A Multi-center, Randomized, Controlled Trial Evaluating the Effects of Early High-Dose Cryoprecipitate in Adult Patients With Major Trauma Hemorrhage Requiring Major Hemorrhage Protocol (MHP) Activation
Phase: PHASE3
Conditions: Trauma Injury
Sponsor: Bryan Cotton

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A multi-centre, randomised, controlled trial evaluating the effects of early high-
dose cryoprecipitate in adult patients with major trauma haemorrhage requiring 
major haemorrhage protocol (MHP) activation 
 
NCT04704869 
 
Version Date: 09/30/2019 
 

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A multi-centre, randomised, controlled trial evaluating the 
effects of early high-dose cryoprecipitate in adult patients 
with major trauma haemorrhage requiring major 
haemorrhage protocol (MHP) activation 
 
CRYOSTAT-2 
Early cryoprecipitate in trauma 
Version: 2.0 
 
Date: 
30/09/2019 
CTU Ref: 
57 
ISRCTN: 
ISRCTN 14998314 
IRAS ref: 
210735 
 
Protocol Development Group: 
 
Name 
Affiliation 
Authors’ Contributions 
Karim Brohi 
QMUL 
KB, SS, RD, NC conceived of the study. 
KB, RD, NC, SS, JBe, LGr initiated the 
study design and AD, JBr and CF helped 
with implementation. 
KB is the grant holder. 
DC, HT provided statistical expertise in 
clinical trial design and will oversee the 
statistical analysis. 
SM provided health economic expertise. 
All authors contributed to refinement of the 
study protocol and approved the final 
version 
Simon Stanworth 
NHSBT 
Ross Davenport 
QMUL 
Nicola Curry 
OUHFT 
Claire Foley 
NHSBT 
Alison Deary 
NHSBT 
Jonathan Benger 
University of West of 
England 
Dave Collett 
NHSBT 
Helen Thomas 
NHSBT 
Laura Green 
NHSBT/ Barts’ Health 
Stephen Morris 
UCL 
 
 
 
 
 

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Approved by: 
Name 
Role 
Signature 
Date 
Professor Karim Brohi 
Chief Investigator 
Professor Simon Stanworth Co-Chief Investigator 
Helen Thomas 
Lead Statistician 
Alison Deary 
Head of Operations, 
CTU 
Renate Hodge 
Clinical Data Services 
Manager 

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General Information 
This document was constructed using the National Health Service Blood and Transplant 
Clinical Trials Unit (NHSBT CTU) Protocol Template FRM4468 Version 1.0, which is based 
on the MRC CTU Protocol template Version 4.0 and the SPIRIT guidelines 2013.(1, 2) It 
describes the CRYOSTAT-2 trial, coordinated by the NHSBT CTU and provides 
information about procedures for entering patients/participants into it. The protocol should 
not be used as an aide-memoire or guide for the treatment of other patients. Every care 
has been taken in drafting this protocol, but corrections or amendments may be necessary. 
These will be circulated to the registered investigators in the trial, but sites entering 
participants for the first time are advised to contact the Trial Manager to confirm they have 
the most up to date version. 
Compliance 
The trial will be conducted in compliance with the approved protocol, the Declaration of 
Helsinki the Principles of Good Clinical Practice (GCP), European Commission Directive 
2005/28/EC with the implementation in national legislation in the UK by Statutory 
Instrument 2004/1031 and subsequent amendments, the UK Data Protection Act 2018, the 
National Health Service Research Governance Framework for Health and Social Care 
(RGF) and any other applicable national regulations. 
 
Queen Mary University of London (QMUL) and NHSBT have a responsibility as joint data 
controllers to ensure compliance with the General Data Protection Regulation (GDPR) and 
Section 251 of the NHS Act 2006 (originally Section 60 of the Health and Social Care Act 
2001), which provides the statutory power to ensure that NHS patient identifiable 
information needed to support essential NHS activity can be used without the consent of 
patients. 
 
Sponsor 
The Queen Mary, University of London (QMUL) is the primary trial sponsor and has 
delegated responsibility for the overall management of the CRYOSTAT-2 trial to the 
NHSBT CTU. Queries relating to the QMUL sponsorship of the trial should be addressed 
to: Mays Jawad, JRMO, QMUL Innovation Department, 5 Walden Street, London, E1 2EF, 
E-mail: research.governance@qmul.ac.uk. 
Funding 
This is a study funded by NIHR Health Technology Assessment Board – grant number: 
15/57/02 
Authorisations and Approvals 
This trial was approved by the National Institute of Health Research and is, therefore, part 
of the Clinical Research Network Portfolio of Studies. Health and Care Research Wales 
has also approved the study. 
 
Trial Registration 
This trial has been registered with the International Standard Randomised Clinical Trials 
Register, where it is identified as ISRCTN 4998314 
Trial Administration 

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Please direct all enquiries to the Trial Manager in the first instance. Clinical queries will be 
passed to the Chief Investigator via the Trial Manager. 
 
CTU Details 
 
NHSBT CTU 
Administration Office: 
01223 588088 
Fax: 
01223 5848136 
NHS Blood and Transplant 
Email: 
cryostat2@nhsbt.nhs.uk 
Long Road 
Cambridge 
CB2 0PT 
 
Coordinating CTU Staff Details 
 
Trial Manager 
Joanne Lucas 
Tel: 
01223 588720 
Email: joanne.lucas@nhsbt.nhs.uk 
Trial Coordinator 
Amy Evans 
Tel: 
01223 588016 
Email: amy.evans@nhsbt.nhs.uk 
Data Manager 
Rupa Sharma 
Tel: 
01223 5880923 
Email: rupa.sharma@nhsbt.nhs.uk 
Statistician 
Helen Thomas 
Tel: 
01179 757485 
Email: helen.thomas@nhsbt.nhs.uk 
Clinical Operations 
Manager 
Claire Foley 
Tel: 
07823 351738 
Email: claire.foley@nhsbt.nhs.uk 
 
Chief Investigator 
 
Professor 
Karim Brohi 
Tel: 
020 7882 2483 
Address 
Centre for Trauma 
Sciences, Blizard Institute, 
Queen Mary University of 
London, Barts and the 
London School of Medicine 
and Dentistry, 4, Newark 
Street 
Email: 
k.brohi@qmul.ac.uk 
City 
London 
County, Post Code 
E1 2AT 
Fax: 
020 7882 2200 
Country 
UK 
Co- Chief Investigator 
Professor 
Simon Stanworth 
Tel: 
01865 387976 
NHS Blood and Transplant 
and Department of 
Haematology, Oxford 
University Hospitals NHS 
Foundation Trust, 
Email: 
simon.stanworth@nhsbt.n 
hs.uk 

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Level 2, John Radcliffe 
Hospital, Headley Way 
Headington, Oxford 
OX3 9BQ 
 
Co-Investigators 
 
 
Professor Jonathan Benger 
University of the West of England 
Helen Thomas 
NHSBT CTU 
Dr Nicola Curry 
Oxford University Hospitals NHS 
Foundation Trust 
Dr Ross Davenport 
Queen Mary University of London 
Dr Laura Green 
NHSBT and Barts’ Health NHS Trust 
Professor Stephen Morris 
University of Cambridge 
Alison Deary 
NHSBT CTU 
For full details of Trial Committees, please refer to Section 15. 

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Study Synopsis 
 
Scientific title of clinical study 
A multi-centre, randomised, controlled trial evaluating the 
effects of early high-dose cryoprecipitate in adult patients with 
major trauma haemorrhage requiring major haemorrhage 
protocol (MHP) activation. 
Public title of clinical study 
Early cryoprecipitate for severe bleeding after trauma. 
Protocol Short Title/Acronym 
CRYOSTAT-2: early cryoprecipitate in trauma. 
Protocol Version and Date 
Version 2.0 
03/07/2019 
Primary Sponsor 
QMUL 
Funder 
NIHR Health Technology Assessment Board 
ISRCTN 
14998314 
Date Study Registered 
24/04/2017 
Study design 
• 
Interventional phase III study 
• 
Multi-centre, interventional, randomised, unblinded, parallel 
controlled trial 
• 
Participants will be randomised 1:1 via opaque sealed 
envelopes held securely in participating EDs 
• 
The study will be run and conducted at sites in UK and USA. 
Health Condition(s) or 
Problem(s) Studied 
Major trauma haemorrhage 
Key inclusion and exclusion 
criteria 
Inclusion criteria: 
Patients are eligible for this trial if: 
1. The participant is judged to be an adult, aged 16 years or 
older in the UK (or according to local guidance) and has 
sustained severe traumatic injury 
2. The participant is deemed by the attending clinician to have 
active haemorrhage 
AND REQUIRES: 
3. Activation of the local major haemorrhage protocol for 
management of severe blood loss 
AND HAS STARTED or HAS RECEIVED: 
4. at least one unit of any blood component 
Exclusion criteria: 
A patient will not be eligible for this study if he/she fulfils one or 
more of the following criteria: 
1. The participant has been transferred from another hospital 
2. The trauma team leader deems the injuries incompatible 
with life 
3. More than 3 hours have elapsed from the time of injury 

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Setting 
Emergency departments, operating theatres and intensive care 
units of participating trauma centres 
Interventions to be compared 
Intervention arm: 
Early intravenous infusion of cryoprecipitate (3 pools of 
cryoprecipitate – the equivalent to 15 single units of 
cryoprecipitate or 6g fibrinogen), within 90 minutes of arrival at 
hospital in addition to standard major haemorrhage therapy 
Comparator arm: 
Major haemorrhage therapy alone 
Study hypothesis 
Major bleeding after injury is exacerbated by a clotting 
abnormality – ‘acute traumatic coagulopathy’ (ATC). ATC is 
characterised by hypofibrinogenaemia and fibrinolysis. Early 
replacement of fibrinogen will treat the coagulopathy and may 
reduce bleeding and improve outcomes. This study will evaluate 
whether early fibrinogen supplementation in the form of 
cryoprecipitate (equivalent of 6g fibrinogen replacement) during 
major traumatic haemorrhage will reduce mortality. 
Primary outcome measure(s) 
All-cause mortality at 28 days 
Key Secondary outcome 
measure (s) 
1. All-cause mortality (including death from bleeding) at 6 
hours, 24 hours, 6 months and 12 months from admission 
2. Death from bleeding at 6 hours and 24 hours 
3. Transfusion requirements, in numbers of units, for RBC, 
platelets, FFP & cryoprecipitate at 24 hours from admission, 
including pre-hospital transfusion 
4. Destination of participant at time of discharge from hospital 
5. Quality of life measures: EQ5D-5L and Glasgow Outcome 
Score at discharge/day 28 and 6 months after injury 
6. Hospital resource use up to discharge or day 28, including 
ventilator days, hours spent in critical care and in-patient 
stays. 
7. Symptomatic thrombotic events 
Duration of Study 
Duration of set up – 4 months to obtain all ethical/regulatory 
approvals, finalise contracts, prepare essential documents and 
study database and start to initiate study centres. 
Duration of recruitment – The trial is expected to recruit over 36 
months, based on an average recruitment rate of 1.5 
participants/month at each UK MTC (n = 25) and Level 1 trauma 
centres in USA (n=4). 
Duration of follow-up for each participant will be 12 months. 

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Duration of study close-out – 8 months to complete all data 
cleaning and statistical analysis and site close out. 
The planned total trial duration is 48 months. 
Countries of recruitment 
UK and USA. 
Target Sample Size 
784 participants per arm 
Approximately 1142 from UK and 426 from sites in the USA 
Date of first enrolment 
1st July 2017 
Contact Details for Public 
Queries 
Claire Foley 
07823 351738 
claire.foley@nhsbt.nhs.uk 
Contact Details for Scientific 
Queries 
Professor Karim Brohi 
020 7882 2483 
k.brohi@qmul.ac.uk 
Lay Summary of Study 
Bleeding is a major cause of death in severely injured patients. 
Many of these patients rapidly develop an abnormality of the 
clotting system, known as ‘acute traumatic coagulopathy’ (ATC). 
The two most important abnormalities in ATC are a low 
fibrinogen and increased clot breakdown. It has been 
hypothesised, and there are some non-randomised studies that 
show, that treatment of trauma patients who are bleeding with 
fibrinogen therapy stops bleeding more effectively than standard 
care, reduces transfusion needs and may reduce death rates. 
This study will look at the effects of transfusing early high dose 
cryoprecipitate (which is a concentrated source of fibrinogen), to 
adult trauma patients with severe bleeding within 90 minutes of 
arrival at hospital. This study will evaluate whether early 
cryoprecipitate reduces death rates when major bleeding occurs 
after injury. 

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Study Schema 
 
 
 
 
 

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Contents 
General Information .......................................................................................................3 
Study Synopsis ................................................................................................................ 6 
Study Schema ..................................................................................................................9 
Contents ........................................................................................................................ 10 
Abbreviations and Glossary ........................................................................................13 
1. 
Background .............................................................................................................. 15 
1.1 
Introduction ......................................................................................................... 15 
1.2 
Summary of existing knowledge ..........................................................................16 
1.2.1 
Need for a trial ..............................................................................................17 
1.2.2 
Dose selection of intervention ......................................................................17 
1.2.3 
Explanation for choice of comparators .........................................................18 
1.3 
Potential benefits and risks of Intervention ..........................................................18 
1.4 
Study Objectives ................................................................................................. 19 
1.4.1 
Description of trial design .............................................................................19 
2. 
Study Setting .............................................................................................................20 
3. 
Selection of Sites/Clinicians ....................................................................................21 
3.1 
Site/Investigator Inclusion Criteria ...................................................................... 21 
3.2 
PI Qualifications and Agreements .......................................................................21 
4. 
Selection of Participants ..........................................................................................22 
4.1 
Participant Inclusion Criteria ................................................................................22 
4.2 
Participant Exclusion Criteria .............................................................................. 22 
4.3 
Patients who object to a blood transfusion ......................................................... 23 
4.4 
Co-Enrolment Guidelines ....................................................................................23 
4.4.1 
Screening Procedures and Pre-randomisation Investigations .................... 23 
5. 
CONSENT.................................................................................................................. 24 
5.1 
Consent Procedures ........................................................................................... 24 
5.2 
Screening Log ......................................................................................................26 
6. 
Randomisation ..........................................................................................................27 
6.1 
Allocation – sequence generation ...................................................................... 27 
6.2 
Allocation – concealment mechanism ................................................................ 27 
6.3 
Allocation – implementation ................................................................................ 27 
6.4 
Randomisation Practicalities ...............................................................................28 
6.5 
Randomisation Codes ........................................................................................ 28 
6.6 
Co-enrolment Guidelines .....................................................................................28 
6.7 
Blinding ................................................................................................................28 
7. 
Treatment of Participants ....................................................................................... 29 
7.1 
Introduction ......................................................................................................... 29 
7.2 
Interventions ........................................................................................................29 
7.2.1 
Intervention to be studied .............................................................................29 
7.2.2 
Comparator ...................................................................................................29 
7.2.3 
Standard major haemorrhage protocol .........................................................29 
7.2.4 
Preparation of Intervention ...........................................................................30 
7.2.5 
Administration of Intervention .......................................................................30 
7.2.6 
Concomitant Medications .............................................................................30 
7.2.7 
Transfusions not permitted ...........................................................................30 
7.2.8 
Medications not permitted ............................................................................30 
8. 
Study Outcomes ...................................................................................................... 31 
8.1 
Primary Outcome Measure ..................................................................................31 

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8.1.1 
Secondary Outcome Measures .................................................................... 31 
8.1.2 
Safety Outcome Measures ........................................................................... 31 
9. 
Assessments and Follow-up .................................................................................... 32 
9.1 
Trial Assessment Schedule ................................................................................. 32 
9.2 
Procedures for Assessing Efficacy ...................................................................... 32 
9.2.1 
Screening Procedures .................................................................................. 33 
9.2.2 
Enrolment Procedures .................................................................................. 33 
9.2.3 
Procedures at the time of early cryoprecipitate administration ..................... 33 
9.2.4 
Procedures at 6 hours after arrival at hospital ..............................................34 
9.2.5 
Procedures at 24 hours after arrival at hospital ............................................ 34 
9.2.6 
Procedures for day 28 follow up or day of discharge .................................... 34 
9.2.7 
Procedures for day 28 follow up ................................................................... 34 
9.2.8 
Procedures for follow up post discharge in the event that written informed 
consent is not obtained ...............................................................................................35 
9.3 
Procedures in the event of death ......................................................................... 35 
9.4 
Procedures for Assessing Quality of Life (all sites in England and international 
sites depending on resource) at day 28 follow up or day of discharge and 6 months .....36 
9.5 
Procedures for Assessing Safety ......................................................................... 36 
9.6 
Other Assessments.............................................................................................. 38 
9.7 
Participant transfers ............................................................................................. 38 
9.8 
Loss to Follow-Up ................................................................................................ 38 
9.9 
Trial Closure ......................................................................................................... 38 
10. Safety Reporting ....................................................................................................... 39 
10.1 
Definitions of Adverse Events .............................................................................. 39 
10.1.1 
Expected Serious Adverse Events................................................................ 39 
10.1.2 
Investigator Responsibilities ......................................................................... 40 
10.1.3 
Investigator Assessment of SAEs ................................................................. 40 
10.1.4 
Investigator Notification ................................................................................ 40 
10.2 
Sponsor’s Responsibilities (QMUL with NHSBT CTU delegated responsibility) .. 40 
10.3 
Statutory Reporting .............................................................................................. 41 
11. Quality Assurance and Control ............................................................................... 42 
11.1 
Risk Assessment ................................................................................................. 42 
11.2 
Central Monitoring at CTU ...................................................................................42 
11.3 
On-Site Monitoring ............................................................................................... 42 
11.3.1 
Direct access to participant records .............................................................. 42 
11.3.2 
Confidentiality ............................................................................................... 42 
11.4 
Auditing ................................................................................................................ 42 
12. Statistical Considerations ........................................................................................ 43 
12.1 
Sample size ......................................................................................................... 43 
12.2 
Interim Monitoring and Analyses .......................................................................... 43 
12.3 
Analysis Plan ....................................................................................................... 44 
12.3.1 
Analysis of primary and secondary outcomes .............................................. 44 
12.3.2 
Health Economic Analyses ........................................................................... 45 
12.3.3 
Analysis Population and Missing Data .......................................................... 46 
13. Ethical and Regulatory Issues ................................................................................. 47 
13.1 
Compliance .......................................................................................................... 47 
13.1.1 
Site Compliance ............................................................................................ 47 
13.1.2 
Data Collection and retention........................................................................ 47 
13.1.3 
Access to Data .............................................................................................. 47 
13.2 
Ethical Conduct of the Study ................................................................................ 47 
13.2.1 
Ethical Considerations .................................................................................. 47 

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13.3 
Confidentiality ......................................................................................................48 
13.4 
Other approvals ...................................................................................................48 
14. Indemnity .................................................................................................................. 49 
14.1 
Declaration of interests ....................................................................................... 49 
15. Oversight and Trial Committees .............................................................................50 
15.1 
Trial Management group (TMG) ......................................................................... 50 
15.2 
Trial Steering Committee .....................................................................................50 
15.3 
Independent Data Monitoring Committee ............................................................50 
15.4 
Role of Study Sponsor ........................................................................................ 50 
16. Publication ................................................................................................................ 51 
16.1 
Dissemination ..................................................................................................... 51 
16.2 
Authorship and acknowledgements.....................................................................51 
16.3 
Approvals ............................................................................................................ 52 
16.4 
Identification ........................................................................................................ 52 
17. Protocol Amendments ............................................................................................ 53 
18. References ................................................................................................................ 54 
Appendix A: Overview of consent process in England and Wales ............................57 

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Abbreviations and Glossary 
AE 
Adverse Event 
AIS 
Abbreviated Injury Scale 
AR 
ARDS 
ATC 
Adverse Reaction 
Acute Respiratory Distress Syndrome 
Acute Traumatic Coagulopathy 
CI 
Chief Investigator 
CLRN 
Comprehensive Local Research Network 
COM 
Clinical Operations Manager 
CRF 
CTCOFR 
Case Report Form 
Composite Time To Organ Failure Resolution 
CTU 
NHSBT Clinical Trials Unit 
DCR 
Damage Control Resuscitation 
DH 
Department Of Health 
DM 
DMC 
DPA 
DVT 
Data Manager 
Data Monitoring Committee 
Data Protection Act 
Deep Venous Thrombosis 
ED 
Emergency Department 
Fg 
FgC 
FFP 
Fibrinogen 
Fibrinogen Concentrate 
Fresh Frozen Plasma 
GCP 
Good Clinical Practice 
GCS 
Glasgow Coma Scale 
GDPR 
General Data Protection Regulation 
GP 
General Practitioner 
HE 
HDU 
HR 
HRA 
Health Economics 
High Dependency Unit 
Haemostatic Resuscitation 
Health Research Authority 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
ISRCTN 
International Standard Randomised Controlled Trial Number 
IRAS 
Integrated Research Application System 
MHP 
Major Haemorrhage Protocol 
MI 
MOF 
Myocardial Infarction 
Multiple Organ Failure 
NHS 
National Health Service 
NHSBT 
NHS Blood and Transplant 
NIHR 
National Institute for Health Research 
ONS 
Office for National Statistics 
PALS 
PDS 
PE 
Patient Advice and Liaison Service 
Patient Demographic System 
Pulmonary Embolism 
PI 
Principal Investigator 
PIS 
Patient Information Sheet 
PROMs 
Patient Reported Outcome Measures 
QA 
Quality Assurance 
QC 
Quality Control 

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QMUL 
Queen Mary, University of London 
QoL 
RBC 
Quality Of Life 
Red Blood Cells 
RCT 
Randomised Controlled Trial 
R&D 
Research And Development 
RN 
Research Nurse 
RR 
Respiratory Rate 
SABRE 
Serious Adverse Blood Reactions And Events 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SBP 
Systolic Blood Pressure 
SHOT 
Serious Hazards Of Transfusion 
SOP 
Standard Operating Procedure 
STRAR 
Serious Transfusion Related Adverse Reaction 
SSI 
Site Specific Information 
TARN 
The Trauma Audit and Research Network 
TBI 
Traumatic Brain Injury 
TMF 
Trial Master File 
TMG 
Trial Management Group 
TSC 
TXA 
Trial Steering Committee 
Tranexamic Acid 

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1. 
Background 
1.1 
Introduction 
Worldwide, trauma accounts for 5.8 million deaths every year [1], equivalent to one death 
every nine minutes and it is the leading cause of death in persons under the age of 44. 
The impact on life years lost is significant and equal to the life years lost from cancer, heart 
disease and HIV combined. Bleeding accounts for 40% of all injury-related deaths, many 
within hours of injury and there is a high burden of major haemorrhage for both patients 
and the NHS. A recent NIHR PgfAR [2] identified that approximately 7780 people suffer 
major haemorrhage in England & Wales each year, of which an estimated 2800 will die, at 
a total cost of nearly £150m to the NHS [3]. This value does not include any societal 
effects, such as lost working days. The lost economic output to the UK annually from death 
and disability has been estimated to be up to £3.7 billion [4]. 
 
25% of all trauma patients have abnormal blood clotting known as acute traumatic 
coagulopathy (ATC), which causes higher rates of bleeding, major haemorrhage and a 
three- to four-fold increased risk of death [5]. There are two main clotting abnormalities in 
ATC: low fibrinogen levels [6] and increased clot breakdown (fibrinolysis) [7]. Data from 
over 500 trauma patients in the NIHR PGfAR study [2] have established that low fibrinogen 
levels are common at hospital admission and are independently associated with 24 hour 
and 28 day survival. Fibrinogen is the key pro-coagulant factor needed for stable clot 
formation. It forms insoluble fibrin strands, is the ligand for platelets and forms the 
haemostatic plug at sites of bleeding. Fibrinogen is the earliest coagulation protein to fall 
during active major bleeding [8], and this abnormality will limit the formation of stable clots. 
 
The beneficial effects of correcting fibrinolysis in trauma haemorrhage have been 
addressed in a global RCT - CRASH-2. This study evaluated the effects of an anti- 
fibrinolytic drug, tranexamic acid (TXA) on mortality [9]. CRASH-2 data have not only 
confirmed the importance of TXA therapy as a means to improve clinical outcome, but 
have also shown that it is vital to deliver haemostatic therapy early (i.e. within 3 hours of 
injury) [10]. This has been confirmed with the recent findings from the PROPPR study 
[11]. 
 
Trauma patients who present to hospital with major haemorrhage are treated using an 
integrated approach known as damage control resuscitation (DCR). This focuses on 1) 
diagnostic and treatment pathways aimed at identifying and stopping on-going bleeding 
e.g. emergency surgery or interventional radiology and 2) best supportive care, known as 
‘haemostatic resuscitation’ – which includes blood transfusion (using major haemorrhage 
protocols (MHP)), reversal of blood acidosis and active re-warming of patients. 
Haemostatic resuscitation is defined by the early (empiric) and simultaneous delivery of 
RBCs and FFP in high ratio and in conjunction with TXA [12,13]. Low dose fibrinogen 
supplementation (in the form of cryoprecipitate in the UK) is recommended as part of the 
treatment for major haemorrhage in national guidelines [12] although therapy is often 
triggered by fibrinogen blood results. In a recent UK epidemiological study conducted at 22 
trauma centres and units across England & Wales [14] significant delays in the 
administration of cryoprecipitate to bleeding trauma patients were reported (median time 
for cryoprecipitate administration - 184 minutes), by which time 25% of patients had died. 
 
This trial will evaluate the effects of early administration of high dose cryoprecipitate (within 
90 minutes of arrival at hospital) when used as treatment for major trauma haemorrhage. 
The primary endpoint will be all-cause mortality at day 28. Secondary measures will 

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include: transfusion requirements, total ventilator days, hospital stay including ICU/HDU 
stay up to study day 28, all-cause mortality (up to 12 months) and safety measures 
evaluating arterial and venous thrombotic events up to study day 28 (or date of discharge 
from an acute care facility, whichever is the sooner). Quality of life measures will include: 
destination of patient at discharge from hospital; Glasgow Outcome Score and EQ5D-5L at 
discharge and at 6 months post-injury. Hospital resource use up to discharge or day 28 will 
be calculated. 
 
 
1.2 
Summary of existing knowledge 
 
Early clinical data suggest that fibrinogen supplementation may improve outcomes for 
trauma haemorrhage, by improving clot strength [15], reducing blood loss [16,17] and 
increasing survival [18]. In an uncontrolled observational study of 131 haemorrhagic 
patients, mortality rates were reported to fall by 14% after fibrinogen treatment [18]. Two 
observational cohort trauma studies [19-21] have also reported reduction of mortality in 
patients receiving higher fibrinogen content during massive transfusion therapy. Despite 
very high doses of fibrinogen supplementation (up to 12g), plasma levels did not increase 
beyond the normal range in health and there were no reported adverse events [18]. 
 
Recent systematic reviews appraising the management of major bleeding, focusing on 
transfusion therapy and the use of fibrinogen supplementation, have been published [22- 
24]. A Cochrane review evaluating the effectiveness of fibrinogen concentrate for bleeding 
patients found six small trials in elective surgery, all of low quality and underpowered for 
mortality but with a clear reduction in the incidence of allogeneic transfusions (RR 0.47, 
95% CI 0.32 to 0.72) [23]. Twelve completed fibrinogen concentrate trials have been 
identified in an ongoing Cochrane review evaluating pro-haemostatic agents [25], but none 
in trauma. There are five small ongoing RCTs in trauma which are evaluating fibrinogen 
concentrate (NCT01475344), (NCT02203968), (NCT02344069), (NCT01545635), 
(EudraCT2015 - 000875-28), aiming to recruit 300 patients in total. All use surrogate 
outcomes and none evaluate mortality. There are no other trials evaluating cryoprecipitate 
in trauma outwith the feasibility trial CRYOSTAT1. 
 
A feasibility RCT evaluating the early use of cryoprecipitate in major trauma haemorrhage 
has been completed (CRYOSTAT1) [26]. This study demonstrated that it was possible to 
conduct a randomised trial in 43 adult trauma patients with severe bleeding at two major 
trauma centres in the UK (Royal London Hospital and John Radcliffe, Oxford) with a 
parallel study conducted by the UK military at Camp Bastion, Afghanistan. Although not 
powered for clinical outcomes, the results confirmed that it was feasible to deliver 
cryoprecipitate within 90 minutes of admission and also suggested that early 
cryoprecipitate therapy maintained blood fibrinogen levels above 1.8 g/L during active 
bleeding with a signal for reduced mortality (2 deaths vs. 6 deaths) in the treatment arm of 
the study. Of particular interest to this study was that patients entered into the CRYOSTAT 
study in both intervention and comparator arms had mean blood fibrinogen levels at 
admission of 1.55 g/L, i.e. within the normal range. Treatment with early cryoprecipitate 
raised the fibrinogen blood levels during the first haemorrhagic episode, but by 24 hours 
there was no difference in fibrinogen levels between arms. In addition, no thrombotic 
events were seen in the intervention arm. This feasibility trial emphasised the importance 
of pragmatic inclusion criteria and a simple case report form for focused outcome and 
adverse event data collection. 

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There are two main sources of fibrinogen replacement: cryoprecipitate and fibrinogen 
concentrate. A recent systematic review comparing the efficacy of cryoprecipitate and 
fibrinogen concentrate reported a scarcity of high quality data [27]. However, the four 
included studies (three observational, 1 RCT) showed no difference in fibrinogen 
increment; transfusion requirement; thromboembolic events or bleeding between the 
products. In vitro and ex vivo work have also shown that these two blood products lead to 
similar improvements in coagulopathy during trauma haemorrhage and the effects are 
dependent on fibrinogen concentration rather than formulation [6]. Cryoprecipitate is one 
quarter of the cost per gram of fibrinogen and a recent economic evaluation confirmed that 
even after cryoprecipitate wastage, fibrinogen concentrate is at least twice as expensive 
[28]. 
 
 
1.2.1 
Need for a trial 
 
Fibrinogen levels are lower in trauma patients who present to hospital with coagulopathy 
and bleeding and are an independent predictor of mortality at 24 h and 28 days [6]. 
Fibrinogen is known to be rapidly depleted during major traumatic haemorrhage (Figure A) 
and recent work has shown that it is not restored despite the use of haemostatic 
resuscitation. 
 
(A) 
(B) 
 
(A) Fibrinogen is low immediately on admission and falls precipitously during MHP transfusion of RBC units (U) 
without supplementation. (B) In the CRYOSTAT1 trial early supplementation with fibrinogen (cryoprecipitate) 
was able to restore fibrinogen levels to the recommended range (>2 g/L) by the time of administration of the 
4th RBC unit. 
 
 
In the pilot study (CRYOSTAT1) it was shown that early replacement of fibrinogen with 
cryoprecipitate was able to rapidly restore fibrinogen levels (Figure B) and may reduce 
mortality from trauma haemorrhage [26]. 10% of all cryoprecipitate, which is the current 
standard source of concentrated fibrinogen in UK, is transfused to trauma patients [29] and 
no large study has evaluated the clinical importance of fibrinogen therapy. 
 
 
1.2.2 
Dose selection of intervention 
 
The dose of fibrinogen concentrate for this study was chosen using results from ex vivo 
coagulation testing and CRYOSTAT1 data. CRYOSTAT1 used a 4g dose of fibrinogen (2 
pools of cryoprecipitate) and results were suggestive of a beneficial clinical effect, without 

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a safety risk. Clauss fibrinogen levels were maintained above 1.8g/L during active 
haemorrhage in patients in receipt of early cryoprecipitate (i.e. 4g fibrinogen). Ex vivo 
data, where increasing concentrations of either fibrinogen concentrate or cryoprecipitate 
were added to coagulopathic whole blood samples from trauma patients, showed an 
incremental benefit of fibrinogen supplementation between 3g and 12g, dependent on 
dose of fibrinogen administered [6]. A 6g dose of fibrinogen, as cryoprecipitate or 
fibrinogen concentrate, resulted in significant increases in ROTEM clot strength values, 
suggestive of clinical efficacy. 
 
The aim of this study is to evaluate 3 pools of cryoprecipitate (i.e. 6g fibrinogen) that will 
afford the most benefit to patients with the least associated risk. The CRYOSTAT1 study 
reported no thromboembolic events in the intervention arm and the average increase in 
Clauss fibrinogen level during active bleeding was 0.8g/L which is in-line with other studies 
[26]. When patients with major bleeding are treated with 4g fibrinogen supplementation, on 
average the blood fibrinogen level rises by 1g/L [30-32]. We have shown that trauma 
patients with major bleeding and ATC have fibrinogen levels of 1.6 g/L upon hospital 
admission [6]. Three pools of cryoprecipitate would be expected to increase the blood 
fibrinogen level by 1-1.5g/L and this would mean that the highest expected level of Clauss 
fibrinogen during active bleeding will be 3.0–3.5g/L; well within the normal range. This is 
not expected to be associated with an increase in thromboembolic disease. 
 
 
1.2.3 
Explanation for choice of comparators 
This trial will evaluate the intervention: 3 pools of cryoprecipitate (15 units – 6g fibrinogen) 
IV, given as rapidly as possible, in addition to the standard major haemorrhage protocol. 
 
The comparator will be the standard major haemorrhage protocol alone. 
 
All participants in the intervention arm will receive 3 pools of cryoprecipitate (i.e. 15 units or 
6g fibrinogen). This decision has been based on data from the CRYOSTAT trial, as well as 
prospectively collected fibrinogen blood levels in 517 trauma patients and previous patient 
data [30,31]. 
 
The early cryoprecipitate will be an additional treatment, over and above standard practice. 
Current standard practice for the management of trauma patients with severe bleeding is 
to use a major haemorrhage protocol (MHP) which enables rapid delivery and infusion of 
high ratio red blood cells and fresh frozen plasma. 
 
For practical reasons, this trial is unblinded and is being conducted without a placebo 
comparator. The risks to the trial integrity is minimised given that the primary outcome of 
28 day mortality is a hard endpoint. 
 
1.3 
Potential benefits and risks of Intervention 
The potential benefits of the intervention are: an increase in blood levels of fibrinogen; 
improved haemostatic potential, reduction in bleeding and need for transfusion therapy 
and increased survival. 
 
There are two main potential risks from the infusion of cryoprecipitate: a) thromboembolic 
disease and b) transfusion related adverse events which include transfusion transmitted 
infection and transfusion associated circulatory overload. These potential risks will be 
evaluated by the safety outcome data. The CRYOSTAT1 study administered 4g fibrinogen 

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and found no venous or arterial thrombotic adverse events within the intervention arm and 
at 24 h and up to 28 days after randomisation the intervention group had fibrinogen levels 
that were no different to the comparator group. All participants entered into CRYOSTAT-2 
will be expected to receive appropriate thromboprophylaxis (as per NICE guidelines [33]). 
 
 
1.4 
Study Objectives 
This study will investigate the following: 
• 
The effects of early fibrinogen supplementation in the form of 3 pools (15 units – 6g 
fibrinogen) of cryoprecipitate on 28-day mortality 
 
1.4.1 
Description of trial design 
 
This is a randomised, unblinded, parallel group, controlled, multi-centre trial. 

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2. 
Study Setting 
 
This study will be conducted in the Emergency Departments of participating Major Trauma 
Centres (MTCs) in the UK and at 4 Level 1 Trauma Centres in the USA. 
 
Participating UK sites include: 
 
Royal London Hospital, London 
John Radcliffe Hospital, Oxford 
Southampton Hospital, Southampton 
St George’s Hospital, London 
St Mary’s Hospital, London 
Kings College Hospital, London 
Derriford Hospital, Plymouth 
Addenbrooke’s Hospital, Cambridge 
Southmead Hospital, Bristol 
James Cook University Hospital, Middlesbrough 
Leeds General Infirmary, Leeds 
Queen’s Medical Centre, Nottingham 
Royal Victoria Infirmary, Newcastle 
Hull Royal Infirmary, Hull 
Northern General Hospital, Sheffield 
Queen Elizabeth Hospital, Birmingham 
Royal Preston Hospital, Preston 
University Hospital, Coventry 
University Hospital of North Staffordshire, Stoke on Trent 
Manchester Royal Infirmary, Manchester 
Royal Salford Hospital, Salford 
Aintree University Hospital, Liverpool 
University Hospital of Wales, Cardiff 
 
Participating sites in the USA include: 
 
University of Texas Health Science Center, Houston 
Shock Trauma Center, University of Maryland 
LA County, University of Southern California 
Ben Taub Hospital, Houston. 

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3. 
Selection of Sites/Clinicians 
In the UK, all adult MTCs will be included in this study. 
 
For other sites, selection will be based on the presence of appropriate clinical and 
research infrastructure including adequate local resources and facilities to support 
recruitment, and adequate qualified staff to conduct the trial properly and safely. 
The site selection process will include an evaluation of the site’s potential rate of accrual to 
the trial, which will review the types of patient treated, an assessment of how many 
patients would be eligible, and how many patients may be recruited given the site level 
resource. Site selection will include a review of any barriers to recruitment such as other 
trials recruiting from the same patient population. 
 
The trial sponsor has overall responsibility for site and Investigator selection. 
 
3.1 
Site/Investigator Inclusion Criteria 
To participate in the CRYOSTAT-2 trial, investigators and clinical trial sites must either be 
a UK MTC or fulfil a set of basic criteria that have been prepared by the CRYOSTAT-2 
Trial Management Group (TMG) and are defined below. 
The clinical trial sites should: 
A) Be designated a Level 1 trauma centre and/or admit > 50 adult trauma patients per 
year who require activation of the major haemorrhage protocol in Emergency 
Departments (ED) 
B) Have an established research infrastructure in ED, enabling recruitment of actively 
bleeding trauma patients 
C) Have a defined Major Haemorrhage Protocol (MHP) 
 
3.2 
PI Qualifications and Agreements 
The investigator should be qualified by education, training and experience to assume 
responsibility for the proper conduct of the trial at their site and should provide evidence 
of such qualifications through an up to date curriculum vitae and/or other relevant 
documentation requested by the Sponsor, the REC, and/or the regulatory authorities. 

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4. 
Selection of Participants 
 
Adult trauma patients will be identified as follows: (1) at scene by the Air Ambulance team 
who will notify the receiving hospital; (2) by the trauma team leader on arrival of the patient 
at the emergency department or (3) by the research team personnel following a trauma 
call activation. Patients will be assessed for eligibility to enter the trial according to the 
criteria set out below. 
 
In England and Wales:If patients are eligible for entry into the study following initial 
screening, they will be enrolled automatically under a waiver of consent. 
 
 
 
4.1 
Participant Inclusion Criteria 
Patients are eligible for this trial if: 
 
1. 
The participant is judged to be an adult (according to local practice, e.g. 16 years or 
older in UK) and has sustained severe traumatic injury 
 
2. 
The participant is deemed by the attending clinician to have on-going active 
haemorrhage 
 
AND REQUIRES: 
3. Activation of the local major haemorrhage protocol for management of severe 
blood loss 
 
AND HAS STARTED or HAS RECEIVED: 
4. at least one unit of any blood component 
 
 
4.2 
Participant Exclusion Criteria 
 
A patient will not be eligible for this trial if he/she fulfils one or more of the following 
criteria: 
 
1. 
The participant has been transferred from another hospital 
 
2. 
The trauma team leader deems the injuries incompatible with life* 
 
3. 
More than 3 hours have elapsed from the time of injury (taken as time of the 999 
call if unknown by medical team). 
* Incompatible with life: While some situations are objective, such as decapitation, others 
will remain in the experienced, but subjective opinion of the physician. These include 
catastrophic brain injury, severe truncal injuries, and a constellation of injuries that results 
in the patient being declared dead on arrival (DOA) or that will likely result in death within 
30 minutes of arrival, regardless of resuscitative efforts. Further examples of patients 
inappropriate for the trial include: (1) Moribund patient- expected to die within one hour of 
ED admission (per trauma team attending); (2) Severe traumatic brain injury patients in 
which further care has been deemed “futile” by neurosurgical examination and evaluation 

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of CT findings; (3) Received greater than five minutes of cardiopulmonary resuscitation 
(CPR) in the pre-arrival or ED setting; (4) Patients with concomitant burns greater than 
20% total body surface area (TBSA) burns or documented inhalation injury. 
 
 
4.3 
Patients who object to a blood transfusion 
Patients who object to a blood transfusion will not be eligible for this study. As part of the 
eligibility criteria assessment, patients will be excluded if they have not received at least 
one unit of any blood component. This criterion will therefore exclude patients who refuse 
a blood transfusion. 
 
In the UK: Patients who are known Jehovah’s witnesses or with an advanced directive 
refusing blood transfusion will not be eligible for this study. 
 
In the USA: As part of the rigorous community consultation process we will specifically 
approach those in communities that have noted objections to blood transfusion for 
religious reasons and consult with them directly. In addition to medic-alert bracelets or 
other IDs that they may already carry, we will offer them other identifiers of “opt-out” such 
as bracelets, free of charge. This will be in addition to local practice at the participating 
institution who will already be practicing their standards of care for identifying those with 
medic-alert bracelets and other identifiers. 
 
Patients will be considered eligible for enrolment in this trial if they fulfil all of the inclusion 
criteria and none of the exclusion criteria detailed above. 
 
4.4 
Co-Enrolment Guidelines 
See Section 6.6 “Co-enrolment Guidelines” 
 
 
4.4.1 
Screening Procedures and Pre-randomisation Investigations 
1. 
The local trauma team (or in some centres the research team) will be responsible 
for identifying suitable participants 
2. 
The eligibility checklist will be completed. 
3. 
A screening log will be completed (see section 5.1.1). 

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5. 
CONSENT 
5.1 
Consent Procedures 
 
5.1.1 Consent Procedures in England and Wales 
The consent procedures described below apply to sites in England and Wales. 
 
This study seeks to include participants who have been affected by injury that has resulted 
in uncontrolled bleeding. These participants will be incapacitated at the time of screening 
for this study for a variety of reasons including the circumstances of the traumatic event, 
the nature of their injuries, being in severe pain, being under anaesthesia, having reduced 
consciousness, and/or the use of strong analgesia. Furthermore, sudden traumatic injury 
cannot be predicted or foreseen, and there is no opportunity to seek consent in advance. 
The participants will therefore be incapable of giving consent prior to enrolment in the 
study. 
 
Severe trauma haemorrhage is an emergency condition and any treatment needs to be 
given as soon as possible. The need for urgent treatment in this study means that the 
implementation of the research cannot be delayed until advice can be obtained from a 
professional or personal consultee. As injury is an unexpected event, it is uncommon that 
relatives are present at the time of arrival at hospital, and they too are unable to go through 
the consultee process in the timeframe required of the intervention. Participants who are 
incapable of giving consent in emergency situations are an established exception to the 
general rule of informed consent in clinical trials. This is acknowledged in the Declaration 
of Helsinki, 2013: 
 
‘Research involving subjects who are physically or mentally incapable of giving consent, 
for example, unconscious patients, may be done only if the physical or mental condition 
that prevents giving informed consent is a necessary characteristic of the research 
population. In such circumstances the physician should seek informed consent from the 
legally authorised representative. If no such representative is available and if the research 
cannot be delayed, the study may proceed without informed consent provided that the 
specific reasons for involving subjects with a condition that renders them unable to give 
informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research study should 
be obtained as soon as possible from the subject or a legally authorised representative.’ 
 
The following procedure, which is in accordance with the Declaration of Helsinki, 2013, will 
be used for giving information and enrolling participants in England and Wales into the 
CRYOSTAT-2 study. 
 
5.1.1 1 Study entry in England and Wales 
All participants will be enrolled in the study without informed participant consent due to the 
emergency nature of the trial (i.e. a “waiver of consent” will be applied). The participant will 
then be randomised and the allocated intervention will be delivered within ninety minutes. 
This may be before the participant regains capacity or there is any opportunity to identify 
and approach a personal consultee. As a result, consent can only be sought for the 
participant to remain in the study through the ongoing collection of follow-up data, and 
“retrospective consent” for the administration of cryoprecipitate is not possible. As soon as 
appropriate after the administration of the intervention, a personal consultee for the 

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participant will be identified and approached, given an information sheet and asked to 
provide their advice for the participant to remain in the trial. If the participant remains 
incapacitated and a personal consultee is not available, or if approaching the personal 
consultee is likely to induce a delay or it is deemed by the research team to be 
inappropriate to approach the personal consultee, advice from a professional consultee will 
be sought. 
 
For the purpose of this study, a professional consultee is defined as a clinician (qualified 
doctor or registered nurse) with appropriate training (according to local Trust policies) to 
take on the role of professional consultee. Professional consultees must not be directly 
involved in the patient’s care and cannot be a member of the core research team at site. 
Professional consultees should be aware of the aims of the study and know what the 
intervention is. 
 
Sites should obtain the advice of a professional consultee as soon as possible after 
randomisation to enable continued collection of data should the patient be discharged/self- 
discharge/transferred to another NHS Trust before the research team can approach the 
patient and/or personal consultees for consent/advice. 
 
The research team will monitor the ongoing status of the participant and their ability to 
provide informed consent. If the participant does not regain capacity, a personal and/or 
professional consultee’s advice is sufficient for the participant to remain in the study for the 
ongoing collection of follow-up data at site up to day 28, discharge or death. 
 
5.1.1.2 Information giving and written informed consent in England and Wales 
When a participant regains capacity to give consent, full information will be provided to 
them and they will be asked to sign a consent form agreeing to their continuation in the 
study. It will be explained to the participant that they have already received the study 
treatment. 
 
If a patient is discharged/self-discharges or is transferred to another NHS Trust before 
consent is obtained, researchers should contact the participant at home to complete the 
consent process. Up to three attempts to contact participants at home are permitted (a 
combination of telephone calls and letters at the researchers’ discretion). In some 
situations, it may not be possible for the research team to locate or contact the participant 
post discharge, and in such circumstances, section 251 approval will be sought via the 
Confidentiality Advisory Group to permit continued data collection for mortality status via 
NHS Digital (see section 9). 
 
For any participant who is enrolled but does not regain capacity up to study day 
28/discharge, or who did not have capacity prior to being injured, the opinion of a personal 
consultee will be sought, under the provisions of the Mental Capacity Act, at the earliest 
opportunity and no later than the day 28 follow-up point. 
 
In the event that a participant dies during their hospital stay, an opinion regarding the 
participant’s likely wishes may already have been sought from a personal consultee as 
described above. In some situations, where a participant’s death occurs soon after hospital 
arrival, there may have been no opportunity for contact between the research team and 
the personal consultee prior to the participant’s death. In this instance, we recognise that 
approaching a personal consultee to ask their opinion is likely to be distressing and without 
benefit. Families of bereaved participants should not be contacted by the research team 

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after participant death to obtain personal consultee advice. In these cases, advice from a 
professional consultee should be sought so that data collection can be completed at site. 
 
In this circumstance the local clinician in charge of the participant’s care will access and 
anonymise the data to be provided to the study teams. These procedures will be 
conducted in accordance with the Access to Health Records Act 1990. Although we will 
not approach a personal consultee to seek their opinion when a participant dies before any 
contact has been made with the research team, in all other cases we will make every effort 
to inform relatives that the participant was entered into the trial. 
 
In the rare event that a participant is found to be below 16 years of age after the point of 
entry, consent will be obtained from the participant’s Parent/Guardian and assent will be 
sought from the child if and when sufficiently recovered. This will be evidenced by 
parental/guardian signature on the personal consultee form. 
 
A participant or their consultee is free to withdraw their consent or change their opinion 
regarding continuation in the trial at any time without penalty, loss of benefits or alterations 
to the care which they receive. Participants can withdraw with or without permission for 
follow-up data collection. If participants withdraw and do not provide permission for 
continued data collection, data collected up to the point of withdrawal will be retained for 
continued data collection. Although the participant is not required to give a reason for 
withdrawing consent, a reasonable effort will be made to establish this reason while fully 
respecting the participant’s rights. 
 
The requirements of the relevant ethics committee will be adhered to at all times. 
 
 
 
 
5.1.3 Consent procedures for US sites 
Participants enrolled at international sites will be subject to the regional or national ethical 
code of practice for conducting research in incapacitated adults and this may include 
waiver of consent procedures e.g. “Exception From Informed Consent” (USA). 
 
 
5.2 
Screening Log 
 
A screening log will be completed once a week at each site which will record all patients 
considered for eligibility for enrolment in the trial. The log will include age, gender, 
inclusion/exclusion criteria and other reasons for non-enrolment. The screening log data 
will be reviewed at regular intervals by the CTU. 
 
The local principal investigator and research nurse will be responsible for completing the 
screening log after an eligible patient has been identified and considered for participation 
in the trial. 

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6. 
Randomisation 
 
6.1 
Allocation – sequence generation 
The allocation sequence will be produced by the trial statistician using SAS statistical 
software. The allocation sequence will have a varying block size that will not be disclosed, 
and will be stratified by centre. 
 
Participants will be allocated to a 1:1 ratio intervention (early cryoprecipitate) vs. 
comparator (standard MHP) arm. 
See Section 10. 
 
6.2 
Allocation – concealment mechanism 
Allocation cards will be prepared, which will be contained within sequentially numbered 
opaque sealed envelopes, independently and in advance by the CTU and provided to 
participating sites. Each envelope will contain a randomisation number and the allocated 
treatment. Envelopes will be opened in sequential order. 
 
These envelopes will be tested for 100% concealment and closed with a tamper-proof 
seal, preventing opening and resealing. Envelopes will be securely stored in a locked 
cupboard at each site, access to which is controlled by the research team. Envelopes will 
be sequentially released by the CTU in small batches sufficient to support projected 
recruitment and replace used envelopes. 
 
6.3 
Allocation – implementation 
Randomisation can take place in the Emergency Department or the Transfusion 
Laboratory/Blood Bank. 
 
Members of clinical teams, research teams and transfusion teams will enrol participants 
and assign them to the randomised treatment. 
 
Participant allocation will be made by selecting the next pre-sealed randomisation 
envelope in sequence at each site. The number on the envelope will be checked against 
an enrolment log to ensure that the correct envelope has been selected. 
 
The recruiting staff will complete the enrolment log each time an envelope is taken for use 
and will sign and date the envelope across the unbroken seal to confirm that the next 
available and lowest numbered envelope of the batch has been taken, that it is unopened 
and bears no evidence of tampering. 
 
The participant's initials, date of birth and hospital number will also be written on the 
envelope prior to opening. (If initials and date of birth are not known, document the unique 
identifiers used at your participating hospital for identifying unknown patients). Correct and 
sequential use of envelopes will be strictly audited by the site research team and CTU trial 
coordinator at site monitoring visits. 
 
If the randomised intervention differs from that the participant received, a reason for this 
will be requested. These processes will allow for clear and regular auditing of the 
randomisation process through comparison with the randomisation list held by the 
statistician. 

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Defrosted cryoprecipitate for early administration will be supplied to the ED by the site’s 
blood bank/transfusion laboratory. This is an unblinded trial and as soon as the 
cryoprecipitate reaches the participant’s bedside it will be administered. 
 
The cryoprecipitate that is used for study purposes (rather than for standard major 
haemorrhage therapy) will be specifically labelled as CRYOSTAT-2 cryoprecipitate to 
facilitate tracking for study purposes and to distinguish the intervention from cryoprecipitate 
given as part of the standard major haemorrhage protocol. This can be achieved by use of 
the yellow study bags provided by NHSBT CTU or by locally designed labels. 
 
6.4 
Randomisation Practicalities 
Eligibility for enrolment will be assessed with reference to the specific inclusion and 
exclusion criteria, described in Sections 4.1 and 4.2 
 
The local PI/delegate is responsible for informing the participant’s General Practitioner 
(GP) of the patient’s participation in the trial, and for placing a label indicating trial 
participation in the participant’s medical notes or annotating their electronic notes 
appropriately. 
 
The cryoprecipitate for early administration in the trial will be stored in the blood 
bank/transfusion laboratory in keeping with national guidelines for the storage and 
administration of blood products. 
 
The PI or delegate must update the site screening log by adding randomisation numbers 
for all participants randomised. 
 
 
6.5 
Randomisation Codes 
The participant ID (randomisation) number consists of a 6 character number, the first 
character denoting R and the remaining 5 digits the unique participant number from 00001 
to 99999 e.g. R00001. 
 
 
6.6 
Co-enrolment Guidelines 
Participation in any other type of intervention trial will be considered for each individual trial 
and must be approved by the Trial Management Group or Co-Investigator. 
 
6.7 
Blinding 
This is an unblinded trial. The risks to the trial integrity is minimised given that the primary 
outcome of 28 day mortality is a hard endpoint. 

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7. 
Treatment of Participants 
7.1 
Introduction 
Participants will be randomised 1:1 to either the intervention (early cryoprecipitate) or 
comparator (standard MHP) arm. 
 
The early cryoprecipitate will be started as per randomisation as soon as possible and 
within 90mins after arrival in ED. 
 
The participant’s eligibility criteria MUST be confirmed to ensure they are still eligible prior 
to administration of the trial product. 
 
The cryoprecipitate for early administration will be stored and defrosted in the blood 
bank/transfusion laboratory at the participating hospital and sent to the Emergency 
department on request. 
 
7.2 
Interventions 
 
7.2.1 
Intervention to be studied 
 
Early cryoprecipitate – 3 pools (equivalent to 15 single units cryoprecipitate or 6g 
fibrinogen supplementation), infused as rapidly as possible, within 90 minutes of arrival 
at hospital. 
 
IN ADDITION to standard major haemorrhage protocol 
 
 
7.2.2 
Comparator 
Standard major haemorrhage protocol only 
 
 
7.2.3 
Standard major haemorrhage protocol 
Standard treatment of major traumatic haemorrhage involves administering red blood 
cells, fresh frozen plasma and platelets following a major haemorrhage protocol (MHP). 
 
Each participating site will follow their local standardised MHP which will broadly align 
with the current accepted best practice for transfusion therapy i.e. Damage Control 
Resuscitation, and which will include: 
 
High ratio empiric delivery of RBC, FFP and platelets in a balanced resuscitation. 
 
The recent PROPPR randomised clinical trial reported that there was no difference in 
overall survival between early administration of plasma, platelets and red blood cells in a 
1:1:1 ratio compared to 1:1:2. However more patients in the 1:1:1 group achieved 
‘anatomic’ haemostasis and fewer experienced death due to exsanguination by 24 hours 
[11]. The MHP will comprise a balanced resuscitation with blood products and will be 
standardised as much as possible across participating sites, however some degree of 
variation is inevitable and pragmatic, reflecting actual clinical practice. Furthermore, the 
transfusion products given may vary to some extent from the target ratio according to 
blood product availability and the participant’s ongoing clinical condition. 

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7.2.4 
Preparation of Intervention 
Early cryoprecipitate (3 pools = 6g fibrinogen) will be stored in its frozen state and will be 
defrosted according to the local standard operating procedures for each blood 
bank/transfusion laboratory at participating sites. In UK these procedures will be in 
accordance with the ‘red book’ transfusion guidelines [34]. 
 
Cryoprecipitate can be defrosted within 15-20 minutes and will be made available as 
quickly as possible. The bags of cryoprecipitate for early administration will be labelled with 
a trial specific label in order to differentiate trial cryoprecipitate from any cryoprecipitate 
given as standard of care. 
 
As an alternative and depending on approval for use, pre thawed cryoprecipitate may also 
be used during the trial. 
 
7.2.5 
Administration of Intervention 
The early cryoprecipitate will be started as soon as possible and within 90 minutes of 
participant arrival at hospital and enrolment. 
 
The 3 pools (15 units) of cryoprecipitate will be administered as rapidly as possible via an 
intravenous line and in accordance with local practice. 
 
The cryoprecipitate must not be mixed with platelets prior to infusion. 
 
 
7.2.6 
Concomitant Medications 
There are no restrictions on treatments that can/cannot be given during this trial as long as 
the treatments are part of standard care and are not administered as part of another trial 
(unless authorised by the TMG or delegated Co-Investigator). 
 
7.2.7 
Transfusions not permitted 
None 
 
7.2.8 
Medications not permitted 
None 

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8. 
Study Outcomes 
Please also refer to the section on sample size for a discussion about outcomes. 
 
 
8.1 
Primary Outcome Measure 
 
All-cause mortality at 28 days 
 
8.1.1 
Secondary Outcome Measures 
 
All-cause mortality (including death from bleeding) at 6 hours, 24 hours, 6 months and 12 
months from admission 
 
Death from bleeding at 6 hours and 24 hours 
 
Transfusion requirements, in numbers of units, for RBC, platelets, FFP & cryoprecipitate at 
24 hours from admission, including pre-hospital transfusion 
 
Destination of participant at time of discharge from hospital 
 
Quality of life measures: EQ5D-5L and Glasgow Outcome Score at discharge/day 28 and 
6 months after injury 
 
Hospital resource use up to discharge or day 28, including ventilator days, hours spent in 
critical care and in-patient stays 
 
 
8.1.2 
Safety Outcome Measures 
 
Symptomatic thrombotic events: venous thromboembolism (DVT, PE) and arterial 
thrombotic events (eg MI, stroke) from randomisation up to day 28 or discharge from 
hospital. 

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9. 
Assessments and Follow-up 
9.1 
Trial Assessment Schedule 
 
Timepoint* 
On arrival at 
hospital 
Enrolment 
Post randomisation 
T0 
T1 
T2 
T3 
T4 
T5 
T6 
ENROLMENT 
Eligibility Screen 
X 
Emergency waiver 
X 
Randomisation/allocation 
X 
INTERVENTION 
 
Cryoprecipitate (3 pools, 15 
units) in addition to MHP 
X 
Major haemorrhage protocol 
(MHP) alone 
X 
ASSESSMENTS 
Participant characteristics 
X 
Clinical assessment 
X 
TXA administration 
X 
RBC, FFP, cryo, platelets 
(including given pre-hospital) 
X 
X 
Mortality 
X 
X 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
Participant destination at 
discharge 
X 
Glasgow Outcome Score 
X 
X 
EQ5D-5L 
X 
X 
*Timepoints are: 
To – Enrolment & allocation of early cryoprecipitate, must be 
within 90 minutes of arrival at hospital 
T1 – cryoprecipitate administered, must be started within 90 
minutes of arrival at hospital 
T2 – 6 h (± 1 h) from arrival at hospital 
T3 - 24h (± 4 h) from arrival at hospital 
T4 – date of discharge or day 28 (± 4 days) from arrival at 
hospital whichever is the sooner 
T5 - 6 months (± 14 days) 
T6- ≥12 months (mortality data  post discharge to be captured by flagging  
with the ONS) 
 
9.2 
Procedures for Assessing Efficacy 
Data collection will be the responsibility of the local clinical team led by the local PI and 
research personnel at each site. Data will be recorded on paper CRFs which will be 
compiled by the CTU. Three participant identifiers (Participant ID allocated at enrolment, 
initials and site) will be captured on the CRF. 
 
Assessments will be performed according to the schedule in Section 9.1. Overall 
responsibility for collating data from all centres will reside with the Trial Manager. CRF data 
will be anonymised with participants assigned a unique participant ID number at 
enrolment. A copy of consent and withdrawal forms will be filed in the participant’s hospital 

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notes, investigator site file and a copy will be given to the participant and participant 
representative (as appropriate). Completed consent forms will not be sent to the CTU. The 
procedure for SAE reporting is detailed in Section 10. 
 
 
9.2.1 
Screening Procedures 
 
It will be the responsibility of the local trauma teams or the local researcher(s) to identify 
eligible adult trauma patients with active bleeding who activate the local major 
haemorrhage protocol. Assessment of inclusion/exclusion criteria will be performed at 
screening. Once final eligibility is confirmed and agreement for study entry is obtained, the 
adult trauma patient will be enrolled into the study. 
 
The screening log will be completed as set out in section 5.1.1. 
 
9.2.2 
Enrolment Procedures 
 
Enrolment will occur as soon as possible after screening and agreement for entry (or 
waiver) into the study has been gained. Background data (participant characteristics) will 
be collected and include; mechanism of injury, injury type and severity, participant age and 
gender. 
 
Clinical data will also be collected, and this will include: vital signs (SBP, HR, and GCS) at 
the first hospital measurement. Data will also be collected on blood product infusions given 
to the participants including all red blood cells and other blood component therapy. The 
injury severity score will be determined retrospectively using the AIS dictionary by each 
participating site. 
 
At the time of enrolment, the following procedures will be completed: 
• 
Documentation of arrival time (as identified in the ED trama notes or 999 call time) 
• 
Documentation of numbers of units of RBC, FFP, platelets, cryoprecipitate, whole 
blood (red cells and plasma in one unit), given from injury to arrival at the ED 
 
 
9.2.3 
Procedures at the time of early cryoprecipitate administration 
 
The start time will be recorded. The time recorded will be the start time for the first of the 
three pools (15 units) of early cryoprecipitate. 
 
If there is a delay in cryoprecipitate infusion (i.e. the start of the infusion is >90 minutes 
from arrival at hospital), study personnel must document the reason(s) that have led to 
protocol deviation. 
 
It is still permissible to start the early cryoprecipitate infusion up to 3 hours from the time of 
injury. If more than 3 hours from injury have elapsed the study cryoprecipitate must not be 
started. If it is discovered retrospectively that participants were enrolled more than 3 hours 
from injury, study personnel must document the reason(s) that led to protocol deviation. 

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9.2.4 
Procedures at 6 hours after arrival at hospital 
Data collection will be undertaken at 6 hours ± 1 hour after arrival at hospital. 
The following procedures will be undertaken: 
• 
Mortality at 6 hours 
• 
Documentation of adverse events (including SAEs) 
 
9.2.5 
Procedures at 24 hours after arrival at hospital 
Data collection will be undertaken at 24 hours ± 4 hours after arrival at hospital. 
The following procedures will be undertaken: 
• 
Recording of numbers of all RBC and other blood components administered from 
arrival at hospital to 24 hours 
• 
Administration of TXA 
• 
Mortality at 24 hours 
• 
Documentation of adverse events (including SAEs) 
 
9.2.6 
Procedures for day 28 follow up or day of discharge 
 
At day 28 (± 4 days) or day of discharge (whichever is the sooner) the following data will 
be collected: 
• 
Length of stay in hospital including length of stay in ICU or HDU (times and dates 
when a participant is transferred to ICU/HDU and from ICU/HDU to the ward will be 
collected) 
• 
Ventilator days 
• 
Thromboembolic adverse events (see below for definitions) 
• 
Injury severity score 
• 
Thromboprophylaxis measures 
• 
Documentation of serious adverse events 
• 
Date of discharge and destination of participant i.e. home, transfer to another 
hospital 
• 
Glasgow Outcome Score (see section 9.3) 
• 
EQ5D-5L (see section 9.3) 
• 
Documentation of mortality (ONLY if data collection falls within 24 – 32 days of 
study entry i.e. day 28 (± 4 days)) 
 
9.2.7 
Procedures for day 28 follow up 
At day 28 (± 4 days) the following data will be collected: 
• 
Documentation of mortality 
 
If a participant has been discharged prior to day 28 (±4 days) – centralised mortality data 
will be captured via the Office for National Statistics (ONS). 
 
Patients’ health records enrolled at MTCs in England will be flagged for death up to 1 year 
from date of admission via a data access agreement with NHS Digital (who hold the 

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mortality data on behalf of ONS). Flagging data (including patient name, NHS or CHI 
number, date of birth, sex and postcode) will be submitted to NHS Digital on a periodic 
basis for the receipt of mortality data including date and cause of death (if applicable). 
Flagging data will be stored on password protected secure NHS servers and access 
restricted to appropriate members of the research team. Patients will be asked to consent 
to their identifiable data being shared for this purpose. Patient confidentiality will be 
maintained by use of a unique trial identifier and only sex, age and initials will be captured 
on the study database. NHSBT and QMUL will carefully manage this process, in 
accordance with GDPR and the necessary permissions from NHS Digital/CAG. 
 
In the unlikely event that mortality data are not available, or a patient is considered lost to 
follow up, the research team at the study centre will be asked to contact the patient’s GP to 
confirm their survival status, and if appropriate, contact the patient. Patients will be fully 
informed of this mechanism and asked to consent to being contacted in such 
circumstances via written informed consent. 
 
 
9.2.8 
Procedures for follow up post discharge in the event that written informed 
consent is not obtained 
In some cases, it is not possible to obtain written informed consent from participants. 
 
Examples include: 
• 
Unexpected discharge (e.g. overnight or weekends) 
• 
Unexpected self-discharge (including absconding from authorities) 
• 
Participants who are rapidly discharged to police custody or returned to the custody 
of HM Prison Service 
• 
Participants who are rapidly transferred to mental health trusts under section 
• 
Participants who have been repatriated to a non-participating hospital or residential 
nursing care home or rehabilitation centre 
• 
Participants who provide false details or refuse to give any details to hospital staff 
• 
Participants who are homeless with no listed general practitioner 
• 
Participants in hospital who are abusive, aggressive or violent and the research 
team have been advised not to approach the patient 
• 
Participants in hospital who are abusive, aggressive or violent and the research 
team have been advised not to approach the patient 
• 
Participants who have considerable language difficulties where it has not been 
possible to provide an NHS translator or ask a family member to translate 
information about the trial 
 
During admission, every attempt will be made by the research team to consent participants 
once capacity has been restored. In the event that informed consent is not obtained prior 
to discharge, irrespective of whether a participant has a personal or professional 
consultee, permission will be sought from the Confidentiality Advisory Group (CAG) under 
Section 251 approval to collect and transfer patient identifiable data (patient name, NHS or 
CHI number, date of birth, sex and postcode) to TARN and NHS Digital in order to capture 
quality of life data at 6 months post-admission and mortality status up to 1-year post- 
admission. 
 
9.3 
Procedures in the event of death 
If a recruited participant dies during the first 28 day period, the following information will be 
documented: 

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• 
Date and time of death 
• 
Primary cause of death will be documented and if possible categorised according 
to the following clinical causes: 
o uncontrolled bleeding; vascular occlusion (myocardial infarction, stroke); 
pulmonary embolism; multi-organ failure; traumatic brain injury; multiple 
injury; sepsis; other (reason). 
 
 
9.4 
Procedures for Assessing Quality of Life (all sites in England and international 
sites depending on resource) at day 28 follow up or day of discharge and 6 
months 
PROMs (Patient Reported Outcome Measures) questionnaires including the EQ5D-5L and 
the Glasgow Outcome Scale (GOS) are routinely collected from eligible patients at all 
major trauma centres across the UK as part of an ongoing TARN PROMs Project. 
CRYOSTAT-2 will use this ongoing initiative to collect PROMs questionnaires at two 
timepoints for all enrolled patients – (a) during first hospital admission (by research team) 
and (b) at 6 months from injury by TARN (±14 days). The Glasgow Outcome Scale during 
first hospital admission is not collected routinely as PROMS data and therefore will be 
collected by the local research team for CRYOSTAT-2. 
 
The PROMs data (EQ5D-5L) will be collected by the research team during first hospital 
admission at study day 28 or at hospital discharge. Each hospital in UK participating in 
CRYOSTAT-2 should have an agreed local policy for the completion of PROMs 
questionnaires on behalf of those participants who do not regain mental capacity during 
admission either by patient representative or Investigator as appropriate. 
 
TARN eligible participants will be contacted by TARN at 6 months from the time of injury (± 
14 days) by letter to complete the EQ5D-5L and GOS questionnaires (as well as additional 
PROM questionnaire data). This is a routine part of the TARN PROMs project. The 
questionnaires may be completed on paper or via an on-line questionnaire. Standard 
checks will be undertaken to check the participant is alive prior to contact. For the 
purposes of this study, those participants competent to consent to the study during their 
hospital stay, and who remain alive, will be assumed to have capacity at 6 months. 
 
For participants entered into CRYOSTAT-2 who provide PROMs data, the same patient 
identifiers collected for NHS Digital mortality data (participant name, NHS or CHI number, 
Questionnaire Identification number (QID), date of birth, sex and postcode) will be 
submitted to TARN to enable data transfer between TARN and the NHSBT CTU. Patients 
will be asked to consent to their identifiable data being shared for this purpose. 
 
For participants where it has not been possible to obtain written informed consent and the 
patient was alive on discharge, Quality of Life data at 6 months post-admission will be 
obtained from TARN under Section 251 approval. 
 
 
9.5 
Procedures for Assessing Safety 
Safety outcomes will be assessed for all participants until day 28 (or death) or until 
discharge from the acute medical facility (whichever is the sooner). Each safety outcome 
will be recorded and the presence or absence of each safety outcome will be reported. 

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The following outcomes will be assessed: 
 
a) Symptomatic venous thrombotic events 
o 
Pulmonary embolus 
o Deep venous thrombosis (of the limbs or other significant veins i.e. portal 
vein) 
b) Symptomatic arterial thrombotic events 
o 
Myocardial infarction 
o 
Ischaemic stroke 
o 
Other (occlusion of any other artery) 
 
For a VTE to be diagnosed and reported in this trial there must be clinical symptoms and 
definitive radiological evidence as set out in the table below: 
 
Type of venous thromboembolism 
Diagnosis 
Deep venous thrombosis 
Accepted methods of diagnosis include: 
• 
compression  ultrasound 
• 
venography 
• 
CT   scan/MR   venogram if more 
proximal leg veins or abdominal 
veins involved 
Pulmonary embolism 
Accepted methods of diagnosis include: 
• 
CT – pulmonary angiogram (CTPA) 
• 
Ventilation-Perfusion scan (V/Q or Q 
scan as per local guidelines) 
• 
SPECT scan 
 
Definitions of ischaemic events: 
 
Type of ischaemic event Diagnosis 
Myocardial infarction 
The term myocardial infarction (MI) should be used when 
there is evidence of myocardial necrosis in a clinical setting 
consistent with myocardial ischaemia. Under these conditions 
presence of one of the following criteria meets the diagnosis 
of MI: 
• 
Detection of rise of troponin with at least one value above 
the 99th percentile of the ULN, plus evidence of 
myocardial ischaemia with at least 1 of the following: 
o symptoms of ischaemia 
o ECG changes indicative of new ischaemia [ST-T 
changes, or LBBB] 
o development of pathological Q waves in ECG 
o imaging 
evidence 
of 
new 
loss 
of 
viable 
myocardium 
or 
new 
regional 
wall 
motion 
abnormality 
• 
Sudden, unexpected cardiac death, often with cardiac 
symptoms, and accompanied by new ECG changes, but 
before blood tests could be taken or death occurred 
before the appearance of cardiac biomarkers in the blood 

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• 
Pathological findings of acute MI 
Ischaemic stroke 
Clinical report of brain imaging consistent with an ischaemic 
stroke in association with new onset focal or generalised 
neurological deficit (defined as deficit in motor, sensory or co- 
ordination function). 
 
(The definition for MI is taken from a consensus document published on behalf of the Joint 
ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction, 2007). 
 
Transfusion related serious adverse events will be documented, as defined by SHOT. 
 
9.6 
Other Assessments 
Hospital resource use up to discharge or day 28 (whichever is the sooner) will be 
calculated from information provided as part of the study CRF, and will be detailed in the 
trial analysis plan. 
 
 
9.7 
Participant transfers 
If a participant is transferred to another participating hospital (MTC), responsibility for 
ongoing data collection and safety reporting is transferred to the research team at the 
receiving hospital. 
 
If a participant is transferred to non-participating hospital or moves from the area after 
discharge from the acute facility, every effort will be made to maintain contact to allow the 
follow-up study procedures to be completed. This will be the responsibility of the 
participating site. 
 
9.8 
Loss to Follow-Up 
A participant will be considered lost to follow-up for the primary endpoint (28 day mortality) 
if the participant has been discharged from hospital prior to day 28; has no data reported 
via the ONS and NHS Digital reporting system; and the research team is unable to confirm 
their survival status with their GP or unable to contact the participant by telephone. 
 
A participant will be considered lost to follow-up for the 6 month data collection if they do 
not respond to two attempts by TARN to contact them for the 6 month quality of life 
assessment. 
 
9.9 
Trial Closure 
The trial will be considered closed when all surviving participants have completed the 6 
month follow up, been deemed lost to follow-up or withdrawn, and all the data have been 
cleaned and the database locked. At this point, the participating sites will be contacted and 
visited to ensure that the documentation for study closure is complete and archived 
appropriately. 

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10. Safety Reporting 
The principles of ICH GCP require that both investigators and sponsors follow specific 
procedures when notifying and reporting adverse events or reactions in clinical trials. 
These procedures are described in this section. 
 
10.1 Definitions of Adverse Events 
The definitions to be applied to adverse events recorded in this trial are given in Table 1a 
below. As this is a trial using cryoprecipitate, events of interest are those related to major 
trauma haemorrhage and cryoprecipitate transfusion, which are also study outcomes. 
Table 1a: Definitions 
 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant or clinical trial 
subject to whom a blood component has been administered. 
Transfusion Related 
Adverse Reaction or 
Event 
Any untoward and unintended response to a transfused blood 
component. 
Serious Adverse Event 
(SAE) or Serious 
Transfusion related 
Adverse Reaction 
Respectively any adverse event, adverse transfusion reaction 
or unexpected adverse transfusion reaction that: 
results in death 
is life-threatening* 
requires 
hospitalisation 
or 
prolongation 
of 
existing 
hospitalisation** 
results in persistent or significant disability or incapacity 
Unexpected Adverse 
Transfusion Reaction 
An adverse reaction, the nature or severity of which is not 
consistent with the known reactions to transfusion of a blood 
component (in the case of this trial, cryoprecipitate). 
*The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the participant was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe. 
**Hospitalisation is defined as an inpatient admission, regardless of length of stay, even if the hospitalisation is 
a precautionary measure for continued observation. Hospitalisations for a pre-existing condition (including 
elective procedures that have not worsened) do not constitute an SAE. 
 
10.1.1 Expected Serious Adverse Events 
Participants in this study have suffered traumatic injury and by definition will have multiple 
serious adverse events during their admission. In this study serious adverse events 
relating to the nature of their traumatic injuries will not be recorded apart from: 
• 
Death (cause of death will be documented and if possible categorised according to the 
following clinical causes: uncontrolled bleeding; vascular occlusion (myocardial 
infarction, stroke); pulmonary embolism; multi-organ failure; traumatic brain injury; 
multiple injury; sepsis; other (reason). 
• 
Thromboembolic events (including Pulmonary embolus, Deep venous thrombosis (of 
the limbs or other significant veins i.e. portal vein), Myocardial infarction, Ischaemic 
stroke, Peripheral ischaemia causing tissue loss and other occlusion of any other 
artery) 
• 
Serious transfusion related adverse reactions which relate to the administration of the 
cryoprecipitate transfusion (definitions of these will in accordance with SHOT/SABRE 
guidelines). 
Any other adverse or serious adverse event not listed above will not require reporting. 

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10.1.2 
Investigator Responsibilities 
The Chief Investigator (CI) has overall responsibility for the conduct of the study. As this is 
a multi-site study, the Principal Investigator (PI) has responsibility for the research at their 
local site and is responsible for informing the CTU of all SAEs occur at their site following 
the guidelines below. 
 
10.1.3 Investigator Assessment of SAEs 
The Principal Investigator is required to consider seriousness, causality and expectedness 
of any SAE. Causality will be assessed according to the following categories: 
Table 7b: Definitions of Causality 
 
Relationship 
Description 
Unrelated 
There is no evidence of any causal relationship 
Unlikely 
There is little evidence to suggest there is a causal relationship (e.g. the event 
did not occur within a reasonable time after administration of the trial transfusion). 
There is another reasonable explanation for the event (e.g. the participant’s 
clinical condition, other concomitant treatment). 
Possible 
There is some evidence to suggest a causal relationship (e.g. because the event 
occurs within a reasonable time after administration of the trial transfusion). 
However, the influence of other factors may have contributed to the event (e.g. 
the participant’s clinical condition, other concomitant treatments). 
Probable 
The evidence is clearly in favour of attributing the adverse reaction to the blood 
or blood component. 
Definitely 
There is conclusive evidence beyond reasonable doubt attributing the adverse 
reaction to the blood or blood component. 
 
 
10.1.4 Investigator Notification 
• 
The CTU should be notified within 24 hours of the investigator becoming aware of a 
SAE. Investigators should notify the CTU of all SAEs occurring during the study 
period. 
• 
The SAE form must be completed by the Investigator (the consultant named on the 
delegation of responsibilities log who is responsible for the participant’s care). In 
the absence of the Investigator, the form should be completed and signed by a 
member of the site trial team and emailed to NHSBT CTU. The responsible 
Investigator should subsequently check, annotate and sign the form and re- 
fax/email to the CTU as soon as possible. The initial report must be followed by 
detailed written reports as appropriate. 
• 
The investigator must follow-up all reported SAE’s until resolution or the event is 
considered stable. 
• 
Investigators must supply the CTU, REC and relevant NHS Trust R&D with any 
supplementary information they request. 
 
10.2 Sponsor’s Responsibilities (QMUL with NHSBT CTU delegated responsibility) 
• 
The CTU will forward all reported serious adverse events received to the Chief 
Investigator (or a medically qualified delegate) for review. 
• 
The DMC will review the safety aspects of this study on a biannual basis. 

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SAE REPORTING 
Within 24 hours of becoming aware of a reportable SAE, please scan and email to: 
serious_adverse_events@nhsbt.nhs.uk 
 
 
• 
The CTU is responsible for the reporting of any unexpected serious transfusion 
related adverse cryoprecipitate reactions to the research ethics committee (REC), 
should any occur, and for preparing annual safety reports to the REC, on behalf of 
the Sponsor. 
 
10.3 Statutory Reporting 
Hospital staff remain responsible for reporting all transfusion related adverse 
events to SHOT/SABRE according to standard procedures, as required under the 
regulations of the EU Blood Directive. 
 

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11. Quality Assurance and Control 
11.1 Risk Assessment 
A Risk assessment has been conducted which acknowledges the potential risks to the 
trial. This section provides an overview of the Quality Assurance (QA) and Quality Control 
(QC) measures that will be put in place to ensure the trial is performed and data generated 
and recorded in accordance with the principles of ICH GCP. 
 
11.2 Central Monitoring at CTU 
The CTU data managers will review all data received for errors and missing data points. 
 
11.3 On-Site Monitoring 
The frequency, type and intensity for routine monitoring and the requirements for “cause 
for concern” monitoring will be detailed in a separate monitoring plan. 
 
11.3.1 Direct access to participant records 
Participating investigators should agree to allow trial-related monitoring, including audits, 
ethics committee review and regulatory inspections by providing direct access to source 
data and documents as required. Participant consent must be obtained for this. 
 
11.3.2 Confidentiality 
Study data will be handled in accordance with the principles of General Data Protection 
Regulation (GDPR) and UK Data Protection Act 2018. 
 
11.4 Auditing 
 
In addition to potential GCP inspections or audits by the host R&D department, NHSBT 
CTU reserves the right to conduct site audits, either as part of its on-going audit 
programme, or in response to adverse observations during monitoring visits. 

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12. Statistical Considerations 
12.1 Sample size 
 
The CRYOSTAT-2 study is designed to detect an absolute mortality difference of 7% from 
a baseline mortality of 26%, i.e. a reduction to 19%. The baseline mortality chosen for 
CRYOSTAT-2 is based on several sources: the feasibility study CRYOSTAT-1 which 
reported a 28% mortality [26]; the national epidemiological study of trauma transfusion 
practice which reported a 39% mortality in patients receiving 10 or more units of RBC in 24 
hours (classified as having ‘massive haemorrhage’) [14]; and the PROPPR study of 
bleeding trauma patients conducted at Level 1 trauma centres in North America [11] which 
had a baseline mortality of 26%. 
 
CRYOSTAT-2 will evaluate a specific population of severely injured patients who will have 
a much higher background death rate than found overall in CRASH-2 [9]. The relative risk 
reduction for CRYOSTAT-2 should be considered alongside the findings in the CRASH-2 
study which showed that TXA therapy improved mortality from bleeding, with an overall 
odds ratio of 0.71 (95%CI: 0.61 – 0.82). The potential observed mortality difference in 
CRYOSTAT-1 was 14%, and larger improvements were observed in cohort studies. 
 
This study will use 90% power to detect a reduction in 28 day all-cause mortality of 7% 
using a 5% level of significance and a two tailed test. An initial blinded analysis after the 
first 300 participants have been recruited and followed-up to 28 days will allow us to 
reassess sample size requirements and recruitment rates, and if necessary modify the 
design of the study. A group sequential design has been used to allow for the Data 
Monitoring Committee reviewing the primary outcome for evidence of harm or benefit after 
500 and 1000 participants have been followed-up for 28 days. Allowing for the interim 
analyses in this way, the required sample size to meet specified power requirements is 
1530 participants in total. We have increased this by 2.5% to allow for drop out leading to a 
total of 1568 participants. 
 
Preliminary data from all 22 adult MTCs in UK show that MHPs are activated between 75- 
150 every year at each site or approximately 1500 times per year nationally for trauma 
patients. Assuming a 25% recruitment rate, we would need to recruit 2 participants per 
month at each MTC to achieve a target of 380 participants per year in the UK (1142 
participants in total over 3 years). 
 
Target international recruitment is 140 participants per year (426 participants in total over 3 
years) with accrual rates based on results from the recent PROPPR study [11] conducted 
at 12 centres in the USA and Canada. 
 
 
12.2 Interim Monitoring and Analyses 
 
An internal pilot phase will be completed 12 months from the date of the first recruited 
participant. We aim to open recruitment at 15 major trauma centres (MTCs) by month 6, 
and 22 MTCs by month 12. Recruitment will increase over the first 6 – 12 months whilst 
centres open, and we expect to randomise 93 participants by 6 months and 300 by 12 
months. Our enrolment criteria for progression to the full trial will be i) stop if fewer than 

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200 participants are recruited at 12 months, ii) recruit additional centres if between 200- 
300 participants, iii) continue if at or above target (300 participants) at 12 months. 
 
If the pilot determines the trial continues, an interim blinded analysis will be performed after 
300 participants have been recruited and been followed up to Day 28. The primary 
purpose will be to confirm the sample size for the primary efficacy outcome of all-cause 
mortality. If the sample size is similar to, or less than, the sample size used to plan the trial, 
the trial will be continued until the required sample size of 1568 patients has been 
achieved. If the re-evaluated sample size is appreciably larger than 1568 in total (>5% 
larger), detailed consideration, involving the Trial Steering Group and the funding agencies 
will be given to whether it is clinically important, cost-effective and feasible to continue the 
study. 
 
The Data Monitoring Committee (DMC) will monitor safety during the study and will inform 
the Trial Steering Committee (TSC) of any concerns regarding safety, futility or trial 
continuation. If the pilot and first interim analysis determine the trial continues, further 
interim analyses will be performed after 500 and 1000 patients have been recruited and 
followed-up for 28 days. At these points, O’Brien-Fleming stopping rules for harm or 
benefit will be used to guide the DMC review of the primary outcome data. The stopping 
rules will be used as a guideline, alongside the other safety data available to the DMC, and 
used as part of their overall assessment of the trial. They will have overall oversight and 
can recommend terminating the trial early for these or any other safety concerns. 
Participant recruitment will be assessed each month throughout the trial with active 
measures taken at each centre to address any concerns over target enrolment rates. 
 
12.3 Analysis Plan 
The analyses will be described in detail in a full Statistical Analysis Plan. This section 
summarises the main issues. 
 
12.3.1 Analysis of primary and secondary outcomes 
At the first interim analysis, an updated estimate of the underlying mortality rate will be 
used to re-estimate the sample size [35]. This will be a blinded sample size re-evaluation 
using the overall event rate to estimate the variance of the primary outcome variable. At 
subsequent interim analyses, the standardised effect of the intervention on the primary 
outcome will be compared against O’Brien-Fleming stopping boundaries, preserving an 
overall significance level of 5% at the end of the trial. 
 
All analyses will be performed on an intention to treat basis, and will include all randomised 
participants (including those randomised in error) on whom values of a response variable 
have been obtained. All analyses will be two-sided and the significance level will be 5%. 
The primary outcome, all-cause mortality at 28 days from arrival at hospital, will be 
determined as the proportion of participants in each treatment arm who have died within 
28 days. The odds ratio for death within 28 days (with 95% confidence interval and p-value 
for the treatment arm term) will be presented, adjusted for centre using a random effect 
term, and this will be the primary analysis of the outcome. . This will be supplemented by 
logistic regression analysis so that account can be taken of any factors (detailed in trial 
analysis plan) that may differ between the treatment arms. Mortality according to timing of 
cryoprecipitate administration will also be presented, using categories of ≤45 mins from 
arrival at hospital, 46 – 60 mins, 61 – 90 mins and over 90 mins. 

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Per protocol analysis, using only those participants who receive treatment within the 
timeframe, will also be completed for all mortality endpoints up to 28 days (6h, 24h and 
28d), transfusion requirements, hospital stay and thrombotic events. Two further per 
protocol analyses will present all mortality endpoints up to 28 days and will additionally 
exclude any participants who died within 90 minutes of arrival at hospital, and then any 
participants in the standard arm who received the intervention as per the protocol. 
 
Multiple imputation based on full conditional specification will be used to impute values of 
potential risk adjustment factors. Particular attention will be given to the set of variables 
that will feature in the multiple imputation models. Primary and secondary outcome 
measures will not be imputed and these will be treated as missing data. 
 
The methods used for the analysis of secondary outcomes in the form of proportions will 
be similar to that described for the primary outcome. 
 
Survival times and rates will be estimated using the Kaplan-Meier method and compared 
using a log rank test. Transfusion requirements will be summarised as the median and 
interquartile range of the number of units administered from injury to 24 hours post-arrival 
at hospital. Hospital stay, critical care stay and ventilator days will be estimated using a 
competing risks analysis with discharge/extubation as the event and death as the 
competing risk. 
 
The number of symptomatic thrombotic events up to day 28 will be presented overall and 
by treatment arm. In particular, the number of venous thromboembolisms (PE, DVT) and 
arterial thrombotic events (MI, stroke) will be calculated. 
 
The primary outcome analysis will be repeated to assess the heterogeneity of treatment 
effects for the following subgroups: 
a) UK participants vs non-UK participants 
b) head AIS <4 vs ≥4 
c) participant sex 
d) participant age <70 vs ≥70 years 
e) injury type blunt vs penetrating 
The secondary outcome analysis of 6 and 24 hour mortality will also be repeated for 
subgroup analysis b) head AIS < 4 vs ≥4. 
 
 
12.3.2 Health Economic Analyses 
 
The health economic analysis will comprise comprehensive short-run and long-run 
analyses with full sensitivity analyses, plus a budget impact analysis and value of 
information analysis. A detailed analysis will be undertaken of the cost and cost- 
effectiveness of early cryoprecipitate plus standard of care versus the standard of care 
alone from an NHS and personal social services perspective. Within-trial analysis and 
long-run analysis will be undertaken, the former based on 28-day data in the trial (short-run 
analysis), the latter extrapolating beyond the end of the trial over the expected lifetime of 
the participant using pre-existing data (lifetime analysis). 
 
In the short-run analysis we will focus on resource use and outcomes during the first 28 
days only, and extrapolate beyond this period using modelling in the lifetime analysis. Our 

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analysis will conform to accepted economic evaluation methods [36]. Costs in the short-run 
analysis will take an NHS perspective. Those in the long-run will be based on the 
perspective of the NHS and personal social services (PSS). Costs will be presented in 
consistent prices, inflated where appropriate, and future costs and benefits beyond the first 
year will be discounted using recommended rates [36]. 
 
 
12.3.3 Analysis Population and Missing Data 
Strategies to minimise the extent of missing data will include prompt review of data as it is 
received by data management and queries for missing or anomalous data. Data query 
resolution will be followed up by the data manager with assistance from the trial manager 
as appropriate. 
 
In cases of discharge from hospital before day 28, data from the ONS will be used to 
determine the primary outcome. In the unlikely event that mortality data are not available, 
or a patient is considered lost to follow up, the GP or participant will be contacted directly. 
 
Where possible, missing outcome data will be inferred from other data available for a 
participant. Full details will be given in the Statistical Analysis Plan. 

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13. Ethical and Regulatory Issues 
13.1 Compliance 
This trial complies with the Declaration of Helsinki 2013. It will also be conducted in 
compliance with the approved protocol, the principles of Good Clinical Practice (GCP), the 
UK Data Protection Act and the National Health Service (NHS) Research Governance 
Framework for Health and Social Care (RGF). 
 
13.1.1 Site Compliance 
The site will comply with the above regulations and guidelines. An agreement will be in 
place between the site and NHSBT, setting out respective roles and responsibilities. 
 
The site will inform the CTU as soon as they are aware of a possible serious breach of 
compliance, so the CTU can report the breach if necessary, within 7 days as per the UK 
regulatory requirements. For the purposes of this regulation, a serious breach is one that 
is likely to affect to a significant degree: 
 
• 
The safety or physical or mental integrity of the subjects in the trial, or 
• 
The scientific value of the trial. 
 
13.1.2 
Data Collection and retention 
The Principal Investigator has overall responsibility for data collection at Sites on 
designated paper Case Report Forms. Participant data will be sent to NHSBT CTU for 
data entry onto the trial database, MACRO™, a commercially available FDA 21 CRF 
Part 11 compliant clinical trial database system produced by Elsevier. Following 
completion of analysis, the trial database will be archived in accordance with NHSBT’s 
policies. 
 
The sites must keep the signed Informed Consent forms, all trial documentation and 
source documents collected during the trial in a secure location (e.g. locked filing 
cabinets in a room with restricted access. All data must be accessible to the competent 
authorities, the Sponsor and NHSBT CTU with suitable notice for inspection. All trial 
documentation must be retained for at least 20 years after trial completion or termination. 
In addition, the Investigator must not discard or destroy any trial specific materials unless 
otherwise instructed by NHSBT. 
 
 
13.1.3 Access to Data 
Custody of the final data set will reside with the Chief Investigator and NHSBT CTU (for 
audit purposes). Access to the final data set for additional analyses will be permitted under 
the agreement of the Trial Steering Committee, according to the publication policy in 
section 16. 
 
13.2 Ethical Conduct of the Study 
 
13.2.1 Ethical Considerations 
 
Before initiation of the trial at each clinical site, the protocol, all informed consent forms 
and any information to be provided to the prospective participant will be submitted to a 

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Research Ethics Committee for ethical approval. Any subsequent amendments will be 
submitted to, and approved by, the same Research Ethics Committee. 
 
 
13.3 Confidentiality 
Trial data which is non identifiable will be collected at each site on the Case Report Form 
(CRF). Each participant will have a unique ID allocated to them which will be recorded on 
the CRF for reporting purposes. Only study sites and designated members of the research 
team authorised to do so, will have access to the identifiable information to maintain 
participant confidentiality. CRF data will be submitted to NHSBT CTU at pre-specified 
intervals and logged into the regulatory compliant, secure MACRO™ database. Only 
authorised personnel at NHSBT CTU will have password protected access to the study 
database. 
 
13.4 Other approvals 
The protocol will be submitted by those delegated to do so to the HRA for approval. A copy 
of the HRA approved Patient Information Sheet, Consultee Declaration Form, Patient 
Informed Consent Form and GP Information letter on local headed paper should be 
provided to the CTU before any participant is entered onto the study. 

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14. Indemnity 
Indemnity for Centres 
The sponsor will provide indemnity in accordance with the agreement with the trial centre. 
The investigator is required to have adequate current insurance to cover claims for 
negligence and/or malpractice. The sponsor will provide insurance cover for the clinical 
trial as required by national regulations. 
 
 
14.1 Declaration of interests 
 
None of the individuals named in this protocol have any competing interests to declare. 
The NHSBT CTU requires serving members of all Oversight Committees to sign a 
declaration of interests form on appointment and declare any competing interests which 
may develop during the conduct of the trial to be declared at the start of every meeting. 

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15. Oversight and Trial Committees 
There are a number of committees involved with the oversight of the trial. These 
committees are detailed below. 
 
15.1 Trial Management group (TMG) 
A Trial Management Group (TMG) comprising the Chief Investigator, other lead 
investigators and members of the CTU. The TMG will be responsible for the day to day 
running and management of the trial. It will meet at least four times a year, more often 
during set up and close down phases of the trial. At least one face to face meeting will be 
held each year. 
 
15.2 Trial Steering Committee 
The Trial Steering Committee (TSC) has membership from the TMG and independent 
members, including the Chair. The role of the TSC is to provide overall supervision for the 
trial and provide advice through its’ independent chair. The ultimate decision on 
continuation of the trial lies with the TSC. 
 
15.3 Independent Data Monitoring Committee 
The CTU has a core Independent Data Monitoring Committee (IDMC) for all of its trials, 
chaired by Professor Timothy Coats, University of Leicester. The group will act as IDMC to 
this study, provide advice to the Chair of the TSC and can recommend premature closure 
of the trial. For the purposes of this study, the core IDMC will be joined by an independent 
member who can provide expert disease specific advice. 
 
15.4 Role of Study Sponsor 
QMUL as Sponsor for the CRYOSTAT 2 trial is responsible for the initiation and 
management of the study, whereby activities are delegated to NHSBT CTU as appropriate. 

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16. Publication 
16.1 Dissemination 
 
The final study data set will be analysed and results published as soon as possible 
following completion of study follow up, final data checks and database lock. Individual 
Clinicians must not publish data concerning their participants that are directly relevant to 
questions posed by the trial until the Trial Management Group has published its report. 
The Trial Management Group will form the basis of the Writing Committee and will advise 
on the nature of publications 
 
All outputs from the trial will be made publicly available via the CRYOSTAT-2 study 
website. Study findings will be presented to academic and non-academic groups. Our PPI 
group, PAIR, will play an important part in disseminating the study findings into the public 
domain. 
Dissemination 
to 
non-academic 
audiences 
including 
service 
users, 
commissioners, clinicians and service providers will be facilitated through the use of 
existing networks e.g. email lists, social media. 
 
All research teams and PPI members involved in the study will be invited to a close out 
meeting to discuss the findings of CRYOSTAT-2. Surviving study participants will receive a 
trial completion newsletter summarising the main results of the trial. These networks will be 
utilised to drive traffic to a study website which will act as a repository of materials 
designed to increase the accessibility of research and to maximise impact. Main study 
findings will be published on the CRYOSTAT-2 study website as well as websites for the 
Centre for Trauma Sciences (C4TS), NHSBT and Bart’s Charity with press releases 
available for newspapers and media websites. 
 
Open access, peer reviewed academic outputs and research reports together with 
associated summaries and key findings will be produced for funders, policy makers and 
NHS audiences and held on the trial website. Early phase results evaluating in-hospital 
outcomes will be released within 3 months of the final participant enrolment. Data on 
longer term outcomes and health economic evaluation will be published after the 6 month 
follow up period has been completed. We will use email lists and Twitter to publicise and 
encourage active commentary on our outputs and to generate debate within the academic 
field. Other user friendly, innovative ways of packaging and disseminating findings will be 
investigated such as animations and video presentations. 
 
16.2 Authorship and acknowledgements 
Authorship for any publications arising from this study will follow the rules set out by the 
International Committee of Medical Journal Editors definitions of Authorship and 
Contributorship, http://www.icmje.org/ethical_1author.html 
 
For the main report of this study submitted for publication, the members of the TSC and 
IDMC should be listed with their affiliations in the Acknowledgements/Appendix of the main 
publication and the support of the NHSBT CTU, and Funder acknowledged in all 
publications/presentations. 

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16.3 Approvals 
Study results will be embargoed and not disseminated until authorised by the CI and TSC. 
Final manuscripts and presentations will be approved by the CI and TSC prior to 
publication. Similarly, any subsequent sub-study analysis will require authorisation by the 
CI and TSC prior to publication. Sub-study manuscripts must not be published prior to the 
publication of the main study. 
 
 
16.4 Identification 
A trial identifier will be included on all presentations and publications. (ISRCTN14998314) 

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17. Protocol Amendments 
 
Revision History: 
Version 
Author 
Date 
Reason for revision 
2.0 
Trial Management 
Group 
Clarification of consent processes for 
England and Wales. 
Clarification of continued follow up data 
in accordance with GDPR and CAG 
approval. 

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32. Fenger-Eriksen C, Jensen TM, Kristensen BS, Jensen KM, Tonnesen E, Ingerslev J, Sorensen 
B. (2009) Fibrinogen substitution improves whole blood clot firmness after dilution with 
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Appendices 
Appendix A 
Overview of consent procedure in England and Wales 
 
 
 

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