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)

The primary objective of this study is to evaluate the **efficacy** of the combination therapy Dirocaftor/Posenacaftor/Nesolicaftor (DIR/POS/NES) after 8 weeks in patients with **Cystic Fibrosis** (CF) who have rare CFTR mutations. This evaluation is conducted in two distinct 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 targeted treatment options for CF patients with rare mutations, which could lead to improved management and outcomes in this subset of the CF population.

Secondary objectives include evaluating the safety, tolerability, and durability of efficacy of DIR/POS/NES in CF patients with rare CFTR mutations. These assessments are crucial for understanding the long-term implications and potential risks associated with the therapy, ensuring that it is not only effective but also safe for sustained use in the target patient population.

The clinical trial involves a total of **four participants** diagnosed with **Cystic Fibrosis**. The study population includes both male and female subjects who are 18 years of age or older. Participants were selected based on their completion of the HIT-CF Organoid Study and are required to have a confirmed diagnosis of Cystic Fibrosis, characterized by a sweat chloride value of ≥60 mmol/L or two CF-causing mutations, along with chronic sinopulmonary disease or gastrointestinal/nutritional abnormalities. The participants are clinically stable, with a forced expiratory volume in one second (FEV1) between 40% and 90% of the predicted value, and a body mass index (BMI) ranging from 16 kg/m² to 30 kg/m². All participants are non-smokers and non-tobacco users, having abstained for at least 30 days prior to screening, and they agree to maintain this status throughout the study. The trial does not involve a vulnerable population, and participants are required to adhere to a stable medication regimen for Cystic Fibrosis from 28 days before the start of the trial through its conclusion. Selection was based on organoid response or random selection by an unblinded coordinating team.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, crossover study 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 in patients with rare CFTR mutations, both with and without pre-selection based on organoid response. The primary endpoint is the average of the percent predicted forced expiratory volume in one second (ppFEV1) measurements taken after 4, 6, and 8 weeks of treatment. Secondary endpoints include the course of efficacy parameters over 24 weeks, average sweat chloride measurements, weight measurements, and Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain measurements taken after 4, 6, and 8 weeks of treatment.

The trial is expected to last until September 30, 2024, with recruitment having started on November 1, 2022. Participants will be involved in the study for a maximum treatment period of 16 weeks. The study includes an initial screening visit to confirm eligibility, followed by multiple treatment visits at 4, 6, and 8 weeks, and a final end-of-study visit. Participants are required to be clinically stable, with no significant changes in health status within 28 days prior to the first day of treatment. They must also meet specific inclusion criteria, such as a confirmed diagnosis of Cystic Fibrosis, a forced expiratory volume in one second (FEV1) between 40% and 90% of predicted, and a body mass index (BMI) between 16 kg/m² and 30 kg/m².

Participants are expected to remain on a stable medication regimen for Cystic Fibrosis from 28 days before the first day of treatment through the last study visit. Conditions that may lead to early termination from the study include significant changes in health status, inability to comply with study procedures, or withdrawal of consent. The trial is conducted under strict adherence to ethical guidelines, ensuring the safety and well-being of all participants throughout the study duration.

The clinical trial involves the administration of several investigational medicinal products, including **PTI-801**, **PTI-428**, and **PTI-808**, each provided in the form of a hard capsule. **PTI-801** contains the active substance **posenacaftor**, a chemical compound, and is administered orally. The maximum daily dose for **PTI-801** is 600 mg, with a total treatment period of up to 16 weeks. The administration schedule is designed to ensure consistent dosing, and participant compliance is monitored throughout the study.

**PTI-428** is another investigational product, containing the active substance **nesolicaftor**. This compound is also administered orally in the form of a hard capsule. The maximum daily dose for **PTI-428** is 10 mg, with a treatment duration of up to 16 weeks. The dosing schedule is structured to maintain therapeutic levels, and adherence to the regimen is closely monitored.

**PTI-808** contains the active substance **dirocaftor** and is administered in a similar manner as the other investigational products. The maximum daily dose for **PTI-808** is 300 mg, with a treatment period extending up to 16 weeks. The oral administration of this compound is designed to optimize absorption and efficacy, with compliance checks in place to ensure participant adherence.

In addition to the investigational products, the study includes the use of placebos corresponding to each investigational product: Placebo for IMP PTI-808, Placebo for IMP PTI-801, and Placebo for IMP PTI-428. These placebos are utilized in the double-blind, placebo-controlled design of the trial to assess the efficacy and safety of the investigational treatments. The placebos are administered in a manner consistent with the active treatments to maintain the integrity of the study blinding.

The efficacy of the investigational products in the clinical trial will be assessed using several key endpoints. The primary endpoint is the average of the percent predicted **forced expiratory volume in 1 second (ppFEV1)** measurements taken after 4, 6, and 8 weeks of treatment. This parameter is crucial for evaluating lung function improvement in subjects with **Cystic Fibrosis**. Secondary endpoints include the course of efficacy parameters over 24 weeks of treatment, the average of sweat chloride measurements, weight measurements, and the Cystic Fibrosis Questionnaire Revised (CFQ-R) respiratory domain measurements, all taken after 4, 6, and 8 weeks of treatment.

The trial is designed as a multicentre, randomised, double-blind, placebo-controlled, crossover study. The efficacy assessments will be conducted at specified timepoints to ensure consistent data collection and analysis. The use of validated scales and laboratory tests will facilitate the accurate measurement of these endpoints. The trial aims to evaluate the efficacy of the combination of Dirocaftor, Posenacaftor, and Nesolicaftor in subjects with Cystic Fibrosis, focusing on those with rare CFTR mutations. The study is expected to conclude by September 2024, with recruitment having started in November 2022.