CRASH2 Protocol Organisation

PROTOCOL

BACK

Organisation

Data Monitoring Committee

Professor Rory Collins, Chair	Professor Adrian Grant
Professor John A Myburgh

Standard Operating Procedures: The Data Monitoring and Ethics Committee (DMEC) has the responsibility for deciding whether, while randomisation is in progress, the unblinded results (or the unblinded results for a particular subgroup), should be revealed to the Trial Steering Committee (TSC). The DMEC terms of reference state that they will do this if, and only if, two conditions are satisfied: (1) the results provide proof beyond reasonable doubt that treatment is on balance either definitely harmful or definitely favourable for all, or for a particular category of, patients in terms of the major outcome; (2) the results would, if revealed, be expected to substantially change the prescribing patterns of doctors who are already familiar with any other trial results that exist. Exact criteria for "proof beyond reasonable doubt" are not, and cannot be, specified by a purely mathematical stopping rule, but they are strongly influenced by such rules. DMEC members have expressed sympathy with the stopping rule proposed in Part I of the 1976 report to the MRC Leukaemia Committee, whereby an interim analysis of major endpoint would generally need to involve a difference between treatment and control of at least three standard errors to justify premature disclosure. An interim subgroup analysis would, of course, have to be even more extreme to justify disclosure. This rule has the advantage that the exact number and timing of interim analyses need not be pre-specified. In summary, the stopping rules (as successfully applied in other trials including the MRC International Stroke Trial, which randomised 19,436 acute stroke patients) require extreme differences to justify premature disclosure and involve an appropriate combination of mathematical stopping rules and scientific judgement.

Steering Committee

Professor Ian Franklin (chair) University of Glasgow and Scottish Blood Transfusion Service	Ms Brigitte Chaudhry RoadPeace
Professor Tim Coats University of Leicester	Dr Charles Deakin Southampton General Hospital
Dr Steve Goodacre University of Sheffield	Dr Beverley J Hunt Guy's & St Thomas' Hospital NHS Trust
Dr David Meddings World Health Organization	Professor Sir Richard Peto University of Oxford
Professor Ian Roberts London School of Hygiene & Tropical Medicine	Professor Peter Sandercock University of Edinburgh

The steering committee consists of respected and experienced trauma and haematology experts, clinical trialists as well as a lay representative. Face to face meetings will be held at regular intervals determined by need but not less than once a year. Routine business is conducted by email and post.

Standard Operating Procedures: The Steering Committee, in the development of this protocol and throughout the trial, will take responsibility for:

major decisions such as a need to change the protocol for any reason
monitoring and supervising the progress of the trial
reviewing relevant information from other sources
considering recommendations from the DMEC
informing and advising the management group on all aspects of the trial

Collaborators' Responsibilities

Co-ordination within each participating hospital will be through a local collaborator who will:

Discuss the trial with medical and nursing staff who see trauma patients and ensure that they remain aware of the state of the current knowledge, the trial and its procedures (there are wall charts, pocket summaries and a set of slides to assist with this)
Ensure that adults with trauma are considered promptly for the trial
Ensure that the patient entry forms (in non-telephone randomising centres) and single sided outcome forms are completed
Ensure the trial is conducted in accordance with ICH GCP and fulfils all national and local regulatory requirements
Allow access to source data for audit and verification

Co-ordinating Centre Responsibilities

Provide study materials and a 24-hour randomisation (and unblinding) service
Give collaborators regular information about the progress of the study
Help ensure complete data collection at discharge
Respond to any questions (e.g. from collaborators) about the trial
Assure data security and quality
Ensure trial is conducted in accordance with ICH GCP

Publication

The success of CRASH 2 will be dependent entirely upon the collaboration of nurses and doctors in the participating hospitals. Hence, the chief credit for the study will be assigned to the collaborators from each participating centre and they will be named personally in the main publications. The results of the trial will be reported first to trial collaborators. Dissemination of results to patients will take place via the media, trial website and relevant patient organisations.

Indemnity

CRASH 2 is funded by the London School of Hygiene & Tropical Medicine (LSHTM) and the World Health Organization (WHO) and not the manufacturers of tranexamic acid. LSHTM as the Co-ordinating Centre for the trial accepts responsibility attached to its sponsorship of the trial and, as such, would be responsible for claims for any non-negligent harm suffered by anyone as a result of participating in this trial.

Financial Support

LSHTM and WHO funding covers meetings and central organisational costs only. The design, management and finance of the study are entirely independent of the manufacturers of tranexamic acid, which is not a new product. Large trials of such drugs, involving many hospitals, are important for future patients but are practicable only if those collaborating in them do so without payment (except for recompense of any minor local costs that may arise).

TOP