Hematologic Malignancies, Hypoproliferative Thrombocytopenia
Conditions
Keywords
hypoproliferative thrombocytopenia, hematologic malignancies, thrombocytopenia, platelet therapy, apheresis, pathogen reduction therapy
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.
Interventions
DEVICEMirasol platelets (MIR PLTs)
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.
DEVICEReference platelets (REF PLTs)
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.
Sponsors
Biomedical Advanced Research and Development Authority
Terumo BCTbio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
DOUBLE (Investigator, Outcomes Assessor)
Masking description
Though this is not a blinded study, treatment assignment is obtained through electronic system and should not be shared those performing the primary outcome assessment or assessors of adverse events.
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
1. Weight \> 10 kg (22 lbs) 2. Subject has a hematologic malignancy with hypoproliferative thrombocytopenia and is expected to have PLT count(s) ≤ 10,000/µL requiring ≥ 2 PLT transfusions 3. Laboratory results within 5 days prior to anticipated initiation of the first post randomization PLT transfusion: 1. Prothrombin time (PT) and/or international normalized ratio (INR) ≤ 1.3 × the upper limit of normal (ULN) 2. Activated partial thromboplastin time (aPTT) ≤ 1.3 × ULN 3. Fibrinogen ≥ 100 mg/dL 4. 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 5. 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
1. Treatment with pathogen-reduced blood products within previous 6 months 2. Subject has been previously enrolled in this study and received at least 1 per protocol PLT transfusion 3. 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) 4. Subject has ≥ grade 2 bleeding at the time of randomization 5. Planned administration of bedside LR PLT transfusion(s) 6. Presently with or a history of acute promyelocytic leukemia (APML), idiopathic thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), or hemolytic uremic syndrome (HUS) 7. HLA and/or HPA-alloimmunization and/or platelet refractory as determined by the investigator 8. Hypersplenism as evidenced by splenomegaly based on investigator assessment at baseline 9. History or diagnosis of a disease affecting hemostasis 10. 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 11. Acute or chronic medical disorder that, in the opinion of the investigator, would impair the ability of the subject to receive protocol treatment 12. Subject is pregnant or lactating 13. Inability of the subject to comply with study procedures and/or follow-up
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Days of ≥ Grade 2 Bleeding | From the first post-randomization platelet transfusion through 28 days following the first transfusion. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number and Percentage of Subjects With Human Leukocyte Antigen (HLA) Alloimmunization | HLA antibodies were measured at Baseline and Days 14, 28, and 56. | 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). |
| Number and Percentage of Subjects With ≥ Grade 2 Bleeding | From the first post-randomization platelet transfusion through 28 days following the first transfusion. | 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 |
| Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | From the first post-randomization platelet transfusion through 28 days following the first transfusion. | The time to first ≥ Grade 2 bleeding was analyzed using a log-rank test comparing survival curves stratified by treatment group. |
| Number and Percentage of Subjects With PLT Refractoriness | From the first post-randomization platelet transfusion through 28 days following the first transfusion. | 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. |
| Number and Percentage of Subjects With Immune Platelet Refractoriness | Initial post-randomization platelet transfusion through high Class I HLA development. | 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. |
| Number and Percentage of Subjects With ≥ Grade 3 Bleeding | From the first post-randomization platelet transfusion through 28 days following the first transfusion. | 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). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number and Percentage of Subjects With Unanticipated Adverse Device Effects (UADEs) | From initial post-randomization PLT transfusion through 72 hours following the last per protocol PLT transfusion. | UADEs are identified as treatment emergent adverse events reported by the investigator as serious, unanticipated, at least possibly related to study device or at least possibly related to treatment. UADEs were coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 19.1 |
Countries
United States
Participant flow
Recruitment details
Recruitment occurred at 11 hospital sites within the US. Enrollment occurred between 05 MAY 2017 and 07 APR 2020.
Pre-assignment details
Full Analysis Set (FAS) - all randomized subjects. Safety Set (SS) - randomized subjects who received at least 1 PLT transfusion post-randomization, independent of the outcome or successful completions of the procedure. Modified Intent-to-Treat (mITT) - all randomized subjects who had at least 1 study transfusion according to randomized study group. 422 subjects consented, 92 screen failed, 330 FAS, 28 received no transfusion, 302 SS, 5 received no transfusion per assigned group, 297 mITT.
Participants by arm
| Arm | Count |
|---|---|
| MIRASOL Randomized to leukoreduced, Trima Accel® apheresis platelets stored in 100% plasma, pathogen reduced with the Mirasol® Pathogen Reduction Technology (PRT) System
Mirasol platelets (MIR PLTs): 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. | 141 |
| CONTROL Randomized to leukoreduced, apheresis platelets stored in 100% plasma
Reference platelets (REF PLTs): 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. | 161 |
| Total | 302 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 3 |
| Overall Study | Did not require PLT transfusion, had HLA positive | 10 | 12 |
| Overall Study | Lost to Follow-up | 3 | 3 |
| Overall Study | Physician Decision | 5 | 4 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | MIRASOL | CONTROL | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 6 Participants | 10 Participants | 16 Participants |
| Age, Categorical >=65 years | 41 Participants | 51 Participants | 92 Participants |
| Age, Categorical Between 18 and 65 years | 94 Participants | 100 Participants | 194 Participants |
| Age, Continuous | 54.8 years STANDARD_DEVIATION 16.32 | 54.1 years STANDARD_DEVIATION 18.24 | 54.4 years STANDARD_DEVIATION 17.34 |
| Body Surface Area (BSA) | 1.975 square meters STANDARD_DEVIATION 0.3157 | 1.934 square meters STANDARD_DEVIATION 0.3613 | 1.953 square meters STANDARD_DEVIATION 0.3408 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants | 8 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 130 Participants | 147 Participants | 277 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 6 Participants | 9 Participants |
| Height (cm) | 170.29 centimeters STANDARD_DEVIATION 15.039 | 167.88 centimeters STANDARD_DEVIATION 18.472 | 169.01 centimeters STANDARD_DEVIATION 16.972 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 10 Participants | 12 Participants |
| Race/Ethnicity, Customized Black or African American | 16 Participants | 10 Participants | 26 Participants |
| Race/Ethnicity, Customized Missing | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Other | 2 Participants | 2 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 120 Participants | 137 Participants | 257 Participants |
| Region of Enrollment United States | 141 Participants | 161 Participants | 302 Participants |
| Sex: Female, Male Female | 53 Participants | 56 Participants | 109 Participants |
| Sex: Female, Male Male | 88 Participants | 105 Participants | 193 Participants |
| Weight (kg) | 86.96 kilograms STANDARD_DEVIATION 23.876 | 84.95 kilograms STANDARD_DEVIATION 25.4 | 85.89 kilograms STANDARD_DEVIATION 24.68 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 141 | 3 / 161 |
| other Total, other adverse events | 97 / 141 | 100 / 161 |
| serious Total, serious adverse events | 22 / 141 | 33 / 161 |
Outcome results
Primary
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.
Time frame: From the first post-randomization platelet transfusion through 28 days following the first transfusion.
Population: The Modified Intent-to-Treat Analysis Set was used for this analysis. Modified Intent-to-Treat Analysis Set = all randomized subjects who had at least 1 study transfusion according to randomized study group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MIRASOL | Days of ≥ Grade 2 Bleeding | 1.7 Days | Standard Deviation 4.05 |
| CONTROL | Days of ≥ Grade 2 Bleeding | 0.6 Days | Standard Deviation 1.51 |
Comparison: The MIRASOL and CONTROL groups were compared with respect to the number of days of WHO ≥ Grade 2 bleeding. This was carried out by fitting a negative binomial regression model with an offset defined as the natural logarithm (LN) of the number of days that bleeding was assessed in order to account for the fact that subjects had different numbers of bleeding assessment days.95% CI: [1.67, 4.67]
Secondary
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.
Time frame: From the first post-randomization platelet transfusion through 28 days following the first transfusion.
Population: The mITT Set was used for this analysis. Subjects that did not experience a ≥ Grade 2 bleed were censored at Day 27 or at date of transfusion independence (10th day without a PLT transfusion prior to last follow-up day or Day 27, whichever occurred earlier), where appropriate. Subjects that did not complete the study or were lost to follow-up were censored on the date of their last study visit in the treatment period.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MIRASOL | Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | Day 12 | 72 Participants |
| MIRASOL | Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | Day 20 | 11 Participants |
| MIRASOL | Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | Day 8 | 92 Participants |
| MIRASOL | Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | Day 24 | 5 Participants |
| MIRASOL | Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | Day 16 | 33 Participants |
| MIRASOL | Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | Day 28 | 4 Participants |
| MIRASOL | Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | Day 4 | 115 Participants |
| CONTROL | Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | Day 28 | 11 Participants |
| CONTROL | Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | Day 4 | 128 Participants |
| CONTROL | Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | Day 8 | 110 Participants |
| CONTROL | Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | Day 12 | 85 Participants |
| CONTROL | Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | Day 16 | 48 Participants |
| CONTROL | Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | Day 20 | 27 Participants |
| CONTROL | Number and Percentage of Subjects at the First Timepoint of ≥ Grade 2 Bleeding | Day 24 | 13 Participants |
p-value: 0.07Log-rank test
Secondary
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
Time frame: From the first post-randomization platelet transfusion through 28 days following the first transfusion.
Population: The Modified Intent-to-Treat Analysis Set was used for this analysis. Modified Intent-to-Treat Analysis Set = all randomized subjects who had at least 1 study transfusion according to randomized study group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MIRASOL | Number and Percentage of Subjects With ≥ Grade 2 Bleeding | 58 Participants |
| CONTROL | Number and Percentage of Subjects With ≥ Grade 2 Bleeding | 46 Participants |
Comparison: The null hypothesis was H0: pt/pc \> 1.2 (ie, MIRASOL had more than a 20% higher probability of a patient experiencing at least one WHO ≥ Grade 2 bleed compared to CONTROL).p-value: 0.727495% CI: [0.97, 1.81]Wald Non-inferiority Test
Secondary
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).
Time frame: From the first post-randomization platelet transfusion through 28 days following the first transfusion.
Population: The Modified Intent-to-Treat Analysis Set was used for this analysis. Modified Intent-to-Treat Analysis Set = all randomized subjects who had at least 1 study transfusion according to randomized study group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MIRASOL | Number and Percentage of Subjects With ≥ Grade 3 Bleeding | 6 Participants |
| CONTROL | Number and Percentage of Subjects With ≥ Grade 3 Bleeding | 2 Participants |
p-value: 0.1649Fisher Exact
Secondary
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).
Time frame: HLA antibodies were measured at Baseline and Days 14, 28, and 56.
Population: The Modified Intent-to-Treat Analysis Set was used for this analysis. Modified Intent-to-Treat Analysis Set = all randomized subjects who had at least 1 study transfusion according to randomized study group. Subjects who tested positive at the high assay threshold (5 SD normalized background ratio cutoffs \>59.2, LABScreen Mixed LSM12, One Lambda) at Baseline were excluded from this analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MIRASOL | Number and Percentage of Subjects With Human Leukocyte Antigen (HLA) Alloimmunization | 4 Participants |
| CONTROL | Number and Percentage of Subjects With Human Leukocyte Antigen (HLA) Alloimmunization | 2 Participants |
Secondary
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.
Time frame: Initial post-randomization platelet transfusion through high Class I HLA development.
Population: The Modified Intent-to-Treat Analysis Set was used for this analysis. Modified Intent-to-Treat Analysis Set = all randomized subjects who had at least 1 study transfusion according to randomized study group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MIRASOL | Number and Percentage of Subjects With Immune Platelet Refractoriness | 1 Participants |
| CONTROL | Number and Percentage of Subjects With Immune Platelet Refractoriness | 1 Participants |
Secondary
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.
Time frame: From the first post-randomization platelet transfusion through 28 days following the first transfusion.
Population: The Modified Intent-to-Treat Analysis Set was used for this analysis. Modified Intent-to-Treat Analysis Set = all randomized subjects who had at least 1 study transfusion according to randomized study group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MIRASOL | Number and Percentage of Subjects With PLT Refractoriness | 41 Participants |
| CONTROL | Number and Percentage of Subjects With PLT Refractoriness | 20 Participants |
p-value: 0.001595% CI: [1.32, 3.49]Fisher Exact
Other Pre-specified
Number and Percentage of Subjects With Unanticipated Adverse Device Effects (UADEs)
UADEs are identified as treatment emergent adverse events reported by the investigator as serious, unanticipated, at least possibly related to study device or at least possibly related to treatment. UADEs were coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 19.1
Time frame: From initial post-randomization PLT transfusion through 72 hours following the last per protocol PLT transfusion.
Population: The Safety Set was used for this analysis. Safety Set = randomized subjects who received at least 1 PLT transfusion post-randomization, independent of the outcome or successful completions of the procedure.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MIRASOL | Number and Percentage of Subjects With Unanticipated Adverse Device Effects (UADEs) | Blood and Lymphatic System Disorders/ Febrile Neutropenia | 1 Participants |
| MIRASOL | Number and Percentage of Subjects With Unanticipated Adverse Device Effects (UADEs) | No UADEs | 140 Participants |
| CONTROL | Number and Percentage of Subjects With Unanticipated Adverse Device Effects (UADEs) | Blood and Lymphatic System Disorders/ Febrile Neutropenia | 0 Participants |
| CONTROL | Number and Percentage of Subjects With Unanticipated Adverse Device Effects (UADEs) | No UADEs | 161 Participants |