Evaluation of Long-term Safety and Efficacy of Tezacaftor, Deutivacaftor, and Vanzacaftor Combination Therapy in Patients with Cystic Fibrosis

The primary objective of this Phase 3, open-label study is to evaluate the long-term **safety** and tolerability of the combination therapy VX-121/tezacaftor/deutivacaftor (VX-121/TEZ/D-IVA) in subjects with **Cystic Fibrosis**. This is clinically relevant as it aims to ensure that the treatment is safe for prolonged use, which is crucial for managing a chronic condition like Cystic Fibrosis.

Secondary objectives include:

• To evaluate the long-term efficacy of VX-121/TEZ/D-IVA. This will help determine the sustained effectiveness of the treatment over an extended period, providing insights into its potential benefits in improving patient outcomes.

The clinical trial involves a total of **513 participants** diagnosed with **Cystic Fibrosis**, aiming to evaluate the long-term safety and tolerability of VX-121/tezacaftor/deutivacaftor (VX-121/TEZ/D-IVA). The study population includes both male and female subjects, encompassing a diverse age range. Participants were selected based on their previous involvement in related studies, ensuring they did not withdraw consent and completed necessary study visits. The trial includes a vulnerable population, indicating special considerations for participant safety and ethical compliance. Participants are required to maintain a stable Cystic Fibrosis treatment regimen throughout the study duration. The selection process emphasizes the ability to comply with study protocols, including scheduled visits and treatment plans.

The clinical trial is a **Phase 3, open-label study** designed to evaluate the long-term safety and efficacy of the combination therapy VX-121/tezacaftor/deutivacaftor in subjects with **cystic fibrosis**. The trial aims to assess the safety and tolerability of the treatment based on adverse events, clinical laboratory values, ECGs, vital signs, and pulse oximetry. Secondary endpoints include the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1), absolute change from baseline in sweat chloride, and the number of pulmonary exacerbations. The trial is expected to run until April 16, 2027, with recruitment having started on March 7, 2023.

Participants will be involved in the study for a maximum treatment period of 96 weeks. The trial includes an initial screening visit to confirm eligibility based on inclusion criteria, such as the ability to comply with study procedures and a stable cystic fibrosis treatment regimen. Participants must not have withdrawn consent from a parent study or Part A of the trial. Follow-up visits will be scheduled to monitor the safety and efficacy of the treatment, with assessments conducted at regular intervals. The end-of-study visit will conclude the participant's involvement, where final evaluations will be performed.

Participants may be terminated early from the study if they experience significant adverse events, fail to comply with study procedures, or withdraw consent. The study is not a low-intervention trial and involves the administration of a film-coated tablet containing the active substances tezacaftor, deutivacaftor, and vanzacaftor, taken orally. The maximum daily dose is 20 mg. The trial is sponsored by Vertex Pharmaceuticals, Incorporated, and the product is designated as an orphan drug, indicating its use in treating a rare disease.

The clinical trial involves the administration of an **experimental medication** known as VX-121/VX-661/VX-561, which is a combination therapy consisting of the active substances **tezacaftor**, **deutivacaftor**, and **vanzacaftor**. This medication is provided in the form of a **film-coated tablet**. The route of administration is **oral**, and the maximum daily dose is 20 mg. The treatment period extends up to 96 weeks. The medication is developed by Vertex Pharmaceuticals, Incorporated, and is designated as an orphan drug for the treatment of **cystic fibrosis**.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is on evaluating the long-term safety and tolerability of the VX-121/tezacaftor/deutivacaftor combination therapy. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial is designed to assess the efficacy and safety of the treatment over an extended period, providing valuable data on its potential benefits for individuals with cystic fibrosis.

The efficacy of the combination therapy VX-121/TEZ/D-IVA in subjects with **Cystic Fibrosis** will be assessed through several secondary endpoints. These include the absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1), the absolute change from baseline in sweat chloride (SwCl) levels, and the number of pulmonary exacerbations (PEx). These parameters will be measured at specified intervals throughout the trial to evaluate the therapeutic impact of the treatment regimen.