Informations générales (source: ClinicalTrials.gov)
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 (CHOICES)
Interventional
Phase 2
Kors van der Ent (Voir sur ClinicalTrials)
juin 2024
juin 2025
25 juin 2024
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.
Etablissements
| Les établissements sans correspondance certaine dans le répertoire FINESS dont les données sont issues de ClinicalTrials.gov Origine et niveau de fiabilité des données | |||||
|---|---|---|---|---|---|
| CHU de Nice - Nice - France | Sylvie Leroy | Contact (sur clinicalTrials) | |||
| Hôpital Larrey CHU Toulouse - Toulouse - France | Marlène Murris | Contact (sur clinicalTrials) | |||
Critères
Tous
Inclusion Criteria:
A subject must meet ALL the following criteria in order to participate:
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:
- 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
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 (Section
13.3.1)
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
A subject must meet ALL the following criteria in order to participate:
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:
- 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
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 (Section
13.3.1)
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
A subject who meets ANY of the following criteria will be excluded from participation:
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, 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
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. 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
10. 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.
11. Subject is currently taking or has taken a CFTR modulator within 28 days prior to
Day 1
12. 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
13. History of cancer (excluding cervical carcinoma in situ and non-melanoma skin cancer
with curative therapy for at least 5 years prior to screening)
14. History of organ or hematologic transplantation
15. History or current evidence of alcohol or drug abuse or dependence within 12 months
of screening, in the opinion of the investigator
16. Initiation of any new chronic therapy (eg, ibuprofen, hypertonic saline,
azithromycin, dornase alfa, aztreonam for inhalation solution, and tobramycin) or
any change in chronic therapy (excluding pancreatic enzyme replacement therapy)
within 28 days prior to Day 1
17. Known or suspected hypersensitivity or idiosyncratic reaction to the study drugs or
any components thereof
18. Pregnant or nursing women
19. Special or vulnerable status (e.g. institutionalized, or person related to or an
employee of the sponsor, FAIR Therapeutics, or investigator)