A phase IIb, multicentre, randomised, double-blind, placebo-controlled, crossover study to evaluate the efficacy and safety of dirocaftor/posenacaftor/nesolicaftor in subjects with cystic fibrosis aged 18 years or older
Treatment of Cystic Fibrosis (CF) in patients with CFTR mutations who are responders in the organoid assay
CHOICES is a randomized, double-blind, placebo-controlled, cross-over trial. The study population will comprise of subjects with a diagnosis of CF who are ≥18 years of age (at the time of informed consent) and have completed organoid screening (conducted by the HIT-CF consortium; HIT-CF Organoid Study [NTR7520]) prior to screening for this study. The study will consist of two groups. The first group will consist of 26 subjects of the HIT-CF Organoid Study with the highest organoid response to the combination of DIR/POS/NES. For the second group, 26 subjects, no such pre-selection criteria and no such screening will be performed (i.e. a simple random sample will be drawn instead). This approach will allow unbiased evaluation of the treatment effect in both populations, as well as for exploratory assessment of a possible difference in treatment effects. An unblinded coordinating team will be responsible for subject selection based on a subject’s organoid response and the detailed description will be captured in a separate sample and subject selection plan. Subjects will participate in an 8-week, double blind, placebo controlled, cross-over study including an approximate 8 week washout period. In both groups, eligible subjects will be randomized at a 1:1 randomization ratio into one of 2 treatment sequences: Either DIR/POS/NES once daily for 8 weeks followed by placebo once daily for 8 weeks, or placebo once daily for 8 weeks followed by DIR/POS/NES once daily for 8 weeks.
1. Male or female subjects who completed the HIT-CF Organoid Study and are 18 years of age or older on the date of informed consent 2. Confirmed diagnosis of CF as follows: 2.1. Sweat chloride value of ≥60 mmol/L based on quantitative pilocarpine iontophoresis (at screening) OR 2 CF-causing mutations AND 2.2. chronic sinopulmonary disease or gastrointestinal/nutritional abnormalities 3. Clinically stable CF disease in the opinion of the investigator with no significant changes in health status within 28 days prior to Day 1 4. Forced expiratory volume in one second (FEV1) ≥40% of predicted to ≤90% of predicted at the Screening Visit, based on the Global Lung Function Initiative (GLI) -2012 multi-ethnic all-age reference equations 5. Body mass index (BMI) ≥16 kg/m² and ≤30 kg/m² 6. Non-smoker and non-tobacco user (including all inhalational nicotine delivery systems) for a minimum of 30 days prior to screening, and subject agrees not to smoke or use tobacco for the duration of the study 7. Subjects of childbearing potential must meet contraception requirements 8. Willing to remain on a stable medication regimen for CF from 28 days before Day 1 through the last study visit 9. Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, and other study procedures 10. Selected by an unblinded coordinating team based on organoid response or random selection 11. Subject will sign and date an informed consent form (ICF)
1. Subject has at least one of the following CFTR-mutations: F508del, G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, R117H, A455E, 3849+10kbC>T OR A combination of any two of the following mutations: any nonsense mutation, 1717-1G>A, 621+1G>T, 3120+1G>A, 1898+1G->A, CFTRdele2,3, and 2183AA->G 2. History or current evidence of any clinically significant cardiac (eg, heart failure, left ventricular hypertrophy, myocardial infarction, and arrhythmia), endocrinologic, hematologic, hepatobiliary (eg, clinically significant cirrhosis with or without portal hypertension), immunologic, metabolic, urologic, pulmonary (besides CF), neurologic (eg, subarachnoid haemorrhage, intracranial haemorrhage, cerebrovascular accident, intracranial trauma, and autonomic neuropathy), dermatologic, psychiatric, renal, or other major disease, that is unstable or could interfere with the subject’s participation in or completion of the study, in the opinion of the investigator 3. Clinically significant screening results that would exclude subject from the study (eg, medical history, physical examination, ECG, vital sign, pulse oximetry, and laboratory profiles) or any conditions that, would make the subject unsuitable for enrolment or could interfere with the subject’s participation in or completion of the study, in the opinion of the investigator. The medical monitor must be contacted for review of any subjects with screening results or conditions that may make them unsuitable for enrolment or could interfere with participation in or completion of the study. 4. Prolonged QTcF >450 msec at screening 5. Abnormal liver function as defined by AST, ALT, gamma-glutamyl transferase (GGT), or alkaline phosphatase ≥3 times or total bilirubin ≥2 times upper limit of the normal range 6. Haemoglobin <10 g/dL 7. Platelet count <150,000 cells/mm³ 8. Abnormal renal function at screening defined as creatinine clearance <60 mL/min using the Modified Diet in Renal Disease (MDRD) 9. Hospi