A Study of VX-445 in Healthy Subjects and Subjects With Cystic Fibrosis

Vertex Pharmaceuticals

Status and phase

Completed

Phase 2

Phase 1

Conditions

Cystic Fibrosis

Treatments

Drug: Matched Placebo

Drug: VX-445

Drug: TEZ

Drug: VX-561

Drug: TEZ/IVA

Drug: IVA

Study type

Interventional

Funder types

Industry

Identifiers

NCT03227471

VX16-445-001

2017-000797-11 (EudraCT Number)

Details and patient eligibility

About

This is a first-in-human and proof-of-concept study of VX-445. The study includes 6 parts. Parts A, B, and C were conducted in healthy subjects. Parts D, E, and F were conducted in subjects with Cystic Fibrosis (CF) who are homozygous for the F508del mutation of the CF transmembrane conductance regulator (CFTR) gene (F/F genotype), or who are heterozygous for the F508del mutation and a minimal function (MF) CFTR mutation not likely to respond to TEZ, IVA, or TEZ/IVA (F/MF genotypes).

Enrollment

225 patients

Sex

All

Ages

18+ years old

Volunteers

Accepts Healthy Volunteers

Inclusion and exclusion criteria

Key Inclusion Criteria:

Parts A, B, and C:

Female subjects must be of non-childbearing potential.
Between the ages of 18 and 55 years, inclusive.
Body mass index (BMI) of 18.0 to 32.0 kg/m2, inclusive, and a total body weight >50 kg

Parts D, E, and F:

Body weight ≥35 kg.
Subjects must have an eligible CFTR genotype:
- Parts D and F: Heterozygous for F508del and an MF mutation (F/MF)
- Part E: Homozygous for F508del (F/F)
FEV1 value ≥40% and ≤90% of predicted mean for age, sex, and height.

Key Exclusion Criteria:

Parts A, B, and C:

Any condition possibly affecting drug absorption.
History of febrile illness within 14 days before the first study drug dose.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Parts D, E, and F:

History of clinically significant cirrhosis with or without portal hypertension.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency.
Lung infection with organisms associated with a more rapid decline in pulmonary status.
History of solid organ or hematological transplantation.

Other protocol defined Inclusion/Exclusion criteria may apply.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

Quadruple Blind

225 participants in 15 patient groups, including a placebo group

Part A: Pooled Placebo (Except Cohort A7)

Placebo Comparator group

Description:

Participants without CF who received single dose of placebo matched to VX-445 in Cohort A1 to A5.

Treatment:

Drug: Matched Placebo

Part A: VX-445 (Except Cohort A7)

Experimental group

Description:

Participants without CF who received single ascending dose of VX-445 tablet starting from 20 milligrams (mg) to 360 mg in Cohort A1 to A5.

Treatment:

Drug: VX-445

Part A: VX-445 (Cohort A7)

Experimental group

Description:

Participants without CF who received single dose of VX-445 100 mg tablet on Day 1 in fasted state and on Day 7 in fed state, followed by VX-445 20 mg intravenous (IV) injection on Day 13 in fed state in Cohort A7.

Treatment:

Drug: VX-445

Part B: Pooled Placebo (Cohort B1 to B4)

Placebo Comparator group

Description:

Participants without CF who received multiple doses of placebo matched to VX-445 once daily (qd) for 10 days in Cohort B1 to B4.

Treatment:

Drug: Matched Placebo

Part B: VX-445 (Cohort B1 to B4)

Experimental group

Description:

Participants without CF who received VX-445 tablet qd for 10 days in Cohort B1 (60 mg), B2 (120 mg), B3 (240 mg) and B4 (340 mg).

Treatment:

Drug: VX-445

Part C: Pooled Placebo (Cohort C1 to C3)

Placebo Comparator group

Description:

Participants without CF who received placebo matched to VX-445/TEZ/IVA triple combination (TC) qd in the morning and placebo matched to IVA in the evening for 14 days.

Treatment:

Drug: Matched Placebo

Part C: VX-445/TEZ/IVA TC (Cohort C1 to C3)

Experimental group

Description:

Participants without CF who received VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C1; VX-445 280 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C2 and VX-445 100 mg qd/TEZ 100 mg qd/IVA 150 mg q12h in Cohort C3 for 14 days.

Treatment:

Drug: IVA

Drug: TEZ/IVA

Drug: VX-445

Part D: Placebo

Placebo Comparator group

Description:

Participants with CF, F/MF genotype who received placebo matched to VX-445/TEZ/IVA TC qd in the morning and placebo matched to IVA qd in the evening for 4 weeks in the TC treatment period.

Treatment:

Drug: Matched Placebo

Part D: VX-445/TEZ/IVA TC - Low Dose

Experimental group

Description:

Participants with CF, F/MF genotype who received VX-445 50 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period.

Treatment:

Drug: IVA

Drug: TEZ/IVA

Drug: VX-445

Part D: VX-445/TEZ/IVA TC - Medium Dose

Experimental group

Description:

Participants with CF, F/MF genotype who received VX-445 100 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period.

Treatment:

Drug: IVA

Drug: TEZ/IVA

Drug: VX-445

Part D: VX-445/TEZ/IVA TC - High Dose

Experimental group

Description:

Participants with CF, F/MF genotype who received VX-445 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h for 4 weeks in the TC treatment period.

Treatment:

Drug: IVA

Drug: TEZ/IVA

Drug: VX-445

Part E: TEZ/IVA

Active Comparator group

Description:

Following run-in period of 4 weeks with TEZ/IVA, participants with CF, F/F genotype who received TEZ 100 mg qd/IVA 150 mg q12h and placebo matched to VX-445 for 4 weeks in the TC treatment period.

Treatment:

Drug: TEZ/IVA

Part E: VX-445/TEZ/IVA TC

Experimental group

Description:

Following run-in period of 4 weeks with TEZ/IVA, participants with CF, F/F genotype who received VX-445 200 mg qd/TEZ 100 mg qd /IVA 150 mg q12h for 4 weeks in the TC treatment period.

Treatment:

Drug: IVA

Drug: TEZ/IVA

Drug: VX-445

Part F: Placebo

Placebo Comparator group

Description:

Participants with CF, F/MF genotype who received placebo matched to VX-445/TEZ/VX-561 for 4 weeks in the TC treatment period.

Treatment:

Drug: Matched Placebo

Part F: VX-445/TEZ/VX-561 TC

Experimental group