Cystic Fibrosis
Conditions
Brief summary
This is a Phase 2, randomized, double-blind, placebo- and active-controlled, parallel group, multicenter study to evaluate the safety, tolerability, and efficacy of VX-440 in dual and triple combination with tezacaftor (TEZ; VX-661) and ivacaftor (IVA; VX-770) in subjects with cystic fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F508del/F508del), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ and/or IVA therapy (F508del/MF).
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
* Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures. * To prevent pregnancy, female participants of childbearing potential and their male partners will be required to use pre-specified, highly effective methods of non-hormonal contraception. Male participants with female partners of childbearing potential will be required to use a condom. * Body weight ≥35 kg. * Sweat chloride value ≥60 mmol/L from test results obtained during screening. * Subjects must have an eligible CFTR genotype: * Heterozygous for F508del and a minimal function (MF) mutation known or predicted not to be responsive to TEZ and/or IVA. * Homozygous for F508del * Subjects must have an FEV1 ≥40% and ≤90% of predicted normal for age, sex, and height at the Screening Visit * Stable CF disease as judged by the investigator. * Willing to remain on a stable CF medication regimen through the planned end of treatment or, if applicable, the Safety Follow up Visit.
Exclusion criteria
* History of any comorbidity that, in the opinion of the investigator, might confound the results of the study or pose an additional risk in administering study drug to the subject. * History of cirrhosis with portal hypertension. * Risk factors for Torsade de Pointes * History of hemolysis. * Glucose-6-phosphate dehydrogenase (G6PD) deficiency assessed at Screening. * Clinically significant abnormal laboratory values at screening * An acute upper or lower respiratory infection, pulmonary exacerbation, or changes in therapy for pulmonary disease within 28 days before the first dose of study drug. * Lung infection with organisms associated with a more rapid decline in pulmonary status * An acute illness not related to CF within 14 days before the first dose of study drug * A standard digital ECG demonstrating QTc \>450 msec at screening. * History of solid organ or hematological transplantation. * History or evidence of cataract or lens opacity determined to be clinically significant by the ophthalmologist or optometrist based on the ophthalmologic examination during the Screening Period. * History of alcohol or drug abuse in the past year, including but not limited to, cannabis, cocaine, and opiates, as deemed by the investigator. * Ongoing or prior participation in an investigational drug study, with certain exceptions. (e.g., ongoing participation in NCT02565914) * Use of commercially available CFTR modulator (e.g., Kalydeco, Orkambi) within 14 days before screening (applies only to the Heterozygous F508del/MF cohorts; does not apply to the Homozygous F508del/F508del Cohort). * Pregnant or nursing females: Females of childbearing potential must have a negative pregnancy test at screening and Day 1.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 the Treatment Period through Safety Follow-up Visit (Up to Day 57 for Part 1 and Day 85 for Part 2) | — |
| Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | From Baseline through Day 29 | 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 Concentrations | From Baseline through Day 29 | Sweat samples were collected using an approved collection device. |
| Relative Change in ppFEV1 | From Baseline through Day 29 | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. |
| Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | From Baseline at Day 29 | 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. |
| Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | Predose at Day 8, Day 15 and Day 29 | — |
Countries
Australia, Austria, Belgium, Canada, Denmark, Germany, Italy, Spain, United Kingdom, United States
Participant flow
Recruitment details
Of the 74 participants enrolled (47 participants in Part 1 and 27 participants in Part 2), 1 participant in Part 2 discontinued in the Run-in Period because continuation criteria were not met and was not randomized in the Treatment Period. Therefore, only 73 participants are included in the results below.
Pre-assignment details
Four parts were originally planned for the study; only Parts 1 and 2 were conducted. Part 3 was removed in protocol Version 2.0. Part 4 was not conducted at the Sponsor's discretion.
Participants by arm
| Arm | Count |
|---|---|
| Part 1: Placebo - Cohort 1A and 1B Combined Participants received placebo matched to VX-440/TEZ/IVA as triple combination for 4 weeks. | 11 |
| Part 1 Cohort 1A: Triple Combination (TC) Participants received VX-440 200 mg q12h/TEZ 100 mg qd/IVA 150 mg q12h as triple combination for 4 weeks. | 9 |
| Part 1 Cohort 1B: TC Low Dose Participants received VX-440 200 mg q12h/TEZ 50 mg q12h/IVA 150 mg q12h as triple combination for 4 weeks. | 9 |
| Part 1 Cohort 1B: TC High Dose Participants received VX-440 600 mg q12h/TEZ 50 mg q12h/IVA 300 mg q12h as triple combination for 4 weeks. | 18 |
| Part 2: TEZ/IVA Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received placebo matched to VX-440 and TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period. | 6 |
| Part 2: TC-2 Following a 4-week run-in period on TEZ 100 mg qd/IVA150 mg q12h, participants received VX-440 600 mg q12h/ TEZ 50 mg q12h/IVA 300 mg q12h for 4 weeks for 4 weeks in treatment period and TEZ 100 mg qd/IVA150 mg q12h for 4 weeks in washout period. | 20 |
| Total | 73 |
Baseline characteristics
| Characteristic | Part 1: Placebo - Cohort 1A and 1B Combined | Part 1 Cohort 1A: Triple Combination (TC) | Part 1 Cohort 1B: TC Low Dose | Part 1 Cohort 1B: TC High Dose | Part 2: TEZ/IVA | Part 2: TC-2 | Total |
|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 9 Participants | 9 Participants | 18 Participants | 6 Participants | 20 Participants | 73 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 9 Participants | 8 Participants | 17 Participants | 6 Participants | 18 Participants | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 10 Participants | 9 Participants | 9 Participants | 18 Participants | 6 Participants | 20 Participants | 72 Participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 4 Participants | 11 Participants |
| Sex: Female, Male Male | 9 Participants | 8 Participants | 6 Participants | 17 Participants | 6 Participants | 16 Participants | 62 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 9 | 0 / 9 | 0 / 18 | 0 / 6 | 0 / 20 |
| other Total, other adverse events | 9 / 11 | 9 / 9 | 9 / 9 | 15 / 18 | 5 / 6 | 15 / 20 |
| serious Total, serious adverse events | 0 / 11 | 0 / 9 | 0 / 9 | 2 / 18 | 2 / 6 | 1 / 20 |
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 through Day 29
Population: Full Analysis Set (FAS) included all randomized participants who have received at least 1 dose of study drug in the Treatment Period. As per pre-specified planned analysis, reporting group Part 1 Cohort 1A: TC and Part 1 Cohort 1B: TC Low Dose were pooled for the purpose of efficacy analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Placebo - Cohort 1A and 1B Combined | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 1.4 percentage points |
| Part 1 Cohort 1A: Triple Combination (TC) | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 10.0 percentage points |
| Part 1 Cohort 1B: TC Low Dose | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 12.0 percentage points |
| Part 1 Cohort 1B: TC High Dose | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | -2.5 percentage points |
| Part 2: TEZ/IVA | Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) | 9.5 percentage points |
p-value: 0.001695% CI: [3.5, 13.8]Mixed-effects Model for Repeated Measure
p-value: 0.000195% CI: [5.5, 15.8]Mixed-effects Model for Repeated Measure
p-value: 0.000195% CI: [6.7, 17.4]Mixed-effects Model for Repeated Measure
Primary
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 the Treatment Period through Safety Follow-up Visit (Up to Day 57 for Part 1 and Day 85 for Part 2)
Population: Safety Set included all participants who received at least 1 dose of study drug in the Treatment Period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Part 1: Placebo - Cohort 1A and 1B Combined | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 9 participants |
| Part 1: Placebo - Cohort 1A and 1B Combined | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 0 participants |
| Part 1 Cohort 1A: Triple Combination (TC) | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 9 participants |
| Part 1 Cohort 1A: Triple Combination (TC) | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 0 participants |
| Part 1 Cohort 1B: TC Low Dose | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 9 participants |
| Part 1 Cohort 1B: TC Low Dose | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with SAEs | 0 participants |
| Part 1 Cohort 1B: TC High Dose | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 15 participants |
| Part 1 Cohort 1B: TC High Dose | 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 |
| Part 2: 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 | 6 participants |
| Part 2: 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 | 2 participants |
| Part 2: TC-2 | Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) | Participants with AEs | 15 participants |
| Part 2: TC-2 | 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 |
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 Day 29
Population: FAS. As per pre-specified planned analysis, reporting group Part 1 Cohort 1A: TC and Part 1 Cohort 1B: TC Low Dose were pooled for the purpose of efficacy analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Placebo - Cohort 1A and 1B Combined | Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | 2.2 units on a scale |
| Part 1 Cohort 1A: Triple Combination (TC) | Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | 18.3 units on a scale |
| Part 1 Cohort 1B: TC Low Dose | Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | 20.7 units on a scale |
| Part 1 Cohort 1B: TC High Dose | Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | -7.8 units on a scale |
| Part 2: TEZ/IVA | Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score | 12.3 units on a scale |
95% CI: [5.4, 26.8]
95% CI: [7.9, 29.1]
95% CI: [11.9, 28.4]
Secondary
Absolute Change in Sweat Chloride Concentrations
Sweat samples were collected using an approved collection device.
Time frame: From Baseline through Day 29
Population: FAS. As per pre-specified planned analysis, reporting group Part 1 Cohort 1A: TC and Part 1 Cohort 1B: TC Low Dose were pooled for the purpose of efficacy analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Placebo - Cohort 1A and 1B Combined | Absolute Change in Sweat Chloride Concentrations | 1.6 millimole per liter (mmol/L) |
| Part 1 Cohort 1A: Triple Combination (TC) | Absolute Change in Sweat Chloride Concentrations | -20.7 millimole per liter (mmol/L) |
| Part 1 Cohort 1B: TC Low Dose | Absolute Change in Sweat Chloride Concentrations | -33.1 millimole per liter (mmol/L) |
| Part 1 Cohort 1B: TC High Dose | Absolute Change in Sweat Chloride Concentrations | 2.1 millimole per liter (mmol/L) |
| Part 2: TEZ/IVA | Absolute Change in Sweat Chloride Concentrations | -31.3 millimole per liter (mmol/L) |
95% CI: [-32.1, -12.4]
95% CI: [-44.7, -24.8]
95% CI: [-48.5, -18.3]
Secondary
Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA
Time frame: Predose at Day 8, Day 15 and Day 29
Population: Pharmacokinetic Set (PK) included all participants who have received at least 1 dose of study drug in Treatment Period. Here Number Analyzed signifies those participants who were evaluable at specified time points. Day 8 assessment was planned for only TC-1A arm and VX-440 Ctrough category was not applicable for TEZ/IVA arm.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | TEZ: Day 29 | 761 nanogram per milliliter (ng/mL) | Standard Deviation 320 |
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-IVA: Day 29 | 702 nanogram per milliliter (ng/mL) | Standard Deviation 372 |
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-TEZ: Day 15 | 3490 nanogram per milliliter (ng/mL) | Standard Deviation 486 |
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-TEZ: Day 8 | 3160 nanogram per milliliter (ng/mL) | Standard Deviation 645 |
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-IVA: Day 15 | 854 nanogram per milliliter (ng/mL) | Standard Deviation 427 |
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | VX-440: Day 29 | 1090 nanogram per milliliter (ng/mL) | Standard Deviation 1010 |
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | VX-440: Day 8 | 1670 nanogram per milliliter (ng/mL) | Standard Deviation 1910 |
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-IVA: Day 8 | 795 nanogram per milliliter (ng/mL) | Standard Deviation 327 |
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | IVA: Day 29 | 209 nanogram per milliliter (ng/mL) | Standard Deviation 112 |
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | TEZ: Day 8 | 810 nanogram per milliliter (ng/mL) | Standard Deviation 323 |
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | TEZ: Day 15 | 749 nanogram per milliliter (ng/mL) | Standard Deviation 271 |
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | VX-440: Day 15 | 1840 nanogram per milliliter (ng/mL) | Standard Deviation 1460 |
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | IVA: Day 15 | 245 nanogram per milliliter (ng/mL) | Standard Deviation 92.7 |
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | IVA: Day 8 | 281 nanogram per milliliter (ng/mL) | Standard Deviation 167 |
| Part 1: Placebo - Cohort 1A and 1B Combined | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-TEZ: Day 29 | 3560 nanogram per milliliter (ng/mL) | Standard Deviation 378 |
| Part 1 Cohort 1A: Triple Combination (TC) | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | VX-440: Day 29 | 1440 nanogram per milliliter (ng/mL) | Standard Deviation 1870 |
| Part 1 Cohort 1A: Triple Combination (TC) | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | VX-440: Day 15 | 1120 nanogram per milliliter (ng/mL) | Standard Deviation 707 |
| Part 1 Cohort 1A: Triple Combination (TC) | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | TEZ: Day 15 | 1070 nanogram per milliliter (ng/mL) | Standard Deviation 422 |
| Part 1 Cohort 1A: Triple Combination (TC) | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | TEZ: Day 29 | 1040 nanogram per milliliter (ng/mL) | Standard Deviation 659 |
| Part 1 Cohort 1A: Triple Combination (TC) | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-TEZ: Day 15 | 4610 nanogram per milliliter (ng/mL) | Standard Deviation 1170 |
| Part 1 Cohort 1A: Triple Combination (TC) | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-TEZ: Day 29 | 4180 nanogram per milliliter (ng/mL) | Standard Deviation 1950 |
| Part 1 Cohort 1A: Triple Combination (TC) | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | IVA: Day 15 | 192 nanogram per milliliter (ng/mL) | Standard Deviation 97 |
| Part 1 Cohort 1A: Triple Combination (TC) | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | IVA: Day 29 | 164 nanogram per milliliter (ng/mL) | Standard Deviation 108 |
| Part 1 Cohort 1A: Triple Combination (TC) | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-IVA: Day 15 | 566 nanogram per milliliter (ng/mL) | Standard Deviation 245 |
| Part 1 Cohort 1A: Triple Combination (TC) | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-IVA: Day 29 | 520 nanogram per milliliter (ng/mL) | Standard Deviation 338 |
| Part 1 Cohort 1B: TC Low Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-TEZ: Day 29 | 3050 nanogram per milliliter (ng/mL) | Standard Deviation 1260 |
| Part 1 Cohort 1B: TC Low Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | VX-440: Day 29 | 6650 nanogram per milliliter (ng/mL) | Standard Deviation 3500 |
| Part 1 Cohort 1B: TC Low Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | IVA: Day 29 | 219 nanogram per milliliter (ng/mL) | Standard Deviation 139 |
| Part 1 Cohort 1B: TC Low Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-IVA: Day 29 | 792 nanogram per milliliter (ng/mL) | Standard Deviation 466 |
| Part 1 Cohort 1B: TC Low Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-TEZ: Day 15 | 3400 nanogram per milliliter (ng/mL) | Standard Deviation 1270 |
| Part 1 Cohort 1B: TC Low Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | TEZ: Day 29 | 846 nanogram per milliliter (ng/mL) | Standard Deviation 514 |
| Part 1 Cohort 1B: TC Low Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | VX-440: Day 15 | 8540 nanogram per milliliter (ng/mL) | Standard Deviation 6850 |
| Part 1 Cohort 1B: TC Low Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | TEZ: Day 15 | 928 nanogram per milliliter (ng/mL) | Standard Deviation 558 |
| Part 1 Cohort 1B: TC Low Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-IVA: Day 15 | 850 nanogram per milliliter (ng/mL) | Standard Deviation 546 |
| Part 1 Cohort 1B: TC Low Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | IVA: Day 15 | 233 nanogram per milliliter (ng/mL) | Standard Deviation 149 |
| Part 1 Cohort 1B: TC High Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-TEZ: Day 15 | 4640 nanogram per milliliter (ng/mL) | Standard Deviation 1730 |
| Part 1 Cohort 1B: TC High Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-TEZ: Day 29 | 4060 nanogram per milliliter (ng/mL) | Standard Deviation 1560 |
| Part 1 Cohort 1B: TC High Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | TEZ: Day 15 | 2240 nanogram per milliliter (ng/mL) | Standard Deviation 1010 |
| Part 1 Cohort 1B: TC High Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | IVA: Day 15 | 1040 nanogram per milliliter (ng/mL) | Standard Deviation 352 |
| Part 1 Cohort 1B: TC High Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | IVA: Day 29 | 902 nanogram per milliliter (ng/mL) | Standard Deviation 344 |
| Part 1 Cohort 1B: TC High Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-IVA: Day 29 | 1580 nanogram per milliliter (ng/mL) | Standard Deviation 764 |
| Part 1 Cohort 1B: TC High Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-IVA: Day 15 | 1640 nanogram per milliliter (ng/mL) | Standard Deviation 218 |
| Part 1 Cohort 1B: TC High Dose | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | TEZ: Day 29 | 1420 nanogram per milliliter (ng/mL) | Standard Deviation 565 |
| Part 2: TEZ/IVA | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | VX-440: Day 15 | 12900 nanogram per milliliter (ng/mL) | Standard Deviation 9940 |
| Part 2: TEZ/IVA | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-IVA: Day 15 | 1220 nanogram per milliliter (ng/mL) | Standard Deviation 796 |
| Part 2: TEZ/IVA | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-IVA: Day 29 | 1080 nanogram per milliliter (ng/mL) | Standard Deviation 732 |
| Part 2: TEZ/IVA | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | TEZ: Day 15 | 1250 nanogram per milliliter (ng/mL) | Standard Deviation 837 |
| Part 2: TEZ/IVA | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | TEZ: Day 29 | 893 nanogram per milliliter (ng/mL) | Standard Deviation 579 |
| Part 2: TEZ/IVA | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-TEZ: Day 15 | 3940 nanogram per milliliter (ng/mL) | Standard Deviation 1200 |
| Part 2: TEZ/IVA | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | VX-440: Day 29 | 10300 nanogram per milliliter (ng/mL) | Standard Deviation 7340 |
| Part 2: TEZ/IVA | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | M1-TEZ: Day 29 | 3280 nanogram per milliliter (ng/mL) | Standard Deviation 1230 |
| Part 2: TEZ/IVA | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | IVA: Day 29 | 290 nanogram per milliliter (ng/mL) | Standard Deviation 263 |
| Part 2: TEZ/IVA | Pre-dose Plasma Concentration (Ctrough) of VX-440, TEZ, M1-TEZ, IVA and M1-IVA | IVA: Day 15 | 380 nanogram per milliliter (ng/mL) | Standard Deviation 312 |
Secondary
Relative Change in ppFEV1
FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration.
Time frame: From Baseline through Day 29
Population: FAS. As per pre-specified planned analysis, reporting group Part 1 Cohort 1A: TC and Part 1 Cohort 1B: TC Low Dose were pooled for the purpose of efficacy analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part 1: Placebo - Cohort 1A and 1B Combined | Relative Change in ppFEV1 | 2.6 percent change |
| Part 1 Cohort 1A: Triple Combination (TC) | Relative Change in ppFEV1 | 17.3 percent change |
| Part 1 Cohort 1B: TC Low Dose | Relative Change in ppFEV1 | 21.7 percent change |
| Part 1 Cohort 1B: TC High Dose | Relative Change in ppFEV1 | -3.4 percent change |
| Part 2: TEZ/IVA | Relative Change in ppFEV1 | 16.6 percent change |
95% CI: [5.3, 24.2]
95% CI: [9.7, 28.6]
95% CI: [10.8, 29.1]