PRACTICAL ASPECTS

Topics

How to randomise a patient

Trial Materials

Good Clinical Practice Guidance

Frequently Asked

Questions

Maintaining your Hospital

Site File

Reporting Adverse Events

EmergencyUnblinding

Getting the trial started at your hospital

How to send your data

Patient Information & Consent

Trial TreatmentHow to give the

trial drugs

Contacts &further

information

Introduction• Your TRIAL SITE FILE contains all the

information and instructions you need for conducting the trial – please use it

• If you have any questions about the trial please contact the co-ordinating centre staff

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Getting the trial started (1)

Before the trial can start at your hospitalwe must have the following documents:

• Ethics Approval (local and/or national)• National regulatory approval (if required)• Approval of your hospital (if required)• A signed copy of the Principal Investigator’s

Statement• A copy of our Hospital Information & CV Form• A copy of the approved Patient Information

Sheet & Consent (if different from the protocol sent to you)

CREATEA TRIALTEAM

Nominate someone to be responsible in your absence

Identify people to be responsible for specific

trial process – they must be interested in

the trial

Every speciality must be represented:• Nurses• Traumatologists• Intensivists• General Surgeons• Neurosurgeons• Orthopaedics• Clerical Staff• Pharmacy• Managers• Administrators

Coordinating Centre is also part of your team:o Good communication is essentialo Ask for help & advice if neededo hare your successes and difficulties

Provide information and training about the

trial to all members

Getting the trial started (2)

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• CRASH-2: involve patients who have suffered serious injuries and are at risk of life threatening haemorrhage

• Most patients will have some impairment in their level of consciousness caused either by blood loss or coexisting head injury

• Patients may not be able to provide written informed consent

• Trial treatment has to be administered as soon as possible after injury

Consent (1)

• Need to comply with local approved consent process

• Should your Ethics Committee require changes to the Patient Information Sheet, please send a copy of the approved version to us – this will be used to provide you with copies in the patient treatment packs.

Consent (2)

Patient Information & Consent• If written consent is required, please

ensure that all the original signed forms are kept in the study Site File

• If you have told us that consent is legally required, we will request confirmation that consent has been obtained

• When requested, please send a copy of the relevant section of your Randomisation Log (found in your Site File)

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There are two ways to randomise a patient:

RANDOMISE BY TELEPHONE: • Country and hospital must have access to the freecall service.• Your Site File and Randomisation Posters will have the telephone number you need to use – this number is unique to each country• All the information on the Entry Form will be required by the operator• The operator will give you the allocated treatment pack number

Complete the entry form first to ensure the patient fulfils the eligibility criteria. If the patient is suitable for

the trial:

NON-TELEPHONE: •After completing the Entry Form, select lowest numbered treatment pack. •You must send the completed Entry Form to the co-ordinating centre as soon as possible after randomisation

How to randomise a patient (1)

How to randomise a patient (2)

All patients randomised or considered for randomisation must be recorded in your Site

File

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Trial treatmentEach treatment BOX has:• a 4 digit unique number e.g. 4121• 8 individual patients packs each

numbered with the box/pack number e.g. 4121/21

• Paper Entry Forms• Paper Outcome Forms• Patient Information Sheet/consent

Each treatment PACK has:• 4 ampoules of tranexamic acid/placebo• 100mL bag Sodium Chloride 0.9%• 10 mL syringe• needle

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How to give the trial drug (1)

ALL AMPOULES ARE IDENTICAL AND CONTAIN 500mg OF

EITHER TRANEXAMIC ACID OR PLACEBO LOADING DOSE - 2 ampoules over 10 minutesGive immediately after randomisationPRESCRIBE: “CRASH-2 Trial (1 gram of tranexamic acid/placebo) over 10 minutes”

• Using syringe provided in the treatment pack draw up 10 mL (2 ampoules of

tranexamic acid / placebo) and add to 100 ml bag of Sodium Chloride 0.9%

provided - Mix well• Fill in date of randomisation on all 6 peelable labels on the cover of the pack

• Peel off a pre-printed INFUSION label and attach to bag • If required, complete and attach a hospital infusion label to bag• Connect infusion to patient’s IV line and infuse over 10 minutes• Peel off a pre-printed DRUG CHART label, place at the front of prescription chart

• Peel off pre-printed randomisation labels and place one on PATIENT MEDICAL

RECORDS, one on ENTRY FORM and one on OUTCOME FORM

TXA solution for injection should not be mixed with blood for transfusion or infusion solutions containing penicillin

ENSURE PATIENT DETAILS ARE RECORDED ON RANDOMISATION LOG IN THE SITE FILE

MAINTENANCE DOSE - 2 ampoules over 8 hours

Start immediately after completion of loading dose

PRESCRIBE: “CRASH-2 Trial (1 gram of tranexamic acid / placebo). Infuse at 60 L/hour”

• Draw up 10mL (2 ampoules of tranexamic acid / placebo) and add to 500mL bag of Sodium Chloride 0.9% (to be provided by trial site)*

• Peel off a pre-printed INFUSION label and attach to bag • If required, complete and attach a hospital infusion label to bag• Connect infusion to patient’s IV line and infuse at 60mL/hour• If infusion is terminated early for any reason, please record end time on

prescription chart

How to give the trial drug (2)

* Or other compatible solutions e.g dextrose 5% and Ringer’s solution

INCOMPATIBILITIES

TXA solution for injection should not be mixed

with blood for transfusion or infusion solutions

containing penicillin.

How to give the trial drug (3)

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Data Collection (1)

In your Site File you have 3 guidance sheets:

1.How to complete patient entry form2.How to complete the outcome form3.How to send your Entry and Outcome

Data Forms

Please use these to help you send your data

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Internet: Primary data collection is to be done via the ‘collaborators’ intranet’ on our website www.crash2.lshtm.ac.uk

A username and password to use this site will be sent to you by email before you start the trial. If for any reason you do not receive them, please email crash@lshtm.ac.uk

Email: data can also be submitted using the ‘electronic data forms’. These forms can be found on a disk at the front of your study site file. We can also email you these forms to you if required.

These two are the preferred methods for sending your data as they will eliminate data queries.

Data Collection (2)

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If you are using fax to send forms it would be useful to attach a treatment pack sticker on an outcome form ready for use as soon as possible after randomisation. If a treatment pack sticker is no longer available, please write the BOX/PACK number in the box on the top right corner of the form.

Fax to +44 20 7299 4663

POST SHOULD BE USED ONLY AS A LAST RESORT: As there is a delay in us receiving your data, this will disrupt your drug supply. Please photocopy your data forms, keep the original in your Site File and post the copy to: CRASH TRIALS CO-ORDINATING CENTRELondon School of Hygiene & Tropical MedicineKeppel Street, London WC1E 7HTUnited Kingdom

Data Collection (3)

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Emergency UnblindingIn general there should be no need to un-blind the allocated treatment.

If some contraindication to tranexamic acid develops after randomisation, the trial treatment should simply be stopped.

Unblinding should be done only in those rare cases when the doctor believes that clinical management depends importantly upon knowledge of whether the patient received tranexamic acid or placebo (e.g. suspected anaphylaxis).

In those few cases when urgent unblinding is considered necessary, the randomisation service should be telephoned. The telephone number is in your Site File. Please give your hospital name or ID code and the box/pack number.

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Record in medical notesSERIOUS NOT SERIOUS

1. Results in death2. Is life-threatening3. Requires hospitalisation or 4. Prolongation of existing hospitalisation 5. Results in persistent or significant disability or incapacity 6. Is a congenital anomaly or birth defect

EXPECTED SIDE EFFECTS LISTED IN PROTOCOL (page 8) DO NOT REQUIRE REPORTING (these are outcome data):

• Death – unless believed to be directly due to the trial treatment• Pulmonary Embolism• Deep Vein thrombosis• Stroke• Myocardial Infarction• Gastro Intestinal Bleeding• Multi-organ failure• Result of trauma suffered by patient• Medical events expected in severe injury

UNEXPECTED SIDE EFFECTS:

1. Complete a Serious Adverse Event Form

2. Telephone Randomisation Service (phone number as per Randomisation Poster or site file) to register Serious Adverse Reaction; give the information on the form

3. Fax/email completed form to the Co-ordinating Centre within 24 hours

Adverse Event Reporting

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Trial materials

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BEFORE YOU START THE TRIAL YOU WILL RECEIVE• a site file compiled specifically for your hospital, containing contact details, further information, guidance, spare forms and space for completed data

• training CD with a PowerPoint presentation

• randomisation posters with step by step instructions

TREATMENT PACKS• initially one box of 8 patient packs

• stock level is monitored by received patient entries

• we will send new packs when you reach your minimum stock level which is dependent on your randomisation rate

PROTOCOLS• protocol summaries and pocket cards

TRAINING AND PRESENTATIONSPlease contact the Co-ordinating Centre if • you need more training materials for staff sessions• you are presenting the trial in meetings or conferences

You will soon be able to order all trial materials via the COLLABORATORS’ INTRANET on the trial website www.crash2.lshtm.ac.uk

Investigator’s Master File to be maintained(legal obligation)

• Screened patient – not randomised• Randomisation List• Original Signed Consent Forms (if

required)• Original Data• All correspondence

Site file

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Question: Is CRASH-2 a Head Injury Trial?Answer: No – All adult trauma patients with ongoing haemorrhage OR at risk of significant haemorrhage can be randomised. Patients with

concurrent head injury can be included.

Frequently asked questions and answers can be found on the trial website & your site filePlease let us know of questions you get asked frequently and we will add these to the website

Example of question:

FAQs

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CRASH-2 WILL BE CONDUCTED IN ACCORDANCE WITH THE PRINCIPLES OF ICH-GCP

The Principles of ICH-GCP and the Declaration of Helsinki can be found in your Site File.

Full versions can be found on our website

Please be aware of your own country’s GCP Guidelines

Good Clinical PracticeGood Clinical Practice (GCP): is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects.

Compliance with this standard provides public assurance that the rights, safety and well-being of trial subjects are protected in accordance with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

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ContactsEmail addresses are formed like this: forename.surname@Lshtm.ac.uk

Ian RobertsClinical Co-ordinator

Haleema ShakurTrial Manager

Lin BarnetsonData Manager

Maria RamosAdministrator

Donna ToothAssistant Co-ordinator

Pablo PerelResearch Fellow

(Spanish Speaker)

Phil EdwardsResearch Fellow

Tony BradyProgrammer

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