Clinical Trial to Evaluate the Efficacy and Safety of Dirocaftor/Posenacaftor/Nesolicaftor in Adults With CF
NCT Number: NCT06468527
Acronym: CHOICES
Status: RECRUITING
Study Type: INTERVENTIONAL
Phases: PHASE2
Conditions: Cystic Fibrosis
Interventions: DRUG: Diponecaftor|DRUG: Placebo
Sponsor: Kors van der Ent
Collaborators: European Union
Sex: ALL
Age: ADULT, OLDER_ADULT
Enrollment: 52
Study Design: Allocation: RANDOMIZED|Intervention Model: CROSSOVER|Masking: QUADRUPLE (PARTICIPANT, CARE_PROVIDER, INVESTIGATOR, OUTCOMES_ASSESSOR)|Primary Purpose: TREATMENT
Start Date: 2024-06-03
Completion Date: 2025-06-01
Locations: UZ Leuven, Leuven, Vlaams-Brabant, Belgium|CHU de Nice, Nice, France|Hôpital Larrey CHU Toulouse, Toulouse, France|Charité Universitätsmedizin Berlin, Berlin, Germany|Medizinische Hochschule Hannover, Hanover, Germany|Instituto Giannina Gaslini, Genova, Italy|Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy|Ospedale Pediatrico Bambino Gesù, Rome, Italy|Azienda Ospedaliera Universitaria Integrata, Verona, Italy|UMC Utrecht, Utrecht, 3584 CX, Netherlands|Hospital de Santa Maria, Lisboa, Portugal|Hospital Vall d'Hebron, Barcelona, Spain|Sahlgrenska University Hospital, Gothenburg CF center, Gothenburg, Sweden|University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom|Royal Brompton Hospital, London, United Kingdom|University Hospital Southampton, Southampton, United Kingdom

Summary:
CF is caused by mutations in the gene that encodes the 'Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)' channel. To re-establish the function of this complex chloride channel, typically two to three drug modes of action are needed. To date, clinical studies of CFTR modulators have focused on patients carrying the F508del CFTR mutation, which is present in approximately 80% of CF patients, or gating mutations which are present in 5% of CF patients (gating mutations result in a reduced opening of the CFTR-channel at the cell surface which limits the flow of chloride ions through the CFTR channel). Although CF is a monogenetic disease, the 15% remaining patients represent more than 2000 different rare and mostly uncharacterized CFTR mutations. Multiple pharma companies have one or more CF drugs in their developmental pipeline. However, it is not known which patients may respond to the drugs in the pipeline. It is hypothesized that by using individual patient's intestinal organoids to screen for drug response, a subset of patients with rare CFTR mutations can be identified who will clinically respond to drugs in the developmental pipeline. The Human Individualized Therapy of CF (HIT-CF) project has been designed to further evaluate this hypothesis. The project has received funding from the European Union's Horizon 2020 research and innovation program under grant agreement No 755021. The core of the project consists of a two-step approach to identify patients outside the existing drug label who may also benefit from CFTR-modulator treatment. In the first step of the project (HIT-CF Organoid Study, NTR7520), novel CFTR modulators and their combinations were tested on organoids from over 500 European and Israeli CF patients with rare CFTR mutations to identify patients who are predicted to clinically benefit from these treatments. The second step will evaluate the predicted clinical effect of the CFTR modulators in subjects identified by their organoid response to investigational products. CFTR modulators from the HIT-CF participating pharmaceutical company, FAIR Therapeutics, will be evaluated in the CHOICES clinical study described in this protocol. Data from this clinical study will be compared with the HIT-CF Organoid Study results to validate the organoid model.

Primary Outcome Measures: Mean percent predicted forced expiratory volume in 1 second (ppFEV1), The primary endpoint in both groups is the mean percent predicted forced expiratory volume in 1 second (ppFEV1) of measurements taken after 4, 6 and 8 weeks of treatment. Period baseline values will be corrected for in the analysis., Measurements taken at 4, 6 and 8 weeks of treatment
Secondary Outcome Measures: Sweat chloride, The average of the sweat chloride measurements taken after 4, 6 and 8 weeks of treatment., Measurements taken at 4, 6 and 8 weeks of treatment|Body weight, The average of the body weight measurements taken after 4, 6 and 8 weeks of treatment, Measurements taken at 4, 6 and 8 weeks of treatment|Cystic Fibrosis Questionnaire Revised (CFQ R) respiratory domain, The average of the Cystic Fibrosis Questionnaire Revised (CFQ R) respiratory domain measurements taken after 4, 6 and 8 weeks of treatment. Scores range from 0 to 100, with higher scores indicating better health., Measurements taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Safety and tolerability assessments based on treatment-emergent Adverse Events (AEs), Through study completion, an average of 30 weeks|Safety and tolerability assessments, Safety and tolerability assessments based on treatment-emergent Serious Adverse events (SAEs), Through study completion, an average of 30 weeks|Safety and tolerability assessments, Platelet count, Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Liver function (total bilirubin), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Liver function (alkaline phosphatase (ALP)), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Liver function (alanine transaminase (ALT)), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Liver function (gamma-glutamyl transferase (GGT)), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Anemia (Haemoglobin (Hb)), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Anemia (Haematocrit), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Anemia (Red blood cell count), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, White blood cell count (including differential), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Glucose measured in blood, Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Sodium in blood, Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Cholesterol in blood, Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Total protein in blood, Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Potassium in blood, Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Chloride in blood, Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Bicarbonate in blood, Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Lactate dehydrogenase in blood, Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Albumine in blood, Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Calcium in blood, Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, GFR MDRD (equation based on sex, ethnicity, age, blood urea nitrogen (BUN), creatinine), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Ketonuria (ketones measured by urine dipstick), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Proteinuria (protein measured by urine dipstick), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Hematuria (blood measured by urine dipstick), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Glucosuria (glucose measured by urine dipstick), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, pH of urine (pH measured by urine dipstick), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Specific gravitiy of urine (measured by urine dipstick), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Coagulation (activated partial thromboplastin time (aPTT)), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Coagulation (prothrombin time international normalized ratio (PT-INR)), Measurement taken at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, ECG QT Interval, Measurement taken at 4 weeks of treatment|Safety and tolerability assessments, Systolic and diastolic blood pressure, Measurement taken at start of treatment and at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Heart rate, Measurement taken at start of treatment and at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Respiratory rate, Measurement taken at start of treatment and at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Body temperature, Measurement taken at start of treatment and at 4, 6 and 8 weeks of treatment|Safety and tolerability assessments, Pulse oximetry measurements, Measurement taken at start of treatment and at 4, 6 and 8 weeks of treatment