The His Optimised Pacing Evaluated for Heart Failure Trial (HOPE-HF).

Study Overview
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Brief Summary
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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 (Cardiac Resynchronisation Therapy) pacemaker 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 is not active. A double-blinded cross-over design will then be employed to investigate the effect of His bundle pacing. Patients will be allocated in random order to six month treatment periods in each of the following two states (1) No pacing; (2) AV optimised direct 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 and the patient. 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 recruited to allow for patient drop-out.

Detailed Description
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Patients entering the study will attend for implantation of a CRT pacemaker device with one lead positioned on the His bundle. This will be performed either at the patient's local hospital or at Imperial College NHS healthcare Trust, no later than 4 months after the patient's screening visit. 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 direct 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. 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 direct 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). AV delay optimisation will be performed using acute non-invasive blood pressure acquired using the Finometer device (Finapres Medical systems, Netherlands). The BHF (British Heart Foundation) alternation protocol will be used in order to minimise the effect of background noise. 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 bundle pacing therapy during this period.(Back up only pacing and defibrillator function will be enabled). Two months after patients are implanted with their device, patients will be randomised to either receive active pacing treatment or back up only pacing (pacemaker programmed to VVI 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.

Official Title
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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.

Conditions
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Heart Failure

Intervention / Treatment
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* Device: Pacemaker: AV optimised, His pacing.


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pacemaker: AV optimised, His pacing<br>Subjects will remain in this arm for 6 months before being crossed-over. See below intervention details. | Device: Pacemaker: AV optimised, His pacing.<br>* Direct His bundle pacing: a Medtronic Select Secure 3830 pacing lead will be positioned at the His bundle. If selective direct His bundle pacing cannot be achieved then non-selective His bundle pacing will be accepted. AV delay optimisation: will be performed using acute non-invasive blood pressure acquired using the Finometer device (Finapres Medical systems, Netherlands).<br>|
| No Intervention: No pacing<br>Subjects will remain in this arm for 6 months before being crossed-over. The pacemaker will be programmed to VVI 30 bpm. Dynamic AV delay will be programmed off throughout the study. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in exercise capacity. | Measured using peak oxygen uptake (VO2). | Baseline, 6 months and 12 months post randomisation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Echocardiographic measurement of left ventricular function (Ejection Fraction) | Measured during echocardiogram. | Baseline, 6 months and 12 months post randomisation. | 
| Changes in B-type Naturietic Peptide (BNP). | Measured from blood sample. | Baseline, 6 months and 12 months post randomisation. | 
| Changes in Quality of Life Scores. | Measured using Quality of Life Questionnaire. | Baseline, 6 months and 12 months post randomisation. | 
| Cost effectiveness analysis (using a custom designed Resource Utilisation Questionnaire) | The analysis will be based on an intention-to-treat (ITT) principle. The economic evaluation will compare incremental costs and incremental outcomes of the direct His-bundle pacing against the standard medical care. The study will be performed from a societal perspective, which takes all relevant cost-categories and effects into account. 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 EQ5D and Minnesota questionnaire scores. | Baseline. | 
| Changes in percentage pacing. | Measured during pacing check. | Baseline, 6 months and 12 months post randomisation. | 
| Changes in arrythmia burden (%). | Measured during pacing check. | Baseline, 6 months and 12 months post randomisation. | 
| Changes in pacing thresholds (Volts). | Measured during pacing check. | Baseline, 6 months and 12 months post randomisation. | 
| Changes in R wave amplitude. | Measured from electrocardiogram (ECG). | Baseline, 6 months and 12 months post randomisation. | 
| Changes in lead impedance (Ohms). | Measured during pacing check. | Baseline, 6 months and 12 months post randomisation. | 
| Fluoroscopy time during device insertion. | Measured by time in minutes. | Baseline. |