Study Protocol - heart.bmj.com

Study Protocol

Randomised controlled trial of the LoDED (Limit of Detection of Troponin

and ECG Discharge) strategy versus usual care in adult chest pain

patients attending the Emergency Department.

Version 3.1, Final - Dated 17/01/2019

Chief Investigator: Dr Edward Carlton

Emergency Department

Southmead Hospital

North Bristol NHS Trust

Southmead Road

Bristol, BS10 5NB

Tel 01174144985

Study Sponsor: North Bristol NHS Trust

IRAS Number: 235662

ISRCTN:

REC Ref: 18/SW/0038

BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any relianceSupplemental material placed on this supplemental material which has been supplied by the author(s) Heart

doi: 10.1136/heartjnl-2020-316692–1594.:1586 106 2020;Heart, et al. Carlton EW

LoDED Study Protocol Version 3.1 Final 17.01.2019 Page 2 of 33

TABLE OF CONTENTS

Section Page

1 SIGNATURE PAGE 4

2 KEY CONTACT DETAILS 5

3 LIST OF ABBREVIATIONS 7

4 STUDY SUMMARY 8

5 BACKGROUND AND RATIONALE 8

6 AIMS AND OBJECTIVES 10

6.1 Aim 10

6.2 Objectives 10

7 TRIAL DESIGN 10

7.1 Summary of trial design 10

7.2 Blinding and strategies for minimising

bias

12

7.3 Duration of participation 12

8 TRIAL ENDPOINTS 12

8.1 Primary Outcome 12

8.2 Secondary Outcomes 12

9 PARTICIPANT SELECTION 12

9.1 Inclusion Criteria 13

9.2 Exclusion Criteria 13

10 CLINICAL PROCEDURES 13

10.1 Baseline ECG 13

10.2 Baseline blood sampling 14

10.3 Repeat troponin tests 14

10.4 Laboratory analysis 14

11 SCREENING,RECRUITMENT AND

CONSENT

14

12 RANDOMISATION 15

13 TRIAL STRATEGIES 15

13.1 Usual rule-out strategies (control) 15

13.2 LoDED strategy (intervention) 16

14 POST INVESTIGATION PROCEDURES 16

14.1 Clinical management 16

14.2 Participant advice 16

14.3 Patient satisfaction survey and EQ-5D 16

15 FOLLOW-UP PROCESSES 16

15.1 Participants with an initial hs-troponin

below the LoD

17

15.2 Remaining participants 17

16 DATA TO BE COLLECTED 18

17 OUTCOME ADJUDICATION 19

18 INTEGRATED QUALITATIVE STUDY 18

18.1 Qualitative analysis 19

19 SAFETY 20

19.1 Definitions 20

19.2 Reporting non-serious adverse events 21

19.3 Reporting serious adverse events 21

20 STUDY COMPLETION 21

20.1 Premature termination of the study 22

21 PARTICIPANT WITHDRAWAL 22

21.1 Withdrawal from intervention 22

21.2 Withdrawal from follow-up 22

22 DATA MANAGEMENT 22




22.1 Subject numbering 22

22.2 Data collection personnel 23

22.3 Source data and source documents 23

22.4 Data collection forms 23

22.5 Clinical record-keeping 23

22.6 Follow-up data collection 23

22.7 Data handling and record keeping 23

22.8 Data security, data protection and

patient confidentiality

24

22.9 Access to data 24

22.10 Archiving 25

23 STATISTICAL CONSIDERATIONS 25

23.1 Sample size 25

23.2 Statistical analysis 25

24 ECONOMIC EVALUATION 26

24.1 Health economic data collection 26

24.2 Health economic analysis 26

25 DATA MONITORING AND QUALITY

ASSURANCE

26

26 TRIAL OVERSIGHT 27

26.1 Trial Management Group (TMG) 27

26.2 Trial Steering Committee (TSC) 27

26.3 Competing interests for the CI and

members of oversight committees

27

26.4 Patient and Public Involvement (PPI) 28

27 ETHICS AND REGULATORY

APPROVALS

28

27.1 Study Sponsor 28

27.1 Research Governance 28

28 STATEMENT OF INDEMNITY 28

29 DISSEMINATION POLICY 29

30 FINANCE 29

REFERENCES 30




1 SIGNATURE PAGE

Role Name Signature Date

Chief Investigator Dr Edward Carlton

Statistician Mrs Hazel Taylor

Sponsor’s representative

Ms Helen Lewis-White

Principal Investigator




2 KEY CONTACT DETAILS

Chief Investigator

Dr Edward Carlton

Emergency Department, Southmead Hospital

North Bristol NHS Trust

Southmead Road

Bristol

BS10 5NB

Email: [email protected]

Sponsor Representative

Ms Helen Lewis-White

Operations Manager, Research and Innovation

Floor 3 Learning and Research

Southmead Hospital

Southmead Road

Bristol

BS10 5NB


Study Statistician

Mrs Hazel Taylor

University Hospitals Bristol NHS Foundation Trust

Upper Maudlin Street

Bristol, BS2 8HW


Health Economist

Dr Rebecca Kandiyali

University of Bristol

Oakfield House

Oakfield Grove

Bristol, BS8 2BN




mailto:[email protected]




Qualitative Research Lead

Dr Jenny Ingram

Senior Research Fellow

Centre for Child and Adolescent Health

University of Bristol

Oakfield House

Oakfield Grove

Bristol, BS8 2BN


Senior Trial Manager

Sarah Campbell

Peninsula Clinical Trials Unit

N16/17 ITTC Building 1

Plymouth Science Park

Davy Road

Plymouth

PL6 8BX


Assistant Trial Manager

Rebecca Chapman

Peninsula Clinical Trials Unit

N16/17 ITTC Building 1

Plymouth Science Park

Davy Road

Plymouth

PL6 8BX








3 LIST OF ABBREVIATIONS

ACS

AE

Acute Coronary Syndrome

Adverse Event

AMI

CI

Acute Myocardial Infarction

Chief Investigator

CRF Case Report Form

CTU

ECG

Clinical Trials Unit

Electrocardiogram

ED

EDOU

EQ-5D

GHAA

HEART

Emergency Department

Emergency Department Observation Unit

EuroQoL 5D-5L health status questionnaire

Group Health Association of America

History, ECG, Age, Risk Factors and Troponin

Hs-troponin

ICH GCP

High-sensitivity troponin

International Conference on Harmonisation Good Clinical Practice

LoD Limit of Detection

LoDED Limit of Detection of troponin and ECG Discharge strategy

MACE

MACS

Major Adverse Cardiac Event

Manchester Acute Coronary Syndromes

NICE

NIHR

National Institute for Health and Care Excellence

National Institute for Health Research

PAG

PenCTU

PIS

Patient Advisory Group

Peninsula Clinical Trial Unit

Participant Information Sheet

PPI

REC

SAE

SOP

TIMI

TMG

TSC

Patient and Public Involvement

Research Ethics Committee

Serious Adverse Event

Standard Operating Procedure

Thrombolysis in Myocardial Infarction

Trial Management Group

Trial Steering Committee




4 STUDY SUMMARY

Title Randomised controlled trial of the LoDED (Limit of Detection of Troponin and ECG

Discharge) strategy versus usual care in adult chest pain patients attending the Emergency

Department.

Study Location NHS Emergency Departments in England and Wales

Study Question Does a novel diagnostic strategy for ruling out major adverse cardiac events (MACE) in

emergency department patients with suspected cardiac chest pain increase rates of early

discharge, reduce resource use and prove acceptable to patients, when compared to usual

care?

Study Objectives 1. Conduct a randomised controlled trial of the LoDED strategy compared to usual care to

compare the proportion of patients successfully discharged within four hours of arrival,

with no MACE during the following 30 days.

2. Measure admission rates, hospital bed usage, length of stay, resource use and patient

satisfaction, facilitating a health economic evaluation.

3. Determine whether the LoDED strategy is acceptable to patients.

Study Design Pragmatic multi-centre 1:1 randomised controlled trial

Main inclusion

criteria

• Age ≥18 years

• Presenting to ED with chest pain and triggering the chest pain investigation pathway

i.e. treating clinician intends to perform investigation to rule out a cardiac cause

• Peak symptoms occurred <6 hours prior to presentation to the ED

Main exclusion

criteria

• ST-elevation myocardial infarction or ischaemic ECG (new T wave inversion >3mm or

ST depression >1mm) as judged by the treating clinician

• Clear non-ACS cause for chest pain found at presentation (e.g. pulmonary embolism,

pneumonia, aortic dissection)

• Initial hs-troponin result known to the treating clinician

• Admission indicated due to other medical/social reasons

• Chest pain due to arrhythmia

• Unable/unwilling to provide written informed consent

• Pain too severe to provide written informed consent

• Follow-up will be impossible i.e. live abroad/no fixed abode

• Previous inclusion in the study

Planned sample 594 participants

Study Interventions

Control arm Participant admitted or discharged based on usual rule-out strategy operating in that

hospital (varies between recruiting centres). Usual care includes ECG on arrival and usually

two hs-troponin tests. All centres take the first sample at presentation, but the minimum

time delay between the two samples varies.

Intervention arm

(LoDED Strategy)

Participant discharged after a single hs-troponin test at presentation to ED if hs-troponin is

below the LoD. Participant not fulfilling discharge criteria will have a second hs-troponin

test after 1-6 hours as per usual care.

Summary of outcome measures

Primary Successful early discharge, defined as discharge from hospital within four hours of arrival,

without MACE occurring within 30 days of ED attendance.

Secondary 1. Length of ED/ED Observation Unit (EDOU) stay, measured in hours

2. Hospital admission and subsequent length of stay

3. Incidence of MACE, within 30 days of the index ED attendance

4. Comparative costs.

5. Patient satisfaction (quantitative survey).

6. Acceptability to patients (qualitative methodology).

Study schedule

End of Trial 30 (+5) days after the date the last participant is recruited

5 BACKGROUND AND RATIONALE

The number of patients attending Emergency Departments (EDs) across England and Wales

continues to rise, with over 22 million attendances in 2014.1 Chest pain makes up nearly 10% of ED




attendances and is the most common reason for emergency hospital admission.2 The majority of

patients with chest pain have prolonged hospital stays during which they undergo testing to rule

out acute myocardial infarction (AMI), yet 90% of patients are found to have a benign cause of

chest pain, such as gastro-oesophageal reflux.2 Prolonged assessment leads to increased NHS

costs, patient anxiety, and ED overcrowding.3

The need for prolonged assessment is driven by limitations in current diagnostic strategies.

Clinicians rely on three elements to rule out AMI: patient history, ECG and blood test biomarkers.

Patient history is an unreliable predictor of AMI4 and few patients (14%) have an ECG that is

diagnostic,2 therefore the majority of patients require biomarker testing. The current biomarker

used to rule-out AMI is troponin, a protein released into the blood when myocardial injury occurs.

Recently highly sensitive troponin (hs-troponin) assays have been developed, meaning that very

low concentrations can be measured.5 This has led to improved diagnostic accuracy earlier after

chest pain onset.6 Current consensus guidelines recommend that rule-out hs-troponin testing can

be undertaken using two samples taken at presentation and 1 to 3 hours later.7,8 Due to

limitations clinical and laboratory processing times with strategies reliant on two blood tests, most

patients will still not be discharged until at least 4 hours after ED attendance.9 A substantial

proportion of patients could potentially be discharged much earlier with a single hs-troponin test

taken at presentation to ED.10

It has been proposed that a single hs-troponin test at presentation to ED, could be used to rule-out

AMI in 9-60% of patients with very high diagnostic accuracy,11-17 using an “undetectable” cut-off

for ruling out AMI. This undetectable cut-off is called the Limit of Detection (LoD; lowest analyte

concentration at which detection is feasible). Current data supporting the LoD cut-off are from

observational studies and in patients who were not actually discharged based on hs-troponin

results. Evaluating new diagnostic technology with observational research alone has important

limitations. It is possible that beneficial effects will be diluted because clinicians do not abide by

their recommendations. Furthermore, unanticipated effects such as rebound overuse of resources

have previously been reported and have meant that apparently safe strategies are not cost-

effective.18,19 Therefore the clinical and cost-effectiveness of the LoD cut-off remains unknown.

There are two hs-troponin assays currently approved by NICE: Roche hs-troponin T and Abbott hs-

troponin I.7 The majority of centres within LoDED study use the Roche hs-troponin T assay,

reflecting current UK practice (information from manufacturer). The LoD for this assay is <5ng/L.

Some centres will use the Abbott hs-troponin I assay. The LoD for this assay is <2ng/L. In addition,

an emerging hs-troponin I assay (Beckman Coulter Access hs-troponin I) meets criteria to be

defined as a high-sensitivity assay but is yet to be evaluated by NICE.20 Similarly, the LoD for this

assay is <2ng/L. Performance of all three assays at the LoD appears similar, with similar

proportions of patients being eligible for safe early discharge.17,19 The LoD alone does not have the

required diagnostic accuracy for clinical implementation.10 However, combining the LoD with ECG

findings improves diagnostic accuracy (LoDED strategy). In a meta-analysis of over 9000 patients

evaluating the LoDED strategy with hs-troponin T, pooled sensitivity for 30-day major adverse

cardiac events (MACE), was 98.0% (95% Confidence Interval [CI] 94.7% to 99.3%), with 30% of

patients eligible for early discharge.16 For the Abbott hs-troponin I assay a pooled analysis of 3155

patients, pooled sensitivity for MACE was 97.9% (95% CI 95.4% to 99.2%), with 25% of patients

eligible for discharge.15 For the Beckman hs-troponin I assay, sensitivity for the rule-out of AMI has

been shown to be >99%, in an analysis of 1871 patients, with 34% of patients eligible for




discharge.17 These data demonstrate efficacy (safety) of the LoDED strategy, yet they are all from

observational cohort studies, where no patient was discharged based on their recommendations,

therefore the clinical effectiveness of LoDED across populations remains unknown.

The 2016 update to the NICE “chest pain of recent onset” guidelines also support the use of hs-

troponin with a cut-off at the LoD. However, the strategy recommended by NICE22 requires that

the LoD cut-off be combined with a risk score, such as the Thrombolysis in Myocardial Infarction

(TIMI) score,23 rather than a normal electrocardiogram (ECG) as we propose in the LoDED strategy.

Importantly, we have validated the NICE approach and demonstrate that approximately 15% of

patients will be suitable for early discharge using the NICE approach, in contrast to 30% using the

LoDED strategy.21

The LoDED strategy is a straightforward diagnostic tool. Current observational evidence suggests it

is safe for implementation. However, further evidence is needed to establish whether the LoDED

strategy works under real-life conditions, when compared to usual care. The critical question this

trial will answer is whether the LoDED strategy works when implemented in practice, with

clinicians actually discharging patients early in significant numbers, without rebound increases in

downstream costs and in a way that is acceptable to patients.

6 AIMS AND OBJECTIVES

6.1 Aim

The aim of this study is to establish whether a novel diagnostic strategy for ruling out major

adverse cardiac events (MACE) in Emergency Department patients with suspected cardiac chest

pain increases rates of early discharge, reduces resource use and is acceptable to patients, when

compared to usual care.

6.2 Objectives

1. Conduct a randomised controlled trial of the LoDED strategy versus usual care to compare the

proportion of patients successfully discharged within four hours of arrival, with no MACE during

the following 30 days.

2. Measure admission rates, hospital bed usage, length of stay, resource use and patient

satisfaction, facilitating a health economic evaluation.

3. Determine whether the LoDED strategy is acceptable to patients.

7 TRIAL DESIGN

7.1 Summary of trial design

This is a pragmatic, multi-centre, randomised controlled parallel group trial in adult patients

presenting to the ED with suspected cardiac chest pain and who trigger the chest pain

investigation pathway. Five hundred and ninety four participants will be randomised in a 1:1 ratio

to be managed according to the LoDED strategy (allowing discharge after a single hs-troponin test

at presentation to ED if a participant has no new ischaemic ECG changes and the hs-troponin is

below the LoD) or usual care rule-out strategy in current clinical use at each study site (Figure 1).




Usual care will usually include two hs-troponin blood tests taken between 1-6 hours after

presentation and may vary between sites.




Figure 1: Participant flow diagram




7.2 Blinding and strategies for minimising bias

This is an open study. Participants’ study allocations will only be blinded to those performing

central review of data for the assessment of MACE and the statistician analysing the results. All

patients will be consented and randomised before their initial hs-troponin results are known.

Patients will be ineligible to participate in the trial once the initial hs-troponin result is known to

the treating clinician in order to prevent selection bias. The decision to discharge a patient will be

made after clinical assessment by the treating clinician. In the event of ongoing clinical concern

the clinician may proceed with further testing and/or admission at their discretion, and contrary to

the allocated strategy. Information on protocol adherence will be collected in order to complete a

per-protocol analysis as well as the primary intention to treat analysis.

7.3 Duration of participation

For all participants, individual trial participation will be from the time of written informed consent

until 30 (+5) days after initial ED attendance at which point the presence or absence of MACE

occurring up to that point will be recorded. A subset of 25 participants will be selected through

purposive sampling to undertake a detailed telephone interview for the integrated qualitative

study. This will be completed within 60 days of initial attendance to the ED.

8 TRIAL ENDPOINTS

8.1 Primary Outcome

The primary outcome is successful early discharge, defined as discharge from hospital within four

hours of arrival, without MACE occurring within 30 days of ED attendance.

The safety endpoint of MACE occurring within 30 days, included within the primary outcome, will

be defined as cardiac death, AMI or emergency revascularisation occurring within 30 days of

attendance (including the index presentation). AMI will be defined according to the universal

definition, which states that a rise and/or fall of troponin above the 99th percentile value confirms

the diagnosis.24 A significant rise and/or fall will be defined as an absolute change in troponin over

time of at least half the 99th percentile value of either assay.25

8.2 Secondary Outcomes

1. Length of ED/EDOU stay, measured in hours.

2. Hospital admission and subsequent length of stay

3. Incidence of MACE occurring within 30 days of ED attendance.

4. Comparative costs.

5. Participant satisfaction (quantitative survey).

6. Acceptability to patients (qualitative methodology).

9 PARTICIPANT SELECTION

The screening and recruitment of patients, delivery of intervention and recording of outcomes will

be carried out within participating EDs in the UK. Participants will be recruited from adult patients




attending these EDs with chest pain who trigger the cardiac chest pain investigation pathway i.e.

the treating clinician intends to perform investigation to rule out a cardiac cause.

9.1 Inclusion criteria

Potential participants must satisfy the following criteria to be enrolled in the study:

• Age ≥18 years

• Presenting to the ED with chest pain and triggering the chest pain investigation pathway

i.e. the treating clinician intends to perform investigation to rule out a cardiac cause

• Peak symptoms occurred <6 hours prior to presentation to the ED

9.2 Exclusion criteria

Potential participants who meet any of the following criteria will be excluded from participation:

• ST-elevation myocardial infarction or ischaemic ECG (new T wave inversion >3mm or ST

depression >1mm) as judged by the treating clinician

• Clear non-ACS cause for chest pain found at presentation (e.g. pulmonary embolism,

pneumonia, aortic dissection)

• Initial hs-troponin result known to the treating clinician

• Hospital admission indicated due to other medical/social reasons

• Chest pain due to arrhythmia (new-onset atrial fibrillation, atrial flutter, sustained

supraventricular tachycardia, second-degree or complete heart block, or sustained or

recurrent ventricular arrhythmias)

• Unable to provide written informed consent (lacks capacity)

• Unwilling to provide written informed consent

• Pain too severe to provide written informed consent

• Follow-up will be impossible i.e. lives abroad or no fixed abode

• Previous inclusion in the study

• Prisoners

• Pregnancy

• Pre-existing renal failure requiring dialysis

10 CLINICAL PROCEDURES

Study participants will have undergone the standard clinical assessment of patients with chest

pain in the ED undertaken at presentation. This includes a triage history assessment, routine

initial observations of pulse, blood pressure, respiratory rate, oxygen saturation and the recording

of a 12 lead electrocardiogram (ECG). Standard clinical practice dictates that routine blood

sampling for the assessment of full blood count, urea and electrolytes and troponin is undertaken

at presentation.

10.1 Baseline ECG

A baseline 12 lead ECG will be recorded in all patients with chest pain as part of standard clinical

care. Patients identified by treating clinicians as having an ECG diagnostic of an ST-Elevation




myocardial infarction or evidence of new ischaemia (new T-wave inversion >3mm or ST depression

>1mm) will be ineligible.

10.2 Baseline blood sampling

All participants will have a blood sample taken for troponin measurement on, or shortly after

arrival as part of the standard clinical assessment of patients with chest pain. No additional blood

sampling is required for study purposes. All study centres have access to high-sensitivity troponin

assays which already form part of standard care.

Given the pragmatic nature of the trial, “presentation” blood sampling will be defined as the first

blood sample taken after arrival in the ED. Blood sample results will not be delayed for trial

purposes. Some blood test results, in particular hs-troponin, may therefore be available to

treating clinicians prior to assessment and the decision to trigger the chest pain investigation

pathway. Patients will be ineligible to participate in the trial if the initial hs-troponin result is

already known to the treating clinician, in order to prevent selection bias.

Standard laboratory reporting of hs-troponin results and other routine baseline blood tests will be

used for both clinical assessment and for data collection purposes. At all sites this is through an

electronic clinical record. Data from the laboratory system will be anonymously recorded within

the CRF.

10.3 Repeat troponin tests

The default strategy will be existing rule-out strategies used in study centres (the control group).

Therefore, a second hs-troponin test may be taken within these strategies so as not to delay

routine clinical care. However, if allocation is to the LoDED strategy, clinicians will not be required

to obtain the results of the second hs-troponin test and immediate discharge can occur.

10.4 Laboratory analysis

Clinical blood samples will be analysed locally in central hospital laboratories for the Elecsys hs-

troponin T assay (Roche Diagnostics, 99th percentile 14ng/L, co-efficient of variation <10%, LoD

5ng/L), Architect STAT high sensitive troponin I (Abbott Diagnostics, 99th percentile cut-off of

26ng/L, co-efficient of variation 4%, LoD 2ng/L) or Access hs-troponin I (Beckman Coulter, 99th

percentile cut-off of 18ng/L, co-efficient of variation <10%, LoD 2ng/L). Results will be made

available to clinicians using laboratory reporting systems as per routine clinical care.

11 SCREENING, RECRUITMENT AND CONSENT

Potentially eligible patients will be identified at the time of arrival in ED by clinical staff or research

nurses. During triage or initial assessment, the patient will be given the written study participant

information sheet (PIS) by a member of the ED clinical team or research nurse. This might be

before the chest pain investigation pathway has been triggered, so that a number of patients who

have been given the participant information sheet to read may subsequently be ineligible to enter

the study. Due to the time taken for laboratory processing of blood samples (>60 minutes after

presentation) and time waiting to be assessed by a doctor, it is anticipated that eligible

participants will have over one hour to consider the PIS prior to being approached for consent.




Patients will be screened for inclusion in the study by clinical staff or research nurses, and

fulfilment of initial eligibility criteria will be recorded on a study-specific screening form. The

written consent process will be undertaken by an appropriately trained (ICH Good Clinical

Practice) attending clinician or an appropriate member of the research team depending on

individual circumstances. All members of the clinical and/or research team delegated by the

Principal Investigator to undertake the consent procedure must be listed on the study delegation

log at the relevant site.

Once any questions have been answered satisfactorily, patients who are eligible and willing to

participate in the study will be asked to complete and sign a Consent Form, which will be

countersigned by the staff member receiving consent. A record of the patient’s consent to

participate will be documented in the patient’s Emergency Department records, using a pre-

prepared sticker. A copy of the completed consent form should be provided to the patient, a copy

filed in the investigator site file and a further copy must be filed with a copy of the study PIS in the

participant’s ED records.

12 RANDOMISATION

For all participants, randomisation will occur before initial hs-troponin results are known, to reflect

clinical practice where rule-out strategies are applied to a whole group of patients once it has

been determined by clinicians that rule-out testing is required.

After written consent has been obtained, participants will be randomised to be evaluated using

either the existing rule-out strategy used in study centres (control) or the LoDED strategy

(intervention) in a 1:1 ratio. The Peninsula Clinical Trials Unit (PenCTU), in conjunction with the

study statistician, will provide web-based randomisation, stratified by centre and minimised by

age and gender. Appropriate staff at all sites, as delegated by the PI, will be provided with log-in

details for the study website.

To randomise a participant, the recruiting doctor, ED nurse or research nurse will access the

secure website and enter brief participant details (initials, date of birth, gender, study site). Once

the randomisation process is complete, the computer screen will indicate to treating clinicians

which diagnostic strategy to follow, including details of the local rule-out strategy for control

participants as a reminder for site staff. A print-out of the allocation generated by the

randomisation website will be taken and filed in the participant’s ED records.

13 TRIAL STRATEGIES

Participants fulfilling the inclusion/exclusion criteria will be randomised to be managed according

to the existing local rule-out strategy (control) or the LoDED strategy (intervention).

13.1 Usual rule-out strategies (control)

Usual care varies between study sites but includes ECG on arrival and usually two hs-troponin

tests. All sites take the first sample at presentation, but the minimum time delay between the two

samples varies. The existing rule-out strategy in use at each study site will be documented at study

commencement and filed in the relevant investigator site file. The PI at each site is responsible for




reporting any changes in clinical practice during the study to the Chief Investigator so that changes

in clinical practice can be documented and the randomisation website kept updated.

13.2 LoDED strategy (intervention)

Participants randomised to the LoDED strategy arm will be eligible for discharge after a single hs-

troponin test at presentation to ED if the hs-troponin is below the Limit of Detection for the assay

in use at the study centre.

Any participant not fulfilling this discharge criterion will revert to the existing rule-out strategy in

use at that study site and have a second hs-troponin test after 1-6 hours as per usual care.

The decision to discharge a patient will be made after clinical assessment by the treating clinician.

In the event of ongoing clinical concern the clinician may proceed with further testing and/or

admission at their discretion, and contrary to the allocated strategy. Information on adherence to

the protocol will be collected in order to complete a per-protocol analysis as well as the primary

intention to treat analysis.

14 POST INVESTIGATION PROCEDURES

14.1 Clinical management

Once hs-troponin results are available (for either control or intervention pathways) the discharge

decision will be entirely at the discretion of the treating clinician. Onward referral for outpatient

investigation, such as chest pain clinics, will follow local guidance and will not be altered for trial

purposes.

14.2 Participant advice

All participants discharged according to the LoDED strategy will be given a study-specific leaflet

containing written information about the tests they have had done during their stay and what to

do should their chest pain returns, or if they have any concerns. Feedback will be sought during

the study on the content of this information sheet and its wording refined for patient use if the

LoDED strategy is adopted clinically (Section 18: Integrated Qualitative Study).

14.3 Patient satisfaction survey and EQ-5D

All participants, irrespective of group allocation, with the exception of those admitted to an

inpatient ward bed for further clinical management, will be asked to complete a bespoke written

patient satisfaction questionnaire17 upon discharge from the ED (or ED observation ward) to

compare satisfaction of their treatment during their ED attendance, between the two study

groups. Completed questionnaires will be returned to the CTU by the research nurse or another

member of the team.

Participants with an initial hs-troponin below the LoD (irrespective of group allocation) will also be

asked to complete a baseline EQ-5D health status questionnaire upon ED/EDOU discharge

(Section 24: Economic Evaluation).

15 FOLLOW-UP PROCESSES (Table 1)




15.1 Participants with an hs-troponin at presentation below the LoD

All participants with an initial hs-troponin below the LoD (irrespective of group allocation) will be

followed-up by telephone by the research nurse, or by e-mail, at 30 (+5) days after index

presentation to capture information about any adverse events and any primary care or secondary

care health service use since discharge from the ED. At the request of the participant, follow up

questionnaires can be sent to them by the CTU.

If the participant indicates that s/he has attended any health service provider in any capacity since

discharge from the ED, but there is concern over patient recall of events, then research nurses will

review hospital records (where available) to verify outcomes.

To explore the acceptability of the LoDED strategy to participants and inform patient discharge

information resources, a qualitative research assistant will undertake semi-structured interviews

with a sample of trial participants within 90 days of index admission (Section 18: Integrated

Qualitative Study).

15.2 Remaining participants

Participants with an initial hs-troponin above the LoD will be sent a screening text message after

30 (+5) days by the study team. This text will ask: “Since you came to the Emergency Department

with chest pain have you needed to see your GP or re-attend an Emergency Department or visit an

outpatient clinic for assessment of chest pain?” Patients answering “No” will require no further

follow-up. Participants who fail to respond, or answer “Yes”, will be followed-up by telephone by

the research nurse or routine data will be collected from local hospital electronic patient records

on initial diagnosis, local re-attendance and outpatient follow-up.




Table 1 : Summary of information provision, survey and follow-up processes

Randomisation LoDED Strategy

Usual Care

Participant Group Undetectable hs-

troponin*

hs-troponin

above LoD**

Undetectable hs-

troponin

Remaining

participants

Study specific “early discharge”

information sheet ●

Satisfaction survey completed

upon discharge ● ● ● ●

Baseline EQ-5D

(on discharge) ● ●

If admitted as in-patient,

discharge summary and

diagnosis recorded

● ● ● ●

30-Day follow-up

(telephone/by e-mail): EQ-

5D,patient reported resource

use and AE review

● ●

30-Day follow-up text message

for MACE screening and phone

call or notes review if “yes” to

text

● ●

Qualitative telephone

interview (n=25) ● ●

Non-serious AEs recorded (if possibly, probably or definitely

related to the study)

● ●

SAEs ● ● ● ●

* In the event of ongoing clinical concern the clinician may proceed with further testing and/or admission at their

discretion, and contrary to the allocated strategy

**Participants with an hs-troponin above LoD at presentation, allocated to the LoDED strategy, will revert to usual

care and have a second hs-troponin test after 1-6 hours.

16 DATA TO BE COLLECTED

Demographic and clinical data will be recorded after randomisation by the treating clinician or

member of the study team, using a paper Case Report Form (CRF). Routine creatinine and eGFR

levels from initial presentation will be recorded. Simple clinical data to calculate the Thrombolysis

in Myocardial Infarction (TIMI) score23, History, ECG, Age, Risk Factors and Troponin (HEART)

score19 and Manchester Acute Coronary Syndromes (MACS) rule26 will be collected by research

staff to assess for the added value of incorporating a risk score into the LoDED strategy for

secondary analysis. Data on time to troponin sampling, time to availability of troponin results and

time to discharge from the ED/EDOU will be recorded after interrogation of laboratory and ED

electronic systems. Clinicians will be asked to record any reasons for not discharging a patient

according to the LoDED strategy if allocated to this arm.

Discharge from the ED within four hours of attendance will be measured using electronic patient

tracking systems in use at all study sites, according to the time the patient left the ED (including ED




observation units). In the event that a participant is transferred from the ED, to an observation

unit or inpatient bed within four hours of attendance and subsequently discharged, length of stay

(minutes/hours) will be calculated from electronic patient records and tracking systems.

The length of any subsequent inpatient stay (in days) and the final destination of the patient

following discharge will also be recorded.

Resource use data to be collected from all participants with an initial hs-troponin below the LoD,

at 30 (+5) days by telephone/by e-mail and electronic patient records (to include GP records

where available) will include: use of health services in the last 30 days, length of any subsequent

hospital stays (since initial visit to ED); hospital tests carried out during any subsequent hospital

admissions, and time off work in the last 30 days.

Participants with an initial hs-troponin below the LoD (irrespective of group allocation) will also be

asked to complete a second EQ-5D health status questionnaire during their 30 day follow up

(Section 24: Economic Evaluation).

Participants with an initial hs-troponin above the LoD who failed to respond to their text message,

or answered “Yes” to the question “Since you came to the Emergency Department with chest pain

have you needed to see your GP or re-attend an Emergency Department or visit an outpatient

clinic for assessment of chest pain?” will have their electronic patient records reviewed for the

presence of MACE.

17 OUTCOME ADJUDICATION

Incidence of MACE occurring within 30 days of ED attendance will be recorded on the SAE form, by

the local ED Principal Investigator or designee with reference to relevant clinical information and

responses to 30 day follow-up telephone assessments uploaded to the study database. All

participant data will be reviewed by an independent adjudication committee at the end of the

study to confirm the primary outcome.

18 INTEGRATED QUALITATIVE STUDY

The qualitative component of this study aims to explore experiences of the patient’s stay in the

ED, any concerns or anxieties they might have and how best to word patient discharge

information. To explore the acceptability of the LoDED strategy to participants and inform patient

discharge information resources, a qualitative research assistant will undertake semi-structured

interviews with a sample of trial participants. At their 30 day follow-up contact, all participants

with hs-troponin levels below the LoD will be invited to be interviewed. All participants will be

informed about this additional study in the main Participant Information Sheet and agree to be

contacted about the study when they consent to the main study. The research nurse will record on

the study database whether or not the participant is happy to be contacted by the qualitative

researcher. From those participants who consent to being interviewed, a purposive sample will be

selected across all sites to maximise variation in terms of age, sociodemographic status and sex.

Up to 25 participant interviews (lasting approximately 30 minutes) will be conducted by phone

using a topic guide to explore experiences of the participant’s stay in ED, any concerns or anxieties

they might have and how best to word the written patient discharge information. Consent to take




part in this study will be collected before the interview is carried out. Topic guides will be

developed from the literature, input from the patient advisory group and team discussions.

Two GP and practice nurse focus groups will be held towards the end of the recruitment period to

explore their views about the information that they would like to be provided to patients who are

discharged early. Findings from the participant interviews will contribute to these focus group

discussions.

18.1 Qualitative analysis

Interviews and focus groups will be recorded, transcribed, anonymised and analysed using

thematic methods facilitated by NVivo software. Analysis will be ongoing and iterative. Transcripts

will be coded and global themes developed from the codes. Two researchers will code a sample of

transcripts independently, compare coding, discuss and resolve any discrepancies within the

research team to achieve a coding consensus and ensure robust analysis.

Findings from the interviews and focus groups will inform the development of the leaflet that will

be given to participants discharged early according to the LoDED strategy to take home with them.

The format and content will be reviewed by the PAG and their changes incorporated.

19 SAFETY

Participant safety will be monitored by the trial management group and Trial Steering Committee.

Adverse events (AEs) may be non-serious or serious (see definitions below). Adverse events to be

recorded in this study are:-

• All non-serious AEs considered to be related to the study (in the participants with hs-troponin

levels below the LoD only)

• All Serious Adverse Events (in all participants)

AEs/SAEs occurring from the time of consent until the 30 day follow-up time point should be

recorded in the CRF.

19.1 Definitions

An adverse event (AE) is defined as any unfavourable and unintended sign or symptom that

develops or worsens during trial participation, whether or not it is considered to be related to the

study.

An adverse event is classified as a Serious Adverse Event (SAE) if it:

• Results in death

• Is life threatening

• Requires hospitalisation or prolongation of existing hospitalisation

• Results in persistent or significant disability or incapacity

• Or is considered by the investigator to be an important medical event




A non-serious adverse event (AE) is an adverse event which does not satisfy the above definition

of an SAE. Only those non-serious AEs in participants with hs-troponin levels below the LoD

considered by the PI, or authorised delegate, to be possibly, probably or definitely related to the

study will be reported.

The CTU will prepare regular summary reports of reported (S)AEs for discussion at TMG meetings.

Reports and minutes of TMG meetings will be copied to the Sponsor.

19.2 Reporting non-serious adverse events (AE)

AEs may be volunteered by the participant or detected by a member of the research team through

questioning or observation, during either the index ED attendance or the follow-up telephone call.

AEs will be recorded by the research nurse or other member of the research team on the CRF and

in the participants’ clinical notes. These may include unplanned re-attendance to the Emergency

Department.

19.3 Reporting serious adverse events

Any SAE occurring in any participant after discharge from the hospital, must be reported by

emailing or faxing an initial SAE form to the CTU within 24 hours of the research team becoming

aware of the event. If the SAE is considered a MACE, this should be indicated on the SAE form,

and will be adjudicated at the end of the study, as detailed in Section 17. The CTU will notify the

Chief Investigator and Sponsor by email of all reported SAEs. If the PI considers that the SAE is not,

or is unlikely to be, related to the trial, the CTU will obtain a second assessment of causality from

the CI (or other delegated clinician). If a patient is hospitalised during the index visit due to clinical

concern, even if the patient is eligible for discharge using the LoDED strategy, this need not be

recorded as an SAE since the information will be captured elsewhere for study purposes.

Following the initial report, the SAE form must be fully completed within seven days of the event,

signed by the PI and returned to the CTU. Completion of the SAE form must include the PI’s (or

authorised clinician’s) assessment of causality i.e. whether there is a reasonable causal

relationship between the SAE and the study. Following the initial report to the CI of any study

related SAEs, the CI will notify the Chair of the Trial Steering Committee (TSC) within 48 hours of

the event. The Chair will arrange an ad hoc meeting of the TSC to discuss the SAE, and agree any

actions as needed. (See section 26.2 for details of the TSC).

All SAEs will be followed until resolution. The CTU will provide a summary of all SAEs to the Trial

Steering Committee (TSC) and Sponsor on a three-monthly basis. Investigators should also comply

with any internal SAE reporting requirements within their host institution.

There are no expected adverse events related to the study. The Research Ethics Committee (REC)

will be informed within 48 hours if any related and unexpected SAE occurs.

20 STUDY COMPLETION

Individual participants will complete the study after the 30 day follow-up has been completed.

The study itself will end on the date the last participant has completed the 30 day follow-up.




20.1 Premature termination of the study

In the event that the Trial Steering Committee or Sponsor recommends early termination of the

study for any reason, the CTU will notify the REC. The Chief Investigator will be responsible for

informing participating sites of the premature termination of the study.

21 PARTICIPANT WITHDRAWAL

Participants may withdraw from the study at any time and do not have to provide a reason for

doing so. Standard care will not be affected by a participant’s decision to withdraw from the trial.

Participants who withdraw from the study at any stage following randomisation will not be

replaced within the study.

21.1 Withdrawal from intervention

Participants may withdraw from the intervention at any time (e.g. following consent, but before

discharge) if they wish, without having to give a reason. If known, the reason for withdrawal should

be clearly documented using a study-specific form in accordance with a written procedure and in

the participant’s ED records. All randomised participants will be encouraged to complete study

follow-up (30-day follow-up) regardless of study arm or compliance with allocated strategy.

21.2 Withdrawal from follow-up

Participants may withdraw from follow-up at any time without it affecting their care. Participants

should be asked to explain their reason for withdrawing, but are under no obligation to do so.

Withdrawal from trial follow-up, and the reason, if known, should be reported to the CTU using a

study-specific form in accordance with a written procedure. If possible, the withdrawal should also

be clearly documented in the participant’s clinical records.

Data collected prior to withdrawal will be included in the study analysis unless a participant

specifically requests that their data are removed from the database. The research team should

inform the CTU if a participant has requested that their data be destroyed. If the participant does

not make a specific request for their data to be destroyed, their data will be stored and included in

the study analysis

Should a participant lose capacity to consent during the study period after completion of the

consent form, the participant’s data will be used for trial purposes, however 30-day follow-up

questionnaires will not be completed. If the loss of capacity is due to the presence of a Major

Adverse Cardiac Event (such as cardiac arrest) this information will be recorded as an SAE and will

be integral to reporting of the safety of the LoDED strategy.

22 DATA MANAGEMENT

22.1 Subject numbering

Each participant will be allocated a unique study number upon randomisation, from the study

website. Participants will be identified in all study-related documentation by their study number

and initials. All data collected and analysed during the study will be pseudo-anonymised by the use

of this unique identifier. A record of trial participants’ names and contact details, hospital numbers




and assigned trial numbers will be maintained by the research nurse at each site and stored

securely for administrative purposes.

22.2 Data collection personnel

Study data will be collected by GCP-trained ED staff or research practitioners at each site. All persons

authorised to collect and record study data will be listed on the relevant study site delegation logs,

signed by the site PI.

22.3 Source data and source documents

Source documents will include hospital ED and in-patient records, where relevant. All data not

routinely captured during the ED attendance or any subsequent hospital admission but recorded

straight into the CRF will also be classified as source data.

22.4 Data collection forms

Study data collected by the research team at each site will be recorded on study specific data

collection forms provided by the CTU.

Data for the purpose of confirming patient eligibility will be captured on a screening form; data

collected during the patient’s attendance at the ED, and at follow-up, will be collected in the Case

Report Form (CRF).

The data to be collected during the patient’s ED visit itself have been kept to a minimum. Further

demographic and ED visit data will be recorded retrospectively into the CRF from ED records at the

convenience of study site staff, as soon as possible following the ED attendance. The final CRF data

capture relates to the 30 day telephone follow-up visit.

The original completed CRF will be checked, signed and dated by a member of the study site team

before being sent by post to the CTU, in accordance with written instructions within the CRF. Pre-

addressed, Freepost (prepaid) envelopes will be supplied for this purpose. A copy of each CRF page

will be kept at the study site.

22.5 Clinical record-keeping

As a minimum, a record should be made in the participant’s ED record or hospital notes of:

• the participant’s consent and eligibility for study (a pre-written adhesive label is supplied for this

purpose)

• randomisation (printout of allocation filed in notes)

• any adverse event experienced during the ED attendance or any subsequent hospital admission

(as described in Section 19)

22.6 Follow-up data collection

Follow-up information collected during at 30 (+5) days (see section 15) should be recorded directly

on to the relevant CRF page before being transferred to CTU, with a copy held at site.

22.7 Data handling and record keeping

The CTU data management team is responsible for data management, including data entry. Original

CRF pages will be posted to the CTU at agreed time points for double-data entry on to a SQL Server

database using a bespoke, password-protected, website, designed and maintained by the CTU data

programming team. All data collection forms will be tracked by CTU using a web-based trial




management system. Completed CRFs will be checked on receipt at CTU and any obvious errors or

omissions rectified as far as possible by means of a formalised data query/clarification procedure.

Double-entered data will be compared for discrepancies using a stored procedure and discrepant

data will be verified using the original paper data forms. Before database lock, a proportion of

original paper records will be checked against the database to ensure accuracy of the final dataset.

22.8 Data security, data protection and patient confidentiality

The CTU data manager is the data custodian for the duration of the study.

Research teams at all study sites will ensure that participant confidentiality is maintained at all

times. All investigators and study site staff must comply with the requirements of the Data

Protection Act (1998)/General Data Protection Regulation 2018 with regards to the collection,

storage, processing and disclosure of personal information and will uphold the Act’s core principles.

Each study site will keep an enrolment log of all participating patients (with sufficient information

to identify participants and link records for regulatory audit/inspection purposes) as well as all

original signed informed consent forms. Any document linking participant study numbers with

identifiable data will be stored securely at each site by the local research team and separate from

the study data. Pseudonymised copies of signed consent forms, for randomised participants only,

will be sent to the CTU for monitoring purposes.

With the participant’s consent, the participant’s name, e-mail address and contact telephone

number will be recorded by the relevant local research team in order to carry out the 30 day follow-

up. This information will be stored securely at site and be accessible only to the site staff for the

purpose of conducting the follow-up. Once the study is completed, these contact details should be

destroyed.

Within the CTU, pseudo-anonymised paper-based study data will be stored in locked filing cabinets

within a locked office. Electronic records will be stored in a SQL Server database on a restricted

access, secure server maintained by Plymouth University. Data in the SQL Server database will be

backed up as part of Plymouth University’s standard back-up process. The website will be encrypted

using SSL. Direct access to the study data will be restricted to members of the research team and

the CTU, with access granted to the Sponsor on request. Access to the database will be overseen

by the CTU data manager and trial manager. Copies of study data retained at study sites will be

securely stored for the duration of the study prior to archiving.

Any data transfer (e.g. from CTU to the study statistician for analysis purposes) will be done using a

format and method suitable to the requirements of the data being transferred. As a minimum, data

will be secured in a password protected encrypted file and will be anonymised according to the

requirements of the data transfer. All data will be transferred in accordance with the Data

Protection Act and PenCTU standard operating procedures (SOPs).

In the event that any copies of clinical source data need to be forwarded from site to the CTU (e.g.

as part of SAE reporting or follow-up), site staff will be responsible for ensuring that personal

identifiers are removed or obscured and the documents are marked with the participant’s study

number before leaving the site.

22.9 Access to data

Direct access to study site documentation and participants’ clinical notes will be granted to

authorised representatives from the Sponsor, the CTU and the regulatory authorities to permit




trial-related monitoring, audits and inspections. Permission to access participants’ clinical records

will be explicitly requested in the Informed Consent Form for the study.

22.10 Archiving

Following completion of trial data analysis, the Sponsor will be responsible for archiving the study

data and essential documentation in a secure location for at least five years after the end of the

trial, in accordance with the Sponsor’s SOP. No trial-related records should be destroyed unless or

until the Sponsor gives authorisation to do so. Medical case notes containing source data or other

trial-related information should be identified by a label “Keep until dd/mm/yyyy” where the date

given is five years after the last participant’s final visit.

23 STATISTICAL CONSIDERATIONS

23.1 Sample size

Current observational research gives estimates of the proportion of patients with an hs-troponin

<5ng/L in the intervention group of the RCT (LoDED) between 10% and 60%.11-17 United Kingdom

observational data suggest that these patients will be discharged within a median time of 3.5hrs

(taking into account laboratory processing and 60 minutes of decision making time).10 Data

provided to us from a recent pragmatic RCT9 evaluating a 0/2hour hs-troponin rule-out strategy

has demonstrated that only 10% of patients will be discharged within four hours using this

approach. Clinical protocols using rule-out strategies at later time points (e.g. three hours) will be

expected to have even fewer patients discharged within the four hour time frame; similarly the

0/1hour strategy may expect to see a marginal increase in discharges before four hours. These

differences have been taken into account within the power calculation. For the overall population

we anticipate 8% will be discharged within 4 hours using usual care and at least 17% using the

LoDED strategy. Therefore, this study will be powered to detect a 9% difference between the early

discharge rates with 90% power and 5% statistical significance. This will require 282 patients in

each arm and 564 patients in total with primary outcome data. Assuming a 95% follow-up rate,

594 patients need to be recruited.

23.2 Statistical analysis

A statistical analysis plan, detailing the exact analysis to be conducted and reported, will be

developed prior to any comparative analysis. All analysis will be conducted blind to group

allocation by using codes for group allocation which do not indicate which specific group they

refer to. A CONSORT diagram will be used to report numbers of patients screened, recruited and

randomised. It will also detail numbers allocated to each arm and rates of the primary outcome.

The primary outcome of discharge within four hours will be analysed by logistic regression using all

those randomised in an intention to diagnose analysis. The analysis will be stratified by centre to

allow for differences between the proportion discharged within four hours in the control arm at

each of the study sites. Heterogeneity of the odds of early discharge at each centre will be

investigated and only pooled if appropriate. The odds ratio of early discharge controlling for age,




sex and centre will be presented with a 95% confidence interval for each centre individually and

combined across centres. In the event of significant heterogeneity in the control group but

homogeneity within the intervention group the results will be presented as the rate of early

discharge in the intervention group together with 95% confidence intervals. Adherence with the

allocated rule-out strategy will be presented as percentage with 95% confidence intervals.

The analysis of the quantitative secondary outcomes will also control for age, sex and centre; with

a multiple regression analysis and difference in means reported for the comparison of length of

hospital stay between groups and for the total score from the patient satisfaction survey obtained

from summing the individual items. The responses for the individual items of the patient

satisfaction survey will also be reported by group but an adjusted analysis will not be carried out.

The incidence of MACE occurring within 30 days of ED attendance in those discharged according to

the LoDED strategy vs usual care will also be reported with 95% confidence intervals. As the event

rate is expected to be low, it is unlikely to be possible to carry out an adjusted analysis.

There are no pre-planned interim analyses.

24 ECONOMIC EVALUATION

24.1 Health economic data collection

Local secondary and primary care resource use, between index hospital admission and the

following 30 days, will be collected by phone call, by e-mail or review of electronic patient records

and tracking systems for all participants with an initial hs-troponin below the LoD (irrespective of

group allocation) by the research nurse between 30 and 60 days after index presentation.

24.2 Health economic analysis

The primary economic analysis will include all randomised participants (intention to diagnose

analysis) and compare secondary care costs. Secondary care resource use will be valued using

national sources of unit costs. A subgroup analysis will provide extra detail on the primary and

community care costs (in addition to the secondary care costs) and consequences (quality-

adjusted life-years (QALYs)) for any participant with an hs-troponin below the LoD. This applies to

both trial arms. Data collection for the additional primary and community care costs will be based

on participant self-report following administration of a structured resource use questionnaire at

30 days and standard methods of unit costing. QALYs will be derived from the EQ-5D (5 level

version) using the set of preference weights as advised by NICE at the time of analysis.

25 DATA MONITORING AND QUALITY ASSURANCE

The research nurse or other member of the research team will check completed CRFs for missing

data or obvious errors before they are posted to the CTU. Data will be monitored centrally for

quality and completeness by the CTU and every effort will be made to recover data from

incomplete CRFs where possible. The CTU data manager will oversee data tracking and data entry

and initiate processed to resolve data queries where necessary. The CTU trial manager will devise




a monitoring plan specific to the study which will include both central monitoring strategies and

study site visits as appropriate.

All trial procedures will be conducted in compliance with the protocol and according to the

principles of Good Clinical Practice. Procedures specifically conducted by the CTU team (e.g.

randomisation, data management, trial management and study monitoring) will be conducted in

compliance with CTU SOPs. The Principal Investigators and the participating NHS Trusts will be

required to permit the CTU trial manager or deputy to undertake trial-related monitoring to

ensure compliance with the approved trial protocol and applicable SOPs, providing direct access to

source data and documents as requested.

26 TRIAL OVERSIGHT

The CI will be responsible for the overall running of the trial. The CTU will coordinate day-to-day

trial-related activities and provide overall trial management and monitoring. The CTU will also

provide randomisation, build the study database, provide data management services and oversee

safety reporting activities.

26.1 Trial Management Group (TMG)

The project will be led by the trial management group (TMG) which will include the CI, the CTU

trial manager, trial statistician and other relevant personnel (e.g. clinical colleagues, CTU data

manager, Sponsor representative, as required). The TMG will meet regularly (usually monthly)

throughout the duration of the trial to ensure development of study documentation and

approvals, monitor progress (including participant recruitment), resolve day-to-day problems as

they arise, review the budget, discuss analysis, results, draft reports and dissemination.

26.2 Trial Steering Committee (TSC)

The TSC will oversee the conduct and safety of the trial, ensuring that milestones are achieved and

general scientific probity is maintained. The TSC will monitor progress of the trial, adherence to

the protocol and consider new information of relevance to the research question. In the absence

of an independent Data Monitoring Committee, the TSC will also oversee the safety and ethics of

the trial, reviewing recruitment, primary outcome data completeness and adverse events data.

The TSC will include an independent chair (ED clinician), independent cardiologist, an independent

lay representative, an independent statistician, a senior member of the research team and the CI.

26.3 Competing interests for the CI and members of oversight committees

The Chief Investigator and TSC committee members will sign a declaration form to disclose any

financial or other competing interests including, but not limited to:

• any ownership interests that may be related to products, services, or interventions

considered for use in the trial or that may be significantly affected by the trial

• commercial ties including, but not restricted to, any pharmaceutical, behaviour

modification, and/or technology company




• any non-commercial potential conflicts e.g. professional collaborations that may impact

on academic promotion.

These declaration forms will be filed as part of the Trial Master File.

26.4 Patient and Public Involvement (PPI)

The study has a Patient Advisory Group (PAG) comprising four members who will meet on four

occasions to advise the management team. The PAG will be actively involved in the design and

development of trial-specific patient information resources, follow-up questionnaires, topic guides

for interviews and methods for enhancing recruitment and follow-up rates. They will also

contribute to the development of patient discharge information for clinical implementation.

PAG members will be offered a study specific induction pack which will include the INVOLVE Public

Information Pack and relevant study information. Training workshops will also be provided by

People and Research West of England. PAG members will have their travel expenses and meeting

time reimbursed either with vouchers or a meeting payment based on INVOLVE guidance. The

PAG will be consulted at the point of analysis and interpretation of the data from this study, with

findings presented in lay terms at a PAG meeting. The group will be invited to interpret the

significance of the findings, their perception of the efficiency of the LoDED strategy and the clinical

significance of any risks of misdiagnosis, and will advise on routes and formats for dissemination to

patient groups.

27 ETHICS AND REGULATORY APPROVALS

27.1 Study Sponsor

The study Sponsor is North Bristol NHS Trust. Selected sponsorship responsibilities will be formally

delegated to the Peninsula Clinical Trials Unit (PenCTU) under the terms of an appropriate

agreement.

27.2 Research Governance

The study will be undertaken at several UK sites, subject to appropriate Research Ethics

Committee (REC) approval and Health Research Authority approval. The trial will be conducted in

accordance with the protocol, the principles of the Declaration of Helsinki and ICH GCP. Any

amendments of the protocol will be submitted to the REC for approval. On request, the study

investigators and their institutions will permit trial-related monitoring and audits by the Sponsor

and relevant Research Ethics Committee by providing direct access to source data and other

documents (i.e. patients’ hospital notes, laboratory test reports, X-ray reports etc where relevant).

28 STATEMENT OF INDEMNITY

This is an NHS-sponsored research trial. If an individual suffers negligent harm as a result of

participating in the trial, NHS indemnity covers NHS staff and those people responsible for

conducting the trial who have honorary contracts with the relevant NHS Trust. In the case of non-

negligent harm, the NHS is unable to agree in advance to pay compensation, but an ex-gratia

payment may be considered in the event of a claim.




29 DISSEMINATION POLICY

The Chief Investigator and Trial Management Group will establish a writing committee which will

be responsible for preparing scientific reports of the study findings. The aim will be to publish a

primary manuscript in a high impact general medical journal, published as open access, with

secondary analyses described in specialty journals. Primary findings will also be presented at key

meetings e.g. the Annual Conference of the Royal College of Emergency Medicine, the European

Society of Cardiology Annual Congress, the European Society of Emergency Medicine Congress and

the International Conference on Emergency Medicine.

30 FINANCE

The trial is funded by a grant from the National Institute for Health Research (NIHR) Research for

Patient Benefit (RfPB) programme. Study finances will be managed by North Bristol NHS Trust.




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