Complement Inhibition Using Eculizumab to Overcome Platelet Transfusion Refractoriness in Patients With Severe Thrombocytopenia

Background:

- Platelets are tiny cells in the blood that help stop bleeding. Thrombocytopenia happens when people do not have enough normal platelets. Getting a transfusion of another person s platelets can help stop too much bleeding. But because these cells are from other people, the body may reject them,putting them at risk for serious bleeding complications. This conditions is called alloimmune platelet refractoriness . There are evidence that in many patients, platelet counts fail to increase after a platelet transfusion because the transfused platelets are destroyed by the body s defence soldier, called complement . Researchers want to see if a drug, that inhibits complement, can help increase platelet levels and reduce bleeding

Objectives:

- To see if eculizumab increases platelet levels more after a transfusion. To see if it reduces the chance of bleeding too much.

Eligibility:

- Adults 18-75 years old who have thrombocytopenia and alloimmune platelet refractoriness.

Design:

• Participants will be screened with medical history, physical exam, and blood tests.
• Participants will have the procedures listed below. They can have them while they are in the hospital. Or they can go to the outpatient clinic for them. Each visit may take up to 3 hours.
• Participants will get a meningitis vaccine if needed. Then they will get the study drug as an infusion.
• Participants will have a platelet transfusion. Their blood will be drawn every 24 hours until the platelet count is less than 10,000 per 1 microliter of blood.
• They will take antibiotics for 14 days.
• Participants will have a checkup and blood drawn twice a week for 2 weeks. They will get more transfusions if needed.

Study Overview

• Status: Completed
• Conditions: Thrombocytopenia; Alloimmune Platelet Refractoriness
• Intervention / Treatment: Drug: Eculizumab

Detailed Description

Platelet transfusion can be a life-saving procedure in preventing or treating serious bleeding in patients who have low and/or dysfunctional platelets. Treatment of blood cancer and other blood diseases as well as bone marrow transplantation is not possible without platelet transfusion support. Unfortunately, 20-60% of chronically transfused patients will stop responding to these transfusions putting them at risk for serious bleeding complications. Data support the concept that in many patients, platelet counts fail to increase after a platelet transfusion because the transfused platelets are destroyed by the body s complement. In order to overcome this problem, we will inhibit complement activity with the medication eculizumab that specifically binds and suppresses complement. We hypothesize that when we treat patients who have platelet refractoriness with eculizumab, the platelet counts will increase to higher numbers after platelet transfusions, decreasing the risk of bleeding complications associated with having a low platelet count.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:
• Ages 18-75 years inclusive.
• Ability to comprehend the investigational nature of the study and provide informed consent.
• Thrombocytopenia (due to congenital causes, bone marrow failure, hematologic malignancies, and treatment related), defined as <10k/uL without bleeding or <30K/uL with evidence of life threatening bleeding (intracranial hemorrhage, GI bleeding, pulmonary hemorrhage, uncontrolled epistaxis, hematuria).

• Diagnosed with immune platelet refractoriness, characterized by all of the following:

  • Lack of adequate post-transfusion platelet count increment, defined by, CCI <7500/ul at 10-60 min, and CCI <5000/ul at 18-24 hrs (in those who had a CCI at 10-60 min greater than or equal to 5000/microl)after at least 2 consecutive transfusions.
  • Presence of anti-HLA class A and/or B antibody.

EXCLUSION CRITERIA:

• Active meningococcal infection.
• Severe psychiatric illness. Mental deficiency sufficiently severe as to make making informed consent impossible.
• Positive pregnancy test for women of childbearing age within 1 week.
• HIV positive test within 3 months
• Paroxysmal Nocturnal Hemoglobinuria (PNH) disease with evidence of intravascular hemolysis.
• Presence ITP/autoimmune thrombocytopenia
• Immune platelet refractoriness responsive to treatment with IVIG

RE-ENROLLMENT CRITERIA:

• Meet response criteria to the initial treatment or second treatment
• Meets all initial inclusion/exclusion criteria

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Eculizumab; 1200 mg IV infusion over 30-40 min	Drug: Eculizumab; 300 mg single-use vials

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Sustained Platelet Transfusion Responsiveness	To evaluate the safety and efficacy of eculizumab to increase the platelet increment, defined as Corrected Count Increment (CCI) >7500/μL at 10-60 min together with CCI>5000/μL at 18-24 hrs post transfusion in patients with platelet refractoriness following treatment with eculizumab and platelet transfusion.	24 hours

Collaborators and Investigators

• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)

Publications and helpful links

General Publications

• Vo P, Purev E, West KA, McDuffee E, Worthy T, Cook L, Hawks G, Wells B, Shalabi R, Flegel WA, Adams SD, Reger R, Aue G, Tian X, Childs R. A pilot trial of complement inhibition using eculizumab to overcome platelet transfusion refractoriness in human leukocyte antigen allo-immunized patients. Br J Haematol. 2020 May;189(3):551-558. doi: 10.1111/bjh.16385. Epub 2020 Feb 21.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start: November 21, 2014
• Primary Completion (Actual): August 8, 2017
• Study Completion (Actual): August 8, 2017

Study Registration Dates

• First Submitted: November 21, 2014
• First Submitted That Met QC Criteria: November 21, 2014
• First Posted (Estimate): November 24, 2014

Study Record Updates

• Last Update Posted (Actual): January 3, 2019
• Last Update Submitted That Met QC Criteria: December 12, 2018
• Last Verified: January 18, 2018

More Information

Terms related to this study

• Keywords: Eculizumab; Complement Inhibition; Platelet Refractoriness
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Platelet Disorders; Thrombocytopenia; Physiological Effects of Drugs; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Eculizumab
• Other Study ID Numbers: 150015; 15-H-0015

Drug and device information, study documents

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