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For peer review onlyOptimising pacemaker therapy and medical therapy in pacemaker patients for heart failure - the OPT-PACE

randomised controlled trial

Journal: BMJ Open

Manuscript ID bmjopen-2018-028613

Article Type: Protocol

Date Submitted by the Author: 17-Dec-2018

Complete List of Authors: Paton, Maria; University of Leeds, Leeds Institute of Cardiovascular and Metabolic MedicineGierula, John; University of Leeds, Leeds Institute of Cardiovascular and Metabolic MedicineJamil, Haqeel; University of Leeds, Leeds Institute of Cardiovascular and Metabolic MedicineLowry, Judith; University of Leeds, Leeds Institute of Cardiovascular and Metabolic MedicineByrom, Rowena; University of Leeds, Leeds Institute of Cardiovascular and Metabolic MedicineGillott, Richard; Leeds Teaching Hospitals NHS TrustChumun, Hemant; University of Leeds, Leeds Institute of Cardiovascular and Metabolic MedicineCubbon, R.M.; University of Leeds, Cairns, David; University of Leeds, Leeds Institute of of Clinical Trials ResearchStocken, Deborah; University of Leeds, Leeds Institute of Clinical Trials ResearchKearney, Mark; University of Leeds, Leeds Institute of Cardiovascular and Metabolic MedicineWitte, Klaus; University of Leeds Leeds Institute of Health Sciences, Faculty of Medicine and Health; Leeds General Infirmary, Cardiology

Keywords: pacemaker, Optimal medical therapy, Heart failure < CARDIOLOGY, randomised controlled trial, Pacing & electrophysiology < CARDIOLOGY

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

BMJ Open

For peer review only

Optimising pacemaker therapy and medical therapy in pacemaker patients for heart failure - the OPT-pace randomised controlled trial

Maria F Paton1

John Gierula1

Haqeel A Jamil1Judith E Lowry1

Rowena Byrom1

Richard G Gillott2

Hemant Chumun1

Richard M Cubbon1

David A Cairns3

Deborah D Stocken3

Mark T Kearney1

Klaus K Witte1*

Running title: Heart failure in pacemaker patientsClinicalTrials.gov registration number: NCT01819662Word count for Main body: 2917Number of tables: 0Number of figures: 2 Number of supplementary tables: 0Number of supplementary figures: 0

1 Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK 2 Leeds Teaching Hospitals NHS Trust, Department of Cardiology, Leeds, UK3 Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK

* Corresponding author:Dr Klaus K WitteDivision of Cardiovascular and Diabetes Research,Multidisciplinary Cardiovascular Research Centre (MCRC)Leeds Institute of Cardiovascular and Metabolic MedicineLIGHT building, University of LeedsClarendon Way, Leeds, UK, LS2 9JT

Phone: (+44) 113 3926108E-mail: [email protected]

Trial Sponsor : University of LeedsLIGHT building, Clarendon Way, Leeds, UK, LS2 9JT

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mailto:[email protected]


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Abstract

Introduction: Permanent artificial pacemaker implantation is a safe and effective treatment

for bradycardia and is associated with extended longevity and improved quality of life.

However, the most common long-term complication of standard pacemaker therapy is

pacemaker-associated heart failure. Pacemaker follow-up is potentially an opportunity to

screen for heart failure to assess and optimise patient devices and medical therapy.

Methods and Analysis: The study is a multi-centre, phase-3 randomised trial. The 1200

participants will be people who have a permanent pacemaker for bradycardia for at least 12

months, randomly assigned to undergo a transthoracic echocardiogram with their pacemaker

check, thereby tailoring their management directed by left ventricular function, or the

pacemaker check alone, continuing with routine follow-up. The primary outcome measure is

time to all-cause mortality or heart failure hospitalisation. Secondary outcomes include

external validation of our risk stratification model to predict onset of heart failure and quality

of life assessment.

Ethics and Dissemination: Discussion: The trial design and protocol has received national

ethical approval (12/YH/0487) and is registered on ClinicalTrials.gov (NCT01819662).

The results of this randomised trial will provide evidence on the effectiveness of optimising

medical therapy based on echocardiographic and pacing parameters and its role in potentially

reducing the incidence of heart failure in pacemaker patients.

Keywords: Pacemaker, optimal medical therapy, heart failure, randomised controlled trial

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Article Summary

Strengths and Limitations of this study

OPT-PACE is a multicentre, randomised, non-blinded parallel trial funded by the

National Institute for Health Research

Stratification of the participant randomisation is not adopted in this trial due to the

large sample size.

Participant and practitioner blinding are not plausible.

The control arm consists of current standard of care ensuring trial results are reflective

and generalizable.

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Introduction

Permanent artificial pacemaker implantation is a safe and effective treatment for

bradycardia,[1] and is associated with extended longevity [2] and improved quality of life.[3]

An estimated 350,000 people in the UK have a pacemaker, with over 40,000 new implants

per year.

However, long term right ventricular (RV) pacing has been linked to adverse left ventricular

(LV) remodeling, [4, 5] such that the most common long-term complication of standard

pacemaker therapy is pacemaker-associated chronic heart failure (CHF) due to left ventricular

systolic dysfunction (LVSD) [6-8]. Whilst up to 2-3% of the general population have CHF, the

condition is much more common in pacemaker patients with a prevalence up to 50% [7, 9]

and 12% of people admitted with acute decompensated heart failure (HF) (4% with a de novo

admission for heart failure) have a pacemaker [10].

It is clear that right ventricular pacing alone can lead to LVSD, however the risk is especially

high in people requiring a high proportion of ventricular pacing, those with diabetes mellitus,

previous myocardial infarction and raised creatinine [11]. Data examining the relationship

between pacemaker use and cardiac dysfunction predominantly originate from retrospective

cross-sectional analysis or secondary analyses [12-15]. We provided the first evidence that

reducing RV pacing through careful reprogramming is associated with an improvement in LV

function without affecting quality of life or functional capacity,[9] confirming somewhat the

suggestion that RV pacing is contributory to LV dysfunction in pacemaker patients and not

just a bystander in a multi-morbid patient population.

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Although there is increasing recognition of the axis of RV pacing and LVSD, it remains the case

that HF is frequently overlooked in the pacemaker population with symptoms often ascribed

to pacemaker syndrome, chronotropic incompetence, or co-morbidities [6]. HF and

undiagnosed left ventricular dysfunction have a major effect on mortality and morbidity

amongst pacemaker patients [16-18]. Since HF management accounts for approximately 2%

of the healthcare budget in many developed countries, more than 60% of which relates to

hospitalisation costs [19], optimal management of people with HF whether or not they have

a pacemaker is a key strategy for controlling healthcare costs while increasing quality of life

[20].

There are however, no data on the potential benefits of screening people with pacemakers

for heart failure and whilst there are now a series of algorithms to limit RV pacing [21-23], no

clear strategy for the use of these is outlined in current guidelines. This situation is

compounded by a lack of published evidence around the benefits of medical management of

pacemaker related HF since people with pacemakers were excluded from most of the large

heart failure studies.

Prospective randomised studies of pacemaker follow-up programs to risk stratify patients and

optimise management have not yet been of adequate size and duration to assess the clinical

effectiveness of such an approach in a real-world general healthcare setting. Pacemaker

follow-up is a rarely realised opportunity to screen for HF and assess and optimise patient

devices and medical therapy.[24]

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The OPT-PACE (OPTimising PACEmaker therapy) trial has been designed to address these

issues and quantify time to all-cause mortality or heart failure hospitalisation, as well as

validate a HF risk stratification model based on simple variables available in pacemaker clinic.

Secondary aims are to establish whether NT-proBNP improves this risk stratification model.

Subsequently, we aim to provide data on the effects of establishing the presence of left

ventricular systolic dysfunction on medical therapy, device programming and patient quality

of life.

Pilot Data

Risk model

The design of the OPT-PACE trial is informed by an observational cohort [25] including 491

patients listed for a pacemaker generator replacement in a single tertiary centre (Leeds

Teaching Hospitals NHS Trust) invited for pacing therapy information, diagnostic pacing data

and an echocardiogram.

Of this cohort, 40% had an LV ejection fraction of <50%, which was much higher (59%) in

those with >80% RV pacing (p<0.001), demonstrating that patients with RV pacemakers have

a high prevalence of LV systolic dysfunction. After a mean follow-up time of 668 days, 56

patients (12%) had died or been hospitalized for heart failure.

Multivariable analyses identified a number of simple clinical variables; high percentage RV

pacing, high serum creatinine, and previous myocardial infarction as potential independent

predictors of LV systolic dysfunction to identify patients who may benefit from a more

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comprehensive review [11]. This risk model requires external validation planned within the

OPT-PACE trial.

Intervention Development

The design of the pacemaker optimisation intervention used in the OPT-PACE trial is based on

data from an observational cohort of 66 patients, referred for pacemaker generator

replacement, recruited consecutively from a single tertiary centre (Leeds Teaching Hospitals

NHS Trust)[25]. All patients recruited had been referred for pacemaker generator

replacement. Exclusion criteria were inability to consent, underlying complete heart block, a

life expectancy of <1 year in the opinion of the clinician (e.g. terminal malignancy), the

presence of a device-relate complication, or those with known left ventricular ejection

fraction <50%.

In patients recruited with avoidable RV pacing, a pre-specified protocol was followed to

reduce this as outlined in figure 1 including a reduction in the diurnal base rate (BR) to 50

beats/min with nocturnal rate, or hysteresis to 40beats/min along with the deactivation of

rate-adaptive pacing. In addition, where sinus rhythm and heart block had been documented,

the atrioventricular (AV) delays were extended or a device with RV avoidance algorithms was

implanted. The patients were re-assessed 6 months post randomisation. The primary

endpoint was left ventricular ejection fraction (LVEF) at follow-up calculated as an average

over 3 non-paced, normally conducted beats using modified Simpson’s method as per ASE

guidelines [26]. The protocol was tolerated in all but two subjects in whom rate-responsive

pacing was reactivated. Nevertheless, application of the protocol reduced absolute RV pacing

percentage by a mean of 49% (95%CI 41-57%; p<0.0001) from baseline and resulted in a mean

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absolute improvement in LVEF of 6% (95%CI: 2-8%; p<0.0001). This occurred without

reduction in exercise capacity, NT-proBNP, or quality of life. An association was seen between

the reduction in RV pacing and magnitude of change in LVEF (p=0.04). The intervention was

considered safe to use without adaptation in OPT-PACE.

Methods and Analysis

OPT-PACE is a multicentre, randomised, non-blinded parallel trial funded by the National

Institute for Health Research (NIHR) in the UK (NIHR-CS-2012-032) and registered with the

Clinical Trials registry (NCT01819662). The trial design and protocol has received approval

from necessary regulatory and ethics boards as well as an independent trial steering

committee.

The trial will recruit 1200 patients, which began in June 2013 and all patients will be followed

up for a minimum of 12 months.

Trial participation may be terminated via voluntary refusal to continue at any time, or through

significant clinical deterioration assessed by medical staff. Participants suffering from trial-

related problems or adverse events (AE’s) may obtain medical treatment as compensation,

and the trial is insured to compensate.

Patients

Patients are recruited from one tertiary centre (Leeds Teaching Hospitals Trust) and two

district centres (Harrogate District Foundation Trust and Bradford District Trust). Participants

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will have an implantable pacemaker for bradycardia for at least 12 months according to

current accepted clinical guidelines [27] and be able to provide written informed consent.

Participants will be excluded if they have an implantable cardioverter defibrillator or cardiac

resynchronisation device, are less than 18 years old, pregnant, awaiting heart transplantation

or have a severe co-morbidity with life expectancy of <1 year. We will also exclude people

with significant cognitive impairment and any already under the care of HF services.

Randomisation and Interventions

Potential participants will receive a thorough explanation of the process of the trial, be

notified of appointments via post, and associated travel costs will be available to maximise

compliance. Potential participants will be asked to voluntarily provide written informed

consent prior to randomisation in line with the Declaration of Helsinki 2002.

Consecutive pacemaker clinic attendees agreeing to participate will be enrolled and

randomised centrally using a study-specific electronic system. Patients are randomised in a

1:1 ratio to 1) standard care pathway or 2) enhanced care pathway (intervention) (figure 2).

Usual care pathways follow NICE guidelines [28] and patients will undergo routine, usually

annual, pacemaker follow-up. Enhanced care pathway consists of enhanced or optimised care

as pre-determined by each recruiting site. The echocardiographically informed pathways will

consist either of a primary care driven management plan based upon the echocardiogram

which will be forwarded to the primary care team (enhanced care) or a comprehensive care

package consisting of optimised programming and medical therapy coordinated by a regional

heart failure service (optimised care). This latter package will include the RV pacing avoidance

algorithm (figure 1) and in those with LVSD (LVEF<50%) medical therapy following the NICE

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guidelines for the management of chronic heart failure [29]. In the presence of LVSD, patients

recruited at the tertiary centre will be referred to HF clinic, in the district centres, an

echocardiogram report will be sent to the patients’ general practitioner.

Blinding

Practitioners and participants in this trial cannot be blinded to allocation of treatment due to

the nature of the intervention. By not participating in baseline assessments or medical and

device optimisation and having no prior knowledge of participant allocation, the outcome

assessor will remain blinded and thereby safe from detection bias [30]. Unblinding of the

assessors will only be permitted in certain circumstances, for example, when the information

is demanded to ensure appropriate management of the participants (e.g. Serious AE’s).

Outcome Measures

The primary outcome measure is time from randomisation to date of first event of all-cause

mortality or heart failure hospitalisation as assessed by the Endpoint Review Committee. The

endpoint review committee will ensure the quality of conduct and assess protocol deviations

due to the low risk associated with intervention (echocardiography). They will monitor the

safety of the trial and have unblinded access to efficacy data should it be required.

The main secondary outcome measure is the validation of a model to risk stratify people with

a pacemaker for prevalent or future heart failure using simple clinical and pacing variables to

predict the presence of left ventricular systolic dysfunction at baseline and subsequently the

combined outcome of HF hospitalisation and mortality at one year. Validation will be

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achieved by assessing against pre-specified criteria, formed from the confidence intervals of

the initial pilot data analysis of the model [9].

Other secondary outcome measures are to determine 1) the utility of BNP testing as a way to

improve risk score for prevalent left ventricular systolic dysfunction and future admissions, 2)

hospitalisation rates and mortality across randomised arms, 3) utility of a diagnosis of cardiac

dysfunction on achieving standard of care medications and doses and 4) quality of life as

measured by the EuroQol (EQ5D) at baseline and 12 months post enrollment.

All adverse events related to the interventions will be recorded and monitored until resolved.

Medical personnel will decide if continued trial participation is feasible based on these

reports, with the final decision made by the participant.

Data Collection

A clinical research co-ordinator (CRC) will collect information on demographic characteristics

such as: gender, age, vital signs, height and weight and medication history. The patients’

medical history will be taken along with pacemaker data (implant date, implanted device,

programmed pacemaker mode, base rate, and cumulative pacing percentage), and blood

draw will be obtained. Biological specimens will be analysed and stored in the on-site

research pathology laboratory. Patients randomised to intervention will undergo a baseline

transthoracic echocardiogram which will be assessed by the CRC. All data will be stored

anonymously and will be locked once complete.

To ensure protocol adherence, a single research team will undertake all study-specific activity

and be regularly monitored.

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Sample size

The trial is designed to detect a reduction in hospitalisation or mortality rate of 7.5% at one

year in patients identified with cardiac dysfunction from 15% anticipated in patients

randomised to the standard pathway [9]. Given approximately one third of patients in both

randomised arms are estimated to have cardiac dysfunction, a 7.5% reduction would be

diluted to a 9% overall reduction in the enhanced pathway arm. To detect a reduction in

events from 15% to 9% (equivalent to a hazard ratio equal to 0.58) using log-rank analysis

with an overall type 1 error rate of 0.05 (two-sided analysis) and a power of 0.90, requires a

total of 146 events to be observed in at least 1070 participants (nQuery Advisor assuming 18

month recruitment) inflated to 1200 in anticipation of minimal drop-out.

Statistical Analysis Plan

Primary analysis will be performed using the pre-specified endpoints in the intention-to-treat

population (all randomised patients). . Time to event will be summarised across randomised

groups using Kaplan-Meier estimates, hazard ratios and comparison across groups using log-

rank tests, reporting 12 month survival.

Secondary analyses will be based on estimating adjusted treatment effects through Cox

Proportional Hazards regression model the influence of baseline patient characteristics on

outcome. These variables include age, gender, site, co-morbidities, type of device, NYHA class,

medication, blood measures and underlying rhythm. A post-hoc exploratory cost-

effectiveness analysis will be conducted.

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Quality of life data is collected at 2 time points and will be summarised graphically, conditional

on patient survival. Quality adjusted time to event analysis may be appropriate to report

quality adjusted estimates of 12-month survival.

External validation of the risk model will be based on fitting the published model to the OPT-

PACE trial data to report its goodness of fit. Data will be pooled, and stratified by study, to

remodel parameter estimates with the aim of improving precision.

Patient and Public Involvement

The research question developed as a large number of pacemaker patients were seen in HF

clinic with deterioration in their ventricular function and symptoms who were followed-up

annually in pacemaker clinic and yet, these had not been detected. The study was initially

discussed with a well-established local patient and public involvement (PPI) advisory group

(AG) consisting of cardiovascular patients and their families. The AG particularly felt that

undergoing all study assessments in one day was appealing to potential participants but that

the intervention was not a large burden and that it was more important to know the effect

on patient survival and the number of times patients were hospitalised, not just whether

there was an improvement in heart function from optimised care in terms of outcome

measures. Once the final protocol was established, it was reviewed by the PPI-AG along with

patient information sheets to ensure the plain English was at an appropriate level. Regular

updates will be presented regarding recruitment and any adverse events. Study results will

be discussed and an appropriate method of dissemination will be designed together between

the AG and researchers to deliver these to participants.

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Ethics and Dissemination

The trial design and protocol have received ethical approval from the South Yorkshire

research ethics committee (12/YH/0487) and is registered on Clinicaltrials.gov (

NCT01819662). Amendments will be documented.

Trial results will be communicated on a local level to healthcare professionals and patient

involvement groups. Results will be published in international peer-reviewed journals with

authorship as determined by the international committee of medical journal editors’

guidelines [31] and highlighted using social media campaigns. The National Institute of Health

Research will be made aware prior to publication but no publication restrictions apply.

Discussion

Patients with permanent pacemakers are at increased risk of prevalent heart failure with a

reduced quality of life and incident HF leading to hospitalisations and a poorer prognosis.

Despite increasing recognition of this, and the development of device-based options to limit

unnecessary ventricular pacing, patients with permanent pacemakers rarely undergo any

assessment to identify prevalent HF or their future risk of HF. Pacemaker follow-up services

have remained resolutely technical with intervals based upon historical risk of pacemaker

device failure rather than focusing on patient requirements in the face of negligible

pacemaker failure rates and extended battery longevity.

A validated tool combining clinical and technical data by which patients’ risk of the one major

complication of pacemaker therapy - heart failure - could be assessed, allowing individualised

follow-up intervals has the potential to substantially improve patient experience whilst also

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offering the opportunity to focus screening and lead to the initiation of optimal therapy.

Although there are several clinical and pacemaker-related features linked to the presence of

cardiac dysfunction, no validated risk score exists to select those that should be referred for

assessment.

The management pathways used in this trial will offer individualised healthcare, and establish

the relative benefits of primary, secondary and tertiary expertise and interventions. Our

previous data have shown that reprogramming to avoid RV pacing is safe and well tolerated

by patients. Combining this with medical therapy for HF in collaboration with a HF service as

a new model of care for people with pacemakers is feasible and could improve their quality

of life and overall prognosis whilst also being highly cost-effective. We aim to test the clinical

effectiveness of this approach when applied to a large number of patients at multiple sites.

Conclusions

OPT-PACE is an important randomised controlled trial, supported by non-industry funding,

that will investigate whether assessing left ventricular function to inform pacemaker

programming and medical decisions, can improve the morbidity and mortality in pacemaker

patients, compared with usual care.

The results will have implications for the stratification of pacemaker patients and the

organisation of diagnostic and therapeutic pathways to reduce the incidence of HF in this

population.

Abbreviations

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BR: Base rate; CHF: Chronic heart failure; EQ-5D: EuroQol 5-Dimension; HF: Heart failure; LV:

Left ventricle; LVEF: Left ventricular ejection fraction; LVSD: Left ventricular systolic

dysfunction; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; RV: Right

ventricular

Authors Contributions

KW and MP researched the topic and devised the study. MP and KW provided the first draft

of the manuscript. DDS and DAC provide statistical oversight. All other co-authors contributed

equally to data collection and manuscript preparation.

Acknowledgements

The authors would like to express their appreciation for the valuable contributions of

participants with a pacemaker who are, or will, participate in this trial, the PPI-AG for their

practical and insightful suggestions, and for the consistent administrative support of Mrs

Andrea Marchant and Miss Lisa Trueman.

Funding Statement

The research is supported by the National Institute for Health Research (NIHR)

infrastructure at Leeds, and a NIHR clinician scientist fellowship (NIHR-CS-2012-032). The

views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR

or the Department of Health. This research was supported by the National Institute for

Health Research Leeds Clinical Research Facility.

Endpoint Review Committee

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Members: KW, MTK, MP, JF, 2 heart failure specialist nurses

Competing Interests Statement

MP holds a NIHR clinical doctoral fellowship outside of this work. JG holds a NIHR postdoctoral

fellowship outside of this work. RMC holds a fellowship with the BHF. MTK holds a BHF chair.

KKW holds an NIHR clinician scientist award.

Figure Legend

Figure 1: Ventricular pacing avoidance protocol [9]

Figure 2: OPT-PACE study protocol

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17. Brunner, M., et al., Long-term survival after pacemaker implantation: Prognostic importance of gender and baseline patient characteristics. European Heart Journal, 2004. 25(1): p. 88-95.

18. Jahangir, A., et al., Relation between mode of pacing and long-term survival in the very elderly. Journal of the American College of Cardiology, 1999. 33(5): p. 1208-1216.

19. Braunschweig, F., M.R. Cowie, and A. Auricchio, What are the costs of heart failure? Europace, 2011. 13(suppl_2): p. ii13-ii17.

20. Purdy, S., et al., Ambulatory care sensitive conditions: terminology and disease coding need to be more specific to aid policy makers and clinicians. Public health, 2009. 123(2): p. 169-173.

21. Kolb, C., et al., Reduction of right ventricular pacing with advanced atrioventricular search hysteresis: results of the PREVENT study. Pacing and Clinical Electrophysiology, 2011. 34(8): p. 975-983.

22. Sweeney, M., Search AV Extension and Managed Ventricular Pacing for Promoting Atrioventricular Conduction (SAVE PACe) Trial. Minimizing ventricular pacing to reduce atrial fibrillation in sinus-node disease. N Engl J Med, 2007. 357: p. 1000-1008.

23. DAVY, J., et al., Near elimination of ventricular pacing in SafeR mode compared to DDD modes: a randomized study of 422 patients. Pacing and clinical electrophysiology, 2012. 35(4): p. 392-402.

24. Marinskis, G., et al., Practices of cardiac implantable electronic device follow-up: results of the European Heart Rhythm Association survey. Europace, 2012. 14(3): p. 423-425.

25. Anonymous, Technology eases living with heart failure. New implantable devices, stem cell therapy, and monitoring techniques may improve length and quality of life. Health News, 2005. 11(2): p. 7-8.

26. Lang, R.M., et al., Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Journal of the American Society of Echocardiography, 2015. 28(1): p. 1-39. e14.

27. Excellence, N.I.f.H.a.C., Dual-chamber pacemakers for symptomatic bradycardia due to sick sinus syndrome without atrioventricular block (TA324). 2014, NICE: London.

28. NICE, Dual-chamber pacemakers for symptomatic bradycardia due to sick sinus syndrome and/or atrioventricular block. 2017.

29. Excellence, N.I.f.H.a.C., Chronic heart failure in adults: management. 2010, NICE: London.

30. Higgins, J.P.T., S. Green, and Cochrane Collaboration., Cochrane handbook for systematic reviews of interventions. 2011, Cochrane Collaboration: [Oxford]. p. 1 online resource.

31. Editors, I.C.o.M.J. Defining the role of authors and contributors. 2018 [cited 2018 01/02/2018]; Available from: http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-of-authors-and-contributors.html.

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Figure 1. Right ventricular avoidance algorithm

Consent for assessment (pacemaker interrogation,

echocardiogram, blood tests, quality of life questionnaire)

Identify atrial rhythm

Lower base rate to 50beats/min, sleep/rest/hysteresis to

40beats/min, de-activate rate-responsive pacing


40beats/min, de-activate rate-responsive pacing, program right

ventricular pacing avoidance algorithm on or extend atrioventricular delays

Sinus rhythmAtrial Fibrillation

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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description Addressed on page number

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym 1

2a Trial identifier and registry name. If not yet registered, name of intended registry 1Trial registration

2b All items from the World Health Organization Trial Registration Data Set 1,

Protocol version 3 Date and version identifier 8

Funding 4 Sources and types of financial, material, and other support 1, 8, 15

5a Names, affiliations, and roles of protocol contributors 1, 15Roles and responsibilities

5b Name and contact information for the trial sponsor 1

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities

N/A

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee)

11, 15

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Introduction

Background and rationale

6a Description of research question and justification for undertaking the trial, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention

4-8

6b Explanation for choice of comparators 4-7, 10

Objectives 7 Specific objectives or hypotheses 7

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory) 4-9

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained

8,9

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists)

8,9

11a Interventions for each group with sufficient detail to allow replication, including how and when they will be administered

9, 11

11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease)

8, 9, 11

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests)

11

Interventions

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial NA

Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended

10,11

Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure)

8,9, Figure 2

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Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and statistical assumptions supporting any sample size calculations

11

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size 11-12

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence generation

16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restricton (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions

8,9

Allocation concealment mechanism

16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned

8,9

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions

5-8

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how

9

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s allocated intervention during the trial

9,13

Methods: Data collection, management, and analysis

Data collection methods

18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol

9

18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols

11

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Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol

8-11

Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol

12

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) 12

20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) 12

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed

13

21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial

12

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct

11

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor

11

Ethics and dissemination

Research ethics approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval 11, 12

Protocol amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators)

13

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Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and how (see Item 32)

9,11

26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable

N/A

Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial

11

Declaration of interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site 15,16

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that limit such access for investigators

11

Ancillary and post-trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial participation

8

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing arrangements), including any publication restrictions

12,13

31b Authorship eligibility guidelines and any intended use of professional writers 15

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code No plans

Appendices

Informed consent materials

32 Model consent form and other related documentation given to participants and authorised surrogates N/A can be provided on request

Biological specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the current trial and for future use in ancillary studies, if applicable

11,12,13

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items. Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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For peer review onlyOptimising pacemaker therapy and medical therapy in

pacemaker patients for heart failure – protocol for the OPT-pace randomised controlled trial

Journal: BMJ Open

Manuscript ID bmjopen-2018-028613.R1

Article Type: Protocol

Date Submitted by the Author: 30-Apr-2019

Complete List of Authors: Paton, Maria; University of Leeds, Leeds Institute of Cardiovascular and Metabolic MedicineGierula, John; University of Leeds, Leeds Institute of Cardiovascular and Metabolic MedicineJamil, Haqeel; University of Leeds, Leeds Institute of Cardiovascular and Metabolic MedicineLowry, Judith; University of Leeds, Leeds Institute of Cardiovascular and Metabolic MedicineByrom, Rowena; University of Leeds, Leeds Institute of Cardiovascular and Metabolic MedicineGillott, Richard; Leeds Teaching Hospitals NHS TrustChumun, Hemant; University of Leeds, Leeds Institute of Cardiovascular and Metabolic MedicineCubbon, R.M.; University of Leeds, Cairns, David; University of Leeds, Leeds Institute of of Clinical Trials ResearchStocken, Deborah; University of Leeds, Leeds Institute of Clinical Trials ResearchKearney, Mark; University of Leeds, Leeds Institute of Cardiovascular and Metabolic MedicineWitte, Klaus; University of Leeds Leeds Institute of Health Sciences, Faculty of Medicine and Health; Leeds General Infirmary, Cardiology

<b>Primary Subject Heading</b>: Cardiovascular medicine

Secondary Subject Heading: Cardiovascular medicine

Keywords: pacemaker, Optimal medical therapy, Heart failure < CARDIOLOGY, randomised controlled trial, Pacing & electrophysiology < CARDIOLOGY


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1 Optimising pacemaker therapy and medical therapy in pacemaker patients for heart failure – 2 protocol for the OPT-pace randomised controlled trial34 Maria F Paton1

5 John Gierula1

6 Haqeel A Jamil17 Judith E Lowry1

8 Rowena Byrom1

9 Richard G Gillott2

10 Hemant Chumun1

11 Richard M Cubbon1

12 David A Cairns3

13 Deborah D Stocken3

14 Mark T Kearney1

15 Klaus K Witte1*

1617181920 Running title: Heart failure in pacemaker patients21 ClinicalTrials.gov registration number: NCT0181966222 Word count for Main body: 291723 Number of tables: 024 Number of figures: 2 25 Number of supplementary tables: 026 Number of supplementary figures: 02728 1 Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, UK 29 2 Leeds Teaching Hospitals NHS Trust, Department of Cardiology, Leeds, UK30 3 Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK3132 * Corresponding author:33 Dr Klaus K Witte34 Division of Cardiovascular and Diabetes Research,35 Multidisciplinary Cardiovascular Research Centre (MCRC)36 Leeds Institute of Cardiovascular and Metabolic Medicine37 LIGHT building, University of Leeds38 Clarendon Way, Leeds, UK, LS2 9JT3940 Phone: (+44) 113 392610841 E-mail: [email protected]

43 Trial Sponsor : University of Leeds44 LIGHT building, 45 Clarendon Way, Leeds, UK, LS2 9JT464748

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mailto:[email protected]


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49 Abstract

50 Introduction: Permanent artificial pacemaker implantation is a safe and effective treatment

51 for bradycardia and is associated with extended longevity and improved quality of life.

52 However, the most common long-term complication of standard pacemaker therapy is

53 pacemaker-associated heart failure. Pacemaker follow-up is potentially an opportunity to

54 screen for heart failure to assess and optimise patient devices and medical therapy.

55 Methods and Analysis: The study is a multi-centre, phase-3 randomised trial. The 1200

56 participants will be people who have a permanent pacemaker for bradycardia for at least 12

57 months, randomly assigned to undergo a transthoracic echocardiogram with their pacemaker

58 check, thereby tailoring their management directed by left ventricular function, or the

59 pacemaker check alone, continuing with routine follow-up. The primary outcome measure is

60 time to all-cause mortality or heart failure hospitalisation. Secondary outcomes include

61 external validation of our risk stratification model to predict onset of heart failure and quality

62 of life assessment.

63 Ethics and Dissemination: The trial design and protocol has received national ethical approval

64 (12/YH/0487) and is registered on ClinicalTrials.gov (NCT01819662).

65 The results of this randomised trial will be published in international peer-reviewed journals,

66 communicated to healthcare professionals and patient involvement groups, and highlighted

67 using social media campaigns.

68

69 Keywords: Pacemaker, optimal medical therapy, heart failure, randomised controlled trial

70

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72 Article Summary

73 Strengths and Limitations of this study

74 OPT-PACE is a trial independently funded by the National Institute for Health Research

75 Stratification of the participant randomisation is not adopted in this trial due to the

76 large sample size.

77 Participant and practitioner blinding are not plausible.

78 The control arm consists of current standard of care ensuring trial results are reflective

79 and generalizable.

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81 Introduction

82 Permanent artificial pacemaker implantation is a safe and effective treatment for

83 bradycardia,[1] and is associated with extended longevity [2] and improved quality of life.[3]

84 An estimated 350,000 people in the UK have a pacemaker, with over 40,000 new implants

85 per year.

86

87 However, long term right ventricular (RV) pacing has been linked to adverse left ventricular

88 (LV) remodeling, [4, 5] such that the most common long-term complication of standard

89 pacemaker therapy is pacemaker-associated chronic heart failure (CHF) due to left ventricular

90 systolic dysfunction (LVSD) [6-8]. Whilst up to 2-3% of the general population have CHF, the

91 condition is much more common in pacemaker patients with a prevalence up to 50% [7, 9]

92 and 12% of people admitted with acute decompensated heart failure (HF) (4% with a de novo

93 admission for heart failure) have a pacemaker [10].

94

95 It is clear that right ventricular pacing alone can lead to LVSD, however the risk is especially

96 high in people requiring a high proportion of ventricular pacing, those with diabetes mellitus,

97 previous myocardial infarction and raised creatinine [11]. Data examining the relationship

98 between pacemaker use and cardiac dysfunction predominantly originate from retrospective

99 cross-sectional analysis or secondary analyses [12-15]. We provided the first evidence that

100 reducing RV pacing through careful reprogramming is associated with an improvement in LV

101 function without affecting quality of life or functional capacity,[9] confirming somewhat the

102 suggestion that RV pacing is contributory to LV dysfunction in pacemaker patients and not

103 just a bystander in a multi-morbid patient population.

104

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105 Although there is increasing recognition of the axis of RV pacing and LVSD, it remains the case

106 that HF is frequently overlooked in the pacemaker population with symptoms often ascribed

107 to pacemaker syndrome, chronotropic incompetence, or co-morbidities [6]. HF and

108 undiagnosed left ventricular dysfunction have a major effect on mortality and morbidity

109 amongst pacemaker patients [16-18]. Since HF management accounts for approximately 2%

110 of the healthcare budget in many developed countries, more than 60% of which relates to

111 hospitalisation costs [19], optimal management of people with HF whether or not they have

112 a pacemaker is a key strategy for controlling healthcare costs while increasing quality of life

113 [20].

114

115 There are however, no data on the potential benefits of screening people with pacemakers

116 for heart failure and whilst there are now a series of algorithms to limit RV pacing [21-23], no

117 clear strategy for the use of these is outlined in current guidelines. This situation is

118 compounded by a lack of published evidence around the benefits of medical management of

119 pacemaker related HF since people with pacemakers were excluded from most of the large

120 heart failure studies.

121

122 Prospective randomised studies of pacemaker follow-up programs to risk stratify patients and

123 optimise management have not yet been of adequate size and duration to assess the clinical

124 effectiveness of such an approach in a real-world general healthcare setting. Pacemaker

125 follow-up is a rarely realised opportunity to screen for HF and assess and optimise patient

126 devices and medical therapy.[24]

127

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128 The OPT-PACE (OPTimising PACEmaker therapy) trial has been designed to address these

129 issues and quantify time to all-cause mortality or heart failure hospitalisation, as well as

130 validate a HF risk stratification model based on simple variables available in pacemaker clinic.

131 Secondary aims are to establish whether NT-proBNP improves this risk stratification model.

132 Subsequently, we aim to provide data on the effects of establishing the presence of left

133 ventricular systolic dysfunction on medical therapy, device programming and patient quality

134 of life.

135

136 Pilot Data

137 Risk model

138 The design of the OPT-PACE trial is informed by an observational cohort [11] including 491

139 patients listed for a pacemaker generator replacement in a single tertiary centre (Leeds

140 Teaching Hospitals NHS Trust) invited for pacing therapy information, diagnostic pacing data

141 and an echocardiogram.

142

143 Of this cohort, 40% had an LV ejection fraction of <50%, which was much higher (59%) in

144 those with >80% RV pacing (p<0.001), demonstrating that patients with RV pacemakers have

145 a high prevalence of LV systolic dysfunction. After a mean follow-up time of 668 days, 56

146 patients (12%) had died or been hospitalized for heart failure.

147

148 Multivariable analyses identified a number of simple clinical variables; high percentage RV

149 pacing, high serum creatinine, and previous myocardial infarction as potential independent

150 predictors of LV systolic dysfunction to identify patients who may benefit from a more

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151 comprehensive review [11]. This risk model requires external validation planned within the

152 OPT-PACE trial.

153

154 Intervention Development

155 The design of the pacemaker optimisation intervention used in the OPT-PACE trial is based on

156 data from an observational cohort of 66 patients, referred for pacemaker generator

157 replacement, recruited consecutively from a single tertiary centre (Leeds Teaching Hospitals

158 NHS Trust)[9]. All patients recruited had been referred for pacemaker generator replacement.

159 Exclusion criteria were inability to consent, underlying complete heart block, a life expectancy

160 of <1 year in the opinion of the clinician (e.g. terminal malignancy), the presence of a device-

161 relate complication, or those with known left ventricular ejection fraction <50%.

162

163 In patients recruited with avoidable RV pacing, a pre-specified protocol was followed to

164 reduce this as outlined in figure 1 including a reduction in the diurnal base rate (BR) to 50

165 beats/min with nocturnal rate, or hysteresis to 40beats/min along with the deactivation of

166 rate-adaptive pacing. In addition, where sinus rhythm and heart block had been documented,

167 the atrioventricular (AV) delays were extended or a device with RV avoidance algorithms was

168 implanted. The patients were re-assessed 6 months post randomisation. The primary

169 endpoint was left ventricular ejection fraction (LVEF) at follow-up calculated as an average

170 over 3 non-paced, normally conducted beats using modified Simpson’s method as per ASE

171 guidelines [25]. The protocol was tolerated in all but two subjects in whom rate-responsive

172 pacing was reactivated. Nevertheless, application of the protocol reduced absolute RV pacing

173 percentage by a mean of 49% (95%CI 41-57%; p<0.0001) from baseline and resulted in a mean

174 absolute improvement in LVEF of 6% (95%CI: 2-8%; p<0.0001). This occurred without

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175 reduction in exercise capacity, NT-proBNP, or quality of life. An association was seen between

176 the reduction in RV pacing and magnitude of change in LVEF (p=0.04). The intervention was

177 considered safe to use without adaptation in OPT-PACE.

178

179 Methods and Analysis

180

181 OPT-PACE is a multicentre, randomised, non-blinded parallel trial funded by the National

182 Institute for Health Research (NIHR) in the UK (NIHR-CS-2012-032) and registered with the

183 Clinical Trials registry (NCT01819662). The trial design and protocol has received approval

184 from necessary regulatory and ethics boards as well as an independent trial steering

185 committee.

186

187 The trial will recruit 1200 patients, which began in June 2013 and all patients will be followed

188 up for a minimum of 12 months.

189

190 Trial participation may be terminated via voluntary refusal to continue at any time, or through

191 significant clinical deterioration assessed by medical staff. Participants suffering from trial-

192 related problems or adverse events (AE’s) may obtain medical treatment as compensation,

193 and the trial is insured to compensate.

194

195 Patients

196 Patients are recruited from one tertiary centre (Leeds Teaching Hospitals Trust) and two

197 district centres (Harrogate District Foundation Trust and Bradford District Trust). Participants

198 will have an implantable pacemaker for bradycardia for at least 12 months according to any

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199 indication in current accepted clinical guidelines [26] and be able to provide written informed

200 consent. Both atrial and ventricular pacing burdens will be documented. Participants will be

201 excluded if they have an implantable cardioverter defibrillator or cardiac resynchronisation

202 device, are less than 18 years old, pregnant, awaiting heart transplantation or have a severe

203 co-morbidity with life expectancy of <1 year. We will also exclude people with significant

204 cognitive impairment and any already under the care of HF services.

205

206 Randomisation and Interventions

207 Potential participants will receive a thorough explanation of the process of the trial, be

208 notified of appointments via post, and associated travel costs will be available to maximise

209 compliance. Potential participants will be asked to voluntarily provide written informed

210 consent prior to randomisation in line with the Declaration of Helsinki 2002.

211

212 Consecutive pacemaker clinic attendees agreeing to participate will be enrolled and

213 randomised centrally using a study-specific electronic system. Patients are randomised in a

214 1:1 ratio to 1) standard care pathway or 2) interventional pathway (figure 2). Usual care

215 pathways follow NICE guidelines [27] and patients will undergo routine, usually annual,

216 pacemaker follow-up. Interventional pathways consists of enhanced or optimised care pre-

217 determined by each recruiting site. The echocardiographically informed pathways will consist

218 either of a primary care driven management plan based upon the echocardiogram which will

219 be forwarded to the primary care team (enhanced care, n=300) if recruited in one of the

220 district centres, or a comprehensive care package consisting of optimised programming and

221 medical therapy co-ordinated by a regional heart failure service (optimised care, n=300) if

222 recruited in the tertiary centre. This interventional package will include the RV pacing

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223 avoidance algorithm (figure 1) and in those with LVSD (LVEF<50%) medical therapy following

224 the NICE guidelines for the management of chronic heart failure [28]. In the presence of LVSD,

225 patients recruited at the tertiary centre will be referred to an outpatient HF clinic (optimized

226 care), and in the district centres an echocardiogram report will be sent to the patients’ general

227 practitioner (enhanced care).

228

229 Blinding

230 Practitioners and participants in this trial cannot be blinded to allocation of treatment due to

231 the nature of the intervention. By not participating in baseline assessments or medical and

232 device optimisation and having no prior knowledge of participant allocation, the outcome

233 assessor will remain blinded and thereby safe from detection bias [29]. Unblinding of the

234 assessors will only be permitted in certain circumstances, for example, when the information

235 is demanded to ensure appropriate management of the participants (e.g. Serious AE’s).

236

237 Outcome Measures

238 The primary outcome measure is a combined endpoint of time from randomisation to date

239 of first event of all-cause mortality or heart failure hospitalisation as assessed by the Endpoint

240 Review Committee. The endpoint review committee will ensure the quality of conduct and

241 assess protocol deviations due to the low risk associated with intervention

242 (echocardiography). They will monitor the safety of the trial and have unblinded access to

243 efficacy data should it be required.

244

245 The main secondary outcome measure is the validation of a model to risk stratify people with

246 a pacemaker for prevalent or future heart failure using simple clinical and pacing variables to

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247 predict the presence of left ventricular systolic dysfunction at baseline and subsequently the

248 combined outcome of HF hospitalisation and mortality at one year. Validation will be

249 achieved by assessing against pre-specified criteria, formed from the confidence intervals of

250 the initial pilot data analysis of the model [9].

251

252 Other secondary outcome measures are to determine 1) the utility of BNP testing as a way to

253 improve risk score for prevalent left ventricular systolic dysfunction and future admissions, 2)

254 hospitalisation rates and mortality across randomised arms, 3) utility of a diagnosis of cardiac

255 dysfunction on achieving standard of care medications and doses and 4) quality of life as

256 measured by the EuroQol (EQ5D) at baseline and 12 months post enrollment.

257

258 All adverse events related to the interventions will be recorded and monitored until resolved.

259 Medical personnel will decide if continued trial participation is feasible based on these

260 reports, with the final decision made by the participant.

261

262 Data Collection

263 A clinical research co-ordinator (CRC) will collect information on demographic characteristics

264 such as: gender, age, vital signs, height and weight and medication history. The patients’

265 medical history will be taken along with pacemaker data (implant date, implanted device,

266 programmed pacemaker mode, base rate, and cumulative pacing percentages), and blood

267 draw will be obtained. Biological specimens will be analysed and stored in the on-site

268 research pathology laboratory. Patients randomised to intervention will undergo a baseline

269 transthoracic echocardiogram which will be assessed by the CRC. All data will be stored

270 anonymously and will be locked once complete.

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271 To ensure protocol adherence, a single research team will undertake all study-specific activity

272 and be regularly monitored.

273 Digital follow-up will occur at 12 month post recruitment to record mortality and

274 hospitalisation data and changes to medical therapy. Patient data regarding cardiac

275 transplatation or device upgrade will be recorded and subsequently reported.

276

277 Sample size

278 The trial is designed to detect a reduction in hospitalisation or mortality rate of 7.5% at one

279 year in patients identified with cardiac dysfunction from 15% anticipated in patients

280 randomised to the standard pathway [9]. Given approximately one third of patients in both

281 randomised arms are estimated to have cardiac dysfunction, a 7.5% reduction would be

282 diluted to a 9% overall reduction in the enhanced pathway arm. To detect a reduction in

283 events from 15% to 9% (equivalent to a hazard ratio equal to 0.58) using log-rank analysis

284 with an overall type 1 error rate of 0.05 (two-sided analysis) and a power of 0.90, requires a

285 total of 146 events to be observed in at least 1070 participants (nQuery Advisor assuming 18

286 month recruitment) inflated to 1200 in anticipation of minimal drop-out.

287

288 Statistical Analysis Plan

289 Primary analysis will be performed using the pre-specified endpoints in the intention-to-treat

290 population (all randomised patients). . Time to event will be summarised across randomised

291 groups using Kaplan-Meier estimates, hazard ratios and comparison across groups using log-

292 rank tests, reporting 12 month survival.

293

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294 Secondary analyses will be based on estimating adjusted treatment effects through Cox

295 Proportional Hazards regression model the influence of baseline patient characteristics on

296 outcome. These variables include age, gender, site, co-morbidities, type of device, NYHA class,

297 medication, blood measures and underlying rhythm. A post-hoc exploratory cost-

298 effectiveness analysis will be conducted.

299

300 Quality of life data is collected at 2 time points and will be summarised graphically, conditional

301 on patient survival. Quality adjusted time to event analysis may be appropriate to report

302 quality adjusted estimates of 12-month survival.

303

304 External validation of the risk model will be based on fitting the published model to the OPT-

305 PACE trial data to report its goodness of fit. Data will be pooled, and stratified by study, to

306 remodel parameter estimates with the aim of improving precision.

307

308 Patient and Public Involvement

309 The research question developed as a large number of pacemaker patients were seen in HF

310 clinic with deterioration in their ventricular function and symptoms who were followed-up

311 annually in pacemaker clinic and yet, these had not been detected. The study was initially

312 discussed with a well-established local patient and public involvement (PPI) advisory group

313 (AG) consisting of cardiovascular patients and their families. The AG particularly felt that

314 undergoing all study assessments in one day was appealing to potential participants but that

315 the intervention was not a large burden and that it was more important to know the effect

316 on patient survival and the number of times patients were hospitalised, not just whether

317 there was an improvement in heart function from optimised care in terms of outcome

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318 measures. Once the final protocol was established, it was reviewed by the PPI-AG along with

319 patient information sheets to ensure the plain English was at an appropriate level. Regular

320 updates will be presented regarding recruitment and any adverse events. Study results will

321 be discussed and an appropriate method of dissemination will be designed together between

322 the AG and researchers to deliver these to participants.

323

324 Ethics and Dissemination

325 The trial design and protocol have received ethical approval from the South Yorkshire

326 research ethics committee (12/YH/0487) and is registered on Clinicaltrials.gov (

327 NCT01819662). Amendments will be documented.

328

329 Trial results will be communicated on a local level to healthcare professionals and patient

330 involvement groups. Results will be published in international peer-reviewed journals with

331 authorship as determined by the international committee of medical journal editors’

332 guidelines [30] and highlighted using social media campaigns. The National Institute of Health

333 Research will be made aware prior to publication but no publication restrictions apply.

334

335 Discussion

336 Patients with permanent pacemakers are at increased risk of prevalent heart failure with a

337 reduced quality of life and incident HF leading to hospitalisations and a poorer prognosis.

338 Despite increasing recognition of this, and the development of device-based options to limit

339 unnecessary ventricular pacing, patients with permanent pacemakers rarely undergo any

340 assessment to identify prevalent HF or their future risk of HF. Pacemaker follow-up services

341 have remained resolutely technical with intervals based upon historical risk of pacemaker

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342 device failure rather than focusing on patient requirements in the face of negligible

343 pacemaker failure rates and extended battery longevity.

344

345 A validated tool combining clinical and technical data by which patients’ risk of the one major

346 complication of pacemaker therapy - heart failure - could be assessed, allowing individualised

347 follow-up intervals has the potential to substantially improve patient experience whilst also

348 offering the opportunity to focus screening and lead to the initiation of optimal therapy.

349 Although there are several clinical and pacemaker-related features linked to the presence of

350 cardiac dysfunction, no validated risk score exists to select those that should be referred for

351 assessment.

352

353 The management pathways used in this trial will offer individualised healthcare, and establish

354 the relative benefits of primary, secondary and tertiary expertise and interventions. Our

355 previous data have shown that reprogramming to avoid RV pacing is safe and well tolerated

356 by patients. Combining this with medical therapy for HF in collaboration with a HF service as

357 a new model of care for people with pacemakers is feasible and could improve their quality

358 of life and overall prognosis whilst also being highly cost-effective. We aim to test the clinical

359 effectiveness of this approach when applied to a large number of patients at multiple sites.

360

361 Conclusions

362 OPT-PACE is an important randomised controlled trial, supported by non-industry funding,

363 that will investigate whether assessing left ventricular function to inform pacemaker

364 programming and medical decisions, can improve the morbidity and mortality in pacemaker

365 patients, compared with usual care.

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366

367 The results will have implications for the stratification of pacemaker patients and the

368 organisation of diagnostic and therapeutic pathways to reduce the incidence of HF in this

369 population.

370

371 Abbreviations

372 BR: Base rate; CHF: Chronic heart failure; EQ-5D: EuroQol 5-Dimension; HF: Heart failure; LV:

373 Left ventricle; LVEF: Left ventricular ejection fraction; LVSD: Left ventricular systolic

374 dysfunction; NT-proBNP: N-terminal prohormone of brain natriuretic peptide; RV: Right

375 ventricular

376

377 Authors Contributions

378 KW MFP JG MTK and RMC researched the topic and devised the study. MP and KW provided

379 the first draft of the manuscript. DDS and DAC provide statistical oversight and RGG managed

380 data storage and aided analysis. MFP JG HAJ JEL RB HC RMC MTK and KW contributed equally

381 to data collection and all authors contributed to manuscript preparation.

382

383 Acknowledgements

384 The authors would like to express their appreciation for the valuable contributions of

385 participants with a pacemaker who are, or will, participate in this trial, the PPI-AG for their

386 practical and insightful suggestions, and for the consistent administrative support of Mrs

387 Andrea Marchant and Miss Lisa Trueman.

388

389 Funding Statement

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390 The research is supported by the National Institute for Health Research (NIHR)

391 infrastructure at Leeds, and a NIHR clinician scientist fellowship (NIHR-CS-2012-032). The

392 views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR

393 or the Department of Health. This research was supported by the National Institute for

394 Health Research Leeds Clinical Research Facility.

395

396 Endpoint Review Committee

397 Members: KW, MTK, MP, JF, 2 heart failure specialist nurses

398

399 Competing Interests Statement

400 MFP holds a NIHR clinical doctoral fellowship outside of this work. JG holds a NIHR

401 postdoctoral fellowship outside of this work. RMC holds a fellowship with the BHF. MTK holds

402 a BHF chair. KKW holds an NIHR clinician scientist award.

403

404 Figure Legend

405 Figure 1: Ventricular pacing avoidance protocol [9]

406 Figure 2: OPT-PACE study protocol

407

408

409

410

411

412 References

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413 1. Epstein, A.E., et al., 2012 ACCF/AHA/HRS focused update incorporated into the 414 ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm 415 abnormalities. Circulation, 2013. 127(3): p. e283-e352.416 2. Shaw, D.B., et al., Survival in second degree atrioventricular block. Heart, 1985. 53(6): 417 p. 587-593.418 3. Lamas, G.A., et al., Quality of life and clinical outcomes in elderly patients treated 419 with ventricular pacing as compared with dual-chamber pacing. New England Journal 420 of Medicine, 1998. 338(16): p. 1097-1104.421 4. Lee, M.A., et al., Effects of long-term right ventricular apical pacing on left ventricular 422 perfusion, innervation, function and histology. Journal of the American College of 423 Cardiology, 1994. 24(1): p. 225-232.424 5. Begg, G., et al., 154 Patients receiving standard pacemaker generator replacements 425 frequently have impaired left ventricular function and exercise intolerance, related to 426 the percentage of right ventricular pacing. Heart, 2011. 97(Suppl 1): p. A86-A86.427 6. Sweeney, M.O., et al., Adverse effect of ventricular pacing on heart failure and atrial 428 fibrillation among patients with normal baseline QRS duration in a clinical trial of 429 pacemaker therapy for sinus node dysfunction. Circulation, 2003. 107(23): p. 2932-430 2937.431 7. Thackray, S.D., et al., The prevalence of heart failure and asymptomatic left 432 ventricular systolic dysfunction in a typical regional pacemaker population. European 433 Heart Journal, 2003. 24(12): p. 1143-1152.434 8. ZHANG, X.H., et al., New-onset heart failure after permanent right ventricular apical 435 pacing in patients with acquired high-grade atrioventricular block and normal left 436 ventricular function. Journal of cardiovascular electrophysiology, 2008. 19(2): p. 136-437 141.438 9. Gierula, J., et al., Pacing-associated left ventricular dysfunction? Think 439 reprogramming first! Heart, 2014. 100(10): p. 765-769.440 10. Nieminen, M.S., et al., EuroHeart Failure Survey II (EHFS II): a survey on hospitalized 441 acute heart failure patients: description of population. European heart journal, 2006. 442 27(22): p. 2725-2736.443 11. Gierula, J., et al., Patients with long-term permanent pacemakers have a high 444 prevalence of left ventricular dysfunction. Journal of Cardiovascular Medicine, 2015. 445 16(11): p. 743-750.446 12. Shen, W.-K., et al., Long-term survival after pacemaker implantation for heart block 447 in patients≥ 65 years. The American journal of cardiology, 1994. 74(6): p. 560-564.448 13. JELIĆ, V., et al., Survival in 1,431 pacemaker patients: prognostic factors and 449 comparison with the general population. Pacing and Clinical Electrophysiology, 1992. 450 15(2): p. 141-147.451 14. Mayosi, B.M., F. Little, and R.N.S. MILLAR, Long-term survival after permanent 452 pacemaker implantation in young adults: 30 year experience. Pacing and clinical 453 electrophysiology, 1999. 22(3): p. 407-412.454 15. Sweeney, M.O., et al., Reduced ejection fraction, sudden cardiac death, and heart 455 failure death in the mode selection trial (MOST): implications for device selection in 456 elderly patients with sinus node disease. Journal of cardiovascular electrophysiology, 457 2008. 19(11): p. 1160-1166.

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458 16. Shen, W.-K., et al., Survival and functional independence after implantation of a 459 permanent pacemaker in octogenarians and nonagenarians: a population-based 460 study. Annals of internal medicine, 1996. 125(6): p. 476-480.461 17. Brunner, M., et al., Long-term survival after pacemaker implantation: Prognostic 462 importance of gender and baseline patient characteristics. European Heart Journal, 463 2004. 25(1): p. 88-95.464 18. Jahangir, A., et al., Relation between mode of pacing and long-term survival in the 465 very elderly. Journal of the American College of Cardiology, 1999. 33(5): p. 1208-466 1216.467 19. Braunschweig, F., M.R. Cowie, and A. Auricchio, What are the costs of heart failure? 468 Europace, 2011. 13(suppl_2): p. ii13-ii17.469 20. Purdy, S., et al., Ambulatory care sensitive conditions: terminology and disease 470 coding need to be more specific to aid policy makers and clinicians. Public health, 471 2009. 123(2): p. 169-173.472 21. Kolb, C., et al., Reduction of right ventricular pacing with advanced atrioventricular 473 search hysteresis: results of the PREVENT study. Pacing and Clinical 474 Electrophysiology, 2011. 34(8): p. 975-983.475 22. Sweeney, M., Search AV Extension and Managed Ventricular Pacing for Promoting 476 Atrioventricular Conduction (SAVE PACe) Trial. Minimizing ventricular pacing to 477 reduce atrial fibrillation in sinus-node disease. N Engl J Med, 2007. 357: p. 1000-478 1008.479 23. DAVY, J., et al., Near elimination of ventricular pacing in SafeR mode compared to 480 DDD modes: a randomized study of 422 patients. Pacing and clinical 481 electrophysiology, 2012. 35(4): p. 392-402.482 24. Marinskis, G., et al., Practices of cardiac implantable electronic device follow-up: 483 results of the European Heart Rhythm Association survey. Europace, 2012. 14(3): p. 484 423-425.485 25. Lang, R.M., et al., Recommendations for cardiac chamber quantification by 486 echocardiography in adults: an update from the American Society of 487 Echocardiography and the European Association of Cardiovascular Imaging. Journal 488 of the American Society of Echocardiography, 2015. 28(1): p. 1-39. e14.489 26. Excellence, N.I.f.H.a.C., Dual-chamber pacemakers for symptomatic bradycardia due 490 to sick sinus syndrome without atrioventricular block (TA324). 2014, NICE: London.491 27. NICE, Dual-chamber pacemakers for symptomatic bradycardia due to sick sinus 492 syndrome and/or atrioventricular block. 2017.493 28. Excellence, N.I.f.H.a.C., Chronic heart failure in adults: management. 2010, NICE: 494 London.495 29. Higgins, J.P.T., S. Green, and Cochrane Collaboration., Cochrane handbook for 496 systematic reviews of interventions. 2011, Cochrane Collaboration: [Oxford]. p. 1 497 online resource.498 30. Editors, I.C.o.M.J. Defining the role of authors and contributors. 2018 [cited 2018 499 01/02/2018]; Available from: 500 http://www.icmje.org/recommendations/browse/roles-and-501 responsibilities/defining-the-role-of-authors-and-contributors.html.502

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Figure 1. Right ventricular avoidance algorithm

Consent for assessment (pacemaker interrogation,

echocardiogram, blood tests, quality of life questionnaire)

Identify atrial rhythm


40beats/min, de-activate rate-responsive pacing


40beats/min, de-activate rate-responsive pacing, program right

ventricular pacing avoidance algorithm on or extend atrioventricular delays

Sinus rhythmAtrial Fibrillation

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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description Addressed on page number

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym 1

2a Trial identifier and registry name. If not yet registered, name of intended registry 1Trial registration

2b All items from the World Health Organization Trial Registration Data Set 1,

Protocol version 3 Date and version identifier 8

Funding 4 Sources and types of financial, material, and other support 1, 8, 15

5a Names, affiliations, and roles of protocol contributors 1, 15Roles and responsibilities

5b Name and contact information for the trial sponsor 1

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities

N/A

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee)

11, 15

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Introduction

Background and rationale

6a Description of research question and justification for undertaking the trial, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention

4-8

6b Explanation for choice of comparators 4-7, 10

Objectives 7 Specific objectives or hypotheses 7

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory) 4-9

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained

8,9

Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists)

8,9

11a Interventions for each group with sufficient detail to allow replication, including how and when they will be administered

9, 11

11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease)

8, 9, 11

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests)

11

Interventions

11d Relevant concomitant care and interventions that are permitted or prohibited during the trial NA

Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended

10,11

Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure)

8,9, Figure 2

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Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and statistical assumptions supporting any sample size calculations

11

Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size 11-12

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence generation

16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restricton (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions

8,9

Allocation concealment mechanism

16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned

8,9

Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions

5-8

Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how

9

17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s allocated intervention during the trial

9,13

Methods: Data collection, management, and analysis

Data collection methods

18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol

9

18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols

11

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Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol

8-11

Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol

12

20b Methods for any additional analyses (eg, subgroup and adjusted analyses) 12

20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation) 12

Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed

13

21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial

12

Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct

11

Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor

11

Ethics and dissemination

Research ethics approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval 11, 12

Protocol amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators)

13

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Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and how (see Item 32)

9,11

26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable

N/A

Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial

11

Declaration of interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site 15,16

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that limit such access for investigators

11

Ancillary and post-trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial participation

8

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing arrangements), including any publication restrictions

12,13

31b Authorship eligibility guidelines and any intended use of professional writers 15

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code No plans

Appendices

Informed consent materials

32 Model consent form and other related documentation given to participants and authorised surrogates N/A can be provided on request

Biological specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the current trial and for future use in ancillary studies, if applicable

11,12,13

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items. Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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