Efficacy and Safety Evaluation of Rilzabrutinib in Adults and Adolescents with Persistent or Chronic Immune Thrombocytopenia: A Phase 3 Randomized Study

The primary objective of this study is to demonstrate the efficacy of **rilzabrutinib** versus placebo in patients with refractory or relapsed **Immune Thrombocytopenia (ITP)**. This is assessed based on the durability of platelet response during the last 12 weeks of the 24-week blinded treatment period, in the absence of rescue therapy. This objective is clinically relevant as it aims to establish the potential of rilzabrutinib to provide a sustained platelet response, which is crucial for managing bleeding risks in ITP patients.

Secondary objectives include:

• Evaluating the change from baseline in the Idiopathic Thrombocytopenic Purpura Bleeding Scale (IBLS).
• Assessing the stability of platelet response to rilzabrutinib treatment.
• Evaluating the safety and tolerability of rilzabrutinib in pediatric and adult participants with refractory/relapsed ITP.
• Characterizing the pharmacokinetics of rilzabrutinib in pediatric and adult participants.
• Evaluating the effect of rilzabrutinib on the general and disease-specific quality of life in adult patients.
• Assessing the effect of rilzabrutinib on disease-specific quality of life in pediatric participants.
• Evaluating the effect of rilzabrutinib versus placebo on the number of weeks with specific platelet counts over the 24-week period without rescue therapy.
• Assessing the time to first platelet count meeting specific criteria.
• Evaluating the proportion of patients requiring rescue therapy.
• Assessing the change from baseline on Item 10 of the ITP-Patient Assessment Questionnaire (ITP-PAQ) regarding physical fatigue in adult participants at Week 13.

The clinical trial involves a total of **171 participants** diagnosed with **Immune Thrombocytopenia (ITP)**. The study population includes both male and female subjects, with an age range encompassing pediatric participants aged 12 to less than 18 years, and adults aged 18 years and above. Pediatric participants aged 10 to less than 12 years are included only in the EU (EEA countries). Participants were selected based on their refractory or relapsed ITP status, with specific criteria regarding their platelet counts and previous responses to standard ITP therapies. The trial population is characterized by adequate hematologic, hepatic, and renal function, and all participants must be able to provide informed consent or assent. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, ensuring that all contraceptive use aligns with local regulations for clinical studies.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, parallel-group study with an open-label extension to evaluate the efficacy and safety of oral **rilzabrutinib** in adults and adolescents with persistent or chronic **immune thrombocytopenia** (ITP). The trial aims to demonstrate the efficacy of rilzabrutinib versus placebo based on the durability of platelet response during the last 12 weeks of the 24-week blinded treatment period, in the absence of rescue therapy. The trial is expected to conclude by November 20, 2026, with recruitment having commenced on April 16, 2021.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as platelet counts and previous responses to standard ITP therapies. The trial includes a 24-week blinded treatment period, during which participants will receive either rilzabrutinib or placebo. Follow-up visits will be conducted to monitor platelet counts, assess the need for rescue therapy, and evaluate any adverse events. The end-of-study visit will occur after the completion of the treatment period, where final assessments will be made regarding the primary and secondary endpoints.

The expected length of participant involvement is approximately 24 weeks, with conditions for early termination including the need for rescue therapy or the occurrence of significant adverse events. Participants must meet inclusion criteria, such as having a primary ITP diagnosis for a specified duration, previous response to certain therapies, and adequate hematologic, hepatic, and renal function. Exclusion criteria are not specified in the provided data. The trial will measure primary endpoints, such as the proportion of adult participants achieving platelet counts at or above 50,000/µL for at least 8 out of the last 12 weeks of the treatment period, and secondary endpoints, including the number of weeks with specific platelet counts and changes in quality of life assessments.

The clinical trial involves the administration of **Rilzabrutinib**, an investigational medicinal product, in the form of a **tablet**. Rilzabrutinib is a synthetically manufactured chemical compound developed by Principia Biopharma, Inc. The active substance, Rilzabrutinib, is administered orally. The maximum daily dose is 800 mg, with a total maximum dose of 1,391,200 mg over the course of the study. The treatment period extends up to 1,739 days. The primary objective of the trial is to evaluate the efficacy and safety of Rilzabrutinib in patients with persistent or chronic immune thrombocytopenia (ITP), focusing on the durability of platelet response during the last 12 weeks of the 24-week blinded treatment period.

The study also includes a **placebo** group for comparison. The placebo is formulated to be identical to the investigational medicinal product, except that the 400 mg of the active ingredient is replaced with 400 mg of mannitol. The placebo is administered in the same pharmaceutical form and via the same oral route as Rilzabrutinib. This design ensures that any observed effects can be attributed to the active treatment rather than other variables. Participant compliance with the dosing schedule is monitored throughout the study to ensure the integrity of the trial results.

The efficacy of rilzabrutinib in the treatment of **Immune Thrombocytopenia (ITP)** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of adult participants achieving platelet counts at or above 50,000/µL for at least 8 out of the last 12 weeks of the 24-week blinded treatment period, without the need for rescue therapy. Secondary endpoints include the number of weeks with platelet counts ≥50,000/µL or between 30,000/µL and <50,000/µL, provided these counts are at least doubled from baseline over the 24-week period, again in the absence of rescue therapy. Additional secondary endpoints involve the time to first platelet count of ≥50,000/µL or between 30,000/µL and <50,000/µL with a doubling from baseline, the proportion of participants requiring rescue therapy, and changes from baseline in various patient-reported outcomes and quality of life measures.

These efficacy parameters will be measured and collected at specified timepoints throughout the trial, including at Week 13 and Week 25, using validated scales such as the Idiopathic Thrombocytopenic Purpura Bleeding Scale (IBLS) and the ITP Patient Assessment Questionnaire (ITP-PAQ). The trial will also assess changes in disease-specific quality of life using the Kids’ ITP Tools (ITP-KIT) score for pediatric participants. Plasma concentrations of rilzabrutinib will be monitored to correlate with clinical outcomes. The analysis of these endpoints will provide comprehensive data on the efficacy of rilzabrutinib in managing ITP, contributing to the understanding of its therapeutic potential in this patient population.