The Cryopreserved vs. Liquid Platelets Trial (CLIP II)

A Phase III Multicentre Blinded Randomised Controlled Clinical Non-inferiority Trial of Cryopreserved Platelets vs. Conventional Liquid-stored Platelets for the Management of Surgical Bleeding

This trial is a phase III multicentre blinded randomised controlled clinical non-inferiority trial of cryopreserved platelets vs. conventional liquid-stored platelets for the management of surgical bleeding. The aim of the study is to assess the efficacy, safety and cost effectiveness of cryopreserved platelets, compared to conventional liquid-stored platelets, for the management of surgical bleeding. This trial will recruit cardiac surgical patients deemed to be at high risk of surgical bleeding and who may potentially require transfusion of platelets. It is estimated to require 808 high-risk cardiac surgical patients to be recruited, to obtain 202 patients who receive transfused study platelets for surgical bleeding.

Study Overview

• Status: Active, not recruiting
• Conditions: Hemorrhage; Surgical Blood Loss
• Intervention / Treatment: Biological: Cryopreserved platelets; Biological: Liquid-stored platelets

Detailed Description

For logistic reasons and in order to use this scarce resource optimally, liquid-stored platelets are not stored in smaller hospitals, or in deployed military hospitals. Patients in these hospitals therefore currently have limited or no access to platelet transfusion. Cryopreservation of platelets is a promising technology that would allow smaller hospitals to provide platelet transfusions, reduce overall platelet wastage, and possibly produce better patient outcomes through more effective haemostasis.

This is a phase III multicentre blinded randomised controlled clinical non-inferiority trial of cryopreserved platelets vs. conventional liquid-stored platelets for the management of surgical bleeding. The aim of the study is to assess the efficacy, safety and cost effectiveness of cryopreserved platelets, compared to conventional liquid-stored platelets, for the management of surgical bleeding. This trial will recruit cardiac surgical patients deemed to be at high risk of surgical bleeding and who may potentially require transfusion of platelets. It is estimated to require 808 high-risk cardiac surgical patients to be recruited, to obtain 202 patients who receive transfused study platelets for surgical bleeding. The study will recruit patients in Australian tertiary hospitals.The study hypothesis is that cryopreserved platelets will be at least as effective as conventional liquid-stored platelets in the treatment of active bleeding due to surgery.

• Study Type: Interventional
• Enrollment (Actual): 388
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Belinda D Howe; Phone Number: +61 3 99030340; Email: belinda.howe@monash.edu

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4032
      • The Prince Charles Hospital
    • Douglas, Queensland, Australia, 4814
      • Townsville Hospital
    • Southport, Queensland, Australia, 4215
      • Gold Coast University Hospital
  • Victoria
    • Fitzroy, Victoria, Australia, 3065
      • St Vincent's Hospital Melbourne
    • Heidelberg, Victoria, Australia, 3084
      • Austin Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Cardiac surgery patients identified preoperatively as having a high risk of platelet transfusion by either:

   • the ACSePT (Australian Cardiac Surgery Platelet Transfusion (score)) risk prediction tool score ≥1 OR
   • the judgement of the clinicians caring for the patient
2. Written informed consent obtained prior to surgery

Exclusion Criteria:

1. Aged less than 18 years
2. Females of child-bearing age (18- 55 years) who are RhD (Rhesus type D)-negative or whose RhD (Rhesus type D) status is unknown
3. Receipt of platelet transfusion during this hospital admission
4. Deep Vein Thrombosis or Pulmonary Emboli first diagnosed within the preceding 6 months
5. More than one lifetime episode of Deep Vein Thrombosis or Pulmonary Emboli

6. Known inherited or acquired bleeding disorder (e.g. haemophilia, von Willebrand Disease, idiopathic thrombocytopenic purpura, aplastic anaemia, haematological malignancy, chronic liver disease), or any undiagnosed bleeding condition, if (and only if) such a disorder or condition is associated with a significant laboratory abnormality at the time of preoperative screening. i.e.

   • preoperative platelet count <50 000 or
   • INR (International Normalised Ratio) >2 or
   • aPTT (Activated Partial Thromboplastin Time) > 2 x upper limit of normal.
7. Treatment with warfarin, IV heparin or low-molecular weight heparin at "full" therapeutic anticoagulant doses, or other anticoagulant or anti-platelet medications such as factor Xa inhibitors (rivaroxaban, apixaban); factor II inhibitors (dabigatran); adenosine diphosphate receptor inhibitors (clopidogrel, prasugrel, ticagrelor, ticlopidine); glycoprotein IIB/IIIA inhibitors (abciximab, eptifibatide, tirofiban); phosphodiesterase inhibitors (cilostazol); or adenosine reuptake inhibitors (dipyridamole) UNLESS this medication has been discontinued in advance of surgery and its effect allowed to dissipate.
8. Known allergy to dimethylsulphoxide (DMSO)
9. Planned presence of an arterial line and central venous catheter for less than 12 hours postoperatively.
10. Known objection to receipt of human blood components
11. The treating physician believes it is not in the best interest of the patient to be randomised in this trial
12. Previous enrolment during this admission in a clinical trial of a medication or technique thought to influence bleeding, with the exception of any trial of aspirin (i.e. trials involving aspirin are permitted), OR previous enrolment in a clinical trial with a protocol that affects the transfusion of blood products.
13. Previous enrolment in this study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cryopreserved platelets; Platelets that have undergone a process to freeze, store and reconstitute platelets, extending their expiry to 2 years	Biological: Cryopreserved platelets; Platelets that have undergone a process to freeze, store and reconstitute platelets, extending their expiry to 2 years
Active Comparator: Liquid-stored platelets; Platelets that have been liquid stored, with an expiry of 5 days.	Biological: Liquid-stored platelets; Liquid-stored platelets as per standard practice

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Volume of post-surgical bleeding in the first 24 hours	Volume of post-surgical bleeding in the chest drains after cardiac surgery	First 24 hours from the time of ICU admission

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total volume of post-surgical chest drain bleeding	Total volume of post-surgical chest drain bleeding, beginning from the time of ICU admission until drain removal	From ICU admission up to removal of drains, death or day 28, whichever occurs first
Composite bleeding outcome using the BARC4 criteria	Composite bleeding outcome using the Bleeding Academic Research Consortium (BARC4) criteria (intracranial bleeding within 48 hours; reoperation after closure of sternotomy; transfusion of ≥5 Units whole blood or RBCs (red blood cells) within the 48 hour intra- or post-operative period (excluding cell saver blood); chest tube output ≥2 Litres within a 24 hour period)	Up to ICU discharge, death or Day 90, whichever occurs first
Number of units of Packed red blood cells transfused	Number of units of Packed red blood cells transfused in the first 24 hours after admission to ICU	in the first 24 hours after admission to ICU
Total number of units of Packed red blood cells transfused	Total number of units of Packed red blood cells transfused by the time of ICU discharge, including intraoperative transfusion	From operation commencement up to ICU discharge, death or day 90, whichever occurs first
Occurrence of any one of the following pre-specified potential complications	Occurrence of any one of the following specified potential complications: venous thromboembolism arterial occlusion acute coronary syndrome acute respiratory distress syndrome	Up to ICU discharge, death or day 90, whichever occurs first

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Volume of post-surgical chest drain bleeding	Volume of post-surgical chest drain bleeding in the first 6, 12, 18, 48 hours, beginning from the time of ICU admission	in the first 6, 12, 18, 48 hours, beginning from the time of ICU admission
Individual elements of the Bleeding Academic Research Consortium (BARC4) composite bleeding outcome	Individual elements of the Bleeding Academic Research Consortium (BARC4) composite bleeding outcome (intracranial bleeding within 48 hours; reoperation after closure of sternotomy; transfusion of ≥5 Units whole blood or RBC (red blood cells) within the 48 hour intra- or post-operative period (excluding cell saver blood); chest tube output ≥2 Litres within a 24 hour period)	Up to ICU discharge, death or day 90, whichever occurs first
Number of units of blood products	Number of units of blood products (Packed red blood cells, plasma, cryoprecipitate, open-label platelets, fibrinogen concentrate, recombinant factor VIIa, prothrombin complex concentrate, whole blood) transfused intraoperatively, in the first 6, 12, 18, 24, 48 hours, and at ICU discharge	in the first 6, 12, 18, 24, 48 hours*, and at ICU discharge or day 90, death or day 90, whichever occurs first
Delay between platelet order and commencement of first study platelet infusion	Delay between platelet order and commencement of first study platelet infusion	Delay between platelet order and commencement of first study platelet infusion, assessed up to 24 hours
Volume of blood in chest drains at the time of ICU admission	Volume of blood in chest drains at the time of ICU admission	From operation commencement up to ICU admission, death or 24 hours, whichever occurs first
Time to commencement of postoperative aspirin and prophylactic heparin	Time to commencement of postoperative aspirin and prophylactic heparin	From ICU admission up to commencement of aspirin and prophylactic heparin, death or day 90, whichever occurs first
Volume of fluid resuscitation recorded on the anaesthetic chart	Volume of fluid resuscitation recorded on the anaesthetic chart intraoperatively, following ICU admission in the first 6, 12, 18, 24, 48 hours, and at ICU discharge	intraoperatively, following ICU admission in the first 6, 12, 18, 24, 48 hours, and at ICU discharge, death or day 90, whichever occurs first
Haemoglobin concentration	Haemoglobin concentration, on day 1 postop and on the last measurement prior to ICU discharge, death or day 28, whichever occurs first	results measured on day 1 postop and on the last measurement prior to ICU discharge, death or day 28, whichever occurs first
Platelet count	Platelet count on day 1 postop and on the last measurement prior to ICU discharge, death or day 28, whichever occurs first	results measured on day 1 postop and on the last measurement prior to ICU discharge, death or day 28, whichever occurs first
Fibrinogen concentration	Fibrinogen concentration, on day 1 postop and on the last measurement prior to ICU discharge, death or day 28, whichever occurs first	results measured on day 1 postop and on the last measurement prior to ICU discharge death or day 28, whichever occurs first
INR (International Normalised Ratio)	INR (International Normalised Ratio) on day 1 postop and on the last measurement prior to ICU discharge, death or day 28, whichever occurs first	results measured on day 1 postop and on the last measurement prior to ICU discharge, death or day 28, whichever occurs first
APTT (Activated Partial Thromboplastin Time)	APTT (Activated Partial Thromboplastin Time) on day 1 postop and on the last measurement prior to ICU discharge, death or day 28, whichever occurs first	results measured on day 1 postop and on the last measurement prior to ICU discharge, death or day 28, whichever occurs first
Incidence of potential complications of DMSO (preservative used in cryopreserved platelets)	Incidence of potential complications of DMSO (preservative used in cryopreserved platelets) such as nausea, headache,tachyacrdia, bradycardia, hypertension	Up to hospital discharge, death or day 90, whichever occurs first
Duration of mechanical ventilation	Duration of mechanical ventilation in the first 90 postoperative days for the index admission	in the first 90 postoperative days for the index admission
Length of postoperative stay in ICU and in hospital	Length of postoperative stay in ICU and in hospital	up to ICU and hospital discharge, death or day 90, whichever occurs first
Total estimated healthcare cost, incorporating the cost of provision of cryopreserved or liquid-stored platelets	Total estimated healthcare cost, incorporating the cost of provision of cryopreserved or liquid-stored platelets	Up to hospital discharge, death or day 90, whichever occurs first
mortality at ICU, hospital and 90 days post-enrolment	mortality at ICU, hospital and 90 days post-enrolment	up to 90 day
ROTEM:EXTEM Clotting time (seconds)	ROTEM: EXTEM Clotting time (seconds)	Results before and after last study platelet transfusion (where performed) through study completion up to day 28.
ROTEM: EXTEM Clot formation time (seconds)	ROTEM: EXTEM Clot formation time (seconds)	Results before and after last study platelet transfusion (where performed) through study completion up to day 28.
ROTEM: EXTEM alpha angle (degrees)	ROTEM:EXTEM alpha angle (degrees)	Results before and after last study platelet transfusion (where performed) through study completion up to day 28.
ROTEM:EXTEM A10 (mm)	ROTEM:EXTEM A10 (mm)	Results before and after last study platelet transfusion (where performed) through study completion up to day 28.
ROTEM: EXTEM Maximum Clot Firmness (mm)	ROTEM: EXTEM Maximum Clot Firmness (mm)	Results before and after last study platelet transfusion (where performed) through study completion up to day 28.
ROTEM: EXTEM Lysis Index 30 min after CT (LI30) (%)	ROTEM: EXTEM Lysis Index 30 min after CT (LI30) (%)	Results before and after last study platelet transfusion (where performed) through study completion up to day 28.
TEG: Standard (Kaolin) Reaction (R) time (seconds)	TEG: Standard (Kaolin) Reaction (R) time (seconds)	Results before and after last study platelet transfusion (where performed) through study completion up to day 28.
TEG: Standard (Kaolin) Clot formation (K) time (seconds)	TEG: Standard (Kaolin) Clot formation (K) time (seconds)	Results before and after last study platelet transfusion (where performed) through study completion up to day 28.
TEG: Standard (Kaolin) Alpha angle (degrees)	TEG: Standard (Kaolin) Alpha angle (degrees)	Results before and after last study platelet transfusion (where performed) through study completion up to day 28.
TEG: Standard (Kaolin) Maximum amplitude (mm)	TEG: Standard (Kaolin) Maximum amplitude (mm)	Results before and after last study platelet transfusion (where performed) through study completion up to day 28.
TEG: Standard (Kaolin) Lysis at 30 mins (LY30) (%)	TEG: Standard (Kaolin) Lysis at 30 mins (LY30) (%)	Results before and after last study platelet transfusion (where performed) through study completion up to day 28.

Collaborators and Investigators

• Sponsor: Australian and New Zealand Intensive Care Research Centre
• Collaborators: Australian Red Cross
• Investigators: Study Chair: Michael Reade, ANZIC-Research Centre; Australian Defence Force, University of Queensland,

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2021
• Primary Completion (Estimated): July 1, 2024
• Study Completion (Estimated): August 1, 2024

Study Registration Dates

• First Submitted: May 9, 2019
• First Submitted That Met QC Criteria: June 17, 2019
• First Posted (Actual): June 19, 2019

Study Record Updates

• Last Update Posted (Actual): April 17, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Intraoperative Complications; Hemorrhage; Blood Loss, Surgical
• Other Study ID Numbers: ANZIC-RC/MR002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: At the completion of the study, at the discretion of the trial Management Committee and Monash University, an extract of the trial data without any patient identifiers may be made available on a case-by-case basis to investigators from reputable research organisations with a defined protocol and analysis plan, using the principles to protect patient anonymity described by the UK Medical Research Council. In accordance with the Australian & New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG) Terms of Reference for an endorsed trial, the CTG Chair must approve sharing of data with any third party, manuscripts derived from shared data must be submitted for CTG endorsement prior to publication and must acknowledge the role of the CTG in the original study, and a copy of the published manuscript must be provided to the CTG office.
• IPD Sharing Time Frame: De-identified data availability will begin 9 months after publication of the individual patient data meta-analysis combining both trial results, and end 36 months after this publication.
• IPD Sharing Access Criteria: Submissions to use data with investigators from reputable research organisations with a defined protocol and analysis plan, using the principles to protect patient anonymity described by the UK Medical Research Council.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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