Clinical trial NCT04543591: Ravulizumab in Thrombotic Microangiopathy After Hematopoietic Stem Cell Transplant
Official title: 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)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Thrombotic Microangiopathy
Keywords: Thrombotic Microangiopathy (TMA) Ultomiris
Ravulizumab
Hematopoietic Stem Cell Transplant (HSCT) Transplant-associated TMA
HSCT-TMA
Lead sponsor: Alexion Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2020-09-10
Enrollment: 146
Sex: ALL
Minimum age (years): 12
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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.

Primary outcomes:
measure: Event Free Survival
timeFrame: 26 weeks (treatment period)
Secondary outcomes:
measure: Time To TMA Response
timeFrame: 26 weeks (treatment period)
measure: Change from Baseline in eGFR
timeFrame: 26 weeks (treatment period) and 52 weeks
measure: Overall Survival
timeFrame: Day 100, 26 weeks (treatment period), and 52 weeks
measure: Non-relapse Mortality
timeFrame: Day 100, 26 weeks (treatment period), and 52 weeks
measure: Hematologic Response
timeFrame: 26 weeks (treatment period)
measure: TMA response and time to response for each individual component of TMA
timeFrame: 26 weeks (treatment period)
measure: Time to Hematologic Response
timeFrame: 26 weeks (treatment period)
measure: Hemoglobin Response
timeFrame: 26 weeks (treatment period)
measure: Partial Response
timeFrame: 26 weeks (treatment period)
measure: Loss of TMA Response
timeFrame: 26 weeks (treatment period)
measure: Duration of TMA Response
timeFrame: 26 weeks (treatment period) and 52 weeks
measure: Changes from Baseline in Haptoglobin, Platelets, LDH, and Hemoglobin
timeFrame: 26 weeks (treatment period) and 52 weeks
measure: Modified TMA Response
timeFrame: 26 weeks (treatment period)
measure: Change from baseline in TMA-associated organ dysfunction in renal system, cardiovascular system, pulmonary system, CNS, and GI system
timeFrame: 26 weeks (treatment period) and 52 weeks
measure: TMA Relapse
timeFrame: Follow-up Period
measure: Platelet Response
timeFrame: 26 weeks (treatment period)
Other outcomes:
Locations:
city: Tampa
country: United States
facility: Research Site
state: Florida
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Boston
country: United States
facility: Research Site
state: Massachusetts
city: Grosse Pointe Farms
country: United States
facility: Research Site
state: Michigan
city: Durham
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state: North Carolina
city: Columbus
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state: Ohio
city: Pittsburgh
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state: Pennsylvania
city: Seattle
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state: Washington
city: Murdoch
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city: Parkville
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city: Brugge
country: Belgium
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city: Bruxelles
country: Belgium
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city: Chênée
country: Belgium
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city: Leuven
country: Belgium
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city: Jaú
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city: Porto Alegre
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city: São Paulo
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city: Calgary
country: Canada
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state: Alberta
city: Toronto
country: Canada
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state: Ontario
city: Beijing
country: China
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city: Beijing
country: China
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city: Beijing
country: China
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city: Chengdu
country: China
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city: Chengdu
country: China
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city: Guangzhou
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city: Hangzhou
country: China
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city: Hefei
country: China
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city: Shanghai
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city: Shanghai
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city: Suzhou
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city: Tianjin
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city: Angers
country: France
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city: La Tronche
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city: Nice
country: France
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city: Toulouse
country: France
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city: Berlin
country: Germany
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city: Berlin
country: Germany
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city: Chemnitz
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city: Halle (Saale)
country: Germany
facility: Research Site
city: Hamburg
country: Germany
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city: Mainz A. Rhein
country: Germany
facility: Research Site
city: Ulm
country: Germany
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city: Athens
country: Greece
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city: Athens
country: Greece
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city: Athens
country: Greece
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city: Patras
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city: Thessaloniki
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city: Halfa
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city: Ramat Gan
country: Israel
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city: Avellino
country: Italy
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city: Cuneo
country: Italy
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city: Firenze
country: Italy
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city: Milano
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city: Milano
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city: Napoli
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city: Roma
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city: San Giovanni Rotondo
country: Italy
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city: Torino
country: Italy
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city: Torrette Di Ancona
country: Italy
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city: Udine
country: Italy
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city: Akita-shi
country: Japan
facility: Research Site
city: Anjo
country: Japan
facility: Research Site
city: Chiba-shi
country: Japan
facility: Research Site
city: Fukushima-shi
country: Japan
facility: Research Site
city: Isehara-shi
country: Japan
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city: Kanazawa-shi
country: Japan
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city: Kobe-shi
country: Japan
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city: Kumamoto-shi
country: Japan
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city: Kurashiki-shi
country: Japan
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city: Minato-ku
country: Japan
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city: Okayama-shi
country: Japan
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city: Osaka-shi
country: Japan
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city: Osakasayama-shi
country: Japan
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city: Sapporo-shi
country: Japan
facility: Research Site
city: Suita-shi
country: Japan
facility: Research Site
city: Sunto-gun
country: Japan
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city: Tsukuba-shi
country: Japan
facility: Research Site
city: Wakayama-shi
country: Japan
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city: Goyang-si
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
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city: Seoul
country: Korea, Republic of
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city: Suwon
country: Korea, Republic of
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city: Groningen
country: Netherlands
facility: Research Site
city: Maastricht
country: Netherlands
facility: Research Site
city: Gdansk
country: Poland
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Granada
country: Spain
facility: Research Site
city: L'Hospitalet de Llobregat
country: Spain
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city: Madrid
country: Spain
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city: Madrid
country: Spain
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city: Madrid
country: Spain
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city: Madrid
country: Spain
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city: Madrid
country: Spain
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city: Malaga
country: Spain
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city: Oviedo
country: Spain
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city: Palma de Mallorca
country: Spain
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city: Pamplona
country: Spain
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city: Salamanca
country: Spain
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city: Sevilla
country: Spain
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city: Huddinge
country: Sweden
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city: Lund
country: Sweden
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city: Glasgow
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Nottingham
country: United Kingdom
facility: Research Site
Study officials:
References: