrough) of VX-661, VX-661 Metabolites (M1-VX-661), Ivacaftor (IVA) and IVA Metabolite (M1-IVA) | M1-IVA | 1450 nanogram per milliliter (ng/mL) | Standard Deviation 828 |