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 heterozygous for F508del and a gating or residual function mutation (F/G and F/RF genotypes).
Interventions
DRUGELX/TEZ/IVA
FDC tablet for oral administration.
DRUGIVA
Mono-tablet for oral administration.
DRUGTEZ/IVA
Fixed-dose combination (FDC) 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: * Subject has a confirmed diagnosis of CF and is heterozygous for F508del and either a gating or residual function mutation (F/G and F/RF genotypes) * 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) for ELX/TEZ/IVA Group | From 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 |
|---|---|---|
| Absolute Change in ppFEV1 for the ELX/TEZ/IVA Group Compared to the Control Group | From 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 SwCl for ELX/TEZ/IVA Group Compared to the Control Group | From Baseline Through Week 8 | Sweat samples were collected using an approved collection device. |
| Absolute Change in Sweat Chloride (SwCl) for ELX/TEZ/IVA Group | From Baseline Through Week 8 | Sweat samples were collected using an approved collection device. |
| Absolute Change in CFQ-R Respiratory Domain Score for ELX/TEZ/IVA Group Compared to the Control Group | 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. |
| Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Day 1 up to Week 12 | — |
| Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for ELX/TEZ/IVA Group | 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. |
Countries
Australia, Belgium, Canada, Denmark, France, Germany, Ireland, Israel, Italy, Netherlands, Spain, United Kingdom, United States
Participant flow
Recruitment details
A total of 271 participants were enrolled in this study out of which 12 participants discontinued in run-in period. Of 259 participants, 1 participant was randomized but not dosed in the treatment period. Therefore, results are presented for only 258 participants.
Pre-assignment details
This study was conducted in cystic fibrosis (CF) participants aged 12 years or older.
Participants by arm
| Arm | Count |
|---|---|
| Control: IVA or TEZ/IVA Following an IVA or TEZ/IVA run-in period of 4 weeks, participants either received IVA 150 mg q12h or TEZ 100 mg qd/IVA 150 mg q12h in the treatment period for 8 weeks. | 126 |
| TC: ELX/TEZ/IVA Following an IVA or 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 8 weeks. | 132 |
| Total | 258 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Total | TC: ELX/TEZ/IVA | Control: IVA or TEZ/IVA |
|---|---|---|---|
| Age, Continuous | 37.7 years STANDARD_DEVIATION 14.5 | 37.7 years STANDARD_DEVIATION 14.7 | 37.6 years STANDARD_DEVIATION 14.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 5 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 231 Participants | 117 Participants | 114 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 18 Participants | 10 Participants | 8 Participants |
| Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 67.6 percentage points STANDARD_DEVIATION 16 | 67.1 percentage points STANDARD_DEVIATION 15.7 | 68.1 percentage points STANDARD_DEVIATION 16.4 |
| Race/Ethnicity, Customized Aboriginal | 3 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Latin-American | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Lebanese | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Collected per Local Regulations | 18 Participants | 9 Participants | 9 Participants |
| Race/Ethnicity, Customized White | 232 Participants | 122 Participants | 110 Participants |
| Race/Ethnicity, Customized White, American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 128 Participants | 67 Participants | 61 Participants |
| Sex: Female, Male Male | 130 Participants | 65 Participants | 65 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 126 | 0 / 132 |
| other Total, other adverse events | 47 / 126 | 35 / 132 |
| serious Total, serious adverse events | 11 / 126 | 5 / 132 |
Outcome results
Primary
Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for ELX/TEZ/IVA Group
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time frame: From Baseline Through Week 8
Population: Full analysis set (FAS) included all randomized participants who have the intended CF transmembrane conductance regulator (CFTR) allele mutation and received at least 1 dose of study drug in the treatment period. This outcome measure was applicable only for the triple combination arm.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TC: ELX/TEZ/IVA | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) for ELX/TEZ/IVA Group | 3.7 percentage points |
Secondary
Absolute Change in CFQ-R Respiratory Domain Score for ELX/TEZ/IVA Group Compared to the Control Group
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 8
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TC: ELX/TEZ/IVA | Absolute Change in CFQ-R Respiratory Domain Score for ELX/TEZ/IVA Group Compared to the Control Group | 1.6 units on a scale |
| TC: ELX/TEZ/IVA | Absolute Change in CFQ-R Respiratory Domain Score for ELX/TEZ/IVA Group Compared to the Control Group | 10.3 units on a scale |
p-value: <0.000195% CI: [5.3, 12.1]Mixed-effects model for repeated measure
Secondary
Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for ELX/TEZ/IVA Group
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 8
Population: FAS. This outcome measure was applicable only for the triple combination arm.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TC: ELX/TEZ/IVA | Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score for ELX/TEZ/IVA Group | 10.3 units on a scale |
Secondary
Absolute Change in ppFEV1 for the ELX/TEZ/IVA Group Compared to the Control Group
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time frame: From Baseline Through Week 8
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TC: ELX/TEZ/IVA | Absolute Change in ppFEV1 for the ELX/TEZ/IVA Group Compared to the Control Group | 0.2 percentage points |
| TC: ELX/TEZ/IVA | Absolute Change in ppFEV1 for the ELX/TEZ/IVA Group Compared to the Control Group | 3.7 percentage points |
p-value: <0.000195% CI: [2.2, 4.7]Mixed-effects model for repeated measure
Secondary
Absolute Change in SwCl for ELX/TEZ/IVA Group Compared to the Control Group
Sweat samples were collected using an approved collection device.
Time frame: From Baseline Through Week 8
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TC: ELX/TEZ/IVA | Absolute Change in SwCl for ELX/TEZ/IVA Group Compared to the Control Group | 0.7 mmol/L |
| TC: ELX/TEZ/IVA | Absolute Change in SwCl for ELX/TEZ/IVA Group Compared to the Control Group | -22.3 mmol/L |
p-value: <0.000195% CI: [-26.1, -20.1]Mixed-effects model for repeated measure
Secondary
Absolute Change in Sweat Chloride (SwCl) for ELX/TEZ/IVA Group
Sweat samples were collected using an approved collection device.
Time frame: From Baseline Through Week 8
Population: FAS. This outcome measure was applicable only for the triple combination group.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| TC: ELX/TEZ/IVA | Absolute Change in Sweat Chloride (SwCl) for ELX/TEZ/IVA Group | -22.3 millimole per Liter (mmol/L) |
Secondary
Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time frame: Day 1 up to Week 12
Population: Safety set included all participants who received at least 1 dose of study drug in the treatment period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| TC: 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 | 83 participants |
| TC: 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 | 11 participants |
| TC: 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 | 88 participants |
| TC: 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 |