AV Optimisation Delivered With Direct His Bundle Pacing, in Patients With Heart Failure, Long PR Without Left Bundle Branch Block: Randomised Multi-centre Clinical Outcome Study.
Phase: NA
Conditions: Heart Failure
Sponsor: Imperial College London

HOPE-HF 
Sponsor: Imperial College (study ref: 15HH2828)  
V 6.0    25 Jan 2018 
 
 
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CLINICAL STUDY PROTOCOL 
 
 
Study Title: 
AV optimisation delivered with direct His bundle pacing, in 
patients with heart failure, long PR without left bundle branch 
block: randomised multi-centre clinical outcome study. 
 
The His Optimised Pacing Evaluated for Heart Failure Trial 
(HOPE-HF)  
 
 
 
 
Sponsor: 
 
 
Imperial College London 
 
 
Sponsor’s reference: 
15HH2828 
 
REC Reference no. : 
15/LO/1402 
 
 
Version no:                       6.0            
 
 
 
 
 
Protocol Date:  
 
25 Jan 2018 
 
 
 
 
 
 
 
 
 
 
Property of Imperial College 
May not be used, divulged or published without the consent of IC 
 

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CONTACT LIST 
 
Chief Investigator  
 
Dr Zachary Whinnett 
Department of Cardiology 
Division of Surgery, Cancer and Cardiovascular Sciences 
Hammersmith Hospital  
160 Du Cane Road,  
London W12  0HS 
 
Tel: 
0208 383 4967 
Fax: 0203 313 4095 
 
Name of contact person 
Dr Daniel Keene 
Research Fellow 
Department of Cardiology 
Division of Surgery, Cancer and Cardiovascular Sciences 
Hammersmith Hospital  
160 Du Cane Road,  
London W12  0HS 
 
Tel: 
0208 383 7380 
 
Sponsor 
 
Joint Research Compliance Office 
Imperial College London and Imperial College Healthcare NHS Trust 
Room 215, Level 2, Medical School Building 
Norfolk Place 
London, W2 1PG 
 
Ms Becky Ward 
Tel: 
0207 594 9459 
Email: becky.ward@imperial.ac.uk 
 
Funders 
 
British Heart Foundation 
Greater London House 
180 Hampstead Road 
London 
NW1 7AW 
Tel: 0207 5540434 
Medtronic  
Operational headquarters 
710 Medtronic Parkway 
Minneapolis 
MN 
USA 
Tel: 001 (763) 514 4000 
 
 
 
 
ICTU Operations Manager  

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Hilda Tsang 
68 Wood Lane 
London 
W12 7RH 
Tel: 
0207 594 1337 
 
Senior Trial Statistician  
Emanuela Falaschetti 
68 Wood Lane 
London 
W12 7RHTel: 
0207 594 1846 
 
Health Economist 
Daan Mathijssen 
Faculty of health, Medicine and life Sciences 
Maastricht University 
6200 MD MAASTRICHT  
Tel: 06-38151206  
 
 
 
Device Manufacturer 
 
Medtronic  
Operational headquarters 
710 Medtronic Parkway 
Minneapolis 
MN 
USA 
Tel: 001 (763) 514 4000 
 
 
Name of contact person 
Dr Berthold Stegemann 
Principal Scientist 
External Research Programme 
Endepolsdomein 5 
6229GW Maastricht 
Netherlands 
Tel: 
+49 228 9289 4161 
Email: berthold.stegemann@medtronic.com 
 

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ABBREVIATIONS (amend as necessary) 
 
AE 
Adverse Event 
CI 
Chief Investigator 
CRF 
Case Report Form 
DMC 
Data Monitoring and Ethical Committee 
GCP 
Good Clinical Practice 
ICMJE 
International Committee of Medical Journal Editors 
ICTU 
Imperial Clinical Trials Unit 
REC 
Research Ethics Committee 
QA 
Quality Assurance 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOP 
Standard Operating Procedure 
TMG 
Trial Management Group  
TSC 
Trial Steering Committee 
 
 

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Table of Contents 
Contents 
TRIAL SUMMARY 
7 
1 
INTRODUCTION 
9 
1.1 
Rationale for the study 
9 
1.2  
Intervention details 
10 
1.3  
Risk / Benefit Assessment 
11 
2 
OBJECTIVES and endpoints 
12 
2.1 
Primary Objective 
12 
2.2 
Secondary Objective 
12 
2.3 
Primary Endpoint 
12 
2.4 
Secondary Endpoints 
12 
3 
STUDY DESign 
13 
3.1 
Design 
13 
3.2 
Treatment regimens 
13 
4 
PARTICIPANT ENTRY 
13 
4.1 
Study population 
13 
(i) 
Inclusion criteria ............................................................................................................. 13 
(ii) 
Exclusion criteria ............................................................................................................ 13 
5 
PROCEDURES AND MEASUREMENTS 
14 
5.1 
Screening and pre-randomisation evaluations 
14 
5.2 
Visit Schedule 
14 
5.3 
Treatment 
15 
5.4 
Randomisation and Crossover 
16 
5.5 
Study assessments 
16 
5.6 
Final study visit 
17 
5.7  
Unblinding 
17 
6 
TREATMENTs 
18 
6.1  
Medical Devices 
18 
6.2 
Labelling and Packaging 
18 
6.3 
Storage and Administration 
18 
6.4   
Monitoring Device Performance 
18 
6.5 
Device Precautions 
18 
6.6 
Permanent Discontinuation of Study Treatment and Withdrawal from Study 
19 
7 
ADVERSE EVENTS AND Device vigilance 
19 
7.1  
Adverse Event (AE) 
19 
7.2 
Adverse Event recording 
19 
(i) 
Severity of Adverse Events ............................................................................................ 19 
(ii) 
Causality of Adverse Events .......................................................................................... 20 
7.3 
Serious Adverse Events (SAE) 
20 
i) Definition of SAE .................................................................................................................. 20 
(ii) 
Reporting of SAEs ......................................................................................................... 20 
7.4 
Adverse Device Effects 
21 
7.5   
Reporting of Unexpected and Serious Adverse Events 
21 
8 
STATISTICAL ANALYSES 
22 
8.1 
Sample Size and power considerations 
22 
8.2 
Data Analysis 
22 
(i) 
Endpoint Analysis .......................................................................................................... 22 
(ii) 
Safety Analysis .............................................................................................................. 23 
iv)  
Sub-group Analysis ........................................................................................................ 23 

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9 
REGULATORY, ETHICAL AND LEGAL ISSUES 
24 
9.1 
Declaration of Helsinki 
24 
9.2 
Good Clinical Practice 
24 
9.3 
Independent Ethics Committee Approval 
24 
(i) 
Initial Approval ............................................................................................................... 24 
(ii) 
Approval of Amendments ............................................................................................... 24 
(iii) 
Annual Progress Reports ............................................................................................... 24 
(iv) 
End of Trial Notification .................................................................................................. 25 
9.4 
Sponsorship, Insurance and Indemnity 
25 
9.5 
Trial Registration 
25 
9.6  
Informed Consent 
25 
9.7 
Contact with General Practitioner 
25 
9.8 
Subject Confidentiality 
25 
9.9 
End of Trial 
26 
9.10 
Study Documentation and Data Storage 
26 
10 
DATA MANAGEMENT 
26 
10.1 
Source Data 
26 
10.2 
Language 
26 
10.3 
Database 
26 
10.4 
Data Collection 
26 
11 
STUDY MANAGEMENT STRUCTURE 
27 
11.1 
Trial Steering Committee 
27 
11.2 
Trial Management Group 
27 
11.3 
Data Monitoring Committee 
27 
11.4 
Early Discontinuation of the Study 
27 
11.5 
Risk Assessment 
27 
11.6  
Monitoring 
27 
11.7 
Quality Control and Quality Assurance 
27 
11.8  
Disclosure of Data and Publication 
27 
12  
REFERENCES 
28 
SIGNATURE PAGE 1 (Chief Investigator) 
32 
SIGNATURE PAGE 2 (SPONSOR) 
33 
SIGNATURE PAGE 3 (STATISTICIAN) 
34 
SIGNATURE PAGE 4 (principal INVESTIGATOR) 
35 
Appendix 1. Treatment Regimens 
1 
Appendix 2. Summary of study procedures/assessments by visit 
2 
 
 
 
 

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TRIAL SUMMARY 
 
TITLE  
AV optimisation delivered with direct His bundle pacing, in patients with heart failure, long 
PR without left bundle branch block: randomised multi-centre clinical outcome study. The 
His Optimised Pacing Evaluated for Heart Failure Trial (HOPE-HF) 
 
OBJECTIVE 
To evaluate whether, a group of heart failure patients who are not currently targeted for 
pacing therapy for heart failure, will obtain benefit from pacing therapy delivered to allow 
optimisation of LV preload by shortening Atrioventricular delay. 
 
DESIGN 
This is a multi-centre, prospective randomised double-blinded cross over study, recruiting a 
sub-population of patients with heart failure. 
All patients will be implanted with a CRT device with one of the leads positioned on the His 
bundle in order to obtain direct His-bundle capture. There will be a 2-month run-in period 
where the device will be programmed not to deliver His pacing therapy during this period. 
A double-blinded cross-over design will then be employed to investigate the effect of His 
pacing. Patients will be allocated in random order to six month treatment periods in each of 
the following two states (1) No His pacing; (2) AV optimised His-bundle pacing. Endpoint 
measurements will be taken at baseline, 6 months and 12 months post randomisation. 
Treatment allocation will be blinded to the endpoint assessor.  
 
SAMPLE SIZE 
126 patients will be needed to detect the expected effect size on the primary endpoint with 
90% power. A total of 160 patients will be randomised to allow for patient drop-out.   
 
INCLUSION CRITERIA 
• Aged 18 or above 
• Ventricular Ejection Fraction (EF) ≤ 40%; BNP needs to be ≥250ng/L for patients with 
EF 36-40%  
• New York Heart Association (NYHA) class II-IV 
• PR interval ≥200ms 
• Narrow QRS duration (≤140ms) or prolonged QRS duration with typical Right Bundle 
Branch Block (RBBB) morphology on 12 lead ECG and sinus rhythm 
 
EXCLUSION CRITERIA 
• Permanent or persistent atrial fibrillation (AF)   
• Paroxysmal atrial fibrillation with history of sustained AF (more than 24 hours) in the 
6 months prior to screening   
• Patients who are unable to perform cardiopulmonary exercise testing  
• Other serious medical condition with life expectancy of less than 1 year  
• Lack of capacity to consent 
• Pregnancy 
• Contraindication to use of the relevant study device or leads (as per current 
manuals from manufacturer) 
 
 
 

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TREATMENT/MAIN STUDY PROCEDURES 
Implantation of pacemaker or Implantable cardioverter defibrillator. In all patients leads will 
be positioned in the right atrium and at the His bundle. Participants who are not eligible for 
ICD implantation will have a lead positioned in a lateral ventricular branch of the coronary 
sinus. Those receiving an ICD will have an ICD lead positioned in the RV apex or RV 
septum.  
 
AV delay optimisation will be performed using continuous non-invasive blood pressure 
measurements, with an algorithm to minimise the effect of noise. 
 
PRIMARY ENDPOINT 
The primary outcome measure will be exercise capacity, measured using peak oxygen 
uptake (VO2). 
 
SECONDARY ENDPOINTS 
 
Secondary outcome measures will be echocardiographic measurement of left ventricular 
dimensions, quality of life scores, daily activity levels as recorded by the implanted device, 
cost effectiveness, changes in B-type Natriuretic Peptide (BNP), arrhythmia burden, pacing 
parameters (e.g. pacing thresholds, R Wave amplitude and lead impedance) and 
fluoroscopy time at time of device insertion. 
 

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1 
INTRODUCTION  
Heart failure is a major clinical problem, causing a high symptom burden and high mortality 
rates1,2. In the UK heart failure accounts for 1 million days of inpatient stay per year, this is 
~ 2% of all NHS hospital inpatient days and 5% of emergency admissions3. 
Hospitalisation for heart failure is expected to rise by 50% over the next 25 years. Heart 
failure also causes significant mortality (35% mortality in the first year after diagnosis and 
then 10% thereafter). There are currently ~900 000 patients in the UK with heart failure3. 
 
Cardiac resynchronisation therapy (CRT) is an important treatment, which has been shown 
to improve symptoms, reduce hospital admissions4,5 and decrease mortality6. 
However, CRT is only applicable to some patients with heart failure: those who have left 
bundle branch block7. Therefore a new method of pacing therapy that can benefit a group 
of heart failure patients not currently targeted for CRT would be a major advance. 
Currently patients with narrow QRS duration or right bundle branch block are not routinely 
selected for treatment with CRT because, when tested in a bias-resistant manner, the results 
have not been favourable8,9. However, these studies did not specifically target the group 
who are most likely to derive benefit, namely those with a long PR interval. In addition 
classical CRT when applied to patients with good intraventricular conduction appears to 
induce a degree of iatrogenic intraventricular dyssynchrony, which may partly offset the 
benefits of PR interval shortening10. 
PR prolongation in heart failure is associated with poor outcomes (58% higher mortality) 
regardless of QRS duration11. Shortening a prolonged PR interval with pacing therapy 
appears to have beneficial effects. In CRT studies performed in patients with LBBB, longer 
baseline PR interval predicted greater benefit12. In COMPANION, patients with a long PR 
interval had a 17% greater risk reduction compared to those with a normal PR interval13, an 
effect size on par with that of mandatory drugs in heart failure14. Similarly in the 
MADIT-CRT trial, participants with non-LBBB QRS broadening derived a prognostic benefit 
from CRT only when the PR interval was above 230 ms, whereas the opposite effect was 
found when the PR was shorter than 230 ms15. 
In our institution, patients with PR prolongation account for 30% of the non-left bundle 
branch block heart failure population. Therefore in the UK alone this group of patients is 
likely to represent ~180,000 patients. 
1.1 
Rationale for the study 
Optimising left ventricular filling by shortening AV delay has been demonstrated to have a 
powerful effect on acute cardiac function, which is reflected by changes in LV dp/dtmax, 
stroke volume, coronary artery flow and systolic blood pressure16,17,18. We have developed 
a haemodynamic method for identifying optimal AV delay settings with pacing therapy for 
heart failure. The advantage of using systolic pressure is that this is an extra cardiac 
measure, which reflects the net change in cardiac function occurring as a result of 
adjustments in intra cardiac timing. In patients with heart failure, contrary to the general 
population, higher blood pressure is associated with lower mortality19. The increased blood 
pressure occurring with more optimal AV delays is reflected by a sustained increase in 
stroke volume20. 
We have previously shown that when haemodynamic measurements are used for AV 
delay optimisation it is essential to use a method that minimises the effect of noise. Noise 
occurs with all haemodynamic measurements, regardless of whether they are made 

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invasively or non-invasively21. The protocol we have developed for performing AV delay 
optimisation utilises several steps to ensure precise and reproducible measures are 
obtained. These include comparing each tested delay to a reference setting and using the 
mean value of multiple alternations to and from the reference setting22. We have shown 
that it is most efficient to sample immediately after a transition21, to use a sampling window 
which includes the number of beats occurring in 1 respiratory cycle and to perform 
measurements at an elevated heart rate23. We have shown that this method is highly 
reproducible when used for AV delay optimisation22,17. 
As discussed above, improving LV preload by shortening AV delay appears to be an 
important mechanism through which CRT delivers its beneficial effect in patients with left 
bundle branch block and heart failure13. Patients with narrow QRS duration and PR 
prolongation may also be expected to obtain benefit from AV delay optimisation. However, 
applying CRT pacing to patients with good intraventricular conduction appears to induce a 
degree of iatrogenic intraventricular dyssynchrony which has the potential to partly offset 
the benefits of PR interval shortening10. 
In patients with an intact intraventricular conduction system, a special form of pacing called 
direct His-bundle pacing, offers the potential to stimulate ventricular contraction while 
preserving ventricular activation patterns24,25,26. Permanent direct His pacing has been 
shown to be feasible when it has been applied in patients who have a bradycardia 
indication for pacing27 or to reverse proximal LBBB in patients who have failed a 
conventional LV lead implant28. 
Permanent direct His pacing has never been assessed as a method for delivering AV 
delay optimisation to patients with narrow QRS duration or RBBB and heart failure. We 
have assessed the acute haemodynamic effect in this patient population and found 
favourable results29. 
Therefore in this study we will evaluate whether, a new group of heart failure patients who 
are not currently targeted for pacing therapy for heart failure, obtain benefit from pacing 
therapy delivered to allow optimisation of LV preload by shortening AV delay. 
Our study involves two novel aspects. Firstly, in order to reduce the risk of causing harm 
by inducing ventricular electrical dyssychrony, we will use a special form of pacing – direct 
His bundle pacing- which has not previously evaluated in this context. Secondly, we will 
use a novel method for identifying optimal AV delay, which is designed to ensure precise 
and reproducible values are obtained. 
 
1.2  
Intervention details  
 
All patients will be implanted with a Pacemaker or Implantable cardioverter defibrillator 
(ICD).  
All participants will have pacemaker leads positioned in the right atrium (typically the right 
atrial appendage) and on the His bundle in order to obtain His-bundle capture. If it is not 
possible to successfully implant a His-bundle lead with selective direct His bundle capture 
or non-selective capture with < 40ms prolongation of the QRS duration, then a lead will be 
implanted in a lateral branch of the coronary sinus as an alternative approach. 
In patients who do not have an indication for an Implantable cardioverter defibrillator (ICD) 
a second ventricular lead will be implanted in a lateral branch of the coronary sinus. If His 
pacing has not been successfully achieved then a further lead will be positioned at the RV 
apex. In patients who have an indication for an Implantable cardioverter defibrillator the 
ICD lead will be positioned in the right ventricle (either RV apex or RV septum). 

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Implantation procedure:  
Implanters will undergo training in His bundle pacing and will be provided with detailed 
guidance regarding the device implantation protocol. In brief the implant process will 
include the following steps. 
Venous access will be obtained in the standard way and an atrial lead will be implanted in 
the right atrial appendage. In patients receiving Implantable cardioverter defibrillator the 
ICD lead will next be implanted in the conventional way targeting the RV apex or RV 
septum.  
His bundle pacing: a Medtronic Select Secure 3830 pacing lead will be positioned at the 
His bundle using a 9 French delivery sheath (either the Medtronic C315 fixed shaped 
catheters or the Medtronic SelectSite C304 deflectable catheter). His capture will be 
confirmed using the criteria previously described by Deshmukh et al18.  In brief these 
consist of confirming the following: a) 12 lead ECG morphology match with direct His 
bundle pacing compared with intrinsic conduction, b) similar time delay between the 
stimulation artefact and the onset of the QRS complex compared with the intrinsic His to 
QRS time, c) His bundle capture in an all or none-fashion, demonstrated by the absence of 
QRS widening at a lower pacing output. 
If selective His bundle pacing cannot be achieved then non-selective His bundle pacing 
will be accepted. Non-selective His pacing is defined as the direct capture of the basal 
ventricular myocardium in addition to His bundle capture. 
Patients will be randomised to 6 months of the following: 
1) Active treatment: His bundle pacing with the AV delay programmed to the optimal 
sensed and paced delays identified during the optimisation process  
2) No His pacing treatment: pacemaker programmed to avoid pacing as per the implanting 
physicians discretion utilising the non His ventricular lead (suggested modes are VVI 30, 
DDD/I 30 etc). His pacing should only be programmed on active treatment. 
 
Dynamic AV delay will be programmed off throughout the study.  
 
1.3  
Risk / Benefit Assessment 
The risks associated with pacemaker implantation include: 
• ~1% of developing pneumothorax 
• ~1% of infection of pacemaker 
• ~1% of lead displacement or device malfunction 
• < 1% risk of pericardial effusion 
• ~ 3% risk of haematoma  
• ~2% risk of access vein clot 
 
In order to minimise these risks, procedures will be carried out by highly experienced, high 
volume pacemaker implanters. All procedures will be carried out in centres which have the 
facilities and expertise available to manage complications should they occur. 
 
Potential benefits of pacing in this population 
• Improvement in heart failure symptoms 
• Prevention of bradycardia (while this population do not have a pacing indication for 
bradycardia they are at increased risk of developing higher degrees of conduction 

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block or sinus bradycardia). The pacemaker will prevent bradycardia from occurring 
and symptoms occurring as a result of this. 
• Patients with prolonged PR interval and heart failure are at higher risk of adverse 
outcomes including death. While this study is not powered to assess for a mortality 
benefit it is possible that the risk of death will be reduced with pacing therapy. 
 
The Data Monitoring Committee will meet regularly and will review adverse event rates. If 
they are found to be higher than expected then appropriate action will be taken. 
 
 
2 
OBJECTIVES AND ENDPOINTS 
 
2.1 
Primary Objective 
To evaluate whether, a group of heart failure patients who are not currently targeted for 
pacing therapy for heart failure, will obtain benefit from pacing therapy delivered to allow 
optimisation of LV preload by shortening Atrioventricular delay. 
 
2.2 
Secondary Objective 
To assess direct His pacing characteristics in this population (including acute and chronic 
pacing thresholds). 
 
 
2.3 Primary Endpoint 
The primary outcome measure will be exercise capacity, measured using peak oxygen 
uptake (VO2). 
 
 
2.4 Secondary Endpoints  
Secondary outcome measures are: 
(1) Echocardiographic measurement of left ventricular function and remodelling 
(2) Changes in B-type Naturietic Peptide (BNP) 
(3) Changes in Quality of Life Scores 
(4) Changes in daily activity levels recorded using objective metrics from the pacemaker 
device 
(5) Cost effectiveness analysis  
(6) Percentage pacing will be recorded, as will arrhythmia burden (atrial fibrillation, atrial 
flutter and ventricular arrhythmias), pacing thresholds, R wave amplitude and lead 
impedance. Fluoroscopy time during device insertion will also be reported. 
 
  

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3 
STUDY DESIGN   
3.1 
Design 
This is a multi-centre, prospective randomised double-blinded cross over study, recruiting a 
sub-population of patients with heart failure from multiple investigational sites in the UK. 
Recruitment is expected to take place over about 2 years.  
All patients will be implanted with a Pacemaker or Implantable Cardioverter Defibrillator with 
one of the leads positioned on the His bundle in order to obtain His-bundle capture. There 
will be a 2-month run-in period where the device will be programmed not to deliver His pacing 
therapy during this period. Patients will be allocated in random order to six month treatment 
periods in each of the following two states (1) No His bundle pacing; (2) AV optimised His-
bundle pacing. Endpoint measurements will be taken at baseline, 6 months and 12 months 
post randomisation. Treatment allocation will be blinded to the endpoint assessor.  
 
 
3.2 
Treatment regimens  
Treatment regimens are summarised in the flow diagram in Appendix 1.  
 
 
 
4 
PARTICIPANT ENTRY 
4.1 
Study population 
       
(i) 
Inclusion criteria 
 
1. Aged 18 or above 
2. *Ventricular Ejection Fraction (EF) ≤ 40%; BNP needs to be ≥250ng/L for 
patients with EF 36-40%,  
3. New York Heart Association (NYHA) class II-IV 
4. **PR interval ≥200ms  
5. **Narrow QRS duration (≤140ms) or prolonged QRS duration with typical Right 
Bundle Branch Block (RBBB) morphology on 12 lead ECG and sinus rhythm 
 
* Ejection Fraction should be based on patient’s echocardiograph within the last 18 
months; if that is not available a new echo will be performed. Patients with EF 36-40% 
must have at least one BNP result within the last 18 months having a value of ≥ 250ng/L, 
otherwise, a blood test will be done to assess BNP. Some centres use NT-pro BNP test 
instead of BNP. An NT-pro BNP result of ≥600ng/L is acceptable. 
 
** ECG criteria should be based on patient’s ECG within the last 18 months; if that is not 
available a new ECG will be performed. 
 
(ii) 
Exclusion criteria  
1 ***Permanent or persistent atrial fibrillation (AF)   
2 Paroxysmal atrial fibrillation with history of sustained AF (more than 24 hours) 
in the 6 months prior to screening   
3 Patients who are unable to perform cardiopulmonary exercise testing  
4 Other serious medical condition with life expectancy of less than 1 year  
5 Lack of capacity to consent 

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6 Pregnancy (female participants of reproductive age will be eligible for inclusion 
in the study, subject to a negative pregnancy test prior to randomisation) 
7 Contraindication to use of the relevant study device or leads (as per current 
manuals from manufacturer) 
 
***Patients who have persistent AF in their medical history but has then resolved can be 
included. 
 
Eligible patients can be sub-divided into 2 groups: A) patients who do not have an indication 
for an implantable ICD (this group will receive His CRT-P); and B) patients who do have an 
indication for an implantable ICD (this cohort will receive His CRT-D) 
 
Patients who meet the study inclusion criteria, but have completed other research studies 
or concurrently participating in a non-interventional study (e.g. observational studies) may 
be invited to take part in the trial at the Investigator’s discretion. 
 
 
5 
PROCEDURES AND MEASUREMENTS  
 
5.1 Screening and pre-randomisation evaluations 
Written informed consent will be obtained before the subject undergoes any screening 
procedures. 
Potential study participants will be identified following the review of medical notes of patients 
attending; general cardiology clinics, Heart Failure clinics, ICD clinics or during admission 
to hospital. 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. 
 
All subjects will be assigned a study-specific subject number at the screening visit and the 
following tests/assessments will be performed: 
1. ECG (can be taken at the visit or within the past 18 months; this ECG determines 
patient eligibility and will be reviewed centrally) 
2. Echocardiography (new echo will be performed if no report is available within the past 
18 months) 
3. BNP or NTproBNP in some centres (sample is only taken for patients with EF 36-
40% and have no available BNP result within the past 18 months).  
4. Demographics 
5. Medical History 
6. Physical Examination 
7. Pregnancy test will be performed for women of childbearing age 
 
Eligible patients will be asked to complete a resource utilisation questionnaire at this visit.   
 
5.2 Visit Schedule  
A summary of study procedures/assessments by visit is presented in table 1.  
Patients will be screened at participating hospitals and have implantation performed at the 
participating hospital or at the lead research site - Hammersmith Hospital, which is Imperial 

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College Healthcare NHS Trust. Two months after patients are implanted with their device, 
patients will attend 3 more study visits at Imperial College Healthcare NHS Trust. 
Patients coming from other hospitals will be registered with the Hammersmith Hospital for 
study visits.   
 
5.3 Treatment 
Patients entering the study will then attend for implantation of their device, this will be 
performed either at their local hospital or at Imperial College NHS Healthcare Trust, no 
later than 4 months of the patient’s screening visit  
Prior to implantation, blood tests will be performed to assess clotting function, full blood 
count and electrolytes. Additionally, blood will be taken for group and save if required as 
per local clinical practice. Antibiotic prophylaxis, analgesia and sedation can all be given 
as per the implanting institution's local policies and normal practice. As is standard clinical 
practice for pacemaker implantation, the following routine blood tests will be performed: 
creatinine level, haemoglobin level, prothrombin time (PT; clotting), and Group and Save 
(G+S). Tests performed up to a specified date prior to the implantation day can be 
accepted, please refer to Appendix 2 for details.  
All patients will be implanted with a Pacemaker or Implantable cardioverter defibrillator 
(ICD). In all patients, a pacing lead will be positioned in the right atrium (typically the right 
atrial appendage). All patients will have a pacemaker lead positioned on the His bundle in 
order to obtain His-bundle capture. If it is not possible to successfully implant a His-bundle 
lead with selective His bundle capture or non-selective capture with < 40ms prolongation 
of the QRS duration, then a lead will be implanted in a lateral branch of the coronary sinus. 
In patients who do not have an indication for an Implantable cardioverter defibrillator (ICD), 
a second ventricular lead will be implanted in a lateral branch of the coronary sinus. If His 
pacing has not been successfully achieved then a further lead will be positioned at the RV 
apex. In patients who do have an indication for an Implantable cardioverter defibrillator, the 
ICD lead will be positioned in the right ventricle (either RV apex or RV septum). 
A chest X-Ray will be taken after the procedure to ensure the pacemaker leads are in 
position.   
AV delay optimisation: will be performed using acute non-invasive blood pressure acquired 
using the Finometer device (Finapres Medical Systems, Netherlands). The BHF alternation 
protocol we have previously described will be used in order to minimise the effect of 
background noise 22. 
The optimal AV delay will be determined during atrial sensing and atrial pacing. For atrial 
pacing the optimisation will be performed at 10-20 bpm above the resting heart rate 
provided AV conduction is 1:1 during AAI pacing at this heart rate. If Wenkebach 
conduction or heart block occurs at this rate then we will lower heart rate in order to 
achieve 1:1 conduction. If 1:1 conduction is not achievable at the lower heart rate, then the 
paced AV delay optimisation will be performed with a reference setting of His pacing with 
an AV delay of 120ms. 
For atrial sensing, optimisation will be performed at resting heart rate. 
 
 

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After implantation of the device, there will be a 2 month run-in period prior to 
randomisation, the device will be programmed not to deliver His pacing therapy during this 
period.  
 
5.4 Randomisation and Crossover 
Two months after patients are implanted with their device, patients will be randomised to 
either receive active His pacing treatment or no His pacing treatment (e.g. pacemaker 
programmed to VVI or DDD/I 30 bpm). After a further 6 months, they will be crossed over to 
the alternative treatment arm. Treatment allocation will be obtained using an Interactive Web 
Response System (IWRS) programmed with a randomisation schedule provided by the trial 
statistician. Appropriate blocking will be used. 
The patient will have study assessments listed in table 1 and described in the section 5.5.   
The physiologists performing study tests will be blinded to the treatment arm. A separate 
investigator will be responsible for programming the device.  
 
5.5 Study assessments 
Physical examination 
Patients will have a physical examination where vital signs will be taken.  
Cardiopulmonary exercise testing:  
Patients will exercise on a treadmill using a “smoothed modified Bruce” protocol 30. A 
physiologist and another HOPE HF study team member (e.g. research nurse, research 
fellow or another physiologist) will be present for this test. For safety reasons, it is 
necessary to perform ECG monitoring during this test. It may be possible to see pacing 
spikes in the ECG. Therefore to ensure that the physiologist who is leading the exercise test 
is blinded, the screen displaying the ECG will only be visible to the second study personnel 
who will be responsible for monitoring ECG. They will only request that a test is stopped if 
there are ECG findings which make this necessary on clinical safety grounds. This way both 
the patient and the physiologist leading the exercise test will remain blinded to the treatment 
arm. Exercise capacity will be measured as peak exercise oxygen consumption in 
ml/kg/min.  
BNP:  
We will take 5mls of blood to measure B type Natriuretic Peptide (BNP) in an EDTA bottle. 
The samples will be analysed at the Hammersmith hospital and no sample will be stored. 
Echocardiography:  
Patients will have a standard HOPE HF echo protocol performed including left ventricular 
dimensions, volumes, ejection fraction and quantification of mitral regurgitation. No ECG will 
be recorded during the echocardiogram once the patient is randomised. The physiologist 
performing the test will be blinded to the treatment arm. 
Daily Activity Measurement: 
All implanted devices in the study can provide data on daily activity measured in minutes 
per day. The comparison will be made between the His pacing and no His pacing arms. 
  

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Quality of Life (QOL) and Cost Effectiveness Evaluation questionnaires: 
The economic evaluation will compare incremental costs and incremental outcomes of the 
direct His-bundle pacing against standard medical care. The economic evaluation will 
consist of two parts, a cost-effectiveness analysis (CEA) and a cost utility analysis (CUA). 
In the CEA the incremental cost-effectiveness ratio (ICER) will be expressed as the 
incremental costs per point improvement in exercise capacity in peak VO2. The primary 
outcome measure in the CUA will be Qualitative Adjusted Life Years (QALYs), based on the 
EuroQoL EQ-5D scores.  
In order to measure the costs of the resources patients use, a resource use measurement 
(RUM) questionnaire will be developed and validated for the HOPE-HF study. The RUM 
questionnaire consists of a standard RUM questionnaire with small adaptations specific to 
the subject of heart failure patients.  
We will use the Minnesota Living with Heart Failure Questionnaire (MLHFQ) 
(http://www.mlhfq.org/) and EQ-5D to assess for changes in quality of life (QoL). The 
MLHFQ questionnaire is a validated condition-specific measure with good sensitivity and 
discrimination. It will be complemented with the EuroQoL EQ-5D both of these are well 
validated generic measures of QoL. 
The trial staff administering these questionnaires will be blinded to the treatment arm. 
 
5.6 Final study visit  
At 12 months post randomisation, the patient will have a final study visit and the above tests 
performed. After this treatment allocation will be revealed and the patient will have the 
chance to decide whether they wish to continue receiving AV optimised His pacing. If they 
prefer not to decide the decision will be left to their direct medical care team.  
The patient’s GP and direct medical care team will be notified that the patient has completed 
the study and the patient will return to routine clinical care.  
At the final study visit, participants will also be given the option of whether they would like to 
be contacted when the study results are available. They will be given the following options: 
• 
Written communication of results 
• 
Telephone call from research team 
• 
Visit to discuss results with research team 
• 
Meeting with direct medical care team to discuss results  
 
Once patients have been informed of the study results they will be given the option of 
changing their choice of pacing treatment (1) Active treatment: His pacing with the AV delay 
programmed to the optimal sensed and paced delays identified during the optimisation 
process or 2) No His pacing treatment: device is programmed according to clinical 
indication). Should the patient want more time to consider this decision, further reviews or 
telephone communications could be scheduled. 
 
5.7  
Unblinding 
Patients will be blinded to treatment arm. We anticipate that some patients may request a 
change in their treatment arm, particularly if there is a change in their symptom status. If 
this occurs we will try to encourage patients to continue with their designated treatment 
(either His pacing or no His pacing) until they cross over to the other treatment to complete 

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the study. However, if they are not willing to continue treatment then their request for a 
change in treatment will be met. Our analysis will be made on an intention to treat basis. 
The master randomisation list will be stored electronically within a specialised ‘blinded’ 
folder in the statistics section of the Trial Master File (TMF) to ensure that the trial 
statistician does not have access to the list. A copy will also be made available to 
dedicated personnel in the research unit who will support unblinding of individual patient’s 
treatment allocation upon request. Requests for unblinding should be discussed with the 
Chief Investigator or delegate beforehand. 
 
6 
TREATMENTS 
 
6.1  
Medical Devices 
Medtronic CRT-D or CRT-P devices which meet the following criteria: 
 
1. contains an IS1 port for the His lead (required)  
2. contains a DF4 slot for the defibrillator lead (preferred) 
3. certified MRI conditional 
The His-bundle will be paced with a Medtronic SelectSecure 3830 69cm steroid eluting, 
bipolar, implantable, non-retractable screw-in catheter delivered transvenous pacemaker 
lead. The lead will be positioned using the C315 His delivery catheter, the SelectSite C304-
L69/C304-S59 or other His delivery sheaths as per the implanting operator’s discretion. 
 
6.2 
Labelling and Packaging  
 
Refer to current manuals for the relevant product from the manufacturer.    
 
6.3 
Storage and Administration  
 
Refer to current manuals for the relevant product from the manufacturer.    
 
6.4   
Monitoring Device Performance 
Device data will be reviewed in person when patients attend for review at Visit 3, 4 and 5 (2 
months, 8 months and 14 months post device implantation respectively). This will provide 
details on pacing thresholds, R wave amplitude and lead impedance. Details of any 
arrhythmia will also be seen. This data will be included in reports to the DMC for monitoring 
of any adverse consequences.  
Device follow-up after cessation of the trial will be at the patient's local cardiology centre. 
 
 
6.5 
Device Precautions 
 
Patients will be advised that prior to any future MRI scan or procedures that involve the use 
of diathermy, they should seek advice from their local pacing department so that their device 
settings can be adjusted to make the MRI/diathermy procedure safe and arrangements can 
be made to interrogate the device after the procedure. 
 
 

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6.6 Permanent Discontinuation of Study Treatment and Withdrawal from Study  
(i) 
 Permanent discontinuation of study treatment 
Subjects may discontinue study treatment for the following reasons: 
• At the request of the subject. 
• Adverse event/ Serious Adverse Event 
• If the investigator considers that a subject's health will be compromised due to 
adverse events or concomitant illness that develop after entering the study. 
 
(ii) 
 Withdrawal from Study 
Withdrawal from the study refers to discontinuation of study treatment and study procedures 
and can occur for the following reasons: 
• Subject decision 
• Loss to follow-up 
 
(iii) Procedures for Withdrawal from Study 
If a patient wishes to withdraw from the study, they will be asked at what level they wish to 
withdraw i.e. if they would like to terminate pacing treatment but are willing to attend follow-
up visits, or if they do not wish to be contacted about the study including results of the study. 
Reason for and level of withdrawal must be recorded in the eCRF and medical records. 
Patients will not be replaced and follow-up should continue if the patient agrees. In the event 
that a subject wishes to terminate treatment after implantation of the study device, the 
patient’s GP or direct medical care team will be notified and the patient will return to routine 
clinical care. 
 
 
7 
ADVERSE EVENTS AND DEVICE VIGILANCE 
 
7.1  
Adverse Event (AE) 
Any untoward medical occurrence, unintended disease or injury or any untoward clinical 
signs (including an abnormal laboratory finding) in subjects, users or other persons whether 
or not related to the medical device.  
 
7.2 
Adverse Event recording 
All adverse events will be recorded using the InForm System with the following exceptions. 
 
Exemptions: 
All planned elective non-cardiac admissions/procedures/surgeries do not need to be 
reported as adverse events. 
 
 
(i) 
Severity of Adverse Events 
 

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Mild:  
Awareness of event but easily tolerated 
Moderate: 
Discomfort enough to cause some interference with usual activity 
Severe: 
Inability to carry out usual activity 
 
 (ii) 
Causality of Adverse Events 
 
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 administration of the medical 
device). 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 (e.g. because the 
 event occurs within a reasonable time after administration of the medical 
device). 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 are unlikely. 
Definite: 
There is clear evidence to suggest a causal relationship and other possible 
 
 
contributing factors can be ruled out. 
 
 
7.3 
Serious Adverse Events (SAE) 
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 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. 
** “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 
All SAEs will be reported to the Sponsor within 24 hours of an Investigator becoming aware 
of the event. Reporting procedures are detailed in the study’s SAE reporting instructions. If 
the investigator becomes aware of safety information that appears to be related to the 

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medical device or study procedures, involving a subject who participated in the study, even 
after an individual subject has completed the study, this should be reported to the Sponsor. 
 
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 (InForm). 
 
7.4 Adverse Device Effects 
Relatedness should be assessed in relation to both the medical device and to the 
procedures which are associated with the device function (e.g., insertion, removal).    
Incidents related to the device will be reported to the Device Manufacturer (Medtronic) within 
48 hours of the event happening to the designated Medtronic contact. 
 
(i) 
Adverse Device Effects (ADE) 
An ADE is defined as an AE related to the use of the medical device and includes any AEs 
resulting from insufficient or inadequate instructions for use, deployment, installation or 
operation, or any malfunction of the medical device (device deficiency). It also includes any 
AE resulting from user error or from intentional misuse of the medical device. 
Anticipated Device adverse events are listed in the corresponding current device manual. 
 
(ii) 
Serious Adverse Device Effect (SADE) 
A SADE is an ADE that results in any of the consequences characteristic of an SAE. 
 
(iii) 
Unanticipated Serious Adverse Device Effect (USADE)  
Those SADEs which by nature, incidence, severity or outcome have not been identified in 
the current protocol or device brochure are considered an Unanticipated Serious Adverse 
Device Effect (USADE). 
 
(iv) 
Anticipated Serious Adverse Device Effect (ASADE) 
An ASADE is an effect which by nature, incidence, severity or outcome has been identified 
in the current device manual. 
The Sponsor will be informed of all SADEs, either unanticipated or anticipated. 
 
7.5   
Reporting of Unexpected and Serious Adverse Events 
Any SAE occurring to a study participant should be reported to the REC if in the opinion of 
the Chief Investigator the event was: 
Related – that is, it resulted from administration of the medical device or any of the 
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Unexpected – that is, the type of event is not listed in the protocol/device manual as 
an expected occurrence and serious adverse events will be reported to the REC 
Reporting of related and unexpected SAEs should be submitted within 15 days of the Chief 
Investigator becoming aware of the event. 
Safety reports will be included in the annual progress report submitted to the Sponsor and 
the Ethics Committee. 
  
 
8 
STATISTICAL ANALYSES 
8.1 
Sample Size and power considerations 
 
We will use a smoothed modified Bruce protocol for patients with heart failure. This enables 
improved reproducibility of peak VO230. With this approach, reproducibility in heart failure 
patients between two separate visits to the hospital is 2.4 ml/kg/min, expressed as the 
standard deviation of the difference between two independent measurements31. 
Implantation of a cardiac resynchronisation therapy pacemaker in patients with broad QRS 
duration and heart failure results in a 0.5-2.5 (mean 1.5) ml/kg/min increase in peak V0232-
37. Our published pilot data is that switching on classical cardiac resynchronisation therapy 
in patients with a broad QRS duration increments LV systolic blood pressure by 
~10.3mmHg, and switching on direct His-bundle pacing in long-PR/narrow-QRS patients 
increment blood pressure by ~6.3mmHg, i.e. ~60% of that effect. Pro-rata we would 
therefore expect an estimated increment in peak VO2 of 60% of 1.5ml/kg/min, i.e. 0.9 
ml/kg/min. 
Adopting a conservative approach, a two-sided alpha of 0.05 is chosen. Using a paired t-
test, in order to detect a difference of 0.7 with SD of 2.4, to achieve a power of 90% would 
require a total of 126 evaluable patients. Allowing for a combined mortality/dropout of 21%, 
the study would require a total sample size of 160 patients. Consequently, 160 patients will 
be randomised in a 1:1 manner to the treatment groups. 
Detailed analysis methods will be documented in the study’s Statistical Analysis Plan (SAP). 
 
8.2 
Data Analysis 
Patient characteristics will be summarized. Summaries of 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. 
The analysis will be performed according to the intention to treat principle. 
(i) 
Endpoint Analysis 
The primary outcome will be analysed using a two-level hierarchal model. We will include 
treatment, period and sequence effect within the model. Random subject effects will also be 
included in the regression model if appropriate.  Differences in secondary outcomes will also 
be analysed using aforementioned two level hierarchal model. Normality will be checked 
and appropriate transformation or non-parametric methods will be used if it is not met. 
All statistical tests will be two-tailed with a 5% significance level.  
A separate statistical analysis plan will be prepared and finalised prior to database lock. 
 

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(ii) 
Safety Analysis  
 
Safety analysis will consist of descriptive statistics of fluoroscopy time at the time of device 
insertion, pacing thresholds, R wave amplitude, lead impedance, the frequency of lead 
malfunction, hospitalisations and death. This will be reviewed by the Data Monitoring 
Committee.  
 
(iii) 
Economic evaluation 
The analysis will be based on an intention-to-treat (ITT) principle. The comparability of the 
groups, in both costs and outcomes, will be examined by a baseline analysis. When both 
groups are not comparable methods will be applied to control for these differences. Normal 
distribution of the costs and effects will be tested by Kolmogorov-Smirnov test. When the 
normal distribution is not present, non-parametric bootstrapping will be performed to analyse 
the differences between the intervention and control group. The bootstrap method will be 
used to calculate the 95% confidence intervals (CI). The incremental cost-effectiveness ratio 
(ICER) will be based on the incremental costs and incremental effects of the intervention 
group and the control group and will be calculated as followed: ICER = Δcosts/Δeffects. 
Δcosts and Δeffects are respectively the differences in costs and effects of the intervention 
and control group. Within the cost-effectiveness analysis the ICER will be expressed as 
costs per outcome rate and within the cost-utility analysis, the ICER will be expressed as 
the costs per QALY gain. A cost-effectiveness plane will be plotted with bootstrapped ICERs.  
 
iv)  Sub-group Analysis 
1) Around 30% of patients (40 patients) recruited into the study are expected to have 
right bundle branch block. We will perform subgroup analysis to determine if the 
magnitude of haemodynamic response to AV optimised direct His bundle pacing is 
of a similar magnitude to that obtained in patients with narrow QRS duration. 
 
2) We will perform analysis to determine whether a change in peak V02 and the 
haemodynamic response is related to baseline PR interval.  
 
 
3) We will perform analysis to determine whether a change in peak VO2 and the 
haemodynamic response is related to E-A fusion as observed by baseline 
echocardiography. 
 
4) We will perform analysis to determine the effect of AV delay optimised His Bundle 
pacing on daily activity level compared to control measured objectively in minutes per 
day by the CRT device. 
 
5) If there are significant numbers of patients with non-selective His capture (where both 
the His and local ventricular myocardium are captured by the pacing stimulus) then 
we will perform subgroup analysis to determine whether there is a difference in the 
magnitude of either acute haemodynamic or change in peak V02.   
 
6) If there are significant numbers of patients who are implanted with an LV lead due to 
the failure of His lead implantation we will perform subgroup analysis to determine 
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compared to their control state and compared with the successful His implanted lead 
cohort.  
 
7) A sub-group analysis will be performed to investigate patients recruited with a 
Ventricular Ejection Fraction of 35% and below against those recruited with an EF or 
greater than 35% for primary and secondary endpoints. Where possible, the analysis 
will be stratified by PR Interval in order to investigate whether PR is a predictor for 
treatment response.  
 
8) It is anticipated that the vast majority of patients will have an indication for an 
implantable ICD. In the event where there is an even split between the two groups, 
an additional exploratory analysis may be carried out on the trial outcomes, using 
indication group as an additional stratification factor. 
 
9) We will perform an analysis to assess the relationship between pacing device effect 
(in terms of change in peak VO2 and haemodynamic response) and BMI. 
 
9 
REGULATORY, ETHICAL AND LEGAL ISSUES 
9.1 
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. 
 
9.2 
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 guidelines).  
 
9.3 
Independent Ethics Committee Approval  
 
(i) 
Initial Approval 
Prior to the shipment of the medical device and accessories and the enrolment of subjects, 
the REC must provide written approval of the conduct of the study at named sites, the 
protocol and any amendments, the Subject Information Sheet and Consent Form, any other 
written information that will be provided to the subjects, any advertisements that will be used 
and details of any subject compensation. HRA approval is also needed before study start at 
each participating site. 
 
(ii) 
Approval of Amendments 
Proposed amendments to the protocol and aforementioned documents must be submitted 
to the REC for approval as instructed by the Sponsor. 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 subjects may 
be implemented prior to receiving Sponsor or REC approval. However, in this case, approval 
must be obtained as soon as possible after implementation.  
HRA approval is also needed for implementation of amendments at respective participating 
sites. 
 
(iii) 
Annual Progress Reports 
The Sponsor and REC will be sent annual progress reports in accordance with national 
requirements. 

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(iv) 
End of Trial Notification 
 
The Sponsor and REC will be informed about the end of the trial, within the required 
timelines. 
 
9.4 
Sponsorship, Insurance and Indemnity 
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. Imperial College 
London holds negligent harm and non-negligent harm insurance policies which apply to this 
study. 
  
9.5 
Trial Registration 
The study will be registered on a trial database in accordance with requirements of the 
International Committee of Medical Journal Editors (ICMJE) regulations. The trial will be 
registered on clinicaltrials.gov. 
9.6  
Informed Consent 
 
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. Should a patient lose the capacity to consent during the trial follow-up period, 
the participant would be withdrawn from the study. Identifiable data or blood sample already 
collected with consent would be retained and used in the study. No further data or sample 
would be collected or any other research procedures carried out on or in relation to the 
participant. 
 
9.7 
Contact with General Practitioner  
It is the investigator’s responsibility to inform the subject’s General Practitioner by letter that 
the subject is taking part in the study provided the subject agrees to this, and information to 
this effect is included in the Subject Information Sheet and Informed Consent. A master letter 
template will be kept in the Investigator Site File. A copy of the letter sent to each 
participant’s GP should be filed in the patient’s medical notes.  
 
9.8 
Subject Confidentiality 
The investigator must ensure that the subject’s confidentiality is maintained. On the CRF or 
other documents submitted to the Sponsor, subjects will be identified by a subject 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. 
To facilitate follow-up visits of patients recruited at hospitals other than the Hammersmith 
Hospital, patients will be registered with the Hammersmith. Patient contact details and GP 
details will be made available to study’s research team at Imperial College London. The 
research team will have access to data on InForm collected at earlier study visits. Patient 
medical records will be requested only if deemed necessary. 
 

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The investigator shall permit direct access to subjects’ records and source document for the 
purposes of monitoring, auditing, or inspection by the Sponsor, authorised representatives 
of the Sponsor, Regulatory Authorities and RECs. 
 
Principles of Data Protection Act 1998 will be adhered to.  
 
9.9 
End of Trial 
 
The end of the trial will be after the last subject last visit and once the study database is 
locked.  
 
9.10 
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. Subject 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, a written agreement must be obtained from the 
Sponsor. 
 
10 
DATA MANAGEMENT 
10.1 
Source Data 
Source documents will be specified for CRFs that required source data verification. Where 
data are directly entered into the eCRF it will also be documented. 
 
10.2 
Language 
CRFs will be in English. Generic names for concomitant medications should be recorded in 
the CRF wherever possible. All written material to be used by subjects must use vocabulary 
that is clearly understood, and be in the language appropriate for the study site. 
 
10.3 
Database 
The electronic data capture system InFormTM will be used in this study. The database will 
have built-in validation checks and generate auto-queries. The Trial Monitor will raise 
manual queries as required.   
 
10.4 
Data Collection 
Details of procedures for eCRF completion will be provided in a study manual. 
 
 

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11 
STUDY MANAGEMENT STRUCTURE  
 
11.1 
Trial Steering Committee  
A Trial Steering Committee (TSC) will be convened including an independent Chair, 
independent clinician, the Chief Investigator and Trial Manager. The role of the TSC is to 
provide overall supervision of trial conduct and progress. 
 
11.2 Trial Management Group 
A Trial Management Group (TMG) will be convened including the Chief Investigator, co-
investigators and key collaborators, trial statistician and trial manager. The TMG will be 
responsible for the day-to-day conduct of the trial and operational issues. 
 
11.3 Data Monitoring Committee 
A data monitoring committee composed of three independent professionals and including 
an independent statistician will be convened. The frequency of meeting and the data to be 
reviewed and whether the data will be blinded/unblinded will be documented in the DMC 
charter. 
 
11.4 
Early Discontinuation of the Study 
The DMC will define the criteria for early discontinuation and make recommendations to the 
TSC as required.  
 
11.5 
Risk Assessment 
A study-specific risk assessment will be performed prior to the start of the study to assign a 
risk category. The 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. 
 
11.6  
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 guidelines and other national requirements 
and to review the completeness, accuracy and consistency of the data. 
 
11.7 
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. 
 
11.8  
Disclosure of Data and Publication 
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 and related studies in the 
future. 
All information obtained as a result of the study will be regarded as CONFIDENTIAL, at least 
until appropriate analysis and review by the investigator(s) are completed. 

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Anonymised study data will be shared with the other research institutions as well as 
private sector companies within and outside of the European Union, where data protection 
laws may not be the same. These data will be used for non-commercial research 
purposes.   All reasonable steps will be taken to protect your privacy.   
12  REFERENCES 
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Guidance. Chronic Heart Failure: National Clinical Guideline for Diagnosis and 
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disease and stroke statistics--2013 update: a report from the American Heart 
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3. Coronary heart disease statistics: heart failure supplement [press release]. British 
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4. Linde C, Braunschweig F, Gadler F, Bailleul C, Daubert JC. Long-term 
improvements in quality of life by biventricular pacing in patients with chronic heart 
failure: results from the Multisite Stimulation in Cardiomyopathy study (MUSTIC). 
The American journal of cardiology. 2003;91(9):1090-5.  
5. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al. Cardiac 
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The effect of cardiac resynchronization on morbidity and mortality in heart failure. 
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7. Cleland JG, Abraham WT, Linde C, Gold MR, Young JB, Claude Daubert J, et al. 
An individual patient meta-analysis of five randomized trials assessing the effects of 
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resynchronization therapy in heart failure with a narrow QRS complex. NEJM. 
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9. Thibault B, Harel F, Ducharme A, White M, Ellenbogen KA, Frasure-Smith N, et al. 
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10. Ploux S, Eschalier R, Whinnett ZI, Lumens J, Derval N, Sacher F, Hocini M, Jais P, 
Dubois R, Ritter P, Haissaguerre M, Wilkoff BL, Francis DP, Bordachar P. Electrical 
dyssynchrony induced by biventricular pacing: implicatinos for patient selection and 
therapy improvement. Heart Rhythm. 2015;12:782-91 
11. Crisel RK, Farzaneh-Far R, Na B, Whooley MA. First-degree atrioventricular block 
is associated with heart failure and death in persons with stable coronary artery 
disease: data from the Heart and Soul Study. European heart journal. 
2011;32(15):1875-80.  
12. Gervais R, Leclercq C, Shankar A, Jacobs S, Eiskjaer H, Johannessen A, et al. 
Surface electrocardiogram to predict outcome in candidates for cardiac 
resynchronization therapy: a sub-analysis of the CARE-HF trial. European journal of 
heart failure. 2009;11(7):699-705.  
13. Olshansky B, Day JD, Sullivan RM, Yong P, Galle E, Steinberg JS. Does cardiac 

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resynchronization therapy provide unrecognized benefit in patients with prolonged 
PR intervals? The impact of restoring atrioventricular synchrony: an analysis from 
the COMPANION Trial. Heart rhythm. 2012;9(1):34-9.  
14. Fox KM. Efficacy of perindopril in reduction of cardiovascular events among 
patients with stable coronary artery disease: randomised, double-blind, placebo-
controlled, multicentre trial (the EUROPA study). Lancet. 2003;362(9386):782-8.  
15. Kutyifa V, Stockburger M, Daubert JP, Holmqvist F, Olshansky B, Schuger C, Klein 
H, Goldenberg I, Brenyo A, McNitt S, Merkely B, Zareba W, Moss AJ. PR Interval 
Identifies Clinical Response in Patients With Non-Left Bundle Branch Block: A 
Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization 
Therapy Substudy. Circ Arrhythm Electrophysiol. 2014:645- 51. doi: 
10.1161/CIRCEP.113.001299.  
16. Auricchio A, Stellbrink C, Block M, Sack S, Vogt J, Bakker P, Klein, Kramer A, Ding 
J, Salo R, Tockman, Pochet T, Spinelli J. Effect of pacing chamber and 
atrioventricular delay on acute systolic function of paced patients with congestive 
heart failure. Circ. 1999;99:2993-3001.  
17. Whinnett ZI, Francis DP, Denis A, Willson K, Pascale P, van Geldorp I, De 
Guillebon M, Ploux S, Ellenbogen K, Haïssaguerre M, Ritter P, Bordachar P. 
Comparison of different invasive hemodynamic methods for AV delay optimization 
in patients with cardiac resynchronization therapy: Implications for clinical trial 
design and clinical practice. Int J Cardiology. 2013;168:2228-37. 
doi:10.1016/j.ijcard.2013.01.216.  
18. Kyriacou A, Whinnett ZI, Sen S, Pabari PA, Wright I, Cornelussen R, et al. 
Improvement in coronary blood flow velocity with acute biventricular pacing is 
predominantly due to an increase in a diastolic backward-travelling decompression 
(suction) wave. Circulation. 2012;126(11):1334-44.  
19. Raphael CE, Whinnett ZI, Davies JE, Fontana M, Ferenczi EA, Manisty CH, et al. 
Quantifying the paradoxical effect of higher systolic blood pressure on mortality in 
chronic heart failure. Heart. 2009;95(1):56-62.  
20. Manisty CH, Al-Hussaini A, Unsworth B, Baruah R, Pabari PA, Mayet J, Hughes 
AD, Whinnett ZI, Francis DP. The Acute Effects of Changes to AV Delay on Blood 
Pressure and Stroke Volume: Potential Implications for Design of Pacemaker 
Optimization Protocols. Circulation Arrhythm Electrophysiol. 2012;5:122-30.  
21. Whinnett ZI, Nott G, Davies JER, Willson K, Manisty CH, Kanagaratnam P, Peters 
NS, Davies DW, Hughes AD, Mayet J, Francis DP. Maximizing efficiency of 
alternation algorithms for hemodynamic optimization of the AV delay of Cardiac 
Resynchronisation Therapy. Pacing Clin Electrophysiol. 2011;34(2):217-25.  
22. Whinnett ZI, Davies JER, Willson K, Chow AW, Foale RA, Davies DW, Hughes AD, 
Francis DP, Mayet J. Determination of optimal atrioventricular delay for cardiac 
resynchronization therapy using acute non-invasive blood pressure. Europace 
2006;8:358-366.  
23. Whinnett ZI, Briscoe C, Davies JER, Willson K, Manisty CH, Davies DW, Peters 
NS, Kanagaratnam P, Hughes AD, Mayet J, Francis DP. The atrioventricular delay 
of cardiac resynchronization can be optimized hemodynamically during exercise 
and predicted from resting measurements. Heart Rhythm. 2008;5:378- 386.  
24. Deshmukh P, Casavant DA, Romanyshyn M, Anderson K. Permanent, direct His-
bundle pacing: a novel approach to cardiac pacing in patients with normal His-
Purkinje activation. Circulation. 2000;101:869-877.  
25. Kronborg MB, Poulsen SH, Mortensen PT, Nielsen JC. Left ventricular performance 

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during para-His pacing in patients with high-grade atrioventricular block: an acute 
study. Europace. 2012;14:841-6. doi: 0.1093/europace/eur368.  
26. Catanzariti D, Maines M, Cemin C, Broso G, Marotta T, Vergara G. Permanent 
direct his bundle pacing does not induce ventricular dyssynchrony unlike 
conventional right ventricular apical pacing. An intrapatient acute comparison study. 
J Interv Card Electrophysiol. 2006;16:81-92.  
27. Zanon F, Svetlich C, Occhetta E et al. Safety and performance of a system 
specifically designed for selective site pacing. Pacing Clin Electrophysiol. 
2011;34:339-347.  
28. Lustgarten DL, Calame S, Crespo EM, Calame J, Lobel R, Spector PS. Electrical 
resynchronization induced by direct His-bundle pacing. Heart Rhythm. 2010 ;7:15-
21. doi: 10.1016/j.hrthm.2009.09.066.  
29. Sohaib SM, Lim E, Wright I, Moore P, Lefroy DC, Lim B, Davies DW, Linton N, 
Peters N, Kanagaratnam P, Francis D, Whinnett Z. AV delay optimisation delivered 
with direct His bundle pacing improves acute hemodynamic function in patients with 
systolic heart failure, narrow QRS duration and PR prolongation. Heart Rhythm 
2015;12 S307 
30. Scott AC, Francis DP, Davies CL, Coats AJS, Piepoli MF. Validation of a treadmill 
exercise test protocol with improved metabolic plateau formation in patients with 
chronic congestive heart failure. Am J Cardiol. 2001;87:1328- 1331 
31. Davies LC, Wensel R, Georgiadou P, Cicoira M, Coats AJ, Piepoli MF, Francis DP. 
Enhanced prognostic value from cardiopulmonary exercise testing in chronic heart 
failure by non-linear analysis: oxygen uptake efficiency slope. Eur Heart J. 2005; 
27(6):684-90. 
32. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, Huth C, Schondube F, 
Wolfhard U, Bocker D, Krahnefeld O, Kirkels H; Pacing Therapies in Congestive 
Heart Failure (PATH-CHF) Study Group. Long-term clinical effect of 
haemodynamically optimised cardiac resynchronisation therapy in patients with 
heart failure and ventricular conduction delay. J Am Coll Cardiol. 2002;39:2026-33. 
33. Auricchio A, Stellbrink C, Butter C, Sack S, Vogt J, Misier AR, Bocker D, Block M, 
Kirkels JH, Kramer A, Huvelle E; Pacing Therapies in Congestive Heart Failure II 
Study Group, Guidant Heart Failure Research Group. Clinical efficacy of cardiac 
resynchronisation therapy using left ventricular pacing in heart failure patients 
stratified by severity of ventricular conduction delay. J Am Coll Cardiol. 
2003;42:2109-16. 
34. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, 
Kappenberger L, Haywood GA, Santini M, Bailleul C, Daubert J. The multisite 
stimulation in cardiomyopathies (MUSTIC) study investigators. Effects of multisite 
pacing in patients with heart failure and intraventricular conduction delay. N Engl J 
Med 2001;344:873-880. 
35. Leclercq C, Walker S, Linde C, Clementy J, Marshall AJ, Ritter P, Djiane P, Mabo 
P, Levy T, Gadler F, Bailleul C, Daubert JC. Comparative effects of permanent 
biventricular and right-univentricular pacing in heart failure patients with chronic 
atrial fibrillation. Eur Heart J. 2002;23:1780-7. 
36. Abraham WT, Young JB, Leon AR, Adler S, Bank AJ, Hall SA, Lieberman R, Liem 
LB, O'Connell JB, Schroeder JS, Wheelan KR; Multicenter InSync ICD II Study 
Group. Effects of cardiac resynchronisation on disease progression in patients with 
left ventricular systolic dysfunction, an indication for an implantable cardioverter-

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defibrillator, and mildly symptomatic chronic heart failure. Circulation 
2004;110:2864-8. 
37. Young JB, Abraham WT, Smith AL, Leon AR, Lieberman R, Wilkoff B, Canby RC, 
Schroeder JS, Liem LB, Hall S, Wheelan K; Multicenter InSync ICD Randomized 
Clinical Evaluation (MIRACLE ICD) Trial Investigators. Combined cardiac 
resynchronisation and implantable cardioversion defibrillation in advanced chronic 
heart failure: the MIRACLE ICD Trial. JAMA. 2003;289:2685-94. 
 
 

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SIGNATURE PAGE 1 (Chief Investigator) 
 
The signature below constitutes approval of this protocol by the signatory 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: 
 
 
 
AV optimisation delivered with direct His bundle pacing, in patients with heart failure, long 
PR without left bundle branch block: randomised multi-centre clinical outcome study. The 
His Optimised Pacing Evaluated for Heart Failure Trial (HOPE-HF) 
 
 
Sponsor’s reference : 
15HH2828 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Dr Zachary Whinnett 
 
 
 
Senior Lecturer in Electrophysiology and  
 
 
 
Honorary Cardiologist and Electrophysiologist 
 
 
 
Imperial College London 
 
 
 
Hammersmith Hospital  
 
 
 
 
 
 
 
 
 
Date:  
 
_____________________ 
  

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SIGNATURE PAGE 2 (SPONSOR) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title:  
 
 
AV optimisation delivered with direct His bundle pacing, in patients with heart failure, long 
PR without left bundle branch block: randomised multi-centre clinical outcome study. The 
His Optimised Pacing Evaluated for Heart Failure Trial (HOPE-HF) 
 
 
Sponsor’s reference : 
15HH2828 
 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Ms Becky Ward 
 
 
 
Research Governance Manager 
 
 
 
Joint Research Compliance Office 
 
 
 
Imperial College London and Imperial College Healthcare NHS Trust 
 
 
 
Date:  
 
_____________________ 

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SIGNATURE PAGE 3 (STATISTICIAN) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title:  
 
 
AV optimisation delivered with direct His bundle pacing, in patients with heart failure, long 
PR without left bundle branch block: randomised multi-centre clinical outcome study. The 
His Optimised Pacing Evaluated for Heart Failure Trial (HOPE-HF) 
 
 
 
Sponsor’s reference : 
15HH2828 
 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Ms Emanuela Falaschetti 
 
 
 
Senior Clinical Trial Statistician 
 
 
 
Imperial Clinical Trials Unit 
 
 
 
Imperial College London 
 
 
Date:  
 
_____________________ 
 
 

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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:  
 
 
AV optimisation delivered with direct His bundle pacing, in patients with heart failure, long 
PR without left bundle branch block: randomised multi-centre clinical outcome study. The 
His Optimised Pacing Evaluated for Heart Failure Trial (HOPE-HF) 
 
 
 
Sponsor’s reference : 
15HH2828 
 
 
Address of Institution:  
____________________________________________ 
 
 
 
 
 
 
 
 
 
 
____________________________________________ 
 
 
 
 
 
 
____________________________________________ 
 
 
 
Signed: 
 
 
____________________________________________ 
 
 
Print Name and Title: 
____________________________________________ 
 
 
Date:  
 
 
_____________________ 
 

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Appendix 1. Treatment Regimens 
 
 
 
 
 
 
 
Set as preferred 
by patient
8 months 
14 months
2 months 
post 
implant with 
device off 
Six 
months 
at one 
setting 
Six
months
at other
setting
AV Optimised
His Pacing 
His Pacing OFF 
Tests: 1.Cardiopulmonary ex test
2. Echo
3. BNP & QOL questionnaire
Tests: 1.Cardiopulmonary ex test
2. Echo
3. BNP & QOL questionnaire 
. 
0 months 
Eligibility and consent 
Device implantation
2 months 
AV Optimised
His Pacing
His Pacing OFF 
Tests: 1.Cardiopulmonary ex test
2. Echo
3. BNP & QOL questionnaire 
4. Determine haemodyn. opt. 
Tests: 1.Cardiopulmonary ex test
2. Echo
3. BNP & QOL questionnaire
4. Determine haemodyn. opt. 
Tests: 1.Cardiopulmonary ex test
2. Echo
3. BNP & QOL questionnaire
4. Determine haemodyn. opt. 

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Appendix 2. Summary of study procedures/assessments by visit 
ǂ Visit at local hospital where patient was identified 
 
 
# Either at local hospital or at Imperial College Healthcare NHS Trust 
˄ Performed at Imperial College Healthcare NHS Trust 
 
£ Taken on the day or within the last 12 months 
& Taken at screening visit or within the past 18 months 
 
$ Taken on the day of implantation or within the past 30 days 
* RUM questionnaire only at visit 1, all questionnaires for visits 3-5 
+ Taken at screening visit or within the past 18 months for patients with EF 36-40% 
 
 
Screeningǂ 
Implantation# 
Randomisation˄ 
Cross-over˄ 
End of Study˄ 
Visit  
1 
2 
3 
4 
5 
Month/Week/Day 
 
- 2 to 6 months 
-2 months 
(± 14 days) 
0 
6 months 
(± 14 days) 
12 months 
(± 14 days) 
Informed consent 
X 
 
 
 
 
Inclusion & exclusion criteria 
X 
 
 
 
 
Demography 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
Concomitant medication 
X 
 
 
 
 
Pregnancy test for women of child bearing age 
X 
 
 
 
 
Safety blood tests 
(Creatinine, Haemoglobin, PT, G+S) 
 
X£ 
 
 
 
ECG 
X& 
X$ 
 
 
 
Device Implantation 
 
X 
 
 
 
Post implantation chest radiograph 
 
X 
 
 
 
Pacing check 
 
 
X 
X 
X 
Device programmed on/off 
 
 
X 
X 
X 
CPET 
 
 
X 
X 
X 
Echocardiography 
X& 
 
X 
X 
X 
BNP 
X+ 
 
X 
X 
X 
QOL and Cost Effectiveness questionnaires 
(EQ5D-5L/MLHFQ and the HOPE-HF RUM) 
X∗ 
 
X 
X 
X 
Haemodynamic optimisation 
 
 
X 
X 
 
Revelation of treatment sequence to patient 
 
 
 
 
X 
His pacing on/off according to patient’s choice 
(Patient can make decision later) 
 
 
 
 
X