CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) intracranial bleeding study: the effect of tranexamic acid in traumatic brain injury - a nested randomised, placebo-controlled trial

Brain imaging outcomes

We obtained two brain CT studies for each participant, the first before randomisation and the second 24–48 hours later. A neuroradiologist (ZM), who was blind to treatment allocation, evaluated the pre-randomisation and 24- to 48-hour scans. She made the readings of the two scans twice (with the second reading blind to the results of the first reading), by central reading of the Digital Imaging and Communications in Medicine (DICOM) image files in Digital Jacket™ (DesAcc, Inc, Chicago, IL, USA) software. She measured the size of four types of intracranial haematomas (intraparenchymal, haemorrhagic contusion, subdural and epidural), subarachnoid haemorrhage, mass effect findings and the overall amount of tissue damage, using validated rating scales based on previous work. The individual ratings and measurements were combined into a rating form developed for the purposes of this study (see Appendix 2). She followed structured guidance to complete the CT scan form. This guidance provided definitions of the overall appearance of the scan, haemorrhagic findings, non-haemorrhagic findings and mass effect findings as detailed in the following section.

Computerised tomography scan guidance

Mass effect findings

Scoring system based on Wardlaw and Sellar:25

• 0 = no swelling

• 1 = effacement of the sulci overlying the infarct

• 2 = 1 + minor effacement of adjacent lateral ventricle

• 3 = 1 + complete effacement of lateral ventricle

• 4 = 1 + effacement of the lateral and third ventricles

• 5 = 4 + shift of the midline away from the side of the ventricle

• 6 = 5 + effacement of the basal cisterns/uncal herniation.

Measurement of midline shift

FIGURE 1.

Computerised tomography scan image showing midline shift.

Method of measurement

1. Define the midline: straight line connecting the fixed anterior and posterior margins of the falx cerebri.

2. Degree of midline shift = longest distance to midline structures (interhemispheric fissure, septum pellucidum or third ventricle) measured perpendicular to the midline.

The primary outcome was the adjusted change in total haemorrhage growth from the first to the follow-up scan, defined as the difference in the combined volume (ml) of all intracranial haemorrhagic lesions (intraparenchymal haematoma + haemorrhagic contusion + subdural haematoma + epidural haematoma) from the first to the second scan. The secondary imaging outcomes were (1) the occurrence of significant haemorrhage growth (any haematoma that increased by 25% in relation to its initial volume), (2) new intracranial haemorrhage (apparent on the follow-up brain CT but not on the baseline brain CT), (3) change in subarachnoid haemorrhage grade, (4) the mass effect and (5) the occurrence of new focal cerebral ischaemic lesions (apparent on the follow-up brain CT, but not on the baseline brain CT).

Clinical outcomes

The clinical outcomes were death and the need for neurosurgical intervention. Dependency was measured using the five-point modified Oxford Handicap Scale (mOHS). 26 The scale was dichotomised into ‘dependent’ (fully dependent requiring attention day and night, or dependent but not requiring constant attention) or ‘independent’ (some restriction in lifestyle but independent, minor symptoms or no symptoms). Clinical outcomes were recorded at hospital discharge, 28 days or death, whichever occurred first. The corresponding form is shown in Appendix 3.

Combined outcome

We defined ‘poor outcome’ as a patient who developed one or more of the following during the scheduled follow-up period: significant haemorrhage growth, new intracranial haemorrhage, new focal cerebral ischaemic lesions, the need for neurosurgery or death.

Intraobserver agreement

The intraobserver agreement between the two CT scan readings by the radiologist was high for all outcomes except new intracranial haemorrhage. The intraclass correlation coefficient for total haemorrhage growth was 0.89 and the corresponding kappas for significant haemorrhage growth, new intracranial haemorrhage, any mass effect and new focal cerebral ischaemic lesions were 0.82, 0.32, 0.81 and 0.89, respectively. Imaging outcomes were available for 249 (99%) of the 251 patients who had an initial CT scan and were alive at 24 hours.

Effect on haemorrhage growth

The mean total haemorrhage growth was 5.9 ml (SD 26.8 ml) and 8.1 ml (SD 29.2 ml) in the TXA and placebo group, respectively. The adjusted analysis showed a reduction in total haemorrhage growth in the arm that received TXA in comparison with placebo (–3.8 ml, 95% CrI –11.5 to 3.9 ml). In patients who had neurosurgical evacuation before the second CT scan, the reduction in total haemorrhage growth in the TXA arm was larger (–12 ml, 95% CrI –45.7 to 15.5 ml). The posterior probability that TXA reduces haemorrhage growth was high for total haematoma and each type separately except for epidural haematoma (Table 3). The change in the subarachnoid haemorrhage scale was –0.11 for TXA-allocated patients and –0.12 for placebo-allocated patients (p = 0.93).

1. Background

CRASH-2 is a large randomised controlled trial of the effect on mortality and transfusion requirements of tranexamic acid (TXA) in trauma patients with significant bleeding (www.crash2.Lshtm.ac.uk). Over 9,000 patients have been enrolled so far and recruitment will continue until 20,000 patients have been randomised. Many of the patients included in the CRASH-2 trial have multiple injuries and in about 40% of patients this includes traumatic brain injury (TBI). The CRASH-2 trial will assess as sub-group analyses, the effect of TXA in patients who also have TBI. These analyses will examine the effect of TXA on mortality, on the need for a neurosurgical operation and on neurological impairment, using a modified version of the Oxford Handicap Score (our previous analyses have shown that this score is strongly correlated with outcome on the Glasgow Outcome Scale at six months).

Traumatic intracranial bleeding: TBI is commonly accompanied by intracranial bleeding, which can be epidural, subdural, subarachnoid or parenchymal. Of the 7,814 patients with TBI enrolled in the MRC CRASH trial who had a computerised tomography (CT) scan, 31% had subarachnoid haemorrhage and 40% had an intracranial haematoma. Overall 56% of TBI patients had some type of intracranial bleeding. 1

Prognostic studies show that intracranial bleeding is associated with increased mortality and disability six months after injury. In the MRC CRASH trial, the presence of subarachnoid haemorrhage, petechial haemorrhage or intracranial haematoma were independently associated with poor outcome at 2 weeks and 6 months. 2 Similarly, the IMPACT study found that after controlling for age, Glasgow Coma Score (GCS) motor score and pupil reactions, subarachnoid and subdural haemorrhages more than doubled the odds of poor outcome at six months. 3 The larger the intracranial bleeding, wherever the location, the worse prognosis it is associated with. The Brain Trauma Foundation Guideline for Surgery takes into account the bleeding size to recommend surgical evacuation: 50 cm³ for parenchymal haematoma, 30 cm³ for epidural and 10 mm for subdural haematoma. 5

In patients with TBI, intracranial bleeding can develop or worsen after hospital admission. Studies involving repeated CT scanning have found that intracranial bleeds can develop or expand in the 24 hours after injury. Ortel studied a group of patients in whom two CT scans were obtained within 24 hours of injury to determine the prevalence of progressive intracranial haemorrhage. 4 Among patients who had their first CT scan within 2 hours of injury, 49% had radiological evidence of progressive haemorrhage. Yadav conducted repeat CT scanning of TBI patients at hospital admission and 24 hours later, and found that 16% of 262 parenchymal haematomas and contusions increased in size in the first 24 hours. 6 Similarly, Sullivan et al. found that traumatic epidural haemorrhages enlarged in 23% of 160 TBI patients treated non-operatively. 7 The mean enlargement was 7 mm, and the mean time to enlargement was 8 hours from injury and 5.3 hours from CT diagnosis. Although these studies provide estimates of the occurrence of intracranial bleeding and expansion they all have limitations. All included patients who have an abnormal initial CT scan and there is little information on the proportion of patients that develop new intracranial bleeds in the first 24 hours who have the potential to benefit from early treatment.

Tranexamic acid and intracranial bleeding: Tranexamic acid is commonly used in surgery to reduce blood loss. A systematic review of randomised controlled trials of TXA in elective surgery showed that it reduces the need for transfusion by one third, reduces donor exposure by one unit, and halves the need for further surgery to control bleeding. 8 A systematic review of randomised trials of TXA in patients with aneurismal subarachnoid haemorrhage showed that TXA reduced the rate of rebleeding by approximately 40%, but because of an increase in cerebral ischaemia there was no overall benefit. 9 However, the duration of TXA treatment in these trials was six weeks and it is possible that a shorter treatment might prevent rebleeding whilst avoiding the risk of ischaemia. The systematic review was conducted in 2003 but since then a randomised controlled trial of the early administration of a short course (3 days) of TXA in aneurysmal subarachnoid haemorrhage found that TXA reduced the occurrence of rebleeding from 10.8% to 2.4% with no evidence of increased side effects. 10 Almost all of the effect on rebleeding was observed within the first few hours after hospital admission. Tranexamic acid could also improve outcome after TBI by reducing systemic blood loss. Hypotension is an established risk factor for poor outcome after TBI.

Hypothesis: Early administration of TXA can prevent the occurrence or increase of intracranial bleeding in patients with TBI and significant bleeding.

Aim: The aim of the proposed substudy is to quantify the effect on intracranial bleeding of the early administration of TXA, in CRASH-2 trial participants with traumatic brain injury.

2. Study design

Methods

Participating hospitals: Participating hospitals have been selected based on level of interest by the principal investigator in the research question, the recruitment rate in the CRASH-2 trial and the ability of the hospital to collect and send the necessary CT scan data to the trial co-ordinating centre. This substudy will be conducted in the hospitals listed in Appendix 1.

Inclusion criteria: All patients meeting the following criteria will be eligible for inclusion in the substudy:

• Fulfils the inclusion criteria for the CRASH-2 trial

• GCS of 14 or less

• Baseline clinical CT scan shows intracranial abnormality consistent with TBI

• Non pregnant

Number of patients needed: Assuming a baseline intracranial bleeding volume of 20 ml, an average increase of 7 ml in the control group and a correlation of 0.6 between baseline and follow-up bleeding, we need to recruit 900 patients to have 80% power (with alpha = 0.05) to detect a 20% reduction in the increase of intracranial bleeding volume in the control group. If 400 patients were recruited the trial could detect a 30% reduction in the primary outcome. A sample size of 200 patients could detect a 40% reduction in the primary outcome.

FIGURE 1.

Eligibility.

Procedures: Patients will follow all procedures as per CRASH-2 protocol; Additional procedures for the substudy are as follows:

Patients enrolled in the substudy will be identified by the completion of one form that will collect data on time since injury, time of initial (pre-randomisation) and follow-up CT scans and the file identifiers of the respective CT scan images. This form will also collect information on whether or not a decision to undertake neurosurgery was taken based on the CT scan result (see Appendix 2). This form will be sent to the trial co-ordinating centre in the same way as the CRASH-2 trial data.

3. Organisation

4. IBS protocol references

Appendix 1 Hospitals that will participate in the substudy

1. Aditya Neuroscience Centre, Dibrugarh, India

2. Sanjivani Hospital, Dibrugarh, India

3. Care Hospital, Visakhapatnam, India

4. Christian Medical College, Ludhiana, India

5. Medical Trust Hospital, Kochi, India

6. Hospital Universitario San Vicente de Paul, Medellín, Colombia

7. Hospital Universitario San Jose De Popayan, Colombia

8. Hospital Pablo Tobon Uribe, Medellín, Colombia

9. Fundacion Clinica Valle del Lili, Colombia

10. Jeevan Jyoti Hospital & Research Centre, Allahabad, India.

Other hospitals may be added if recruitment falls below predicted.

Appendix 2 Investigator computerised tomography scan form

(PDF download)

Appendix 3a Information for relatives and representatives

(PDF download)

Appendix 3b Information for patients

(PDF download)

Prioritisation Group

1. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

2. Professor Imti Choonara, Professor in Child Health, Academic Division of Child Health, University of Nottingham

   Chair – Pharmaceuticals Panel

3. Dr Bob Coates, Consultant Advisor – Disease Prevention Panel

4. Dr Andrew Cook, Consultant Advisor – Intervention Procedures Panel

5. Dr Peter Davidson, Director of NETSCC, Health Technology Assessment

6. Dr Nick Hicks, Consultant Adviser – Diagnostic Technologies and Screening Panel, Consultant Advisor–Psychological and Community Therapies Panel

7. Ms Susan Hird, Consultant Advisor, External Devices and Physical Therapies Panel

8. Professor Sallie Lamb, Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick

   Chair – HTA Clinical Evaluation and Trials Board

9. Professor Jonathan Michaels, Professor of Vascular Surgery, Sheffield Vascular Institute, University of Sheffield

   Chair – Interventional Procedures Panel

10. Professor Ruairidh Milne, Director – External Relations

11. Dr John Pounsford, Consultant Physician, Directorate of Medical Services, North Bristol NHS Trust

    Chair – External Devices and Physical Therapies Panel

12. Dr Vaughan Thomas, Consultant Advisor – Pharmaceuticals Panel, Clinical

    Lead – Clinical Evaluation Trials Prioritisation Group

13. Professor Margaret Thorogood, Professor of Epidemiology, Health Sciences Research Institute, University of Warwick

    Chair – Disease Prevention Panel

14. Professor Lindsay Turnbull, Professor of Radiology, Centre for the MR Investigations, University of Hull

    Chair – Diagnostic Technologies and Screening Panel

15. Professor Scott Weich, Professor of Psychiatry, Health Sciences Research Institute, University of Warwick

    Chair – Psychological and Community Therapies Panel

16. Professor Hywel Williams, Director of Nottingham Clinical Trials Unit, Centre of Evidence-Based Dermatology, University of Nottingham

    Chair – HTA Commissioning Board

    Deputy HTA Programme Director

HTA Commissioning Board

1. Professor of Dermato-Epidemiology, Centre of Evidence-Based Dermatology, University of Nottingham

2. Department of Public Health and Epidemiology, University of Birmingham

3. Professor of Clinical Pharmacology, Director, NIHR HTA programme, University of Liverpool

1. Professor Ann Ashburn, Professor of Rehabilitation and Head of Research, Southampton General Hospital

2. Professor Judith Bliss, Director of ICR-Clinical Trials and Statistics Unit, The Institute of Cancer Research

3. Professor Peter Brocklehurst, Professor of Women’s Health, Institute for Women’s Health, University College London

4. Professor David Fitzmaurice, Professor of Primary Care Research, Department of Primary Care Clinical Sciences, University of Birmingham

5. Professor John W Gregory, Professor in Paediatric Endocrinology, Department of Child Health, Wales School of Medicine, Cardiff University

6. Professor Steve Halligan, Professor of Gastrointestinal Radiology, University College Hospital, London

7. Professor Angela Harden, Professor of Community and Family Health, Institute for Health and Human Development, University of East London

8. Dr Martin J Landray, Reader in Epidemiology, Honorary Consultant Physician, Clinical Trial Service Unit, University of Oxford

9. Dr Joanne Lord, Reader, Health Economics Research Group, Brunel University

10. Professor Stephen Morris, Professor of Health Economics, University College London, Research Department of Epidemiology and Public Health, University College London

11. Professor Dion Morton, Professor of Surgery, Academic Department of Surgery, University of Birmingham

12. Professor Gail Mountain, Professor of Health Services Research, Rehabilitation and Assistive Technologies Group, University of Sheffield

13. Professor Irwin Nazareth, Professor of Primary Care and Head of Department, Department of Primary Care and Population Sciences, University College London

14. Professor E Andrea Nelson, Professor of Wound Healing and Director of Research, School of Healthcare, University of Leeds

15. Professor John David Norrie, Chair in Clinical Trials and Biostatistics, Robertson Centre for Biostatistics, University of Glasgow

16. Dr Rafael Perera, Lecturer in Medical Statisitics, Department of Primary Health Care, University of Oxford

17. Professor Barney Reeves, Professorial Research Fellow in Health Services Research, Department of Clinical Science, University of Bristol

18. Professor Peter Tyrer, Professor of Community Psychiatry, Centre for Mental Health, Imperial College London

19. Professor Martin Underwood, Professor of Primary Care Research, Warwick Medical School, University of Warwick

20. Professor Caroline Watkins, Professor of Stroke and Older People’s Care, Chair of UK Forum for Stroke Training, Stroke Practice Research Unit, University of Central Lancashire

21. Dr Duncan Young, Senior Clinical Lecturer and Consultant, Nuffield Department of Anaesthetics, University of Oxford

1. Dr Tom Foulks, Medical Research Council

2. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

HTA Clinical Evaluation and Trials Board

1. Director, Warwick Clinical Trials Unit, Warwick Medical School, University of Warwick and Professor of Rehabilitation, Nuffield Department of Orthopaedic, Rheumatology and Musculoskeletal Sciences, University of Oxford

2. Professor of the Psychology of Health Care, Leeds Institute of Health Sciences, University of Leeds

3. Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

1. Professor Keith Abrams, Professor of Medical Statistics, Department of Health Sciences, University of Leicester

2. Professor Martin Bland, Professor of Health Statistics, Department of Health Sciences, University of York

3. Professor Jane Blazeby, Professor of Surgery and Consultant Upper GI Surgeon, Department of Social Medicine, University of Bristol

4. Professor Julia M Brown, Director, Clinical Trials Research Unit, University of Leeds

5. Professor Alistair Burns, Professor of Old Age Psychiatry, Psychiatry Research Group, School of Community-Based Medicine, The University of Manchester & National Clinical Director for Dementia, Department of Health

6. Dr Jennifer Burr, Director, Centre for Healthcare Randomised trials (CHART), University of Aberdeen

7. Professor Linda Davies, Professor of Health Economics, Health Sciences Research Group, University of Manchester

8. Professor Simon Gilbody, Prof of Psych Medicine and Health Services Research, Department of Health Sciences, University of York

9. Professor Steven Goodacre, Professor and Consultant in Emergency Medicine, School of Health and Related Research, University of Sheffield

10. Professor Dyfrig Hughes, Professor of Pharmacoeconomics, Centre for Economics and Policy in Health, Institute of Medical and Social Care Research, Bangor University

11. Professor Paul Jones, Professor of Respiratory Medicine, Department of Cardiac and Vascular Science, St George‘s Hospital Medical School, University of London

12. Professor Khalid Khan, Professor of Women’s Health and Clinical Epidemiology, Barts and the London School of Medicine, Queen Mary, University of London

13. Professor Richard J McManus, Professor of Primary Care Cardiovascular Research, Primary Care Clinical Sciences Building, University of Birmingham

14. Professor Helen Rodgers, Professor of Stroke Care, Institute for Ageing and Health, Newcastle University

15. Professor Ken Stein, Professor of Public Health, Peninsula Technology Assessment Group, Peninsula College of Medicine and Dentistry, Universities of Exeter and Plymouth

16. Professor Jonathan Sterne, Professor of Medical Statistics and Epidemiology, Department of Social Medicine, University of Bristol

17. Mr Andy Vail, Senior Lecturer, Health Sciences Research Group, University of Manchester

18. Professor Clare Wilkinson, Professor of General Practice and Director of Research North Wales Clinical School, Department of Primary Care and Public Health, Cardiff University

19. Dr Ian B Wilkinson, Senior Lecturer and Honorary Consultant, Clinical Pharmacology Unit, Department of Medicine, University of Cambridge

1. Ms Kate Law, Director of Clinical Trials, Cancer Research UK

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

Diagnostic Technologies and Screening Panel

1. Scientific Director of the Centre for Magnetic Resonance Investigations and YCR Professor of Radiology, Hull Royal Infirmary

2. Professor Judith E Adams, Consultant Radiologist, Manchester Royal Infirmary, Central Manchester & Manchester Children’s University Hospitals NHS Trust, and Professor of Diagnostic Radiology, University of Manchester

3. Mr Angus S Arunkalaivanan, Honorary Senior Lecturer, University of Birmingham and Consultant Urogynaecologist and Obstetrician, City Hospital, Birmingham

4. Dr Diana Baralle, Consultant and Senior Lecturer in Clinical Genetics, University of Southampton

5. Dr Stephanie Dancer, Consultant Microbiologist, Hairmyres Hospital, East Kilbride

6. Dr Diane Eccles, Professor of Cancer Genetics, Wessex Clinical Genetics Service, Princess Anne Hospital

7. Dr Trevor Friedman, Consultant Liason Psychiatrist, Brandon Unit, Leicester General Hospital

8. Dr Ron Gray, Consultant, National Perinatal Epidemiology Unit, Institute of Health Sciences, University of Oxford

9. Professor Paul D Griffiths, Professor of Radiology, Academic Unit of Radiology, University of Sheffield

10. Mr Martin Hooper, Public contributor

11. Professor Anthony Robert Kendrick, Associate Dean for Clinical Research and Professor of Primary Medical Care, University of Southampton

12. Dr Nicola Lennard, Senior Medical Officer, MHRA

13. Dr Anne Mackie, Director of Programmes, UK National Screening Committee, London

14. Mr David Mathew, Public contributor

15. Dr Michael Millar, Consultant Senior Lecturer in Microbiology, Department of Pathology & Microbiology, Barts and The London NHS Trust, Royal London Hospital

16. Mrs Una Rennard, Public contributor

17. Dr Stuart Smellie, Consultant in Clinical Pathology, Bishop Auckland General Hospital

18. Ms Jane Smith, Consultant Ultrasound Practitioner, Leeds Teaching Hospital NHS Trust, Leeds

19. Dr Allison Streetly, Programme Director, NHS Sickle Cell and Thalassaemia Screening Programme, King’s College School of Medicine

20. Dr Matthew Thompson, Senior Clinical Scientist and GP, Department of Primary Health Care, University of Oxford

21. Dr Alan J Williams, Consultant Physician, General and Respiratory Medicine, The Royal Bournemouth Hospital

1. Dr Tim Elliott, Team Leader, Cancer Screening, Department of Health

2. Dr Joanna Jenkinson, Board Secretary, Neurosciences and Mental Health Board (NMHB), Medical Research Council

3. Professor Julietta Patrick, Director, NHS Cancer Screening Programme, Sheffield

4. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

5. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

6. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Disease Prevention Panel

1. Professor of Epidemiology, University of Warwick Medical School, Coventry

2. Dr Robert Cook, Clinical Programmes Director, Bazian Ltd, London

3. Dr Colin Greaves, Senior Research Fellow, Peninsula Medical School (Primary Care)

4. Mr Michael Head, Public contributor

5. Professor Cathy Jackson, Professor of Primary Care Medicine, Bute Medical School, University of St Andrews

6. Dr Russell Jago, Senior Lecturer in Exercise, Nutrition and Health, Centre for Sport, Exercise and Health, University of Bristol

7. Dr Julie Mytton, Consultant in Child Public Health, NHS Bristol

8. Professor Irwin Nazareth, Professor of Primary Care and Director, Department of Primary Care and Population Sciences, University College London

9. Dr Richard Richards, Assistant Director of Public Health, Derbyshire County Primary Care Trust

10. Professor Ian Roberts, Professor of Epidemiology and Public Health, London School of Hygiene & Tropical Medicine

11. Dr Kenneth Robertson, Consultant Paediatrician, Royal Hospital for Sick Children, Glasgow

12. Dr Catherine Swann, Associate Director, Centre for Public Health Excellence, NICE

13. Mrs Jean Thurston, Public contributor

14. Professor David Weller, Head, School of Clinical Science and Community Health, University of Edinburgh

1. Ms Christine McGuire, Research & Development, Department of Health

2. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

External Devices and Physical Therapies Panel

1. Consultant Physician North Bristol NHS Trust

2. Reader in Wound Healing and Director of Research, University of Leeds

3. Professor Bipin Bhakta, Charterhouse Professor in Rehabilitation Medicine, University of Leeds

4. Mrs Penny Calder, Public contributor

5. Dr Dawn Carnes, Senior Research Fellow, Barts and the London School of Medicine and Dentistry

6. Dr Emma Clark, Clinician Scientist Fellow & Cons. Rheumatologist, University of Bristol

7. Mrs Anthea De Barton-Watson, Public contributor

8. Professor Nadine Foster, Professor of Musculoskeletal Health in Primary Care Arthritis Research, Keele University

9. Dr Shaheen Hamdy, Clinical Senior Lecturer and Consultant Physician, University of Manchester

10. Professor Christine Norton, Professor of Clinical Nursing Innovation, Bucks New University and Imperial College Healthcare NHS Trust

11. Dr Lorraine Pinnigton, Associate Professor in Rehabilitation, University of Nottingham

12. Dr Kate Radford, Senior Lecturer (Research), University of Central Lancashire

13. Mr Jim Reece, Public contributor

14. Professor Maria Stokes, Professor of Neuromusculoskeletal Rehabilitation, University of Southampton

15. Dr Pippa Tyrrell, Senior Lecturer/Consultant, Salford Royal Foundation Hospitals’ Trust and University of Manchester

16. Dr Nefyn Williams, Clinical Senior Lecturer, Cardiff University

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Interventional Procedures Panel

1. Professor of Vascular Surgery, University of Sheffield

2. Consultant Colorectal Surgeon, Bristol Royal Infirmary

3. Mrs Isabel Boyer, Public contributor

4. Mr Sankaran Chandra Sekharan, Consultant Surgeon, Breast Surgery, Colchester Hospital University NHS Foundation Trust

5. Professor Nicholas Clarke, Consultant Orthopaedic Surgeon, Southampton University Hospitals NHS Trust

6. Ms Leonie Cooke, Public contributor

7. Mr Seumas Eckford, Consultant in Obstetrics & Gynaecology, North Devon District Hospital

8. Professor Sam Eljamel, Consultant Neurosurgeon, Ninewells Hospital and Medical School, Dundee

9. Dr Adele Fielding, Senior Lecturer and Honorary Consultant in Haematology, University College London Medical School

10. Dr Matthew Hatton, Consultant in Clinical Oncology, Sheffield Teaching Hospital Foundation Trust

11. Dr John Holden, General Practitioner, Garswood Surgery, Wigan

12. Dr Fiona Lecky, Senior Lecturer/Honorary Consultant in Emergency Medicine, University of Manchester/Salford Royal Hospitals NHS Foundation Trust

13. Dr Nadim Malik, Consultant Cardiologist/Honorary Lecturer, University of Manchester

14. Mr Hisham Mehanna, Consultant & Honorary Associate Professor, University Hospitals Coventry & Warwickshire NHS Trust

15. Dr Jane Montgomery, Consultant in Anaesthetics and Critical Care, South Devon Healthcare NHS Foundation Trust

16. Professor Jon Moss, Consultant Interventional Radiologist, North Glasgow Hospitals University NHS Trust

17. Dr Simon Padley, Consultant Radiologist, Chelsea & Westminster Hospital

18. Dr Ashish Paul, Medical Director, Bedfordshire PCT

19. Dr Sarah Purdy, Consultant Senior Lecturer, University of Bristol

20. Dr Matthew Wilson, Consultant Anaesthetist, Sheffield Teaching Hospitals NHS Foundation Trust

21. Professor Yit Chiun Yang, Consultant Ophthalmologist, Royal Wolverhampton Hospitals NHS Trust

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Pharmaceuticals Panel

1. Professor in Child Health, University of Nottingham

2. Senior Lecturer in Clinical Pharmacology, University of East Anglia

3. Dr Martin Ashton-Key, Medical Advisor, National Commissioning Group, NHS London

4. Dr Peter Elton, Director of Public Health, Bury Primary Care Trust

5. Dr Ben Goldacre, Research Fellow, Division of Psychological Medicine and Psychiatry, King’s College London

6. Dr James Gray, Consultant Microbiologist, Department of Microbiology, Birmingham Children’s Hospital NHS Foundation Trust

7. Dr Jurjees Hasan, Consultant in Medical Oncology, The Christie, Manchester

8. Dr Carl Heneghan, Deputy Director Centre for Evidence-Based Medicine and Clinical Lecturer, Department of Primary Health Care, University of Oxford

9. Dr Dyfrig Hughes, Reader in Pharmacoeconomics and Deputy Director, Centre for Economics and Policy in Health, IMSCaR, Bangor University

10. Dr Maria Kouimtzi, Pharmacy and Informatics Director, Global Clinical Solutions, Wiley-Blackwell

11. Professor Femi Oyebode, Consultant Psychiatrist and Head of Department, University of Birmingham

12. Dr Andrew Prentice, Senior Lecturer and Consultant Obstetrician and Gynaecologist, The Rosie Hospital, University of Cambridge

13. Ms Amanda Roberts, Public contributor

14. Dr Gillian Shepherd, Director, Health and Clinical Excellence, Merck Serono Ltd

15. Mrs Katrina Simister, Assistant Director New Medicines, National Prescribing Centre, Liverpool

16. Professor Donald Singer, Professor of Clinical Pharmacology and Therapeutics, Clinical Sciences Research Institute, CSB, University of Warwick Medical School

17. Mr David Symes, Public contributor

18. Dr Arnold Zermansky, General Practitioner, Senior Research Fellow, Pharmacy Practice and Medicines Management Group, Leeds University

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Mr Simon Reeve, Head of Clinical and Cost-Effectiveness, Medicines, Pharmacy and Industry Group, Department of Health

3. Dr Heike Weber, Programme Manager, Medical Research Council

4. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

5. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health

Psychological and Community Therapies Panel

1. Professor of Psychiatry, University of Warwick, Coventry

2. Consultant & University Lecturer in Psychiatry, University of Cambridge

3. Professor Jane Barlow, Professor of Public Health in the Early Years, Health Sciences Research Institute, Warwick Medical School

4. Dr Sabyasachi Bhaumik, Consultant Psychiatrist, Leicestershire Partnership NHS Trust

5. Mrs Val Carlill, Public contributor

6. Dr Steve Cunningham, Consultant Respiratory Paediatrician, Lothian Health Board

7. Dr Anne Hesketh, Senior Clinical Lecturer in Speech and Language Therapy, University of Manchester

8. Dr Peter Langdon, Senior Clinical Lecturer, School of Medicine, Health Policy and Practice, University of East Anglia

9. Dr Yann Lefeuvre, GP Partner, Burrage Road Surgery, London

10. Dr Jeremy J Murphy, Consultant Physician and Cardiologist, County Durham and Darlington Foundation Trust

11. Dr Richard Neal, Clinical Senior Lecturer in General Practice, Cardiff University

12. Mr John Needham, Public contributor

13. Ms Mary Nettle, Mental Health User Consultant

14. Professor John Potter, Professor of Ageing and Stroke Medicine, University of East Anglia

15. Dr Greta Rait, Senior Clinical Lecturer and General Practitioner, University College London

16. Dr Paul Ramchandani, Senior Research Fellow/Cons. Child Psychiatrist, University of Oxford

17. Dr Karen Roberts, Nurse/Consultant, Dunston Hill Hospital, Tyne and Wear

18. Dr Karim Saad, Consultant in Old Age Psychiatry, Coventry and Warwickshire Partnership Trust

19. Dr Lesley Stockton, Lecturer, School of Health Sciences, University of Liverpool

20. Dr Simon Wright, GP Partner, Walkden Medical Centre, Manchester

1. Dr Kay Pattison, Senior NIHR Programme Manager, Department of Health

2. Dr Morven Roberts, Clinical Trials Manager, Health Services and Public Health Services Board, Medical Research Council

3. Professor Tom Walley, CBE, Director, NIHR HTA programme, Professor of Clinical Pharmacology, University of Liverpool

4. Dr Ursula Wells, Principal Research Officer, Policy Research Programme, Department of Health