A Study Evaluating the Safety and Efficacy of VX-440 Combination Therapy in Subjects With Cystic Fibrosis

Vertex Pharmaceuticals

Status and phase: Completed; Phase 2

Conditions: Cystic Fibrosis

Treatments: Drug: TEZ; Drug: Matched Placebo; Drug: IVA; Drug: VX-440

Study type: Interventional

Funder types: Industry

Identifiers

NCT02951182

2016-000454-36 (EudraCT Number)

VX15-440-101

Details and patient eligibility

About

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).

Enrollment: 74 patients

Sex: All

Ages: 12+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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74 participants in 6 patient groups, including a placebo group

Part 1: Placebo - Cohort 1A and 1B Combined

Placebo Comparator group

Description:

Participants received placebo matched to VX-440/TEZ/IVA as triple combination for 4 weeks.

Treatment:

Drug: Matched Placebo

Part 1 Cohort 1A: Triple Combination (TC)

Experimental group

Description:

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.

Treatment:

Drug: VX-440

Drug: IVA

Drug: TEZ

Part 1 Cohort 1B: TC Low Dose

Experimental group

Description:

Participants received VX-440 200 mg q12h/TEZ 50 mg q12h/IVA 150 mg q12h as triple combination for 4 weeks.

Treatment:

Drug: VX-440

Drug: IVA

Drug: TEZ

Part 1 Cohort 1B: TC High Dose

Experimental group

Description:

Participants received VX-440 600 mg q12h/TEZ 50 mg q12h/IVA 300 mg q12h as triple combination for 4 weeks.

Treatment:

Drug: VX-440

Drug: IVA

Drug: TEZ

Part 2: TEZ/IVA

Active Comparator group

Description:

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.

Treatment:

Drug: Matched Placebo

Drug: IVA

Drug: TEZ

Part 2: TC-2

Experimental group

Description:

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.

Treatment:

Drug: VX-440

Drug: IVA

Drug: TEZ