Clinical Trial to Evaluate the Efficacy and Safety of Dirocaftor/Posenacaftor/Nesolicaftor in Adults With CF

NCT06468527 | Completed Phase 2

• 1 other identifier: HIT-CF-001
• Study Type: interventional
• Target: 41
• Locations: 9 countries
• Sites: 16

Brief 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.

Conditions

Cystic Fibrosis

Keywords

Cystic Fibrosis; CFTR modulator; Intestinal organoids

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (39)

• Sweat chloride

  Measurements taken at 4, 6 and 8 weeks of treatment

• Body weight

  Measurements taken at 4, 6 and 8 weeks of treatment

• Cystic Fibrosis Questionnaire Revised (CFQ R) respiratory domain

  Measurements taken at 4, 6 and 8 weeks of treatment

• Safety and tolerability assessments

  Through study completion, an average of 30 weeks

• Safety and tolerability assessments

  Through study completion, an average of 30 weeks

Study Arms (2)

Diponecaftor/Placebo

OTHER

Diponecaftor once daily for 8 weeks followed by placebo once daily for 8 weeks. In between both periods there will be a washout period to minimize a possible carryover effect.

Drug: Diponecaftor; Drug: Placebo

Placebo/Diponecaftor

OTHER

Placebo once daily for 8 weeks followed by diponecaftor once daily for 8 weeks. In between both periods there will be a washout period to minimize a possible carryover effect.

Drug: Diponecaftor; Drug: Placebo

Interventions

Diponecaftor DRUG

Diponecaftor is a triple combination of DIR/POS/NES. The combination therapy will be administered orally during 8 weeks. The daily dose contains: * DIR 300 mg/day * POS 600 mg/day * NES 10 mg/day

Diponecaftor/Placebo; Placebo/Diponecaftor

Placebo DRUG

Placebo once daily for 8 weeks. Oral administration.

Diponecaftor/Placebo; Placebo/Diponecaftor

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• A subject must meet ALL the following criteria in order to participate:
• 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
• Confirmed diagnosis of CF as follows:
• Sweat chloride value of ≥60 mmol/L based on quantitative pilocarpine iontophoresis (at screening) OR 2 CF-causing mutations AND
• chronic sinopulmonary disease or gastrointestinal/nutritional abnormalities
• Clinically stable CF disease in the opinion of the investigator with no significant changes in health status within 28 days prior to Day 1
• 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
• Body mass index (BMI) ≥16 kg/m2 and ≤30 kg/m2
• 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
• Subjects of childbearing potential must meet contraception requirements (Section 13.3.1)
• Willing to remain on a stable medication regimen for CF from 28 days before Day 1 through the last study visit
• Willing and able to comply with scheduled visits, treatment plan, study restrictions, laboratory tests, and other study procedures
• Selected by an unblinded coordinating team based on organoid response or random selection
• Subject will sign and date an informed consent form (ICF

You may not qualify if:

• A subject who meets ANY of the following criteria will be excluded from participation:
• 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
• 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, hepatitis B or hepatitis C), 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
• 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.
• Prolonged QTcF \>450 msec at screening
• 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
• Haemoglobin \<10 g/dL
• Platelet count \<150,000 cells/mm3
• Abnormal renal function at screening defined as creatinine clearance \<60 mL/min using the Modified Diet in Renal Disease (MDRD)
• Hospitalisation, sinopulmonary infection, CF exacerbation, or other clinically significant infection or illness (in the opinion of the investigator) requiring an increase or addition of medication, such as antibiotics or corticosteroids, within 28 days of Day 1
• Lung infection with organisms associated with a more rapid decline in pulmonary status (eg, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). Subjects who have a current or past history of a positive culture must be reviewed with the medical monitor to confirm clinical stability.
• Subject is currently taking or has taken a CFTR modulator within 28 days prior to Day 1
• Participation in another clinical trial or treatment with an investigational agent within 28 days or 5 half-lives, whichever is longer, prior to screening. The duration of the elapsed time may be longer if required by local regulations
• History of cancer (excluding cervical carcinoma in situ and non-melanoma skin cancer with curative therapy for at least 5 years prior to screening)
• History of organ or hematologic transplantation

Sponsors & Collaborators

• Kors van der Ent: lead
• European Union: collaborator

Study Sites (16)

UZ Leuven

Leuven, Vlaams-Brabant, Belgium

Location

CHU de Nice

Nice, France

Location

Hôpital Larrey CHU Toulouse

Toulouse, France

Location

Charité Universitätsmedizin Berlin

Berlin, Germany

Location

Medizinische Hochschule Hannover

Hanover, Germany

Location

Instituto Giannina Gaslini

Genova, Italy

Location

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico

Milan, Italy

Location

Ospedale Pediatrico Bambino Gesù

Rome, Italy

Location

Azienda Ospedaliera Universitaria Integrata

Verona, Italy

Location

UMC Utrecht

Utrecht, Utrecht, 3584 CX, Netherlands

Location

Hospital de Santa Maria

Lisbon, Portugal

Location

Hospital Vall d'Hebron

Barcelona, Spain

Location

Sahlgrenska University Hospital, Gothenburg CF center

Gothenburg, Sweden

Location

University Hospitals Birmingham NHS Foundation Trust

Birmingham, United Kingdom

Location

Royal Brompton Hospital

London, United Kingdom

Location

University Hospital Southampton

Southampton, United Kingdom

Location

MeSH Terms

Conditions

Cystic Fibrosis

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Study Officials

• C.K. van der Ent

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Project Leader and Coordinating Investigator

Study Record Dates

• First Submitted: June 3, 2024
• First Posted: June 21, 2024
• Study Start: June 3, 2024
• Primary Completion: June 26, 2025
• Study Completion: June 26, 2025
• Last Updated: November 24, 2025

Record last verified: 2025-11

Locations

ES (1); NL (1); FR (2); BE (1); IT (4); PT (1); SE (1); DE (2); GB (3)