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Trial registered on ANZCTR


Registration number
ACTRN12612001261808
Ethics application status
Approved
Date submitted
21/11/2012
Date registered
3/12/2012
Date last updated
3/10/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A pilot multicentre blinded randomised controlled clinical trial of frozen platelets vs. conventional liquid-stored platelets for the management of post-surgical bleeding
Scientific title
A pilot multi-centre blinded randomised controlled clinical trial in patients bleeding after cardiac surgery of cryopreserved platelets versus liquid-stored apheresis platelets assessing safety and effectiveness in controlling coagulopathy and haemorrhage.
Secondary ID [1] 281360 0
Nil
Universal Trial Number (UTN)
U1111-1137-1778
Trial acronym
CLIP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Thrombocytopenia 287607 0
Haemorrhage 287608 0
Condition category
Condition code
Blood 287940 287940 0 0
Clotting disorders
Anaesthesiology 288208 288208 0 0
Other anaesthesiology

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Cryopreserved platelets.
Each cryopreserved platelet unit will be prepared by the Australian Red Cross Blood Service from a unit of standard apheresis platelets. Cryopresevation will occur within 24 hours of platelet collection. The method of cryopreservation will be based closely on that described by the Netherlands Sanquin Blood Bank (Lelkins et al., Transfus.Apher.Sci. 2006; 34: 289-98), using 27% Dimethyl sulphoxide (DMSO) as a cryoprotectant, with removal of most of the DMSO by centrifugation prior to freezing.
Each unit will be reconstituted using approximately 280 ml fresh frozen plasma.

Patients randomised to recieve this intervention will be given a maximim of three cryopreserved units intravenously, as determined necessary by their treating clinicians.

The administration of the platelets will only occur in the Operating Theatre or during the patients stay in the Intensive Care Unit (ICU), which is usually 24-48 hours.

Patients may receive only one bag of platelets, or up to three, over a period of hours as determined by the clinicians. Once the patient is discharged from the ICU, no further study platelets will b given. Conventional platelets will be given if determined to be necessary by the treating clinical team.

At The Prince Charles Hospital, a substudy examining impedance aggregation and viscoelastic parameters at point of care immediately before and at set time points after transfusion of study platelets will be conducted. The intent of this study is two-fold: firstly, to examine whether cryopreserved platelets produce different results to conventional, liquid stored platelets using these relatively new techniques (i.e. “are the platelets different?”) and secondly to examine the relationship between these test results and clinical indices of platelet haemostatic efficacy that will be quantified as part of the main trial (i.e. “do these novel tests of platelet function reflect bleeding outcomes?”). Appendix 1 dated 19 APR 16 for The Prince Charles Hospital substudy of platelet function testing. All participants enrolled at Prince Charles Hospital under that CLIP inclusion/exclusion criteria and will also completee the sub-study.
Intervention code [1] 285852 0
Treatment: Other
Intervention code [2] 286132 0
Treatment: Devices
Comparator / control treatment
Conventional liquid-stored apheresis platelets.

A unit of apheresis platelets is collected from a single blood donor. At the time of blood donation, donated blood enters a device that separates platelets and a small fraction of plasma from the other components of blood, including the red and white blood cells. The red and white blood cells are returned to the donor.

A unit of apheresis platelets contains the same number of platelets as that derived from 4-6 whole blood donations. Apheresis platelets are a standard method of providing platelet transfusions throughout Australia.

Both study groups will receive platelets derived from apheresis donations. The difference between groups will be that the 'intervention' platelets will have been crypopreserved at -80C for up to 2 years, while the 'control' platelets will be stored in liquid form at room temperature for a maximum of 5 days.

The frequency and duration of liquid-stored apheresis platelet transfusion will be exactly the same as in the cyropreserved platelet group, describe din detail above.

After three units of 'control' apheresis study platelets, if more platelets are required the patient will receive open-label (non-study) platelets, which may be either apheresis platelets or pools of 4-6 platelets derived from whole blood donations, according to blood bank availability.
Control group
Active

Outcomes
Primary outcome [1] 288148 0
Protocol feasability, as assessed by:
- anticipated number and proportion of patients enrolled
- intervention delivered as per protocol, and
- outcome measures able to be assessed
Timepoint [1] 288148 0
1 year from first randomisation
Primary outcome [2] 288149 0
Acceptability to clincians in comparison to conventional platelet transfusion, as assessed by:
- willingness to enrol patients into the study (inferred from recruitment rate and proportion of eligible patients)
- willingness to continue with study treatments rather than switch to open-label platelets (inferred from number of protocol violations)
Timepoint [2] 288149 0
1 year from first randomisation
Secondary outcome [1] 299505 0
Volume of post-surgical bleeding, assessed by measurement of the volume of blood in the mediastinal and pleural drains inserted towards the end of the operation.

The volume measured will be that which accumulates from the time of starting to close the surgical incision (t=0) until the time the drain catheters are removed or the time of ICU discharge, whichever is the earlier. An alternative definition of t=0 will also be utilised, in which t=0 is the time of admission to the intensive care unit.

This data will be collected contemporaneously on a case report form at the patient's bedside in the ICU.
Timepoint [1] 299505 0
Removal of intercostal catheters or time of ICU discharge, whichever is the earlier
Secondary outcome [2] 299506 0
Total volume and unit dose (by type) of postoperative blood products (packed red blood cells, study platelets, open-label platelets, cryoprecipitate, fresh frozen plasma, clotting factor concentrates) infused after t=0.

This data will be collected contemporaneously on a case report form at the patient's bedside in the ICU.
Timepoint [2] 299506 0
a. during the ICU stay and
b. in the first 24 hours postoperatively
Secondary outcome [3] 299507 0
Volume of crystalloid, colloid, red cells, and clotting factors (and total volume of all of these fluids) required for postoperative fluid resuscitation infused after t=0.

This data will be collected contemporaneously on a case report form at the patient's bedside in the ICU.
Timepoint [3] 299507 0
a. between t=0 and removal of intercostal catheters or time of ICU discharge, whichever is the earlier.
b. in the first 24 hours postoperatively
Secondary outcome [4] 299508 0
“Thromboelastograph (TEG), thromboelastogram (ROTEM) and / or Multiplate aggregometry”, clotting assessment..
Timepoint [4] 299508 0
a. no more than 1 hour before commencement of the 1st platelet infusion.
b. no more than 3 hours after the expected last dose of platelets
c. as clinically indicated.
Secondary outcome [5] 299509 0
Platelet count, as assayed by the hospital clinical haematology laboratory using patient venous or arterial blood collected into EDTA Vacutainers and assayed using an automated cell counter.
Timepoint [5] 299509 0
a. no more than 1 hour before commencement of the 1st platelet infusion.
b. no more than 3 hours after the expected last dose of platelets
c. as clinically indicated.
Secondary outcome [6] 299510 0
Immediate, short term or medium term adverse effects, especially:
- dimethylsulfoxide (DMSO) toxicity, assessed using a checklist that lists possible features of toxicity (including rash, abdominal pain, agitation, oliguria, somnolence, heart block, systemic vasoconstriction, hypertension, sinus tachycardia or bradycadia), each of which must be declared present or absent every 2 hours until 6 hours after the last study platelet transfusion.
- local or systemic infection, assessed by the treating clinicians and defined as a. the requirement to commence antibiotic therapy, change antibiotic therapy, or continue antibiotic prophylaxis that would otherwise have been discontinued, or b. the removal of any medical device (e.g. intravenous cannula) due to suspicion of infection, or c. one or more positive blood or other body fluid cultures that are considered by the treating clinicians not to be contaminants.
- fever, defined as temperature >38.5C, and assessed for duration in hours and number of discrete episodes.
- venous thromboembolism, defined as a positive duplex ultrasound examination or radio-opaque contrast examination of the arm or leg veins. One Duplex ultrasound examination of the legs will occur between 48-96 hours postoperatively in all patients. Other investigations for venous thromboembolism will be performed as clinically indicated.
- arterial occlusion, defined as peripheral arterial occlusion as identified by duplex ultrasound or radio-opaque contrast examination performed as clinically indicated, or evidence of coronary ischaemia as identified by a change in the 12-lead electrocardiogram consistent with new ischaemia or infarction.
- need for surgical intervention, as defined by the need to open the cardiac surgical wound or make a new surgical approach to the chest cavity, and
- acute respiratory distress syndrome, as defined by the 2012 'Berlin definition' that includes PaO2/FiO2 ratio, chest radiograph appearance, respiratory system compliance, positive end expiratory pressure requirement, and expired minute volume (Ranieri et al, JAMA 2012) and assessed by the treating clinical staff on the contemporaneously-recorded case report form.
Timepoint [6] 299510 0
at time of ICU discharge
Secondary outcome [7] 300041 0
Length of stay in ICU and in hospital post randomisation, as assessed by inspection of the medical record.
Timepoint [7] 300041 0
at time of ICU and hospital discharge
Secondary outcome [8] 300042 0
Total estimated healthcare cost whilst in the ICU, as assessed by inspection of the medical record and application of the ANZICS-defined standard daily cost of ICU admission and hospital admission.
Timepoint [8] 300042 0
at time of ICU discharge
Secondary outcome [9] 300043 0
28 day mortality, as assessed by inspection of the medical record.
Timepoint [9] 300043 0
28 days post-randomisation
Secondary outcome [10] 328254 0
Sub-study specific outcomes
Change in ROTEM viscoelastic EXTEM and FIBTEM results from pre- to post- platelet transfusion in each study group
Timepoint [10] 328254 0
Within 30 minutes prior to starting an infusion of platelets and within 30 minutes after finishing each infusion.
Secondary outcome [11] 328255 0
Change in Multiplate impedance aggregation results from pre- to post- platelet transfusion in each study group
Timepoint [11] 328255 0
Within 30 minutes prior to starting an infusion of platelets and within 30 minutes after finishing each infusion.

Eligibility
Key inclusion criteria
1. Aged 18 years or older
2. Undergoing cardiac surgery with anticipated post-operative management in an ICU
3. Presence of an arterial line, central line and continuous monitoring for the purposes of surgery and postoperative care
4. Written informed consent obtained prior to surgery
5. Patients with any three of the following 28:
a. Preoperative haemoglobin < 13.5 g/dL
b. Female sex
c. Redo surgery
d. Preoperative creatinine >120 umol/L
e. Non-elective surgery
f. Age > 65
g. Body weight < 77kg (estimated or actual)
h. Non-isolated surgery
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Receipt of platelet transfusion during this hospital admission
2. Women of child bearing age (18-55 years)
3. Death is deemed imminent and inevitable in <24hrs
4. Previous enrolment in this study
5. Previous enrolment in a clinical trial of a medication or technique thought to influence bleeding during this admission, with the exception of any trial of aspirin.
6. Known bleeding diathesis (for example, hemophilia or Von Willebrand Disease) or haematological malignancy, associated with abnormal clotting indices on blood investigations taken in the immediate preoperative period (i.e. platelet count <100 000, INR>1.5, aPTT > 1.5 x upper limit of normal)
7. Known allergy to dimethylsulphoxide (DMSO)
8. Known objection to receipt of human blood products
9. Intellectual impairment
10. The treating physician believes it is not in the best interest of the patient to be randomised in this trial

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Patients will be screened for eligibility at the time of their preoperative surgical or anaesthetic consultation. Consent to participate will be sought from eligible patients. Patients will not be randomised at this stage.

Patients will only be randomised into the study if their treating anaesthetist or intensivist has decided they require a platelet transfusion. No patient can be randomised until after the surgeon begins to close the surgical incision.

Central randomisation will be by computer via secure internet connection.

Cryopreserved platelets are suspended in a small volume (approx. 300ml) of fresh frozen plasma as part of the process of reconstitution. This will make the cryopreserved and liquid-stored apheresis platelets appear similar, preserving the blinding of staff to the patients study allocation. Platelets (both cryopreserved and liquid stored) will be supplied with study labels overlying their original labels that obscure their method of storage (cryo- or liquid- preserved), but that retain the original ARCBS information (unique identifier number and bar code, ABO and Rh group, expiry date, and recommended storage conditions).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The treatment allocation will be determined using a minimisation algorithm implemented as part of the web-based system. Randomisation will be stratified by hospital.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,VIC
Recruitment postcode(s) [1] 5820 0
4032
Recruitment postcode(s) [2] 5821 0
3084
Recruitment postcode(s) [3] 6041 0
2050

Funding & Sponsors
Funding source category [1] 286355 0
Commercial sector/Industry
Name [1] 286355 0
Australian Red Cross Blood Service
Address [1] 286355 0
Level 3, 417 St Kilda Road
Melbourne VIc 3004
Country [1] 286355 0
Australia
Funding source category [2] 286356 0
Other Collaborative groups
Name [2] 286356 0
Australian and New Zealand College of Anaesthetists
Address [2] 286356 0
ANZCA House
630 St Kilda Road
Melbourne Vic 3004
Country [2] 286356 0
Australia
Funding source category [3] 286357 0
Government body
Name [3] 286357 0
Australian Defence Force
Address [3] 286357 0
Office of the ADF Surgeon General.
CP2-5-034
Canberra, ACT 2610
Country [3] 286357 0
Australia
Primary sponsor type
University
Name
University of Queensland
Address
Burns, Trauma and Critical Care Research Centre
Level 9, Health Sciences Building
Royal Brisbane & Women's Hospital
Herston Rd
HERSTON QLD
4129 Australia
Country
Australia
Secondary sponsor category [1] 285144 0
None
Name [1] 285144 0
Address [1] 285144 0
Country [1] 285144 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 288431 0
Royal Brisbane and Women's Hospital
Ethics committee address [1] 288431 0
Human Research Ethics Office
Royal Brisbane and Women's Hospital
Level 7, Block 7
Hertston Rd
HERSTON
QLD 4029
Ethics committee country [1] 288431 0
Australia
Date submitted for ethics approval [1] 288431 0
29/01/2013
Approval date [1] 288431 0
28/05/2013
Ethics approval number [1] 288431 0

Summary
Brief summary
Platelets are cells in the blood that help to stop bleeding. The transfusion of platelets can be an essential and life-saving managment for patients bleeding after surgery or trauma. The purpose of this study is to assess the safety and efficacy of cryopreserved (frozen stored) platelets compared to conventional liquid platelets for the treatment of bleeding in cardiac surgical patients.

Hypothesis - That cryopreseved platelets will be at least as effective and safe as conventional liquid stored platelets in the manangment of active bleeding related to surgery.
Trial website
Trial related presentations / publications
Holley AD, Marks D, Johnson L, Reade MC, Badloe JF, Noorman F. Frozen blood products: clinically effective and potentially ideal for remote Australia. Anaesthesia and Intensive Care, in press, accepted 17 OCT 12.

Australian and New Zealand Intensive Care Society Clinical Trials Group Research Spring Forum October 2012
Public notes

Contacts
Principal investigator
Name 34801 0
Prof Professor Michael Reade
Address 34801 0
Consultant Intensivist Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital
Postal: Level 9, UQ Health Sciences Building, Royal Brisbane and Women's Hospital QLD 4029
Country 34801 0
Australia
Phone 34801 0
+61 7 3365 5114
Fax 34801 0
Email 34801 0
m.reade@uq.edu.au
Contact person for public queries
Name 18048 0
Ms Ms Renae Deans
Address 18048 0
Burns, Trauma and Critical Care Research Centre
University of Queensland
Level 9, UQ Health Sciences Building
Royal Brisbane and Women’s Hospital
Herston Rd
HERSTON QLD 4029
Country 18048 0
Australia
Phone 18048 0
+61 7 3646 8894
Fax 18048 0
Email 18048 0
r.deans@uq.edu.au
Contact person for scientific queries
Name 8976 0
Prof Prof. Michael Reade
Address 8976 0
Burns, Trauma and Critical Care Research Centre
University of Queensland
Level 9, UQ Health Sciences Building
Royal Brisbane and Women’s Hospital
Herston Rd
HERSTON QLD 4029
Country 8976 0
Australia
Phone 8976 0
+61 7 3365 5114
Fax 8976 0
Email 8976 0
m.reade@uq.edu.au

No information has been provided regarding IPD availability
Summary results
No Results