Study on the Safety and Efficacy of Cryopreserved Platelets in Hypoproliferative Thrombocytopenic Patients

Study Overview
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Brief Summary
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The purpose of this study is to study the safety and efficacy of pooled buffy-coat derived platelets which had been frozen with dimethyl sulphoxide (DMSO), in the prevention of bleeding for patients with hypoproliferaitve thrombocytopenia. These platelets are hereafter referred to as cryopreserved platelets. Patients who have severely low platelet count due to impaired bone marrow function from chemotherapy or certain haematological conditions may need platelet transfusion to prevent spontaneous bleeding. Currently, platelets are stored in liquid form, and must be used within five to seven days of collection. In this study, DMSO is used to preserve platelets during freezing so that they can be stored for longer than five to seven days. Investigators hope to learn if thawed cryopreserved platelets are functional and safe for transfusion in humans.

Detailed Description
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Platelets are currently stored in liquid form for a maximum of five to seven days. To extend the shelf-life of platelets, DMSO is added to freeze platelets for long-term storage. In vitro studies have shown that such cryopreserved platelets can be kept for at least two years at -80oC. This study is a clinical trial that aims to primarily assess the safety of cryopreserved pooled buffy coat-derived platelets in patients with hypoproliferative thrombocytopenia and no platelet refractoriness. Subjects will be randomised into two arms either a liquid platelet (control) or frozen platelet arm (treatment) and may receive four or more platelet transfusions per thrombocytopenic cycle. Each subject may participate in the study for up to two thrombocytopenic period, assuming a wash-out period of at least five days (during which the subject receives no platelet transfusions) between the two thrombocytopenic periods. If subjects participate in the study for more than one thrombocytopenic period, they will automatically be enrolled in the opposing arm for their second thrombocytopenic period.

Official Title
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Study on the Safety and Efficacy of Cryopreserved Platelets in Hypoproliferative Thrombocytopenic Patients

Conditions
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Hypoproliferative Thrombocytopenia

Intervention / Treatment
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* Biological: Control arm receiving normal (never before frozen) platelets as per current clinical practice
* Biological: Treatment arm receiving cryopreserved platelets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥ 21 years of age Be able to provide written informed consent Current or potential hypoproliferative thrombocytopenia with expected platelet count of <20 X 109/L for a minimum of 5 days in a 28-day period If pre-menopausal female of child bearing potential, then the subject must have a negative serum pregnancy test prior to study commencement, and must be using an acceptable method of contraception during the study. Calculated creatinine clearance of >30 ml/min (as calculated based on the Cockcroft-Gault equation; National Kidney Foundation 2017) at the point of recruitment, and within one week before transfusion Exclusion Criteria: Not meeting the inclusion criteria specified above Pregnant Breastfeeding Current platelet refractoriness History of allergy or adverse reaction to DMSO History of veno-occlusive disease History of acute venous or arterial thromboembolism within the last 3 months. History of unprovoked venous thromboembolism On antiplatelets, NSAIDs or anticoagulants within 1 week, and TCM (traditional Chinese medicine) which are known to decrease platelet count or platelet function or increase bleeding tendency within 2 weeks of study enrolment. Received or will be receiving L-asparaginase chemotherapy within 7 days of platelet transfusion Renal impairment with calculated creatinine clearance of <30ml/min. Non-cutaneous Grade 2 and above bleeding at the time of study assessment Presently with or a history of acute promyelocytic leukemia (APML), immune thrombocytopenic purpura (ITP), thrombotic thrombocytopenic purpura (TTP), haemolytic-uremic syndrome (HUS), or any thrombotic microangiopathy (TMA) Presently with or a history of heparin-induced thrombocytopenia Presently with disseminated intravascular coagulation (DIC) or other risk factor(s) for bleeding other than thrombocytopenia (including platelet dysfunction, PT ≥ 1.3 X upper limit of normal for the laboratory, PTT ≥ 1.3 X upper limit of normal for the laboratory, or fibrinogen ≤ 1 g/L) History of anaphylaxis from blood transfusion Involved in any other therapeutic clinical trials in the last 6 months prior to the start of this research Concomitant participation in other therapeutic clinical trials during the full period of this study Receiving non-trial-related medication that might compromise transfusion safety Known history of congenital bleeding disorder Subject who declined to consent for platelet transfusion

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a phase 1b/2a single centre clinical trial. Eligible hypoproliferative thrombocytopenic adult patients enrolled in the study will be randomised into two arms. One arm is the treatment arm using cryopreserved platelets and the second is the control arm using liquid platelets. A recruitment period of two years is expected for 17 subjects in each arm. Subjects will automatically be crossed over to the other treatment arm once they have completed the first treatment arm and there is at least a 5-days interval without platelet transfusion. Subjects can be both inpatient and outpatient. During the thrombocytopenic period of 28 days, subjects may be required to have multiple platelet transfusions during this period.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Control arm<br>Subjects in the control arm will receive normal pooled platelets for all of their transfusion within a single thrombocytopenic period. If subjects participate in the study for more than one thrombocytopenic period, they will automatically be enrolled in the opposing arm for their second thrombocytopenic period. | Biological: Control arm receiving normal (never before frozen) platelets as per current clinical practice<br>* Liquid platelets arm (control) and may receive multiple platelet transfusions per thrombocytopenic cycle.<br>|
| Experimental: Treatment arm<br>Subjects in the treatment arm will receive thawed cryopreserved pooled platelets for all of their transfusions (except for unplanned or urgent platelet transfusions outside stipulated periods when thawed cryopreserved platelets are unavailable) within a single thrombocytopenic period. If subjects participate in the study for more than one thrombocytopenic period, they will automatically be enrolled in the opposing arm for their second thrombocytopenic period. | Biological: Treatment arm receiving cryopreserved platelets<br>* Cryopreserved platelets arm (treatment) and may receive multiple platelet transfusions per thrombocytopenic cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events related to platelet transfusion. | There would be a close visual observation of the patient throughout the transfusion for the earliest signs of a transfusion reaction. Because patients can experience transfusion reactions several hours after the transfusion is completed, inpatients should be observed for late reactions during the subsequent 24 hour. Outpatient patients and their carer would be counselled about the possibility of the late adverse reactions and given access to immediate clinical help if they develop any symptoms of a transfusion reaction within 24 hour post-transfusion. Patients receiving cryopreserved platelets will be monitored and assessed for the side-effects of DMSO within 24 hour. These side effects include: headache, nausea, sedation, dizziness, abdominal or chest & abdominal discomfort during and after transfusion. It also includes assessment for renal impairment related to DMSO by performing serum renal panel 18 to 30 hours post-transfusion of study platelets. | Monitoring will be for 24 hours (serum test 18-30 hours) post-transfusion. | 
| Non-cutaneous Grade 2 or higher bleeding (as defined on the WHO bleeding scale) | Patients will be monitored daily for bleeding during each thrombocytopenic period if they are inpatients. If they are outpatients, they will be reviewed for bleeding at each clinic visit, and they will be asked to keep a record of any bleeding symptoms which will also be reviewed at each clinical visit during each of the thrombocytopenic periods. | Each thrombocytopenic period is up to 28 days from the first prophylactic platelet transfusion (shorter if platelet count recovers above target level before 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Platelet count increase (absolute increase and corrected count increment) post-platelet trantrsfusion | A pre-transfusion (baseline) venous blood sample for FBC will be taken by a trained phlebotomist/ nurse using Vacutainer tubes from the subject approximately within 24 hours prior to the planned platelet transfusion (for both control and treatment arms). Post-transfusion venous blood sample for FBC will be taken by a trained phlebotomist or nurse using Vacutainer tubes form the subject at 1-4 hour and 18-30 hour after transfusion. | Within approximately 24 hours prior, 1-4 hour and 18-30 hour post-transfusion. | 
| Changes in platelet activity (measured by viscoelastic hemostatic assay) post-platelet transfusion | A pre-transfusion (baseline) venous blood sample for VHA (viscoelastic hemostatic assay) will be taken by a trained phlebotomist/ nurse using Vacutainer tubes from the subject approximately within 24 hours prior to the planned platelet transfusion (for both control and treatment arms). Post-transfusion venous blood sample for VHA will be taken by a trained phlebotomist or nurse using Vacutainer tubes form the subject at 1-4 hour and 18-30 hour after transfusion. | Within approximately 24 hours prior, 1-4 hour and 18-30 hour post-transfusion. | 
| Changes in procoagulant activity post-platelet transfusion | A pre-transfusion (baseline) venous blood sample for procoagulant assays will be taken by a trained phlebotomist/ nurse using Vacutainer tubes from the subject approximately within 24 hours prior to the planned platelet transfusion (for both control and treatment arms). Post-transfusion venous blood sample for procoagulant assays will be taken by a trained phlebotomist or nurse using Vacutainer tubes form the subject at 1-4 hour after transfusion. | Within approximately 24 hours prior and 1-4 hour post-transfusion. | 
| Incidence of all grades of bleeding (as defined on WHO bleeding scale) | Patients will be monitored daily for bleeding during each thrombocytopenic period if they are inpatients. If they are outpatients, they will be reviewed for bleeding at each clinic visit, and they will be asked to keep a record of any bleeding symptoms which will also be reviewed at each clinical visit during each of the thrombocytopenic periods. | Each thrombocytopenic period is up to 28 days from the first prophylactic platelet transfusion of each arm (shorter if platelet count recovers above target level before 28 days) | 
| Total number and type of blood products transfused | For each thrombocytopenic period, subject may receive platelets and other types of blood components. The time and type of blood components administered (including the non-study ones) would be recorded. | Each thrombocytopenic period is up to 28 days from the first prophylactic platelet transfusion of each arm (shorter if platelet count recovers above target level before 28 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoproliferative thrombocytopenia, Cryopreserved, Transfusion, Platelets, Safety, Efficacy