A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study of Ravulizumab in Adult and Adolescent Participants who have Thrombotic Microangiopathy (TMA) after Hematopoietic Stem Cell Transplant (HSCT)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Alexion Pharmaceuticals Inc.

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

27 Oct 2020 → 20 Mar 2026

Decision date (initial)

2024-03-06

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Alexion Pharmaceuticals, Inc.

External identifiers

EU CT number

2023-510107-22-00

EudraCT number

2020-000144-61

ClinicalTrials.gov

NCT04543591

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Others, Pharmacokinetic, Safety, Pharmacodynamic, Therapy

To assess the efficacy of ravulizumab versus placebo in the treatment of adult and adolescent participants with HSCT-TMA.

Secondary objectives 4

1. To assess OS
2. To assess non-relapse mortality
3. To characterize TMA response after treatment with ravulizumab
4. To assess improvement in organ dysfunction

Conditions and MedDRA coding

Hematopoietic stem cell transplant-associated thrombotic microangiopathy

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-001943-PIP02-20

Plan to share IPD

Yes

IPD plan description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal Vivli.org. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared. AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA PhRMA Data Sharing Principles. When a request has been approved AstraZeneca will provide access to the anonymized individual patient-level data via secure research environment https://vivli.org/. Signed Data Usage Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. 12 years of age or older, at the time of signing the informed consent form (ICF)
2. Participants who received HSCT within the past 12 months at the time of Screening)
3. 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: − LDH > ULN for age − Presence of schistocytes ≥ 2 per high power field (HPF) or ≥ 1% in peripheral blood smear • Proteinuria on spot urinalysis • De novo anemia OR the presence of hypertension
4. Participants must have HSCT-TMA that persists despite initial management of any triggering condition (persists for at least 72 hours after management of triggering agent/condition)
5. Body weight ≥ 30 kg at Screening or ≤ 7 days prior to the start of the Screening Period (date of consent).
6. Participants must be vaccinated against meningococcal infections if clinically feasible, according to institutional guidelines for immune reconstitution after HSCT. Participants < 18 years of age must be revaccinated 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. meningiditis for at least 2 weeks after meningococcal vaccination. Participants who cannot receive meningococcal vaccine should receive antibiotic prophylaxis coverage against N. meningiditis the entire Treatment Period and for 8 months following the final dose of ravulizumab
7. 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.
8. Capable of giving signed informed consent or assent which includes compliance with the requirements and restrictions listed in the informed consent and in this protocol

Exclusion criteria 13

1. Known familial or acquired 'a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13' (ADAMTS13) deficiency (activity < 5%).
2. Pregnancy or breastfeeding
3. Known Shiga toxin-related hemolytic uremic syndrome (ST-HUS)
4. Positive direct Coombs test result
5. Clinical diagnosis of disseminated intravascular coagulation (DIC)
6. Known bone marrow/graft failure for the current HSCT
7. Diagnosis of veno-occlusive disease (VOD)
8. Human immunodeficiency virus (HIV) infection evidenced by HIV-1 or HIV-2 antibody titer
9. Unresolved meningococcal disease
10. Presence of sepsis requiring vasopressor support within 7 days prior to enrollment
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 by participating in the study or confound the outcome of the study. Including but not limited to, major cardiac, pulmonary, renal, endocrine, or hepatic disease
13. Previously or currently treated with a complement inhibitor

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Event free survival during the 26-week Treatment Period defined as the time from randomization until the first of the two following events: Death and Clinical worsening

Secondary endpoints 5

1. Overall survival by Day 100, Week 26
2. Non-relapse mortality during the 26-week Treatment Period
3. Number of TMA response criteria met during the 26-week Treatment Period
4. Hematologic response during the 26-week Treatment Period
5. Change from baseline in eGFR at Week 26

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Alexion Pharmaceuticals Inc.

Sponsor organisation

Alexion Pharmaceuticals Inc.

Address

121 Seaport Boulevard

City

Boston

Postcode

02210-2050

Country

United States

Scientific contact point

Organisation

Alexion Pharmaceuticals Inc.

Contact name

European Clinical Trial Information

Public contact point

Organisation

Alexion Pharmaceuticals Inc.

Contact name

European Clinical Trial Information

Third parties 4

Locations

9 EU/EEA countries · 57 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 206 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications