Cystic Fibrosis
Conditions
Brief summary
This study will evaluate the efficacy of VX-659 in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation (F/F).
Interventions
DRUGVX-659/TEZ/IVA
Participants received VX-659/TEZ/IVA orally once daily in the morning.
DRUGTEZ/IVA
Participants received TEZ/IVA orally once daily in the morning.
DRUGIVA
Participants received IVA orally once daily in the evening.
DRUGPlacebo
Participants received placebo matched TEZ/IVA orally once daily in the morning.
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
Key Inclusion Criteria: * Homozygous for the F508del mutation (F/F) * Forced expiratory volume in 1 second (FEV1) value ≥40% and ≤90% of predicted mean for age, sex, and height Key
Exclusion criteria
* Clinically significant cirrhosis with or without portal hypertension * Lung infection with organisms associated with a more rapid decline in pulmonary status * Solid organ or hematological transplantation Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | From Baseline at Week 4 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Sweat Chloride (SwCl) | From Baseline at Week 4 | Sweat samples were collected using an approved collection device. |
| Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | From Baseline at Week 4 | 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. |
| Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first dose of study drug in TC treatment period up to 28 days after last dose of study drug or to the completion of study participation date, whichever occurs first (up to Week 8) | — |
| Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | From Day 1 and Week 4 | — |
Countries
Australia, Germany, Ireland, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 116 participants were enrolled in the study, of which 5 participants were included in the run-in period but were not dosed in TC treatment period. Results are presented for 111 participants dosed in the TC treatment period.
Pre-assignment details
This study was conducted in participants with cystic fibrosis (CF) aged 12 years or older.
Participants by arm
| Arm | Count |
|---|---|
| TEZ/IVA Following a run-in period of 4 weeks with TEZ/IVA, participants received TEZ 100 mg/IVA 150 mg as FDC tablet in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period. | 57 |
| VX-659/TEZ/IVA TC Following a run-in period of 4 weeks with TEZ/IVA, participants received VX-659 240 mg/TEZ 100 mg/IVA 150 mg as FDC tablets in the morning and IVA 150 mg as mono tablet in the evening for 4 weeks in the TC treatment period. | 54 |
| Total | 111 |
Baseline characteristics
| Characteristic | TEZ/IVA | VX-659/TEZ/IVA TC | Total |
|---|---|---|---|
| Age, Continuous | 26.2 years STANDARD_DEVIATION 9.1 | 28.3 years STANDARD_DEVIATION 9.6 | 27.2 years STANDARD_DEVIATION 9.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 56 Participants | 52 Participants | 108 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Forced Expiratory Volume in 1 Second (ppFEV1) | 62.9 percentage points STANDARD_DEVIATION 14.9 | 62.0 percentage points STANDARD_DEVIATION 14.8 | 62.4 percentage points STANDARD_DEVIATION 14.8 |
| 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 | 0 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 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 56 Participants | 54 Participants | 110 Participants |
| Sex: Female, Male Female | 33 Participants | 26 Participants | 59 Participants |
| Sex: Female, Male Male | 24 Participants | 28 Participants | 52 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 57 | 0 / 54 |
| other Total, other adverse events | 19 / 57 | 23 / 54 |
| serious Total, serious adverse events | 0 / 57 | 2 / 54 |
Outcome results
Primary
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 Week 4
Population: Full analysis set (FAS) included all randomized participants who carried the intended CF transmembrane conductance regulator gene (CFTR) allele mutation and received at least 1 dose of study drug in the TC Treatment Period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TEZ/IVA | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 0.3 percentage points | Standard Error 0.9 |
| VX-659/TEZ/IVA TC | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 10.2 percentage points | Standard Error 0.9 |
p-value: <0.000195% CI: [7.4, 12.5]Mixed-effects model for repeated measure
Secondary
Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score
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: From Baseline at Week 4
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TEZ/IVA | Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | 3.0 units on a scale | Standard Error 1.7 |
| VX-659/TEZ/IVA TC | Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | 16.5 units on a scale | Standard Error 1.7 |
p-value: <0.000195% CI: [8.8, 18.3]Mixed-effects model for repeated measure
Secondary
Absolute Change in Sweat Chloride (SwCl)
Sweat samples were collected using an approved collection device.
Time frame: From Baseline at Week 4
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TEZ/IVA | Absolute Change in Sweat Chloride (SwCl) | 1.5 millimole per liter (mmol/L) | Standard Error 1.8 |
| VX-659/TEZ/IVA TC | Absolute Change in Sweat Chloride (SwCl) | -47.2 millimole per liter (mmol/L) | Standard Error 1.9 |
p-value: <0.000195% CI: [-53.9, -43.5]Mixed-effects model for repeated measure
Secondary
Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA
Time frame: From Day 1 and Week 4
Population: Pharmacokinetic analysis set included all participants who received at least 1 dose of study drug in the TC treatment period. Here Number analyzed signifies those participants who were evaluable at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| TEZ/IVA | Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Week 4: M1-TEZ | 5010 nanogram per milliliter (ng/mL) | Standard Deviation 1810 |
| TEZ/IVA | Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Day 1: TEZ | 1780 nanogram per milliliter (ng/mL) | Standard Deviation 832 |
| TEZ/IVA | Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Day 1: IVA | 717 nanogram per milliliter (ng/mL) | Standard Deviation 616 |
| TEZ/IVA | Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Day 1: M1-TEZ | 5170 nanogram per milliliter (ng/mL) | Standard Deviation 1620 |
| TEZ/IVA | Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Week 4: IVA | 722 nanogram per milliliter (ng/mL) | Standard Deviation 642 |
| TEZ/IVA | Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Week 4: TEZ | 1730 nanogram per milliliter (ng/mL) | Standard Deviation 885 |
| VX-659/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Week 4: IVA | 401 nanogram per milliliter (ng/mL) | Standard Deviation 211 |
| VX-659/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Week 4: VX-659 | 720 nanogram per milliliter (ng/mL) | Standard Deviation 589 |
| VX-659/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Day 1: TEZ | 1590 nanogram per milliliter (ng/mL) | Standard Deviation 1020 |
| VX-659/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Week 4: TEZ | 1280 nanogram per milliliter (ng/mL) | Standard Deviation 594 |
| VX-659/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Day 1: M1-TEZ | 4840 nanogram per milliliter (ng/mL) | Standard Deviation 1860 |
| VX-659/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Week 4: M1-TEZ | 4730 nanogram per milliliter (ng/mL) | Standard Deviation 1380 |
| VX-659/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Day 1: IVA | 563 nanogram per milliliter (ng/mL) | Standard Deviation 400 |
| Unknown | Observed Pre-Dose Concentration (Ctrough) of VX-659, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Day 1: VX-659 | — nanogram per milliliter (ng/mL) | — |
Secondary
Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Time frame: From first dose of study drug in TC treatment period up to 28 days after last dose of study drug or to the completion of study participation date, whichever occurs first (up to Week 8)
Population: Safety set included all participants who received at least 1 dose of study drug in the TC treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TEZ/IVA | Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 31 participants |
| TEZ/IVA | Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 0 participants |
| VX-659/TEZ/IVA TC | Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 33 participants |
| VX-659/TEZ/IVA TC | Safety and Tolerability as Assessed Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 2 participants |