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 heterozygous for F508del and a minimal function mutation (F/MF subjects).
Interventions
DRUGVX-445/TEZ/IVA
Participants received VX-445/TEZ/IVA orally once daily in the morning.
DRUGIVA
Participants received IVA orally once daily in the evening
DRUGPlacebo
Participants received placebo matched VX-445/TEZ/IVA orally once daily in the morning and placebo matched to IVA orally once daily in the evening.
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: * Heterozygous for the F508del mutation (F/MF) * 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 |
|---|---|---|
| Number of Pulmonary Exacerbations (PEx) | From Baseline through Week 24 | Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. |
| Absolute Change in Sweat Chloride (SwCl) | From Baseline through Week 24 | Sweat samples were collected using an approved collection device. |
| Absolute Change in Cystic Fibrosis 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. |
| Absolute Change in Body Mass Index (BMI) | From Baseline at Week 24 | BMI was defined as weight in kilogram (kg) divided by height in square meter (m\^2). |
| Absolute Change in Sweat Chloride | From Baseline at Week 4 | Sweat samples were collected using an approved collection device. |
| 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 BMI Z-score for Participants <=20 Years of Age at Baseline | From Baseline at Week 24 | BMI was defined as weight in kg divided by height in m\^2. Z-score is a statistical measure to describe whether a mean was above or below the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher BMI. |
| Absolute Change in Body Weight | From Baseline at Week 24 | — |
| 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 28 weeks) | — |
| Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | Pre-dose on Week 4, 8, 12, and 16 | — |
| Time-to-first Pulmonary Exacerbation (PEx) | From Baseline through Week 24 | Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms. |
Countries
Australia, Austria, Belgium, Canada, Czechia, France, Germany, Greece, Italy, Netherlands, Sweden, United Kingdom, United States
Participant flow
Recruitment details
A total of 405 participants were enrolled in the study, of which 2 participants were enrolled but were not dosed in the triple combination (TC) treatment period. Results are presented for 403 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 |
|---|---|
| Placebo Participants who received placebo matched to VX-445/TEZ/IVA in the morning and placebo matched to IVA in the evening for 24 weeks in the TC treatment period. | 203 |
| VX-445/TEZ/IVA TC Participants who received VX-445 200 mg/TEZ 100 mg/IVA150 mg as FDC tablets in the morning and IVA 150 mg as mono tablet in the evening for 24 weeks in the TC treatment period. | 200 |
| Total | 403 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Withdrawal of consent (not due to AE) | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | VX-445/TEZ/IVA TC | Total |
|---|---|---|---|
| Age, Continuous | 26.8 years STANDARD_DEVIATION 11.3 | 25.6 years STANDARD_DEVIATION 9.7 | 26.2 years STANDARD_DEVIATION 10.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants | 4 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 175 Participants | 187 Participants | 362 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 16 Participants | 9 Participants | 25 Participants |
| Forced Expiratory Volume in 1 Second (ppFEV1) | 61.3 percentage points STANDARD_DEVIATION 15.5 | 61.6 percentage points STANDARD_DEVIATION 15 | 61.4 percentage points STANDARD_DEVIATION 15.2 |
| Race American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race Australian Aboriginal | 0 Participants | 1 Participants | 1 Participants |
| Race Black or African American | 1 Participants | 3 Participants | 4 Participants |
| Race Not Collected per Local Regulations | 16 Participants | 9 Participants | 25 Participants |
| Race Not Otherwise Specified | 1 Participants | 0 Participants | 1 Participants |
| Race Other- Unknown Mixed Heritage | 0 Participants | 1 Participants | 1 Participants |
| Race White | 182 Participants | 185 Participants | 367 Participants |
| Race White, Asian | 1 Participants | 0 Participants | 1 Participants |
| Race White, Black or African American | 1 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Female | 98 Participants | 96 Participants | 194 Participants |
| Sex: Female, Male Male | 105 Participants | 104 Participants | 209 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 201 | 0 / 202 |
| other Total, other adverse events | 180 / 201 | 168 / 202 |
| serious Total, serious adverse events | 42 / 201 | 28 / 202 |
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: Analysis population included all participants in the Full Analysis Set (all randomized participants who carried the intended CFTR allele mutation and received at least 1 dose of study drug) who completed the Week 4 Visit or were randomized at least 28 days before the data cutoff date.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | -0.2 percentage points | Standard Error 0.6 |
| VX-445/TEZ/IVA TC | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 13.6 percentage points | Standard Error 0.6 |
Comparison: The data presented for Primary endpoint was based on interim analysis at Week 4.p-value: <0.000195% CI: [12.1, 15.4]Mixed-effects model for repeated measure
Secondary
Absolute Change in BMI Z-score for Participants <=20 Years of Age at Baseline
BMI was defined as weight in kg divided by height in m\^2. Z-score is a statistical measure to describe whether a mean was above or below the standard. BMI, adjusted for age and sex, was analyzed as BMI-for-age z-score. A z-score of 0 is equal to the mean and is considered normal. Lower numbers indicate values lower than the mean and higher numbers indicate values higher than the mean. Higher values are indicative of higher BMI.
Time frame: From Baseline at Week 24
Population: FAS. Here Overall Number of Participants Analyzed signifies those participants who were \<=20 years of age at Baseline.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change in BMI Z-score for Participants <=20 Years of Age at Baseline | 0.04 z-score | Standard Error 0.05 |
| VX-445/TEZ/IVA TC | Absolute Change in BMI Z-score for Participants <=20 Years of Age at Baseline | 0.34 z-score | Standard Error 0.05 |
95% CI: [0.17, 0.43]
Secondary
Absolute Change in Body Mass Index (BMI)
BMI was defined as weight in kilogram (kg) divided by height in square meter (m\^2).
Time frame: From Baseline at Week 24
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change in Body Mass Index (BMI) | 0.09 kilogram per meter square (kg/m^2) | Standard Error 0.07 |
| VX-445/TEZ/IVA TC | Absolute Change in Body Mass Index (BMI) | 1.13 kilogram per meter square (kg/m^2) | Standard Error 0.07 |
p-value: <0.000195% CI: [0.85, 1.23]Mixed-effects model for repeated measure
Secondary
Absolute Change in Body Weight
Time frame: From Baseline at Week 24
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change in Body Weight | 0.5 kg | Standard Error 0.2 |
| VX-445/TEZ/IVA TC | Absolute Change in Body Weight | 3.4 kg | Standard Error 0.2 |
95% CI: [2.3, 3.4]
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 |
|---|---|---|---|
| Placebo | Absolute Change in Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain Score | -1.9 units on a scale | Standard Error 1.1 |
| VX-445/TEZ/IVA TC | Absolute Change in Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain Score | 18.1 units on a scale | Standard Error 1.1 |
p-value: <0.000195% CI: [16.9, 23.2]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 through Week 24
Population: FAS.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change in Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain Score | -2.7 units on a scale | Standard Error 1 |
| VX-445/TEZ/IVA TC | Absolute Change in Cystic Fibrosis Questionnaire Revised (CFQ-R) Respiratory Domain Score | 17.5 units on a scale | Standard Error 1 |
p-value: <0.000195% CI: [17.5, 23]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 |
|---|---|---|---|
| Placebo | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | -0.4 percentage points | Standard Error 0.5 |
| VX-445/TEZ/IVA TC | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 13.9 percentage points | Standard Error 0.6 |
p-value: <0.000195% CI: [12.7, 15.8]Mixed-effects model for repeated measure
Secondary
Absolute Change in Sweat Chloride
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 |
|---|---|---|---|
| Placebo | Absolute Change in Sweat Chloride | 0.1 mmol/L | Standard Error 1 |
| VX-445/TEZ/IVA TC | Absolute Change in Sweat Chloride | -41.2 mmol/L | Standard Error 1 |
p-value: <0.000195% CI: [-44, -38.5]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 |
|---|---|---|---|
| Placebo | Absolute Change in Sweat Chloride (SwCl) | -0.4 millimole per liter (mmol/L) | Standard Error 0.9 |
| VX-445/TEZ/IVA TC | Absolute Change in Sweat Chloride (SwCl) | -42.2 millimole per liter (mmol/L) | Standard Error 0.9 |
p-value: <0.000195% CI: [-44.4, -39.3]Mixed-effects model for repeated measure
Secondary
Number of Pulmonary Exacerbations (PEx)
Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms.
Time frame: From Baseline through Week 24
Population: FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Number of Pulmonary Exacerbations (PEx) | 113 pulmonary exacerbation events |
| VX-445/TEZ/IVA TC | Number of Pulmonary Exacerbations (PEx) | 41 pulmonary exacerbation events |
p-value: <0.000195% CI: [0.25, 0.55]Negative binomial regression model
Secondary
Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA
Time frame: Pre-dose on Week 4, 8, 12, and 16
Population: Pharmacokinetic (PK) set included all randomized participants who carried the intended CFTR allele mutation and received at least 1 dose of study drug in the TC Treatment Period. Here Number Analyzed signifies those participants who were evaluable for this outcome measure at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | VX-445 (Week 4) | 5.02 microgram per milliliter (mcg/mL) | Standard Deviation 2.68 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | VX-445 (Week 8) | 4.90 microgram per milliliter (mcg/mL) | Standard Deviation 2.75 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | VX-445 (Week 12) | 4.99 microgram per milliliter (mcg/mL) | Standard Deviation 3.11 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | VX-445 (Week 16) | 4.75 microgram per milliliter (mcg/mL) | Standard Deviation 2.58 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | TEZ (Week 4) | 2.16 microgram per milliliter (mcg/mL) | Standard Deviation 1.05 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | TEZ (Week 8) | 2.14 microgram per milliliter (mcg/mL) | Standard Deviation 1.14 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | TEZ (Week 12) | 2.22 microgram per milliliter (mcg/mL) | Standard Deviation 1.48 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | TEZ (Week 16) | 2.32 microgram per milliliter (mcg/mL) | Standard Deviation 1.46 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | M1-TEZ (Week 4) | 5.18 microgram per milliliter (mcg/mL) | Standard Deviation 2.01 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | M1-TEZ (Week 8) | 5.09 microgram per milliliter (mcg/mL) | Standard Deviation 1.95 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | M1-TEZ (Week 12) | 5.06 microgram per milliliter (mcg/mL) | Standard Deviation 1.92 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | M1-TEZ (Week 16) | 5.29 microgram per milliliter (mcg/mL) | Standard Deviation 1.95 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | IVA (Week 4) | 0.748 microgram per milliliter (mcg/mL) | Standard Deviation 0.471 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | IVA (Week 8) | 0.738 microgram per milliliter (mcg/mL) | Standard Deviation 0.484 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | IVA (Week 12) | 0.758 microgram per milliliter (mcg/mL) | Standard Deviation 0.572 |
| Placebo | Observed Pre-dose Concentration (Ctrough) of VX-445, TEZ, M1-TEZ, and IVA | IVA (Week 16) | 0.778 microgram per milliliter (mcg/mL) | Standard Deviation 0.516 |
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 28 weeks)
Population: Adverse events are presented as per Safety Set. Group assignments for participants in the Safety Set were based on actual treatment received, such that 2 participants assigned to Placebo group who inadvertently received one or more doses of VX-445/TEZ/IVA TC regimen were included in VX-445/TEZ/IVA TC group for the purpose of safety analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with TEAEs | 193 Participants |
| Placebo | Safety and Tolerability as Assessed by Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with Serious TEAEs | 42 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 TEAEs | 188 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 Serious TEAEs | 28 Participants |
Secondary
Time-to-first Pulmonary Exacerbation (PEx)
Pulmonary exacerbation was defined as the treatment with new or changed antibiotic therapy (intravenous, inhaled, or oral) for greater than or equal to 4 sinopulmonary signs/symptoms.
Time frame: From Baseline through Week 24
Population: FAS.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time-to-first Pulmonary Exacerbation (PEx) | NA days |
| VX-445/TEZ/IVA TC | Time-to-first Pulmonary Exacerbation (PEx) | NA days |