Cystic Fibrosis
Conditions
Brief summary
This study will evaluate the efficacy, safety, and pharmacodynamics of elexacaftor (ELX, VX-445) in triple combination (TC) with tezacaftor (TEZ) and ivacaftor (IVA) in subjects with cystic fibrosis (CF) who are homozygous for F508del.
Interventions
DRUGELX/TEZ/IVA
FDC tablet for oral administration.
DRUGTEZ/IVA
Fixed-dose combination (FDC) tablet for oral administration.
DRUGIVA
Mono tablet for oral administration.
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 CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score | From Baseline 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | From Baseline Through Week 24 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
| Absolute Change in Sweat Chloride (SwCl) | From Baseline Through Week 24 | Sweat samples were collected using an approved collection device. |
| Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | From Day 1 in the 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 28) | — |
Countries
Australia, Belgium, Germany, United Kingdom
Participant flow
Recruitment details
A total of 176 participants were enrolled in the study. Out of those 176 participants, 1 participant was randomized but not dosed in the treatment period. Therefore, results are presented for only 175 participants.
Pre-assignment details
This study was conducted in cystic fibrosis (CF) participants aged 12 years or older.
Participants by arm
| Arm | Count |
|---|---|
| TEZ/IVA Following TEZ/IVA run-in period of 4 weeks, participants received TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. | 88 |
| ELX/TEZ/IVA Following TEZ/IVA run-in period of 4 weeks, participants received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 24 weeks. | 87 |
| Total | 175 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
Baseline characteristics
| Characteristic | TEZ/IVA | ELX/TEZ/IVA | Total |
|---|---|---|---|
| Age, Continuous | 27.8 years STANDARD_DEVIATION 11 | 27.9 years STANDARD_DEVIATION 11.8 | 27.8 years STANDARD_DEVIATION 11.4 |
| CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score | 73.1 units on a scale STANDARD_DEVIATION 17.6 | 71.2 units on a scale STANDARD_DEVIATION 19.6 | 72.2 units on a scale STANDARD_DEVIATION 18.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 83 Participants | 85 Participants | 168 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 4 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized White | 88 Participants | 84 Participants | 172 Participants |
| Race/Ethnicity, Customized White, Asian | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 45 Participants | 43 Participants | 88 Participants |
| Sex: Female, Male Male | 43 Participants | 44 Participants | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 88 | 0 / 87 |
| other Total, other adverse events | 72 / 88 | 59 / 87 |
| serious Total, serious adverse events | 14 / 88 | 5 / 87 |
Outcome results
Primary
Absolute Change in CF 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 Through Week 24
Population: Full analysis set (FAS) included all randomized participants who carried the intended CF transmembrane conductance regulator (CFTR) allele mutation and received at least 1 dose of study drug in treatment period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TEZ/IVA | Absolute Change in CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score | 1.2 units on a scale | Standard Error 1.5 |
| ELX/TEZ/IVA | Absolute Change in CF Questionnaire-Revised (CFQ-R) Respiratory Domain Score | 17.1 units on a scale | Standard Error 1.5 |
p-value: <0.000195% CI: [11.7, 20.1]Mixed-effects Model for Repeated Measure
Secondary
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 Through Week 24
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TEZ/IVA | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 1.0 percentage points | Standard Error 0.7 |
| ELX/TEZ/IVA | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 11.2 percentage points | Standard Error 0.7 |
p-value: <0.000195% CI: [8.2, 12.1]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 Through Week 24
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| TEZ/IVA | Absolute Change in Sweat Chloride (SwCl) | -3.4 millimole per liter (mmol/L) | Standard Error 1.2 |
| ELX/TEZ/IVA | Absolute Change in Sweat Chloride (SwCl) | -46.2 millimole per liter (mmol/L) | Standard Error 1.3 |
95% CI: [-46.2, -39.3]
Secondary
Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: From Day 1 in the 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 28)
Population: Safety set included all participants who received at least 1 dose of study drug in the treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TEZ/IVA | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants With TEAEs | 81 participants |
| TEZ/IVA | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants With SAEs | 14 participants |
| ELX/TEZ/IVA | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants With TEAEs | 77 participants |
| ELX/TEZ/IVA | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Participants With SAEs | 5 participants |