Long-term Safety and Efficacy Evaluation of Etavopivat in Patients with Sickle Cell Disease or Thalassaemia Transitioning from Previous Etavopivat Studies

The primary objective of this study is to investigate the long-term **safety** of etavopivat in adults, adolescents, and children with Sickle Cell Disease (SCD), Sickle Cell Disease with Thalassaemia (SCDTD), Transfusion-Dependent Thalassaemia (TDT), or Non-Transfusion-Dependent Thalassaemia (NTDT) who are transferring from other studies involving etavopivat. This is clinically relevant as it aims to ensure the sustained safety of etavopivat, a therapeutic agent, in managing these hematological disorders over an extended period.

Secondary objectives include:

• Investigating long-term clinical efficacy measures of etavopivat treatment in adults, adolescents, and children with SCD transferring from other studies with etavopivat.
• Evaluating the effects of etavopivat on hospitalizations in adults, adolescents, and children with SCD transferring from other studies with etavopivat.
• Investigating long-term clinical efficacy measures of etavopivat treatment in adults and adolescents with NTDT transferring from other studies with etavopivat.
• Investigating long-term clinical efficacy measures of etavopivat treatment in adults and adolescents with TDT or SCDTD, transferring from other studies with etavopivat.

The clinical trial involves a total of **279 participants** diagnosed with **Sickle Cell Disease** and **Thalassaemia**. The study population includes both male and female subjects, encompassing a wide **age range** from children to adults. Participants were selected based on their ongoing participation in a parent study involving etavopivat, with the requirement that they have completed a treatment period and derived clinical benefit from the medication. The trial does not focus on a vulnerable population. Lifestyle considerations such as diet and physical activity are not specified, but participants on treatments like hydroxyurea, crizanlizumab, or l-glutamine oral powder must have maintained a stable dose during the parent study. The selection criteria ensure that participants have been compliant with their treatment regimen, as determined by the investigator.

The clinical trial is designed to evaluate the long-term safety and efficacy of **etavopivat** in individuals with **Sickle Cell Disease** and **Thalassaemia**. This is an open-label, multi-centre, rollover study involving adults, adolescents, and children who have completed a treatment period in a previous etavopivat study. The trial is categorized as a phase 3b study and is not considered low intervention. The study will commence recruitment on January 27, 2025, and is estimated to conclude by November 30, 2029.

The trial employs a non-randomized, open-label design, allowing participants to continue receiving etavopivat treatment. Participants must have ongoing participation in an etavopivat parent study and have derived clinical benefit from the treatment. The primary endpoints include the number of treatment-emergent adverse events (TEAEs) and adverse reactions, reported separately for each indication and age group. Secondary endpoints focus on annualized vaso-occlusive crisis (VOC) rates, changes in hemoglobin (Hb) concentration, and the number of red blood cell (RBC) units transfused.

Study visits are structured to ensure comprehensive monitoring and data collection. The inclusion visit, or screening, confirms eligibility based on criteria such as informed consent and previous participation in an etavopivat study. Follow-up visits are scheduled to assess safety and efficacy, with data collected on adverse events, VOC rates, and other clinical parameters. The end-of-study visit marks the conclusion of the participant's involvement, with a final assessment of safety and treatment outcomes.

Participant involvement is expected to last up to 260 weeks, depending on individual circumstances and the study's progression. Conditions that may lead to early termination include withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety. The study aims to provide valuable insights into the long-term use of etavopivat, contributing to the understanding of its safety profile and therapeutic potential in managing **Sickle Cell Disease** and **Thalassaemia**.

The clinical trial involves the administration of **Etavopivat**, a synthetic chemical compound, as the experimental medication. The pharmaceutical form of Etavopivat is a **tablet**, with each tablet containing 200 mg of the active substance. The medication is administered orally. The trial is designed to assess the long-term safety and efficacy of Etavopivat in participants with sickle cell disease or thalassemia who have completed a prior treatment period in an Etavopivat study. The maximum treatment period for this study is 260 days. The medication is not formulated specifically for pediatric use, although it is administered to adults, adolescents, and children. The study does not specify a maximum daily or total dose amount, indicating that dosing may be adjusted based on individual participant needs and responses.

In addition to the experimental treatment, participants may receive standard-of-care therapies as deemed necessary by the study investigators. These non-experimental treatments are not specified in the trial documentation but are expected to align with current medical practices for managing sickle cell disease and thalassemia. The study does not include a placebo or comparator treatment group, focusing solely on the long-term effects of Etavopivat. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the treatment regimen and to evaluate the safety and efficacy outcomes accurately.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints include the number of treatment-emergent adverse events (TEAEs) and adverse reactions, which will be reported separately for each indication and age group. Secondary endpoints will focus on various clinical outcomes, such as the annualized rates of vaso-occlusive crises (VOCs), changes in VOCs, and changes in hemoglobin (Hb) concentration, all reported for each age group. Additionally, the trial will evaluate the annualized number of hospitalizations, the average length of hospital stays, and the number of red blood cell (RBC) units transfused, with changes in these parameters also reported separately for each indication.