TRIGGER Trial: Transfusion in Gastrointestinal Bleeding

1. TRIGGER Trial: Transfusion in Gastrointestinal Bleeding Investigator Meeting NHSBT – Birmingham August 29th 2012 11:00-16:30 Presented by Dr Vipul Jairath Research Fellow and Honorary SpR Gastroenterology NHSBT and Oxford University Hospitals

2. TRIGGER Investigator Meeting • Welcome • Introductions • Apologies • Study Materials • Site Folder • Screening Log and CRFs • Study Handbook

3. Overview of Policy Implementation, Screening and Consent Procedures Vipul Jairath, Ana Mora, Sian Davies 11:30 – 12:15

4. Overview of trial recruitment processes Participant admitted to hospital with suspected AUGIB Algorithm is followed for all patients except those where the clinician feels immediate transfusion is needed when the patient presents, regardless of or prior to obtaining the Hb result, due to severity of bleeding Follow the hospital’s allocated transfusion policy – Restrictive or Liberal Screen and Complete Screening Log Daily If participant declines consent for data use and follow-up, the algorithm is still followed Approach Eligible Patients to seek Consent Complete CRFs for Consenting Patients Collect data – discharge/death/D28 Telephone follow-up at Day 28

5. The Screening Log • Each site should develop their own methods of case-ascertainment • Log should be completed daily Monday – Friday • Should record all new admissions with Acute Upper Gastrointestinal Bleeding (AUGIB) defined by: - Haematemesis: vomiting of blood, blood clots or witnessed coffee grounds - Melaena: passage of dark tarry stools either on clinical history witnessed by medical or nursing staff, or discovered on rectal examination

6. The Screening Log • Screening Log (a): complete for ALL admission with AUGIB • Screening Log (b): only complete for patients considered ‘Ineligible due to severity of bleeding’ • See Screening Log forms (a) and (b) and Study Handbook pages 10 – 11 • Send log through every Monday to CSU

7. Consent – for what? • Randomisation – from the cluster • Intervention – from the cluster • Data collection – from the participant • Follow-up – from the participant

8. Consent – what is capacity? • Mental Capacity Act 2005, Section 2 ‘... a person lacks capacity if at the material time he is unable to make a decision for himself in relation to the matter because an impairment of, or disturbance in, the functioning of the mind or brain’ • The following factors have to considered when assessing if someone has capacity to make a decision, section 3 (1): - whether they are able to understand the information - whether they are able to retain the information related to the decision to be made - whether they are able to use or weigh that information as part of the process of making the decision - whether they are able to communicate that decision – by any means

9. Consent procedures • Spectrum of illness • Anticipate that most patients will be able to provide consent for themselves • Patients who may lack capacity include: - elderly patients with pre-existing cognitive impairment • Patients who may have fluctuating capacity include: - elderly patients with acute confusional state - decompensated liver disease - alcohol withdrawal – especially Delerium Tremens

10. When and How to approach patients • Suggested timeframe to approach eligible patients/delegate: - on the same day for those who present in normal hours - the following day for those who present overnight - Monday for those who present over the weekend ... provided this is appropriate to their clinical condition • Please use the suggested script as a guide which may help explain the transfusion policy – page 15 of Study Handbook Remember – you cannot complete any paperwork other than the anonymised screening log until you have written patient consent

11. Definitions - England • Personal Consultee - ‘... someone whom the person who lacks capacity would trust with important decisions about their welfare, but who is not acting in a professional or paid capacity, e.g you could consult a family member or close friend of the prospective trial participant, but not a paid carer or other professional such as social worker. Remuneration does not cover family members receiving some of the person’s pension or other benefits as a payment towards their share of the household expenses’ • Nominated Consultee - ‘... Someone who is prepared to be consulted by the researcher, but has no connection with the research study, e.g this could be the consultant responsible for the patient’s care, provided they are not a named local PI, and should be of consultant (or equivalent) status. They must have received information about the research and a PIS is considered appropriate’

12. Definitions - Scotland • Relative/Welfare Attorney - ‘... Someone who has been appointed by a court to make decisions on behalf of those lacking capacity’

13. Consent Procedures – England (p.13 SH) CRF Form 1b Does the patient have mental capacity in relation to the study? Yes Approach patient and use information sheet and consent form for participants with capacity No Does a personal consultee exist who can be approached in person? Yes No Approach nominated consultee. Use clinician agreement form Approach personal consultee. Use personal consultee information sheet and declaration form Does the patient regain mental capacity in relation to the study? Use declaration provided by personal consultee No Yes Use information sheet & consent form for participants regaining capacity and data preservation form

14. Consent Procedures – Scotland (p.14 SH) CRF Form 1b Does the patient have mental capacity in relation to the study? Yes Approach patient and use information sheet and consent form for participants with capacity No Does a relative/welfare attorney exist who can be approached in person? Yes No Patient is not enrolled into study Approach relative/WA. Use relative/WA information sheet and declaration form Does the patient regain mental capacity in relation to the study? Use consent provided by relative/WA No Yes Use information sheet & consent form for participants regaining capacity and data preservation form

15. When is a Data Preservation form needed? • All patients who lacked capacity, and proxy consent (consultee/relative/welfare guardian) was obtained, must be approached once they regain capacity • Use Data Preservation form (DPF) if: - a patient who regains capacity (and was enrolled on the basis of proxy consent) then declines to take part further in the study. Use of a Data Preservation Form will allow use of data up to that point, provided the patient agrees to this - a proxy initially provides consent and then decides to with draw this. Use of a Data Preservation Form will allow use of data up to that point, provided the proxy agrees to this

16. Special Considerations - Scotland • Any participant with a pre-existing condition which would render them unable to provide consent would preclude them from participating in the study, e.g dementia • Neither patients nor relatives/welfare guardians should be approached in this circumstance

17. Patients discharged prior to consent • Some centres are more pro-active at discharging lower risk patients from the ED • Those will need to attempt to identify those patients and indicate this option on the weekly screening log • In Scotland - post a cover letter and PIS/Consent Form plus stamped return envelope • In England • same approach applies but you will require R&D approval before you can implement this and these are pending at this time

18. Patients who die prior to consent • We anticipate this in very few circumstances • Currently no approval process in place at this time and under REC review • England – anticipate writing to relative >1 month after the event; this is under review and will not be in place for the start of the trial • Scotland – under review

19. Trial Participant Checklist (p.8 SH) • Screening Log • Consent – document in notes and 3 copies • Insert algorithm into medical and nursing notes and adjacent to blood prescription chart • Inform member of the clinical team of enrolment • Inform Blood Bank if you have a flagging system • Record preferred contact number(s) • Post GP letter • Start completing CRFs 1 – 10b, 15 – 17 • Contact GP surgery to check survival status – D28 • Administer telephone follow-up (Forms 11a – 13f) • Complete End of Study form (Form 14)

21. Special considerations when consenting patients with AUGIB: A first hand nursing perspective Sian Davies – RN 11:30 – 12:15

22. Characteristics of patients who may present with AUGIB • Older patients • Patients with liver cirrhosis/alcoholic liver disease • Patients with gastrointestinal malignancy (oesophageal/gastric/pancreatic) • Patients taking Antiplatelets/NSAIDS

23. Patients with liver cirrhosis • After a GI bleed, patient’s with cirrhosis can decompensate and develop encephalopathy. This often resolves over 48-72 hours once treatment commenced • In some situations encephalopathy is chronic, resulting in persistent fluctuating levels of confusion. Direct consent in this situation is often not achievable

24. Patients withdrawing from alcohol • Some patients (may or may not have cirrhosis) may be withdrawing from alcohol • If withdrawal symptoms are adequately controlled, gaining consent should be straightforward • If withdrawal symptoms are severe, e.g Delerium Tremens, consent would need to be initially sought from a personal consultee/relative/welfare guardian • Day 3-5 of admission is often the most challenging. It should be possible to re-approach the patient after this time

25. Patients with malignancy • Under these circumstances there may be no issues with consenting the patient from a capacity perspective • Patients may be taking high doses of Opioid medication which could effect their ability to consent • Caution around time of approach would be advised after discussion with medical/nursing team

26. Patients taking Antiplatelets/NSAIDS • Antiplatelets – likely to be older patient with co-morbidity. In this case they could suffer with an acute confusional state. Consent would need to be sought from a personal consultee/relative/welfare guardian until confusion resolves • NSAIDS – combination of younger and older patients. Most should be capable of consenting

27. Review of Case Report Forms Vipul Jairath & Ana Mora 12:15 – 13:15

28. Review of CRFs • Tour through each CRF other than follow-up questionnaire (11a – 13f) and SAE forms (16a&b & 17) which will be reviewed later in the day • Open CRFs and Completion Guidance pages 16 – 42 of Study Handbook • All CRFs are the same apart from the front page, page headers and the consent form 1b

29. Forms 1a&b, 2, 3 & 4 – ‘Batch 1’ These should be submitted together as the first batch • Form 1a – Eligibility • Form 1b – Consent England and Scotland • Form 2 – Presenting Signs and Symptoms • Form 3 – First recorded Laboratory Data • Form 4 – Pre-existing Co-morbidities and Medication

30. Forms 5a – 10b, 15 – ‘Batch 2’ These should be submitted together as the second batch • Form 5a&b – Medication administered in Hospital • Form 6a&b – Hb Measurements and RBC Transfusion • Form 7 – Protocol Deviation Form • Form 8a&b – Endoscopy Record • Form 9 – Acute Transfusion Reactions • Form 10a&b – Clinical Outcomes during Hospital Admission • Form 15 – Additional Resource Use

31. Forms 11a – 14, 18 – ‘Batch 3’ These should be submitted together as the third batch • Forms 11a – 13f – Follow-up Questionnaire • Form 14 – End of Study Form • Form 18 – Investigator Declaration Form

32. Transmittal of CRFs • Order of transmittal - Forms 1a – 4 at trial entry - Forms 5a – 10b, 15 at Hospital Discharge - Forms 11a – 14, 18 at end of study • SAE transmittal forms - 16a, 16b & 17 as they occur

34. Lunch13:15-13:45

35. Investigator responsibilities and Safety reporting Alison Deary Clinical Operations Manager NHSBT 13:45-14:15

36. Investigator Responsibilities • These are divided into several areas: • Qualifications and agreements • Resources • Responsibilities to the Participant • Ethics and Governance • Record Keeping • Safety Reporting

37. Qualifications and Agreements • GCP states that the investigator should be qualified by education, training and experience to assume responsibility for the proper conduct of the trial.. • CV/GCP training certificate • Familiar with the protocol and the appropriate use of the investigational product • Delegation of trial-related duties

38. Qualifications and Agreements • Should be aware of, and comply with GCP and applicable regulatory requirements • Should permit monitoring and audit by the sponsor and inspection by regulatory authority • Should maintain a list of appropriately qualified persons to whom trial related duties are delegated

39. Resources • Be able to demonstrate the potential to recruit the required number of suitable participants within the agreed recruitment period • Have sufficient time • Have adequate number of qualified staff and adequate facilities • Ensure all staff are adequately informed

40. Responsibilities to the Participant • Medical care of the participants – make all trial related medical decisions • Ensure adequate care for adverse events • Make a reasonable effort to ascertain reasons for withdrawal from the trial • Ensure participant confidentiality respected at all times • Ensure participant’s medical records reflects their participation • Inform GP

41. Ethics and Governance • Ensure have ethical and trust approval to conduct the study • Conduct study according to current version of the protocol • Document and explain any deviation from the protocol • Not to implement any deviation from study without permission from sponsor (and REC) unless immediate safety concern

42. Ethics and Governance • Obtain informed consent • Ensure using current version of information and consent forms • Until consent obtained, no trial-related activity may commence • Ensure a copy of information and consent form are provided to participant/representative • Follow randomised trial treatment policy

43. Record keeping • Obtain informed consent and document this • Ensure data collected are consistent with source documents • Collect, record and report all study data accurately , completely, legibly and in a timely manner • To sign the completed CRFs • To ensure all trial documentation is maintained appropriately • To ensure essential documents are archived • To ensure annual reports are made to the R&D department

44. Safety Reporting

45. Adverse Event Definitions • An adverse event is defined as “Any untoward occurrence in a subject receiving treatment according to the protocol, including occurrences which are not necessarily caused by or related to administration of the research procedures”

46. Serious Adverse Events (SAE) • Defined as any adverse event that • Results in death • Is life-threatening • Results in hospitalisation or prolongation of existing hospitalisation • Results in persistent disability or incapacity Do not confuse serious with severe

47. Expected or Unexpected? • Section 9 of the protocol contains a list of “expected” SAEs • Only unexpected SAEs – i.e. not on the list of “expected” SAEs - are subject to expedited notification to the CSU • An unexpected related SAE is one that is judged to be possibly, probably or definitely related to the transfusion policy

48. Definitions of Imputability

49. Expected SAEs which are clinical outcome measures • Death • Further bleeding • Need for surgery or radiological intervention to control bleeding • Any element of the composite endpoint of thromboembolic and ischaemic events (MI, stroke, PE, DVT, acute kidney injury) • Acute transfusion reaction

50. Other expected SAEs • Multi-organ failure • Congestive Cardiac Failure • Respiratory complications • Transient ischaemic attack • Decompensated liver disease • Need for paracentesis to drain ascites • Gut infarction