Cystic Fibrosis
Conditions
Brief summary
This study will evaluate the efficacy of VX-445 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-445/TEZ/IVA
Participants received VX-445/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 to VX-445/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 indicate fewer symptoms and better health-related quality of life. |
| Safety and Tolerability as Assessed by 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-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | Day 1 and Week 4 | — |
Countries
Belgium, Netherlands, United Kingdom, United States
Participant flow
Recruitment details
A total of 113 participants were enrolled in the study, of which 6 participants were included in the run-in period but were not dosed in TC treatment period. Results are presented for 107 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. | 52 |
| VX-445/TEZ/IVA TC Following a run-in period of 4 weeks with TEZ/IVA, participants received VX-445 200 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. | 55 |
| Total | 107 |
Baseline characteristics
| Characteristic | TEZ/IVA | VX-445/TEZ/IVA TC | Total |
|---|---|---|---|
| Age, Continuous | 27.9 years STANDARD_DEVIATION 10.8 | 28.8 years STANDARD_DEVIATION 11.5 | 28.4 years STANDARD_DEVIATION 11.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 49 Participants | 52 Participants | 101 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 60.2 percentage points STANDARD_DEVIATION 14.4 | 61.6 percentage points STANDARD_DEVIATION 15.4 | 60.9 percentage points STANDARD_DEVIATION 14.9 |
| 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 | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 52 Participants | 54 Participants | 106 Participants |
| Sex: Female, Male Female | 28 Participants | 31 Participants | 59 Participants |
| Sex: Female, Male Male | 24 Participants | 24 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 52 | 0 / 55 |
| other Total, other adverse events | 25 / 52 | 24 / 55 |
| serious Total, serious adverse events | 1 / 52 | 2 / 55 |
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) | 0.4 percentage points | Standard Error 0.9 |
| VX-445/TEZ/IVA TC | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 10.4 percentage points | Standard Error 0.9 |
p-value: <0.000195% CI: [7.4, 12.6]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 indicate 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 | -1.4 units on a scale | Standard Error 2 |
| VX-445/TEZ/IVA TC | Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | 16.0 units on a scale | Standard Error 2 |
p-value: <0.000195% CI: [11.8, 23]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) | 1.7 millimole per liter (mmol/L) | Standard Error 1.8 |
| VX-445/TEZ/IVA TC | Absolute Change in Sweat Chloride (SwCl) | -43.4 millimole per liter (mmol/L) | Standard Error 1.7 |
p-value: <0.000195% CI: [-50.1, -40.1]Mixed-effects model for repeated measure
Secondary
Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA
Time frame: 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-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | M1-TEZ: Week 4 | 4.86 microgram per milliliter (mcg/mL) | Standard Deviation 1.74 |
| TEZ/IVA | Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | TEZ: Day 1 | 1.71 microgram per milliliter (mcg/mL) | Standard Deviation 0.942 |
| TEZ/IVA | Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | IVA: Day 1 | 0.652 microgram per milliliter (mcg/mL) | Standard Deviation 0.399 |
| TEZ/IVA | Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | M1-TEZ: Day 1 | 4.84 microgram per milliliter (mcg/mL) | Standard Deviation 1.71 |
| TEZ/IVA | Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | IVA: Week 4 | 0.530 microgram per milliliter (mcg/mL) | Standard Deviation 0.297 |
| TEZ/IVA | Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | TEZ: Week 4 | 1.48 microgram per milliliter (mcg/mL) | Standard Deviation 0.829 |
| VX-445/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | IVA: Day 1 | 0.598 microgram per milliliter (mcg/mL) | Standard Deviation 0.428 |
| VX-445/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | VX-445: Day 1 | NA microgram per milliliter (mcg/mL) | — |
| VX-445/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | IVA: Week 4 | 0.652 microgram per milliliter (mcg/mL) | Standard Deviation 0.542 |
| VX-445/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | VX-445: Week 4 | 4.84 microgram per milliliter (mcg/mL) | Standard Deviation 2.59 |
| VX-445/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | TEZ: Day 1 | 1.60 microgram per milliliter (mcg/mL) | Standard Deviation 1.03 |
| VX-445/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | TEZ: Week 4 | 1.89 microgram per milliliter (mcg/mL) | Standard Deviation 0.974 |
| VX-445/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | M1-TEZ: Day 1 | 4.76 microgram per milliliter (mcg/mL) | Standard Deviation 1.78 |
| VX-445/TEZ/IVA TC | Observed Pre-Dose Concentration (Ctrough) of VX-445, TEZ, TEZ Metabolite (M1-TEZ), and IVA | M1-TEZ: Week 4 | 5.28 microgram per milliliter (mcg/mL) | Standard Deviation 2.04 |
Secondary
Safety and Tolerability as Assessed by 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 by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 33 participants |
| TEZ/IVA | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 1 participants |
| VX-445/TEZ/IVA TC | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 32 participants |
| VX-445/TEZ/IVA TC | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 2 participants |