Ravulizumab in Thrombotic Microangiopathy After Hematopoietic Stem Cell Transplant

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of ravulizumab in adult and adolescent participants with hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA). In Stage 1, an open-label, single-arm period, the dosing regimen will be confirmed. In Stage 2, participants will be randomized to receive either blinded ravulizumab plus best supportive care or matching placebo plus best supportive care. The treatment period is 26 weeks (open-label for Stage 1, and randomized, double-blind, and placebo-controlled for Stage 2) followed by a 26-week follow-up period.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Ravulizumab in Adult and Adolescent Participants Who Have Thrombotic Microangiopathy (TMA) After Hematopoietic Stem Cell Transplant (HSCT)

Conditions
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Thrombotic Microangiopathy

Intervention / Treatment
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* Biological: Ravulizumab
* Other: Placebo
* Other: Best supportive care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 12 years of age or older at time of consent/assent. Received HSCT within the past 12 months Diagnosis of TMA that persists for at least 72 hours despite initial management A TMA diagnosis based on meeting the select criteria during the Screening Period and/or <=14 days prior to the Screening Period. Body weight ≥ 30 kilograms at Screening or ≤7 days prior to the start of the Screening Period (date of consent). Female participants of childbearing potential and male participants with female partners of childbearing potential must use highly effective contraception. Participants must be vaccinated against meningococcal infections if clinically feasible. Participants who cannot receive meningococcal vaccine should receive antibiotic prophylaxis. Participants or their legally authorized representative must be capable of giving signed informed consent or assent Exclusion Criteria: Thrombotic thrombocytopenic purpura (TTP) evidenced by ADAMTS13 deficiency Shiga toxin producing Escherichia coli infection Positive direct Coombs test. Clinical diagnosis of disseminated intravascular coagulation (DIC). Known bone marrow/graft failure. Diagnosis of veno-occlusive disease. Human immunodeficiency virus (HIV) infection. Unresolved meningococcal disease. Presence of sepsis requiring vasopressor support. Pregnancy or breastfeeding. Previously or currently treated with a complement inhibitor. Respiratory failure requiring mechanical ventilation. Acute and/or chronic heart failure. Participation in an interventional treatment study of any therapy for TMA.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ravulizumab<br>In Stage 1, all participants will receive open-label ravulizumab plus Best Supportive Care (BSC). In Stage 2, participants will receive blinded ravulizumab plus Best Supportive Care (BSC). | Biological: Ravulizumab<br>* Weight-based doses of ravulizumab will be administered intravenously as loading dose regimen followed by maintenance dosing every 8 weeks.<br>* Other names: Ultomiris, ALXN1210;Other: Best supportive care<br>* Participants will receive medications, therapies, and interventions per standard hospital treatment protocols (unless specifically prohibited by the protocol).<br>|
| Placebo Comparator: Placebo<br>In Stage 2, participants randomized to the placebo arm will receive matching placebo plus BSC. | Other: Placebo<br>* Matching placebo<br>Other: Best supportive care<br>* Participants will receive medications, therapies, and interventions per standard hospital treatment protocols (unless specifically prohibited by the protocol).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| TMA Response |  | 26 weeks (treatment period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time To TMA Response |  | 26 weeks (treatment period) | 
| Change from Baseline in eGFR |  | 26 weeks (treatment period) | 
| Overall Survival |  | 26 weeks (treatment period) | 
| Non-relapse Mortality |  | 26 weeks (treatment period) | 
| Hematologic Response | Hematologic Response as assessed by blood tests to measure lactate dehydrogenase (LDH) and platelet count. (1) If baseline platelet count ≤ 50000/mm3, the following criteria must be met: - Absolute platelet count > 50,000/mm3 without platelet transfusion support during the prior 7 days [or] If baseline platelet count > 50,000/mm3, the following criteria must be met: - ≥ 50% increase in platelet count compared to baseline value without platelet transfusion support during the prior 7 days 2) Normalization of LDH and absence of schistocytes | 26 weeks (treatment period) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thrombotic Microangiopathy (TMA) Ultomiris, Ravulizumab, Hematopoietic Stem Cell Transplant (HSCT) Transplant-associated TMA, HSCT-TMA