Long-term Safety and Efficacy Evaluation of Elexacaftor/Tezacaftor/Ivacaftor in Cystic Fibrosis Patients Aged 12 Months and Older

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** aged 12 months and older. This is clinically relevant as it aims to ensure that the treatment is safe for prolonged use in a pediatric population, which is crucial for managing a chronic condition like Cystic Fibrosis.

Secondary objectives include evaluating the long-term efficacy and pharmacodynamics (PD) of the ELX/TEZ/IVA combination. These objectives are important to determine the sustained effectiveness of the treatment and to understand its biological effects over an extended period, which can inform future therapeutic strategies and patient management.

The clinical trial involves a total of **35 participants** diagnosed with **Cystic Fibrosis**. The study population includes both male and female subjects, with an age range starting from 2 years old. Participants were selected based on their previous involvement in a parent study, where they either completed the study drug treatment or had interruptions but did not permanently discontinue the study drug. The trial population is considered vulnerable, and participants are required to maintain a stable cystic fibrosis treatment regimen throughout the study. The selection process ensures that the legal representatives or guardians of the subjects understand the protocol requirements and can ensure compliance with the study plan. The trial aims to evaluate the long-term safety and tolerability of the combination therapy of elexacaftor, tezacaftor, and ivacaftor.

The clinical trial is designed to evaluate the long-term safety and tolerability of **elexacaftor**, **tezacaftor**, and **ivacaftor** in subjects with **cystic fibrosis** aged 12 months and older. This is a Phase 3, open-label study, which means that both the researchers and participants know which treatment is being administered. The trial is expected to commence recruitment on November 15, 2024, and conclude by August 19, 2027, with a total duration of approximately 33 months.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as the ability of the legal representative to understand protocol requirements and the participant's completion of a parent study. The primary endpoint focuses on safety and tolerability, assessed through adverse events, clinical laboratory values, ECGs, vital signs, and pulse oximetry. Secondary endpoints include the absolute change in sweat chloride levels.

Study visits will be scheduled throughout the trial to monitor the participants' health and response to the treatment. These visits will include follow-up assessments to ensure compliance with the treatment regimen and to evaluate any potential adverse effects. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to gather comprehensive data on the treatment's long-term effects.

Participants are expected to remain in the study for the entire duration unless specific conditions necessitate early termination. These conditions include withdrawal of consent, non-compliance with the study protocol, or any adverse events that may compromise the participant's safety. The trial aims to provide valuable insights into the long-term management of cystic fibrosis with the combination of elexacaftor, tezacaftor, and ivacaftor, contributing to the understanding of its safety and efficacy in a pediatric population.

The clinical trial involves the administration of several experimental medications, primarily focusing on the treatment of **cystic fibrosis**. The first experimental medication is VX-770, also known as **Ivacaftor**, which is provided in the form of granules. The dosage for VX-770 is available in 25 mg, 50 mg, and 75 mg, with a maximum daily dose of 75 mg. The granules are administered orally, and the treatment period extends up to 96 weeks. Ivacaftor is a chemical compound developed by Vertex Pharmaceuticals, Incorporated, and is designated as an orphan drug under the code EU/3/08/556.

Another experimental treatment in the trial is Kalydeco, which contains the active substance Ivacaftor. Kalydeco is available in granules packaged in sachets, with dosages of 25 mg, 50 mg, 59.5 mg, and 75 mg. The maximum daily dose for Kalydeco is 75 mg, administered orally over a treatment period of 96 weeks. This formulation is also recognized as an orphan drug and is marketed by Vertex Pharmaceuticals (Ireland) Limited.

The trial also includes VX-445/VX-661/VX-770, a fixed-dose combination of **Tezacaftor**, **Elexacaftor**, and Ivacaftor. This combination is available in granule form, with a maximum daily dose of 100 mg. The granules are administered orally, and the treatment duration is 96 weeks. This combination is designated as an orphan drug under the code EU/3/18/2116 and is developed by Vertex Pharmaceuticals, Incorporated.

Kaftrio, another treatment in the study, is a combination of Tezacaftor, Elexacaftor, and Ivacaftor, provided in granules within sachets. The available dosages are 60 mg/40 mg/80 mg and 75 mg/50 mg/100 mg, with a maximum daily dose of 100 mg. The administration route is oral, and the treatment period is 96 weeks. Kaftrio is marketed by Vertex Pharmaceuticals (Ireland) Limited and is also recognized as an orphan drug.

Throughout the trial, participant compliance with the dosing schedule is monitored to ensure adherence to the treatment regimen. The study does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. All medications are of chemical origin, and the trial is designed to evaluate the long-term safety and efficacy of these treatments in subjects aged 12 months and older with cystic fibrosis.

The efficacy of the clinical trial will be assessed through specific endpoints designed to evaluate the impact of the investigational treatment on subjects with **Cystic Fibrosis**. The primary efficacy endpoint involves safety and tolerability assessments, which will be determined by monitoring adverse events (AEs), clinical laboratory values, standard 12-lead ECGs, vital signs, and pulse oximetry. These parameters will provide a comprehensive overview of the treatment's safety profile over the course of the study.

Secondary efficacy endpoints include the measurement of the absolute change in sweat chloride (SwCl) levels. This biomarker is a critical indicator of the treatment's effect on the underlying pathophysiology of **Cystic Fibrosis**. The collection and analysis of these efficacy parameters will be conducted at predetermined intervals throughout the trial, ensuring a robust evaluation of the treatment's long-term efficacy. The trial is designed to provide valuable insights into the therapeutic potential of elexacaftor, tezacaftor, and ivacaftor in the target population.