V-IMMUNE® for Immune Thrombocytopenia

TIP Study V-IMMUNE® for Immune Thrombocytopenia: A prospective multicenter study to evaluate the efficacy and safety of Human Immunoglobulin in adult and pediatric participants with immune thrombocytopenia.

Introduction Immune thrombocytopenia is an autoimmune disease characterized by thrombocytopenia (\<100,000/mm³) and an increased risk of bleeding.

Antibody- and/or T-cell-mediated platelet destruction plays a key role in the pathophysiology of immune thrombocytopenia. Newly diagnosed immune thrombocytopenia is characterized by a platelet count \<100,000/mm³ within three months of diagnosis. When remission is not achieved or the treatment response is not sustained within three to twelve months, it is considered persistent immune thrombocytopenia. When thrombocytopenia lasts for more than 12 months, it is considered chronic immune thrombocytopenia.

Bleeding in adults with immune thrombocytopenia can range from mild events, such as cutaneous petechiae, to potentially life-threatening events, such as organ bleeding and intracranial hemorrhage. The goal of treatment is to raise the platelet count to levels that can maintain hemostasis, preventing bleeding events or controlling any active bleeding. Hemorrhagic events are associated with worse outcomes and increased mortality in patients with chronic immune thrombocytopenia. Patients who required hospitalization due to bleeding had a 4.9-fold higher risk of mortality at 1 year and a 3.4-fold higher risk at 5 years compared to those who did not experience bleeding. Although most patients with immune thrombocytopenia present only with mild bleeding, the fear of more severe bleeding can negatively impact patients' quality of life. Therefore, experiencing a severe bleeding event is associated with a poor prognosis, increased risk of mortality, and may have substantial negative impacts on a patient's quality of life.

Treatment guidelines for immune thrombocytopenia in adults suggest maintaining platelet counts \>20,000-30,000/mm³ in symptomatic patients, as the risk of severe bleeding increases below this threshold. In Brazil, the treatment guideline for immune thrombocytopenia in adults from the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy (ABHH)/Guideline Project of the Brazilian Medical Association (AMB) recommends corticosteroids and intravenous immunoglobulin (IVIG) as first-line therapy for patients with platelet counts \<30,000/mm³ and active bleeding. The combination of these therapies may be indicated in emergency situations.

The International Consensus for the treatment of immune thrombocytopenia in pediatrics also recommends observation in newly diagnosed patients without bleeding. Any severe bleeding (grade 4) requires immediate hospitalization for treatment to raise platelet levels until the bleeding subsides. Any moderate bleeding (grade 3) requires consideration for hospitalization and therapy. In cases of moderate or severe bleeding, IVIG and anti-D immunoglobulin (not approved in Brazil for immune thrombocytopenia) may be indicated.

The pediatric immune thrombocytopenia treatment guideline from the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy (ABHH)/Guideline Project of the Brazilian Medical Association (AMB) recommends IVIG or corticosteroids as first-line therapy for newly diagnosed patients with platelet counts \<20,000/mm³ and active bleeding.

In emergency situations, regardless of the phase of the child's immune thrombocytopenia, combined therapy with platelet transfusions, intravenous corticosteroids, and IVIG is indicated. Splenectomy may be considered when there is no response to corticosteroids or IVIG and the patient continues to have significant central nervous system bleeding. Thrombopoietin receptor agonists may also be considered.

IVIG acts in immune thrombocytopenia by blocking the mechanism of peripheral platelet destruction, which involves opsonization mediated by Fc fragments of antibody-coated platelets. The effect of IVIG is rapid, increasing the platelet count within 24 hours of administration. Platelet levels typically continue to rise over the next 24 to 48 hours. The original dose was 0.4 g/kg/day for up to 5 days; however, similar results are achieved with a dose of 1 g/kg/day given in 1 or 2 doses. In elderly patients or those with compromised cardiac or renal function, the lower dose may help prevent acute volume overload.

The availability of new products that demonstrate efficacy and safety for the treatment of immune thrombocytopenia is necessary. Therefore, it becomes essential to conduct this study to appropriately request registration from ANVISA (Brazilian Drug Agency) for the polyvalent human immunoglobulin for intravenous use (V-IMMUNE® ) produced by the Virchow laboratory in India, for potential use in Brazil

OBJECTIVES Primary Objective To evaluate the efficacy of the human normal immunoglobulin preparation V-IMMUNE® in improving platelet counts in patients with immune thrombocytopenia by or before Day 9 after the first infusion.

Secondary Objectives

* To determine the safety and tolerability of V-IMMUNE® at the dose used in this study; * To determine the proportion of individuals with immune thrombocytopenia who achieve a complete or partial therapeutic response by or before Day 9 after the first dose of V-IMMUNE®; * To determine whether V-IMMUNE® maintains platelet counts ≥ 50,000/mm³ in individuals with immune thrombocytopenia for a period similar to that of a historical control after the first treatment cycle; * To compare the occurrence of bleeding in individuals with immune thrombocytopenia after the use of V-IMMUNE® with the results of historical controls.

METHODS Design A prospective, Phase III, open-label, non-randomized, multicenter, single-group study with a historical control, for intravenous administration of V-IMMUNE®.

Recruitment Plan Each participating center must identify and consecutively enroll potentially eligible patients. In case of doubt regarding the eligibility criteria, the center must immediately contact the sponsor's representative before enrolling the patient in the study.

Recruitment will occur through approximately 8 to 15 nationally recognized hematology centers specialized in the treatment of immune thrombocytopenia with intravenous immunoglobulin infusion.

Screening During the screening of potential participants, a standardized form will be used to confirm eligibility criteria. The investigator responsible for presenting the study must explain the protocol in detail to the patient and/or legal guardian/representative who, upon agreeing to participate and signing the Informed Consent Form (ICF), will be registered in the data collection system. Every screened participant who does not meet the inclusion criteria (screening failure) must be recorded along with the reason for non-inclusion.

Approach Patients who meet the inclusion criteria will be approached at the participating centers for enrollment in the TIP study. Once the Informed Consent Form (ICF) is signed, the participant will begin receiving V-Immune® On-Pharma according to the protocol.

Randomization Method and Maintenance of Allocation Concealment As this is a single-group study, there will be no randomization. Blinding As this is a single-group study in which eligible patients have a clinical/therapeutic indication for the use of immunoglobulin, blinding is not necessary.

Experimental Intervention The Investigational Product (IP) is V-IMMUNE®, normal human immunoglobulin I.P. 5% (5g/100 mL), manufactured from qualified human plasma for intravenous use. Each vial contains Human Immunoglobulin 50 g/L, Maltose 100 g/L, and Water for Injection. The 5% Human Immunoglobulin solution for intravenous administration I.P. is a sterile, pyrogen-free preparation of normal human immunoglobulin in a single-dose form for intravenous infusion. Each 10 mL, 50 mL, and 100 mL contains 0.5 g, 2.5 g, and 5 g of normal human immunoglobulin, respectively, and is prepared from qualified human plasma using membrane filtration, combined chromatographic steps, and viral inactivation procedures. The IgA content does not exceed 2 mg/mL. The IgG subclass distribution is similar to that found in normal human serum.

The manufacturing process uses plasma collected from donors who are screened based on medical history, in accordance with regulatory authority guidelines. The blood is tested for mandatory infectious diseases. Only plasma that tests negative for HBsAg, HCV, and HIV antibodies is used in the process.

Storage and Use Conditions of the IMP V-IMMUNE® immunoglobulin must be stored in a secure, access-restricted area, preferably in a refrigerator, protected from light, and maintained at a temperature of 2°C to 8°C. V-IMMUNE® immunoglobulin must not be frozen.

Administration Before use, all vials must be visually inspected for discoloration, particles, or fibers; if the contents of a vial are cloudy or contain particulate matter, it must not be used. V-IMMUNE® must not be shaken, frozen, or used if the solution has been frozen. The IMP should be at room temperature when infused.

Normal human immunoglobulin I.P 5% (5g/100 ml) V-IMMUNE® will be administered at a dose of 1 g/kg, intravenously, once daily for two consecutive days (Day 1 and Day 2). The infusion rate should start at 0.01 ml/kg/min for the first 30 minutes, increasing gradually to 0.06 ml/kg/min if no adverse events occur. This will constitute the first treatment cycle with V-IMMUNE®. The 1 g/kg/day dose for two consecutive days is consistent with recommendations for other IVIG products used in Immune Thrombocytopenia.

If the platelet count is not maintained for the desired duration after the first cycle of V-IMMUNE®, and at the discretion of the investigator and the participant/legal guardian, participants may receive one additional cycle of V-IMMUNE®, using the same dosing schedule as Cycle 1, between Day 15 and Day 30.

All infusions will be administered by trained personnel under the direct supervision of the principal investigator or a designated delegate.

V-IMMUNE® will be administered intravenously (via peripheral or central vein) through a dedicated infusion line. Mixing or administering any other product (including saline) with V-IMMUNE® is strictly prohibited.

If an adverse event (AE) occurs, the infusion should be interrupted for 20 to 30 minutes. The patient should be hydrated and given antihistamines, analgesics, and antiemetics. Once symptoms improve, the infusion may be resumed at a reduced rate, starting again at the initial infusion speed. Intolerance at any infusion rate must be recorded as an adverse event (AE) at that specific rate. If a participant experiences the same AE at the same rate twice and both events are recorded, further increases in infusion rate should not exceed the last tolerated speed. The patient will be observed for 60 minutes after the infusion ends for clinical evaluation and monitoring for potential adverse events.

In cases of clinically significant hypotension and/or anaphylactic reactions, in addition to stopping the infusion and administering appropriate supportive care as deemed necessary by the investigator (which may include epinephrine, antihistamines, corticosteroids, supplemental oxygen, volume expansion, etc.), these events must be documented in the source file and Case Report Form (CRF) as AEs. The participant may, at the investigator's discretion, be withdrawn from the study. In such cases, the participant may still choose to complete the follow-up visits.

For individuals at increased risk of thromboembolism (e.g., advanced age, obesity, hypertension, diabetes mellitus, history of thromboembolic events, known acquired or congenital thrombophilic disorders, prolonged immobilization, severe hypovolemia, hyperviscosity), the infusion rate should be kept as low as possible.

Pre-medication Prior to IMP Infusion In adult in

• Therapeutic response defined as the increase in platelets count [Срок оценки: 9 days]
• Bleeding occurrence classified according to CTCAE version 5.0 [Срок оценки: 30 days]
• Number of days with platelets count ≥ 50,000/mm3 [Срок оценки: 90 days]
• Proportion of infusions during which one or more adverse events (AEs) occurred [Срок оценки: 72 hours]
• Total number of adverse events infusion related during the whole study [Срок оценки: 30 days]
• Mean number of temporally associated adverse events (AEs) per infusion [Срок оценки: 30 days]
• Proportion of patients who experienced one or more adverse events (AEs) [Срок оценки: 90 days]