Efficacy of Mirasol-treated Apheresis Platelets in Patients With Hypoproliferative Thrombocytopenia

Study Overview
=================
Brief Summary
-----------------
This is a prospective, multi-center, controlled, randomized, non-inferiority study to evaluate the clinical effectiveness of Conventional versus Mirasol-treated apheresis platelets in subjects with hypoproliferative thrombocytopenia who are expected to have platelet count(s) ≤ 10,000/μL requiring ≥ 2 platelet transfusions.

Detailed Description
-----------------
Patients will be randomized 1:1 to Mirasol-treated platelets (test platelets) or to conventional, untreated platelets (control platelets). The blood centers will collect the apheresis donor platelets and supply the test platelets to the hospital sites for transfusion into patients. Hospital sites will order control platelets as per their normal process, from their standard vendor. The target population for the MIPLATE study are patients with hematologic malignancies with hypoproliferative thrombocytopenia who are expected to have platelet (PLT) count(s) of ≤ 10,000/μL requiring ≥ 2 PLT transfusions. The primary objective of MIPLATE is to determine if the hemostatic efficacy of Mirasol-treated plasma stored Trima Accel® Aph PLTs are non-inferior to Conventional plasma stored Aph PLTs in subjects with hypoproliferative thrombocytopenia requiring PLT transfusions. The secondary objectives include comparing other efficacy and safety endpoints between the treatment groups. Subjects with hematologic malignancies with hypoproliferative thrombocytopenia are anticipated to experience a transfusion episode where they will require PLT transfusion support until bone marrow recovery. During this period all PLT transfusions required for a study subject will be given according to the subject's treatment allocation for 28 days after the initial PLT transfusion OR until transfusion independence (10 days without PLT transfusion) prior to Day 28. Additionally, serum samples for HLA antibody testing will be collected on Days 14, 28 and 56. At a minimum, the initial post-randomization prophylactic PLT transfusion will be initiated for a PLT count ≤ 10,000/µL. Thereafter, indications for PLT transfusions may be PLT count-related prophylaxis, intervention-related prophylaxis, or therapeutic (treatment of active bleeding) as determined by the treating physician(s). The indication(s) for the transfusion(s) will be captured.

Official Title
-----------------
Clinical Effectiveness of Conventional Versus Mirasol-treated Apheresis Platelets in Patients With Hypoproliferative Thrombocytopenia

Conditions
-----------------
Hematologic Malignancies, Hypoproliferative Thrombocytopenia

Intervention / Treatment
-----------------
* Device: Mirasol platelets (MIR PLTs)
* Device: Reference platelets (REF PLTs)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Weight > 10 kg (22 lbs) Subject has a hematologic malignancy with hypoproliferative thrombocytopenia and is expected to have PLT count(s) ≤ 10,000/µL requiring ≥ 2 PLT transfusions Laboratory results within 5 days prior to anticipated initiation of the first post randomization PLT transfusion: Prothrombin time (PT) and/or international normalized ratio (INR) ≤ 1.3 × the upper limit of normal (ULN) Activated partial thromboplastin time (aPTT) ≤ 1.3 × ULN Fibrinogen ≥ 100 mg/dL Women of childbearing potential must have a negative pregnancy test and agree to practice a medically acceptable contraception regimen for the study duration. Women who are postmenopausal for at least 1 year (> 12 months since last menses) or are surgically sterilized do not require this test IC from the subject or assent from the subject and consent from a parent or guardian, if the subject is < 18 years of age Exclusion Criteria: Treatment with pathogen-reduced blood products within previous 6 months Subject has been previously enrolled in this study and received at least 1 per protocol PLT transfusion a.) Subject is receiving therapeutic doses of antiplatelet agents, antifibrinolytics, and/or PLT specific growth factors within 10 days prior to randomization or b.) Subject is receiving therapeutic doses of anticoagulant, pro-coagulant or antithrombotic agents within 10 days prior to randomization. Subjects can be included if receiving the following: prophylactic dosing of anticoagulants (heparin, any low molecular weight heparin, enoxaparin, or fondaparinux), anticoagulants/thrombolytic agents used to maintain or re-establish the patency of catheters (heparin flushes or tissue-plasminogen activase [TPA], therapeutic doses of anticoagulants with a half-life of < 24 hours if it will be discontinued at least 24 hours prior to the first study transfusion, single periprocedural doses of anticoagulants with a half-life of < 24 hours or low dose aspirin (81 mg per day) Subject has ≥ grade 2 bleeding at the time of randomization Planned administration of bedside LR PLT transfusion(s) Presently with or a history of acute promyelocytic leukemia (APML), idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), or hemolytic uremic syndrome (HUS) HLA and/or HPA-alloimmunization and/or platelet refractory as determined by the investigator Hypersplenism as evidenced by splenomegaly based on investigator assessment at baseline History or diagnosis of a disease affecting hemostasis Currently taking, or participating in a clinical study involving PLT substitutes, PLT growth factors, or pharmacologic agents intended to enhance (i.e, antifibrinolytic agents) or decrease PLT hemostatic function Acute or chronic medical disorder that, in the opinion of the investigator, would impair the ability of the subject to receive protocol treatment Subject is pregnant or lactating Inability of the subject to comply with study procedures and/or follow-up
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mirasol platelets (MIR PLTs)<br>Leukoreduced, Trima Accel® apheresis platelets stored in 100% plasma, pathogen reduced with the Mirasol® Pathogen Reduction Technology (PRT) System | Device: Mirasol platelets (MIR PLTs)<br>* The final product to be transfused to the subject will be leukoreduced (LR), apheresis (Aph) single-donor platelets (PLTs) at the standard therapeutic dose of 1 unit of Aph PLTs containing ≥ 3.0 × 1.0E11 PLTs. MIR PLTs will be treated with the Mirasol pathogen reduction technology system.<br>|
| Active Comparator: Reference platelets (REF PLTs)<br>Leukoreduced, apheresis platelets stored in 100% plasma | Device: Reference platelets (REF PLTs)<br>* The final product to be transfused to the subject will be LR-Aph single-donor PLTs at the standard therapeutic dose of 1 unit of Aph PLTs containing ≥ 3.0 × 1.0E11 PLTs.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Days of ≥ Grade 2 Bleeding | Number of days of Grade 2 or higher bleeding recorded from treatment start date through 28 days following the first transfusion, until transfusion independence (10 days without PLT transfusion) prior to Day 28, or study termination, whichever occurred first. Subjects who obtained transfusion independence prior to Day 28 were assumed to have zero bleeding events between the date of transfusion independence and Day 28. Observed and simulated data for off-protocol transfusion intervals were included. | From the first post-randomization platelet transfusion through 28 days following the first transfusion. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number and Percentage of Subjects With Human Leukocyte Antigen (HLA) Alloimmunization | The outcome was the development of a new HLA Class I antibodies among subjects negative at baseline within each treatment group. Positivity for Class I HLA antibodies was determined by the 5 SD normalized background ratio cutoffs assay threshold (>59.2, LABScreen Mixed LSM12, One Lambda). | HLA antibodies were measured at Baseline and Days 14, 28, and 56. | 
| Number and Percentage of Subjects With ≥ Grade 2 Bleeding | The number and percentage of subjects with at least 1 day of ≥ Grade 2 bleeding from Day 0 through Day 27 (or until transfusion independence was achieved) by treatment group | From the first post-randomization platelet transfusion through 28 days following the first transfusion. | 
| Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | The time to first ≥ Grade 2 bleeding was analyzed using a log-rank test comparing survival curves stratified by treatment group. | From the first post-randomization platelet transfusion through 28 days following the first transfusion. | 
| Number and Percentage of Subjects With ≥ Grade 3 Bleeding | The number and percentage of subjects with at least 1 day of ≥ Grade 3 bleeding from Day 0 through Day 27 (or until transfusion independence was achieved). | From the first post-randomization platelet transfusion through 28 days following the first transfusion. | 
| Number and Percentage of Subjects With PLT Refractoriness | The number and percentage of subjects with PLT refractoriness defined as 2 sequential transfusions, each with corrected count increments (CCIs) < 5000 measured 1 hour post-transfusion. | From the first post-randomization platelet transfusion through 28 days following the first transfusion. | 
| Number and Percentage of Subjects With Immune Platelet Refractoriness | The number and percentage of subjects with PLT refractoriness for each treatment group. Subjects were defined as immune PLT refractoriness based on 2 sequential transfusion episodes, each with CCIs < 5000 measured 1 hour post transfusion, and who also had a positive antibody test within 14 days before or after the onset of PLT refractoriness. | Initial post-randomization platelet transfusion through high Class I HLA development. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hypoproliferative thrombocytopenia, hematologic malignancies, thrombocytopenia, platelet therapy, apheresis, pathogen reduction therapy