A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Crossover Study to Evaluate the Efficacy and Safety of Dirocaftor/Posenacaftor/Nesolicaftor in Subjects with Cystic Fibrosis Aged 18Years or Older (CHOICES)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

University Medical Center Utrecht

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

Decision date (initial)

2022-11-10

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

EU Horizon Project

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Evaluate the efficacy of DIR/POS/NES after 8 weeks in (a) CF patients with rare CFTR mutations and a high organoid response to DIR/POS/NES and (b) CF patients with rare CFTR mutations not pre-selected on organoid response.

Secondary objectives 1

1. Evaluate the safety, tolerability and durability of efficacy of DIR/POS/NES in CF patients with rare CFTR mutations

Conditions and MedDRA coding

Cystic Fibrosis

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 1

1. 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: o Sweat chloride value of ≥60 mmol/L based on quantitative pilocarpine iontophoresis (at screening) OR 2 CF-causing mutations AND o 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 13.22) 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)

Exclusion criteria 1

1. 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 histories, physical exams, ECGs, vital signs, 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The primary endpoint in both trials is the average of the percent predicted forced expiratory volume in 1 second (ppFEV1) measurements taken after 4, 6 and 8 weeks of treatment.

Secondary endpoints 1

1. • The course of efficacy parameters over 24 weeks (TP2 and TP3) of treatment in both groups • The average of the sweat chloride measurements taken after 4, 6 and 8 weeks of treatment • The average of the weight measurements taken after 4, 6 and 8 weeks of treatment • The average of the Cystic Fibrosis Questionnaire Revised (CFQ R) respiratory domain measurements taken after 4, 6 and 8 weeks of treatment

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Placebo 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

University Medical Center Utrecht

Sponsor organisation

University Medical Center Utrecht

Address

Heidelberglaan 100

City

Utrecht

Postcode

3584 CX

Country

Netherlands

Scientific contact point

Organisation

University Medical Center Utrecht

Contact name

Marlou Bierlaagh

Public contact point

Organisation

University Medical Center Utrecht

Contact name

K. van der Ent

Third parties 1

Locations

9 EU/EEA countries · 15 investigational sites

By country

Investigational sites

Application history

1 submissions — initial application plus substantial / non-substantial modifications