Evaluation of Caplacizumab and Immunosuppressive Therapy Without Initial Plasma Exchange in Adult Immune-Mediated Thrombotic Thrombocytopenic Purpura

The primary objective of this study is to evaluate the **efficacy** of caplacizumab in combination with immunosuppressive therapy (IST) without therapeutic plasma exchange (TPE) in adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP). This is clinically relevant as it aims to assess the potential of caplacizumab to effectively manage iTTP without the need for TPE, which is a standard but resource-intensive treatment.

Secondary objectives include:

• Evaluating the need for therapeutic plasma exchange in adult participants with an episode of iTTP treated with caplacizumab and IST.
• Assessing the safety of caplacizumab in combination with IST without first-line TPE in adults with iTTP.
• Determining the effect of treatment with caplacizumab and IST without first-line TPE on clinical response.
• Evaluating the effect on restoring platelet counts.
• Assessing the effect on refractory disease.
• Evaluating the effect on clinically relevant iTTP-related events, including iTTP-related mortality, exacerbation, and relapse.

The clinical trial involves a total of **29 participants** diagnosed with **Thrombotic Thrombocytopenic Purpura** (TTP), specifically focusing on the immune-mediated variant (iTTP). The study population includes both male and female adults, with an age range that encompasses individuals from young adulthood to middle age. Participants were selected based on a confirmed clinical diagnosis of iTTP, characterized by thrombocytopenia, microangiopathic hemolytic anemia, and relatively preserved renal function. The trial does not specify particular lifestyle considerations such as diet or physical activity. The study includes a vulnerable population, indicating that special ethical considerations are in place. The selection criteria ensure that female participants are either not pregnant or breastfeeding, or agree to use contraception, while male participants with partners of childbearing potential must adhere to contraceptive guidance. The trial aims to evaluate the efficacy of caplacizumab in combination with immunosuppressive therapy without the use of therapeutic plasma exchange.

The clinical trial is designed to evaluate the efficacy and safety of **caplacizumab** in combination with immunosuppressive therapy without the use of first-line therapeutic plasma exchange in adults diagnosed with immune-mediated thrombotic thrombocytopenic purpura (iTTP). This study is structured as an open-label, single-arm, multicenter trial. The trial is expected to span approximately two years, with an estimated recruitment start date of November 21, 2022, and an anticipated end date of December 13, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as a clinical diagnosis of iTTP and a French TMA score of 1 or 2. The diagnosis must be confirmed by ADAMTS13 testing within 48 hours. Following the screening, participants will receive the investigational product, **Cablivi 10 mg powder and solvent for solution for injection**, administered either intravenously or subcutaneously. The maximum daily dose is 10 mg, with a total maximum dose of 1690 mg over a treatment period of up to 24 weeks.

Throughout the trial, participants will attend follow-up visits to monitor their response to treatment and assess any adverse events. The primary endpoint is the proportion of participants achieving remission without requiring therapeutic plasma exchange. Secondary endpoints include the proportion of participants achieving remission, the occurrence of adverse events, and the time to platelet count response, among others. The study will conclude with an end-of-study visit to evaluate the overall outcomes and safety of the treatment regimen.

Participant involvement is expected to last up to 168 days, with conditions for early termination including the occurrence of serious adverse events or failure to adhere to the study protocol. The trial aims to provide valuable insights into the treatment of iTTP, potentially offering an alternative therapeutic approach without the need for plasma exchange.

The clinical trial involves the administration of **Cablivi**, a medication containing the active substance **caplacizumab**. Cablivi is provided as a **powder and solvent for solution for injection**, intended for intravenous (IV) or subcutaneous (SC) administration. The pharmaceutical form is a solution for injection, and the medication is manufactured by Ablynx NV. The maximum daily dose of Cablivi is 10 mg, with a total maximum dose of 1690 mg over a treatment period of up to 24 weeks. The active substance, caplacizumab, is a protein of other origin, specifically a nanobody directed towards the human A1 domain of von Willebrand factor. This medication is designated as an orphan drug, with the marketing authorization number EU/1/18/1305/001, 002, and 003, and is authorized for use in the European Union.

In this study, Cablivi is used in combination with **immunosuppressive therapy (IST)**, without the use of first-line therapeutic plasma exchange (TPE), to evaluate its efficacy and safety in adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP). The trial is open-label and single-arm, conducted across multiple centers. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the treatment regimen. The study does not include a placebo or comparator treatment, focusing solely on the effects of Cablivi in conjunction with IST.

The efficacy of the investigational product, **caplacizumab**, in combination with immunosuppressive therapy, will be assessed in a clinical trial involving adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP). The primary endpoint for evaluating efficacy is the proportion of participants achieving remission without requiring therapeutic plasma exchange (TPE). Secondary endpoints include the proportion of participants achieving remission, the requirement for TPE, the occurrence of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs). Additional secondary endpoints involve the proportion of participants achieving clinical response during the on-treatment period (day 1 to day 84) and the overall study period (day 1 to day 168), time to platelet count response, and the proportion of participants refractory to therapy.

Further secondary endpoints include the proportion of participants with TTP-related death and clinical exacerbation or relapse of iTTP, both during the on-treatment period and the overall study period. The efficacy parameters will be measured and collected at specified timepoints throughout the study, with the on-treatment period extending from day 1 to day 84 and the overall study period from day 1 to day 168. The analysis of these parameters will provide insights into the efficacy of caplacizumab in the specified patient population.