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

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.

Study Overview

• Status: Completed
• Conditions: Hypoproliferative Thrombocytopenia
• Intervention / Treatment: Biological: Control arm receiving normal (never before frozen) platelets as per current clinical practice; Biological: Treatment arm receiving cryopreserved platelets

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 169608
    • Singapore General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. ≥ 21 years of age
2. Be able to provide written informed consent
3. 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
4. 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.
5. 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:

1. Not meeting the inclusion criteria specified above
2. Pregnant
3. Breastfeeding
4. Current platelet refractoriness
5. History of allergy or adverse reaction to DMSO
6. History of veno-occlusive disease
7. History of acute venous or arterial thromboembolism within the last 3 months.
8. History of unprovoked venous thromboembolism
9. 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.
10. Received or will be receiving L-asparaginase chemotherapy within 7 days of platelet transfusion
11. Renal impairment with calculated creatinine clearance of <30ml/min.
12. Non-cutaneous Grade 2 and above bleeding at the time of study assessment
13. 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)
14. Presently with or a history of heparin-induced thrombocytopenia
15. 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)
16. History of anaphylaxis from blood transfusion
17. Involved in any other therapeutic clinical trials in the last 6 months prior to the start of this research
18. Concomitant participation in other therapeutic clinical trials during the full period of this study
19. Receiving non-trial-related medication that might compromise transfusion safety
20. Known history of congenital bleeding disorder
21. Subject who declined to consent for platelet transfusion

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control arm; 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; Liquid platelets arm (control) and may receive multiple platelet transfusions per thrombocytopenic cycle.
Experimental: Treatment arm; 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; Cryopreserved platelets arm (treatment) and may receive multiple platelet transfusions per thrombocytopenic cycle.

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Singapore General Hospital
• Collaborators: DSO National Laboratories; Health Sciences Authority, Singapore
• Investigators: Principal Investigator: Ang Ai Leen, Singapore General Hospital

Publications and helpful links

General Publications

• ClinicalTrials.gov: NCT02078284. Phase 1 safety study of dimethyl sulphoxide cryopreserved platelets.
• Dumont LJ, Dumont DF, Unger ZM, Siegel A, Szczepiorkowski ZM, Corson JS, Jones MK, Christoffel T, Pellham E, Bailey SL, Slichter SJ; BEST Collaborative. A randomized controlled trial comparing autologous radiolabeled in vivo platelet (PLT) recoveries and survivals of 7-day-stored PLT-rich plasma and buffy coat PLTs from the same subjects. Transfusion. 2011 Jun;51(6):1241-8. doi: 10.1111/j.1537-2995.2010.03007.x. Epub 2011 Jan 7.
• Dumont LJ, Cancelas JA, Graminske S, Friedman KD, Vassallo RR, Whitley PH, Rugg N, Dumont DF, Herschel L, Siegal AH, Szczepiorkowski ZM, Fender L, Razatos A. In vitro and in vivo quality of leukoreduced apheresis platelets stored in a new platelet additive solution. Transfusion. 2013 May;53(5):972-80. doi: 10.1111/j.1537-2995.2012.03841.x. Epub 2012 Aug 6.
• Noorman F, van Dongen TT, Plat MJ, Badloe JF, Hess JR, Hoencamp R. Transfusion: -80°C Frozen Blood Products Are Safe and Effective in Military Casualty Care. PLoS One. 2016 Dec 13;11(12):e0168401. doi: 10.1371/journal.pone.0168401. eCollection 2016.
• Slichter SJ, Jones M, Ransom J, Gettinger I, Jones MK, Christoffel T, Pellham E, Bailey SL, Corson J, Bolgiano D. Review of in vivo studies of dimethyl sulfoxide cryopreserved platelets. Transfus Med Rev. 2014 Oct;28(4):212-25. doi: 10.1016/j.tmrv.2014.09.001. Epub 2014 Sep 21. Review.

Study record dates

Study Major Dates

• Study Start (Actual): October 25, 2019
• Primary Completion (Actual): March 24, 2021
• Study Completion (Actual): March 24, 2021

Study Registration Dates

• First Submitted: August 2, 2021
• First Submitted That Met QC Criteria: September 23, 2021
• First Posted (Actual): October 5, 2021

Study Record Updates

• Last Update Posted (Actual): October 5, 2021
• Last Update Submitted That Met QC Criteria: September 23, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Safety; Efficacy; Platelets; Transfusion; Cryopreserved; Hypoproliferative thrombocytopenia
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Platelet Disorders; Thrombocytopenia
• Other Study ID Numbers: CPPL-DSO-2018; 2018/2883 (Other Identifier: Centralised Institutional Review Board (CIRB))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: Will not be sharing individual participant data collected in this study to other researchers.

Drug and device information, study documents

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