Physiological vs Right Ventricular Pacing Outcome Trial Evaluated for bradyCardia Treatment
Phase: NA
Conditions: Bradycardia, Pacing, Right Ventricular Pacing, His Bundle Pacing, Left Bundle Branch Area Pacing
Sponsor: Imperial College London

 
 
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CLINICAL STUDY PROTOCOL 
 
 
STUDY COORDINATION CENTRE: Imperial College London  
 
 
 
 
 
Full Study Title: 
 
 
PROTECT-HF: - Physiological vs Right ventricular pacing 
 
 
 
 
 
Outcome Trial Evaluated for bradyCardia Treatment  
 
Short Study title / Acronym: 
PROTECT-HF 
 
 
Sponsor: 
 
 
 
Imperial College London 
 
 
 
 
 
Version no:                         
9         
 
 
 
 
 
Protocol Date:  
 
 
 16 June 2025 
 
 
 
 
 
Property of Imperial Clinical Trials Unit (ICTU)  
May not be used, divulged or published without the consent of ICTU 
 
This protocol has regard for the HRA guidance 
 
 

 
 
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RESEARCH REFERENCE NUMBERS 
 
 
 
IRAS ID: 
312355 
REC Reference Number: 
23/NE/0012 
ISRCTN Number / Clinical trials.gov 
Number: 
NCT05815745 
Sponsor Protocol Number: 
22HH7931 
Funder reference: 
 
CS/F/21/190036 
 
 
 
Keywords: bradycardia, physiological pacing, right ventricular pacing, randomised 
controlled trial, his bundle pacing, left bundle pacing 
 
 
 
 
 

 
 
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CONTACT LIST 
 
Chief Investigator  
 
Dr Daniel Keene 
Address: South – NHLI Cardiovascular Science, 2nd Floor, Block B Hammersmith Hospital, 
Hammersmith Hospital,160 Du Cane Road Imperial College London, London, W12 0NN   
 
Tel: 
07749576830 
Email: d.keene@imperial.ac.uk & protect-hf@imperial.ac.uk 
 
 
Sponsor 
 
Imperial College London 
Research Governance and Integrity, Room 221, Medical School Building, St Mary’s 
Campus, Norfolk Place, London, W2 1PG 
 
Contact person: 
Mrs Ruth Nicholson 
Tel: +44 (0)207 594 1862 
 
Clinical queries 
 
Clinical queries should be directed to the Chief Investigator or ICTU Study Manager who will 
direct the query to the appropriate person. 
 
Funder 
 
British Heart Foundation 
Greater London House, 5th Floor,  
180 Hamstead Road, London, NW1 7AW 
 
 
ICTU Operations Manager 
 
Dr Ana Boshoff  
 
Address: Imperial Clinical Trials Unit, 1st Floor Stadium House, White City Campus, London, 
W12 7TA 
Email: a.boshoff@imperial.ac.uk  
 
 
 
 
 

 
 
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ICTU Study Monitor  
 
Name: Ms Anurag Pramanik 
Address: Imperial Clinical Trials Unit, 1st Floor Stadium House, White City Campus, 
London, W12 7TA 
 
Tel: 020 7594 1751 
Email: a.pramanik@imperial.ac.uk  
 
Senior Statistician 
 
Ms Emanuela Falaschetti  
Address: Imperial Clinical Trials Unit, 1st Floor Stadium House, White City Campus, 
London, W12 7TA 
 
Tel: 
0207 594 1846 
Email: e.falaschetti@imperial.ac.uk 
 
 
Protocol development group  
 
Dr Zachary Whinnett 
Dr Daniel Keene 
Ms Emanuela Falaschetti  
Dr Ana Boshoff 
Dr Daniel Kramer 
Dr John Cleland 
Professor Darrel Francis 
This protocol describes the PROTECT-HF trial and provides information about procedures 
for enrolling participants to the trial. The protocol should not be used as a guide for the 
treatment of other participants; every care was taken in its drafting, but corrections or 
amendments may be necessary. These will be circulated to investigators in the study, but 
centres enrolling participants for the first time are advised to contact the Trial Coordination 
centre to confirm they have the most recent version. Problems relating to this trial should 
be referred, in the first instance, to the Trial Coordination centre.  
This trial will adhere to the principles outlined in the Medicines for Human Use (Clinical 
Trials) Regulations 2004 (SI 2004/1031), amended regulations (SI 2006/1928) and the 
International Conference on Harmonisation Good Clinical Practice (ICH GCP) guidelines. 
It will be conducted in compliance with the protocol, the Data Protection Act 2018 and 
other regulatory requirements as appropriate.

 
 
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ABBREVIATIONS  
 
AE 
Adverse Event 
BVP 
Biventricular Pacing 
CI 
Chief Investigator 
CRF 
Case Report Form 
DMC 
Data Monitoring Committee 
eCRF 
Electronic Case Report Form 
HBP 
His Bundle Pacing 
HRA 
Health Research Authority 
ICHNT 
Imperial College Healthcare NHS Trust 
ICMJE 
International Committee of Medical Journal Editors 
ICTU 
Imperial Clinical Trials Unit 
ITT 
Intention to Treat 
LBBP 
Left Bundle Branch Pacing 
LV 
Left ventricular 
PICM 
Pacing Induced Cardiomyopathy  
QA 
Quality Assurance 
REC 
Research Ethics Committee 
RSI 
Reference Safety Information 
RV 
Right ventricular 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
Standard of Care 
SOP 
Standard Operating Procedure 
TMG 
Trial Management Group  
TSC 
Trial Steering Committee 
 
 
 
 
 
 
 
 

 
 
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Table of Contents 
RESEARCH REFERENCE NUMBERS 
2 
CONTACT LIST 
3 
TRIAL SUMMARY 
8 
BACKGROUND 
10 
1.1 Existing Research and rationale for the study ................................................................ 10 
1.2 Need for RCT ................................................................................................................. 12 
2. 
OBJECTIVES AND ENDPOINTS 
12 
2.1 Primary Objective ........................................................................................................... 12 
2.2 Secondary Objectives .................................................................................................... 12 
2.3 Primary Endpoint ........................................................................................................... 12 
2.4 Secondary Endpoints (all adjudicated by blinded endpoint committee) .......................... 12 
3. 
STUDY DESIGN 
13 
3.1 Study setting and population .......................................................................................... 17 
4. 
PROCEDURES AND MEASUREMENTS 
17 
4.1 Identification and recruitment of participants .................................................................. 17 
4.2 Screening and pre-randomisation evaluations ............................................................... 17 
4.3 Randomisation and Blinding........................................................................................... 18 
4.4 Visit Schedule ................................................................................................................ 18 
4.5 Interventions .................................................................................................................. 19 
4.6 Assessments ................................................................................................................. 19 
4.7 Follow Up ....................................................................................................................... 20 
4.8 Follow Up: In Person Pacing Checks ............................................................................. 21 
4.9 Follow Up Period ............................................................................................................ 21 
4.10 Endpoints ....................................................................................................................... 21 
5. 
EARLY DISCONTINUATION OF PARTICIPANTS 
23 
5.1 Withdrawal from study.................................................................................................... 23 
5.2 Permanent discontinuation of trial intervention ............................................................... 23 
5.3 Procedures for permanent discontinuation or withdrawal from the trial ........................... 23 
6. 
SAFETY REPORTING 
23 
6.1 Adverse Event (AE) ....................................................................................................... 23 
6.2 Causality ........................................................................................................................ 23 
6.3 Severity of Adverse Events ............................................................................................ 24 
6.4 Adverse Event recording ................................................................................................ 24 
6.5 Serious Adverse Events (SAE) ...................................................................................... 25 
6.6 Reporting urgent safety measures ................................................................................. 27 
7. 
STATISTICAL ANALYSES 
27 
7.1 Sample Size and power considerations ......................................................................... 27 
7.2 Planned recruitment rate ................................................................................................ 28 
7.3 Statistical analysis .......................................................................................................... 28 
8. 
REGULATORY, ETHICAL AND LEGAL ISSUES 
30 
8.1 Declaration of Helsinki ................................................................................................... 30 
8.2 Good Clinical Practice .................................................................................................... 30 
8.3 Research Ethics Committee (REC) Approval ................................................................. 30 
8.4 HRA approval ................................................................................................................ 31 
8.5 Non-Compliance and Serious Breaches ........................................................................ 31 
8.6 Insurance and Indemnity and Sponsor ........................................................................... 32 
8.7 Trial Registration ............................................................................................................ 32 
8.8 Informed Consent .......................................................................................................... 32 
8.9 Contact with General Practitioner ................................................................................... 33 
8.10 Participant Confidentiality ............................................................................................... 33 

 
 
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8.11 Data Protection and Participant Confidentiality .............................................................. 33 
8.12 End of Trial .................................................................................................................... 33 
8.13 Study Documentation and Data Storage ........................................................................ 34 
9. 
DATA MANAGEMENT 
34 
9.1 Source Data ................................................................................................................... 34 
9.2 Database ....................................................................................................................... 34 
9.3 Data Collection .............................................................................................................. 34 
9.4 Archiving ........................................................................................................................ 34 
10. 
STUDY MANAGEMENT STRUCTURE 
35 
10.1 Trial Steering Committee ............................................................................................... 35 
10.2 Trial Management Group ............................................................................................... 35 
10.3 Adjudication Committees ............................................................................................... 35 
10.4 Data Monitoring Committee ........................................................................................... 35 
10.5 Early Discontinuation of the Study ................................................................................. 36 
10.6 Risk Assessment ........................................................................................................... 36 
10.7 Monitoring ...................................................................................................................... 36 
10.8 Quality Control and Quality Assurance ........................................................................... 36 
10.9 Peer review .................................................................................................................... 36 
10.10 Patient and Public Involvement ..................................................................................... 36 
10.11 Publication and Dissemination policy ............................................................................. 37 
11. 
APPENDIX 
37 
11.1 International Sites .......................................................................................................... 37 
12. 
REVISION HISTORY 
39 
13. 
REFERENCES 
42 
14. 
SIGNATURE PAGE 1 (CHIEF INVESTIGATOR) 
46 
SIGNATURE PAGE 2 (SPONSOR) 
47 
SIGNATURE PAGE 3 (STATISTICIAN) 
48 
SIGNATURE PAGE 4 (PRINCIPAL INVESTIGATOR) 
49 
 
 
 
 
 

 
 
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TRIAL SUMMARY 
 
TITLE: PROTECT-HF: - Physiological vs Right ventricular pacing Outcome Trial 
Evaluated for bradyCardia Treatment 
 
OBJECTIVES:  
• Does physiological pacing reduce mortality and unplanned heart failure acute care 
(hospital admissions or ambulatory diuretic therapy)? 
• Does physiological pacing improve daily patient activity and patient reported quality 
of life? 
• Does physiological pacing reduce the need for later upgrade to biventricular 
pacemaker? 
• Does physiological pacing better maintain cardiac function (Left Ventricular Volumes 
and Ejection Fraction)?  
 
DESIGN: This is a multi-centre, patient blinded, randomised controlled (Physiological pacing 
vs Right Ventricular pacing) trial including approximately 40 hospital sites in England, Wales 
and Scotland together with approximately 6 international sites. Recruitment and pacemaker 
implantation will be carried out at each participating centre. The trial will include an initial 
Vanguard Phase to demonstrate safety and feasibility. The primary analysis will be intention 
to treat. We will also perform an on-treatment analysis. 
 
SAMPLE SIZE: 2600 
 
INCLUSION CRITERIA: 
• Adults aged 18 or above with  
• Left ventricular ejection fraction >35% from any clinical echocardiogram (including V 
scan and MRI if ECHO cannot be done) performed any time in the 12 months prior 
to study enrolment.  
• And one or more of the following guideline based ventricular pacing indications: 
a) Permanent or intermittent 3rd degree AV block 
b) Permanent or intermittent Mobitz type II AV block 
c) First Degree AV block with a pacing indication 
d) Slow chronic Atrial Fibrillation or Proposed AV node ablation 
e) Bifasicular block with a pacing indication 
f) Trifasicular block with a pacing indication 
g) Wenckebach with a pacing indication  
 
 
EXCLUSION CRITERIA: 
• Patients who are likely to only need occasional ventricular pacing, i.e. those with 
isolated sick sinus syndrome 
• Pregnant women 
• Unable to provide informed consent  
• Those with comorbidity leading to a life expectancy <1year 
 
INTERVENTION: 

 
 
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A physiological pacing strategy will be compared with right ventricular pacing (apical or 
septal lead locations as per the implanting physicians’ normal practice). 
 
MAIN STUDY PROCEDURES  
 
• Planned intervention: 
 
Physiological pacing will be compared with right ventricular pacing. The approach for 
physiological pacing will be either His bundle pacing or left bundle pacing at the 
operator’s discretion, (biventricular pacing will be offered should both of these 
attempts fail).  
 
Following the implant, patients (or their nominated representative) will be contacted 
at 6 monthly intervals, for a median duration of 4 years (max 6.5 years, min 3 years). 
During each encounter, mortality and heart failure events will be collated together 
with data on participant’s quality of life and general health.  
 
Information will also be collected remotely from the pacemaker relating to daily patient 
activity and arrhythmia.  
 
A 500-patient sub-study will assess within patient, and between groups, 
echocardiographic changes over a 24-month period to try and improve mechanistic 
understanding of PICM. 
 
PRIMARY ENDPOINT: 
• Death and unplanned heart failure acute care 
SECONDARY ENDPOINTS 
 
• Via the pacemaker and adjudicated by blinded endpoint committee: 
o Atrial fibrillation (duration >6minutes) 
o Ventricular arrhythmia incidence 
o Daily patient activity (hours stratified by device vendor) 
• Patient quality of life assessed via questionnaires (EQ5D and SF-36) 
• Monthly Symptom assessment 
• Incidence of upgrade of pacing device 
• Safety Endpoints 
 
Sub-study Endpoint:  
• 
Within group differences of Left Ventricular End Systolic Volume (>10mls) 
 
 

 
 
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BACKGROUND 
 
1.1 
Existing Research and rationale for the study 
 
~40,000 people a year in the UK and ~1,000,000 worldwide, develop cardiac conduction 
system disease and require pacing therapy to prevent potentially life-threatening 
bradycardia.  
 
For the past 60 years, ventricular pacing using a right ventricular (RV) lead has been routine 
practice. However, chronic right ventricular pacing can be harmful, leading to impaired 
ventricular function (Pacing Induced Cardiomyopathy, PICM). PICM develops in 12 - 37% 
of patients, as reported in RCTs over a mean follow up of 4 years. PICM is believed to result 
from the non-physiological sequence of activation of ventricular myocytes. The activation 
wave-front begins near the lead tip and spreads slowly from the RV to the left ventricle via 
cell-to-cell conduction, producing uncoordinated and inefficient ventricular contraction.  
 
Physiological forms of pacing, which maximally utilise the heart’s own natural high-speed 
conduction system, have been developed with the aim of reducing the abnormality of the 
activation wavefront and thereby preventing right ventricular pacing cardiomyopathy.  
In this study we will assess whether physiological pacing reduces mortality and heart failure 
morbidity compared with RV pacing, in patients without severely impaired ventricular 
function (EF>35%) and conduction system disease requiring ventricular pacing.  
 
The clinical impact of the health problem  
 
Heart failure is a major clinical problem, causing a high symptom burden and high mortality. 
In the UK, heart failure accounts for 1 million days of inpatient stay per year, which is ~2% 
of all NHS hospital inpatient days and 5% of emergency admissions. Heart failure causes 
significant mortality (35% mortality in the first year after diagnosis and 10% thereafter). 
There are currently ~900000 patients in the UK with heart failure. This study will establish 
whether we can reduce the incidence of heart failure by preventing pacing-induced heart 
failure.  
 
What is already known about the topic  
 
Harm from standard pacing  
 
Right ventricular pacing saves lives in the short term by preventing bradycardia, but can lead 
to left ventricular impairment in the longer term, increasing the rate of heart failure and death.  
 
The MOST trial randomised 2010 patients with normal ventricular function and a bradycardia 
indication for pacing, between dual chamber pacing and VVI pacing. Both arms had the 
same programmed lower rate intervals and therefore the same amount of pacing, but the 
dual chamber group had the benefit of native conduction for times when atrial pacing was 
sufficient (i.e. sinus bradycardia). This difference was important enough that the VVI group, 
whose pacing was always RV, had substantially increased heart failure hospitalisations (HR 
1.37; 95% CI 1.05– 1.79; P=0.02). Most startling was the observation that every 10% 

 
 
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increase in time spent receiving RV pacing, was associated with a 20% increase in heart 
failure hospitalisations.  
 
Even more dramatic was the DAVID trial, where RV pacing in patients with left ventricular 
impairment markedly increased heart failure and death from 16.1% to 26.7% (HR 1.61; 95% 
CI 1.06-2.44).  
 
Physiological pacing utilises the heart’s natural conduction system to provide ventricular 
activation, using a pacing lead at either the His or left bundle. Biventricular pacing may also 
provide a method to deliver a more physiological pacing strategy than standard RV pacing. 
 
1) His bundle pacing:  
The pacing stimulus captures the specialised His-Purkinje conduction system, producing 
normal, rapid and coordinated biventricular activation and contraction. Many centres have 
avidly taken up conduction system pacing, producing an increasing body of observational 
data, which now has systematic reviews and meta-analyses. These data show that His 
bundle pacing can be safely delivered and will chronically in the main remain stable. Pacing 
thresholds are typically slightly higher than RV pacing (mean 1.3V versus 0.59V) and 
procedural times slightly longer (70 minutes versus 55 minutes), as seen in a recent 765-
patient observational study. There is a ~7% lead reintervention rate which is similar to that 
reported for LV leads. However, these potential disadvantages appear to be offset by more 
physiological ventricular activation as evidenced by narrower paced QRS complexes 
(128ms versus 166ms with RV pacing) and subsequent improved cardiac function. In the 
mentioned observational study these physiological improvements, in patients who required 
more than 20% ventricular pacing, were associated with a lower rate of death and heart 
failure hospitalisations when compared with RV pacing (25.3% vs 35.6%, p = 0.02). Although 
promising, these findings need to be tested in an adequately powered randomised control 
trial.  
 
2) Left bundle pacing:  
The pacing lead is positioned on or near to the left bundle (i.e. slightly more distal than the 
His bundle site). This provides the advantage of coordinated left bundle activation even 
when His pacing is impractical due to high thresholds or a non-treatable infra-Hisian block, 
at the cost of slower right ventricular activation. Happily, experiments show that pacing the 
left bundle rather than the His bundle does not seem to impair left ventricular synchrony, 
even in patients with narrow intrinsic QRS). Implant success rates are high (>94%), pacing 
thresholds low (0.6V@0.5ms) and R wave amplitude large.  Safety across 12 observational 
studies totalling 1162 patients has been demonstrated with a lead complication rate of only 
2.8%, similar to the 2.6% of RV pacing.   
 
3) Biventricular pacing:  
BVP pacing delivers more physiological pacing compared to RV pacing, with more rapid 
ventricular activation time. However, activation still relies on slow cell to cell activation rather 
than physiological activation via the conduction system, as a result left ventricular activation 
time is prolonged compared to normal intrinsic activation. In the BLOCK-HF trial BVP was 
compared with RV pacing in patients with a bradycardia indication for pacing and an EF40% 
as an alternative to RV pacing. Finally, the ACC/AHA give 2a to denovo CRT or 
Physiological Pacing (despite no RCTs) for those with EF 35- 50% and ESC pacing 
guidelines advocate that His pacing is reasonable for those patients with an EF >40%. Our 

 
 
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proposed PIs agree there is clinical equipoise in this group of patients. Therefore, we are 
proposing including all patients with an EF greater than 35% in the PROTECT-HF trial which 
will provide the needed RCT evidence for future guidelines. 
 
1.2 
Need for RCT 
 
Physiological pacing strategies may be associated with slightly longer procedural time, 
higher thresholds and slightly higher lead related complications than RV pacing which has 
been the standard of care of >60 years. However, whether these potential issues are offset 
by the potential benefit of improved cardiac activation and therefore function needs to be 
determined in an adequately powered RCT. This is what PROTECT-HF aims to do. 
 
2. OBJECTIVES AND ENDPOINTS 
 
2.1 
Primary Objective 
• 
Does physiological pacing reduce mortality and unplanned heart failure acute care 
(hospital admissions or ambulatory diuretic therapy)? 
 
2.2 
Secondary Objectives 
• Does physiological pacing improve objectively measured patient activity and quality 
of life? 
• Does physiological pacing reduce the need for later upgrade to biventricular 
pacemaker? 
• Does physiological pacing better maintain cardiac function (Left Ventricular 
Volumes and Ejection Fraction)? 
 
2.3 
Tertiary Objectives 
 
• Determine whether endpoint data collection utilising wholly digital means (NHS 
digital data for patients residing in England) matches endpoint data collection 
utilising traditional methods, i.e. direct participant contact. 
• Determine whether there are genetic variations which may accurately detect which 
patients are at highest risk of pacing-induced cardiomyopathy and whether the 
detrimental effect of a genetic variation can be offset with the improved cardiac 
activation patterns provided by a physiological pacing approach.  
 
 
2.4 
Primary Endpoint 
• Death and adjudicated unplanned heart failure acute care (hospital admissions or 
ambulatory diuretic therapy i.e. diuretic lounge visit). 
 
2.5 
Secondary Endpoints (all adjudicated by blinded endpoint committee) 
• Via the pacemaker:  
a) Atrial fibrillation (duration >6minutes) 
b) Ventricular arrhythmia incidence 
c) Daily patient activity (hours stratified by device vendor) 

 
 
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• Incidence of clinically indicated upgrade to conventional biventricular pacing (CRT 
device)  
• Patient quality of life assessed via questionnaires (EQ5D, SF-36 and health 
resource every 6-months) 
• Safety endpoints: Device infections (requiring device extraction), pacing thresholds, 
need for lead revision or reimplantation, generator change, haematoma and 
pneumothorax.  
 
Echo Sub-study (optional) 
• Within patient changes and between group differences in LV volumes and EF will 
be assessed for differences according to treatment allocation. 
 
Genetics Sub-Study (optional) 
Available only at certain sites depending on the availability of appropriate equipment/personnel. 
Please ask your local study team if this is sub-study is available at your participating hospital. 
 
• Genetic variations which may accurately detect which patients are at highest risk of 
pacing-induced cardiomyopathy and whether the detrimental effect of a genetic 
variation can be offset with the improved cardiac activation patterns provided by a 
physiological pacing approach. 
 
3. STUDY DESIGN   
 
The PROTECT-HF study will be performed at approximately 40 investigational sites in 
England, Wales, Scotland, and Northern Ireland, together with approximately 6 international 
investigational sites. The study will be a multi-centre, prospective, 1:1 randomised, patient-
blinded trial with an initial Vanguard Phase to demonstrate safety and feasibility. The primary 
analysis will be intention to treat. We will also perform an on-treatment analysis.  
 
The trial will include an initial Vanguard Phase to demonstrate safety and feasibility in 
recruitment. This phase will last 24 months and will aim to meet pre-specified recruitment 
targets (>80%) with cross-over rate of less than 30% This will be reviewed within the trial 
steering committee and a decision taken at the time regarding continuation of the trial as is, 
activation of additional sites or consideration of early termination. 
 
Patients will be identified from clinical services as those requiring cardiac pacing and then 
invited to participate. 
 
If eligible, informed consent will be obtained. If patient is unable to sign the informed consent 
form themselves due to blindness or other disability which doesn't affect their understanding 
of the study/capacity, a witness can sign on behalf of the patient.  Where verbal consent is 
used to consent patient to the trial, randomisation cannot occur until the patient or witness 
physically signs the informed consent form.  Demographic data and medical history 
information will be collected at screening. Patients will then be randomised following written 
consent to either standard of care RV pacing - this pacing lead can be placed either apically 
or septally at the operator’s discretion, or to a physiological pacing strategy. Patients will be 
blinded to the strategy they are allocated. If allocated to a physiological strategy – this can 
be either His or Left Bundle pacing at the operator’s discretion. If physiological pacing cannot 
be appropriately delivered utilising the initial choice, approach operators must transition to 

 
 
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try the alternative conduction system pacing method i.e. if fail His pacing move to Left bundle 
pacing if they are trained in the alternate method as well. If neither are successful operators 
should implant an LV lead to deliver biventricular pacing as this delivers a more physiological 
approach than standard RV pacing. Crossover to the RV arm would occur if available 
physiological approaches were attempted and unsuccessful. 
 
A CSP Capture adjudication committee will review all implant data at 6 monthly intervals to 
provide an assessment of whether CSP was achieved. If operators have high cross over 
rates or failure rates to deliver CSP they will be asked to undertake further training. 
 
Device Programming: Programming is at the discretion of the clinical team. Pacing 
avoidance modes are advised, as per guidelines, with one modification. Unlike RV pacing, 
physiological pacing need not be avoided in patients with very long AV delays, (physiological 
pacing does not induce dramatic mechanical dyssynchrony which would otherwise be 
present with obligatory dual-chamber RV pacing58) therefore DDD modes with shorter AV 
delays are acceptable or utilising programming options that mode switch with prolonged AV 
intervals. Ultimately programming decisions are at the discretion of the implanting physician 
as the trial aims to test the implantation strategy. 
 
Initial data will be collected on patients pacing indication, comorbidity and medication. 
Pacing data will be collected from implant including paced ECG and threshold data to 
demonstrate the type of capture delivered. This will be adjudicated by a core lab based at 
Imperial College London to confirm capture type for subsequent analysis by pacing type.  
 
His Capture 
 
1) One of:  
 
(A) Selective Capture 
• Isoelectric line on ECG in all leads 
• Stim to onset of QRS >30ms  
• Local ventricular distinct from pacing stimulus on EGM 
 
(B) Change in paced QRS morphology with change in pacing output or programmed 
stimulation 
• Non-selective to selective capture (loss of delta wave, step out of local ventricular 
electrogram) 
• Non-selective to myocardial capture (increase in QRS duration and change in QRS 
morphology)  
 
(C) If neither of above:  
• His to end of intrinsic QRS = Stim to end of QRS (within 10ms) if narrow QRS 
• Mid to end QRS: paced QRS = intrinsic Morphology (pattern matching) 
 
 
 

 
 
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Left Bundle Capture: 
 
 
Patients or a nominated representative will then be contacted every 6 months to ascertain 
end point data – this will be remotely from the central trial hub at Imperial for mortality, heart 
failure events, and QOL. If events have occurred source data will be obtained for 
adjudication as to cause of events.  
 
In some international centres, patients will be contacted by their local site teams instead of 
the central trial hub. Some international centres may conduct streamlined follow-up, 
collecting data on HFH and mortality only. Some international centres may also conduct 1-
yearly follow-up instead of 6-monthly follow-up and this may be based on data from a 
national registry instead of via telephone calls to participants directly.  
 
Furthermore, for patients living in England, NHS digital data downloads will be collected at 
two year intervals for data on mortality and hospital acute care. We will compare the 
reporting of events between the standard approach and via the NHS digital route thus 
allowing us to gain insight into future trial design. 
 

 
 
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For patients recruited to the echo sub study (optional) an echocardiogram will be performed 
at the local centre within 6 weeks of initial pacemaker implantation and then after 24 months. 
All echocardiograms will be analysed by a core lab based at Imperial College London. 
 
For patients recruited to the genetics sub-study (optional), a blood sample of 3mls (in a 
EDTA tube) will be taken for gene sequencing and analysis by a laboratory based at Imperial 
College London Pseudonymised samples will additionally be sent to an external lab for 
specific analyses. 
 
 
 
 
 
 

 
 
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PARTICIPANT ENTRY 
 
3.1 
Study setting and population 
We will recruit patients who are referred for clinically indicated pacemaker 
implantation 
 
(i) Inclusion criteria 
• Adults aged 18 or above with  
• Left ventricular ejection fraction >35% from any clinical echocardiogram (including 
MRI and V scan if ECHO cannot be done)performed any time in the 12 months prior 
to study enrolment.  
• And one or more of the following guideline based ventricular pacing indications: 
a) Permanent or intermittent 3rd degree AV block 
b) Permanent or intermittent Mobitz type II AV block 
c) First Degree AV block with a pacing indication 
d) Slow chronic Atrial Fibrillation or Proposed AV node ablation 
e) Bifasicular block with a pacing indication 
f) Trifasicular block with a pacing indication 
g) Wenckebach with a pacing indication  
 
(ii) Exclusion criteria  
• Patients who are likely to only need occasional ventricular pacing, i.e. those with 
isolated sick sinus syndrome.  
• Pregnant women.  
• Unable to provide informed consent.  
• Those with comorbidity leading to a life expectancy <1year.  
 
4. PROCEDURES AND MEASUREMENTS  
 
4.1 
Identification and recruitment of participants  
 
We will recruit patients who are referred for clinically indicated cardiac pacemaker 
procedures. Patients who potentially fulfil the study inclusion criteria and none of the 
exclusion criteria will be identified and approached by members of their direct healthcare 
team to discuss study participation. Many patients will be identified by clinical teams during 
acute admissions to hospital with bradycardia. Clinical teams will alert the study teams within 
the hospital to facilitate trial enrolment.  
 
4.2 
Screening and pre-randomisation evaluations 
 
Written informed consent will be obtained before the participant undergoes any screening 
procedures. If patient is unable to sign the informed consent form themselves due to 
blindness or other disability which doesn't affect their understanding of the study/capacity, a 
witness can sign on behalf of the patient.  Where verbal consent is used to consent patient 
to the trial, randomisation cannot occur until the patient physically signs the informed 

 
 
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consent form. All subjects will be assigned a study-specific subject number at the screening 
visit and the following tests/assessments will be performed: 
 
• Medical History 
• Review of clinical echocardiographic data 
• Review of clinical ECG and pacing indication 
• Concomitant medication 
• Pregnancy test (where required) as per standard of care  
 
4.3 
Randomisation and Blinding  
 
Randomisation will take place using a fully validated, high quality, real-time electronic data 
capture system (OpenClinica database). Randomisation will be 1:1 between receiving 
ventricular myocardial pacing from a lead in the Right Ventricle versus a Physiological 
Pacing approach. Randomisation will occur once a patient has signed the informed consent 
form. The randomisation list will be programmed by the statistician using variable block 
length and stratified by site. Patients will be blinded to treatment allocation in a single blinded 
fashion. All endpoints will be adjudicated by blinded committee of clinicians with expertise 
in heart failure. 
 
4.4 
Visit Schedule  
 

 
 
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4.5 
Interventions 
 
Participants will attend the catheter laboratory for their clinically indicated procedure. 
 
Intervention and comparator: Physiological pacing will be compared with right ventricular 
pacing (apical or septal lead locations as per the implanting physicians’ normal practice).  
The approach for physiological pacing will be either His bundle pacing or left bundle pacing 
at the operator’s discretion.  
 
His bundle pacing: Conduction system capture will be confirmed using previously defined 
criteria (see above). If there is evidence of infra-Hisian block during the resting state or whilst 
pacing at higher heart rates (up to 130 bpm) then either a more distal His pacing position 
will be attempted or left bundle pacing will be performed.  
 
Left bundle pacing using the technique described by Huang previously defined criteria will 
be used to confirm left conduction system capture (see above).  
 
An acute pacing threshold of >1.5V @1ms, or unsatisfactory R wave sensing (less than 1.5 
mV) will not be accepted and the lead will be repositioned or an alternative approach for 
conduction system pacing will be attempted.  
 
In patients in whom conduction system pacing is not possible or pacing parameters are not 
acceptable a lead should be placed in the coronary sinus to reduce cross-over rates to RV 
pacing.  
 
Evidence of the achieved physiological pacing response must be submitted for adjudication 
as to the type of capture achieved. The minimum required data set will include upload of the 
paced QRS with the pacing output shown, the lead EGM at the final position and evidence 
of a manoeuvre that demonstrates a transition in capture morphology demonstrating 
conduction system capture. 
 
All patients will undergo a post-procedure chest radiograph to confirm lead position and rule 
out a pneumothorax if this is standard of care at the site. An AP image of this will need to be 
uploaded to the trial hub. 
 
4.6 
Assessments 
 
Implant Visit 
At the implant visit, after randomisation the following procedures will take place: - 
• ECG 
• Concomitant medication collection 

 
 
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• Device Implantation 
• Post implant chest radiograph (if this is standard of care at the site)  
• Pacing Check 
• Vital signs 
 
 ECHO Sub study 
 
For patients recruited to the echo sub study echocardiography will be performed at the local 
site within 6 weeks of the initial implant. Multiple recordings of apical 4 chamber and 2 
chamber windows will be obtained for determination of blinded assessment of chamber 
dimensions, volumes and function. Atrial size and valvular function will be reported too. 
 
ECHOs should be submitted via your site specific OneDrive link. All ECHOs should be 
identified by patient ID and timepoint.los 
 
Genetic Sub-study  
For patients recruited to the genetics sub-study (optional), a blood sample of 3mls (in a 
EDTA tube) will be taken for gene sequencing and analysis by a laboratory based at 
Imperial College London.  
 
The samples will be stored and transported to the central trial hub for analysis. They will 
be stored in -80 freezers at Imperial College and tracked on the appropriate tracking 
software (LabVantage or equivalent) according to local governance. Sample tubes will be 
barcode-labelled with the StudyID and aliquot number. Imperial College Laboratory space 
is only accessible by security access.  
 
For those participants in the optional genetic sub-study, 3mls of blood will be drawn at 
either the screening or implant visit. If not taken at this stage, they will be drawn at any 
other point in the trial.  
 
 
 
4.7 
Follow Up 
 
Follow up at all UK centres will be conducted by a central trial hub utilising:  
1. Online questionnaires and/or telephone contact with the participant or their 
nominated representative completing questions onto the OpenClinica ePRO 
database. This will occur every 6 months starting from device implantation.  
2. Remote follow-up from a participant’s pacemaker where available, downloads will 
be scheduled every 6 months. Where possible data will be transferred from device 
companies to the trial team either directly or via the implanting/recruiting centre.  
3. For participants residing in England – mortality and hospital statistics will be 
obtained by data draws every 24 months from nationally held records. 
 

 
 
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Additionally, the central staff will contact participants if made aware by local study team or 
by the participant of an adverse events and will follow this up accordingly.  
 
Incidental findings identified as part of the research protocol will be reviewed and reported 
by the clinical members of the research team.  Any incidental findings identified will be 
communicated to the patient’s clinical team as well as their GP as per standard protocol. 
 
In some international centres, patients will be contacted by their local site teams instead of 
the central trial hub. Some international centres may conduct streamlined follow-up, 
collecting data on HFH and mortality only. Some international centres may also conduct 1-
yearly follow-up instead of 6-monthly follow-up and this may be based on data from a 
national registry instead of via telephone calls to participants directly.  
 
Participants can withdraw from questionnaire and where this is noted, the applicable 
participants will be followed up on their medical records only, if participants consents to this. 
A protocol deviation should be raised where participants want to withdraw from 
questionnaires. 
 
4.8 
Follow Up: In Person Pacing Checks 
 
While in most centres, virtually all follow-up will be coordinated by the central trial hub, we 
would like to capture the in-house pacing check data. In-house pacing checks are to be 
performed as per routine standard of care. Frequency of the pacing checks to be done as 
per local site standard of care (do not have to coincide with 6 monthly follow-up visits). 
Information from these pacing checks should be collected and entered onto the OpenClinica 
database as they occur. If this is not possible, ventricular paced ECG and/ or in-house 
pacing check report, is to be sent to the central trial hub via NHS email or SharePoint. 
 
4.9 
Follow Up Period 
 
The trial has a planned 3.5 year recruitment window followed by a 3 year follow up period. 
This means the first recruited participant will have 6.5 years of follow up and the last patient 
3 years with estimated median follow up of 4 years for the trial.  
 
For participants residing in England, NHS digital data draws will occur every two years in 
October. This will continue until the formal end of the trial.  
 
4.10 Endpoints 
 
Mortality Status and HF morbidity 
 
This will be determined by direct contact with patient or their nominated representative at 6 
monthly intervals. Additional notification may come from reporting of adverse events by the 
participant or the local study teams. Furthermore, for patients residing in England, mortality 
and hospital events will also be assessed and confirmed using NHS digital records.  
 

 
 
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Local study teams may be contacted to request further information from participant medical 
records, regarding adverse events, reported to the central team.  
 
 
Questionnaires 
 
Quality of Life and healthcare utilisation assessments will be performed by 
telephone/online/post questionnaires. The EQ5D, SF36 and a health resource use 
questionnaire will be completed at baseline and then every 6 months. The custom health 
resource utilisation form will enquire about change in employment status due to ill health as 
well as collate number and type of hospital visits. 
 
 
Device Upgrade 
 
Incidence of clinically indicated upgrade to conventional biventricular pacing will be obtained 
either from direct contact with the participant or their nominated representative at the 6 
monthly contact or if reported by local study teams. Clinical adjudication of appropriateness 
will be considered by a blinded committee, they will meet every 12 months. The committee 
will review and agree these criteria but will include EF drop to ≤35% or a ≥10% drop from 
baseline, a raised BNP or a Hospitilisation for Heart Failure. 
 
Pacemaker Reported Endpoints 
 
Pacemaker parameters, Pacemaker-derived (remotely transmitted) objective metrics 
including atrial fibrillation (duration >6minutes) and ventricular arrhythmia incidence and 
daily patient activity (hours/day stratified by device vendor) will be collected as will 
percentage pacing. For those participants without remote monitoring a percentage pacing 
as a minimum will be obtained at least annually from clinical in-office reviews.  
 
For patients with remote monitoring enabled devices we will aim to establish a “trial patient 
clinic” for read-only access of their data. Alternatively, the device manufacturers including 
Medtronic, Boston Scientific, Biotronik and Abbott will supply periodic spreadsheets of data 
for trial patients to the local PIs to be passed to the trial team. A trial patient clinic is a virtual 
read-only space within each manufacturers’ clinical device platform (CareLink for Medtronic, 
Merlin for Abbott, Latitude for Boston Scientific and Biotronik Home Monitoring for Biotronik) 
used as standard of care for remote monitoring of devices. The pacemaker parameters 
which are transmitted to the device manufacturers’ platforms as part of standard of care will 
be viewable within a dedicated virtual space on the platform to the research team. Clinical 
teams will access this information as per routine standard of care and there will be no change 
to this process. Where this workflow is not enabled, we will rely on the local PIs to pass 
information on where collected.  
 
Medication Information 
 
Medication information will also be collected at each contact with study participants so that 
changes in medication can be tracked.  
 
Safety Endpoints  

 
 
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Device infections (requiring device extraction), pacing thresholds, need for lead revision or 
reimplantation, generator change, haematoma and pneumothorax. These events will be 
regularly reviewed by the trial Data Safety Monitoring Board. 
 
5. EARLY DISCONTINUATION OF PARTICIPANTS 
 
5.1 
Withdrawal from study 
 
Withdrawal from the study, which is different to withdrawal from QOL, qolrefers to 
discontinuation of study follow-up and can occur for the following reasons: 
• Participant decision 
• Loss to follow-up – where patient has been contacted multiple times during the follow-
up over a period of time and unable to get in touch with them and/or hasn’t been 
attending any appointments 
 
5.2 
Permanent discontinuation of trial intervention 
 
Participants may discontinue trial intervention for the following reasons: 
• At the request of the participant 
• Due to an Adverse Event / Serious Adverse Event 
• If the investigator considers that a participant's health will be compromised due to 
adverse events or concomitant illness that develop after entering the trial. 
 
5.3 
Procedures for permanent discontinuation or withdrawal from the trial 
 
• If a participant permanently discontinues the trial intervention, they will be invited to 
continue to attend trial visits if possible to allow for collection of key outcome and 
safety data. 
• If the participant withdraws consent to further be contacted at all for the study 
purposes, this will be documented on the electronic case report form (eCRF) and in 
the medical notes. No attempts of further contact will be made. 
• Participants who have discontinued the trial intervention and/or have withdrawn from 
the trial will not be replaced. 
 
6. SAFETY REPORTING 
 
6.1 
Adverse Event (AE) 
 
An AE is any untoward medical occurrence in a patient or clinical trial subject. An AE can 
therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding), symptom, whether or not considered related to the trial protocol.  
 
6.2 
Causality  
 
Definitions for assessment of causality: 
 

 
 
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Unrelated: 
No evidence of any causal relationship 
Unlikely: 
There is little evidence to suggest there is a causal relationship (e.g. the 
event did not occur within a reasonable time after device implantation. There 
is another reasonable explanation for the event (e.g. the patient’s clinical 
condition, other concomitant treatment). 
Possible: 
There is some evidence to suggest a causal relationship. However, the 
influence of other factors may have contributed to the event (e.g. the patient’s 
clinical condition, other concomitant treatments). 
Probable: 
There is evidence to suggest a causal relationship and the influence of other 
factors is unlikely. 
Definite: 
There is clear evidence to suggest a causal relationship and other possible 
 
 
contributing factors can be ruled out. 
 
6.3 
Severity of Adverse Events 
 
Definitions for assessment of severity: 
 
Mild:  
Awareness of event but easily tolerated 
Moderate: 
Discomfort enough to cause some interference with usual activity 
Severe: 
Inability to carry out usual activity  
 
6.4 
Adverse Event recording 
 
For the purposes of this trial, only adverse events related to the study, defined medically 
important events and cardiac events and conditions after consent has been obtained will be 
recorded and reported on the database. Please see the complete list below of adverse 
events that must be reported. All related and unexpected serious adverse events must be 
reported as stipulated in the Safety Reporting instructions, regardless of whether they are in 
the list of defined reportable adverse events. Expected AEs in this population of patients 
with Heart Failure will include hospitalisations related to arrhythmia, worsening shortness of 
breath and chest pain. Other expected events include those that are related to known 
complications of pacemaker insertion. This includes, but is not limited to, lead displacement 
+/- revision, wound or device infection, pneumothorax, haematoma and deep vein 
thrombosis. For the purposes of this trial, AEs, both serious and non-serious, as described 
above, will be followed up according to local practice until the event has stabilised or 
resolved, or the Follow-up Visit, whichever is the sooner. This may require the central team 
to contact local teams, to provide further information from the participant medical records, 
regarding an adverse event.  
 
 
All other adverse events, both serious and non-serious will not be reported and recorded on 
the study database; however, they must still be documented in the medical notes and 
followed up as per local practice by clinical teams. They will not be monitored for the purpose 
of this study.  
 
 
 

 
 
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Adverse Events that must be reported are: 
 
• Heart Failure Hospitalisation (HFH) 
• Ambulatory Heart Failure events (e.g., Ambulatory diuretic therapy) 
• Suspected Heart Failure Hospitalisation (HFH) 
• Device issues: 
o Device infection (requiring device extraction) 
o Device infection (requiring antibiotics, with or without device extraction) 
o Significant rise in pacing thresholds 
o Lead displacement or perforation  
o Lead revision or reimplantation 
o Generator change 
o Haematoma 
o Pneumothorax 
o  Inappropriate pacing function 
• Device upgrade 
• Major bleeding or haemorrhage related to device implant 
• Any cardiac related hospital admission 
• Any cardiac related events, including but not limited to: 
o Myocardial Infarction 
o Arrhythmia events 
▪ Atrial Fibrillation 
▪ Ventricular Arrhythmia 
o EF changes 
▪ EF drop to ≤35% OR 
▪ EF drop to ≥10% drop from baseline 
o Shortness of breath 
o Worsening peripheral oedema 
o Lung atelectasis 
o Pericardial effusion 
o Pleural effusion 
o Chest Pain 
o Changes in cardiac blood markers (BNP, Troponin)  
• Any cardiac related Accident & Emergency visit, day-case admission, or 
unplanned outpatient event or procedure 
• Loss of capacity 
• Delirium 
• Dementia 
• Stroke 
• Non cardiac death 
• Sudden cardiac death (Ventricular Tachycardia / Ventricular Fibrillation arrest) 
• Cardiac death 
 
6.5 
Serious Adverse Events (SAE) 
 

 
 
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(i) Definition of SAE 
 
An SAE is defined as any event that  
• Results in death;  
• Is life-threatening*; 
• Requires hospitalisation or prolongation of existing inpatient’s hospitalisation**; 
• Results in persistent or significant disability or incapacity; 
• Is a congenital abnormality or birth defect; 
 
* “Life-threatening” in the definition of “serious” refers to an event in which the participant 
was at risk of death at the time of the event; it does not refer to an event which hypothetically 
might have caused death if it were more severe. 
 
** “Hospitalisation” means any unexpected admission to a hospital department. It does not 
usually apply to scheduled admissions that were planned before study inclusion or visits to 
casualty (without admission).  
 
Medical judgement should be exercised in deciding whether an adverse event/reaction is 
serious in other situations. Important adverse events/reactions that are not immediately life-
threatening, or do not result in death or hospitalisation but may jeopardise a subject or may 
require intervention to prevent one of the other outcomes listed in the definition above should 
also be considered serious.  
 
(ii) Reporting of SAEs 
 
Reporting of all SAEs, occurring during the study must be performed as detailed in the study-
specific Safety reporting instructions.  
 
Active monitoring of participants after the end of the trial is not required.  
 
All SAEs will be reviewed by the Chief Investigator or a designated medically qualified 
representative to confirm expectedness and causality. 
 
Expected AEs in this population of patients with Heart Failure will include hospitalisations 
related to arrhythmia, worsening shortness of breath and chest pain. 
 
Reporting of SAEs and review by the CI will be via the trial data collection system 
(OpenClinica).  
 
(iii) Related SAEs 
 
Related: resulted from administration of any of the research procedures 
 
(iv) Unexpected SAEs 
 
Unexpected: type of event is not listed in the protocol as an expected occurrence 
 

 
 
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(v) Reporting of SAEs that are related and unexpected 
 
SAEs that are related and unexpected should be notified to the relevant REC and the 
Sponsor in accordance with local requirements. For Imperial-Sponsored studies related and 
unexpected SAEs must be reported to the Sponsor within 15 days of the investigator 
becoming aware of the event. 
 
Follow up of participants who have experienced a related and unexpected SAE should 
continue until recovery is complete or the condition has stabilised. Reports for related and 
unexpected SAEs should be unblinded prior to submission if required by national 
requirements. 
 
(vi) Annual reporting of Serious Adverse Events 
 
Annual Progress reports will be submitted to the Sponsor and the Ethics Committee in 
accordance with local requirements. The Annual Progress Report will detail all SAEs 
recorded. 
 
6.6 
Reporting urgent safety measures  
 
If any urgent safety measures are taken the CI/Sponsor shall immediately and in any event 
no later than 3 days from the date the measures are taken, give written notice to the relevant 
REC of the measures taken and the circumstances giving rise to those measures. 
 
Contact details for reporting SAEs 
Please send SAE forms to: protect-hf@imperial.ac.uk 
Tel: 07749576830 (Mon to Fri 09.00 – 17.00) 
 
7. STATISTICAL ANALYSES 
 
7.1 
Sample Size and power considerations 
 
Event rate. We used a conservative 27.5% rate of death or unplanned Heart Failure acute 
care at four years. For context, BLOCK HF saw 39% in the RV pacing mild/moderate LV 
impairment group, and Abdelrahman et al saw 36% rate in the patients with significant RV 
pacing.  
 
Effect Size detectable. We plan to be able to detect a 19% relative risk reduction, which is 
an effect size which would change clinical practice. For context, Biventricular pacing in the 
BLOCK HF trial delivered a relative risk reduction of 27%1. Observational data comparing 
conduction system pacing with RV pacing shows a 35% lower rate in the physiological 
pacing group. 
 
Assuming 3.5 years recruitment and 3 years follow up, a conservative survival probability at 
4 years of 0.725 (event rate of 27.5%) in the control group and a Hazard Ratio of 0.78 
(relative risk of 0.81), 2048 patients would give 85% power with a two-sided α level of 0.05. 

 
 
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Adjusting for a slower recruitment rate in the first 12 months, a 7.5% cross over from 
physiological pacing to RV pacing and 7% drop-out, we would need 2539.  
 
7.2 
Planned recruitment rate 
 
We will recruit 2600, as a total across both UK and international centres. We expect sites to 
recruit approximately 2.5 patients per month once activated. 
 
Planned recruitment timelines are as below: 
0 to 24 months: Vanguard recruitment:  
0 to 6 months: ≥ 12 sites active,  
6 to 12 months: ≥ 24 sites active, 
12 to 24 months: 36 sites active.  
Expected 1296 patients recruited by 24 months 
24 to 42 month: Main recruitment phase: 36 sites. Reach 2600 patients.  
42 to 78 month: Follow up phase: Follow-up will range from 36 to 78 months 
 
7.3 
Statistical analysis 
 
Data will be entered into a validated eCRF developed by ICTU. Continuous variables will be 
presented as means and standard deviations if normally distributed, and as medians and 
inter-quartile ranges for skewed data, whilst categorical variables will be presented as 
frequencies and percentages. Normality will be checked, and appropriate transformation 
performed if not normally distributed. All statistical tests will be two-tailed with a 5% 
significance level.  
 
A detailed description of all the analyses will be given in the statistical analysis plan (SAP) 
that will be prepared and finalised prior to database lock. Any deviations from the SAP will 
be justified and documented in the final report.   
 
(i) Analysis populations 
 
The primary analysis will be performed according to the intention to treat principle, including 
all participants who are randomised to a study arm, according to their allocated arm, 
regardless of treatment received.  
 
Per-Protocol (PP) populations will also be defined: 
Those who received CSP as per adjudication 
Those who received His bundle pacing as per adjudication 
Those who received Left bundle pacing as per adjudication 
Those who received selective His bundle pacing as per adjudication 
Those who received non-selective His bundle pacing as per adjudication 
Those with an EF <50% at enrolment 
Those with an EF >50% at enrolment 
Those with an mean pacing percentage >20% during the trial 
Those with a mean pacing percentage >40% during the trial 
Those with a mean pacing percentage >80% during the trial 
Those with AF at baseline 

 
 
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Those with complete AV block at baseline 
 
(ii) Primary Endpoint Analysis 
 
Survival curves for primary endpoint will be estimated by Kaplan and Meier and the log-
rank test methods. The hazard ratio and respective 95% confidence interval will be 
computed using the Cox proportional hazards regression model, or appropriate 
alternative. In secondary analysis the model will be adjusted for clinical important 
confounders that will be pre-specified in the statistical analysis plan. The underlying 
assumptions of any fitted model will be assessed as appropriate. 
 
(iii) Secondary Endpoint Analysis 
 
Secondary outcomes will be analysed using the appropriate generalised linear model 
depending on the distribution of the outcome, like linear regression for continuous and 
logistic regression for binary outcomes. When measurements are collected at multiple 
time points, repeated measurements mixed models will be used. All implant pacing 
parameters will be recorded including X-ray time as a surrogate for procedure time and 
pacing thresholds, sensed R wave, impedance and pacing amplitudes. These metrics 
will be compared between arms. 
 
Quality of life will be assessed over time and treatment groups compared using 
longitudinal analysis with appropriate recognition for informative dropout, using joint 
modelling to account for events. 
 
Our planned subgroup analyses will be performed by adding the interaction term 
between treatment and the subgroup variable into the model.  
 
Planned Subgroup / Sub-study Analyses 
 
i. Mechanistic Echocardiographic Sub-study of 500 patients. At trial enrolment, 500 patients 
will enter the Echo sub-study, with echocardiograms at baseline (within 6 weeks of 
implant) and 24 months later. The sub-study will analyse group mean effects and 
individual patient changes, focusing on LV volumes and ejection fraction. The data will 
be analysed using a core lab blinded to treatment allocation. We will also conduct an 
exploratory analysis using the AI technology developed and validated in our institution.  
 
We have chosen LV end systolic volume as the primary endpoint variable of this sub-
study because was found to be a powerful predictor of heart failure hospitalisations and 
mortality in previous clinical trials. A 10ml increase in volumes in the BLOCK HF study 
was associated with a 7% increase in death and 10% increase in heart failure 
hospitalisations.  
 
The sample size is designed to detect a between-arm difference in change of LVESV of 
10mls, with 90% power at the 5% significance level, assuming SD of differences is 27mls 
based on previous trials. We assume 7.5% cross over rate at implant but a dropout rate 
of 15% (because some patients may decline to attend for the follow-up echo when the 
time comes). This requires 426 patients. We plan to recruit 500 patients.  
 

 
 
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ii. Effect of physiological pacing stratified by percentage of ventricular pacing. Because 
randomisation is unlikely to affect the proportion of beats that require ventricular pacing, 
we will be able to validly analyse all the endpoints of the study with proportion of 
ventricular pacing as an input covariate. This means we may see a progressively larger 
difference between arms as the proportion of ventricular pacing increases. This will be a 
useful indicator for the mechanism of any effect seen. 
 
iii. By pre-implant LV function. Similarly, we will test whether pre-implant (clinically 
documented without cost to the BHF) ejection fraction predicts the difference in outcomes 
between arms. 
 
iv. By pacing type. On-treatment analysis is planned that will report outcomes for: selective 
His bundle pacing, non-selective His bundle pacing, selective left bundle pacing, non-
selective left bundle pacing and pacing via the coronary sinus. Capture type will be 
adjudicated by blinded committee reviewing predefined manoeuvres designed to confirm 
the type of capture present. 12 lead ECG’s and intracardiac electrograms will be collected 
at the time of implantation. 12 lead ECG’s will also be collected during in person pacing 
follow up.   
 
v. NHS Digital follow up. For England-recruited patients we plan to utilise NHS digital data 
to confirm mortality status and hospital episodes for the duration of the study. We 
anticipate ~1500 patients will be recruited from England. 
 
vi. Cost Effectiveness analysis. Data as recommended by our health-economist for cost 
effectiveness analysis will be collected; health care utilization including number of hospital 
admissions, days in hospital, other unplanned visits to hospital, GP and outpatient visits.  
 
 
8. REGULATORY, ETHICAL AND LEGAL ISSUES 
 
8.1 
Declaration of Helsinki 
 
The investigator will ensure that this study is conducted in full conformity with the 7th revision 
of the 1964 Declaration of Helsinki. 
 
8.2 
Good Clinical Practice  
 
The study will be conducted in accordance with the guidelines laid down by the International 
Conference on Harmonisation for Good Clinical Practice (ICH GCP E6 R2 guidelines).  
 
8.3 
Research Ethics Committee (REC) Approval  
 
(i) Initial Approval 
 
Prior to the enrolment of participants, the REC must provide written approval of the conduct 
of the study at named sites, the protocol and any amendments, the Participant Information 

 
 
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Sheet and Consent Form, any other written information that will be provided to the 
participants, any advertisements that will be used and details of any participant 
compensation.  
 
(ii) Approval of Amendments 
 
Proposed amendments to the protocol and aforementioned documents must be submitted 
to the REC for approval. Amendments requiring REC approval may be implemented only 
after a copy of the REC’s approval letter has been obtained.  
 
Amendments that are intended to eliminate an apparent immediate hazard to participants 
may be implemented prior to receiving Sponsor or REC approval. However, in this case, 
approval must be obtained as soon as possible after implementation. 
 
The trial team, in collaboration with the Sponsor will assess whether a proposed amendment 
is substantial or non-substantial/ For each proposed amendment, a revised version of the 
protocol will be prepared using tracked changes, a new version assigned and the revised 
document will be reviewed and approved by the Sponsor prior to submission to the REC 
and Health Research Authority *HRA). The amendment protocol will be sent to participating 
sites for local approval to be granted and the approved version will be shared with all staff 
involved in the trial. 
 
(iii) Annual Progress Reports 
 
Annual Progress Reports will be submitted to the Research Ethics Committee (REC) and 
the Sponsor in accordance with national requirements.  
 
(iv) End of Trial Notification 
 
The REC will be informed about the end of the trial, within the required timelines.  
The end of trial notification will be submitted within 90 days of the end of trial definition being 
met. In the event of a premature halt of the trial, the timeframe is 15 days, and the reasons 
should be clearly explained in the notification. 
 
8.4 
HRA approval 
 
Health Research Authority (HRA) approval will be obtained prior to starting the study. Each 
participating site will confirm capacity and capability prior to commencing. 
 
The HRA and all participating sites also need to be notified of all protocol amendments to 
assess whether the amendment affects the institutional approval for each site.  
 
8.5 
Non-Compliance and Serious Breaches  
 
All protocol deviations and protocol violations will be reported via the eCRF/CRF and 
reviewed by the Chief Investigator and reported to the ICTU QA manager on a monthly 
basis. Protocol violations will be reported to the Sponsor. 
 

 
 
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Due to the nature of this trial, occasional accidental unblinding of participants is expected. 
Unblinding of participants does not affect the trial’s primary endpoint and should be reported 
as protocol deviation 
 
An assessment of whether the protocol deviation/violation constitutes a serious breach will 
be made.  
 
A serious breach is defined as: 
 
A breach of the conditions and principles of GCP in connection with a trial or the trial 
protocol, which is likely to affect to a significant degree:  
 
• The safety or physical or mental integrity of the UK trial participants; or 
• The overall scientific value of the trial 
 
The Sponsor will be notified within 24 hours of identifying a likely Serious Breach. If a 
decision is made that the incident constitutes a Serious Breach, this will be reported to the 
REC within 7 days of becoming aware of the serious breach. 
 
8.6 
Insurance and Indemnity and Sponsor 
 
Imperial College London will act as the main Sponsor for this study.  Delegated 
responsibilities will be assigned to the NHS trust taking part in this study. Imperial College 
London holds negligent harm and non-negligent harm insurance policies which apply to this 
study. 
 
8.7 
Trial Registration 
 
The study will be registered on clinicaltrials.gov in accordance with requirements of the 
International Committee of Medical Journal Editors (ICMJE) regulations. 
 
8.8 
Informed Consent 
 
Patients who clinically require a pacemaker for slow heart rates will be screened and 
identified by a member of the trial study team in the patient’s local hospital. 
 
The patient will be approached either face-to-face or via telephone before any consent 
(whether electronic or paper) is signed, and the trial rationale and methods explained. A 
face-to-face approach will be adopted whenever possible. They will be given a written 
information leaflet which will detail the known risks and potential risks.  They will be given 
time to consider whether they would like to participate in the trial and ask questions if they 
so wish.  
 
If they decide they would like to participate, they will be asked to sign a consent form either 
paper or electronically sent via a link emailed by OpenClinica. The electronic consent 
method will comply to UK eIDAS Regulations (SI 2016/696). They will be made aware that 
they can leave the trial at any time and can withdraw consent at any time. They will be made 
aware that this will not affect their clinical care. Where verbal consent is used to consent 

 
 
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patient to the trial, randomisation cannot occur until the patient physically signs the informed 
consent form. 
 
Only patients with capacity to consent will be considered eligible for recruitment. Subjects 
should be provided with a copy of the signed Subject Information Sheet/Informed Consent 
Form document. The original Informed Consent Form should be retained with the source 
documents. If patient is unable to sign the informed consent form themselves due to 
blindness or other disability which doesn't affect their understanding of the study/capacity, a 
witness can sign on behalf of the patient.   
 
Some people with capacity will consent to take part in research, but then may lose capacity 
before the end of the study. We will assume capacity is present unless established 
otherwise; should concerns arise, members of our clinical team will take steps to assess 
capacity status. If we become aware that a participant has lost capacity prior to implant they 
will be withdrawn from the study at this time-point. If a participant has lost capacity after 
implant there are no risks involved in the follow-up as both arms are receiving guideline 
indicated therapies. Primary endpoint data will be collected via their healthcare records and 
when necessary liaising with local research and clinical teams.  For participants who lose 
capacity and are consented to the echo sub-study, they will not have their echocardiograms, 
if they have yet to have one or both. The participant and nominated other will not be 
contacted in any way or for any reason to obtain information required for endpoint data, this 
includes stopping the 6-monthly telephone follow-up visits. 
 
8.9 
Contact with General Practitioner  
 
It is the investigator’s responsibility to inform the participant’s General Practitioner (by letter 
that the participant is taking part in the study provided the participant agrees to this, and 
information to this effect is included in the Participant Information Sheet and Informed 
Consent. A copy of the letter should be filed in the patients’ medical records. 
 
8.10 Participant Confidentiality 
 
The investigator must ensure that the participant’s confidentiality is maintained. On the CRF 
or other documents submitted to the Sponsors, participants will be identified by a participant 
ID number only. Documents that are not submitted to the Sponsor (e.g., signed informed 
consent form) should be kept in a strictly confidential file by the investigator. 
 
The investigator shall permit direct access to participants’ records and source documents 
for the purposes of monitoring, auditing, or inspection by the Sponsor, authorised 
representatives of the Sponsor, NHS, Regulatory Authorities and RECs. 
 
8.11 Data Protection and Participant Confidentiality 
 
The investigators and study site staff will comply with the requirements of the Data Protection 
Act 2018 concerning the collection, storage, processing and disclosure of personal 
information and will uphold the Act’s core principles. 
 
8.12 End of Trial 
 

 
 
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For safety reporting and regulatory purposes, End of Trial will be when all study visits are 
complete, all data are captured on the database and the study database is declared clean 
and hard-locked.  
 
8.13 Study Documentation and Data Storage 
 
The investigator must retain essential documents until notified by the Sponsor, and for at 
least ten years after study completion. Participant files and other source data (including 
copies of protocols, CRFs, original reports of test results, correspondence, records of 
informed consent, and other documents pertaining to the conduct of the study) must be 
retained. Documents should be stored in such a way that they can be accessed/data 
retrieved at a later date. Consideration should be given to security and environmental risks. 
 
No study document will be destroyed without prior written agreement between the Sponsor 
and the investigator. Should the investigator wish to assign the study records to another 
party or move them to another location, written agreement must be obtained from the 
Sponsor. 
 
9. DATA MANAGEMENT 
 
9.1 
Source Data 
 
Source documents include original documents related to the trial, to medical treatment and 
to the history of the participant, and adequate source documentation must be maintained to 
allow reliable verification and validation of the trial data. What constitutes the source data 
for this trial will be outlined in the trial Monitoring Plan. 
 
Generic names for concomitant medications should be recorded in the CRF wherever 
possible. All written material to be used by participants must use vocabulary that is clearly 
understood and be in the language appropriate for the study site. 
 
9.2 
Database 
 
Trial data will be collected on an electronic case report form (eCRF). The principal means 
of data collection from participant visits will be Electronic Data Capture (EDC) via the internet 
using the OpenClinica database. Data is entered into the EDC system by trained site 
personnel. All data recorded in the eCRF will be signed off by the Investigator or his/her 
appropriate designee. All changes made following initial submission of data will have an 
electronic audit trail with a date. Specific instructions and further details will be outlined in 
the study specific eCRF manual.  
 
9.3 
Data Collection 
 
Data from all trial visits will be collected and entered on the trial eCRF built in the 
OpenClinica system. Details of procedures for eCRF/CRF completion will be provided in a 
study manual. 
 
9.4 
Archiving  
 

 
 
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All trial documentation, including that held at participating sites and the trial coordinating 
centre, will be archived for a minimum of 10 years (following the end of the study).  
 
10. STUDY MANAGEMENT STRUCTURE  
 
The trial will be managed by the United Kingdom Clinical Research Collaboration (UKCRC) 
registered Imperial Clinical Trials Unit (ICTU).  
 
The following groups and trial committees will be established: 
 
10.1 Trial Steering Committee  
 
A Trial Steering Committee (TSC) will be convened including as a minimum an independent 
Chair, independent clinician, the Chief Investigator, a lay person and members of ICTU (Trial 
Manager, Operations Manager and Statisticians). The role of the TSC is to provide overall 
supervision of trial conduct and progress. Details of membership, responsibilities and 
frequency of meetings will be defined in a separate Charter. 
 
10.2 Trial Management Group 
 
A Trial Management Group (TMG) will be convened including the Chief Investigator, co-
investigators and key collaborators, Senior and trial statisticians, Operations Manager and 
trial manager. The TMG will be responsible for day-to-day conduct of the trial and operational 
issues. Details of membership, responsibilities and frequency of meetings will be defined in 
separate terms of Reference.  
 
10.3 Adjudication Committees 
 
Endpoint Event Adjudication Committee – this will adjudicate primary and secondary 
endpoint events, including death, all unplanned heart failure acute care (hospital admissions 
or ambulatory diuretic therapy) events, atrial fibrillation episodes and ventricular arrhythmia 
incidences. 
 
Capture Adjudication Committee – this will adjudicate all capture responses for patients 
assigned to the physiological pacing strategy. 
 
Upgrade Adjudication Committee – this will evaluate all patients in the trial that receive 
an upgrade to conventional biventricular pacing to assess whether the upgrade was deemed 
clinically appropriate. 
 
10.4 Data Monitoring Committee 
 
A fully independent Data Monitoring and Ethics Committee (DMEC) will be set up to monitor 
progress, participant safety, blinding fidelity, operator variability and any ethical issues 
involved in this trial. They will review trial progress, recruitment rates, safety, and data 
emerging from other trials and make recommendations to the TSC as to whether there are 
any reasons why the trial should not continue.  
 

 
 
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A separate DMEC Charter will be drawn up defining their responsibilities, frequency of 
meetings and reporting to the TSC. 
 
The DMEC are permitted to have access to the unblinded data for review and any 
comparisons between groups where appropriate.   
 
10.5 Early Discontinuation of the Study 
 
The DMC will define the criteria for early discontinuation and make recommendations to the 
TSC as required.  
 
10.6 Risk Assessment 
 
A study-specific risk assessment will be performed prior to the start of the study to assign a 
risk category of ‘low’, ‘medium’ or ‘high’ to the trial. Risk assessment will be carried out by 
the ICTU QA Manager in collaboration with the Study Manager and the result will be used 
to guide the monitoring plan. The risk assessment will consider all aspects of the study and 
will be updated as required during the course of the study. 
 
10.7 Monitoring  
 
The study will be monitored periodically by trial monitors to assess the progress of the study, 
verify adherence to the protocol, ICH GCP E6 R2 guidelines and other national/international 
requirements and to review the completeness, accuracy and consistency of the data. 
 
Monitoring procedures and requirements will be documented in a Monitoring Plan, 
developed in accordance with the risk assessment. 
 
10.8 Quality Control and Quality Assurance 
 
Quality Control will be performed according to ICTU internal procedures. The study may be 
audited by a Quality Assurance representative of the Sponsor and/or ICTU. All necessary 
data and documents will be made available for inspection. 
 
The study may be participant to inspection and audit by regulatory bodies to ensure 
adherence to GCP and the UK policy for health and social care research. 
 
10.9 Peer review 
 
The trial has undergone independent peer review via the BHF funding programme. The trial 
has also been reviewed by senior members of ICTU and researchers at Imperial College 
London.  
 
10.10 Patient and Public Involvement  
    
PPI members were involved in reviewing the plain English summary in the grant and the 
REC application, and will be part of the Trial Steering Committee, supporting the creation of 
patient facing materials, identifying the most effective ways to share information with 

 
 
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potential participants in order to maximise recruitment, promoting the trial during the 
recruitment phase and disseminating the trial results. 
 
10.11 Publication and Dissemination policy 
 
We will seek to publish the results of the study in internal reports, scientific presentations 
and peer-reviewed scientific journals. All analysis and decisions to publish will be made the 
scientific team and will not be determined by funder. 
 
Information concerning the study, patent applications, processes, scientific data or other 
pertinent information is confidential and remains the property of the Sponsor. The 
investigator may use this information for the purposes of the study only. 
 
A Clinical Study Report summarising the study results will be prepared and submitted to the 
REC within a year of the end of study.  
 
 
 
 
11. APPENDIX 
11.1 International Sites  
 
University Medical Centre Ljubljana 
 
Slovenia 
Helsinki University Hospital 
Finland 
Beacon Hospital 
Ireland 
Rigsholpitalet, Copenhagen 
Denmark 
Zealand University Hospital, Roskilde 
Denmark 
Sherbrooke Hospital 
Canada 
University Hospital London Health Sciences 
Centre 
Canada  
University Hospital Antwerp 
Belgium 
Semmelweis University Hospital 
Hungary 
Sarawak Heart Centre 
Malaysia 
Queen Elizabeth II Hospital 
Malaysia 
National University Heart Centre 
Singapore 
Canberra Heart Rhythm Centre 
Australia 
 
 
Appendix Revision History 
 
1.0 
30 April 2024 
Addition of 1) University Medical Centre Ljubljana 2) Helsinki 
University Hospital 3) Beacon Hospital 
2.0 
17 July 2024 
Addition of 1) Rigsholpitalet, Copenhagen, Denmark 2) 
Zealand University Hospital, Roskilde, Denmark 3) Sherbrooke 

 
 
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Hospital, Canada and 4) University Hospital London Health 
Sciences Centre, Ontario, Canada 
3.0 
04 December 2024 
Addition of 1) Semmelweis University Hospital, Budapest, 
Hungary 2) University Hospital Antwerp, Antwerp, Belgium 3) 
Canberra Heart Rhythm Centre, Canberra, Australia  4) 
Sarawak Heart Centre, Sarawak, Malaysia 5) Queen Elizabeth 
II Hospital, Sabah, Malaysia 6) National University Heart 
Centre, Singapore   
 
 

 
 
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12. REVISION HISTORY  
 
Version  
Date 
Summary of changes 
1.0 
02/Dec/2022 
First version  
2.0 
14/Mar/2023 
Second version, following initial submission to 
REC. Changes made: addition and clarification of 
Endpoint Event Adjudication Committee; removal 
of reference to Consultee, associated 
documentation and participant advanced directive 
in section “Informed Consent”; removed additional 
custom sentence from SAE section as not 
required; formatting changes. Change to what 
adverse events require reporting. 
3.0 
29/Jun/2023 
Third version, related to NSA02. (1) Change to 
study design inclusion criteria (specifying 
indications more precisely to facilitate clinical 
interpretation) and (2) Removal of non-applicable 
abbreviations in protocol, (3) Amendment of 
typographical error in Protocol (UK written in error 
instead of England). 
4.0 
25/Jul/2023 
Fourth Version, related to NSA03. (1) Change to 
study design, Echocardiogram baseline visit 
window (baseline echocardiogram visit now to be 
within 6 weeks of implant), and (2) Removal of 
non-applicable abbreviations in protocol, addition 
of monitor details to Contact List on protocol, 
correction to inclusion criteria lettering under Trial 
Summary and section 3.1, and addition of Northern 
Ireland to description of UK sites in protocol under 
Section 3 Study Design, (i) Inclusion criteria.  
5.0  
30/Aug/2023 
Fifth version, related to NSA04. (1) Paragraph 
added to clarify differences in follow-up (timing, 
researchers and data collection) for international 
sites (this is to improve feasibility at these sites, 
and support recruitment + retention of participants 
but will not affect the scientific integrity of the study 
as it is powered for our primary endpoint which is 
heart failure hospitalisations and mortality).  (2) 
Protocol: change in phone number for CI, change 
in name of study manager; (3) Change in 
researchers due to changes in staff for trial 

 
 
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manager and trial statistician  and (4) Change to 
study design at all NHS sites and international 
sites clarifying that monthly symptom 
questionnaires will be sent only if patients have 
provided an email address and that post-procedre 
chest x-rays will be done only if this is standard of 
care at the respective site. Clarified that patients 
will receive a monthly symptom questionnaire only 
if they have provided an email address at the time 
of enrolment and that post-procedure X-ray will be 
done only if standard of care. This will not affect 
the scientific integrity of the study as it is powered 
for our primary endpoint which is heart failure 
hospitalisations and mortality. 
6.0 
18/12/2023 
Sixth version related to NSA05. Amendment of 
protocol to a) clarify switching to alternate method 
of physiological pacing if operator trained in this 
method, b) clarify that pregnancy tests to be 
administered pre-implant as per standard of care, 
c) state pre-implant ECG can be from an time prior 
to implant (previously 'within 2 months'). This 
revision is to align with clinical practise as ECG 
data preceding 2 months is often used and this 
doesn't affect study integrity or findings in any way 
d) state that RV pacing ECGs post-implant can be 
obtained at any time post-implant. A 12-lead ECG 
is asked for at time of implant as there are potently 
changes in the ECG from time of implant and 
during follow-up. However for RV pacing, tis is not 
the case.As such, the RVpaced ECG can be 
obtained at any time post-implant - this facilitates 
data collection for the trial and e) this is further 
clarification that X-rays to be undertaken post-
implant if standard of care at that site. This was 
submitted as part of NSA04 but was not corrected 
throughout the protocol f) additional adverse event 
of protocol (inappropriate pacing function) 
7.0 
30/04/2024 
Addition of Appendix to the Protocol detailing 
participating international sites.  
8.0 
28/08/2024 
Reference SA 01 dated 28/08/2024. 
Pg 12 – new paragraph under tertiary objectives 
describing aims of the genetics sub-study to 
determine if genetic variants may detect patients at 
risk of pacing induced cardiomyopathy and if 
physiological pacing improves cardiac activation 
patterns in patients with identified genetic variants.  

 
 
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Pg 13 – new sub heading and details for genetics 
sub-study 
Pg 13, 15, 20, 21, 32 – removal of sentences 
relating to monthly symptom scale as this is no 
longer a study assessment 
Pg 16 – additional detail relating to genetics stub-
study explaining blood samples will be collected for 
gene sequencing and analysis 
Pg 8 & 17 Further explicit clarification of inclusion 
criteria that the source data which demonstrates a 
patient's ejection fraction is 35% or greater (key 
inclusion criteria of the trial) is from a scan within 
the last 12 months. 
Pg 18 – annotation to the schedule of events at 
bottom of table to clarify that baseline echo is 
taken from screening or within the last 12 months 
Pg 19 – sub-heading and detail relating to genetic 
sub-study under the assessments heading, stating 
how blood will be collected and stored.  
Pg 22 – paragraph updated to include all device 
manufacturers (Medtronic, Boston Scientific, 
Biotronik and Abbott) in the “trial patient clinic” 
work flow. Previously, this only included Medtronic. 
Pg 24 – additional wording under adverse event 
reporting to include known pacemaker 
complications as expected events in this cohort. 
Pg 31 – additional sentence stating that accidental 
unblinding of study participants is to be recorded 
as a protocol deviation only (and not a protocol 
violation) 
 
 
 
 
 
 
 
 

 
 
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28.  Zanon F, Baracca E, Aggio S, et al. A feasible approach for direct his-bundle pacing 
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29.  Occhetta E, Bortnik M, Marino P. Permanent parahisian pacing. Indian Pacing 
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31.  Pastore G, Zanon F, Noventa F, et al. Variability of left ventricular electromechanical 
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pacing site. Pacing Clin Electrophysiol 2010;33(5):566–74.  
32.  Zanon F, Svetlich C, Occhetta E, et al. Safety and performance of a system 
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33.  Catanzariti D, Maines M, Manica A, Angheben C, Varbaro A, Vergara G. Permanent 
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34.  Pastore G, Aggio S, Baracca E, et al. Hisian area and right ventricular apical pacing 
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37.  Pastore G, Zanon F, Baracca E, et al. The risk of atrial fibrillation during right 
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38.  Teng AE, Lustgarten DL, Vijayaraman P, et al. Usefulness of his bundle pacing to 
achieve electrical resynchronization in patients with complete left bundle branch 
block and the relation between native QRS axis, duration, and normalization. Am J 
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39.  Teng AE, Massoud L, Ajijola OA. Physiological mechanisms of QRS narrowing in 
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rates of permanent His-bundle pacing in patients with narrow QRS: a single-centre 
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block: Feasibility, safety, and acute effect. Heart Rhythm 2019;16(12):1766–73.  
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implantation depth of 3830 electrode predict QRS correction by left bundle branch 
area pacing. Pacing Clin Electrophysiol 2020;43(1):110–7.  
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heart failure with a narrow QRS complex. N Engl J Med 2013;369(15):1395–405.  
56.  Vijayaraman P, Dandamudi G, Zanon F, et al. Permanent His bundle pacing: 
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57.  Huang W, Su L, Wu S, et al. A novel pacing strategy with low and stable output: 
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58.    Keene D, Shun-Shin MJ, Arnold AD, et al. Within-patient comparison of His-bundle 
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Sponsor: 
Imperial College London 
 
V9.0 16-Jun-
2025  
 
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14. SIGNATURE PAGE 1 (CHIEF INVESTIGATOR) 
 
The signature below constitutes approval of this protocol by the signatory, on behalf of the 
Protocol Development Group, and provides the necessary assurances that this study will be 
conducted according to all stipulations of the protocol including all statements regarding 
confidentiality. 
 
 
Study Title:  
 
PROTECT-HF: - Physiological vs Right ventricular pacing  
 
 
 
 
Outcome Trial Evaluated for bradyCardia Treatment  
 
 
 
Protocol Number:  
22HH7931 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Dr Daniel Keene 
 
 
 
Clinical Senior Lecturer in Cardiac Electrophysiology and Devices 
 
 
 
Imperial College London 
 
 
 
 
 
Date:  
 
_____________________ 
 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Dr Zachary Whinnett 
Reader in Cardiac Electrophysiology/ Consultant Cardiologist & 
Electrophysiologist (ICHT) 
 
 
 
Imperial College London 
 
 
 
 
 
Date:  
 
_____________________ 
 
  

 
 
Protocol No: 
22HH7931 
Sponsor: 
Imperial College London 
 
V9.0 16-Jun-
2025  
 
Confidential 
 
Page 47 of 49 
 
 
 
 
 
 
 
SIGNATURE PAGE 2 (SPONSOR) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title:  
 
PROTECT-HF: - Physiological vs Right ventricular pacing  
 
 
 
 
Outcome Trial Evaluated for bradyCardia Treatment  
 
 
 
Protocol Number:  
22HH7931 
 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Becky Ward 
Research Governance and Integrity Manager, Research Governance 
and Integrity Team (RGIT),  
Imperial College London 
 
 
 
 
 
 
Date:  
 
_____________________ 

 
 
Protocol No: 
22HH7931 
Sponsor: 
Imperial College London 
 
V9.0 16-Jun-
2025  
 
Confidential 
 
Page 48 of 49 
 
 
 
 
 
 
 
SIGNATURE PAGE 3 (STATISTICIAN) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title:  
 
PROTECT-HF: - Physiological vs Right ventricular pacing  
 
 
 
 
Outcome Trial Evaluated for bradyCardia Treatment  
 
 
Protocol Number:  
22HH7931 
 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Ms Emanuela Falaschetti 
Research Fellow in Clinical Trial Statistics at the Imperial Clinical Trial 
Unit (ICTU), Imperial College London 
 
 
 
 
 
 
Date:  
 
_____________________ 
 
 

 
 
Protocol No: 
22HH7931 
Sponsor: 
Imperial College London 
 
V9.0 16-Jun-
2025  
 
Confidential 
 
Page 49 of 49 
 
 
 
 
 
 
 
SIGNATURE PAGE 4 (PRINCIPAL INVESTIGATOR) 
 
The signature of the below constitutes agreement of this protocol by the signatory and 
provides the necessary assurance that this study will be conducted at his/her investigational 
site according to all stipulations of the protocol including all statements regarding 
confidentiality. 
 
 
Study Title:  
 
PROTECT-HF: - Physiological vs Right ventricular pacing  
 
 
 
 
Outcome Trial Evaluated for bradyCardia Treatment  
 
 
 
Protocol Number:  
22HH7931 
 
 
Address of Institution:  
____________________________________________ 
 
 
 
 
 
 
 
 
 
 
____________________________________________ 
 
 
 
 
 
 
____________________________________________ 
 
 
 
Signed: 
 
 
____________________________________________ 
 
 
Print Name and Title: 
____________________________________________ 
 
 
Date:  
 
 
_____________________