Ravulizumab in Thrombotic Microangiopathy Associated With a Trigger
Condition: Thrombotic Microangiopathy
MeSH terms: Vascular Diseases; Thrombotic Microangiopathies
Intervention: Ravulizumab; Placebo; Best Supportive Care
Intervention description: Body weight-based doses of ravulizumab will be administered intravenously as loading dose regimen followed by maintenance dosing every 8 weeks.; Matching placebo; Participants will receive medications, therapies, and interventions per standard hospital treatment protocols (unless specifically prohibited by the protocol).
Intervention MeSH terms: Ravulizumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Complement; Trigger; Secondary thrombotic microangiopathy; Acute kidney injury

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          1. 18 years of age or older

          2. Body weight ≥ 30 kilograms

          3. 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

          4. TMA associated with a trigger (autoimmune disease, infection, solid organ transplant,
             drugs, and malignant hypertension)

          5. 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:

          1. Any known gene mutation that causes atypical hemolytic uremic syndrome (aHUS)

          2. Postpartum aHUS

          3. Known chronic kidney disease

          4. TMA due to hematopoietic stem cell transplantation ≤ 12 months of Screening

          5. Primary and secondary glomerular diseases other than lupus

          6. Diagnosis of primary antiphospholipid antibody syndrome

          7. Shiga toxin-producing Escherichia coli infections including but not limited to Shiga
             toxin-related hemolytic uremic syndrome

          8. Known familial or acquired 'a disintegrin and metalloproteinase with a thrombospondin
             type 1 motif, member 13' (ADAMTS13) deficiency (activity < 5%)

          9. Positive direct Coombs test which in the judgement of the Investigator is indicative
             of a clinically significant immune-mediated hemolysis not due to TMA

         10. Clinical diagnosis of disseminated intravascular coagulation (DIC) in the judgement of
             the Investigator

         11. Presence of sepsis requiring vasopressors within 7 days prior to or during Screening

         12. Presence of monoclonal gammopathy including but not limited to multiple myeloma

         13. Known bone marrow insufficiency or failure evidenced by cytopenias

         14. Unresolved N. meningitidis infection

         15. 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

         16. Use of any complement inhibitors within the past 3 years

         17. Respiratory failure requiring mechanical ventilation