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)

The primary objective of this study is to evaluate the **efficacy** of the combination of Dirocaftor, Posenacaftor, and Nesolicaftor (DIR/POS/NES) after 8 weeks of treatment compared to placebo in patients with **Cystic Fibrosis** (CF) who have rare CFTR mutations. This evaluation is conducted in two groups: (a) CF patients with a high organoid response to DIR/POS/NES and (b) CF patients with rare CFTR mutations not pre-selected based on organoid response. The clinical relevance of this objective lies in its potential to provide a targeted therapeutic option for CF patients with rare mutations, who may not respond to existing treatments.

Secondary objectives include: - Evaluating the safety, tolerability, and efficacy of DIR/POS/NES in CF patients with rare CFTR mutations. - Assessing the pharmacokinetics (PK) of DIR/POS/NES and their respective metabolites, when relevant. These secondary objectives are crucial for understanding the overall safety profile and metabolic behavior of the treatment, which can inform dosing and long-term management strategies for this patient population.

The clinical trial involves a total of **4 participants** diagnosed with **Cystic Fibrosis**. The study population includes both male and female subjects who are 18 years of age or older. Participants have completed the HIT-CF Organoid Study and have a confirmed diagnosis of Cystic Fibrosis, characterized by a sweat chloride value of 60 mmol/L or higher, or two CF-causing mutations along with chronic sinopulmonary disease or gastrointestinal/nutritional abnormalities. The participants are clinically stable, with no significant health changes within 28 days prior to the start of the study. They have a predicted FEV1 between 40% and 90% according to the Global Lung Function Initiative and a body mass index (BMI) between 16 kg/m² and 30 kg/m². All participants are non-smokers and non-tobacco users for at least 30 days before screening and agree to abstain from tobacco use throughout the study. The trial population was selected based on organoid response or through random selection by an unblinded coordinating team. The study includes a vulnerable population, and lifestyle considerations such as smoking and tobacco use are significant factors in participant selection.

The clinical trial is a **Phase IIb**, multicenter, randomized, double-blind, placebo-controlled, crossover study designed to evaluate the efficacy and safety of the combination of **dirocaftor**, **posenacaftor**, and **nesolicaftor** in subjects with **cystic fibrosis** aged 18 years or older. The trial aims to assess the efficacy of the drug combination after 8 weeks compared to placebo in patients with rare CFTR mutations, both with and without pre-selection based on organoid response. The primary endpoint is the mean percent predicted forced expiratory volume in 1 second (ppFEV1) measured after 4, 6, and 8 weeks of treatment. Secondary endpoints include sweat chloride levels, body weight, CFQ-R respiratory domain scores, and safety assessments.

The trial is expected to commence recruitment on May 1, 2024, and conclude by June 30, 2025. Participants will be involved in the study for a maximum of 16 weeks, with the treatment period lasting up to 8 weeks. The study involves several visits, starting with a screening visit to confirm eligibility based on criteria such as age, confirmed diagnosis of cystic fibrosis, and clinical stability. Follow-up visits will occur at 4, 6, and 8 weeks to monitor treatment effects and safety. The end-of-study visit will finalize data collection and assess the overall health status of participants.

Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The study drugs, PTI-801, PTI-808, and PTI-428, are administered orally in the form of hard capsules, with maximum daily doses of 600 mg, 300 mg, and 10 mg, respectively. Placebos corresponding to each investigational product are also utilized to maintain the double-blind design. The trial is not categorized as low intervention and is conducted under the sponsorship of FAIR THERAPEUTICS B.V.

The clinical trial involves the administration of three experimental medications, each in the form of a **hard capsule**. The first medication, PTI-801, contains the active substance **posenacaftor**. It is administered orally with a maximum daily dose of 600 mg. The treatment period for PTI-801 is up to 16 weeks. The medication is produced by FAIR THERAPEUTICS B.V. and is of chemical origin.

The second experimental medication, PTI-808, contains the active substance **dirocaftor**. This medication is also administered orally in the form of a hard capsule. The maximum daily dose for PTI-808 is 300 mg, with a treatment period of up to 8 weeks. Like PTI-801, PTI-808 is manufactured by FAIR THERAPEUTICS B.V. and is chemically derived.

The third experimental medication, PTI-428, contains the active substance **nesolicaftor**. It is administered orally in a hard capsule form, with a maximum daily dose of 10 mg. The treatment period for PTI-428 extends up to 16 weeks. This medication is also produced by FAIR THERAPEUTICS B.V. and is of chemical origin.

In addition to the experimental medications, the study includes the use of placebos corresponding to each investigational product: Placebo for IMP PTI-801, Placebo for IMP PTI-808, and Placebo for IMP PTI-428. These placebos are utilized in the double-blind, placebo-controlled design of the trial to evaluate the efficacy and safety of the experimental treatments in subjects with **cystic fibrosis**. The placebos do not contain any active substances and are used to ensure the integrity of the study's results.

The efficacy of the investigational combination of **dirocaftor**, **posenacaftor**, and **nesolicaftor** in subjects with Cystic Fibrosis will be assessed through a series of primary and secondary endpoints. The primary endpoint is the mean percent predicted forced expiratory volume in 1 second (ppFEV1), with measurements taken after 4, 6, and 8 weeks of treatment. These measurements will be adjusted for period baseline values in the analysis to ensure accuracy.

Secondary endpoints include the average of sweat chloride measurements, body weight measurements, and the Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain scores, all collected at the same timepoints of 4, 6, and 8 weeks. Additionally, safety and tolerability will be evaluated through treatment-emergent adverse events (AEs) and serious adverse events (SAEs), alongside clinical laboratory tests, physical examinations, electrocardiography (ECG), and vital signs. Pharmacokinetic (PK) parameter estimates and metabolites of the drug combination will also be derived from plasma samples.