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NHSBT/MRC Clinical Studies Unit TRIGGER Trial: Transfusion in Gastrointestinal Bleeding Presented by Dr Vipul Jairath Research Fellow and Honorary SpR.

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Presentation on theme: "NHSBT/MRC Clinical Studies Unit TRIGGER Trial: Transfusion in Gastrointestinal Bleeding Presented by Dr Vipul Jairath Research Fellow and Honorary SpR."— Presentation transcript:

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

2 NHSBT/MRC Clinical Studies Unit TRIGGER Investigator Meeting Welcome Introductions Apologies Study Materials –Site Folder –Screening Log and CRFs –Study Handbook

3 NHSBT/MRC Clinical Studies Unit Overview of Policy Implementation, Screening and Consent Procedures Vipul Jairath, Ana Mora, Sian Davies 11:30 – 12:15

4 NHSBT/MRC Clinical Studies Unit Overview of trial recruitment processes Follow the hospital’s allocated transfusion policy – Restrictive or Liberal 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 Screen and Complete Screening Log Daily Approach Eligible Patients to seek Consent Complete CRFs for Consenting Patients Collect data – discharge/death/D28 Telephone follow-up at Day 28 If participant declines consent for data use and follow-up, the algorithm is still followed

5 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit Consent – for what? Randomisation – from the cluster Intervention – from the cluster Data collection – from the participant Follow-up – from the participant

8 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit Definitions - Scotland Relative/Welfare Attorney - ‘... Someone who has been appointed by a court to make decisions on behalf of those lacking capacity’

13 NHSBT/MRC Clinical Studies Unit Consent Procedures – England (p.13 SH) CRF Form 1b Does the patient have mental capacity in relation to the study?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? Approach personal consultee. Use personal consultee information sheet and declaration form Approach nominated consultee. Use clinician agreement form Yes Does the patient regain mental capacity in relation to the study? Use declaration provided by personal consultee Use information sheet & consent form for participants regaining capacity and data preservation form YesNo Yes No

14 NHSBT/MRC Clinical Studies Unit Consent Procedures – Scotland (p.14 SH) CRF Form 1b Does the patient have mental capacity in relation to the study?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? Approach relative/WA. Use relative/WA information sheet and declaration form Patient is not enrolled into study Yes Does the patient regain mental capacity in relation to the study? Use consent provided by relative/WA Use information sheet & consent form for participants regaining capacity and data preservation form YesNo Yes No

15 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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)

20 NHSBT/MRC Clinical Studies Unit

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

22 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit Patients with liver cirrhosis After a GI bleed, patient’s with cirrhosis can decompensate and develop encephalopathy. This often resolves over 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit Review of Case Report Forms Vipul Jairath & Ana Mora 12:15 – 13:15

28 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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

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34 Lunch 13:15-13:45

35 NHSBT/MRC Clinical Studies Unit Alison Deary Clinical Operations Manager NHSBT 13:45-14:15 Investigator responsibilities and Safety reporting

36 NHSBT/MRC Clinical Studies Unit Investigator Responsibilities These are divided into several areas: –Qualifications and agreements –Resources –Responsibilities to the Participant –Ethics and Governance –Record Keeping –Safety Reporting

37 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit Safety Reporting

45 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit Definitions of Imputability RelationshipDescription PossibleThere is some evidence to suggest a causal relationship, however the influence of other factors may have contributed to the event ProbableThe evidence is clearly in favour of attributing the SAE to the transfusion policy DefiniteThere is conclusive evidence beyond reasonable doubt attributing the SAE to the transfusion policy

49 NHSBT/MRC Clinical Studies Unit 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 NHSBT/MRC Clinical Studies Unit 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

51 NHSBT/MRC Clinical Studies Unit Other expected SAEs Rise in serum Troponin I or E GI perforation or obstruction Post-operative complication Need for repeat endoscopy for any reason Non-acute transfusion reaction

52 NHSBT/MRC Clinical Studies Unit Notification within one working day Any unexpected SAE Death Further bleeding Any element of the composite endpoint of thromboembolic and ischaemic events (MI, stoke, PE, DVT, acute kidney injury)

53 NHSBT/MRC Clinical Studies Unit Reporting to IDMC When received at the CSU, the reports of the events listed will be sent to the IDMC and the CI Be prepared to answer any queries in a timely manner The IDMC will know which treatment regimen the site has been randomised to

54 NHSBT/MRC Clinical Studies Unit When to collect SAEs Collect on all participants from enrolment to Study Day 28 Include any that occur following discharge if before Day 28, in particular infection, further bleeding and thromboembolic/ischaemic events

55 NHSBT/MRC Clinical Studies Unit Responsibilities -PI Ensure notification of all SAEs in the appropriate timeframe SAE forms must be completed by the PI, or, if a designate, counter-signed by the PI Initial report must contain at least patient identifier, name of event, date of occurrence and causality Further more detailed information can be provided later

56 NHSBT/MRC Clinical Studies Unit Responsibilities - Sponsor The CI will review all reported SAEs and Clinical Outcomes. Any disagreement with regard to imputability will be recorded but the PI opinion cannot be over-ruled. Unexpected related SAEs will be reported to REC within 15 days

57 NHSBT/MRC Clinical Studies Unit Form Completion Review of Forms 16a&b, 17 SAE transmittal

58 NHSBT/MRC Clinical Studies Unit

59 Case-Study 1 68 year old female admitted with UGIB and found to have a large ulcer at endoscopy which is treated. Has further bleeding 72 hours later and a repeat endoscopy and therapy. Discharged home 5 days later uneventfully. How many SAEs in this scenario? Are they expected or unexpected? Within what timeframe should they be notified to the CSU?

60 NHSBT/MRC Clinical Studies Unit Case-Study 1 Answer 68 year old female admitted with UGIB and found to have a large ulcer at endoscopy which is treated. Has further bleeding 72 hours later and a repeat endoscopy and therapy. Discharged home 5 days later uneventfully. How many SAEs in this scenario? - One Are they expected or unexpected? Expected Within what timeframe should they be notified to the CSU? Within 1 working day

61 NHSBT/MRC Clinical Studies Unit Case-Study 2 45 year old female with alcoholic liver disease admitted with a variceal bleed. Varices successfully banded at endoscopy but she was combative during the procedure and it was prolonged. She then developed an aspiration pneumonia requiring antibiotics. She was discharged without further complications How many SAE’s are there in this scenario? Are they expected or unexpected? Within what timeframe should they be notified to the CSU?

62 NHSBT/MRC Clinical Studies Unit Case-Study 2 Answer 45 year old female with alcoholic liver disease admitted with a variceal bleed. Varices successfully banded at endoscopy but she was combative during the procedure and it was prolonged. She then developed an aspiration pneumonia requiring antibiotics. She was discharged without further complications How many SAE’s are there in this scenario? One Are they expected or unexpected? Expected Within what timeframe should they be notified to the CSU? Within one week

63 NHSBT/MRC Clinical Studies Unit Case-Study 3 54 year old male has a successfully treated duodenal ulcer at endoscopy. He has further bleeding and then goes straight to radiological embolisation. He has further bleeding and then has surgery. He is due for discharge 10 days later but develops a wound infection and is kept in for a further 4 days for antibiotics. How many SAE’s are there in this scenario? Are they expected or unexpected? Within what timeframe should they be notified to the CSU?

64 NHSBT/MRC Clinical Studies Unit Case-Study 3 Answer 54 year old male has a successfully treated duodenal ulcer at endoscopy. He has further bleeding and then goes straight to radiological embolisation. He has further bleeding and then has surgery. He is due for discharge 10 days later but develops a wound infection and is kept in for a further 4 days for antibiotics. How many SAE’s are there in this scenario? Four Are they expected or unexpected? All expected Within what timeframe should they be notified to the CSU? Further bleeding within one working day; Embolisation/surgery/wound infection within one week

65 NHSBT/MRC Clinical Studies Unit Case-Study 4 78 year old man previous heart attacks and “mini-strokes” taking life-long aspirin and dypiridamole. Found to have a gastric cancer at endoscopy. Anti-platelets are withheld and he develops a stroke with a dense right hemi-paresis. How many SAE’s are there in this scenario? Are they expected or unexpected? Within what timeframe should they be notified to the CSU?

66 NHSBT/MRC Clinical Studies Unit Case-Study 4 Answer 78 year old man previous heart attacks and “mini-strokes” taking life-long aspirin and dypiridamole. Found to have a gastric cancer at endoscopy. Anti-platelets are withheld and he develops a stroke with a dense right hemi-paresis. How many SAE’s are there in this scenario? One Are they expected or unexpected? Expected Within what timeframe should they be notified to the CSU? Within one working day

67 NHSBT/MRC Clinical Studies Unit Case-Study 5 A 32 year old alcoholic went on a binge and was vomiting for 24 hours. He was found to have a Mallory-Weiss tear at endoscopy. His alcohol withdrawal symptoms were severe and he fell on the ward whilst mobilising to the toilet, banged his head and required 4 stitches. How many SAE’s are there in this scenario? Are they expected or unexpected? Within what timeframe should they be notified to the CSU?

68 NHSBT/MRC Clinical Studies Unit Case-Study 5 Answer A 32 year old alcoholic went on a binge and was vomiting for 24 hours. He was found to have a Mallory-Weiss tear et endoscopy. His alcohol withdrawal symptoms were severe and he fell on the ward whilst mobilising to the toilet, banged his head and required 4 stitches. How many SAE’s are there in this scenario? None! This is an adverse event, not a serious adverse event. Adverse events do not need reporting.

69 NHSBT/MRC Clinical Studies Unit Elizabeth Stokes Researcher Health Economics Research Centre-University of Oxford 14:15-14:40 Health Economics Evaluations: What are they and what will we do in TRIGGER

70 NHSBT/MRC Clinical Studies Unit Overview of session 1.Introduction to health economic evaluation –Rationale for it –What it is –How it is conducted and results interpreted 2.Health economics in TRIGGER 3.Data collection forms in TRIGGER

71 NHSBT/MRC Clinical Studies Unit What is health economic evaluation? Premise: scarce (health care) resources Aim: to maximise health gain with the resources available Method: compare costs and outcomes of two or more interventions Definition: “The comparative analysis of alternative courses of action in terms of both their costs and their consequences” (Drummond et al. 2005) Explicit way of making choices

72 NHSBT/MRC Clinical Studies Unit Types of health economic evaluation TypeCostsOutcomes Cost-effectiveness analysis Monetary units Natural units e.g. cases detected, life years gained, episode-free day Cost-utility analysisMonetary units Quality Adjusted Life Years (QALYs) Cost-benefit analysisMonetary units

73 NHSBT/MRC Clinical Studies Unit Quality Adjusted Life Years (QALYs) Composite endpoint combining: 1.Quantity of life (survival) 2.Health related quality of life (HRQoL) measured on a 0 (dead) to 1 (full health) scale Patient 1 = = 1.4 QALYs Patient 2 = = 0.55 QALYs QALY difference = 0.85 QALYs Health related quality of life 0 1 Survival time (years)

74 NHSBT/MRC Clinical Studies Unit Cost-effectiveness framework Intervention 1 Cost 1 Effectiveness 1Effectiveness 2 Incremental cost- effectiveness ratio (ICER) = Cost 1 - Cost 2 Effect 1 – Effect 2 Cost 2 Intervention 2

75 NHSBT/MRC Clinical Studies Unit Incremental Costs and Outcomes: Example – chronic low back pain Surgery £7, QALYs Rehabilitation £4, QALYs £7,830 - £4, QALY QALY = £48,588 per QALY Rivero-Arias et al. BMJ 2005; 330(7502): 1239

76 NHSBT/MRC Clinical Studies Unit Health Economics in TRIGGER Feasibility trial Feasibility of gathering data required in a cost-effectiveness analysis to inform data collection for the phase III trial –Pilot resource use data collection forms –Assess feasibility of collecting inpatient data from routine hospital information systems, post-discharge data from patients by telephone, and HRQoL data using the EQ-5D Feasibility of using these data within a cost-effectiveness model to identify parameters with the potential to be key drivers of cost-effectiveness –These will require detailed measurement in phase III trial

77 NHSBT/MRC Clinical Studies Unit Costs I Perspective of National Health Service, patients / their carers, and employers Data will be collected from each trial patient on inpatient health care resource use, including: –RBCs and other blood products transfused –Endoscopies –Time spent in ICU, HDU, general wards –Adverse events –Discharge / transfer to another hospital / facility Data collection integrated into the CRFs

78 NHSBT/MRC Clinical Studies Unit Costs II Primary and secondary health care resource use post discharge will be captured via a telephone contact with patients at 28 days Also in this questionnaire patients will be asked about –any unpaid care received from relatives or friends and any costs they have incurred –and about return to paid employment Unit costs from a variety of sources will be used to cost this resource use data.

79 NHSBT/MRC Clinical Studies Unit Effects I Measured using Quality Adjusted Life Years (QALYs) EuroQol EQ-5D questionnaire used to classify a person’s health state by telephone at day 28 EQ-5D asks respondents whether they have no problems, some problems or extreme problems with Responses are converted into a single index value on the scale 0 to 1, dead to perfect health, using an accompanying scoring tariff - Mobility- Self-care - Usual activities- Pain / discomfort - Anxiety / depression

80 NHSBT/MRC Clinical Studies Unit Effects II Survival data available for each trial patient to 28 days HRQoL assessed at 28 days using the EQ-5D questionnaire No baseline values due to unplanned nature of the condition Quality and quantity of life combined and used as inputs into decision model

81 NHSBT/MRC Clinical Studies Unit Key drivers of cost-effectiveness Trial data will allow exploration of mean costs and QALYs per patient for each trial arm to 28 days Feasibility trial, so the time horizon is short Model acute upper GI bleeding (AUGIB) patient pathway & associated costs and outcomes beyond 28 days to identify parameters with the potential to be key drivers of cost-effectiveness –Use trial data, and other sources such as audit of AUGIB

82 NHSBT/MRC Clinical Studies Unit Summary This feasibility trial will allow us to Determine workable data collection methods for resource use, unit costs and outcomes (quality of life) for the phase III trial Identify key parameters for focussed measurement in the phase III trial

83 NHSBT/MRC Clinical Studies Unit Data Collection Forms in TRIGGER All data collection is integrated into the CRFs Form 15 - length of stay around various departments and wards of hospital Follow up telephone contact at day 28 –Form 12a – EQ-5D –Forms 13a-f – resource use GP verification of patient reported events

84 NHSBT/MRC Clinical Studies Unit Tania Reed Clinical Data Manager NHSBT 14:40-14:55 The Do’s and Dont’s of CRF Completion

85 NHSBT/MRC Clinical Studies Unit All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation, and verification. (Principle 11 - Records, WHO Good Clinical Research Practice)

86 NHSBT/MRC Clinical Studies Unit The Importance of Data Quality and Integrity in Clinical Trials Data quality refers to the extent to which data is accurate, legible, complete, original, and attributable to the person generating it Data integrity refers to the extent to which data is credible, consistent and verifiable It is important that we maximise data quality and integrity when recording information on CRFs and resolving data queries, in the TRIGGER trial

87 NHSBT/MRC Clinical Studies Unit Objectives of Clinical Data Management To ensure the quality and integrity of clinical trial data To ensure that trial data is collected in accordance with the clinical trial protocol To provide a data set that is of sufficient quality for statistical analysis, interpretation and reporting To work in accordance with ICH-GCP principles

88 NHSBT/MRC Clinical Studies Unit Things to remember when recording information on CRFs: Write in black ink If you make an error put a make sure your original entry is visible, write your correction alongside, sign and date Do not scribble over your original entry Do not change numbers by writing over them Do not use correction fluid Do not destroy CRFs if you make an error (s)

89 NHSBT/MRC Clinical Studies Unit Things to remember when recording information on CRFs: If you make an error effecting the whole CRF page, put a line across the page, write ‘In error’, sign and date. Make sure the original entry is visible. Keep the copy in the patients file Write clearly, make sure it is legible Make sure that your writing is readable on fax or scanned copies

90 NHSBT/MRC Clinical Studies Unit Things to remember when recording information on CRFs: If data is unknown or not recorded write ‘UNK’ or ‘NR’ in boxes or write ‘UNKNOWN’ or ‘NOT RECORDED', alongside, sign and date When transcribing from source documents e.g. patient records, laboratory records, double check what you have written Include leading zeros e.g. write 8.23 as Complete decimal places if boxes are provided for them, if no decimal place enter zero e.g. 4 should be 4.0

91 NHSBT/MRC Clinical Studies Unit Things to remember when recording information on CRFs: Use dd-mm-yyyy format for dates, if there are no boxes provided Use hh:mm format for times Double check your calculations before recording on CRF e.g. Blatchford score, Rockall score If you add any additional comments to CRFs remember to sign and date each one If sending any additional pages or documents with CRFs - include the patient’s trial no, date of birth and initials on each page

92 NHSBT/MRC Clinical Studies Unit Sending CRFs to the CSU: Check that all questions on the CRF have been completed Check that the patient’s trial no, initials and date of birth are correct and the same on all CRF pages Check that you have printed your name, signed and dated at the bottom of all CRF pages Do not write any patient identifiable information on any documents to be sent to the CSU

93 NHSBT/MRC Clinical Studies Unit Sending CRFs to the CSU: Always use a CRF transmittal form Send copies of the Screening Log every Monday Send CRFs in 3 batches for each patient (1) Trial entry (Forms 1a – 4) (2) Discharge or Day 28 (Forms 5a – 10b) (3) End of study/Follow up (Forms 11a – 14 & 18) Always complete a safety event transmittal form when sending Serious Adverse Events and Serious Transfusion Related Adverse Event CRFs

94 NHSBT/MRC Clinical Studies Unit Sending CRFs to the CSU: The preferred method of sending the CRFs is by scanning and ing or by post or fax SAE forms At the CSU the Trial data manager will send an to confirm that the CRF pages or Screening log pages have been received

95 NHSBT/MRC Clinical Studies Unit Resolving Data Queries: Data Queries are usually raised due to:- Missing data Missing CRF pages Data anomalies The Trial Data Manager will send an to site staff, with details of the query

96 NHSBT/MRC Clinical Studies Unit Resolving Data Queries: Data clarification forms are generated by the database during data entry, and will be attached to the query as a pdf Data clarification form specifies the site, patient, form, question and the actual query text Site staff should clarify the discrepancy, provide missing data or missing CRF(s) Record the amended or missing data on the CRF Write the requested information in the ‘Answer’ section below the query text

97 NHSBT/MRC Clinical Studies Unit Resolving Data Queries: If no data clarification form send an back responding to the query and attach or send a copy of the amended CRF Print your name, sign and date each data clarification form Send a copy of the amended CRF and/or missing CRF pages to CSU Keep the original amended CRF(s), and data clarification form in the site file

98 NHSBT/MRC Clinical Studies Unit Summary Discussed best practice when completing CRFs and resolving data queries The aim of following this best practice is to maximise data quality and integrity during the TRIGGER trial Reduce the number of data queries sent to you - thereby reducing your workload!

99 NHSBT/MRC Clinical Studies Unit Exercise in pairs How many discrepancies can you find on this CRF - Haemoglobin Measurements and RBC Transfusion Record – Form 6a?

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106 Tea 14:55-15:10

107 NHSBT/MRC Clinical Studies Unit Ana Mora 15:10-15:20 Trial Site File

108 NHSBT/MRC Clinical Studies Unit Investigator Site File An Investigator Site File (ISF) contains essential documents on the trial and forms/documents used by the individual site The responsibility to hold and maintain an up to date ISF, including all superseded documents, is with the Principal Investigator at each participating site When new or amended trial documents become available (e.g. protocols, PIS, reports, etc), it is the responsibility of the Trial coordinating team to provide copies to the Investigator Site together with relevant Ethics approvals

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113 Site Initiation/Activation Before enrolling patients each site must ensure they have: An Investigator Site file Written permission from the site R&D A signed study site agreement A signed delegation log.

114 NHSBT/MRC Clinical Studies Unit Vipul Jairath, Ana Mora, Elizabeth Stokes, Tania Reed, Alison Deary 15:20-16:20 Open Forum for Q’s&A’s

115 NHSBT/MRC Clinical Studies Unit Lower Gastrointestinal Bleeding Pragmatic study – patient will have been included on the basis of a suspected UGIB which later turns out to be a LGIB. Stop completing any further CRFs and proceed to end of study form (Form 14) and indicate the patient did NOT complete the study as planned with the reason. Do not complete Day 28 follow up questionnaire Do return all completed CRFs and end of study form

116 NHSBT/MRC Clinical Studies Unit Co-Enrolment Guidelines The only competing study we are currently aware of is the early TIPSS study in Edinburgh and Glasgow. Patients can be co-enrolled to this study. Any future competing studies will be considered on a case by case level after discussion with each trial steering committee.

117 NHSBT/MRC Clinical Studies Unit Vipul Jairath & Ana Mora 16:20-16:30 Trial Website and Close

118 NHSBT/MRC Clinical Studies Unit


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