Ravulizumab in Thrombotic Microangiopathy Associated With a Trigger

A Phase 3, Randomized, Double-blind, Placebo-Controlled, Multicenter Study to Evaluate the Efficacy and Safety of Ravulizumab in Adult Participants Who Have Thrombotic Microangiopathy Associated With a Trigger

This study will investigate the efficacy and safety of ravulizumab compared to placebo in adult participants with thrombotic microangiopathy (TMA) associated with a trigger. Participants will be randomized to receive either ravulizumab plus best supportive care or placebo plus best supportive care. The treatment period is 26 weeks followed by a 26-week off-treatment follow-up period.

Study Overview

• Status: Terminated
• Conditions: Thrombotic Microangiopathy
• Intervention / Treatment: Other: Placebo; Biological: Ravulizumab; Other: Best Supportive Care

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Belgium, Belgium, 1200
    • Research Site
  • Brussels, Belgium, 1070
    • Research Site
  • Edegem, Belgium, 2650
    • Research Site
  • Leuven, Belgium, 3000
    • Research Site
  • Liege, Belgium, 4000
    • Research Site
• Brazil
  • Belo Horizonte, Brazil, 30150-221
    • Research Site
  • Botucatu, Brazil, 18618-687
    • Research Site
  • Campinas, Brazil, 13083-894
    • Research Site
  • Fortaleza, Brazil, 60430-375
    • Research Site
  • Porto Alegre, Brazil, 90110-270
    • Research Site
  • Ribeirão Preto, Brazil, 14051-040
    • Research Site
  • Salvador, Brazil, 41253-190
    • Research Site
  • Sao Paulo, Brazil, 05403-000
    • Research Site
  • São Paulo, Brazil, 04036-002
    • Research Site
• Canada
  • Quebec, Canada, G1R 3S1
    • Research Site
  • Ontario
    • Kingston, Ontario, Canada, K7L 3N6
      • Research Site
    • Toronto, Ontario, Canada, M5B 1W8
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H2X 3E4
      • Research Site
• France
  • Bordeaux, France, 33076
    • Research Site
  • Chambéry Cedex, France, 73011
    • Research Site
  • Lille, France, 59037
    • Research Site
  • Montpellier, France
    • Research Site
  • PARIS Cedex 12, France, 75571
    • Research Site
  • Paris, France, 75020
    • Research Site
  • Tours Cedex 09, France, 37044
    • Research Site
• Germany
  • Essen, Germany, 45147
    • Research Site
  • Hannover, Germany, 30625
    • Research Site
• Italy
  • Bergamo, Italy, 24127
    • Research Site
  • Roma, Italy, 00168
    • Research Site
• Japan
  • Bunkyo-ku, Japan, 113-8431
    • Research Site
  • Iruma-Gun, Japan, 350-0495
    • Research Site
  • Mitaka-shi, Japan, 181-8611
    • Research Site
  • Miyazaki-shi, Japan, 889-1692
    • Research Site
  • Nagoya, Japan, 466-8650
    • Research Site
  • Nagoya-shi, Japan, 466-8560
    • Research Site
  • Osaka, Japan, 565-0871
    • Research Site
  • Sapporo-shi, Japan, 060-8648
    • Research Site
  • Sendai-shi, Japan, 980-8574
    • Research Site
  • Shinjuku-ku, Japan, 162-8666
    • Research Site
• Korea, Republic of
  • Daegu, Korea, Republic of, 42415
    • Research Site
  • Gwangju, Korea, Republic of, 61469
    • Research Site
  • Seoul, Korea, Republic of, 03080
    • Research Site
  • Seoul, Korea, Republic of, 02841
    • Research Site
  • Seoul, Korea, Republic of, 04401
    • Research Site
  • Seoul, Korea, Republic of, 6591
    • Research Site
  • Seoul, Korea, Republic of, 06973
    • Research Site
  • Seoul, Korea, Republic of, 134-727
    • Research Site
• Netherlands
  • Amsterdam, Netherlands, 1100 DD
    • Research Site
  • Groningen, Netherlands, 9713 GZ
    • Research Site
  • Maastricht, Netherlands, 6229 HX
    • Research Site
  • Nijmegen, Netherlands, 6500 HB
    • Research Site
• Spain
  • Barcelona, Spain, 08036
    • Research Site
  • Granada, Spain, 18014
    • Research Site
  • Las Palmas de Gran Canaria, Spain, 35016
    • Research Site
  • Madrid, Spain, 28040
    • Research Site
• Taiwan
  • Kaohsiung, Taiwan, 81362
    • Research Site
  • Kaohsiung City, Taiwan, 833401
    • Research Site
  • New Taipei, Taiwan, 23561
    • Research Site
  • Taichung, Taiwan, 40705
    • Research Site
  • Taichung, Taiwan, 40447
    • Research Site
  • Taipei, Taiwan, 11217
    • Research Site
• United Kingdom
  • Bristol, United Kingdom, BS10 5NB
    • Research Site
  • Carshalton, United Kingdom, SM5 1AA
    • Research Site
  • Exeter, United Kingdom, EX2 5DW
    • Research Site
  • Leicester, United Kingdom, LE3 9QP
    • Research Site
  • Liverpool, United Kingdom, L7 8XP
    • Research Site
  • London, United Kingdom, SE5 9RS
    • Research Site
  • London, United Kingdom, SE1 9RT
    • Research Site
  • London, United Kingdom, NW3 2QG
    • Research Site
  • London, United Kingdom, SW17 0QT
    • Research Site
  • London, United Kingdom, NW1 2BH
    • Research Site
  • Manchester, United Kingdom, M13 9WL
    • Research Site
  • Newcastle-upon-Tyne, United Kingdom, NE1 4LP
    • Research Site
  • Nottingham, United Kingdom, NG5 1PB
    • Research Site
  • Oxford, United Kingdom, OX3 9DU
    • Research Site
  • Salford, United Kingdom, M6 8HD
    • Research Site
  • Stevenage, United Kingdom, SG1 4AB
    • Research Site
• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Research Site
  • California
    • Orange, California, United States, 92868
      • Research Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Research Site
  • Florida
    • Gainesville, Florida, United States, 32610
      • Research Site
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Research Site
    • Louisville, Kentucky, United States, 40202
      • Research Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Research Site
    • Boston, Massachusetts, United States, 02115
      • Research Site
    • Boston, Massachusetts, United States, 02118
      • Research Site
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Research Site
  • New York
    • New York, New York, United States, 10032
      • Research Site
    • Valhalla, New York, United States, 10595
      • Research Site
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27103
      • Research Site
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Research Site
    • Cleveland, Ohio, United States, 44106
      • Research Site
    • Columbus, Ohio, United States, 43203
      • Research Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Research Site
    • Pittsburgh, Pennsylvania, United States, 15212
      • Research Site
  • Utah
    • Salt Lake City, Utah, United States, 84115
      • Research Site
  • West Virginia
    • Morgantown, West Virginia, United States, 26505
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 18 years of age or older
2. Body weight ≥ 30 kilograms
3. Female participants of childbearing potential and male participants with female partners of childbearing potential must use highly effective contraception starting at screening and continuing until at least 8 months after the last dose of ravulizumab
4. TMA associated with a trigger (autoimmune disease, infection, solid organ transplant, drugs, and malignant hypertension)
5. Vaccinated against meningococcal infection (Neisseria meningitidis), within 3 years prior to, or at the time of, randomization. Participants who initiate study drug treatment less than 2 weeks after receiving a meningococcal vaccine must receive appropriate prophylactic antibiotics for at least 2 weeks after the vaccination. If participant cannot receive the meningococcal vaccine, then participant must be willing to receive antibiotic prophylaxis coverage against N. meningitidis during the entire Treatment Period and for 8 months following the final dose of study drug. Additional vaccination (Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae) may be considered based on individual patient condition.

Exclusion Criteria:

1. Any known gene mutation that causes atypical hemolytic uremic syndrome (aHUS)
2. Postpartum aHUS
3. Known chronic kidney disease
4. TMA due to hematopoietic stem cell transplantation ≤ 12 months of Screening
5. Primary and secondary glomerular diseases other than lupus
6. Diagnosis of primary antiphospholipid antibody syndrome
7. Shiga toxin-producing Escherichia coli infections including but not limited to Shiga toxin-related hemolytic uremic syndrome
8. Known familial or acquired 'a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13' (ADAMTS13) deficiency (activity < 5%)
9. Positive direct Coombs test which in the judgement of the Investigator is indicative of a clinically significant immune-mediated hemolysis not due to TMA
10. Clinical diagnosis of disseminated intravascular coagulation (DIC) in the judgement of the Investigator
11. Presence of sepsis requiring vasopressors within 7 days prior to or during Screening
12. Presence of monoclonal gammopathy including but not limited to multiple myeloma
13. Known bone marrow insufficiency or failure evidenced by cytopenias
14. Unresolved N. meningitidis infection
15. History of malignancy within 5 years of Screening with the exception of nonmelanoma skin cancer or carcinoma in situ of the cervix that has been treated with no evidence of recurrence
16. Use of any complement inhibitors within the past 3 years
17. Respiratory failure requiring mechanical ventilation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Matching placebo; Other: Best Supportive Care; Participants will receive medications, therapies, and interventions per standard hospital treatment protocols (unless specifically prohibited by the protocol).
Experimental: Ravulizumab	Biological: Ravulizumab; Body weight-based doses of ravulizumab will be administered intravenously as loading dose regimen followed by maintenance dosing every 8 weeks.; Other Names: Ultomiris; ALXN1210; Other: Best Supportive Care; Participants will receive medications, therapies, and interventions per standard hospital treatment protocols (unless specifically prohibited by the protocol).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Complete Thrombotic Microangiopathy (TMA) Response at Week 26	TMA response required the following: 1) Normalization of platelet count without transfusion support during the prior 7 days. 2) Normalization of LDH. 3) Improvement in glomerular filtration rate (eGFR) of >= 30% compared to baseline. Participants must meet each TMA criterion at 2 separate assessments obtained at least 24 hours apart, and any measurement in between.	Week 26

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Complete TMA Response	The Kaplan-Meier estimate of time to event of complete TMA response is reported. TMA response required the following: 1) Normalization of platelet count without transfusion support during the prior 7 days. 2) Normalization of LDH. 3) Improvement in eGFR of >= 30% compared to baseline. Participants must meet each TMA criterion at 2 separate assessments obtained at least 24 hours apart, and any measurement in between. Participants who did not have a response were censored at the date of last visit or study discontinuation at the time when the analysis was performed.	Baseline through Week 26
Number of Participants With Hematologic Response at Week 26	Hematologic response required the following: (1) Normalization of platelet count without transfusion support during the prior 7 days, and (2) normalization of LDH.	Week 26
Number of Participants With Renal Response at Week 26	Renal response is improvement in eGFR of >= 30% compared to baseline. If a participant is on dialysis ≤5 days prior to the date of eGFR assessment, the eGFR will be set to 10 milliliter/minute/1.73 meter square (mL/min/1.73 m^2) for that assessment. If a participant is on dialysis during the entire 26 week randomized Treatment Period, or through early discontinuation of study drug, then the change in eGFR was not calculated.	Week 26
Number of Participants On Dialysis at Week 26		Week 26
Change From Baseline in eGFR at Week 26	If a participant is on dialysis during the entire 26 week randomized Treatment Period, or through early discontinuation of study drug, then the change in eGFR was not calculated.	Baseline, Week 26

Collaborators and Investigators

• Sponsor: Alexion Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2021
• Primary Completion (Actual): December 22, 2022
• Study Completion (Actual): December 22, 2022

Study Registration Dates

• First Submitted: January 28, 2021
• First Submitted That Met QC Criteria: February 4, 2021
• First Posted (Actual): February 8, 2021

Study Record Updates

• Last Update Posted (Actual): October 1, 2024
• Last Update Submitted That Met QC Criteria: September 16, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Complement; Acute kidney injury; Trigger; Secondary thrombotic microangiopathy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Hematologic Diseases; Thrombocytopenia; Blood Platelet Disorders; Cytopenia; Vascular Diseases; Thrombotic Microangiopathies; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Ravulizumab
• Other Study ID Numbers: ALXN1210-TMA-315; 2020-005328-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No