Solutions to the Challenges of Conduction System Pacing
Conditions: Conduction System Pacing, Pacing Therapy
Sponsor: Imperial College London

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Solutions to the challenges of conduction system pacing 
 
 
Version 6.1 29.09.2023 
 
 
 
MAIN SPONSOR: Imperial College London  
FUNDERS: British Heart Foundation 
STUDY COORDINATION CENTRE: Dr Akriti Naraen 
IRAS Project ID: 324395 
REC reference: 23/WS/0122 
 
 
 
Protocol authorised by: 
 
Name & Role 
Date 
Signature 
Dr Zachary Whinnett 
Investigator 
29/09/23 
Dr Zachary Whinnett 
 
 
 
 
 
 
 
 
Study Management Group 
 
Chief Investigator: Dr Zachary Whinnett 
 
Co-investigators: Dr Akriti Naraen, Dr Ahran Arnold 
 
Statistician: Prof Darrel Francis 
 
Study Management: Dr Akriti Naraen 
 
 

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Study Coordination Centre  
 
For general queries, supply of study documentation, and collection of data, please contact: 
 
Study Coordinator: Dr Akriti Naraen 
Registration: MBCHb, MRCP 
Address: NHLI, B Block, Hammersmith Hospital, Du Cane Road, W12 0HS 
 
 
    
 
Tel: 02033133000  
 
 
 
 
E-mail: anaraen@ic.ac.uk 
Fax:  n/a 
 
 
 
 
 
 
 
 
 
Clinical Queries 
 
Clinical queries should be directed to Dr Akriti Naraen who will direct the query to the appropriate 
person 
 
Sponsor 
 
Imperial College London is the main research Sponsor for this study.  For further information 
regarding the sponsorship conditions, please contact the Head of Regulatory Compliance at: 
 
 
 
Head Research Governance and Integrity 
Imperial College London and Imperial College Healthcare NHS Trust 
Room 215, Level 2, Medical School Building 
Norfolk Place 
London, W2 1PG 
Tel: 0207 594 1862 
Imperial College - Research Governance and Integrity Team (RGIT) Website 
 
 
Funder 
 
This study will be funded by the British Heart Foundation.  
 
This protocol describes the study and provides information about procedures for entering participants.  
Every care was taken in its drafting, but corrections or amendments may be necessary. These will be 
circulated to investigators in the study.  Problems relating to this study should be referred, in the first 
instance, to the Chief Investigator.  
 
This study will adhere to the principles outlined in the UK Policy Frame Work for Health and Social 
Care Research. It will be conducted in compliance with the protocol, the Data Protection Act and other 
regulatory requirements as appropriate.  
 
 
 

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Table of Contents 
GLOSSARY OF TERMS ...................................................................................................................................................... 4 
STUDY SUMMARY ........................................................................................................................................................... 5 
1. 
INTRODUCTION ..................................................................................................................................................... 7 
1.1 
BACKGROUND ........................................................................................................................................................... 7 
1.2 
ORIGINAL HYPOTHESIS ................................................................................................................................................ 9 
1.3 
RATIONAL FOR CURRENT STUDY .................................................................................................................................... 9 
2. 
STUDY OBJECTIVES ................................................................................................................................................ 9 
3. 
RECRUITMENT ....................................................................................................................................................... 9 
4. 
METHODOLOGY ................................................................................................................................................... 12 
4.1 
DERIVATION ............................................................................................................................................................ 12 
4.2 
VALIDATION ......................................................................................................................................................... 15 
4.3 
BURDEN/RISK ...................................................................................................................................................... 16 
4.4 
STUDY OUTCOME MEASURES ..................................................................................................................................... 16 
5 
PARTICIPANT ENTRY ............................................................................................................................................ 17 
5.1 
PRE-REGISTRATION EVALUATIONS ................................................................................................................................ 17 
5.2 
INCLUSION CRITERIA ................................................................................................................................................. 17 
5.3 
EXCLUSION CRITERIA ................................................................................................................................................. 17 
5.4 
WITHDRAWAL CRITERIA ............................................................................................................................................. 17 
5.5 
CONSENT ................................................................................................................................................................ 17 
6 
ADVERSE EVENTS ................................................................................................................................................. 18 
6.1 
DEFINITIONS ............................................................................................................................................................ 18 
6.2 
REPORTING PROCEDURES ........................................................................................................................................... 18 
6.3 
NON SERIOUS AES .................................................................................................................................................... 18 
6.4 
SERIOUS AES ........................................................................................................................................................... 18 
7 
ASSESSMENT AND FOLLOW-UP ............................................................................................................................ 19 
8 
STATISTICS AND DATA ANALYSIS ......................................................................................................................... 19 
9 
REGULATORY ISSUES ........................................................................................................................................... 20 
9.1 
ETHICS APPROVAL ..................................................................................................................................................... 20 
9.2 
CONSENT ................................................................................................................................................................ 20 
9.3 
CONFIDENTIALITY ..................................................................................................................................................... 21 
9.4 
INDEMNITY ............................................................................................................................................................. 21 
9.5 
SPONSOR ................................................................................................................................................................ 21 
9.6 
FUNDING ................................................................................................................................................................ 21 
9.7 
AUDITS .................................................................................................................................................................. 21 
10 
STUDY MANAGEMENT ......................................................................................................................................... 21 
11 
PUBLICATION POLICY ........................................................................................................................................... 21 
12 
APPENDIX ............................................................................................................................................................ 22 
13 
REFERENCES ........................................................................................................................................................ 23 
 
 
 

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Glossary of Terms 
 
CSP: Conduction system pacing 
CT: Computed tomography 
ECG: Electrocardiogram 
EGM: Electrogram 
HBP: His-bundle pacing 
ICE: Intracardiac echocardiogram 
LBBB: Left bundle branch block 
LBP: Left bundle pacing 
LBAP: Left bundle area pacing 
LV: Left ventricle 
LVAT: Left ventricular activation time 
MRI: Magnetic resonance imaging 
RV: Right ventricle 
TOE: Transoesophageal echocardiogram 
TTE: Transthoracic echocardiogram 
 
 
 

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Study Summary 
 
TITLE 
Solutions to the challenges of conduction system pacing 
 
DESIGN 
Cohort observational study and interventional at validation phase 
AIMS 
1. 
Provide a simplified standardised conduction system lead implantation protocol  
2. Define capture diagnostics of left bundle pacing from left septal pacing 
 
 
OUTCOME 
MEASURES 
Primary Outcomes:  
A1: Success rates of conduction system lead implant (novel workflow vs conventional 
methods) 
B1: Assess accuracy of conduction system diagnosis by the device with additional 
information from 2-lead ECG 
Secondary Outcomes: 
A2: Procedure and fluoroscopy times of the streamlined workflow to current 
conventional methods of His-bundle and Left-bundle pacing 
A2: Procedure and fluoroscopy times of the streamlined workflow of conduction 
system implant to current right ventricular pacing 
A2: Assess capture threshold of His-bundle and Left-bundle pacing from the 
optimised workflow to that of conventional methods of conduction system 
implantation  
A2: Define left bundle area capture diagnostics and delineate differences between 
left ventricular septal pacing. 
B2: Improvement in device battery life with novel device algorithm applied 
 
 
Figure 1: A illustration to demonstrate the primary and secondary outcomes of Study 
A and Study B.  
* Sample size calculations indicate 50 patients will provide >80% power (see 
Section 8, statistics and data analysis for more information) 
 
 
 

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POPULATION 
Patients with any indication for a pacemaker 
ELIGIBILITY 
Inclusion criteria:  
1. Indication for pacemaker implant 
Exclusion criteria:  
5. Unable to give consent 
5. Children age < 18 years or adults >100 years old 
5. Pregnant patients  
DURATION 
 3 years 
 
 
 

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1. Introduction 
 
1.1 Background 
 
Discovering how to clinically deliver conduction system pacing efficiently could be a paradigm shift. 
Early work on conduction system pacing focused on the His bundle, with right atrial mapping for the 
His signal and deployment of a lumenless pacing lead(1). Left bundle pacing (LBP) then emerged as 
an alternative, approaching via the basal right ventricular septum to deploy a lead through the septum 
to capture the left bundle on the left side of the septum(2,3) 
 
Current literature report improved left ventricular function, heart failure outcomes and mortality in 
conduction system pacing(4,5). Additionally, LBP has a larger target area, can be done with low 
capture thresholds, has better threshold stability and large amplitude R waves(3). Widespread roll out 
of conduction system pacing clinically, however, faces three major challenges. 
 
Challenge A1: Identifying target area for lead deployment 
Despite growing adoption, conduction system pacing implants remains challenging. Even experienced 
device consultants take time to learn the technique. Experienced centres achieve implant success of 
95%, but centres with new conduction system implanters (but highly experienced pacemaker 
implanters) have rates as low as 56%(6,7). 
 
Fluoroscopic interpretation is challenging, for several reasons. The target area is smaller than 
conventional right ventricular pacing, and can be even smaller when there is fibrosis in the septum. 
The chambers may well be dilated, which displaces not only the fluoroscopic position of the target, but 
also its orientation. The lead can also be difficult to advance, because of septal fibrosis, unrecognised 
lead entanglement and unclear trans-septal trajectory. Interpretation of surface ECG and lead data is 
not straightforward either: there are many levels in the conduction system at which block can occur 
and it is difficult to distinguish them confidently. Lead entanglement and mal-orientation may be 
detectable with elaborate equipment such as intracardiac echocardiography (ICE) but we do not know 
what fluoroscopic or electrical features might provide routine clinical operators with a timely warning. 
Previous approaches to address these issues have involved normal-heart cadaveric studies which do 
not give the electrical context of a clinical implant(8).  
 
Challenge A2: Defining left bundle area capture. 
Although there are various expert consensus’ in the diagnosis of left bundle capture, the capture 
diagnostics has yet to be validated.  In view of the limitations of left bundle capture confirmation, it 
remains difficult to establish confidently if there is left conduction system capture rather than left 
ventricular septal capture only. Furthermore, it is unclear if there is a clinically relevant advantage to 
left conduction system capture to left ventricular septum capture. This requires further investigation.  
 
The paced activation patterns of the left ventricle during the lead deployment will be collected; at the 
left ventricular septal area (defined as more than half way beyond the septum) and the left bundle. At 
these points the electrical data from the pacing lead will be collected. The distal and proximal left 
bundle will be paced and restoration of physiological left ventricular activation will be assessed. 
 
Challenge B: Reduced battery longevity due to high thresholds as result of limited conduction 
system capture discrimination by the device. 
In conventional pacing, it is easy to describe to the device how to detect adequate capture, and 
therefore easy to have the device monitor adequacy of capture and adjust output to strike an efficient 
balance between ensuring capture and minimising energy consumption(9) (Figure 1). In conduction 
system pacing, we do not know how to check conduction system capture reliably using purely device-
based information. Therefore, we cannot safely set the output to optimise battery life; instead, outputs 
are set unnecessarily high to ensure continued conduction system capture.  
 
 
 

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Checking correct capture is more difficult for conduction system pacing than conventional. It is not 
enough to detect capture: the device must confidently distinguish between several possible response 
patterns. Each patient may exhibit several patterns at different outputs. Misinterpreting the type of 
capture can cause harm. For example, in heart failure, if myocardium-only capture is mistakenly 
accepted as left bundle recruitment, patients would receive harmful right ventricular pacing rather than 
beneficial resynchronisation.  
 
My aim is to develop an algorithm that can use the lead signals to reliably detect capture and classify 
the type of capture. I will augment the conventional lead signals with a 2 lead surface ECG from within 
the generator pocket. This may provide crucial additional information on type of capture. 
 
Figure 2: Comparison of battery saving algorithms with fixed output 
 
 
 
 
2V
Pacing 
output
Time (Years)
Loss of capture
A dynamically adjusted 
pacing output using the 
results of Study C
Actual threshold required for 
conduction system capture
Current fixed pacing output 
0V
1V
Wasted battery
Loss of capture
Wasted battery
3V
1
2

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1.2 Original Hypothesis 
 
Hypothesis A: A conduction system pacing protocol can be devised for use in any cath lab.  
Hypothesis B: Lead data with a novel sensing vector can detect and categorise conduction system 
capture, which will allow automated conduction system capture discrimination on implanted devices.  
 
1.3 Rational for Current Study 
 
Currently conductions system pacing is undertaken by experts in tertiary centres with the support of 
specialised expensive equipment. However, most conventional pacemakers are implanted without 
this expertise and the advanced equipment. In order to facilitate a wider adoption of conduction 
system pacing a standardised and simplified implant protocol is required. Our study will devise a 
simplified, standardised conduction system implantation protocol in order to increase the access to 
the benefits seen in conduction system pacing.  
2. Study Objectives 
 
Primary Objective 
The primary objective of this study is to simplify conduction system capture implantation thereby 
increasing accessibility of the procedure to more operators worldwide.  
 
Secondary Objective 
The secondary objectives will be  
1. To reduce the overall procedure and fluoroscopy time with utilisation of targeted lead 
deployment.  
2. Improve conduction system capture discrimination by the device and subsequently increase 
battery longevity, through development of a unique algorithm.  
 
3. Recruitment 
 
300 patients will be recruited to this study. 100 patients will be recruited to the invasive aspect of this 
study. These 100 patients will be divided into two-groups: patients 1-50 will be the derivation cohort 
and will undergo the tests in the derivation arms of Study A and Study B, patients 51-100 will be the 
validation cohort and will undergo the tests in the validation arms of Study A and Study B. 
 
200 patients with a conduction system device in situ prior to commencement of this study, under 
pacing follow-up will also be recruited.  
 
Invasive study recruitment 
100 prospective patients with an indication for a pacemaker will be recruited from Imperial College 
Healthcare NHS trust. The direct care team will screen the records and identify patients that are 
suitable for the study. There will be two groups of patients: 
 
1. Derivation cohort 
These patients will undergo the research protocols of the studies. The data will be collated and 
analysed to develop our unique algorithms. This group will consist of the first fifty patients recruited 
(patients 1-50). 
 
 
 

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There will be three groups in this cohort 
 
1. Group 1 (all 50 patient): These will undergo 
a. Preimplant: ECG, echocardiography, ultra-high frequency ECG and MRI 
b. Intra-implant: Right ventricular mapping, ultra-high frequency ECG and 
echocardiography  
2. Group 2 (24 patients): These patients will undergo 
a. Preimplant: ECG, echocardiography, ultra-high frequency ECG, MRI  
b. Intra-implant: Right ventricular mapping, ultra-high frequency ECG, echocardiography 
and ECGi 
3. Group 3 (15 patients): These patients will undergo 
a. Preimplant: ECG, echocardiography, ultra-high frequency ECG and MRI 
b. Intra-implant: Right ventricular mapping, ultra-high frequency ECG echocardiography 
and arterial access for left ventricular mapping and invasive blood pressure 
monitoring 
 
 
2. Validation cohort 
The step by step algorithms devised from the data collected from the derivation cohort to improve the 
conduction system lead implant will be prospectively applied on these patients and the outcomes will 
be assessed. This group will consist of the second fifty patients recruited (patients 51-100). 
 
 
Conduction system implant follow-up recruitment 
Prospective, pseudonymised electrical data from 200 patients with a chronic conduction system 
device in situ, that are under follow up will be collected. They will undergo the standard clinical 
pacing checks and manoeuvres. 
 
The 100 prospectively recruited patients and the 200 patients with a chronic conduction system lead 
will undergo a consent process. The direct care team will obtain consent to share their information 
with the research care team. Once the patient has consented to their information being shared, a 
member of the research team will contact the patient and explain the details of the research study. 
Written consent will be gained prior to any procedures taking place.  
 
Patients will be consented to take part in the ECGi (Derivation Cohort, Group 2), invasive blood-
pressure monitoring and left ventricular mapping (Derivation cohort, Group 3) sub-studies at the 
time of recruitment, until recruitment target for these sub-studies are met. 
 

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Figure 3: A diagram to illustrate patient recruitment for Study A. A total of 100 patients will be 
recruited. Patients 1-50 will be the derivation cohort and 51-100 will be the validation cohort. 
Within the derivation cohort, some patients will undergo ECGi, additional arterial access and 
intracardiac echo (ICE), some will undergo two of these additional tests, some will undergo one and 
some will not undergo any at all. All patients in the derivation cohort will undergo preimplant ECG, 
echocardiography, ultra-high frequency ECG (UHF ECG) and MRI, as well as right ventricular 
mapping, UHF ECG and echocardiography during the implant. 
 
 

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Figure 4: Recruitment of patients in Study B 
 
4. Methodology 
4.1 Derivation 
 
Study A:  
In Study A the derivation cohort will comprise of 50 prospectively recruited patients. These patients 
will undergo the research protocol. In these patients, we will attempt to implant a permanent 
conduction system pacing lead, in lieu of the RV or LV lead. The lead will be implanted by operators 
who have implanted more than 40 leads to overcome the learning curve.  
 
The participants will undergo the following procedural steps after written informed consent is gained: 
 
1. Pre-implant Cardiac MRI (Non-invasive) 
Patients will undergo cardiac MRI as part of their standard clinical care. As it is an MRI there 
will be no radiation exposure. Gadolinium contrast will be used to better define anatomy and to 
assess fibrosis.  
 
2. Pre-implant 12-lead ECG 
Patients will undergo a surface 12-lead ECG as part of their standard clinical care. 
 
3. Pre-implant echocardiogram 
Patients will undergo transthoracic echocardiogram as part of their standard clinical care. 
 
4. Pre- and intra-procedural UHF-ECG (Non-invasive) 
UHF-ECG will be recorded with the aim of assessing the level of conduction system block 
(during intrinsic conduction) and to establish capture type and degree of correction of 
conduction system disease. This could potentially help in choosing between His-bundle pacing 

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and left bundle pacing. This is a non-invasive surface ECG, similar to a 12-lead ECG, that is 
collected over several heart beats.  
 
5. ECGi (Non-invasive activation map)  
With pre-procedural CT 
A subgroup of patients will undergo non-invasive electrical mapping using a specialised vest 
with multiple electrodes called ECGi. The ECGi system involves a 252 electrode ECG vest to 
record activation of the entire heart in a single beat. Patients have a CT scan with the vest on, 
so the exact anatomical location of the electrodes relative to the heart can be determined. 
ECGi can provide electrical activation maps and can be used to calculate the left ventricular 
activation time (LVAT). This is an optional procedure and the patient can participate in the 
study without the ECGi map.  
 
6. Electro-anatomical 3D mapping (Invasive) 
As standard, an infraclavicular incision will be made and access to the venous system gained. 
 
a. Right ventricular map 
The mapping catheter will be passed into the right ventricle via a sheath through the same 
venous access site used for the pacemaker leads. Once the anatomical and electrical maps 
are collected of the right heart, the mapping catheter will be removed and the conduction lead 
will be placed in the same sheath.  
 
We will then pace from multiple sites during the process of endocardial mapping. The lead will 
not be deployed at these sites. The lead tip will be in contact with the myocardium. This form 
of electrical pace mapping is standard clinical practice during pacemaker implantation. I will 
collect the electrical information from the lead, ECGs and EGMs at these sites in order to 
identify reliable hallmarks to guide lead deployment at the target site. Through this process I 
will identify areas of successful and unsuccessful implantation and areas to avoid lead 
deployment. 
 
The anatomy maps will be correlated with fluoroscopy and cardiac MRI to characterise the 
appearance of the lead in relation to the the structures of the heart, not only within normal 
chamber dimensions but also abnormal chamber dimensions.  
 
In the event of difficult lead implantation and lead deployment in unconventional areas, cardiac 
MRI will be used retrospectively to identify areas of septal fibrosis and variations in anatomy. 
The electrical hallmarks of fibrosis will be identified using EGM, lead parameters and 12-lead 
ECG. 
 
b. Left ventricular map  
If the patients consent, 15 of the 50 participants will undergo left ventricular electro-anatomical 
mapping to assess ventricular activation patterns when a left bundle lead is deployed through 
the septum. The patients will have additional access from the right femoral artery in order to 
access the aortic circulation. The mapping catheter will be delivered to the left ventricle 
through a retrograde approach. The left ventricle will be mapped at two points of lead 
deployment 
1. Lead in deep septum 
2. Lead at left bundle 
The lead will pace at each of these points of deployment and the activation maps will be 
collected.  
 
Haemodynamic outcomes of left septal and left bundle pacing, using invasive and non-
invasive blood pressure monitoring will be assessed. Invasive blood pressure will be collected 
from the femoral arterial access already obtained for the mapping catheter, where the sheath 
will be connected to a pressure inducer. Non-invasive blood pressure will be collected using a 
high precision beat by beat blood pressure cuff that is placed on the index finger (Finometer). 
 

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These patients will undergo additional consent in which the risks and benefits of the arterial 
access and the left ventricular maps will be explained. This is an optional procedure and the 
patient can participate in the study without undergoing a left ventricular map or invasive blood 
pressure monitoring.  
 
 
5. Echocardiogram (Invasive and Non-invasive) 
During lead deployment we will visualise lead-septum interaction from echo and fluoroscopic 
imaging. Echocardiography directly visualises lead orientation, entanglement and progression. 
Characteristics of successful and unsuccessful deployment, lead progression and lead 
trajectory will be identified and how this is seen on fluoroscopy. The aim is to use this data to 
develop the algorithm to inform us whether deployment is progressing well or not well and if 
so, what is the reason for failure of lead progression.  
 
In a subgroup of patients, we will perform intracardiac echo to visualise the lead, if patients 
consent to this test. This will involve access from the right femoral vein for these patients. 
These patients will be additionally consented on implications and benefits of intracardiac echo 
to the procedure. This is an optional procedure and the patient can participate in the study 
without undergoing intracardiac echocardiogram.  
 
Those who do not undergo an intracardiac echocardiogram, will have their leads visualised by 
transthoracic echocardiography (if there are adequate windows) or paediatric 
transoesophageal echocardiography (TOE), which will eliminate the need for sedation. 
Participants undergoing TOE will have additional consent. 
 
The right heart mapping will add 10 minutes to the overall procedure time. Left ventricular maps, will 
add a total of 14 minutes (7 minutes per map). The echocardiography will add 5 minutes to the overall 
procedure time which will include gaining additional access in ICE, visualisation of the lead and 
removal.  
 
The aim is that the protocol we will develop will use information which can be acquired from the 
pacing lead, surface ECG and fluoroscopy without the need for pre-procedure MRI scans, electro-
anatomical mapping or intra-procedure echocardiography (we will use these systems in our study to 
help develop and validate the algorithm in addition to understanding and correcting mechanisms of 
failure). 
 
The ECG, lead parameters (seen on the pacing system analyser (PSA), a machine used to test the 
pacemaker leads) and fluoroscopic hallmarks of optimal initial deployment positions and optimal lead-
septum interactions will be converted to a step-by-step guide for implanters without the need of 
specialised EP equipment, to achieve conduction system pacing in a systematic and reliable way. The 
diagnostic characteristics on 12-lead ECG and lead parameters will be analysed by software that can 
be integrated into the PSA. 
 
Study B: 
In patients 1-50 undergoing implantation of conduction system pacemakers, I will collect a 2-lead 
surface ECG alongside conventional lead data. A surface 12-lead ECG will be collected as well. The 
patients will undergo the standard pacing manoeuvres for conduction system pacing. The patient will 
be paced using the PSA and a 12-lead ECG and 2-lead ECG will be collected via Bard, a computer 
software that is able to collect highly accurate ECG traces of the heart using mapping catheters 
placed inside the heart and the surface ECG.  
 
I will also collect prospective data from 200 patients with a chronic conduction system lead implant 
under device follow-up to obtain EGM, 12 -lead ECG and the 2-lead ECG recordings of multiple 
pacing and sensing configurations. These patients will be attending for routine appointments. The 
pacing and sensing configurations are undertaken as part of routine checks. The direct care team will 
identify the patients that are suitable and obtain consent for participating sharing their information with 
the research team. The research team will contact the patients and obtain informed written consent. 

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During the follow-up appointment, a member of the research team will apply the 2-lead ECG and the 
direct care team will perform the manoeuvres. The research team will collect data. 
 
I will work with my team to develop algorithms to reduce the impact of local muscle noise. I will 
improve device diagnosis of conduction system capture using standard lead data, plus the 2-lead 
ECG. I expect this to be achievable by identifying EGM features that are highly discriminant and 
organising these into a systematic algorithm with a defined sensitivity and specificity for each capture 
type.  
 
1.2 Validation 
 
Study A: 
A further 50 patients will be prospectively recruited that will make up the validation cohort for Study A. 
These patients will undergo a conduction system pacemaker as standard clinical practice. We will 
prospectively apply the step-by-step algorithm derived above to implant the conduction system lead 
using standard equipment alone; fluoroscopy, PSA and 12-lead ECG. We will assess the success 
rate, conduction system capture threshold, procedure time and fluoroscopy time. Although all 
operators will be highly experienced device implanters, these implants will include operators who are 
new to conduction system lead implantation. 
The outcomes will be assessed against patients undergoing conventional methods of conduction 
system implantation (50 patients) and right ventricular pacing (50 patients).  
 
Study B: 
I will run the device algorithm to discriminate capture on patients 51 to 100. Through this I will 
establish my algorithm’s accuracy with the addition of the 2-lead ECG against the gold-standard of 
combined 12-lead ECG, EGM and pacing manoeuvre diagnoses. These are standard clinical 
practices. I will test whether inclusion of the pocket EGM contributes to the algorithm’s accuracy. 
 
Follow-up 
Patients will be followed up 6 weeks after device implantation and again at 1 year. These follow-up 
appointments will include a wound check at 6 weeks and device interrogation at 6 weeks and 1 year. 
 
Figure 5: A flow diagram demonstrating the investigations the patient will undergo during the course of 
the Study A 
 
 
 
3. MRI of the heart 

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1.3 Burden/Risk 
The main burdens for the patient include: 
1. The extra time taken to perform the experiments and experimental procedures during their 
scheduled clinical procedure due to the additional diagnostic investigations. The right heart 
electro-anatomical mapping will add 10 minutes. The echocardiography will add an additional 
5 minutes. Those who consent to left ventricular maps will have an additional 14 minutes (7 
minutes per map).  
2. The extra access in the groin in those who consent to have an intracardiac echocardiography 
or left ventricular map (femoral vein and artery respectively). 
3. The extra procedure of transoesophageal echocardiography in those who consent for this  
4. Patients receiving unconventional therapy with conduction system lead implantation 
 
The burden will be mitigated by the minimum extra time being used to complete the experiments, the 
use of local anaesthetic and the immediate removal of extra research related sheaths as soon as they 
are not needed 
 
The main risks for the patient are:  
A conduction system pacing wire is not known to have a higher complication rate compared to a 
conventional pacing wire. Conduction system pacing wires have been shown to be as effective as 
conventional pacing wires at preventing slow heart rates and improving heart pumping. If a 
complication occurs and the conduction system pacing wire cannot be implanted or does not perform 
as expected during follow-up a procedure will be performed to convert your pacing system to a 
conventional pacing system. 
 
The additional risks of arterial tube placement include:  
• 
1% risk of bruising around the area 
• 
1 in 1000 risk of damage to the blood vessels requiring surgery 
• 
Less than 1 in 500 risk of stroke 
The additional risks of transoesophageal echocardiogram include 
• 
1% risk of damaging the food-pipe or wind-pipe including a 1 in 1000 risk of perforating the 
food-pipe.  
The additional risks of intracardiac echocardiogram include 
• 
1% risk of bruising around the access area in the leg 
• 
Less than 1 in 1000 risk of heart perforation 
The additional risks of electro-anatomical mapping include 
• 
Less than 1 in 1000 risk of heart perforation 
 
Therefore, the overall risk of serious complications arising from taking part in the research study are 
less than 4 in 1000 (0.4%) 
 
Participants in this study will have a chest CT scan which is not part of standard care. Pacemaker 
implantation involves exposure to ionising radiation to visualise lead implantation. Taking part in this 
study involves exposure to additional exposure to radiation above the standard clinical procedure due 
to the additional measurements that will be taken. 
 
Ionising radiation can cause cell damage that may, after many years or decades, turn cancerous. We 
are all at risk of developing cancer during our lifetime. The normal risk is that this will happen to about 
50% of people at some point in their life. Taking part in this study will increase the chances of this 
happening to you from 0.01% to 0.1% 
 
1.4 Study Outcome Measures 
Primary Outcome Measures 
A1: Success rates of conduction system lead implant (novel workflow vs conventional methods) 
B1: Assess accuracy of conduction system diagnosis by the device with additional information 
from 2-lead ECG 

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Secondary Outcome Measures 
 
A2: Procedure and fluoroscopy times of the streamlined workflow to current conventional 
methods of His-bundle and Left-bundle pacing 
A2: Procedure and fluoroscopy times of the streamlined workflow of conduction system implant 
to current right ventricular pacing 
A2: Assess capture threshold of His-bundle and Left-bundle pacing from the optimised workflow 
to that of conventional methods of conduction system implantation  
A2: Define left bundle area capture diagnostics and delineate differences between left ventricular 
septal pacing. 
B2: Improvement in device battery life with novel device algorithm applied 
 
5 Participant Entry  
5.1 Pre-registration Evaluations 
5.2 Inclusion Criteria 
 
1. Patients with a ventricular pacing indication: high grade atrioventricular block and symptomatic 
trifasicular, bifasicular block or left bundle branch block LBBB for cardiac resynchronisation 
therapy 
2. Adults willing to take part (ages 18 – 100 years old)   
3. Able to give consent. 
 
5.3 Exclusion Criteria 
 
1. Unable to give consent 
2. Children age < 18 years and adults > 100 years old 
3. Pregnant patients 
As per standard of care, female patients of child-bearing age will have a urine pregnancy test 
prior to their procedure.   
 
5.4 Withdrawal criteria 
 
The research protocol will be terminated early if  
1. Patients lose their capacity to consent or become clinically unstable  
2. The patient chooses to withdraw from the study 
3. The sponsor, the chief investigator or the research team review the data and decide to stop 
the study 
 
5.5 Consent 
 
Patients will be identified by members of their direct care team when they attend clinic appointments 
or are admitted as an inpatient to the hospital. Patient records may be reviewed to assess suitability 
and this will be performed by members of the direct care team. Participation in the study will be 
discussed with the patients by their direct care team and information will only be passed on to the 
research team with the patients consent. Verbal consent will be gained by the direct care team for 
personal contact information to be shared with the research team. This will be documented in the 
patient notes. 
 

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The direct care team will make patients aware that participation is voluntary and that if they do not 
wish to participate it will not affect their usual care.  
 
Consent for the study of the prospectively recruited patients will be obtained by a member of the 
research team, this will be a physician who is experienced in performing conduction system 
implantation. Patients will have details of the study discussed with them and any family members or 
friends the patients wish to be present. They will also be provided with written information (patient 
information sheets). Patients will be given as much time as they wish, with a minimum of at least 24 
hours, to decide whether they wish to participate in the study and will be offered additional visits to 
further discuss the study if they wish. Patients are able to withdraw their consent from the study at any 
time. Patients will be made aware that their participation is voluntary and that if they do not want to 
take part it will not affect their usual care. Patients who agree to take part in the study will sign a 
consent form, a copy of the form will be given to the patients and a second copy will be kept in their 
study record file. A copy will also be kept in the site file.  
6 Adverse events 
6.1 Definitions  
 
Adverse Event (AE): any untoward medical occurrence in a patient or clinical study subject.   
 
Serious Adverse Event (SAE): any untoward and unexpected medical occurrence or effect that: 
• 
Results in death 
• 
Is life-threatening – refers to an event in which the subject 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 
• 
Requires hospitalisation, or prolongation of existing inpatients’ hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
 
Medical judgement should be exercised in deciding whether an AE is serious in other situations.  
Important AEs that are not immediately life-threatening or do not result in death or hospitalisation but 
may jeopardise the subject or may require intervention to prevent one of the other outcomes listed in 
the definition above, should also be considered serious. 
 
6.2 Reporting Procedures 
 
All adverse events should be reported.  Depending on the nature of the event the reporting procedures 
below should be followed.  Any questions concerning adverse event reporting should be directed to the 
Chief Investigator in the first instance.   
 
6.3 Non serious AEs 
 
All such events, whether expected or not, should be recorded.   
 
6.4 Serious AEs 
 
An SAE form should be completed and faxed to the Chief Investigator within 24 hours.  However, 
hospitalisations for elective treatment of a pre-existing condition do not need reporting as SAEs. 
 
All SAEs should be reported to the West of Scotland (REC 4) where in the opinion of the Chief 
Investigator, the event was: 
• 
‘related’, ie resulted from the administration of any of the research procedures; and 
• 
‘unexpected’, ie an event that is not listed in the protocol as an expected occurrence 
 

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Reports of related and unexpected SAEs should be submitted within 15 days of the Chief Investigator 
becoming aware of the event, using the NRES SAE form for non-IMP studies.  The Chief Investigator 
must also notify the Sponsor of all related and unexpected SAEs. 
 
Local investigators should report any SAEs as required by their Local Research Ethics Committee, 
Sponsor and/or Research & Development Office.  
 
 
Contact details for reporting SAEs 
RGIT@imperial.ac.uk 
Dr Zachary Whinnett email: z.whinnett@imperial.ac.uk 
Please send SAE forms to: Hammersmith Hospital, Du Cane road, London W12 0HS. 
Tel: 020 8383 4967 (Mon to Fri 09.00 – 17.00) 
7 Assessment and Follow-up 
 
Patients will be followed up for a 1 year period. During this time they will undergo the device 
interrogation and wound check at 6 weeks as part of standard clinical care. One year after device 
implantation, patients will undergo a device interrogation follow-up appointment. Any incidental 
findings that we identify during the study will be reviewed by the research team and reported to the 
GP and also the cardiology team normally looking after the patient.  
 
 
Definition of end of Study 
The end of the study will be defined as completion of the 1 year follow-up of the 100 prospectively 
recruited patients for the invasive aspect of the study. This will be the date of the final visit of the last 
participant at 1 year.  
8 Statistics and data analysis 
 
The following statistical analysis has been reviewed and approved by our statistician, Prof. Darrel 
Francis. 
 
In Study A, I want the validation cohort to be big enough to calculate the success rate percentage 
with an error margin (standard error) of <10 percentage points in line with primary outcome A1. 
Similarly, for Study B, I want the validation cohort to show the accuracy of my algorithm with an SE 
under 10 percentage points in line with primary outcome B1. The standard error of a proportion p, in a 
sample of n patients, is √[p(1-p)/n], i.e. n=p(1-p)/SE2. Applying SE=0.1 (worst-case proportion 0.5) 
reveals the bare-minimum n required is 0.5*0.5/0.12=25. I will have 50, to ensure the SE <10 
percentage points.  
 

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Figure 1: A illustration to demonstrate the primary and secondary outcomes of Study A and Study B.  
* Sample size calculations indicate 50 patients will provide >80% power (see Section 8, statistics 
and data analysis for more information) 
 
9 Regulatory issues 
 
9.1 Ethics approval 
 
The Study Coordination Centre has obtained approval from the “Name of REC when allocated” and 
Health Research Authority (HRA). The study must also receive confirmation of capacity and capability 
from each participating NHS Trust before accepting participants into the study or any research activity 
is carried out. The study will be conducted in accordance with the recommendations for physicians 
involved in research on human subjects adopted by the 18th World Medical Assembly, Helsinki 1964 
and later revisions. 
 
9.2 Consent  
 
Consent to enter the study must be sought from each participant only after a full explanation has been 
given, an information leaflet offered and time allowed for consideration.  Signed participant consent 
should be obtained.  The right of the participant to refuse to participate without giving reasons must be 
respected.  After the participant has entered the study the clinician remains free to give alternative 
treatment to that specified in the protocol at any stage if he/she feels it is in the participant’s best interest, 
but the reasons for doing so should be recorded.  In these cases the participants remain within the 
study for the purposes of follow-up and data analysis.  All participants are free to withdraw at any time 
from the protocol treatment without giving reasons and without prejudicing further treatment. 
 
 

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9.3 Confidentiality 
 
The Chief Investigator will preserve the confidentiality of participants taking part in the study and is 
registered under the Data Protection Act.  
Data will be pseudonymised. 
 
9.4 Indemnity 
 
Imperial College London hold negligent harm and non-negligent harm insurance policies which apply 
to this study. 
 
9.5 Sponsor 
 
Imperial College London will act as the main Sponsor for this study.  Delegated responsibilities will be 
assigned to the NHS trusts taking part in this study.   
 
9.6 Funding 
 
The British Heart Foundation. 
 
9.7 Audits  
 
The study may be subject to inspection and audit by Imperial College London under their remit as 
sponsor and other regulatory bodies to ensure adherence to GCP and the UK Policy Frame Work for 
Health and Social Care Research 
10 Study Management 
 
The day-to-day management of the study will be co-ordinated by Dr Akriti Naraen. 
11 Publication Policy 
 
Our aim to publish in a major international cardiology journal and present at international cardiology 
conferences. 
 
 
 
 
 

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12 Appendix 
 
Table 1: Time consuming and complex criteria for conduction system capture. (1,11,12) 
Intrinsic 
QRS 
Degree of BBB 
correction 
His Bundle Pacing 
S-HPB 
NS HBP 
Normal 
QRS 
Nil 
Stim-QRSend = H-QRSend 
Paced QRSd = intrinsic QRSd 
Stim-vent = H-vent 
Single capture threshold 
Stim-QRSend < H-QRSend +/- pseudodelta 
wave 
Paced QRSd > intrinsic QRSd 
Two distinct capture thresholds  
LBBB 
Full correction 
Normal QRS appearance 
Stim-QRSend < H-QRSend 
Paced QRSd <120ms < intrinsic QRSd 
Pre-excited normal QRS appearance 
Stim-QRSend usually < H-QRSend 
Paced QRSd > 120ms 
Paced QRSd usually < intrinsic QRSd 
 
Partial correction 
LBBB morphology 
Stim-QRSend < H-QRSend 
Paced QRSd < instrinsic QRSd 
LBBB QRS morphology 
Stim-QRSend < / = H-QRSend 
Paced QRSd >120ms 
Paced QRSd usually < intrinsic QRSd 
 
No correction 
Stim-QRSend = H-QRSend 
LBBB morphology 
Paced QRSd = intrinsic QRSd 
LBBB morphology 
Paced QRSd > intrinsic QRSd 
 
Myocardium only 
capture 
LBBB morphology 
Stim QRSend usually > H-QRSend 
Paced QRSd > intrinsic QRSd 
 
RBBB 
Bundle recruitment 
Normal QRS appearance 
Stim-QRSend < H-QRSend 
Paced QRSd < 120ms < intrinsic QRSd 
Pre-excited normal QRS appearance 
Stim-QRSend < H-QRSend 
Paced QRSd </=/> intrinsic QRSd 
 
Resynchronisation 
NS-HBP without right bundle recruitment 
 
Pre excited normal QRS appearance  
Stim-QRSend < H-QRSend /paced QRSd < 
intrinsic QRSd 
 
No bundle 
recruitment or 
resynchronisation 
S-HBP without right bundle recruitment 
 
RBBB morphology 
Stim-QRSend = H-QRSend /paced QRSd = 
intrinsic QRSd 
 
Myocardium only 
capture 
LBBB morphology 
Stim-QRSend > H-QRSend /paced QRSd 
>intrinsic QRSd 
 
 
 
 
 

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13 References 
 
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Arnold AD, Shun-Shin MJ, Keene D, Howard JP, Chow JJ, Lim E, et al. Electrocardiographic 
predictors of successful resynchronization of left bundle branch block by His bundle pacing. J 
Cardiovasc Electrophysiol. 2021;32(2).  
3. 
Huang W, Chen X, Su L, Wu S, Xia X, Vijayaraman P. A beginner’s guide to permanent left 
bundle branch pacing. Heart Rhythm. 2019;16(12).  
4. 
Ali N, Shin MS, Whinnett Z. The Emerging Role of Cardiac Conduction System Pacing as a 
Treatment for Heart Failure. Vol. 17, Current Heart Failure Reports. 2020.  
5. 
Upadhyay GA, Vijayaraman P, Nayak HM, Verma N, Dandamudi G, Sharma PS, et al. On-
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Bhatt AG, Musat DL, Milstein N, Pimienta J, Flynn L, Sichrovsky T, et al. The Efficacy of His 
Bundle Pacing: Lessons Learned From Implementation for the First Time at an Experienced 
Electrophysiology Center. JACC Clin Electrophysiol. 2018;4(11).  
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Sharma PS, Naperkowski A, Bauch TD, Chan JYS, Arnold AD, Whinnett ZI, et al. Permanent 
his bundle pacing for cardiac resynchronization therapy in patients with heart failure and right 
bundle branch block. Circ Arrhythm Electrophysiol. 2018;11(9).  
8. 
Jastrzȩbski M, Moskal P, Hołda MK, Strona M, Bednarek A, Kiełbasa G, et al. Deep septal 
deployment of a thin, lumenless pacing lead: A translational cadaver simulation study. 
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Burri H, Gerritse B, Davenport L, Demas M, Sticherling C. Fluctuation of left ventricular 
thresholds and required safety margin for left ventricular pacing with cardiac resynchronization 
therapy. Europace. 2009;11(7).  
10. 
Bland M. An Introduction to Medical Statistics. 4th ed. Oxford: Oxford University Press; 2015.  
11. 
Deshmukh A, Deshmukh P. His bundle pacing: Initial experience and lessons learned. Vol. 49, 
Journal of Electrocardiology. 2016.  
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Vijayaraman P, Dandamudi G, Zanon F, Sharma PS, Tung R, Huang W, et al. Permanent His 
bundle pacing: Recommendations from a Multicenter His Bundle Pacing Collaborative Working 
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