Study of Ravulizumab in Pediatric Participants With HSCT-TMA

Alexion Pharmaceuticals, Inc.41 enrolled

Overview

This study will evaluate the safety, efficacy, pharmacokinetics, and pharmacodynamics of ravulizumab administered by intravenous infusion to pediatric participants, from 1 month to \< 18 years of age, with HSCT-TMA. The treatment period is 26 weeks, followed by a 26-week off-treatment follow-up period.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Thrombotic Microangiopathy

Interventions

RavulizumabDRUG

Weight-based doses of ravulizumab will be administered intravenously as a loading dose regimen followed by maintenance dosing every 4 or 8 weeks, depending upon weight.

Best Supportive CareOTHER

Participants will receive medications, therapies, and interventions per standard hospital treatment protocols (unless specifically prohibited by the protocol).

Eligibility

Sex: ALLMax age: 17 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. ≥ 28 days of age up to \< 18 years of age at the time of signing the informed consent. 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 ≥ 5 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 (VOD) 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 1 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. Previously or currently treated with a complement inhibitor. 15. Participation in an interventional treatment study of any therapy for TMA.

Locations (26)

Research Site

Tucson, Arizona, United States

Research Site

Outcomes

Primary Outcomes

Participants With Thrombotic Microangiopathy (TMA) Response

The criteria for TMA response were: 1. Normalization of platelet count (defined as platelet count ≥ 50000 mm\^3 or \>=50% increase in platelet count) without transfusion support during the prior 7 days. 2. Normalization of lactate dehydrogenase (LDH, defined as LDH ≤ upper limit of normal \[ULN\]) and absence of schistocytes. 3. At least 50% reduction in protein/creatinine ratio from baseline. Participants must meet each TMA criterion at 2 separate assessments obtained at least 24 hours apart, with no criteria failures or more than 1 missed scheduled visit in between. Additionally, all intervals in which the criteria were met must overlap for at least 1 day.

Time frame: Up to Week 26

Secondary Outcomes

Time to TMA Response During the 26-Week Treatment Period

Time to TMA response was defined as the time from first infusion to the first time point at which all criteria for TMA response was met. Participants were assigned as responders at the time of their TMA response and were censored at the earlier of last assessment with all 3 TMA response components available (including measurements collected after treatment discontinuation), or death if they did not respond by then. TMA response required the following: 1. Normalization of platelet count (defined as platelet count ≥ 50000 mm\^3 or \>=50% increase in platelet count) without transfusion support during the prior 7 days. 2. Normalization of LDH (defined as LDH ≤ULN) and absence of schistocytes. 3. At least 50% reduction in protein/creatinine ratio from baseline.

Time frame: Day 1 through Week 26

Participants With Hematologic Response

Hematologic response required the following: (1) Normalization of platelet count (defined as platelet count ≥ 50000 mm\^3 or \>=50% increase in platelet count) without transfusion support during the prior 7 days and (2) Normalization of LDH (defined as LDH ≤ULN) and absence of schistocytes.

Time frame: Up to Week 26

Time to Hematologic Response During the 26-Week Treatment Period

Data from ClinicalTrials.gov

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Aurora, Colorado, United States

Research Site

Atlanta, Georgia, United States

Research Site

Chicago, Illinois, United States

Research Site

Portland, Oregon, United States

Research Site

Dallas, Texas, United States

Research Site

Salt Lake City, Utah, United States

Research Site

Madison, Wisconsin, United States

Research Site

Haifa, Israel

Research Site

Jerusalem, Israel

...and 16 more locations

Time to Hematologic response was defined as the time from first infusion to the first time point at which all criteria for hematologic response was met. Participants were assigned as responders at the time of their response and were censored at their discontinuation time or at the end of available follow-up if they did not respond by then. Hematologic response required the following: (1) Normalization of platelet count (defined as platelet count ≥ 50000 mm\^3 or \>=50% increase in platelet count) without transfusion support during the prior 7 days and (2) Normalization of LDH (defined as LDH ≤ULN) and absence of schistocytes.

Time frame: Day 1 through Week 26

Participants With Hemoglobin Response

Hemoglobin response was defined as the ability to maintain hemoglobin ≥ 10 g/dL without RBC transfusion support. The criterion must have been met at 2 separate assessments obtained at least 24 hours apart, and any measurement in between, and without RBC transfusion support during the prior 7 days.

Time frame: Up to Week 26

Participants With Platelet Response

Normalization of platelet count was defined as baseline platelet count ≤ 50000 mm\^3 or \> 50000 mm\^3, absolute platelet count \> 50000 mm\^3 or \>=50% increase in platelet count without transfusion support during the prior 7 days.

Time frame: Up to Week 26

Participants With Partial TMA Response

Partial response was defined as a participant meeting at least 1, but not all, criteria for TMA response. TMA response required the following: 1. Normalization of platelet count (defined as platelet count ≥ 50000 mm\^3 or \>=50% increase in platelet count) without transfusion support during the prior 7 days. 2. Normalization of LDH, (defined as LDH ≤ULN) and absence of schistocytes. 3. At least 50% reduction in protein/creatinine ratio from baseline.

Time frame: Up to Week 26

Participants With Loss of TMA Response

Loss of response occurred when a participant who had previously achieved a TMA response failed to meet criteria for one or more components of TMA response at a subsequent visit in treatment period. At least one parameter must fail to meet response criteria at 2 separate assessments obtained at least 24 hours apart, and any measurement in between. TMA response required the following: 1. Normalization of platelet count (defined as platelet count ≥ 50000 mm\^3 or \>=50% increase in platelet count) without transfusion support during the prior 7 days. 2. Normalization of LDH (defined as LDH ≤ULN) and absence of schistocytes. 3. At least 50% reduction in protein/creatinine ratio from baseline.

Time frame: Up to Week 26

Duration of TMA Response Through Week 52

This analysis includes data for each participant after TMA response through final follow-up. Participants with TMA response who do not experience these events are censored at their end of study date. TMA response required following: 1. Normalization of platelet count (defined as platelet count ≥ 50000 mm\^3 or \>=50% increase in platelet count) without transfusion support during the prior 7 days. 2. Normalization of LDH (defined as LDH ≤ULN) and absence of schistocytes. 3. At least 50% reduction in protein/creatinine ratio from baseline. The estimate is calculated based on Kaplan-Meier method.

Time frame: Day 1 through Week 52

Participants With TMA Relapse

For participants that meet criteria for TMA response during 26-week Treatment Period, TMA relapse is defined as evidence of worsening hematologic and renal dysfunction due to TMA during post-treatment Follow-up Period that requires treatment intervention, as determined by Investigator. TMA response required the following: 1. Normalization of platelet count (defined as platelet count ≥ 50000 mm\^3 or \>=50% increase in platelet count) without transfusion support during the prior 7 days. 2. Normalization of LDH (defined as LDH ≤ULN) and absence of schistocytes. 3. At least 50% reduction in protein/creatinine ratio from baseline.

Time frame: Up to Week 52

Overall Survival

The Kaplan-Meier method was used to measure overall survival estimate. Overall survival was calculated from date of treatment start to date of a documented death event (death due to any cause) or date of censoring. Participants who survived were censored at the earliest of an additional hematopoietic stem cell transplant (HSCT), Week 52, or their last known date alive.

Time frame: Day 1 through Week 52

Non-relapse Mortality During the 52-Week Treatment Period

Cumulative incidence was estimated using a competing risk model. Non-relapse mortality was defined as a participant's death due to any cause during the study, with the exception of death due to underlying disease progression or relapse.

Time frame: Day 1 through Week 52