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)

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]

Trial duration

27 May 2024 → 21 Jun 2025

Decision date (initial)

2024-05-03

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

EU Horizon Project

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

To evaluate the efficacy of DIR/POS/NES after 8 weeks compared to placebo 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. To evaluate the safety and tolerability and efficacy of DIR/POS/NES in CF patients with rare CFTR mutations and to evaluate PK of DIR/POS/NES and their respective metabolites, when relevant.

Conditions and MedDRA coding

Cystic Fibrosis

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Male or female subjects who have completed the HIT-CF Organoid Study and are ≥18 years of age 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 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. FEV1 ≥40% to ≤90% predicted according to the Global Lung Function Initiative (GLI)
5. Body mass index (BMI) ≥16 kg/m2 and ≤30 kg/m2
6. Non-smoker and non-tobacco user 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. Selected by an unblinded coordinating team based on organoid response or random selection

Exclusion criteria 2

1. Key exclusion criteria include: • Any CF patient meeting either of the following two criteria is defined as having a ‘common’ CFTR mutation(s): o At least one of the following mutations: F508del, G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, S549R, R117H, A455E, 3849+10kbC>T; OR o 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. Subject is currently taking or has taken a CFTR modulator within 28 days prior to Day 1

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 5

1. The average of the sweat chloride measurements taken after 4, 6 and 8 weeks of treatment
2. The average of the body weight measurements taken after 4, 6 and 8 weeks of treatment
3. The average of the Cystic Fibrosis Questionnaire Revised (CFQ R) respiratory domain measurements taken after 4, 6 and 8 weeks of treatment
4. Safety and tolerability assessments based on treatment-emergent Adverse Events (AEs) and Serious Adverse events (SAEs), clinical laboratory tests (ie, haematology, serum chemistry, coagulation studies, and urinalysis), physical examinations, electrocardiography (ECG), and vital signs
5. PK parameter estimates and metabolites of DIR/POS/NES derived from plasma

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

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 58 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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