Phase 3 Study on Rilzabrutinib Efficacy and Safety in Sickle-Cell Disease Patients Aged 10-65 for Vaso-Occlusive Crisis Prevention

The primary objective of this study is to assess the **efficacy** of rilzabrutinib in preventing clinical vaso-occlusive crisis (VOC), which is an acute painful crisis in patients with sickle-cell disease (SCD). This is clinically relevant as VOCs are a significant cause of morbidity in SCD, leading to severe pain and potential organ damage, thus improving prevention strategies can enhance patient outcomes.

Secondary objectives include: - Evaluating the time to first clinical VOC. - Assessing the rate of visits due to SCD-related complications. - Determining the annualized rate of home-managed VOCs. - Evaluating the effect of rilzabrutinib on fatigue in both adults and pediatric participants. - Assessing the effect on **hemoglobin** (Hb) levels. - Evaluating the safety of rilzabrutinib. - Assessing the effect on blood transfusion requirements. - Evaluating the effect on analgesic usage during the double-blind period.

The clinical trial involves a total of **135 participants** diagnosed with **sickle-cell disease** (SCD), a condition categorized under blood and lymphatic diseases. The study population includes both male and female subjects, with an age range of 10 to 18 years. Participants were selected based on their history of experiencing between 2 to 10 documented acute clinical vaso-occlusive crises (VOC) within 12 months prior to the screening visit. The trial population is characterized by individuals who either are not on hydroxyurea and/or L-glutamine at the screening visit or have been on a stable dose of these medications for a minimum of 6 months. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status grade of 2 or lower, indicating a relatively stable general health status. The study does not involve a vulnerable population, and contraceptive use is mandated in accordance with local regulations. The selection criteria ensure that participants are suitable for assessing the efficacy of rilzabrutinib in preventing clinical VOC in SCD patients.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled**, parallel-group, Phase 3 study designed to evaluate the efficacy and safety of **rilzabrutinib** in patients aged 10 to 65 years with **sickle cell disease**. The trial aims to assess the efficacy of rilzabrutinib for the prevention of clinical vaso-occlusive crisis (VOC), an acute painful crisis in sickle cell disease patients. The study is expected to last for 52 weeks, with an estimated recruitment start date of May 15, 2025, and an estimated end date of August 4, 2028.

Participants will be required to attend several study visits throughout the trial. The initial visit, known as the inclusion or screening visit, will determine eligibility based on criteria such as a confirmed diagnosis of sickle cell disease, a history of 2 to 10 documented acute clinical VOC episodes within the past 12 months, and a stable treatment regimen if applicable. Following the screening, eligible participants will be randomized to receive either rilzabrutinib or a matched placebo, administered orally in tablet form. The maximum daily dose of rilzabrutinib is 800 mg, with a total treatment period of up to 36 weeks.

Subsequent follow-up visits will be scheduled to monitor the participants' health, assess the primary endpoint of the annualized rate of clinical VOC, and evaluate secondary endpoints such as time to first clinical VOC incidence, changes in fatigue levels, and incidence of treatment-emergent adverse events. The end-of-study visit will conclude the trial, during which final assessments will be conducted to gather comprehensive data on the efficacy and safety of the treatment.

Participant involvement is expected to last for the entire 52-week duration of the trial, unless early termination is warranted. Conditions that may lead to early termination include the occurrence of serious adverse events, non-compliance with study protocols, or withdrawal of consent by the participant. The trial is conducted in accordance with ethical standards and regulatory requirements, ensuring the safety and well-being of all participants throughout the study period.

**Rilzabrutinib** is the experimental medication being evaluated in this clinical trial. It is administered in the form of a **tablet** and is intended for oral consumption. The maximum daily dosage of rilzabrutinib is 800 mg, and the treatment period can extend up to 36 weeks. The active substance, **rilzabrutinib**, is chemically synthesized and is provided by Principia Biopharma, Inc. The primary objective of the trial is to assess the efficacy of rilzabrutinib in preventing clinical vaso-occlusive crises in patients with sickle-cell disease. Participants are required to adhere to the dosing schedule, and compliance will be monitored throughout the study.

The study also includes a **placebo** group, which receives a matched placebo for comparison purposes. The placebo is designed to mimic the appearance of the rilzabrutinib tablet but does not contain any active pharmaceutical ingredients. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment assignments. This approach allows for an unbiased assessment of the efficacy and safety of rilzabrutinib in the target population.

The efficacy of **rilzabrutinib** in the clinical trial will be assessed primarily through the annualized rate of clinical vaso-occlusive crisis (VOC) in patients with sickle-cell disease. Secondary endpoints include the time to first clinical VOC incidence, the annualized rate of visits due to sickle-cell disease-related complications as assessed by the investigator, and the annualized rate of home-managed VOCs as reported in the Sickle Cell Pain Crisis (SCPC) eDiary. Additional secondary endpoints involve changes in fatigue levels measured by the PROMIS SF v1.0 Fatigue 13a total score for adults and the PedsQL Multidimensional Fatigue Scale total score for pediatric participants, changes in hemoglobin (Hb) levels, and the incidence of treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs), adverse events of special interest (AESIs), and adverse events leading to discontinuation.

Further assessments will include the incidence of potentially clinically significant laboratory, vital signs, and ECG abnormalities, the absolute number of simple and exchange blood transfusions, and the number of days requiring acetaminophen, NSAID, and/or short-acting opioid usage. These efficacy parameters will be collected and analyzed at specified intervals throughout the 52-week study period, utilizing validated scales and patient-reported outcomes where applicable. The trial is designed as a multicenter, randomized, double-blind, placebo-controlled, parallel-group, group sequential, Phase 3 study, ensuring rigorous evaluation of the treatment's efficacy and safety profile.