Phase 3 Multicenter Study of Ravulizumab Plus Best Supportive Care in Pediatric Patients with HSCT-Associated Thrombotic Microangiopathy
- Trial ID
- 2023-507850-33-00
- Protocol
- ALXN1210-TMA-314
- Sponsor
- Alexion Pharmaceuticals Inc.
Trial statistics
Objectives
The primary objective of this Phase 3, open-label, single-arm, multicenter study is to assess the **efficacy** of ravulizumab in combination with best supportive care (BSC) for the treatment of pediatric participants with hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA). This objective is clinically relevant as HSCT-TMA is a serious complication following hematopoietic stem cell transplantation, and effective treatment options are limited. Evaluating the efficacy of ravulizumab could provide significant insights into improving outcomes for affected pediatric patients.
Secondary objectives include evaluating the **safety** and tolerability of ALXN1210 (ravulizumab) and additional efficacy measures. These objectives are crucial for understanding the overall benefit-risk profile of the treatment in this vulnerable population.
Participants
The clinical trial involves a total of **33 participants** diagnosed with **hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA)**. The study population comprises pediatric subjects ranging from 28 days to less than 18 years of age, including both male and female participants. All participants have undergone a hematopoietic stem cell transplant within the past 12 months and meet specific diagnostic criteria for thrombotic microangiopathy. The trial population was selected based on their persistence of HSCT-TMA for at least 72 hours after initial management of any triggering agent or condition. Participants are required to have a body weight of at least 5 kg at the time of screening. Lifestyle considerations include adherence to local regulations regarding contraceptive use and vaccination against meningococcal infections, with additional prophylactic measures as per institutional guidelines. The trial includes a vulnerable population, necessitating informed consent from participants or their legally authorized representatives.
Plans and Procedures
The clinical trial is a **Phase 3**, open-label, single-arm, multicenter study designed to evaluate the efficacy of **ravulizumab** in addition to best supportive care in pediatric participants with **hematopoietic stem cell transplant-associated thrombotic microangiopathy (HSCT-TMA)**. The trial aims to assess the primary endpoint of TMA response, with secondary endpoints including time to TMA response, changes in TMA-associated organ dysfunction, TMA relapse, overall survival, non-relapse mortality, platelet response, and hematologic response. The study is expected to conclude by May 30, 2025, with recruitment having commenced on December 14, 2020.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, recent HSCT, and TMA diagnosis. The trial will include follow-up visits to monitor treatment response and safety, with the end-of-study visit marking the conclusion of participant involvement. The expected duration of participant involvement is up to 26 weeks, corresponding to the maximum treatment period with **ravulizumab**. Conditions that may lead to early termination from the study include non-compliance with the protocol, adverse events, or withdrawal of consent.
Participants will receive **ravulizumab** via intravenous infusion, with dosing tailored to individual needs and monitored throughout the study. The trial's design, being open-label and single-arm, does not include a control group, and all participants will receive the investigational treatment. The study's methodology ensures rigorous monitoring of safety and efficacy, with data collected at each visit to evaluate the impact of the treatment on HSCT-TMA. The trial's findings will contribute to understanding the therapeutic potential of **ravulizumab** in this patient population.
Treatment
The clinical trial involves the administration of **Ultomiris**, a pharmaceutical product containing the active substance **ravulizumab**. Ultomiris is formulated as a **concentrate for solution for infusion** and is intended for **intravenous use**. Each vial contains 300 mg of ravulizumab in 30 mL of solution. The maximum daily dose is 3600 mg, with a total maximum dose of 26400 mg over the course of the treatment period, which can extend up to 26 weeks. The administration schedule is designed to ensure optimal therapeutic levels of the drug, and compliance will be monitored throughout the study.
In addition to the experimental treatment with ravulizumab, participants will receive **best supportive care (BSC)** as part of the study protocol. BSC is a non-experimental treatment that includes standard-of-care therapies tailored to the individual needs of pediatric participants with thrombotic microangiopathy (TMA) following hematopoietic stem cell transplantation (HSCT). The combination of ravulizumab and BSC aims to assess the efficacy of this treatment regimen in the specified patient population.
Efficacy
The efficacy of **ravulizumab** in the treatment of pediatric participants with Thrombotic Microangiopathy (TMA) following Hematopoietic Stem Cell Transplantation (HSCT) will be assessed through a series of predefined endpoints. The primary endpoint is the TMA response, which will be evaluated to determine the effectiveness of the treatment. Secondary endpoints include the time to TMA response, changes from baseline in TMA-associated organ dysfunction across various systems such as renal, cardiovascular, pulmonary, central nervous system (CNS), and gastrointestinal (GI) systems at 6 months and 1 year. Additionally, TMA relapse during the follow-up period, overall survival, non-relapse mortality, platelet response, and hematologic response will be measured.
The collection and analysis of these efficacy parameters will be conducted at specific timepoints, including 6 months and 1 year, to monitor changes and outcomes over time. The study is designed as a Phase 3, open-label, single-arm, multicenter trial, ensuring a comprehensive evaluation of the treatment's impact on the specified endpoints. The trial aims to provide robust data on the efficacy of ravulizumab in conjunction with best supportive care for this patient population.
Inclusion and Exclusion Criteria
Inclusion Criteria
- ≥ 28 days of age up to < 18 years of age at the time of signing the informed consent
- Participants who received HSCT within the past 12 months at the time of Screening
- A TMA diagnosis, based on meeting all of the following criteria during the Screening Period and/or ≤ 14 days prior to the Screening Period : • De novo thrombocytopenia or platelet transfusion refractoriness • Any one of the following markers of hemolysis: −Lactate dehydrogenase > ULN for age, − Presence of schistocytes ≥ 2 high power field (HPF) or ≥ 1% in peripheral blood smear • Proteinuria on spot urinalysis • De novo anemia OR Presence of hypertension
- Participants must have HSCT-TMA that persists for at least 72 hours after initial management of any triggering agent/condition
- Body weight ≥ 5 kg at Screening or ≤7 days prior to the start of the Screening Period (date of consent)
- Male or female contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
- Vaccinated against meningococcal infections if clinically feasible, according to national guidelines and recommendationsfor immune reconstitution after HSCT. Participants must be re-vaccinated against Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae if clinically feasible, according to institutional guidelines for immune reconstitution after HSCT. All participants should be administered coverage with prophylactic antibiotics according to institutional posttransplant infection prophylaxis guidances including coverage against N. meningitidis for at least 2 weeks after meningococcal vaccination. Participants who cannot receive meningococcal vaccine should receive antibiotic prophylaxis guidance including coverage against N. meningitidis the entire Treatment Period and for 8 months following the final dose of ravulizumab.
- Participants or their legally authorized representative must be capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent or assent form and in this protocol
Exclusion Criteria
- Known familial or acquired 'a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13' (ADAMTS13) deficiency (activity < 5%)
- Known Shiga toxin-related hemolytic uremic syndrome (ST-HUS)
- Positive direct Coombs test
- Clinical diagnosis or suspicion of disseminated intravascular coagulation (DIC)
- Known bone marrow/graft failure for the current HSCT
- Diagnosis of veno-occlusive disease (VOD)
- Human immunodeficiency virus (HIV) infection evidenced by HIV-1 or HIV-2 antibody titer
- Unresolved meningococcal disease
- Presence of sepsis requiring vasopressor support within 7 days prior to enrollment
- Pregnancy or breastfeeding
- Hypersensitivity to murine proteins or to 1 of the excipients of ravulizumab
- Previously or currently treated with a complement inhibitor
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 14 Dec 2020 | 3 |
 Germany | Not Recruiting | 14 Dec 2020 | 5 |
 Italy | Not Recruiting | 14 Dec 2020 | 3 |
 Spain | Not Recruiting | 14 Dec 2020 | 3 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Ultomiris 300 mg/30 mL concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 3600 | 26 | PRD7445250 |