Ravulizumab in Thrombotic Microangiopathy Associated With a Trigger

Study Overview
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Brief Summary
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This study will investigate the efficacy and safety of ravulizumab compared to placebo in adult participants with thrombotic microangiopathy (TMA) associated with a trigger. Participants will be randomized to receive either ravulizumab plus best supportive care or placebo plus best supportive care. The treatment period is 26 weeks followed by a 26-week off-treatment follow-up period.

Official Title
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A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Ravulizumab in Adult Participants Who Have Thrombotic Microangiopathy Associated With a Trigger

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: 18 years of age or older Body weight ≥ 30 kilograms Female participants of childbearing potential and male participants with female partners of childbearing potential must use highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ravulizumab TMA associated with a trigger (autoimmune disease, infection, solid organ transplant, drugs, and malignant hypertension) Vaccinated against meningococcal infection (Neisseria meningitidis), within 3 years prior to, or at the time of, randomization. Participants who initiate study drug treatment less than 2 weeks after receiving a meningococcal vaccine must receive appropriate prophylactic antibiotics for at least 2 weeks after the vaccination. If participant cannot receive the meningococcal vaccine, then participant must be willing to receive antibiotic prophylaxis coverage against N. meningitidis during the entire Treatment Period and for 8 months following the final dose of study drug. Additional vaccination (Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae) may be considered based on individual patient condition. Exclusion Criteria: Any known gene mutation that causes atypical hemolytic uremic syndrome (aHUS) Postpartum aHUS Known chronic kidney disease TMA due to hematopoietic stem cell transplantation ≤ 12 months of Screening Primary and secondary glomerular diseases other than lupus Diagnosis of primary antiphospholipid antibody syndrome Shiga toxin-producing Escherichia coli infections including but not limited to Shiga toxin-related hemolytic uremic syndrome Known familial or acquired 'a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13' (ADAMTS13) deficiency (activity < 5%) Positive direct Coombs test which in the judgement of the Investigator is indicative of a clinically significant immune-mediated hemolysis not due to TMA Clinical diagnosis of disseminated intravascular coagulation (DIC) in the judgement of the Investigator Presence of sepsis requiring vasopressors within 7 days prior to or during Screening Presence of monoclonal gammopathy including but not limited to multiple myeloma Known bone marrow insufficiency or failure evidenced by cytopenias Unresolved N. meningitidis infection History of malignancy within 5 years of Screening with the exception of nonmelanoma skin cancer or carcinoma in situ of the cervix that has been treated with no evidence of recurrence Use of any complement inhibitors within the past 3 years Respiratory failure requiring mechanical ventilation

Ages Eligible for Study
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Minimum Age: 18 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> | Biological: Ravulizumab<br>* Body weight-based doses of ravulizumab will be administered intravenously as loading dose regimen followed by maintenance dosing every 8 weeks.<br>* Other names: 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> | 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 |
| --- | --- | --- |
| Number of Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26 | TMA response required the following: 1) Normalization of platelet count without transfusion support during the prior 7 days. 2) Normalization of LDH. 3) Improvement in glomerular filtration rate (eGFR) of >= 30% compared to baseline. Participants must meet each TMA criterion at 2 separate assessments obtained at least 24 hours apart, and any measurement in between. | Week 26 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Complete TMA Response | The Kaplan-Meier estimate of time to event of complete TMA response is reported. TMA response required the following: 1) Normalization of platelet count without transfusion support during the prior 7 days. 2) Normalization of LDH. 3) Improvement in eGFR of >= 30% compared to baseline. Participants must meet each TMA criterion at 2 separate assessments obtained at least 24 hours apart, and any measurement in between. Participants who did not have a response were censored at the date of last visit or study discontinuation at the time when the analysis was performed. | Baseline through Week 26 | 
| Number of Participants With Hematologic Response at Week 26 | Hematologic response required the following: (1) Normalization of platelet count without transfusion support during the prior 7 days, and (2) normalization of LDH. | Week 26 | 
| Number of Participants With Renal Response at Week 26 | Renal response is improvement in eGFR of >= 30% compared to baseline. If a participant is on dialysis ≤5 days prior to the date of eGFR assessment, the eGFR will be set to 10 milliliter/minute/1.73 meter square (mL/min/1.73 m^2) for that assessment. If a participant is on dialysis during the entire 26 week randomized Treatment Period, or through early discontinuation of study drug, then the change in eGFR was not calculated. | Week 26 | 
| Number of Participants On Dialysis at Week 26 |  | Week 26 | 
| Change From Baseline in eGFR at Week 26 | If a participant is on dialysis during the entire 26 week randomized Treatment Period, or through early discontinuation of study drug, then the change in eGFR was not calculated. | Baseline, Week 26 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Complement, Trigger, Secondary thrombotic microangiopathy, Acute kidney injury