Randomized Controlled Trial Comparing Avatrombopag and Rituximab in Adult Patients with Immune Thrombocytopenia Unresponsive to Corticosteroids

The primary objective of this study is to compare the **efficacy** of the oral thrombopoietin receptor agonist (TPO-RA), Avatrombopag, with Rituximab in adult patients with **Immune Thrombocytopenia (ITP)** who have not achieved an adequate response to a short course of corticosteroids. This comparison is clinically relevant as it aims to identify a more effective second-line treatment option for ITP, potentially improving patient outcomes and management of the disease.

Secondary objectives include evaluating:

• Changes in disease-specific and generic health-related quality of life (HRQoL) during the study.
• Changes in the level of fatigue.
• Rates of Sustained Response Off-Treatment (SROT) at 78 weeks.
• Rates of and time to treatment failure.
• Cost-effectiveness during the first two study phases.
• Patient satisfaction during the first two study phases.
• Duration of response in patients randomized to Avatrombopag or Rituximab.
• Rate and duration of overall response.
• Consumption of corticosteroids and rescue therapy during the first phase of the study.
• Bleeding complications during the first two phases of the study.
• Safety of treatment with Avatrombopag or Rituximab during all study phases.

The clinical trial involves participants diagnosed with **Immune Thrombocytopenia (ITP)**, specifically targeting adult patients who have not achieved an adequate response to a short course of corticosteroids. The study population includes both male and female subjects aged 18 years and older. The trial does not involve a vulnerable population. Participants were selected based on their diagnosis of primary ITP of less than one-year duration, with a platelet count of less than 30 x10⁹/L measured within two weeks prior to inclusion. They must have experienced failure to achieve response or relapse after at least one cycle of dexamethasone or prednisone/prednisolone. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data. The trial aims to compare the efficacy of the oral TPO-RA, Avatrombopag, to Rituximab in this specific patient group.

The clinical trial is designed to evaluate the efficacy of two second-line therapeutic approaches for **Immune Thrombocytopenia (ITP)** in adult patients who have not achieved an adequate response to corticosteroids. This is a **randomized, controlled trial** comparing the oral thrombopoietin receptor agonist, Avatrombopag, with Rituximab, administered as a solution for infusion. The trial is structured to be double-blind to ensure unbiased results. The study is expected to commence on February 1, 2024, and conclude by December 31, 2027, with a total duration of approximately four years.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age (≥18 years), diagnosis of primary ITP of less than one-year duration, and a platelet count of <30 x10⁹/L. Following randomization, participants will receive either Avatrombopag or Rituximab for a maximum treatment period of 28 days. The primary endpoint is the occurrence of a durable platelet response, defined as achieving platelet counts >50 x10⁹/L in more than three of the bi-weekly measurements between weeks 20 and 28, without the use of additional platelet-elevating agents post-randomization, except for rescue therapy before the end of week 10.

Follow-up visits will be conducted bi-weekly to monitor platelet counts and assess the occurrence of treatment failure, adverse events, and changes in quality of life scores. Secondary endpoints include changes in ITP-PAQ and FACIT-Fatigue scores, occurrence of sustained response over time (SROT), and cost-effectiveness analysis. The end-of-study visit will occur at week 78, where final assessments will be made, including the cumulative number of weeks with platelet counts >50 x10⁹/L and the occurrence of adverse events.

Participant involvement is expected to last up to 78 weeks, with conditions for early termination including treatment failure, defined as switching to another platelet-elevating agent, thrombocytopenia, high risk of bleeding, or intolerance to the study drug. The trial aims to provide comprehensive data on the comparative effectiveness and safety of Avatrombopag and Rituximab in the management of ITP, contributing valuable insights into second-line treatment strategies for this condition.

The clinical trial involves the administration of **Rituximab**, an experimental medication used in the study. Rituximab is provided in the form of a **solution for infusion**. The active substance, rituximab, is a protein of non-human origin. The maximum daily dose of Rituximab is 1000 mg, with a total maximum dose of 2000 mg over the treatment period. The medication is administered via **infusion**. The treatment period for Rituximab is set at a maximum of 28 days. Participant compliance with the infusion schedule will be monitored throughout the study to ensure adherence to the dosing regimen.

Another experimental medication used in the trial is **Avatrombopag**, which is administered in the form of a **film-coated tablet**. Avatrombopag is a chemical compound, and the maximum daily dose is 40 mg, with a total maximum dose of 7840 mg over the treatment period. The route of administration for Avatrombopag is **oral use**. Similar to Rituximab, the treatment period for Avatrombopag is also set at a maximum of 28 days. Compliance with the oral dosing schedule will be monitored to ensure participants adhere to the prescribed regimen.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial aims to compare the efficacy of Avatrombopag to Rituximab in adult patients with immune thrombocytopenia who have not responded adequately to a short course of corticosteroids. The study will ensure rigorous monitoring of drug administration and participant compliance to maintain the integrity of the trial results.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the occurrence of a durable platelet response, defined as achieving platelet counts greater than 50 x10⁹/L in more than three of the bi-weekly measurements between weeks 20 and 28, including the last count, without the administration of any other platelet-elevating agents after randomization, except for rescue therapy received before the end of week 10.

Secondary endpoints include several measures: changes in the ITP-PAQ (Overall Quality of Life scale) score and the FACIT-Fatigue score from baseline to weeks 28 and 78; occurrence of SROT, defined as a platelet count greater than 50 x10⁹/L in at least three of the four planned visits between weeks 36 and 78, including week 78, without the administration of platelet-elevating agents; and occurrence of treatment failure, defined as switching to another platelet-elevating agent after randomization to avatrombopag or **rituximab**, or experiencing thrombocytopenia, high risk of bleeding, or intolerance of the study drug.

Additional secondary endpoints include the incremental treatment cost per incremental quality-adjusted life-years (QALY) at the end of the study, changes in summary scores of SF-36 (v2) questionnaires, changes in the Treatment Satisfaction Questionnaire for Medication scores, cumulative number of weeks with platelet count greater than 50 x10⁹/L, occurrence of overall response, cumulative doses of dexamethasone/prednisolone and IVIG, number of platelet transfusions, number and severity of WHO bleeding events, changes in Khellaf score, and occurrence and severity of treatment-emergent adverse events, including infections leading to hospitalization or death, arterial and venous thrombosis, and bone marrow fibrosis.