Thrombotic Microangiopathy
Conditions
Keywords
Thrombotic Microangiopathy (TMA) Ultomiris, Ravulizumab, Hematopoietic Stem Cell Transplant (HSCT) Transplant-associated TMA, HSCT-TMA
Brief summary
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.
Interventions
BIOLOGICALRavulizumab
Weight-based doses of ravulizumab will be administered intravenously as loading dose regimen followed by maintenance dosing every 8 weeks.
OTHERPlacebo
Matching placebo
OTHERBest supportive care
Participants will receive medications, therapies, and interventions per standard hospital treatment protocols (unless specifically prohibited by the protocol).
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
1. 12 years of age or older at time of consent/assent. 2. Received HSCT within the past 12 months. 3. Diagnosis of TMA that persists for at least 72 hours after initial management of any triggering agent/condition. 4. A TMA diagnosis based on meeting the laboratory-based criteria during the Screening Period and/or ≤14 days prior to the Screening Period. 5. Body weight ≥ 30 kilograms at Screening or ≤7 days prior to the start of the Screening Period (date of consent). 6. Female participants of childbearing potential and male participants with female partners of childbearing potential must use highly effective contraception. 7. Participants must be vaccinated against meningococcal infections if clinically feasible. Participants who cannot receive meningococcal vaccine should receive antibiotic prophylaxis. Participants \<18 years of age must be re-vaccinated against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae if clinically feasible. 8. Participants or their legally authorized representative must be capable of giving signed informed consent or assent.
Exclusion criteria
1. Thrombotic thrombocytopenic purpura (TTP) evidenced by ADAMTS13 deficiency 2. Known Shiga toxin-related hemolytic uremic syndrome as demonstrated by positive test. 3. Positive direct Coombs test indicative of a clinically significant immune-mediated hemolysis not due to TMA. 4. Clinical diagnosis of disseminated intravascular coagulation (DIC). 5. Known bone marrow/graft failure for the current HSCT. 6. Diagnosis of veno-occlusive disease which is unresolved at the time of Screening. 7. Human immunodeficiency virus (HIV) infection. 8. Unresolved meningococcal disease. 9. Presence of sepsis requiring vasopressor support. 10. Pregnancy or breastfeeding. 11. Hypersensitivity to murine proteins or to one of the excipients of ravulizumab. 12. Any ongoing or history of medical or psychological conditions unrelated to HSCT-TMA that could increase the risk to the participant or confound the outcome of the study. 13. Respiratory failure requiring mechanical ventilation. 14. Acute and/or chronic heart failure with an ejection fraction ≤ 40%. 15. Previously or currently treated with a complement inhibitor. 16. Participation in an interventional treatment study of any therapy for TMA.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event Free Survival | 26 weeks (treatment period) | Event free survival during the 26 weeks treatment period defined as the time from randomization until the first of the two following events: death and clinical worsening. |
Secondary
| Measure | Time frame |
|---|---|
| Time To TMA Response | 26 weeks (treatment period) |
| Change from Baseline in eGFR | 26 weeks (treatment period) and 52 weeks |
| Overall Survival | Day 100, 26 weeks (treatment period), and 52 weeks |
| Non-relapse Mortality | Day 100, 26 weeks (treatment period), and 52 weeks |
| Hematologic Response | 26 weeks (treatment period) |
| TMA response and time to response for each individual component of TMA | 26 weeks (treatment period) |
| Time to Hematologic Response | 26 weeks (treatment period) |
| Hemoglobin Response | 26 weeks (treatment period) |
| Partial Response | 26 weeks (treatment period) |
| Loss of TMA Response | 26 weeks (treatment period) |
| Duration of TMA Response | 26 weeks (treatment period) and 52 weeks |
| Changes from Baseline in Haptoglobin, Platelets, LDH, and Hemoglobin | 26 weeks (treatment period) and 52 weeks |
| Modified TMA Response | 26 weeks (treatment period) |
| Change from baseline in TMA-associated organ dysfunction in renal system, cardiovascular system, pulmonary system, CNS, and GI system | 26 weeks (treatment period) and 52 weeks |
| TMA Relapse | Follow-up Period |
| Platelet Response | 26 weeks (treatment period) |
Countries
Australia, Belgium, Brazil, Canada, China, France, Germany, Greece, Israel, Italy, Japan, Netherlands, South Korea, Spain, Sweden, United Kingdom, United States
Outcome results
None listed