A Study Evaluating the Safety and Efficacy of VX-440 Combination Therapy in Subjects 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 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).

Official Title
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A Phase 2, Randomized, Double-blind, Controlled Study to Evaluate the Safety and Efficacy of VX-440 Combination Therapy in Subjects Aged 12 Years and Older With Cystic Fibrosis

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: TEZ
* Drug: IVA
* Drug: VX-440
* Drug: Matched Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 12 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part 1: Placebo - Cohort 1A and 1B Combined<br>Participants received placebo matched to VX-440/TEZ/IVA as triple combination for 4 weeks. | Drug: Matched Placebo<br> <br> |
| Experimental: Part 1 Cohort 1A: Triple Combination (TC)<br>Participants received VX-440 200 milligram (mg) every 12 hours (q12h)/TEZ 100 mg once daily (qd)/IVA 150 mg q12h as triple combination for 4 weeks. | Drug: TEZ<br> <br> * Other names: VX-661;Drug: IVA<br> <br> * Other names: VX-770;Drug: VX-440<br> <br> |
| Experimental: Part 1 Cohort 1B: TC Low Dose<br>Participants received VX-440 200 mg q12h/TEZ 50 mg q12h/IVA 150 mg q12h as triple combination for 4 weeks. | Drug: TEZ<br> <br> * Other names: VX-661;Drug: IVA<br> <br> * Other names: VX-770;Drug: VX-440<br> <br> |
| Experimental: Part 1 Cohort 1B: TC High Dose<br>Participants received VX-440 600 mg q12h/TEZ 50 mg q12h/IVA 300 mg q12h as triple combination for 4 weeks. | Drug: TEZ<br> <br> * Other names: VX-661;Drug: IVA<br> <br> * Other names: VX-770;Drug: VX-440<br> <br> |
| Active Comparator: Part 2: TEZ/IVA<br>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. | Drug: TEZ<br> <br> * Other names: VX-661;Drug: IVA<br> <br> * Other names: VX-770;Drug: Matched Placebo<br> <br> |
| Experimental: Part 2: TC-2<br>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. | Drug: TEZ<br> <br> * Other names: VX-661;Drug: IVA<br> <br> * Other names: VX-770;Drug: VX-440<br> <br> |

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 (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) | 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 | Sweat samples were collected using an approved collection device. | From Baseline through Day 29 | 
| Relative Change in ppFEV1 | 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 | 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-440, TEZ, M1-TEZ, IVA and M1-IVA |  | Predose at Day 8, Day 15 and Day 29 |