A multi-center, open-label, single-arm study to evaluate the efficacy and safety of oral rilzabrutinib in adults with immune thrombocytopenia (ITP) who failed first-line treatment

The primary objective of this study is to evaluate whether rilzabrutinib can provide sustained elevation of platelet count in adults with primary immune thrombocytopenia who have failed first-line treatment. This objective addresses a critical clinical need for patients with ITP who demonstrate inadequate response to initial therapies including corticosteroids, intravenous immunoglobulin, and anti-D immunoglobulin. Achieving durable platelet response in this refractory population is clinically relevant as it may reduce bleeding risk and the need for additional rescue therapies.

The secondary objectives include:

• Assessment of the efficacy of rilzabrutinib in adults with ITP throughout the study period

• Evaluation of the safety and tolerability profile of rilzabrutinib

• Assessment of quality of life outcomes in treated patients

This clinical trial enrolled a total of **12 participants** diagnosed with **primary immune thrombocytopenia (ITP)**. The study population included both **male and female participants** aged **18 years and above**. Participants were required to have an **Eastern Cooperative Oncology Group (ECOG) performance status** of grade 2 or lower, indicating relatively preserved functional capacity. Eligible individuals had previously received at least one **first-line therapy** according to international guidelines or local standard of care, such as **oral or parenteral corticosteroids**, **intravenous immunoglobulin (IVIg)**, or **anti-D**, and demonstrated a history of platelet response to such treatment, defined as achieving at least one platelet count above 30,000/μL. Participants were selected based on adequate **hematologic, hepatic, and renal function**, including hemoglobin greater than 9 g/dL, **absolute neutrophil count** of at least 1.5×10⁹/L, liver enzymes within acceptable limits, and **estimated glomerular filtration rate** above 50 mL/min. The trial population was required to have up-to-date vaccination status per local guidelines and to comply with contraceptive requirements consistent with local regulations. The study included a **vulnerable population** as indicated in the trial design.

This is a multi-center, open-label, single-arm Phase III clinical trial designed to evaluate the efficacy and safety of oral rilzabrutinib in adult participants with immune thrombocytopenia who have failed first-line treatment. The study investigates whether rilzabrutinib can provide a long-lasting increase in platelet count in adults with primary immune thrombocytopenia who do not respond to initial therapies including corticosteroids, intravenous immunoglobulin, and/or anti-D immunoglobulin. The investigational medicinal product is administered orally in tablet form at a maximum daily dose of 800 mg, with a maximum total dose of 448,000 mg over a maximum treatment period of 80 weeks. The active substance is rilzabrutinib, a chemical compound manufactured by Principia Biopharma, Inc.

The primary endpoint is the durable platelet response, defined as the percentage of participants who maintain a platelet count of at least 50,000/μL, or between 30,000/μL and 50,000/μL with at least double their baseline count, for at least half of their scheduled platelet assessments conducted every 2 weeks and for at least 4 valid visits during the last 12 weeks of the study, without requiring emergency treatment. Secondary endpoints include overall platelet response, duration of platelet response, changes in the immune thrombocytopenia bleeding scale score from baseline to the end of Week 28, and the corticosteroid-sparing effect measured as the percentage of participants who can discontinue or reduce their corticosteroid dose by 50% or to less than 5 mg from baseline by the end of Week 28.

Eligible participants must be 18 years of age or older at the time of informed consent, with a confirmed diagnosis of primary immune thrombocytopenia and an Eastern Cooperative Oncology Group performance status grade of 2 or lower. Participants must have received at least one first-line therapy according to international guidelines or local standard of care and must have demonstrated a history of platelet response during treatment with first-line therapy, defined as one platelet count above 30,000/μL. Adequate hematologic, hepatic, and renal function is required, including hemoglobin greater than 9 g/dL, absolute neutrophil count of at least 1.5×10⁹/L, AST/ALT up to 1.5 times the upper limit of normal, albumin of at least 3 g/dL, total bilirubin up to 1.5 times the upper limit of normal unless documented Gilbert syndrome is present, and estimated glomerular filtration rate greater than 50 mL/min calculated by the Cockcroft and Gault method. International normalized ratio and activated partial thromboplastin time values must be within 20% of normal ranges. Participants must have up-to-date vaccination status according to local guidelines and must be capable of providing signed informed consent.

The estimated recruitment start date is October 31, 2025, and the estimated end date is December 31, 2028. The maximum duration of participant involvement is 80 weeks of treatment. Participants attend scheduled visits for platelet assessments every 2 weeks throughout the study period, with specific evaluation timepoints at Week 28 for assessment of bleeding scores and corticosteroid-sparing effects. The study protocol includes provisions for early termination based on specific conditions, including the need for emergency treatment or failure to maintain adequate platelet counts according to protocol-defined criteria.

The experimental treatment investigated in this clinical trial is **rilzabrutinib** (sponsor product code PRN1008), a chemical active substance administered in **tablet** form via the **oral route**. The maximum daily dose is **800 mg**, with a maximum total dose of **448,000 mg** administered over a maximum treatment period of **80 weeks**. Rilzabrutinib is manufactured by Principia Biopharma, Inc. and is being evaluated as the test medicinal product in this open-label, single-arm study. The treatment regimen involves oral administration according to the specified dosing schedule throughout the study duration. Participant **compliance monitoring** will be conducted to ensure adherence to the prescribed dosing regimen. The study aims to assess the efficacy and safety of rilzabrutinib in providing a sustained increase in **platelet count** in adults with **primary immune thrombocytopenia** who have failed first-line treatment.

Efficacy will be assessed through multiple parameters evaluating platelet count response and clinical outcomes in adults with **immune thrombocytopenia**. The primary endpoint is durable platelet response, defined as the proportion of participants who maintain a platelet count of at least 50,000/μL (or between 30,000/μL and 50,000/μL with at least a doubling from baseline) for at least half of the scheduled platelet assessments conducted every 2 weeks and for at least 4 valid visits during the final 12 weeks of the study, without requiring emergency treatment.

Secondary efficacy endpoints include overall platelet response, assessed as the proportion of participants achieving 2 platelet counts at least 5 days apart of at least 50,000/μL (or between 30,000/μL and 50,000/μL with at least a doubling from baseline) without emergency treatment in the 4 weeks preceding the first elevated platelet count. Duration of platelet response will be evaluated by determining the total number and proportion of weeks in which participants maintain platelet counts of at least 50,000/μL (or between 30,000/μL and 50,000/μL with at least a doubling from baseline) without emergency treatment in the 4 weeks before the elevated count among responders. Bleeding outcomes will be measured using the change in **immune thrombocytopenia bleeding scale** score from baseline to the end of Week 28. The corticosteroid-sparing effect will be determined by the proportion of participants who discontinue or reduce their corticosteroid dose by 50% or to less than 5 mg from baseline by the end of Week 28.