a study evaluating the safety and efficacy of vx-440 combination therapy in subjects with cystic fibrosis

Conditions: Cystic Fibrosis

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.