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

About the trial

Worldwide, it is estimated that 5.8 million people die annually from trauma with most of those who die under the age of 45. For the same age group that is more than cancer, HIV/AIDS and heart disease combined.

Patient count so far: Email the team

1424
/1568

One of the most common causes of death in trauma patients is uncontrolled bleeding. At present, standard treatment for severe bleeding involves rapid infusion of red blood cells and blood components e.g. plasma and platelets, in large volumes.

Until recently, one in two people who received a massive blood transfusion (more than 10 pints) would die from their injuries. Two important studies involving bleeding trauma patients have been conducted in the last five years showing that early intervention is more effective after injury and may help save lives. Patients who have severe bleeding after injury develop a problem with their clotting system which means that they tend to bleed more. One of the main problems is due to low levels of fibrinogen, a clotting protein normally circulating in the bloodstream. Fibrinogen acts as the ‘glue’ which holds a blood clot together and at low levels, blood clots don’t form properly and bleeding can continue.

Cryoprecipitate is a frozen blood component prepared from plasma and rich in fibrinogen. By transfusing cryoprecipitate early to replace fibrinogen levels in bleeding trauma patients, we believe blood clots will be more stable, reducing bleeding and consequently the number of deaths.

CRYOSTAT 2 is an international, pragmatic, multi-centre, parallel group, randomised controlled trial, which will run at all of the major trauma centres in England and at 8 international centres. It is designed to answer a simple research question of whether the addition of early cryoprecipitate to the current standard of care Major Haemorrhage Protocol (MHP) improves survival from major trauma haemorrhage.

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For investigators

Bleeding accounts for 40% of all deaths from trauma, many within hours of injury. Our recent NIHR Programme Grant for Applied Research found that approximately 7,780 people nationally suffer major haemorrhage each year, of whom an estimated 2,800 will die, at a total cost of nearly £150m to the NHS [Campbell et al, 2015].

Fibrinogen is the key pro-coagulant factor needed for stable clot formation and the earliest clotting protein to fall during active major bleeding [Hiippala et al, 1995]. 25% of all trauma patients have abnormal blood clotting, which causes higher rates of major haemorrhage and four fold increased risk of death. The primary clotting abnormalities in trauma are: increased clot breakdown and low fibrinogen levels.

The CRASH-2 trial has shown that early treatment with tranexamic acid prevents clot breakdown and reduces mortality from trauma haemorrhage [Shakur et al, 2010]. The results of our national observational trauma transfusion study found cryoprecipitate is administered late during the MHP, on average three hours after arrival.

In CRYOSTAT-1 we have shown that early replacement of fibrinogen with cryoprecipitate is able to rapidly restore fibrinogen levels and may halve mortality from trauma haemorrhage [Curry N et al, 2015]. Following on from this work, CRYOSTAT-2 will evaluate whether early administration of high-dose cryoprecipitate, in addition to standard major haemorrhage therapy, improves survival from traumatic bleeding.

The results from this trial will immediately inform transfusion resuscitation practice both nationally and internationally.

Trial aims

This study will investigate the effects of early fibrinogen supplementation in the form of 3 pools (15 units – 6g fibrinogen) of cryoprecipitate on 28 day mortality.

The trial design

CRYOSTAT 2 is a multi-centre interventional parallel group randomised controlled trial.

The study will be managed by the NHS Blood & Transplant Clinical Trials Unit with UK and International sites.

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 three hours have elapsed from the time of injury

Outcomes (n=1,568 patients)

Our primary outcome is all-cause mortality at 28 days.

Additional secondary measures include:

  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 and 6 months after injury.
  6. Hospital resource use up to discharge or day 28, including blood transfusions, surgical procedures, ventilator days, hours spent in critical care and in-patient stays.
  7. Symptomatic thrombotic events

For patients

Emergency treatment of patients affected by serious injury involves many complex treatments being given simultaneously, with the aim of saving a patient’s life. One of these complex treatments is transfusion (e.g. red blood cells, plasma, platelets and cryoprecipitate) which is given both to replace blood that is lost and to reduce bleeding and treat clotting abnormalities. Up to 40% of seriously injured trauma patients die from uncontrolled bleeding.

It is known that patients with significant bleeding have low levels of an important blood clotting protein called fibrinogen. Replacement of this protein early in the transfusion process may stop bleeding more rapidly. We have conducted smaller pilot studies (CRYOSTAT 1 and E-FIT 1 Studies to look at whether the sources of fibrinogen can be given rapidly to patients in a challenging clinical environment.
The main objective of this research study is to test whether giving cryoprecipitate early (within 90 minutes of a patient being admitted to hospital) following a major injury, can reduce bleeding and death.
In this study we are investigating a blood transfusion product rich in fibrinogen called cryoprecipitate, which is already given to patients as part of the routine treatment for major bleeding.
Adult patients with severe injury and major bleeding who are admitted to hospital are potentially eligible. Participating centres will recruit patients directly.

Queen Mary University of London (QMUL) is the Sponsor for this clinical trial which is based in the United Kingdom and has delegated overall management of this study to the Clinical Trials Unit at NHS Blood & Transplant, and will act as joint data controllers. This means that we are responsible for looking after your information and using it properly.

Your information will only be used by researchers to conduct research in accordance with the UK Policy Framework for Health and Social Care Research.

We will be using information from you and your medical records in order to undertake this trial.

As publicly-funded organisations, we have to ensure that it is in the public interest when we use personally-identifiable information from people who have agreed to take part in research.

With your signed consent, we will keep identifiable information about you for 2 years after the study has finished to allow us to complete analysis of the data that we have collected. After this time your identifiable information will be deleted.

To safeguard your rights, we will use the minimum amount of personally-identifiable information possible.

The personally-identifiable information we will collect are: Name, date of birth, sex, NHS number (or CHI number if you live in Scotland) and postcode. This data is shared with NHS Digital so that we can check on your survival status one year after your injury. For some patients, we will also access information collected by the Trauma Audit & Research Network (TARN, hosted by the University of Manchester) about how you feel about your health six months after your injury. By accessing existing TARN data, it means that we do not need to ask you for the same information twice. NHS Blood & Transplant will have contracts with NHS Digital and The University of Manchester that will ensure the security and integrity of your data at all times. This data will only be shared for this purpose and deleted at the end of the study. It will not be shared with any other organisation or published.

NHS Blood & Transplant will have special permission in place to collect personally identifiable data from those participants who take part in the study but have not signed a consent form (e.g. due to the nature of their injury, or who were discharged prior to consent being taken by the research team for any reason). If you did not sign a consent form and you do not wish for your identifiable data to be used, you can contact us on 01223 588720 or via email cryostat2@nhsbt.nhs.uk

You have the right to access, correct or complete the information you have given us. You also have the right to withdraw from the trial at any time and request that your data be deleted (“right to be forgotten”). If you wish to withdraw, please arrange to speak with the doctor or nurse listed at the bottom of your patient information sheet. After the trial has been completed, we will provide QMUL with an anonymised data set produced by the research. This information will not identify you and cannot be combined with other information in a way that could identify you.

You can find out more about how we use your information in research at https://www.hra.nhs.uk/information-about-patients/ or by contacting the Trial Manager by email at cryostat2@nhsbt.nhs.uk

Under GDPR, all NHS organisations are legally required to appoint a Data Protection Officer (DPO). The DPO for NHS Blood & Transplant is Aaron Powell, the Chief Digital Officer, who is responsible for ensuring that all practices and processes within NHS Blood & Transplant are designed to support people’s privacy and data rights. You can contact the DPO by email at dpofficer@nhsbt.nhs.uk

You can also look at the website of the Information Commissioner (https://ico.org.uk/) for more information on the new GDPR legislation and you have the right to speak to them if you are worried that your data is not being appropriately protected or processed.

You can also Download our Privacy Policy in PDF format

One group of patients who take part in the study will receive an early dose of cryoprecipitate (6g) in addition to standard major haemorrhage therapy, whilst the other group will be the standard major haemorrhage treatment alone.

The effects of the two treatments will be compared, in particular focussing on bleeding and death rates.

Download patient information sheet

Meet the team

The CRYOSTAT 2 Team comprises of experts in Trauma, Haematology, Emergency Medicine and clinical trial support staff.

Professor Karim Brohi

Professor Karim Brohi - Chief Investigator

The Lead for the London Major Trauma System, Professor of Trauma Sciences at the Centre for Trauma Sciences, Blizard Institute, Queen Mary University of London, UK.

Dr Simon Stanworth

Professor Simon Stanworth - Chief Investigator

Consultant Haematologist for the National Health Service Blood & Transplant at the John Radcliffe Hospital, Oxford, UK.

Dr Ross Davenport

Dr Ross Davenport - Co-Investigator

Consultant Trauma & Vascular Surgeon and Clinical Lecturer for the Centre for Trauma Sciences, Blizard Institute, Queen Mary University of London, UK.

Nicola Curry

Dr Nicola Curry - Co-Investigator

Consultant Haematologist for the Oxford Haemophilia & Thrombosis Centre, Oxford University Hospitals Trust.

Dr Laura Green

Dr Laura Green - Co-Investigator

Consultant in Haemostasis and Transfusion Medicine NHSBT and Barts Health NHS Trust, UK.

Professor Jonathan Benger

Professor Jonathan Benger - Co-Investigator

Consultant in Emergency Medicine, University Hospitals Bristol NHS Foundation Trust, and Professor of Emergency Care, University of the West of England, Bristol.

Alison Deary

Alison Deary - Head of Clinical Operations

Head of Clinical Operations NHSBT Clinical Trials Unit based in Cambridge, UK.

Claire Foley

Claire Foley - Clinical Operations Manager

Clinical Operations Manager for the NHSBT Clinical Trials Unit based in Cambridge, UK

Joanne Lucas

Joanne Lucas - Clinical Trial Manager

Clinical Trial Manager for the NHSBT Clinical Trials Unit based in Cambridge, UK

Amy Evans

Amy Evans - Trial Coordinator

Trial Coordinator for the NHSBT Clinical Trials Unit based in Cambridge, UK.

Vacant Position - Trauma Operations Manager

This position of Trauma Operations Manager is currently vacant

Helen Thomas

Helen Thomas - Head of Clinical Trial Statistics

Helen Thomas is Head of Clinical Trial Statistics for the NHSBT Clinical Trials Unit based in Bristol, UK.

Rupa Sharma

Rupa Sharma - Data Manager

Data Manager for the NHSBT Clinical Trials Unit based in Cambridge, UK.

Renate Hodge

Renate Hodge - Clinical Data Services Manager

Renate is a Senior Data Manager for the NHSBT Clinical Trials Unit based in Cambridge, UK

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