A Study Evaluating the Safety and Efficacy of VX-440 Combination Therapy in Subjects With Cystic Fibrosis
Condition: Cystic Fibrosis
MeSH terms: Cystic Fibrosis; Fibrosis
Intervention: TEZ; IVA; VX-440; Matched Placebo
Intervention MeSH terms: Ivacaftor
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 74.0
Sex: All
Minimum age: 12 Years
Healthy volunteers: No

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).
    

Eligibility criteria:

        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.