Conditions: Heart Failure
Keywords: sacubritil valsartan left ventricular remodelling asymptomatic left ventricular systolic dysfunction myocardial infarction
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 93
Healthy volunteers: no

Brief summary:
Prior to reperfusion therapy, the major therapeutic breakthrough in myocardial infarction was the demonstration that ACE inhibitors or ARBs, given to prevent adverse "remodelling" (progressive dilatation and decline in systolic function) in high risk patients, reduced the likelihood of developing heart failure and the risk of death. The neurohumoral systems which are activated in patients after myocardial infarction (and in heart failure) are not all harmful and some endogenous systems may be protective. The best recognised of these is the natriuretic peptide system.

A- and B-type natriuretic peptides are secreted by the heart when it is stressed and these peptides promote vasodilation (reducing left ventricular wall stress), stimulate renal sodium and water excretion (i.e. antagonising the retention of salt and water characterising heart failure) and inhibit pathological growth i.e. hypertrophy and fibrosis (key components of the adverse left ventricular remodelling that occurs after infarction and in heart failure).The augmentation of plasma levels of endogenous natriuretic peptides can be achieved through inhibition of neutral endopeptidase, also known as neprilysin (NEP), which is responsible for the breakdown of natriuretic peptides. Recently, the addition of neprilysin inhibition to blockade of the RAAS (using sacubitril/valsartan), compared with RAAS blockade alone, reduced the risk of heart failure hospitalisation and death in patients with HF-REF. These exciting findings may lead to a new approach to the treatment of heart failure, with an angiotensin receptor neprilysin inhibitor (ARNI) replacing an ACE inhibitor as one of the fundamental treatments for this condition. We believe that the same approach may be beneficial in highrisk survivors of myocardial infarction. Recently, sacubitril/valsartan was shown to ameliorate adverse left ventricular remodelling in an experimental model of acute myocardial infarction. The objective of the present proposal is to gather "proof-ofconcept", mechanistic, evidence in humans to support adoption of this new approach in patients at high risk after myocardial infarction as a result of residual left ventricular systolic dysfunction.

Detailed description:
The objective of the present proposal is to obtain information, which is currently not available, on the cardiac effects of sacubitril/valsartan in patients with LVSD, better characterise the neurohumoral actions of sacubitril/valsartan and gather "proof-ofconcept", mechanistic, evidence in humans to support adoption of this new treatment in patients at high risk after myocardial infarction as a result of residual LVSD.

Surprisingly, there is currently limited evidence about how sacubitril/valsartan works in humans. PARADIGM-HF was a large pragmatic mortality/morbidity trial with no mechanistic sub-studies and this is also true of a ongoing trial (PARADISE-MI) in acute myocardial infarction. Moreover, both trials either used or will use an ACE inhibitor (enalapril and ramipril, respectively), rather than an ARB as the active comparator for sacubitril/valsartan; use of valsartan in our study will allow us to precisely define the effects of neprilysin inhibition. A-type (or atrial) natriuretic peptide (ANP), C-type natriuretic peptide (CNP) and adrenomedullin are substrates for neprilysin and may play a role in the action of sacubitril/valsartan but have not been measured in existing clinical trials (in part because of the instability of these peptides and unfeasibility of measuring them in multi-centre, multi-national trials).

Indeed, ANP and CNP are more specific substrates for neprilysin than BNP. As has been mentioned above, cardiac fibrosis appears to be important in the process of LV remodelling in patients with asymptomatic LVSD and the development of HF-REF and is reflected in circulating biomarkers which may be influenced by sacubitril/valsartan

Arms:
arm 1: 24mg/26mg (dose level 1), 49mg/51mg (dose level 2) and 97mg/103mg (dose level 3) twice daily arm 2: 40mg (dose level 1), 80mg (dose level 2) and 160mg (dose level 3) twice daily.

Interventions: intervention 1: sacubitril/valsartan intervention 2: Valsartan
Intervention descriptions: intervention 1: Sacubitril is a prodrug neprilysin inhibitor used in combination with valsartan to reduce the risk of cardiovascular events in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. intervention 2: is an angiotensin II receptor antagonist (commonly called an ARB, or angiotensin receptor blocker), that is selective for the type I (AT1) angiotensin receptor.

Protocol document:
Prot_000.pdf: 
Version 7.0 
24 08 2020 
Page 1
The effects of sacubitril/valsartan compared to valsartan 
on left ventricular remodelling in patients with 
asymptomatic left ventricular systolic dysfunction after 
myocardial infarction:  a randomised, double-blinded, 
active-comparator, cardiac-MR based trial 
 
 
Protocol 
 
 
 
 
 
 
 
Protocol Version:  
 
 
7.0 
Date:   
 
 
 
24 08 2020 
EudraCT Number:   
 
2017-003460-13 
REC Reference Number:   
17/ES/0128 
Sponsor’s Protocol Number:  
GN16CA007 
Sponsors:  
NHS Greater Glasgow & Clyde and The University 
of Glasgow 
Funder:  
 
 
 
BHF Project Grant no. PG/17/23/32850 
 
 
 
 
 
IMP supplied by Novartis Pharmaceuticals UK Ltd. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This study will be performed according to the Research Governance Framework for 
Health and Community Care (Second edition, 2006) and The Medicines for Human 
Use (Clinical Trials) Regulations, 2004 SI 2004:1031 (as amended) and World 
Medical Association Declaration of Helsinki Ethical Principles for Medical Research 
Involving Human Subjects 1964 (as amended). 


Version 7.0 
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Contacts 
Chief Investigator  
 
Professor John J.V. McMurray 
Professor of Cardiology 
Institute of Cardiovascular and Medical Sciences 
BHF Glasgow Cardiovascular Research Centre 
126 University Place 
University of Glasgow 
Glasgow, G12 8TA 
 
Co-investigators  
 
Professor Mark C. Petrie 
Consultant Cardiologist 
Glasgow Royal Infirmary/Golden Jubilee National Hospital  
BHF Glasgow Cardiovascular Research Centre 
126 University Place 
Glasgow, G12 8TA 
 
Dr. Ross T. Campbell 
Specialist Registrar/Clinical Lecturer 
BHF Glasgow Cardiovascular Research Centre 
126 University Place 
Glasgow, G12 8TA 
 
Dr. Kieran F. Docherty 
Specialist Registrar/Clinical Research Fellow 
BHF Glasgow Cardiovascular Research Centre 
126 University Place 
Glasgow, G12 8TA 
 
Trial Statistician  
 
Dr. Alex McConnachie 
Assistant Director of Biostatistics 
Robertson Centre for Biostatistics 
Boyd Orr Building, Level 11 
University of Glasgow 
Glasgow, G12 8QQ 
 
Chair of the Trial Steering Committee  
 
Professor Iain Squire  
Professor of Cardiovascular Medicine 
University of Leicester 
Glenfield Hospital 
Leicester 
LE3 9QP  


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Page 3
Pharmacovigilance 
 
Dr. Marc Jones 
Pharmacovigilance and Safety Manager 
NHS Greater Glasgow & Clyde 
Research and Development Management Office 
West Glasgow Ambulatory Care Hospital  
Dalnair Street  
Glasgow, G3 8SW 
 
IMP Management 
 
Dr. Elizabeth Douglas 
Senior Pharmacist, Clinical Trials 
NHS Greater Glasgow & Clyde 
Research and Development Management Office 
West Glasgow Ambulatory Care Hospital  
Dalnair Street  
Glasgow, G3 8SW 
 
Project Manager 
 
Dr. Katriona Brooksbank 
Clinical Trials Manager 
Institute of Cardiovascular and Medical Sciences 
BHF Glasgow Cardiovascular Research Centre 
126 University Place 
University of Glasgow 
Glasgow, G12 8TA 
 
Sponsor  
 
This clinical trial is sponsored by NHS Greater Glasgow & Clyde and the University 
of Glasgow 
 
Sponsor’s representative 
 
Dr. Maureen Travers 
Academic Research Coordinator 
NHS Greater Glasgow & Clyde 
Research and Development Management Office 
West Glasgow Ambulatory Care Hospital  
Dalnair Street  
Glasgow, G3 8SW 
 
Funding Body  
BHF Project Grant no. PG/17/23/32850 
IMP provided by Novartis Pharmaceuticals UK Ltd. 


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Table of Contents 
Contacts .................................................................................................................................... 2 
Table of Contents ..................................................................................................................... 4 
Abbreviations ........................................................................................................................... 6 
Study Synopsis .......................................................................................................................... 8 
Study Flow Chart ................................................................................................................... 10 
1 
Introduction .................................................................................................................... 11 
1.1 
Background .........................................................................................................................11 
1.2 
Study Rationale – hypothesis ............................................................................................12 
2 
Study Objectives............................................................................................................. 13 
2.1 
Primary objective ...............................................................................................................13 
2.2 
Secondary objectives ..........................................................................................................13 
3 
Endpoints ........................................................................................................................ 13 
3.1 
Primary Endpoints .............................................................................................................13 
3.2 
Secondary Endpoints .........................................................................................................13 
3.3 
Tertiary Endpoints .............................................................................................................13 
4 
Investigational Plan ....................................................................................................... 14 
4.1 
Study Design .......................................................................................................................14 
4.2 
Rationale of key elements of the study design .................................................................16 
5 
Patient Population .......................................................................................................... 17 
5.1 
Inclusion Criteria ...............................................................................................................18 
5.2 
Exclusion Criteria ..............................................................................................................18 
5.3 
Women of child bearing potential.....................................................................................18 
5.4 
Males whose partner could become pregnant .................................................................19 
5.5 
Pregnancy ............................................................................................................................19 
6 
Study Treatment ............................................................................................................ 19 
6.1 
Investigational and control drugs .....................................................................................19 
6.2 
Study Drug storage and supply .........................................................................................20 
6.3 
Drug accountability requirements ....................................................................................21 
6.4 
Treatment arms ..................................................................................................................21 
6.5 
Permitted dose adjustments and discontinuation of study treatment ...........................21 
6.6 
Concomitant medications ..................................................................................................23 
6.7 
Identification of participants and treatment assignment ...............................................24 
6.8 
Monitoring of potential side effects ..................................................................................26 
6.8.1 
Management of nephrotoxicity ........................................................................................26 
6.8.2 
Management of hyperkalaemia ........................................................................................27 
6.8.3 
Management of hypotension ............................................................................................28 
6.8.4 
Management of angioedema ............................................................................................28 
6.9 
Withdrawal of treatment ...................................................................................................28 
6.10 
Unblinding procedure ........................................................................................................28 
7 
Assessment and management of risk............................................................................ 29 
8 
Visit schedule and assessments ..................................................................................... 29 
8.1 
Screening .............................................................................................................................29 
8.1.1 
Echocardiography protocol ..............................................................................................30 
8.2 
Pre-randomisation investigations .....................................................................................30 
8.2.1 
Biochemical and hormonal measurements ......................................................................31 
8.2.2 
CMR protocol ..................................................................................................................31 
8.3 
26-week visit ........................................................................................................................31 


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8.4 
52-week visit ........................................................................................................................32 
8.5 
Definition of end of trial.....................................................................................................32 
9 
Assessment, samples and data collection ..................................................................... 32 
10 
Pharmacovigilance ..................................................................................................... 34 
10.1 
Definitions ...........................................................................................................................34 
10.2 
Recording and reporting of Adverse Events....................................................................35 
10.3 
Assessment of adverse events ............................................................................................35 
10.4 
Reporting to sponsor (Pharmacovigilance Office) ..........................................................36 
10.5 
Reporting to the MHRA and MREC................................................................................37 
10.6 
Responsibilities ...................................................................................................................37 
10.7 
Pregnancy reporting ..........................................................................................................38 
10.8 
Development safety update reports ..................................................................................38 
11 
Statistics and data analysis plan ............................................................................... 38 
11.1 
Sample size ..........................................................................................................................38 
11.2 
Planned recruitment rate...................................................................................................39 
11.3 
Statistical analysis ..............................................................................................................39 
12 
Data handling ............................................................................................................. 39 
12.1 
Randomisation ....................................................................................................................39 
12.2 
Case Report Forms.............................................................................................................40 
12.3 
Record Retention ................................................................................................................40 
13 
Trial management ...................................................................................................... 40 
13.1 
Trial steering committee (TSC) ........................................................................................40 
14 
Study monitoring and auditing ................................................................................. 40 
15 
Ethical considerations ................................................................................................ 40 
16 
Statement of indemnity.............................................................................................. 41 
17 
Funding ....................................................................................................................... 41 
18 
Sponsor responsibilities ............................................................................................. 41 
19 
Dissemination of data ................................................................................................ 41 
20 
References ................................................................................................................... 42 
Appendix 1: Clinically notable laboratory values............................................................... 46 
Appendix 2: MRI Information Leaflet ................................................................................ 47 
Appendix 3: Patient global assessment questionnaire .................................................................49 
 
 
Tables and Figures 
 
Table 4-1 Total daily doses of commonly used ACE inhibitors or ARBs 
corresponding to ramipril 2.5mg BD (dose level 2 of study drug) .............. 14 
Table 4-2 Study drug dose levels during treatment period ................................. 15 
Table 4-3 Safety monitoring criteria that must be met for dose up-titration ..... 16 
Table 6-1 Prohibited medications............................................................................ 23 
Table 8-1 Schedule of Assessments ....................................................................... 33 
Table 10-1 Pharmacovigilance Definitions............................................................. 34 
 
Figure 4-1 Study drug initiation and up-titration ................................................... 15 


Version 7.0 
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Abbreviations 
ACE: Angiotensin Converting Enzyme 
AE: Adverse Event 
ANP: Atrial Natriuretic Peptide  
AMI: Acute Myocardial Infarction 
AR: Adverse Reaction 
ARB: Angiotensin Receptor Blocker 
ARNI: Angiotensin Receptor Neprilysin Inhibitor 
AUC: Area Under the Curve 
BHF: British Heart Foundation 
BD:  Bis in Die - twice daily 
BNP: Brain Natriuretic Peptide 
BSA: Body Surface Area 
CCF: Congestive Cardiac Failure 
CCU: Coronary Care Unit 
cGMP: cyclic Guanosine Monophosphate 
CI: Chief Investigator 
CMR: Cardiac Magnetic Resonance imaging 
CNORIS: Clinical Negligence and Other Risks Indemnity Scheme  
CNP: C-type Natriuretic Peptide 
COX-2: Cyclo-oxygenase-2 
CRF: Case Report Form 
CRN: Clinical Research Network 
CRP: C-Reactive Protein  
CTIMP: Clinical Trial of Investigational Medical Product 
CTU: Clinical Trials Unit 
DSUR: Development Safety Update Report 
ECG: Electrocardiograph 
EF: Ejection Fraction 
eGFR: estimated Glomerular Filtration Rate 
FSH: Follicle Stimulating Hormone 
GCP: Good Clinical Practice 
GCRC: Glasgow Cardiovascular Research Centre 
GG&C: Greater Glasgow and Clyde 
GP: General Practitioner 
GRI: Glasgow Royal Infirmary 
HF-REF: Heart Failure with Reduced Ejection Fraction 
HF: Heart Failure 
hsTnT: high sensitivity Troponin-T  
ICFs: Informed Consent Forms 
ICH: International Conference on Harmonisation 
ICTP: carboxy-terminal telopeptide of type I procollagen  
IMP: Investigational Medical Product 
IVRS: Interactive Voice Response Service 
LBBB: Left Bundle Branch Block 
LGE: Late Gadolinium Enhancement 
LV: Left Ventricle 
LVESV: Left Ventricular End Systolic Volume 
LVSD: Left ventricular Systolic Dysfunction 


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MHRA: Medicines and Healthcare Regulatory Authority 
MI: Myocardial Infarction 
MMPs: matrix metalloproteinases  
MR: Magnetic Resonance 
MRA: Mineralocorticoid Receptor Antagonist 
MREC: Medical Research Ethics Committee 
NEP: Neprilysin 
NSAIDs: Non-steroidal anti-inflammatory drugs 
NSTEMI: Non ST Elevation Myocardial Infarction 
NT-proBNP: N-Terminal pro BNP  
NYHA: New York Heart Association 
PGA: Patient Global Assessment 
PICP: carboxy-terminal propeptide of type I procollagen  
PIIINP: amino-terminal propeptide of type III procollagen  
PV: Pharmacovigilance 
QEUH: Queen Elizabeth University Hospital 
RAAS: Renin Angiotensin Aldosterone System 
RAH: Royal Alexandra Hospital 
REC: Research Ethics Committee 
SAE: Serious Adverse Event 
SAR: Serious Adverse Reaction 
SBP: Systolic Blood Pressure 
SDV: Source Data Verification 
SmPC: Summary of Product Characteristics 
STEMI: ST Elevation Myocardial Infarction 
SUSAR: Suspected Unexpected Serious Adverse Reaction 
TIMP: Tissue Inhibitors of Metalloproteinases 
TMG: Trial Management Group 
TSC: Trial Steering Committee 
TTE: Transthoracic Echocardiogram 
U&Es: Urea and Electrolytes  
ULN: Upper Limit of Normal range 
WoCBP: Women of Child Bearing Potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Study Synopsis 
Title of study 
The effects of sacubitril/valsartan compared to valsartan on left ventricular 
remodelling in asymptomatic left ventricular systolic dysfunction after myocardial 
infarction:  a randomised, double-blinded, active-comparator, cardiac-MR based trial 
Short title 
RECOVER-LV 
Study centre 
Queen Elizabeth University Hospital Clinical Research Facility 
Primary 
endpoint 
Change in indexed left ventricular end-systolic volume (LVESVI), from baseline to 12 
months (+/- 3months) measured using cardiac MR. 
Secondary  
endpoints 
• Changes in other CMR based metrics of LV remodeling (LVEDVI, LVEF, LV mass 
index) from baseline to 12 months(+/- 3months)   
• 
Changes in hsTnI from baseline to 12 months (+/- 3months) 
• 
Changes in NT-proBNP from baseline to 12 months (+/- 3months) 
• Change in patient well-being as assessed by a patient global assessment 
questionnaire. 
 
Tertiary  
endpoints 
• 
Changes in biomarkers of LV remodelling (sST2, Galectin 3, TIMP-1, MMP-9, Type 
III Procollagen Peptide and GDF-15) from baseline to 12 months(+/- 3months)   
• 
Changes in neurohormonal levels (BNP, MR-proANP, C-terminal ANP, CNP, MR-
proADM, cGMP, endothelin-1, neprilysin antigen, renin and aldosterone) from 
baseline to 12 months (+/- 3months) 
Rationale 
Prior to reperfusion therapy, the major therapeutic breakthrough in myocardial 
infarction was the demonstration that ACE inhibitors or ARBs, given to prevent 
adverse “remodelling” (progressive dilatation and decline in systolic function) in high 
risk patients, reduced the likelihood of developing heart failure and the risk of death. 
The neurohumoral systems which are activated in patients after myocardial 
infarction (and in heart failure) are not all harmful and some endogenous systems 
may be protective.  The best recognised of these is the natriuretic peptide system.  
A- and B-type natriuretic peptides are secreted by the heart when it is stressed and 
these peptides promote vasodilation (reducing left ventricular wall stress), stimulate 
renal sodium and water excretion (i.e. antagonising the retention of salt and water 
characterising heart failure) and inhibit pathological growth i.e. hypertrophy and 
fibrosis (key components of the adverse left ventricular remodelling that occurs after 
infarction and in heart failure).The augmentation of plasma levels of endogenous 
natriuretic peptides can be achieved through inhibition of neutral endopeptidase, 
also known as neprilysin (NEP), which is responsible for the breakdown of natriuretic 
peptides. Recently, the addition of neprilysin inhibition to blockade of the RAAS 
(using sacubitril/valsartan), compared with RAAS blockade alone, reduced the risk of 
heart failure hospitalisation and death in patients with HF-REF. These exciting 
findings may lead to a new approach to the treatment of heart failure, with an 
angiotensin receptor neprilysin inhibitor (ARNI) replacing an ACE inhibitor as one of 
the fundamental treatments for this condition. We believe that the same approach 
may be beneficial in high-risk survivors of myocardial infarction. Recently, 
sacubitril/valsartan was shown to ameliorate adverse left ventricular remodelling in 
an experimental model of acute myocardial infarction. The objective of the present 
proposal is to gather “proof-of-concept”, mechanistic, evidence in humans to support 
adoption of this new approach in patients at high risk after myocardial infarction as a 
result of residual left ventricular systolic dysfunction.   
Methodology 
Prospective, randomised, active-comparator, double-blinded study. 


Version 7.0 
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Sample size 
100 
Screening 
Patients with EF ≤40% measured by trans-thoracic echocardiography post 
myocardial infarction without evidence of clinical heart failure. 
Inclusion 
criteria 
• Acute myocardial infarction (AMI) at least 3 months prior to recruitment 
• Left ventricular ejection ≤40% as measured by transthoracic echocardiography  
• Ability to provide written, informed consent 
• Age ≥18 years 
• Tolerance of a minimum dose of ACE inhibitor/ARB (ramipril 2.5mg BD or 
equivalent)  
• Treatment with a beta-blocker unless not tolerated or contraindicated. 
Exclusion 
criteria 
• Contraindication to CMR (ferrous prosthesis, implantable cardiac device or 
severe claustrophobia) 
• Clinical and/or radiological heart failure (NYHA≥2)  
• Symptomatic hypotension and/or systolic blood pressure <100mmHg 
• eGFR < 30 mL/min/1.73m2 and/or serum potassium >5.2mmol/L 
• Persistent/permanent atrial fibrillation 
• History of AMI within last 3 months 
• History of hypersensitivity or allergy to ACE-inhibitors/ARB 
• History of angioedema 
• Known hypersensitivity to the active study drug substances, contrast media or 
any of the excipients 
• Obesity (where body girth exceeds MRI scanner diameter) 
• Pregnancy, planning pregnancy, or breast feeding 
• Inability to give informed consent or comply with study protocol 
• Evidence of hepatic disease as determined by any one of the following: AST or 
ALT values exceeding 2 x ULN at Visit 1, history of hepatic encephalopathy, 
history of oesophageal varices, or history of portacaval shunt 
• History of biliary cirrhosis and cholestasis 
• Active treatment with cholestyramine or colestipol resins 
• Active treatment with lithium or direct renin inhibitor 
• Participation in another intervention study involving a drug or device within the 
past 90 days (co-enrolment in observational studies is permitted)  
Study drugs 
Patients will be randomised in a 1:1 fashion to sacubitril/valsartan (target dose 
97mg/103mg BD) or valsartan (target dose 160mg BD) with matched placebo. 
 
• Sacubitril/valsartan: 24mg/26mg (dose level 1), 49mg/51mg (dose level 2) and 
97mg/103mg (dose level 3) twice daily. 
• Valsartan: 40mg (dose level 1), 80mg (dose level 2) and 160mg (dose level 3) 
twice daily. 
Duration of 
treatment: 
12 months (+/- 3months) 
Statistical 
analysis 
The primary outcome will be compared between randomised groups using a  linear 
regression model adjusted for baseline LVESVI value, and whether or not taking 
diuretics at baseline. Similar methods will be used for other outcomes. The 
Robertson Centre for Biostatistics will manage and analyse trial data. All statistical 
analyses will be conducted according to a Statistical Analysis Plan, which will be 
authored by the Trial Statistician and agreed by the Trial Steering Committee prior to 
unblinding of randomised groups. 


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Study Flow Chart  
Version 6.0 – In response to COVID-19 the treatment time and study windrow for the week 52 visit have been 
altered (+/- 3 months) in order to be able to obtain the primary outcome for this clinical trial and ensure 
patient participation has been worthwhile 
 
 
 
 
 


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1 Introduction 
1.1 Background 
The widespread adoption of coronary reperfusion therapy (initially with thrombolysis 
and latterly with percutaneous intervention) has reduced the extent of left ventricular 
damage sustained during acute myocardial infarction and the lives lost due to this 
condition.1–3 Unfortunately, however, LVSD and HF remain relatively common 
among survivors of myocardial infarction.4 A Norwegian nation-wide cohort study 
between 2001-2009 in 63 583 patients with a first presentation of MI reported that 
12.6% of patients were hospitalised or died because of HF over a median follow-up 
of 3.2 years.5 This is because a large proportion of patients are not eligible for 
reperfusion therapy (i.e. those with non ST-segment elevation myocardial infarction) 
and many patients suffer recurrent episodes of infarction, leading to cumulative left 
ventricular damage over time.   
 
Prior to reperfusion therapy, the major therapeutic breakthrough in myocardial 
infarction was the demonstration that angiotensin converting enzyme (ACE) 
inhibitors, given to prevent adverse “remodelling” (progressive dilatation and decline 
in systolic function) in high risk patients, reduced the likelihood of developing heart 
failure and the risk of death.6 These benefits were seen in three seminal trials - 
Survival And Ventricular Enlargement (SAVE, with captopril), Acute Infarction 
Ramipril Efficacy (AIRE) and TRAndolapril Cardiac Evaluation Study (TRACE).6–8 In 
the Valsartan in Acute Myocardial Infarction Trial (VALIANT), the angiotensin 
receptor blocker (ARB)  valsartan was shown to be as effective as captopril used at 
the same dose as in SAVE.9 ACE inhibitors and ARB work by interrupting one of the 
neurohumoral systems activated in patients who have sustained ventricular injury 
after infarction (the renin-angiotensin-aldosterone system or RAAS) and their 
benefits in high-risk myocardial infarction patients parallel similar benefits in patients 
with chronic heart failure due to left ventricular systolic dysfunction or reduced 
ejection fraction (HF-REF).10–12 Indeed, four different neurohumoral antagonists 
(ACE inhibitors or angiotensin receptor blockers, beta-blockers and mineralocorticoid 
receptor antagonists) are life-saving in both conditions.6–19 This is perhaps not 
surprising in that one of the commonest reasons patients develop chronic HF-REF is 
because of myocardial infarction weeks, months, years or decades previously.  Many 
patients progress through an asymptomatic phase of progressive left ventricular 
remodelling and neurohumoral activation after myocardial infarction before 
developing symptomatic HF-REF. Another seminal trial showed that identification 
and treatment of patients with asymptomatic LVSD with an ACE inhibitor may delay 
or prevent the development of symptomatic HF-REF.20 That trial was the prevention 
arm of the Studies of Left Ventricular Dysfunction (SOLVD-P), the sister study of 
SOLVD-T which demonstrated the benefit of the ACE inhibitor enalapril in a broad 
spectrum of patients with symptomatic HF-REF. As has been said (using old-
fashioned terminology), there is a continuum “from the coronary care unit (CCU) to 
congestive cardiac failure (CCF)” and ACE inhibitors are beneficial across this 
continuum. The earliest indication of the potential benefit of ACE inhibitors or ARB in 
high-risk survivors of myocardial infarction was their ability to attenuate adverse left 
ventricular remodelling.21,22 
 


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It is important to recognise that not all of the neurohumoral systems which are 
activated in patients after myocardial infarction (and in heart failure) are harmful and 
some endogenous neurohumoral systems may be protective.  The best recognised 
of these are the natriuretic peptides.  A- and B-type natriuretic peptides are secreted 
by the heart when it is stressed and these peptides promote vasodilation (reducing 
left ventricular wall stress), stimulate renal sodium and water excretion (i.e. 
antagonising the retention of salt and water characterising heart failure) and inhibit 
pathological growth i.e. hypertrophy and fibrosis (key components of the adverse left 
ventricular remodelling that occurs after infarction and in heart failure).23 The 
augmentation of plasma levels of endogenous natriuretic peptides can be achieved 
through inhibition of neutral endopeptidase, also known as neprilysin (NEP), which is 
the enzyme responsible for the breakdown of natriuretic peptides. Recently, in 
PARADIGM-HF, the addition of neprilysin inhibition to blockade of the RAAS (using 
sacubitril/valsartan – formerly known as LCZ696), compared with RAAS blockade 
alone (using the ACE inhibitor enalapril), reduced the risk of heart failure 
hospitalisation and death in patients with HF-REF.24 These exciting findings may 
lead to a new approach to the treatment of heart failure, with an angiotensin receptor 
neprilysin inhibitor (ARNI) replacing an ACE inhibitor or ARB as one of the 
fundamental treatments for this condition.25 We believe that the same approach may 
be beneficial in high-risk survivors of myocardial infarction. Recently, 
sacubitril/valsartan was shown to ameliorate adverse left ventricular remodelling in 
an experimental model of acute myocardial infarction.26  
 
The objective of the present proposal is to obtain information, which is currently not 
available, on the cardiac effects of sacubitril/valsartan in patients with LVSD, better 
characterise the neurohumoral actions of sacubitril/valsartan and gather “proof-of-
concept”, mechanistic, evidence in humans to support adoption of this new treatment 
in patients at high risk after myocardial infarction as a result of residual LVSD. 
Surprisingly, there is currently limited evidence about how sacubitril/valsartan works 
in humans. PARADIGM-HF was a large pragmatic mortality/morbidity trial with no 
mechanistic sub-studies and this is also true of a ongoing trial (PARADISE-MI) in 
acute myocardial infarction. Moreover, both trials either used or will use an ACE 
inhibitor (enalapril and ramipril, respectively), rather than an ARB as the active 
comparator for sacubitril/valsartan; use of valsartan in our study will allow us to 
precisely define the effects of neprilysin inhibition. A-type (or atrial) natriuretic 
peptide (ANP), C-type natriuretic peptide (CNP) and adrenomedullin are substrates 
for neprilysin and may play a role in the action of sacubitril/valsartan but have not 
been measured in existing clinical trials (in part because of the instability of these 
peptides and unfeasibility of measuring them in multi-centre, multi-national trials). 
Indeed, ANP and CNP are more specific substrates for neprilysin than BNP. As has 
been mentioned above, cardiac fibrosis appears to be important in the process of LV 
remodelling in patients with asymptomatic LVSD and the development of HF-REF 
and is reflected in circulating biomarkers which may be influenced by 
sacubitril/valsartan. 
1.2 Study Rationale – hypothesis 
We hypothesise that administration of sacubitril/valsartan, a first in class ARNI, to 
patients with LVSD (LVEF ≤40%) post myocardial infarction and no evidence of 
heart failure will result in a greater reduction in the degree of adverse remodelling, 
than the current standard of care, ARBs. 
 


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2 Study Objectives 
2.1 Primary objective 
To investigate the potential benefit of sacubitril/valsartan compared to the current 
standard of care, valsartan, in attenuating adverse left ventricular remodelling in high 
risk asymptomatic patients post myocardial infarction as a result of residual left 
ventricular systolic dysfunction (i.e. a reduced LVEF without symptoms or signs of 
heart failure). 
 
2.2 Secondary objectives 
To provide understanding of the cardiac effects and mechanisms of action of 
sacubitril/valsartan in patients with LVSD. This will help understanding of the clinical 
benefits seen in PARADIGM-HF. 
 
3 Endpoints 
3.1 Primary Endpoints 
The primary endpoint is the change in indexed left ventricular end-systolic volume 
(LVESVI), from baseline to 12 (+/- 3 months )months, based on cardiac magnetic 
resonance imaging measurements. 
 
3.2 Secondary Endpoints 
• Change in other cardiac magnetic resonance imaging-based metrics (indexed 
LV end-diastolic volume, LVEF, LV mass index) of LV remodelling from 
baseline to 12 (+/- 3 months) months. 
• Changes in hsTnI from baseline to 12 (+/- 3 months) months.  
• Changes in NT-proBNP from baseline to 12 (+/- 3 months) months. 
• Change in patient well-being as assessed by a patient global assessment 
questionnaire. 
 
3.3 Tertiary Endpoints 
• Changes in biomarkers of LV remodelling (sST2, Galectin 3, TIMP-1, MMP-9, 
Type III Procollagen Peptide and GDF-15) from baseline to 12 (+/- 3 months) 
months. 
• Changes in neurohormonal levels (BNP, MR-proANP, C-terminal ANP, CNP, 
MR-proADM, cGMP, endothelin-1, neprilysin antigen, renin and aldosterone) 
from baseline to 12 (+/- 3 months) months.  
 


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4 Investigational Plan 
4.1 Study Design  
This is a single-centre prospective, randomised, double-blind, active-comparator trial 
designed to evaluate the effect of sacubitril/valsartan compared to valsartan on LV 
remodelling post myocardial infarction. We will study patients after myocardial 
infarction (both ST elevation and non-ST elevation) who receive the usual standard 
of care (including beta-blockers and mineralocorticoid receptor antagonists) who are 
at high risk of developing symptomatic HF-REF. Potential study participants will have 
suffered an acute myocardial infarction at least 3 months prior to recruitment, have a 
LVEF ≤ 40% as measured by transthoracic echocardiography without any symptoms 
of HF (NYHA≥2), be tolerant of a minimum dose of ACE inhibitor/ARB (ramipril 
2.5mg BD or equivalent) and be treated with a beta-blocker unless not tolerated or 
contraindicated. Study participants must also be haemodynamically stable, defined 
as systolic blood pressure (SBP) ≥100mmHg. 
 
We will recruit patients with asymptomatic LVSD identified at least 3 months after 
myocardial infarction to ensure resolution of “stunning” (reversible LVSD). This will 
distinguish our study from the PARADISE-MI trial which will enrol patients up to 7 
days after acute infarction and does not require all patients to have LVSD.27 We did 
not consider it ethical to carry out a trial like the one proposed in patients with HF-
REF as sacubitril/valsartan has already been shown to be definitively superior to 
RAAS blockade alone in those patients.24 
 
After assessing eligibility during screening, consenting patients who meet the study 
inclusion and exclusion criteria will be randomised in a double blinded 1:1 fashion to 
sacubitril/valsartan (target dose 97mg/103mg BD) or valsartan (target dose 160mg 
BD) and matching placebo. All patients will require to be tolerant (determined by 
clinical condition, SBP, and renal function) of a minimum dose of ACE inhibitor/ARB 
(ramipril 2.5mg BD or equivalent –Table 4-1) prior to randomisation. If on a lower 
dose at time of first screening, patients may be rescreened after an observed period 
of up-titration to a dose of ramipril 2.5mg BD or equivalent in-line with current 
standard of care and local practice. In order to minimise the potential risk of 
angioedema due to overlapping ACE and NEP inhibition all patients prescribed an 
ACE inhibitor pre-randomisation will undergo a minimum 36-hour “washout” period 
following randomisation prior to first dose of study drug. 
 
Table 4-1 Total daily doses of commonly used ACE inhibitors or ARBs corresponding to 
ramipril 2.5mg BD (dose level 2 of study drug) 
 
ACE inhibitor 
Dose 
ARB 
Dose 
Captopril 
100mg 
Candesartan 
16mg 
Enalapril 
10mg 
Irbesartan 
150mg 
Lisinopril 
10mg 
Losartan 
50mg 
Perindopril 
4mg 
Valsartan 
160mg 
Trandolapril 
2mg 
 
 
 


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Three dose levels of study medication will be administered in a stepwise titration 
(Table 4-2). Study drug will be started at dose level 2 (sacubitril/valsartan 49mg/51mg 
BD or valsartan 80mg BD) and up-titrated after 4 weeks to dose level 3 
(sacubitril/valsartan 97mg/103mg BD or valsartan 160mg BD) if tolerated as 
assessed by clinical review (SBP and symptomatic hypotension) and laboratory 
evaluation (renal function). Patients already on a higher dose equivalent of ACE-
inhibitor/ARB at dose level 2 (Table 4-1), may start at dose level 3 at investigators 
discretion taking into consideration the patient’s prior dose level of ACE-
inhibitor/ARB and clinical condition (SBP and renal function). 
 
A dose level 1 (sacubitril/valsartan 24mg/26mg B.D) will be available during the 
double-blind period of the trial should patients require down-titration but the aim is to 
maintain the patient on the target dose level 3 for as long a duration as possible 
during the trial. (Figure 4-1 Study drug initiation and up-titration) This dose can be also 
be considered at the time of randomisation with a two-step titration to target dose 
over visits 3 and 4 if systolic BP at visit 1 is ≥100 to 110mmHg. Additionally, dose 
level 1 should be considered as initial dose in patients with moderate renal 
impairment (eGFR 30-60 ml/min/1.73 m2). 
Table 4-2 Study drug dose levels during treatment period 
 
Dose Level 
Sacubitril/Valsartan arm 
Valsartan arm 
1 
24mg/26mg B.D. 
40mg B.D. 
2 
49mg/51mg B.D. 
80mg B.D. 
3 
97mg/103mg B.D. 
160mg B.D. 
Figure 4-1 Study drug initiation and up-titration 
 
 
* Equivalent doses detailed in Table 4-1 
# Dose level 1 can be considered for patients with SBP ≥100 to 110mmHg and/or moderate renal 
impairment (eGFR 30-60 ml/min/1.73 m2) at time of randomisation 
Ramipril (or equivalent*):  
2.5mg BD 
Ramipril (or equivalent*):  
>2.5mg BD 
Randomisation 1:1 for Sacubitril/Valsartan vs. Valsartan 
Starting 
dose 
Dose level 2# 
Dose level 2, or 3 
at investigator’s 
discretion# 
Uptitration 
➝
Uptitration to next dose level should occur after four weeks after randomisation 
➝
Uptitration allowed if SBP ≥ 100mmHg, eGFR ≥ 30mL/min/1.73m2 or serum creatinine 
increase <0.5mg/dL (44μmol/L), and K
+ <5.5mmol/L 
➝
Uptitration allowed if no postural symptoms or any AEs that preclude up-titration 
according to the investigator’s judgement  


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+ down titration from dose level 3 to dose level 2 permitted during extention of treatment times in 
response to COVID-19 pandemic  
Following randomisation the aim should be to up-titrate patients to target study drug 
dose level 3 (Table 4-2) after 4 weeks (Visit 4). Slower up-titration will be permitted if 
necessary to ensure patient safety and tolerability. Patients will be allowed to stay at 
dose level 1 or 2 as maintenance dose however efforts should be made to maintain 
patients on the target dose level 3 or maximally tolerated dose level for as long a 
duration as possible during the trial. Adjustments to study drug dose level should be 
based on safety and tolerability with a focus on a) symptomatic hypotension, b) 
clinically significant decline in renal function and c) hyperkalaemia (Table 4.3).  
 
The decision to up-titrate to the next dose level at any study visit will be made based 
on investigator discretion and may be made on the basis of results of the laboratory 
investigations (urea and electrolytes) from a previous visit or those performed in 
routine clinical care provided these are within 14 days of the study visit. Participants 
will have laboratory investigations (urea and electrolytes) performed at each study 
visit but may be advised to await communication from the investigator prior to taking 
their next study drug dose. It is anticipated that results will be available within several 
hours of the study visit occurring and that study participants will be contacted within 
a maximum of 12 hours from the time of the study visit.  The investigator will make 
all reasonable attempts to contact participants within this time period. Based on 
previous results and investigator discretion, the decision to up-titrate may be delayed 
until the results of laboratory investigations are available in which case participants 
will continue on current study dose until the results are available. 
 
Treatment guidance for management of nephrotoxicity, hyperkalaemia and 
hypotension are provided in section 6.8.1, 6.8.2 and 6.8.3 respectively. 
 
Table 4-3 Safety monitoring criteria that must be met for dose up-titration 
 
Parameter 
Criteria 
Blood pressure 
SBP ≥ 100mmHg 
Renal function 
eGFR ≥ 30mL/min/1.73m2 or serum creatinine 
increase <0.5mg/dL (44μmol/L)  
Serum potassium 
K+ <5.5mmol/L 
AEs or symptoms 
No postural symptoms or any AEs that preclude 
up-titration according to the investigator’s 
judgement 
 
Study patients will remain on the allocated study drug for a period of 12 (+/- 
3months) months after which their involvement in the trial will end. In response to the 
covid-19 pandemic down titration from dose level 3 to dose level 2 is permitted. 
Following their involvement in the trial they will be converted to an ACE-inhibitor or 
ARB as per local guidelines at an equivalent dose to their final study drug dose level. 
It is anticipated that recruitment of 100 patients will take 18 months with the final 
patient visit occurring 12 months following this meaning a total trial duration of 30 
months. 
 


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4.2 Rationale of key elements of the study design 
Current guidelines advocate the use of ACE-inhibitors (or angiotensin receptor 
blockers if ACE-inhibitor contraindicated/not tolerated) along with beta-blockers and 
mineralocorticoid receptor antagonists to reduce morbidity and mortality after 
myocardial infarction.25 The role of ACE-inhibitors/ARBs in preventing adverse 
remodelling after myocardial infarction is well established. A meta-analysis of 16 
trials examining ACE-inhibition after myocardial infarction demonstrated a significant 
improvement in reduction of left ventricular volumes at both short and long-term 
follow up in patients with reduced left ventricular ejection who were administered an 
ACE-inhibitor.28 Similarly, in patients with asymptomatic LVSD, usually as a result of 
remote myocardial infarction, ACE inhibitor therapy attenuates the progressive left 
ventricular remodelling.29 
 
To date, the administration of an ARNI has not been studied in patients after 
myocardial infarction. Sacubitril/valsartan (brand name “Entresto”) is a first-in-class 
ARNI, which has been studied in a pivotal trial in the setting of chronic HF-REF in 
patients with LV ejection fractions of ≤40%.24  Sacubitril/valsartan (at a target dose of 
97mg/103mg BD) when compared to the gold standard ACE-inhibitor, enalapril 
(target dose 10mg BD), was associated with a significant reduction in cardiovascular 
death and hospitalisation for heart failure. Recently, sacubitril/valsartan was shown 
to have favourable effects on left ventricular remodelling in an experimental rat 
model of acute myocardial infarction, although in this study sacubitril/valsartan was 
compared to control rather than an ARB.26  
 
The target dose (97mg/103mg BD) of sacubitril/valsartan is based on the clinical 
benefit and safety results seen with this dose in PARADIGM-HF.24 In this trial there 
was a high prevalence of ischaemic cardiomyopathy (60%), with 43% of patients 
having had a prior MI. This target dose delivers equivalent valsartan exposure 
(assessed by AUC) as valsartan 160mg BD and biomarker analysis (increase in 
ANP and cGMP) indicates that this dose delivers approximately 90% of its maximal 
NEP inhibition.30 The target dose of valsartan (160mg BD) was shown to be as 
effective as the ACE inhibitor captopril (target dose 50mg three times daily) in the 
VALIANT trial at reducing mortality, recurrent myocardial infarction and 
hospitalisation for heart failure in patients with LVSD and/or HF post MI.9  
 
CMR is the gold standard means of assessment of LV mass, volumes and ejection 
fraction. It has the additional benefit of allowing assessment of myocardial viability, 
myocardial fibrosis and regional dysfunction.31 LVESVI has been shown to be a 
major determinant of survival after myocardial infarction.32,33 The degree of LV 
remodelling and effect of treatment will be measured by the primary endpoint of the 
change in LVESVI from baseline to 12 (+/- 3months) months. 
 
5 Patient Population 
This study will recruit male and female patients aged ≥18 years with asymptomatic 
left ventricular systolic dysfunction (i.e. no evidence of clinical and/or radiological 
heart failure) > 3 months post acute myocardial infarction. 
 


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Patients will be required to satisfy the following criteria. Eligibility waivers to the 
inclusion / exclusion criteria are NOT permitted. 
 
5.1 Inclusion Criteria 
• Acute myocardial infarction at least 3 months prior to recruitment 
• LVEF ≤ 40% as measured by transthoracic echocardiography 
• Ability to provide written, informed consent 
• Age ≥18 years 
• Tolerance of a minimum dose of ACE inhibitor/ARB (ramipril 2.5mg BD or 
equivalent)  
• Treatment with a beta-blocker unless not tolerated or contraindicated 
 
5.2 Exclusion Criteria 
• Contraindication to CMR (ferrous prosthesis, implantable cardiac device or 
severe claustrophobia) 
• Clinical and/or radiological heart failure (NYHA≥2)  
• Symptomatic hypotension and/or systolic blood pressure <100mmHg 
• eGFR < 30 mL/min/1.73m2 and/or serum potassium >5.2mmol/L 
• Persistent/permanent atrial fibrillation 
• History of AMI within last 3 months 
• History of hypersensitivity or allergy to ACE-inhibitors/ARB 
• History of angioedema 
• Known hypersensitivity to the active study drug substances, contrast media or 
any of the excipients 
• Obesity (where body girth exceeds MRI scanner diameter) 
• Pregnancy, planning pregnancy, or breast feeding 
• Inability to give informed consent or comply with study protocol 
• Evidence of hepatic disease as determined by any one of the following: AST 
or ALT values exceeding 2 x ULN at Visit 1, history of hepatic 
encephalopathy, history of oesophageal varices, or history of portacaval shunt 
• History of biliary cirrhosis and cholestasis 
• Active treatment with cholestyramine or colestipol resins 
• Active treatment with lithium or direct renin inhibitor 
• Participation in another intervention study involving a drug or device within the 
past 90 days (co-enrolment in observational studies is permitted)  
 
5.3 Women of child bearing potential 
Women of childbearing potential must be currently adhering to, or be willing to use, 
highly effective birth control methods for study treatment duration and for seven days 
thereafter including: 
 
• Combined hormonal contraception (oestrogen and progestogen containing 
medication) either orally, intravaginally, or transdermally 
• Progesterone only hormonal contraception either orally, injected, or implanted 
• Progesterone only hormonal contraception either orally, injected, or implanted 


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• Intrauterine device (IUD) 
• Intrauterine hormone release system (IUS) 
• Bilateral fallopian tube occlusion 
• Vasectomised partner 
• Complete sexual abstinence where this is their preferred and usual lifestyle 
 
Women of child bearing potential (WOCBP) comprises women who have 
experienced menarche and who have not undergone successful surgical sterilisation 
(hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who are not post-
menopausal defined as: 
 
• Women who have had amenorrhea for ≥ 12 consecutive months (without 
another medical cause) and who have a documented serum follicle-
stimulating hormone (FSH) level > 35 mIU/mL. 
• Women who have irregular menstrual periods and a documented serum FSH 
level > 35 mIU/mL. 
• Females of childbearing potential must have a negative pregnancy test within 
7 days prior to the initiation of treatment. 
 
Pregnancy tests will be performed in WOBCP at the following visits: Visit 1 (week 0), 
4 (week 4), 6 (week 14), 7 (week 26), 8 (Week 39), and 9 (week 52). Should this test 
be positive, then the patient will be immediately withdrawn from the trial and study 
drug will be discontinued. 
 
5.4 Males whose partner could become pregnant 
To be eligible for this study participants will be taking an ACEI or ARB. These are similar to 
the study medicines and with the information currently available there is no indication that 
men should avoid fathering a child whilst taking the study medicines. Males whose partner 
may have become pregnant during the study must be advised to inform the investigator 
immediately. If the partner consents data may be collected about the pregnancy and the 
health of the partner and their baby.   
 
 
5.5 Pregnancy 
The Investigator must ensure that all patients are aware at the start of a clinical trial 
of the importance of reporting all pregnancies (in themselves and their partners) that 
occur whilst being treated with IMP and occurring up to 1 month after the last IMP 
administration. The Investigator should offer counselling to the patient and/or the 
partner, and discuss the risks of continuing with the pregnancy and the possible 
effects on the foetus. Monitoring of the patient and the baby should continue until the 
conclusion of the pregnancy, if the patient or patient’s partner has consented to this.  
See section 10.7 for information on pharmacovigilance reporting requirements.   
  
 


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6 Study Treatment 
6.1 Investigational and control drugs 
All eligible patients will be randomised 1:1 to either sacubitril/valsartan titrated to a 
target dose of 97mg/103mg B.D. or valsartan titrated to a target dose of 160mg BD 
in a double blinded manner for the duration of the study. Patients will continue on 
optimal standard of care background therapy to treat their index MI and any co-
morbid conditions in accordance with local guidelines with the exception of an ACE 
inhibitor or ARB as this will be replaced by study drug. In order to minimise the 
potential risk of angioedema due to overlapping ACE and NEP inhibition all patients 
prescribed an ACE inhibitor pre-randomisation will undergo a 36-hour “washout” 
period following randomisation prior to first dose of study drug. The use of open label 
ACE inhibitor or ARB in addition to the randomised study drug is strictly prohibited 
for the duration of the trial.  
 
In order for adequate blinding of treatment allocation, patients will be required to take 
a total of two tablets (one tablet from the sacubitril/valsartan or sacubitril/valsartan 
matching placebo pack and one tablet from the valsartan or valsartan matching 
placebo pack) twice a day for the duration of the study. 
 
The following study drugs will be provided: 
 
• Sacubitril/valsartan 24mg/26mg, 49mg/51mg and 97mg/103mg tablets and 
matching placebo. 
• Valsartan 40mg, 80mg and 160mg tablets and matching placebo. 
 
Patients will be supplied with sufficient medication to last to the next visit including a 
small overage at visits 1, 4, 6 and 7. At each study visit where medicines are 
dispensed, patients will be asked to return any unused study drug and this will be 
returned to the pharmacy. In response to the COVID-19 pandemic re supply in 
person at the CRF or through home delivery at unscheduled intervals until the final 
MRI is performed (up to a maximum of 18 months or end of study). 
 
Patients will be advised to take their morning study drug doses at approximately 
08:00 (8 AM) and their evening dose 12 hours later at approximately 20:00 (8PM). 
The study medicines should be swallowed whole with water and can be taken with or 
without food. If a patient misses a dose of either study drug they should skip the 
missed dose and take the next one at the scheduled time. 
 
Compliance will be promoted through use of tablet counts and investigators must 
emphasise the importance of compliance for both patient safety and study validity. If, 
for any reason, patients are unable to take study drug as prescribed then they will be 
told to contact the investigators for further advice. 
 
6.2 Study Drug storage and supply 
Investigational medicinal product (IMP) supplies will only be released to study sites 
by the sponsor once all the appropriate regulatory and governance approvals are in 
place.   


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All study medicines must be stored in a locked, secure area with access limited to 
the Investigator and authorised site staff.  Study supplies should be used as directed 
in the study protocol and not be supplied to any persons other than study 
participants.  Study medicines must be stored at room temperature. 
 
6.3 Drug accountability requirements 
The Investigator or designee must maintain accurate records of all study IMP 
movements for accountability purposes.  They should include dates, quantities, 
batch numbers and expiry. Records must document adequately that: 
 
• the patients were provided the doses specified by the protocol/amendment(s) 
• all study drug provided was fully reconciled. 
 
Unused study drug must not be discarded or used for any purpose other than the 
present study. Further information on storage requirements and supply 
arrangements is provided in the study specific IMP Management and Accountability 
Manual. 
 
6.4 Treatment arms 
Patients will be assigned to one of the following two treatment arms in a ratio of 1:1 
at study visit 1: 
 
• Sacubitril/valsartan at dose levels 1-3 (24mg/26mg, 49mg/51mg and 
97mg/103mg BD) 
• Valsartan at dose levels 1-3 (40mg, 80mg and 160mg BD) 
 
6.5 Permitted dose adjustments and discontinuation of study treatment 
Every attempt should be made to maintain patients at the target study drug dose 
level throughout the trial. If the patient does not tolerate the target study drug dose 
level the investigator can, if appropriate, adjust concomitant background medications 
for co-morbid conditions to rectify the situation, and if necessary down titrate to the 
next lower study drug dose level. Any dose-adjustment of disease-modifying 
background therapy, e.g. beta-blockers or MRAs is discouraged.  
 
Down-titration of the study drug at any time will be allowed based on the safety and 
tolerability criteria defined in Table 4-3 and section 6.8. If down-titration is necessary, 
the patient should be down-titrated to the next lower dose level (Table 4-2) The 
patient may continue receiving the lower dose level for a recommended period of 1 
to 4 weeks before re-challenging the patient with the next higher dose level. For 
example, a patient who encounters tolerability problems at the target dose level 
(dose level 3), should receive the study drug at dose level 2 for 1 to 4 weeks. Then, 
he/she should be re-challenged with up-titration back to dose level 3. If the 
tolerability issues are not alleviated despite down-titration by one dose level, the 
investigator may lower the study drug dose further to the next lower level for 1 to 4 
weeks, up to temporary withdrawal of the study drug. Study drug should be 
reintroduced in those who temporarily discontinue it as soon as medically justified in 


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the opinion of the investigator. Again, once stable, the patient should be re-
challenged with up-titration to the next higher dose level every 1 to 4 weeks in an 
attempt to bring back the patient gradually to the target study drug dose level (dose 
level 3). The investigator may choose the next dose level for down- or up-titration 
according to his or her judgement.  
 
In some instances, according to the safety and tolerability criteria and the 
investigator’s judgment, dose level 1 or 2 could be maintained if he/she considers 
that the patient’s condition would not allow any further up-titration to the target dose 
of study medication (level 3). In this case it would be acceptable to maintain the 
patient at dose level 1 or level 2, whichever is the higher and tolerated dose level by 
the patient.  
 
Any dose change must be recorded on the dosage administration record on the 
eCRF. 
 
Should a patient develop symptomatic heart failure during the study they will be 
offered open-label sacubitril/valsartan. Patients starting open-label 
sacubitril/valsartan or withdrawing from study medication (or study follow-up) ≥6 
months after randomisation will be asked to undergo an end-of-study CMR 
examination (patient withdrawing before 6 months will not be asked to have a 
second CMR as an effect of LV remodelling is unlikely to be detected before this 
time point). 
 
The emergence of the following circumstances will require permanent study drug 
discontinuation: 
 
• Withdrawal of informed consent 
• Investigator thinks that continuation of study drug would be detrimental to the 
patient’s well-being 
• Suspected or confirmed occurrence of clinically significant angioedema. A 
patient with any signs or symptoms of clinically significant angioedema should 
be thoroughly evaluated by the investigator 
• Pregnancy and post-pregnancy during lactation period  
 
The emergence of the following circumstances will require temporary or permanent 
discontinuation (study drug may be restarted once these circumstances no longer 
exist): 
 
• Use of an open label ACE inhibitor, ARB, direct renin inhibitor, lithium, 
cholestyramine or colestipol resins (Table 6-1) 
• Any laboratory abnormalities that in the judgment of the investigator warrant 
discontinuation of study drug after taking into consideration the patient’s 
overall condition 
 
Study drug may be discontinued at the investigator’s discretion if any of the following 
occurs: 
 
• Any severe suspected drug-related AE 


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• Any other protocol deviation that results in a significant risk to the patient’s 
safety  
• Subsequent clinical need for implantable cardiac device insertion (e.g. 
permanent pacemaker, implantable cardioverter defibrillator, cardiac 
resynchronisation therapy) 
 
6.6 Concomitant medications 
Prior to randomisation and at each study visit a list of the patient’s current 
medications will be reviewed and the patient will be instructed to inform the 
investigator about any new medications he/she takes after enrolment in the study. 
Each new medication must be individually assessed against the exclusion criteria 
and list of prohibited medication below (Table 6-1) 
 
Medications known to raise potassium levels 
 
Potassium-sparing diuretics, potassium supplements and any other medications 
known to raise potassium levels should be used with caution while the patient is 
receiving the study drug due to the increased possibility of occurrence of 
hyperkalemia. Patient’s potassium levels will be monitored regularly, especially in 
those who are receiving these medications. 
 
Phosphodiesterase-5 (PDE-5) inhibitors 
 
PDE-5 inhibitors should be used with caution while the patient is receiving study 
medication due to the increased possibility of the occurrence of hypotension. 
 
HMG-CoA reductase inhibitors (statins) 
 
Caution is recommended when co-administering sacubitril/valsartan with atorvastatin 
or other statins because of the potential to raise its plasma level. 
 
Non-steroidal anti-inflammatory drugs (NSAIDs) 
 
In elderly patients, volume-depleted patients (including those on diuretic therapy), or 
patients with compromised renal function, concomitant use of sacubitril/valsartan or 
valsartan and NSAIDs may lead to an increased risk of worsening of renal function. 
Close monitoring of renal function as per study protocol will take place in all patients. 
 
OATP and MRP2 transporters 
 
The active metabolite of sacubitril (LBQ657) and valsartan are OATP1B1, OATP1B3, 
OAT1 and OAT3 substrates; valsartan is also a MRP2 substrate. Therefore, co-
administration of Entresto with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. 
rifampicin, ciclosporin), OAT1 (e.g. tenofovir, cidofovir) or MRP2 (e.g. ritonavir) may 
increase the systemic exposure of LBQ657 or valsartan. Appropriate care should be 
exercised when initiating or ending concomitant treatment with such medicinal 
products. 
 
Prohibited medication 


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Use of the treatments displayed in Table 6-1 is NOT allowed after the start of study 
drug due to safety reasons, unless the actions specified are taken. 
Table 6-1 Prohibited medications 
 
Medication 
Action taken 
Any ACE inhibitor 
Discontinue study drug. The open label ACE 
inhibitor must be stopped for ≥36 hours prior to 
re-initiation of study drug 
 Any ARB  
Discontinue study drug. The open label ARB must 
be stopped prior to re-initiation of study drug 
Any direct renin inhibitor 
Discontinue study drug. The open label direct 
renin inhibitor must be stopped prior to re-
initiation of study drug 
Entresto (commercially 
available sacubitril/valsartan) 
Discontinue study drug. The open label Entresto 
must be stopped for ≥36 hours prior to re-initiation 
of study drug 
Lithium 
Discontinue study drug. Lithium must be stopped 
prior to re-initiation of study drug 
Cholestyramine or colestipol 
resins 
 
Discontinue study drug. Cholestyramine or 
colestipol resins must be stopped prior to re-
initiation of study drug 
 
The concomitant use of open-label ACE inhibitor, ARBs, commercially available 
sacubitril/valsartan (Entresto) or a direct renin inhibitor is strictly prohibited while 
the patient is receiving study drug. If the addition of an ACE inhibitor, ARB, Entresto 
or direct renin inhibitor is necessary, then study drug must be temporarily 
discontinued. If the patient is to be started on open-label ACE inhibitor or Entresto, 
the study drug must be stopped ≥36 hours prior to initiating ACE inhibitor or 
Entresto. If study drug is to be re-started, the open-label ACE inhibitor or Entresto 
must also be stopped ≥ 36 hours prior to re-initiating study drug. ARBs or a direct 
renin inhibitor should be stopped prior to resuming study drug. 
 
6.7 Identification of participants and treatment assignment 
Potentially eligible patients will be identified through the “post MI LVSD” or general 
cardiology out-patient clinics throughout NHS Greater Glasgow and Clyde (NHS 
GG&C) and surrounding health boards. Participants will be identified from electronic 
searching of the cardiac patient databases by a clinical research fellow, who is a 
member of the direct clinical care team. They will also be identified by clinicians and 
nurses responsible for the routine care of these patients, for example cardiac 
rehabilitation nurses, cardiology pharmacists and cardiologists.  
 
Patients will be considered if they have suffered a myocardial infarction at least 3 
months prior to randomisation. 
 


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The definition of myocardial infarction will be in line with the guidelines provided by 
the European Society of Cardiology and the third Universal definition of myocardial 
infarction.34,35 Patients will require to meet the following criteria: 
 
• Detection of rise and/or fall of cardiac biomarker values (preferably troponin) 
with at least one value above the 99th percentile of the upper reference limit 
and with at least one of the following:  
 
o Symptoms of ischaemia;  
o New or presumably new significant ST-T changes or new LBBB; 
o Development of pathological Q waves in the ECG;  
o Imaging evidence of new loss of viable myocardium, or new regional 
wall motion abnormality;  
o Identification of an intracoronary thrombus by angiography or autopsy.  
 
All patients without obvious contraindications to enrolment based on review of case-
notes will be approached with regards to taking part in trial-screening. They will be 
provided with a patient information sheet detailing the trial and given the opportunity 
to ask questions prior to screening. Patients who are agreeable will be consented 
and will undergo screening transthoracic echocardiography (TTE), performed by one 
operator (KD), in order to estimate LVEF (Simpson’s biplane rule). The TTE will be 
performed at least 3 months after the index myocardial infarction. Patients with 
insufficient endocardial definition to allow accurate planimetry will be excluded from 
recruitment. This screening process will continue until the pre-specified target 
population (n=100) has been recruited. Patients who initially fail screening may be 
re-screened once more. Re-screened patients will be allocated a new patient 
number. If the patient has failed screening and is re-screened within 3 months of 
initial screening date the initial screening echocardiogram measurement of ejection 
fraction will be permitted to used for purposes of eligibility unless felt clinically 
relevant to repeat scan. 
 
A log of all patients screened for eligibility will be completed. Anonymised information 
will be collected including: 
• Age 
• Gender 
• Ethnicity  
• Whether the patient is recruited or not recruited to the study 
 
This information will be collated in the study database. Screened patients who are 
not recruited either because they are ineligible or because they decline participation 
will also have the following information recorded: 
 
• The reason not eligible for study participation OR 
• Where eligible, reason declined 
 
However, the right of the patient to refuse consent without giving reasons will be 
respected. This anonymised information will be stored in a locked filing cabinet in the 
BHF Glasgow Cardiovascular Research Centre (GCRC).  
 


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Assenting patients who meet the eligibility criteria and without any contraindications 
to taking part in the study will be given information regarding the trial as detailed in 
the patient information sheet. If agreeable to taking part in the trial, then written, 
informed consent for will be sought. Enrolled patients will be allocated a unique 
patient identifier number which will last for the duration of the entire trial. The 
assessment of eligibility and the informed consent process will be undertaken by a 
member of the research team who is qualified by training and experience in taking 
informed consent to good clinical practice (GCP) standards. Informed, written 
consent is necessary prior to randomisation. A copy of the consent form will be given 
to the patient and another will be uploaded to the patient’s online case notes. The 
original consent form will be filed in the study file and sites will be required to scan 
and upload the consent forms into a secure study database for each consented 
patient. 
 
After all baseline data has been collected and the patient has been confirmed as 
eligible for randomisation, the patient will be randomised via the study web portal. 
Randomisation will be stratified on the basis of LVESVI ≤45ml/m2 / >45ml/m2 as 
measured by CMR, and whether or not the patient is being prescribed diuretics at 
baseline. The portal will inform the researcher of the treatment packs to be allocated 
to the patient. Randomisation may occur up to three months after screening 
echocardiography.  
 
6.8 Monitoring of potential side effects 
6.8.1 Management of nephrotoxicity 
Both study drugs are potentially nephrotoxic and close monitoring of renal function 
(serum urea, creatinine and electrolytes) for the duration of the trial will be 
mandatory. This will include baseline measurements along with measurements prior 
to and after the introduction of the study drug and after any dose change. 
Measurements will also be taken at regular intervals for the duration of the trial. Alert 
ranges for laboratory and other test abnormalities are included in Appendix 1. 
Additional measurements will be used if clinically indicated. All results will be 
reviewed in a timely manner when available and if action is required this will be 
expedited immediately. Each patient will have their renal function (along liver 
function tests) checked at the following time-points: 
 
• Visit 1: 
Week 0 (pre-randomisation) 
• Visit 2: 
Week 1 ( 3 days) 
• Visit 3: 
Week 2 ( 3 days) 
• Visit 4: 
Week 4 ( 3 days - pre up-titration of study drug) 
• Visit 5: 
Week 5 ( 3 days - 1 week post up-titration of study drug) 
• Visit 6: 
Week 14 ( 7 days) 
• Visit 7: 
Week 26 ( 7 days) 
• Visit 8: 
Week 39 ( 7 days) 
• Visit 9: 
Week 52 ( 7 days) 
 
If, at any time after randomisation, eGFR decreases by ≥ 25% from baseline (or if 
serum creatinine concentration increases to 221 µmol/L), potentially reversible cases 
of renal dysfunction will be sought including: non-steroidal anti-inflammatory drug 


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intake, antibiotics, or other nephrotoxic medications; hypovolaemia; and urinary tract 
infection. If felt to be appropriate, the study drug dose can be reduced and continued 
with regular monitoring of renal function. If a patient’s eGFR decreases by ≥ 40% 
from baseline (or if serum creatinine concentration rises above 265 µmol/L, then this 
is an indication to stop the study drug. Thereafter, serum creatinine assessments will 
have to be repeated at least weekly until levels return to acceptable values. Re-
challenging with the study drug at a lower dose level will be considered if deemed 
clinically safe to do so.  
 
6.8.2 Management of hyperkalaemia 
Patients with elevated potassium value will be managed according to the 
corrective actions outlined below. 
 
Serum potassium > 5.3 and less than or equal to 5.5 mmol/L 
• Confirm potassium concentration in a non-haemolysed sample 
• Reinforce low potassium diet and restriction of food/drinks with high 
potassium content 
• (e.g. orange juice, melon, bananas, low-salt substitutes etc.) 
• Review medical regimen (including dietary supplements and over-the-
counter medications) for agents known to cause hyperkalaemia. Consider 
reduction in dose or discontinuation of these agents: 
o Potassium-sparing diuretics (e.g. amiloride and triamterene) 
including in combination products with thiazide or loop diuretics 
o Potassium supplements, e.g., potassium chloride 
o Salt substitutes 
o Non-steroidal anti-inflammatory drugs (NSAIDs) 
o Cyclo-oxygenase-2 (COX-2) inhibitors 
o Trimethoprim and trimethoprim-containing combination products 
o Herbal Supplements: For example, Noni juice, alfalfa (Medicago 
sativa), dandelion (Taraxacum officinale), horsetail (Equisetum 
arvense), nettle (Urtica dioica), milkweed, lily of the valley, Siberian 
ginseng, hawthorn berries 
• Repeat serum potassium measurement within 3 to 5 days 
• If serum potassium remains > 5.3 and ≤ 5.5 mmol/L, regularly monitor 
serum potassium levels to ensure stability (suggested once monthly) 
• Consider down-titration of study medication, according to investigator’s 
medical judgment. 
 
Serum potassium > 5.5 and < 6.0 mmol/L 
• Confirm potassium concentration in a non-haemolysed sample 
• Consider down-titration or temporarily discontinue study drug according to 
investigator medical judgment. 
• Apply all measures outlined for serum potassium > 5.3 and ≤ 5.5 mmol/L 
• Repeat serum potassium measurement after 2-3 days 
• If serum potassium < 5.5 mmol/L, consider resumption of study drug at 
lower dose with repeat potassium within 5 days 
 
Serum potassium greater than or equal to 6.0 mmol/L 
• Immediately discontinue study drug 


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• Confirm potassium concentration in a non-haemolysed sample 
• Urgently evaluate patient and treat hyperkalaemia as clinically indicated 
• Apply all measures outlined for serum potassium > 5.3 and < 6.0 mmol/L 
• Resumption of study drug will be decided on a case-by-case basis by the 
investigators. 
 
6.8.3 Management of hypotension 
Both study drugs can have the potential side effect of symptomatic hypotension 
and/or postural symptoms. Prior to any dose change blood pressure will be checked 
and up-titration will only occur if there is no symptomatic hypotension and systolic 
blood pressure is  100mmHg. If appropriate, at the investigators discretion 
adjustments can be made to doses of diuretic and/or concomitant antihypertensive 
agents to facilitate the patient’s ability to tolerate target study dose. 
 
6.8.4 Management of angioedema 
Angioedema is a potential side effect of combined RAAS and NEP inhibition. 
Angioedema has been reported in patients treated with sacubitril/valsartan. If 
angioedema occurs, study drug should be immediately discontinued and appropriate 
therapy and monitoring should be provided until complete and sustained resolution 
of signs and symptoms has occurred. It must not be re-administered. Any patients 
who experience angioedema during the trial will be withdrawn from the study. 
 
6.9 Withdrawal of treatment 
Any patient enrolled in the trial will be free to withdraw from the study at any time 
without giving reason and without prejudicing any further treatment/care. Following 
their involvement in the trial any patient withdrawing will be converted to an ACE-
inhibitor or ARB as per local practice guidelines at an equivalent dose to their final 
study drug dose level. 
 
6.10 Unblinding procedure 
Breaking of the study blind in an emergency should only be performed where 
knowledge of the treatment is absolutely necessary for further management of the 
patient. In case of any acute illness or major surgery, the study medication should be 
discontinued. Emergency unblinding will be available at all times, via the telephone 
(Interactive Voice Response System, IVRS). Details are included in the study alert 
card. For each unblinding request an email alert will be sent to the appropriate 
members of the research team, including the Chief Investigator (CI). 
Patients will be provided with an alert card at the randomisation visit after verbal 
consent is obtained. They will be asked to carry the alert card with them at all times 
and to show the card to any doctors or healthcare professionals who are involved in 
their care. Patients will also be asked at study visit 4 if they still have this and be 
provided with another if required. The Patient Alert Card will be collected from 
patients at the end of their involvement in the study. 


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Unblinding the treatment allocation may be required when reporting suspected 
unexpected serious adverse reactions (SUSARs) to the regulatory authorities. This 
will be performed by the Sponsor PV Office. 
7 Assessment and management of risk 
The risk to patients participating in the study will be minimised by compliance with 
the inclusion/exclusion criteria and close clinical monitoring. 
 
Patients will be instructed not to take any RAAS blockade medications (ACE inhibitor 
or ARB) from the day they start study drug to avoid excess RAAS blockade. The 
importance of a minimum 36-hour washout period prior to commencement of study 
drug in patients receiving ACE-inhibitors prior to randomisation will be reiterated to 
minimise the risk of angioedema. The risk of discontinuation of pre-randomisation 
ACE inhibitors or ARBs will be minimal as the study treatment will be reflective of the 
typical dosing schedule of most ACE inhibitors and ARBs. All patients will be 
required to continue receiving the rest of their standard of care background 
cardiovascular medications. 
 
In women of child-bearing potential, a possible risk of developmental toxicity cannot 
be excluded. Women of child-bearing potential should therefore use a highly 
effective method of contraception during study participation. If there is any question 
that the patient will not reliably comply, they should not be entered in the study. 
Pregnancy testing will be performed prior to randomisation and at regular intervals 
during the study in women of child-bearing potential.  
 
8 Visit schedule and assessments 
Table 9-1 details all of the visits and indicates with an “x” when study assessments or 
procedures are performed. Patients should be seen for all visits at the designated 
time or as close to as possible. These visits windows are what investigators should 
endeavor to stick to and wherever possible should be met. Any visits out with these 
timeframes will not be considered protocol violations but will be dealt with in the 
statistical analysis plan. 
 
8.1 Screening 
Potentially eligible patients will be identified through the “post-MI LVSD” clinic or 
general cardiology out-patient clinics in NHS Greater Glasgow and Clyde (NHS 
GG&C) and surrounding health boards. Additionally, participants will be identified 
from electronic searching of the cardiac patient database by a clinical research 
fellow, who is a member of the direct clinical care team. They will also be identified 
by clinicians and nurses responsible for the routine care of these patients, for 
example cardiac rehabilitation nurses, cardiology pharmacists and cardiologists. 
 
Potential participants will be approached in one of two ways: 
 
(1) Approach in person by the clinical care team at a routine outpatient appointment. 
Those who demonstrate interest will be given the patient information sheet (PIS), 


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and asked for verbal consent for their details to be passed to the research team. The 
PIS will contain a contact email address and telephone number to allow patients to 
“opt in” to the study or get in contact for further information. If there has been no 
contact from a patient 48 hours after being given the PIS the patient will be 
telephoned by a clinical fellow or research nurse to ascertain interest in participation 
in the study. 
 
(2) Letter drop: letters posted to the patient by the principal investigator with 
information about the study. The same contact information will be provided for 
patients contacted by letter drop to allow them to opt in to the study. These 
patients will also be contacted 5-7 days after posting the letter by a clinical fellow to 
assess interest in participating in the study; Initial screening will be based on a 
telephone discussion with the potential patient who has expressed an interest in 
participating in the study supported by a review of their health records by a clinical 
fellow, as part of their routine clinical care team, and the research team. Where 
possible, any missing biochemical data required as an inclusion criterion will be 
ordered ahead of enrolment as part of standard of care if unrecorded in the last 6 
months. This is to ensure appointments for screening echocardiography are only 
made for patients considered suitable to enter the study and avoid unnecessary 
inconvenience if they are not thought to be eligible based on routine information. 
Telephone discussions with the patient would also aim to ensure their ability to 
adhere with the trial, diagnostic tests, outcomes measures, and their ability to give 
informed consent. If the potential participant wishes to discuss any aspect of the 
study, they will be given the opportunity to do so with a member of the research team 
either over the phone or at the screening study visit and before consent is taken.  
 
If agreeable and eligible on review of their medical case notes, assenting patients 
will then proceed to screening echocardiography. Patients will be consented for 
screening echocardiography and routine biochemical blood tests (U&Es and LFTs) if 
unrecorded in the last 6 months to ensure trial eligibility. 
 
8.1.1 Echocardiography protocol 
Transthoracic echocardiography (TTE) will be performed in the left lateral decubitus 
position. Images will be taken from the standard parasternal, apical and subcostal 
windows. A standard complete exam will be performed and images stored for off-line 
measurements.36 LV ejection fraction will be calculated from apical 4 and 2 chamber 
views using Simpson’s biplane rule. A cut-off of less than or equal to 40% will be 
used for inclusion in the trial. Contrast agents will not be used.   
 
After screening echocardiography, suitable patients will be approached for consent 
to take part in the trial as described above. Patients who have consented will 
undergo the following tests at least 3 months post myocardial infarction and prior to 
randomisation to either sacubitril/valsartan or valsartan. 
 
8.2 Pre-randomisation investigations 
The following investigations will be performed prior to randomisation and all results 
recorded in the eCRF. 
 


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• Full physical examination – including measurement of height, weight and 
resting heart rate and blood pressure 
• A record of the patients past medical history will be obtained. The presence of 
diabetes mellitus (Type-1 or Type-2), hypertension, hyperlipidaemia, 
cerebrovascular disease, peripheral vascular disease, chronic obstructive 
pulmonary disease and smoking history will be recorded. Prescribed 
medication pre-randomisation will also be recorded. 
• 12-lead ECG 
• Spot urine collection 
• Venepuncture – 50ml of venous blood withdrawn for biochemical, biomarker 
and hormonal analysis and baseline renal/liver function for trial eligibility 
• Cardiac MRI with gadolinium contrast 
 
8.2.1 Biochemical and hormonal measurements 
50mls of venous blood will be collected at three time points during the study - pre-
randomisation, study visit 7 (26 weeks) and study visit 9 (52 weeks) for biochemical 
and hormonal analysis. Where possible, samples will be taken as fasting, early 
morning samples to account for the diurnal variation in hormonal measurements. 
Non-fasting samples will be taken in patients with diabetes to avoid any potential risk 
of hypoglycaemia. All samples will be taken after at least 15 minutes of supine rest. 
Spot urine collections will be performed at pre-randomisation, 26 weeks and 52 
weeks. Samples will be used for the following measurements pertaining to the action 
of sacubitril/valsartan and remodelling: Brain Natriuretic Peptide (BNP), N-Terminal 
pro BNP (NT-proBNP), MR-pro Atrial Natriuretic Peptide (MR-proANP), C-terminal 
ANP, C-type natriuretic peptide (CNP), high sensitivity Troponin-I (hsTnI), Urea and 
Electrolytes (U&Es), C-Reactive Protein (CRP), cyclic guanosine monophosphate 
(cGMP), neprilysin antigen , matrix metalloproteinases (MMPs), Tissue inhibitors of 
metalloproteinases-1 (TIMP-1), ST2, galectin-3, amino-terminal propeptide of type III 
procollagen (PIIINP), adrenomedullin (MR-proADM), growth differentiation factor 
(GDF-15), and endothelin-1. Measurements of glycated haemoglobin A1c (HbA1c) 
will be made as per standard clinical practice at baseline, 6 months and 12 months 
for the purposes of screening for, and assessment of diabetic control. Any samples 
remaining will be stored for analysis of any future relevant biomarkers as they 
become available and for use in future ethically approved research studies if 
appropriate. 
 
8.2.2 CMR protocol 
All CMR scans will be performed on a single 3.0 Tesla Siemens MAGNETOM 
Prisma scanner located in the CRF at the QEUH. The MRI scan will include cine 
MRI, T1 and T2 maps, strain encoded MRI, and contrast enhanced imaging 
including first pass perfusion at rest, microvascular obstruction and late gadolinium 
enhancement imaging 10 - 15 min after contrast administration. IV access will be 
required for contrast administration and a full blood count will be obtained before the 
scan in order to measure extracellular volume. Specific details of the CMR protocol 
are detailed in a local Standard Operating Procedure. Patients will be provided with 
an MRI information sheet prior to their visit (Appendix 2). 
 


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8.3 26-week visit 
This will comprise of a half-day visit to the QEUH CRF. A number of the baseline 
investigations will be repeated:  
 
• full physical examination   
• spot urine collection  
• venepuncture – 50ml blood withdrawn for biochemical and hormonal analysis  
 
Patients will also be asked to complete a short patient global assessment 
questionnaire (Appendix 3) at this visit. 
 
8.4 52-week visit (+/- 3 months) 
This will comprise of a half-day visit to the QEUH CRF. A number of the baseline 
investigations will be repeated: 
 
• full physical examination   
• spot urine collection  
• venepuncture – 50ml blood withdrawn for biochemical and hormonal analysis  
• cardiac MRI with gadolinium contrast will be performed. 
 
Patients will also be asked to complete a short patient global assessment (Appendix 
3) questionnaire at this visit. 
 
In response to the COVID-19 pandemic we have allowed an extension of the 
patients IMP treatment by up to 3 months. During this extended time on IMP we 
would anticipate following up with patients by telephone every 6 weeks. Patients 
have the clinical research team contact details should they wish to discuss any 
aspect of the extended involvement themselves. 
 
At this point a patient’s participation in the involvement in the trial will end. They will 
return any unused study drug. Following their involvement in the trial patients will be 
converted to an ACE-inhibitor or ARB as per local practice guidelines at an 
equivalent dose to their final study drug dose level. Prior to commencement of any 
ACE-inhibitor, patients will require to have a 36-hour washout period following their 
last dose of study drug in order to reduce the risk of angioedema associated with 
combined ACE and NEP inhibition. 
 
8.5 Definition of end of trial 
The end of the trial is defined as the date of the last patient’s 52-week (+/- 3 months) 
study visit plus additional 30 days of event reporting. 
 
9 Assessment, samples and data collection 
Trial data will be recorded on trial-specific eCRFs. Only the patient’s unique identifier 
number, date of birth and initials will be recorded on the eCRF in order to identify the 
patient. Any missing or discrepant data queries will be sent to appropriate research 


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team member(s) to be reviewed.  Biochemical samples will be stored in the QUEH 
Biochemistry department and the BHF Glasgow Cardiovascular Research Centre to 
be analysed in batches on completion of the trial. Analysis of echocardiograms and 
CMR imaging will be performed offline.  


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Table 9-1 Schedule of Assessments 
Study Procedure 
Screening 
(>3months post 
myocardial 
infarction) 
Visit 1 - 
Randomisation 
(Week 0) 
Visit 2 
 
(Week 
1  3 
days) 
Visit 3 
 
(Week 
2 3 
days) 
Visit 4 
 
(Week 
4 3 
days) 
Visit 5 
 
(Week 
5 3 
days) 
Visit 6 
 
(Week 
14  7 
days) 
Visit 7 
 
(Week 
26  7 
days) 
Visit 8 
 
(Week 
39  7 
days) 
Visit 9 
 
(Week 
52  3 
months) 
Review Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
Obtain informed consent 
X 
X 
 
 
 
 
 
 
 
 
Cardiac MRI 
 
X 
 
 
 
 
 
 
 
X 
Physical examination 
 
X 
X 
 
X 
 
 
X 
 
X 
Medical history  
X 
X 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs (Blood 
pressure/Heart rate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 Lead ECG 
 
X 
 
 
 
 
 
 
 
 
Spot urine collection 
 
X 
 
 
 
 
 
X 
 
X 
Venepuncture (Urea and 
Electrolytes/FBC and 
LFTs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Venepuncture 
(Biochemical/hormonal/ 
biomarker analysis) 
 
X 
 
 
 
 
 
X 
 
X 
Pregnancy testing in 
WoCBP 
 
X 
 
 
X 
 
X 
X 
X 
X 
Patient global assessment 
questionnaire 
 
 
 
 
 
 
 
X 
 
X 
IMP Dispensing* 
 
X 
 
 
X 
 
X 
X 
 
 
Up-titrate IMP# 
 
 
 
 
X 
 
 
 
 
 
IMP Administration+ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event reporting 
 
 
X 
X 
X 
X 
X 
X 
X 
X  
Study completion 
 
 
 
 
 
 
 
 
 
X 
 
* Study drug will be introduced at equivalent dose to existing ACE-i/ARB treatment (Dose level 2 or 3) at investigator’s discretion 
#Up-titration not required if patient already on dose level 3 but down titration to dose level 2 permitted in response to COVID-19 
If not done in the preceding 6 months 
+Emergency IMP dispensing permitted during COVID-19 pandemic 


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10 Pharmacovigilance 
10.1 Definitions  
Table 10-1 Pharmacovigilance Definitions 
Term 
Definition 
Adverse Event (AE) Any untoward medical occurrence in a participant to 
whom a medicinal product has been administered, 
including occurrences which are not necessarily caused 
by or related to that product. 
Adverse Reaction 
(AR) 
 
An untoward and unintended response in a participant 
to an investigational medicinal product which is related 
to any dose administered to that participant. 
The phrase "response to an investigational medicinal 
product" means that a causal relationship between a 
trial medication and an AE is at least a reasonable 
possibility, i.e. the relationship cannot be ruled out. 
All cases judged by either the reporting medically 
qualified professional or the Sponsor as having a 
reasonable suspected causal relationship to the trial 
medication qualify as adverse reactions. 
Serious Adverse 
Event (SAE) 
A serious adverse event is any untoward medical 
occurrence that: 
results in death 
is life-threatening 
requires inpatient hospitalisation or prolongation of 
existing hospitalisation 
results in persistent or significant disability/incapacity 
consists of a congenital anomaly or birth defect 
Other events that are considered medically significant 
may also be considered serious if they jeopardise the 
participant or require an intervention to prevent one of 
the above consequences. 
NOTE: The term "life-threatening" in the definition of 
"serious" refers to an event in which the participant was 
at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused 
death if it were more severe. 
Serious Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion 
of the reporting Investigator, believed with reasonable 
probability to be due to one of the trial treatments, 
based on the information provided. 
 
Suspected 
Unexpected 
Serious Adverse 
Reaction (SUSAR) 
A serious adverse reaction, the nature and severity of 
which is not consistent with the information about the 
medicinal product in question set out: 


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in the case of a product with a marketing authorisation, 
in the summary of product characteristics (SmPC) for 
that product. 
in the case of any other investigational medicinal 
product, in the investigator’s brochure (IB) relating to the 
trial in question. 
 
 
10.2 Recording and reporting of Adverse Events 
All AEs occurring during the trial that are observed by the Investigator or reported by 
the participant should be recorded in the participant’s medical records whether or not 
attributed to trial medication. 
 
Details of the following adverse reactions will be collected within the eCRF at all 
follow up visits from randomisation until the participants’ final visit. 
 
• Clinically relevant hypotension (syncope, dizziness, etc)  
• Worsening renal function 
• Acute kidney injury 
• Hyperkalaemia 
• Occurrence of angioedema 
 
The seriousness of each adverse reaction will be collected along with the outcome of 
the event at the time of the visit i.e. whether the reaction is ongoing at the time of the 
visit or the participant has recovered. 
 
SAEs will be documented within the eCRF and will be collected from the date of 
randomisation until 30 days post cessation of trial treatment to allow for reporting of 
any ongoing adverse reactions associated with the use of the trial drug. 
 
The following events are excluded from the need for expedited reporting: 
 
• Routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition. 
• Treatment which was elective or pre-planned, for a pre-existing condition not 
associated with any deterioration in condition, e.g. pre-planned hip 
replacement operation which does not lead to further complications. 
• Any admission to hospital or other institution for general care where there was 
no deterioration in condition. 
• Treatment on an emergency, outpatient basis for an event not fulfilling any of 
the definitions of serious as given above and not resulting in hospital 
admission. 
 
10.3 Assessment of adverse events 
All adverse events must be assessed for seriousness. SAEs occurring between the 
date of consent and 30 days post treatment must be assessed for causality, 


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expectedness and severity and notified to the Sponsor. This is the responsibility of 
the CI or designee. 
 
Seriousness 
 
AEs should be assessed for seriousness as per the definitions in section 10.1; those 
meeting the criteria for an SAE are subject to expedited reporting to the sponsor. 
 
Assessment of causality  
 
SAEs must be assessed for their causality i.e. does the event have a reasonable 
causal relationship with the trial medication.  
 
Assessment of expectedness 
 
If an SAE is considered to be related (possibly, probably or definitely) to the study 
medication, an assessment should be made of the expectedness of the reaction i.e. 
is the reaction a recognised adverse effect of the medication. 
 
The expectedness of an adverse reaction must be assessed against the Reference 
Safety Information (RSI) i.e. the list of expected reactions detailed in the Summary of 
Produce Characteristics (SmPC) for the Investigational Medicinal Product approved 
during Clinical Trial Authorisation process. 
 
Expected: consistent with the relevant product information documented in the RSI. 
 
Unexpected: not consistent with the relevant product information documented in the 
RSI. 
 
Assessment of Severity 
 
This should be assessed and described using the following categories: 
• Mild-awareness of event but easily tolerated 
• Moderate-discomfort enough to cause some interference with usual activity 
• Severe-inability to carry out usual activity. 
 
10.4 Reporting to sponsor (Pharmacovigilance Office) 
All SAEs arising during the study will be reported by the Principal Investigator (or 
designee) to the sponsor (PV Office) by completing the trial eCRF as soon as 
reasonably practicable and in any event within 24 hours of first becoming aware of 
the event. Any follow up information should also be reported.  
 
In the event that eCRF reporting is not possible, a paper SAE form (CTIMP) can be 
downloaded from the Glasgow Clinical Trials Unit website: www.glasgowctu.org.  
 
This should be completed and faxed to the PV Office. (Fax No: +44 (0) 141 357 
5588). A copy of the complete form should be placed in the Study Site File. If 
necessary, a verbal report can be given by contacting the PV Office on +44 (0)141 


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330 4870/ +44 (0)141 330 4744. This must be followed up as soon as possible with 
a written report.  
 
10.5 Reporting to the MHRA and MREC 
All SAEs assigned by the PI or delegate and by the CI (on behalf of the sponsor), as 
both suspected to be related to IMP-treatment and unexpected will be classified as 
Suspected Unexpected Serious Adverse Reactions (SUSARs).  These will be 
subject to expedited reporting to the Medicines and Healthcare Products Regulatory 
Agency (MHRA). The Sponsor Pharmacovigilance office will inform the MHRA, the 
REC and the Sponsor of SUSARs within the required expedited reporting 
timescales. 
 
• Fatal or life threatening SUSARs: not later than 7 days after the sponsor had 
information that the case fulfilled the criteria for a fatal or life threatening 
SUSAR, and any follow up information within a further 8 days.  
 
• All other SUSARs: not later than 15 days after the sponsor had information 
that the case fulfilled the criteria for a SUSAR. 
 
10.6 Responsibilities 
Chief Investigator (CI) / delegate or independent clinical reviewer: 
 
1. Clinical oversight of the safety of patients participating in the trial, including an 
ongoing review of the risk / benefit. 
2. Using medical judgement in confirming PI’s assessment of expectedness of 
SAEs for ‘related’ SAEs. 
3. Immediate review of all SUSARs.  
4. Preparing the clinical sections and final sign off of the Development Safety 
Update Report (DSUR). 
 
Principal Investigator (PI):  
 
1. Checking for AEs and ARs when participants attend for treatment / follow-up. 
2. Using medical judgement in assigning seriousness, severity, causality and 
expectedness using the Reference Safety Information approved for the trial. 
3. Ensuring that all SAEs and SARs (including SUSARs) are recorded and 
reported to the Sponsor within 24 hours of becoming aware of the event and 
provide further follow-up information as soon as available.  
4. Ensuring that SAEs meeting the definition of SAEs of special interest are 
marked as such. 
5. Using medical judgement in assigning expectedness of SAEs for ‘related’ 
SAEs. 
 
Sponsor: 
 
1. Central data collection and verification SAEs, SARs and SUSARs according 
to the trial protocol. 


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2. Reporting safety information to the CI, delegate or independent clinical 
reviewer for the ongoing assessment of the risk / benefit according to the Trial 
Monitoring Plan. 
3. Reporting safety information to the independent oversight committees 
identified for the trial (Trial Steering Committee (TSC)) according to the Trial 
Monitoring Plan. 
4. Expedited reporting of SUSARs to the Competent Authority (MHRA in UK) 
and REC within required timelines. 
5. Notifying Investigators of SUSARs that occur within the trial. 
6. Checking for (annually) and notifying PIs of updates to the Reference Safety 
Information for the trial. 
7. Preparing standard tables and other relevant information for the DSUR in 
collaboration with the CI and ensuring timely submission to the MHRA and 
REC. 
 
Trial Steering Committee (TSC):  
 
In accordance with the Trial Terms of Reference for the TSC, periodically reviewing 
safety data and liaising with the CI and TMG regarding safety issues. 
 
 
10.7 Pregnancy reporting  
Pregnancy is not considered an AE or SAE. However, Principal Investigators will 
report pregnancy information on any female participant or female partner of a male 
participant who becomes pregnant while participating in the trial to the sponsor within 
two weeks of first becoming aware of the pregnancy. This report should be provided 
to the PV office on the Pregnancy Notification Form provide by the sponsor (on 
www.glasgowctu.org).  The subject will also be followed to determine the outcome of 
the pregnancy.  Information on the status of the mother and child will be forwarded 
by the PI to the PV Office 
 
10.8 Development safety update reports 
A Development Safety Update Report (DSUR) will be submitted once a year, or on 
request, to MHRA and REC until the trial is declared ended. The report will be 
submitted within 60 days of the anniversary of the issue of the Clinical Trials 
Authorisation for the trial. The report will be prepared by the sponsor (PV Office) in 
liaison with the CI and submitted by the sponsor (PV Office). 
 
11 Statistics and data analysis plan 
11.1 Sample size 
A sample size of 100 patients is proposed. This is based on the calculation that 45 
patients per treatment group provides >90% power (α level = 0.05) to detect a 
difference of 6mL/m2 in LVESVI (standard deviation = 7.8mL/m2) and accounting for 
a discontinuation rate of 10% (lost to follow up, development of heart failure or 


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death).37 A 6mL/m2 difference in LVESVI represents a minimally important 
difference.  
 
11.2 Planned recruitment rate 
Recruitment of 100 patients in 18 months requires a monthly recruitment rate of 5.6 
patients/month or 1.4 patients/week. We have previously recruited patients (n=100) 
in a study with similar inclusion criteria within the time-frame of 12 months.38 Data 
collected from a pharmacy led “post MI clinic” for patients with LVSD following an MI 
report a yearly incidence of around 90 patients with an LVEF ≤ 40% and without any 
evidence of clinical HF (NYHA I). We plan to use the database from these clinics to 
identify suitable patients as well as recruiting patients newly referred to the clinic 
following a MI. Recent restructuring of the health services in Glasgow has resulted in 
the amalgamation of 3 hospitals (Western Infirmary, Southern General and the 
Victoria Infirmary) into a single site at the Queen Elizabeth University Hospital 
(QEUH). We plan to base recruitment at this site given its large catchment 
population of 560,000. We will also recruit patients from QEUH, GRI, RAH, New 
Victoria Hospital, West Glasgow Ambulatory Care Hospital, Inverclyde Hospital, Vale 
of Leven Hospital, Wishaw General Hospital, Hairmyres Hospital and Monklands 
General Hospital via post-myocardial infarction outpatient clinics and general 
cardiology clinics. 
 
11.3 Statistical analysis 
The study will have a comprehensive Statistical Analysis Plan, which will be 
authored by the Trial Statistician and agreed by the Investigators before the final 
unblinded analysis. Analysis will be done on an intention-to-treat basis. The 
Robertson Centre for Biostatistics, functional unit of the Glasgow Clinical Trials Unit, 
a fully registered UK CRN Clinical Trials Unit, will manage and analyse trial data. 
 
The primary analysis will compare LVESVI at 12 months between randomised 
groups using a linear regression model, adjusted for baseline LVESVI, and whether 
or not taking diuretics at baseline. Similar methods will be applied to secondary 
outcomes. Safety data will be summarised without formal statistical comparison. 
 
12 Data handling 
12.1 Randomisation  
Randomisation will be in a 1:1 ratio and stratified by LVESVI ≤45ml/m2 / >45ml/m2 as 
measured by baseline CMR, and whether or not the patient is being prescribed 
diuretics at baseline, with the randomisation schedule computer generated by the 
method of randomised permuted blocks, with random block lengths of 4 and 6. The 
allocation for each patient will not be known to researchers until the point of 
randomisation. The full allocation sequence will be stored in a secure area of the 
Robertson Centre for Biostatistics network, with access restricted to those 
responsible for maintenance of the randomisation system. Study statisticians will not 
have access to the allocation schedule until the database has been locked, and all 


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analysis programs have been validated according to a prespecified statistical 
validation plan. 
 
12.2 Case Report Forms  
A study specific electronic case report form (eCRF) will be used to collect study data. 
It is the investigator's responsibility to ensure completion and to review and approve 
all data captured in the eCRF. All data handling procedures will be detailed in a 
Study Specific Data Management Plan. Data will be validated at the point of entry 
into the eCRF and at regular intervals during the study. Data discrepancies will be 
flagged to the investigators and any data changes will be recorded in order to 
maintain a complete audit trail (reason for change, date change made, who made 
change).  
 
12.3 Record Retention 
To enable evaluations and/or audits from regulatory authorities, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records), all original signed informed consent forms, serious 
adverse event forms, source documents, and detailed records of treatment 
disposition in accordance with EU GCP, local regulations, or as specified in the 
Clinical Study Agreement, whichever is longer. Data will be retained for a minimum 
of 25 years or for the time-period required to meet regulatory requirements defined 
for this trial. 
 
13 Trial management 
13.1 Trial steering committee (TSC) 
A TSC will oversee the running of the trial and ensure that it is being conducted in 
accordance with the principles of GCP and the relevant regulations.  
 
14 Study monitoring and auditing 
Study monitoring visits will be conducted by NHS Greater Glasgow and Clyde 
(GG&C) Monitors. The level of monitoring will be based on the outcome of the 
completed monitoring risk assessment, and will be clearly documented in the 
monitoring plan which will be approved by the NHS GG&C Research Governance 
Manager / Academic Lead Clinical Trial Monitor. As standard, monitoring visit(s) will 
cover site file review, review of Informed Consent Forms (ICFs), Source Data 
Verification (SDV) and Serious Adverse Event (SAE) review as per monitoring plan 
objectives. 
 
15 Ethical considerations 
The study will be carried out in accordance with the World Medical Association 
Declaration of Helsinki (1964) and its revisions (Tokyo [1975], Venice [1983], Hong 
Kong [1989], South Africa [1996] Edinburgh [2000], Seoul [2008] and Fortaleza 


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[2013]). Favourable ethical opinion will be sought from the East of Scotland 
Research Ethics Committee (REC) before patients are entered into this clinical trial. 
Patients will only be allowed to enter the study once wither they have provided 
written informed consent. The CI will be responsible for updating the REC of any 
new information related to the study. The participant will remain free to withdraw 
from the study at any time without giving reasons and without prejudicing his/her 
further treatment. 
 
16 Statement of indemnity 
The trial is sponsored by NHS Greater Glasgow & Clyde and the University of 
Glasgow. The sponsor will be liable for negligent harm caused by the design of the 
trial. NHS indemnity is provided under the Clinical Negligence and Other Risks 
Indemnity Scheme (CNORIS). The NHS has a duty of care to patients treated, 
whether or not the patient is taking part in a clinical study, and the NHS remains 
liable for clinical negligence and other negligent harm to patients under its duty of 
care.  
 
17 Funding  
This trial is funded by the British Heart Foundation (PG/17/23/32850) and trial 
medications are supplied by the drug company Novartis who produce both valsartan 
(the standard treatment) sacubitril/valsartan (the experimental treatment). 
 
18 Sponsor responsibilities 
The sponsor of this clinical study is NHS Greater Glasgow and Clyde/University of 
Glasgow. Sponsor responsibilities undertaken by NHS Greater Glasgow and 
Clyde/University of Glasgow will be as defined in the Research Governance 
Framework for Health and Community Care (Second edition, February 2006).  
 
 
19 Dissemination of data 
The study will be assigned an International Standard Randomised Controlled Trial 
Number (ISRCTN) and will be registered on the clinicaltrials.gov website before 
participant recruitment commences. 
 
Once the study has completed and data has been analysed the results will be 
submitted for publication in a peer-reviewed scientific journal and presented at a 
major conference. The research team will provide a lay-summary of the results to all 
participants where appropriate and inform the patients general practitioner of the 
results of the trial. Data will be made available in an anonymised summary for 
regulatory purposes or on the request of the funder/Sponsor.   
 
 
 


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Appendix 1: Clinically notable laboratory values 
 
Clinically notable laboratory abnormalities for selected tests based on a percent 
change from baseline: 
 
Haematology 
 
Hematocrit >50% increase, >20% decrease 
Haemoglobin >50% increase, >20% decrease 
Platelet count >75% increase, >50% decrease 
RBC Count >50% increase, >20% decrease 
WBC count >50% increase, >50% decrease 
 
Biochemistry 
 
Alkaline phosphatase >100% increase 
ALT >150% increase 
AST >150% increase 
BUN >50% increase 
Chloride >10% increase, >10% decrease 
Creatinine >50% increase 
Potassium >20% increase, >20% decrease 
Total bilirubin >100% increase 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 2: MRI Information Leaflet 
 
 


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Appendix 3: Patient global assessment questionnaire 
 


 
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SAP_001.pdf: 
Glasgow Clinical Trials Unit 
 
RECOVER-LV 
Final Analysis Statistical Analysis Plan 
RECOVER_LV_SAP_v1_1.docx 
Page 1 of 11 
 
 
THE EFFECTS OF SACUBITRIL/VALSARTAN COMPARED TO 
VALSARTAN ON LEFT VENTRICULAR REMODELLING IN PATIENTS 
WITH ASYMPTOMATIC LEFT VENTRICULAR SYSTOLIC 
DYSFUNCTION AFTER MYOCARDIAL INFARCTION: A RANDOMISED, 
DOUBLE-BLINDED, ACTIVE-COMPARATOR, CARDIAC-MR BASED 
TRIAL 
 
RECOVER-LV 
 
STATISTICAL ANALYSIS PLAN 
 
 
Study Title: 
The effects of sacubitril/valsartan compared to valsartan on left 
ventricular remodelling in patients with asymptomatic left ventricular 
systolic dysfunction after myocardial infarction: a randomised, double-
blinded, active-comparator, cardiac-MR based trial 
Short Title: 
RECOVER-LV 
IDs: 
EudraCT Number: 2017-003460-13 
REC Reference Number: 17/ES/0128 
Sponsor’s Protocol Number: GN16CA007 
Sponsor: 
NHS Greater Glasgow & Clyde and The University of Glasgow 
Funded by: 
BHF Project Grant no. PG/17/23/32850 
IMP supplied by Novartis Pharmaceuticals UK Ltd. 
 
Protocol Version: 
 
v7.0 
Date: 
24th August 2020 
SAP Version: 
v1.1 
Date: 
25th August 2020 
 
 
 
 
 
 
Signature 
 Date 
 
 
 
  
Prepared by: 
Bethany Stanley 
 
 
 
 
Junior Biostatistician, Robertson Centre for Biostatistics, University of 
Glasgow 
 
 
 
 
 
Approved by: 
Dr Alex McConnachie 
 
 
 
 
Assistant Director Biostatistics, Robertson Centre for Biostatistics, 
University of Glasgow 
 
 
 
 
Chief Investigator: 
Professor John McMurray 
 
 
 
 
Professor of Cardiology, BHF Glasgow Cardiovascular Research Centre, 
University of Glasgow 


Glasgow Clinical Trials Unit 
 
RECOVER-LV 
Final Analysis Statistical Analysis Plan 
RECOVER_LV_SAP_v1_1.docx 
Page 2 of 11 
 
CONTENTS 
1. Introduction .......................................................................................................................... 5 
1.1. Study Background ........................................................................................................ 5 
1.2. Study Objectives ........................................................................................................... 5 
1.2.1. Primary Objective .................................................................................................. 5 
1.2.2. Secondary objectives ............................................................................................ 5 
1.3. Study Design ................................................................................................................. 5 
1.4. Randomisation .............................................................................................................. 5 
1.5. Sample Size And Power ............................................................................................... 6 
1.6. Study Population........................................................................................................... 6 
1.7. Statistical Analysis Plan (SAP) .................................................................................... 6 
1.7.1. SAP Objectives ....................................................................................................... 6 
1.7.2. General Principles .................................................................................................. 6 
1.7.3. Current Protocol ..................................................................................................... 7 
1.8. Software ......................................................................................................................... 7 
2. Analysis ................................................................................................................................. 7 
2.1. Study Population........................................................................................................... 7 
2.2. Subject Disposition ....................................................................................................... 7 
2.3. Baseline Characteristics ............................................................................................... 7 
2.4. Efficacy Outcomes ........................................................................................................ 8 
2.4.1. Primary Outcome ................................................................................................... 8 
2.4.2. Secondary Outcomes ............................................................................................ 9 
2.4.3. Tertiary (Exploratory) Outcomes ........................................................................ 9 
2.4.4. Subgroup Analysis ................................................................................................. 9 
2.5. Safety Outcomes .......................................................................................................... 9 
2.5.1. Premature Withdrawal .......................................................................................... 9 
2.5.2. Adverse Events of Interest................................................................................. 10 
2.5.3. Serious Adverse Events ...................................................................................... 10 
3. Document History .............................................................................................................. 10 
4. Tables, Figures and Listings ............................................................................................ 11 
 
 
 
 
 
 
 
 


Glasgow Clinical Trials Unit 
 
RECOVER-LV 
Final Analysis Statistical Analysis Plan 
RECOVER_LV_SAP_v1_1.docx 
Page 3 of 11 
 
 
ABBREVIATIONS 
 
ACE 
Angiotensin-converting-enzyme 
ACEi 
Angiotensin-converting-enzyme inhibitor 
AF 
Atrial Fibrillation 
BNP 
B-Type Natriuretic Peptide 
ANP 
Atrial Natriuretic Peptide 
CABG 
Coronary Artery Bypass Graft 
CCS 
Canadian Cardiovascular Society 
cGMP 
Cyclic Guanosine Monophosphate 
CMR 
Cardiovascular Magnetic Resonance imaging 
CNP 
C-type Natriuretic Peptide 
COPD 
Chronic Obstructive Pulmonary Disease 
CRT 
Cardiac Resynchronisation Therapy 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
ED 
Emergency Department 
FSH 
Follicle-Stimulating Hormone 
GDF-15 
Growth Differentiation Factor-15 
GP 
General Practice 
HF 
Heart Failure 
hsTnI 
High Sensitive Troponin-I 
ICD 
Implantable Cardioverter-Defibrillator 
LAVI 
Left Atrial Volume Index 
LVEF 
Left Ventricular Ejection Fraction 
LVESVI 
Left ventricular End-Systolic Volume Index 
LVSD 
Left Ventricular Systolic Dysfunction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
MMP-9 
Matrix Metallopeptidase 9 
MR-proADM 
Mid-Regional pro-Adrenomedullin 
MR-proANP 
Mid-Regional pro-Atrial Natriuretic Peptide 
MRA 
Mineralocorticoid Receptor Antagonist 
MRI 
Magnetic Resonance Imaging 
NT-proBNP 
N-terminal-pro hormone B-Type Natriuretic Peptide 
NYHA 
New York Heart Association 
OTC 
Over-the-Counter 
PT 
Preferred Term 
QTc 
QT interval corrected for heart rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 


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sST2 
Somatostatin Receptor Subtype 2 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TIA 
Transient ischemic attack 
TIMP-1 
Tissue Inhibitor Of Metalloproteinases 1 
 
 
 


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1. INTRODUCTION 
1.1. STUDY BACKGROUND 
Left ventricular systolic dysfunction (LVSD) and heart failure (HF) remain relatively 
common among survivors of myocardial infarction. This is because a large proportion 
of patients are not eligible for reperfusion therapy (i.e. those with non ST-segment 
elevation myocardial infarction) and many patients suffer recurrent episodes of 
infarction, leading to cumulative left ventricular damage over time. 
In PARADIGM-HF, a combination of neprilysin inhibitor (sacubitril) and angiotensin 
receptor blocker (valsartan), reduced the risk of heart failure hospitalisation and death 
in patients with heart failure due to left ventricular systolic dysfunction or reduced 
ejection fraction (HF-REF), compared to an angiotensin-converting-enzyme inhibitor 
(ACEi) (enalapril). 
The objective of RECOVER-LV is to obtain information on the cardiac effects of 
sacubitril/valsartan in patients with LVSD, compared to valsartan alone. 
1.2. STUDY OBJECTIVES 
1.2.1. PRIMARY OBJECTIVE 
To investigate the potential benefit of sacubitril/valsartan vs. valsartan in attenuating 
adverse left ventricular remodelling in high risk asymptomatic patients post myocardial 
infarction as a result of residual left ventricular systolic dysfunction. 
1.2.2. SECONDARY OBJECTIVES 
To provide understanding of the cardiac effects and mechanisms of action of 
sacubitril/valsartan in patients with LVSD. 
1.3. STUDY DESIGN 
Randomised, double-blind, clinical trial. 
1.4. RANDOMISATION 
Section 12.1 of the study protocol states: 
“Randomisation will be in a 1:1 ratio and stratified by LVESVI ≤45ml/m2 / >45ml/m2 
as measured by baseline CMR, and whether or not the patient is being prescribed 
diuretics at baseline, with the randomisation schedule computer generated by the 
method of randomised permuted blocks, with random block lengths of 4 and 6.” 
 


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1.5. SAMPLE SIZE AND POWER 
Section 11.1 of the study protocol states: 
“A sample size of 100 patients is proposed. This is based on the calculation that 45 
patients per treatment group provides >90% power (α level = 0.05) to detect a 
difference of 6mL/m2 in LVESVI (standard deviation = 7.8mL/m2) and accounting for 
a discontinuation rate of 10% (lost to follow up, development of heart failure or 
death). A 6mL/m2 difference in LVESVI represents a minimally important difference.” 
Recruitment of 100 patients in 18 months requires a monthly recruitment rate of 5.6 
patients/month or 1.4 patients/week. 
1.6. STUDY POPULATION 
Patients aged ≥18 years with asymptomatic left ventricular systolic dysfunction (i.e. 
no evidence of clinical and/or radiological heart failure) >3 months post-acute 
myocardial infarction. A full list of inclusion and exclusion criteria is given in section 
5.1 of the study protocol.  
1.7. STATISTICAL ANALYSIS PLAN (SAP) 
1.7.1. SAP OBJECTIVES 
The objective of this SAP is to describe the final statistical analyses to be carried out 
for the randomised controlled trial of the RECOVER-LV study. 
1.7.2. GENERAL PRINCIPLES 
Data will be summarised for all participants and by randomised treatment group where 
appropriate. Categorical variables will be summarised with the number of observations 
and missing values, and number and percentage of participants falling into each 
category. Continuous variables will be summarised using the number of observations 
and number missing, mean, standard deviation (SD), median, 25th and 75th quartiles 
(Q1 and Q3 respectively), minimum and maximum values. Rates of recruitment and 
retention will be summarised as counts and percentages with 95% confidence 
intervals. 
All efficacy outcomes will be analysed using regression analysis models that are 
adjusted for the baseline value of the outcome in question and whether or not taking 
diuretics at baseline. Efficacy outcomes will be summarised at baseline, 12 months and 
for the change from baseline at 12 months, presented overall and by treatment group. 
The model’s intervention group treatment effect (and 95% CI) and p-value will be 
presented for outcome results measured at 12 months. All biomarker outcomes will 
additionally be summarised at 6 months and for the change from baseline at 6 months. 
Furthermore, a repeated measures linear regression model will be performed for each 
biomarker outcome, adjusting for the main effects of time-point and randomised group 
and the interaction between time-point and randomised group. The intervention group 


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treatment effect and time-point effect (and 95% CIs) will be presented with p-values 
for these main effects and their interaction. 
1.7.3. CURRENT PROTOCOL 
The current protocol at the time or writing is version 7.0, dated 24/08/2020. Future 
amendments to the protocol will be reviewed for their impact on this SAP, which will 
be updated only if necessary. If no changes are required to this SAP following future 
amendments to the study protocol, this will be documented as part of the Robertson 
Centre Change Impact Assessment processes. 
1.8. SOFTWARE 
All statistical analyses will be carried out using R v4.0.0 [R Development Core Team 
2020] or higher versions of this program. The final report will be provided as a 
password protected PDF document. Listings will be provided as excel files. 
2. ANALYSIS 
With the exception of analysis detailed in Subsection 2.4.3 Tertiary (exploratory) 
outcomes below, all analysis described in Section 2, in addition to the tertiary outcome 
change in ANP, will be produced in the first wave of outputs. The second wave of 
outputs will include the analysis of the remaining tertiary outcomes outlined. 
2.1. STUDY POPULATION 
The analysis population will comprise of all subjects randomised into the study. 
2.2. SUBJECT DISPOSITION 
The number and percentage of participants consenting to take part in the study will 
be summarised and randomised subjects will be summarised, overall and by 
randomised treatment group. The cumulative numbers of participants randomised to 
each treatment group will be reported in tabular form and graphically. The number 
and percentage of randomised subjects attending each study visit will also be 
presented with those that did not attend classified as either: Lost to follow-up, died, 
or did not attend. Reasons for ineligibility for study participation will be summarised 
for the consenting non-randomised subjects. The number and percentage of subjects 
withdrawing from the study medication and from study follow-up will be presented 
alongside the main reasons for withdrawal. 
2.3. BASELINE CHARACTERISTICS 
The following baseline characteristics will be summarised for all randomised subjects 
and by randomised intervention group, without formal statistical comparison: 


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 
 Cardiac MRI: height (m), weight (kg), BMI (kg/m2), body surface area 
(kg/m2), gadolinium contrast administered 
 Physical Exam: NYHA class, third heart sound, pulmonary crepitations (area 
and location), pleural effusion (location), peripheral oedema (location), any 
other relevant abnormalities 
 Medication history: loop diuretic, thiazide diuretic, ACE inhibitor, angiotensin 
receptor blocker, beta-blocker (except sotalol), mineralocorticoid receptor 
antagonist (MRA), statin, anti-platelet, anti-coagulant, nitrate, calcium 
channel blocker (CCB), alpha blocker, antiarrhythmic 
 Vital signs: SBP (mmHg), DBP (mmHg), heart rate (bpm) 
 Electrocardiogram results: heart rate (bpm), heart rhythm, PR interval (ms), 
QRS duration (ms), bundle branch block, QTc interval (ms), ST segment 
deviation, T wave inversion, Q wave inversion 
 Spot urine collection 
 Venepuncture: urea, creatinine, potassium, eGFR, haemoglobin, bilirubin, 
ALT, AST, ALP, hs-troponin I (hsTnI), HbA1c, NTproBNP 
 Pregnancy: woman of child-bearing potential, FSH level, pregnancy test done, 
pregnancy test result 
 Symptom Review: heart failure since last review, paroxysmal nocturnal 
dyspnoea, orthopnoea, dyspnoea at rest, dyspnoea on effort, fatigue, 
peripheral oedema, emergency admission to hospital, ED visit, urgent clinical 
visit, GP or other primary care consultation, intervention or treatment change 
(started or increased dose for all except ICD/CRT) 
 Previous Medical History: time since index MI, known coronary artery disease, 
angina, MI, treatment for MI, CABG/PCI prior to MI, history of hypertension, 
paroxysmal AF, stroke, TIA, carotid artery disease, peripheral arterial disease, 
lower limb revascularisation, valve replacement, dizziness / hypotension / falls 
etc., COPD, asthma, cancer, diabetes, hypothyroidism and hyperthyroidism, 
smoking (status and pack year), alcohol consumption (intake level, average 
number of units per week), any other significant medical history 
2.4. EFFICACY OUTCOMES 
2.4.1. PRIMARY OUTCOME 
The change in indexed left ventricular end-systolic volume (LVESVI) from baseline to 
the 12 month follow-up visit will be summarised overall and by randomised group and 
compared between randomised groups using a linear regression model adjusted for 
baseline LVESVI, diuretic use at baseline and time from baseline to the 12 month 
follow-up visit. 
 
 
 


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2.4.2. SECONDARY OUTCOMES 
The following outcomes will be analysed as described in section 1.7.2: 
• Change in NT-proBNP  
• Change in hsTnl 
• Change in other cardiac magnetic resonance imaging-based metrics of LV 
remodelling from baseline to 12 months follow-up:  
o Indexed LV end-diastolic volume (LVEDVI) 
o Indexed left atrial volume by body surface area (LAVI) 
o LV ejection fraction (LVEF) 
o LV mass index 
 
• Change in patient well-being as assessed by a patient global assessment 
questionnaire at 12 months follow-up 
2.4.3. TERTIARY (EXPLORATORY) OUTCOMES 
The following outcomes will be analysed as described in section 1.7.2: 
• Change in biomarkers of LV remodelling: sST2, Galectin 3, TIMP-1, MMP-9, 
Type III Procollagen Peptide, GDF-15 and other relevant biomarkers of interest. 
• Change in neurohormonal levels: BNP, MR-proANP, C-terminal ANP, CNP, MR-
proADM, cGMP, endothelin-1, neprilysin antigen, renin and aldosterone and 
other relevant biomarkers of interest. 
• Change in extracellular volume (ECV), left ventricular global function index 
(LVGFI), T1 relaxation time and left ventricular strain as measured using cardiac 
MRI.  
 
 
2.4.4. SUBGROUP ANALYSIS 
 
Due to the impact of the Covid-19 pandemic on the scheduling of end-of-study MRI 
scans, all efficacy outcomes outlined in Section 2.4 will be analysed in three subgroups 
of the randomised population determined by whether the patient had their 12-month 
MRI scan earlier than planned, on-time or later than planned. A scan will be defined 
as: on-time if it occurs within a 7-day window around the scheduled 52-week visit 
date; early if more than 7 days prior; and late if more than 7 days following the 
scheduled visit date. 
2.5. SAFETY OUTCOMES 
2.5.1. PREMATURE WITHDRAWAL 
The number and percentage of subjects who complete the intervention phase will be 
reported. The number and percentage of subjects who actively withdraw from study 
medication and/or the study will be reported and the reasons for withdrawal will be 
summarised if provided. 


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2.5.2. ADVERSE EVENTS OF INTEREST 
Adverse events of interest include: 
• Worsening renal function or acute kidney injury 
• Hyperkalaemia 
• Symptomatic hypotension 
• Symptomatic hypotension with systolic BP <90mmHg 
• Angioedema 
• Cough 
The number and percentage of subjects experiencing one of the adverse events of 
interest listed will be summarised overall and by randomised treatment group. The 
Fisher’s Exact test will be used to assess whether there is a statistical difference 
between number of subjects experiencing each event between treatment groups. The 
following event details will also be summarised and compared between groups: 
seriousness criteria, severity, relationship to study drug and details of action taken. 
Full details of these events are provided in section 10.2 of the study protocol. 
2.5.3. SERIOUS ADVERSE EVENTS 
The number of serious adverse events will be reported and the following event details 
will be summarised for the randomised population overall and by treatment group: 
seriousness criteria, severity, relationship to the study drug, expectedness, event 
outcome and SAE duration (if recovered or fatal). 
The number and percentage of subjects experiencing at least one serious adverse 
event will be reported and summarised by Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class (SOC) and Preferred Term (PT). The Fisher’s Exact test 
will be used to assess whether there is a statistical difference between the number of 
subjects with each type of event between treatment groups. 
The same summaries will be provided for the subsets of serious adverse events that 
are (a) at least possibly related to the study treatment, (b) Suspected Unexpected 
Serious Adverse Reactions (SUSARs) and (c) fatal, (d) prior to 1st March 2020 and (e) 
experienced on or after 1st March 2020. 
All serious adverse events will be listed. 
3. DOCUMENT HISTORY 
This is version 1.1 of the SAP for the RECOVER-LV study, the second version of this 
document. 


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4. TABLES, FIGURES AND LISTINGS 
Summary tables and figures will be generated prior to database lock. Approval of the 
content of these documents will then be required for database lock.