A Study Evaluating the Safety of VX-152 Combination Therapy in Adults With Cystic Fibrosis

Study Overview
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Brief Summary
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This is a Phase 2, randomized, double blind, placebo and active-controlled, parallel group, multicenter study designed to evaluate the safety and tolerability of VX-152 in Triple Combination (TC) with tezacaftor (TEZ; VX-661) and ivacaftor (IVA; VX-770) in subjects with cystic fibrosis (CF) 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), or who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F508del/F508del).

Official Title
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A Phase 2, Randomized, Double Blind, Controlled Study to Evaluate the Safety of VX-152 Combination Therapy in Adults With Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: VX-152
* Drug: TEZ/IVA
* Drug: IVA
* Drug: Placebo
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to comply with scheduled visits, treatment pan, study restrictions, laboratory tests, contraceptive guidelines, and other study procedures. Body weight ≥35 kg. Sweat chloride value ≥ 60 mmol/L from test results obtained during screening. Subjects must have an eligible CFTR genotype: Cohorts 1A, 1B, 1C: Heterozygous for F508del and a minimal function mutation known or predicted not to respond to TEZ and/or IVA. Cohorts 2A, 2B: 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. Use of commercially available CFTR modulator within 14 days before screening (applies only to Cohorts 1A, 1B, and 1C). Pregnant or nursing females: Females of childbearing potential must have a negative pregnancy test at screening and Day 1.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part 1: Placebo<br> | Drug: Placebo<br>* Placebo matched to VX-152/TEZ/IVA triple combination (TC).<br>|
| Experimental: Part 1 Cohort 1A: TC<br> | Drug: VX-152<br>* Tablet for oral administration.<br>Drug: TEZ/IVA<br>* Fixed-dose combination tablet for oral administration.<br>* Other names: Tezacaftor/Ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: Ivacaftor;|
| Experimental: Part 1 Cohort 1B: TC<br> | Drug: VX-152<br>* Tablet for oral administration.<br>Drug: TEZ/IVA<br>* Fixed-dose combination tablet for oral administration.<br>* Other names: Tezacaftor/Ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: Ivacaftor;|
| Experimental: Part 1 Cohort 1C: TC<br> | Drug: VX-152<br>* Tablet for oral administration.<br>Drug: TEZ/IVA<br>* Fixed-dose combination tablet for oral administration.<br>* Other names: Tezacaftor/Ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: Ivacaftor;|
| Active Comparator: Part 2 Cohort 2A: TEZ/IVA<br> | Drug: TEZ/IVA<br>* Fixed-dose combination tablet for oral administration.<br>* Other names: Tezacaftor/Ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: Ivacaftor;Drug: Placebo<br>* Placebo matched to VX-152.<br>|
| Experimental: Part 2 Cohort 2A: TC<br> | Drug: VX-152<br>* Tablet for oral administration.<br>Drug: TEZ/IVA<br>* Fixed-dose combination tablet for oral administration.<br>* Other names: Tezacaftor/Ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: Ivacaftor;|
| Active Comparator: Part 2 Cohort 2B: TEZ/IVA<br> | Drug: TEZ/IVA<br>* Fixed-dose combination tablet for oral administration.<br>* Other names: Tezacaftor/Ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: Ivacaftor;Drug: Placebo<br>* Placebo matched to VX-152.<br>|
| Experimental: Part 2 Cohort 2B: TC<br> | Drug: VX-152<br>* Tablet for oral administration.<br>Drug: TEZ/IVA<br>* Fixed-dose combination tablet for oral administration.<br>* Other names: Tezacaftor/Ivacaftor;Drug: IVA<br>* Tablet for oral administration.<br>* Other names: Ivacaftor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability as Assessed by Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | Day 1 Through Safety Follow-up Visit (Up to Day 43 for Part 1 and Day 71 for Part 2) | 
| Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (ppFEV1) at Day 15 for Part 1 and Part 2 Cohort 2A | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | From Baseline at Day 15 | 
| Absolute Change in ppFEV1 Through Day 29 for Part 2 Cohort 2B | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | From Baseline Through Day 29 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute Change in Sweat Chloride Concentrations at Day 15 for Part 1 and Part 2 Cohort 2A | Sweat samples were collected using an approved collection device. | From Baseline at Day 15 | 
| Absolute Change in Sweat Chloride Concentrations Through Day 29 for Part 2 Cohort 2B | Sweat samples were collected using an approved collection device. | From Baseline Through Day 29 | 
| Relative Change in ppFEV1 at Day 15 for Part 1 and Part 2 Cohort 2A | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | From Baseline at Day 15 | 
| Relative Change in ppFEV1 Through Day 29 for Part 2 Cohort 2B | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. | From Baseline Through Day 29 | 
| Absolute Change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Domain Score at Day 15 for Part 1 and Part 2 Cohort 2A | 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. | From Baseline at Day 15 | 
| Absolute Change From Baseline in CFQ-R Respiratory Domain Score at Day 29 for Part 2 Cohort 2B | 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. | From Baseline at Day 29 | 
| Pre-dose Plasma Concentration (Ctrough) of VX-152, TEZ, M1-TEZ, IVA, and M1-IVA |  | Pre-dose at Day 8, Day 15 and Day 29 |