Long-term Safety and Efficacy Evaluation of Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients with Non-F508del CFTR Genotypes

The primary objective of this Phase 3 open-label study is to evaluate the long-term **safety** and tolerability of the combination therapy elexacaftor (ELX), tezacaftor (TEZ), and ivacaftor (IVA) in subjects with **Cystic Fibrosis** who have non-F508del CFTR genotypes. This is clinically relevant as it aims to ensure that the treatment is safe for long-term use, which is crucial for managing a chronic condition like Cystic Fibrosis.

Secondary objectives include: - Part A Only: To evaluate the long-term efficacy and **pharmacodynamics** (PD) of ELX/TEZ/IVA. This is important for understanding the sustained effectiveness and biological impact of the treatment over an extended period.

The clinical trial involves a total of **28 participants** diagnosed with **Cystic Fibrosis**. The study population includes both male and female subjects, with an age range that encompasses children and adolescents. Participants were selected based on their previous involvement in a parent study, with criteria ensuring they completed or partially completed the study drug treatment and visits. The trial includes a vulnerable population, indicating additional ethical considerations. Participants are required to maintain a stable treatment regimen for Cystic Fibrosis, excluding CFTR modulators, throughout the study duration. The trial aims to evaluate the long-term safety and tolerability of the combination therapy of elexacaftor, tezacaftor, and ivacaftor. Lifestyle factors such as diet and physical activity are not specified, but compliance with study procedures and restrictions is mandatory.

The clinical trial is designed to evaluate the long-term safety and efficacy of a combination therapy consisting of **elexacaftor**, **tezacaftor**, and **ivacaftor** in individuals with **cystic fibrosis** who do not possess the F508del CFTR genotype. This study is structured as a Phase 3, open-label trial, with a primary focus on assessing safety and tolerability through monitoring adverse events, clinical laboratory values, ECGs, vital signs, and pulse oximetry. The trial is expected to span from September 2022 to April 2027, with participants involved for a maximum treatment period of 192 weeks.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific inclusion criteria, such as the ability to comply with study procedures and having completed prior related studies. The trial will include follow-up visits to monitor safety and efficacy endpoints, such as changes in percent predicted forced expiratory volume in one second (ppFEV1), sweat chloride levels, and body mass index. The end-of-study visit will conclude the participant's involvement, ensuring all data is collected and any necessary follow-up care is arranged.

Participant involvement is expected to last up to the full duration of the trial, contingent upon adherence to the study protocol. Conditions that may lead to early termination from the study include withdrawal of consent, inability to comply with study requirements, or the occurrence of significant adverse events. The trial employs a controlled, open-label design, allowing for comprehensive data collection on the long-term effects of the investigational therapy in the target population.

The clinical trial involves the administration of **Kaftrio 37.5 mg/25 mg/50 mg film-coated tablets**, which contain the active substances **tezacaftor**, **elexacaftor**, and **ivacaftor**. These tablets are administered orally. The maximum daily dose is 50 mg, with a total treatment period of up to 192 days. The tablets are packaged and labeled for clinical use and are QP released at the clinical site. The pharmaceutical form is a film-coated tablet, and the product is of chemical origin.

Another treatment used in the trial is the **VX-445/VX-661/VX-770 fixed-dose combination tablet**, also containing tezacaftor, elexacaftor, and ivacaftor. This formulation is administered orally, with a maximum daily dose of 50 mg. The treatment period is also up to 192 days. The tablets are film-coated and of chemical origin, provided by Vertex Pharmaceuticals, Incorporated.

The trial also includes **Kalydeco 75 mg film-coated tablets**, which contain the active substance ivacaftor. These tablets are administered orally, with a maximum daily dose of 75 mg and a treatment period of up to 192 days. The tablets are film-coated and of chemical origin, provided by Vertex Pharmaceuticals (Ireland) Limited.

Additionally, the **VX-770 Film-coated tablet** is used, containing ivacaftor as the active substance. This tablet is administered orally, with a maximum daily dose of 150 mg and a treatment period of up to 192 days. The tablets are film-coated and of chemical origin, provided by Vertex Pharmaceuticals, Incorporated.

Another formulation, **Kaftrio 75 mg/50 mg/100 mg film-coated tablets**, is included in the trial. This product contains tezacaftor, elexacaftor, and ivacaftor, administered orally with a maximum daily dose of 100 mg. The treatment period is up to 192 days. The tablets are film-coated and of chemical origin, provided by Vertex Pharmaceuticals (Ireland) Limited.

The trial also involves the use of **Kalydeco 150 mg film-coated tablets**, containing ivacaftor. These tablets are administered orally, with a maximum daily dose of 150 mg and a treatment period of up to 192 days. The tablets are film-coated and of chemical origin, provided by Vertex Pharmaceuticals (Ireland) Limited.

Lastly, the **VX-445/VX-661/VX-770 film-coated fixed-dose combination tablet** is used, containing tezacaftor, elexacaftor, and ivacaftor. This formulation is administered orally, with a maximum daily dose of 100 mg and a treatment period of up to 192 days. The tablets are film-coated and of chemical origin, provided by Vertex Pharmaceuticals, Incorporated.

The efficacy of the clinical trial will be assessed through a series of secondary endpoints, specifically focusing on the treatment of **Cystic Fibrosis**. The parameters for evaluating efficacy include the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1), sweat chloride (SwCl) levels, Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain (RD) score, body mass index (BMI), and weight. Additionally, the number of pulmonary exacerbations (PEx) will be monitored.

These efficacy parameters will be measured and collected at specified intervals throughout the trial. The absolute changes from baseline will be calculated to determine the impact of the treatment on the participants. The use of validated scales and laboratory tests will ensure the accuracy and reliability of the data collected. The trial is designed to provide a comprehensive evaluation of the long-term efficacy of the combination of elexacaftor, tezacaftor, and ivacaftor in subjects with non-F508del CFTR genotypes.