A Randomised, Controlled, Double-blind, Double-dummy, Clinical Trial Comparing Sacubitril-Valsartan Versus Valsartan in Asymptomatic, Stage A/B HFpEF Patients With Elevated Natriuretic Peptide and Abnormal LAVI. (Previously NCT02682719)
Phase: PHASE2
Conditions: Atrial Remodeling, Myocardial Dysfunction, Left Ventricular Remodeling, Left Ventricular Diastolic Dysfunction, Hypertension, Cardiovascular Morbidity, Fibrosis Myocardial, Inflammatory Myopathy, Atrial Arrhythmia
Sponsor: Mark Ledwidge

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1. STUDY TITLE 
 
Personalised prospective comparison of ARni with ArB in patients with natriuretic 
peptide eLEvation  
 
The PARABLE study. 
 
 
 
HBT-PTCL-01. Version 10.0  
 
Effective date: 18/02/2021 
 
 
 
 
2. STUDY SPONSOR 
 
The Heartbeat Trust 
3 Crofton Terrace,  
Dun Laoghaire,  
Co Dublin 
 
 
 
 
 
CLINICAL TRIAL PROTOCOL 

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3. APPLCIATION DETAILS 
 
Principal Investigators: 
Kenneth McDonald MD, FRCPI 
Consultant Cardiologist 
Heart Failure Unit 
St. Vincent’s University Hospital 
Dublin 4 
 
Mark Ledwidge PhD, MPSI 
Research Director 
Heart Failure Unit 
St. Vincent’s University Hospital 
Dublin 4 
 
 
Co-Investigators: 
Joe Gallagher, MB BCh BAO BA 
Heart Failure Unit 
St. Vincent’s University Hospital 
Dublin 4 
 
Rory O’Hanlon, MD, FRCPI 
Consultant Cardiologist 
Blackrock Clinic,  
Dublin 4 
Chris Watson 
School of Medicine and Medical Science, 
The Conway Institute, 
University College Dublin 
Dublin 4 
 
Fiona Ryan, PhD, MPSI 
Research Pharmacist 
St Michael’s Hospital,  
Dun Laoghaire 
Co Dublin 
Jonathan Dodd, MD, FRCPI 
Consultant Radiologist 
Radiology Department, St Vincent’s 
University Hospital, Dublin 4. 
 
 
 
 
 
Document Type: Protocol  
 
Document Number: HBT-PTCL-01. Version 10  
 
Preparation Date: 17 February 2021 
 
Approval Date (Investigator and Sponsor): 18/02/2021 
 
Effective Date: 18/02/2021 
 
EudraCT Number:  2015-002928-53 
 
 
 
 
 
 
 

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4. SIGNATURES 
 
INVESTIGATOR APPROVAL SIGNATURES 
I agree to conduct the study outlined above according to the terms and conditions of 
the protocol, GCP and applicable regulatory requirements. All information pertaining 
to the study will be treated in a confidential manner. 
 
Prof Ken McDonald 
(M.D., F.R.C,P.I) 
Consultant Cardiologist 
and Director of 
Cardiovascular 
Research, St Vincent’s 
University Hospital, 
Clinical Professor, 
School of Medicine, 
University College, 
Dublin, Ireland 
 
18/02/2021 
Name 
Position 
Signature  
Date 
Prof Mark 
Ledwidge  
(BSc (Pharm), PhD,  
MPSI) 
Research Director, 
Heart Failure Unit, St 
Vincent’s University 
Hospital, UCD 
Professor, School of 
Medicine, University 
College, Dublin, Ireland 
 
 
18/02/2021 
Name 
Position  
Signature  
Date 
 
SPONSOR APROVAL SIGNATURES 
I agree to support the study outlined above according to the terms and conditions of 
the protocol, GCP and applicable regulatory requirements. All information pertaining 
to the study will be treated in a confidential manner. 
Prof 
Mark 
Ledwidge 
(BSc 
(Pharm), 
PhD,  MPSI) 
Co-founder and 
Research Director 
The Heartbeat Trust 
 
 
18/02/2021 
Name 
Position 
Signature  
Date 
 
 
5. CONFIDENTIALITY STATEMENT 
This document contains confidential information that must not be disclosed 
to anyone other than the Sponsor, the funder, the investigative team, 
regulatory authorities and member of the Research Ethics Committee. 
 
 

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TABLE OF CONTENTS 
 
1. 
STUDY TITLE .................................................................................................................................................. 1 
2. 
STUDY SPONSOR .......................................................................................................................................... 1 
3. 
APPLCIATION DETAILS .................................................................................................................................. 2 
4. 
SIGNATURES ................................................................................................................................................. 3 
5. 
CONFIDENTIALITY STATEMENT .................................................................................................................... 3 
6. 
DOCUMENT HISTORY ................................................................................................................................... 7 
7. 
SYNOPSIS .................................................................................................................................................... 16 
8. 
ABBREVIATIONS ......................................................................................................................................... 20 
9. 
INTRODUCTION .......................................................................................................................................... 22 
9.1 
Overview and hypothesis ...................................................................................................................... 22 
9.2 
Background information ........................................................................................................................ 22 
9.3 
Rational for the study ............................................................................................................................ 23 
10. 
OBJECTIVES AND ENDPOINTS ................................................................................................................ 26 
10.1 
Objectives ............................................................................................................................................... 26 
10.2 
Endpoints ................................................................................................................................................ 27 
11. 
TRIAL DESIGN ......................................................................................................................................... 32 
11.1 
General considerations .......................................................................................................................... 32 
11.2 
Selection of study population ................................................................................................................ 33 
11.2.1 
Inclusion criteria ................................................................................................................................ 33 
11.2.2 
Exclusion criteria ................................................................................................................................ 34 
12. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................................. 35 
12.1 
Screening visit (Visit 1) ........................................................................................................................... 35 
12.2 
Baseline visit (Visit 2) ............................................................................................................................. 36 
12.3 
Follow up visits (Visits 3-11) .................................................................................................................. 37 
12.4 
Assessments ........................................................................................................................................... 40 
12.4.1 
Laboratory parameters ...................................................................................................................... 40 
12.4.2 
eGFR assessments .............................................................................................................................. 40 
12.4.3 
Second messenger cGMP (urine) ...................................................................................................... 40 
12.4.4 
Biomarkers ......................................................................................................................................... 40 
12.4.8 
Medical history .................................................................................................................................. 41 
12.4.9 
Demographics .................................................................................................................................... 41 
12.4.10 
Physical exam ..................................................................................................................................... 42 
12.4.11 
Vital signs ........................................................................................................................................... 42 
12.4.12 
Height, weight and waist/hip circumference .................................................................................... 42 
12.4.13 
Ambulatory blood pressure monitoring (ABPM) .............................................................................. 42 
12.4.14 
Pregnancy test ................................................................................................................................... 42 

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12.4.15 
Electrocardiography (ECG) ................................................................................................................. 43 
12.4.16 
Echo-Doppler studies ......................................................................................................................... 43 
12.4.17 
Cardiac magnetic resonance imaging (cMRI) .................................................................................... 44 
12.4.18 
Concomitant medications. Potential drug interactions with LCZ696 and/or valsartan therapy .... 45 
12.4.19 
Questionnaires ................................................................................................................................... 48 
13. 
STUDY DRUG .......................................................................................................................................... 48 
13.1 
Blinding ................................................................................................................................................... 48 
13.2 
Study drug supply and storage .............................................................................................................. 49 
13.3 
Accountability of the study drug ........................................................................................................... 50 
13.4 
Dispensing the study drug ..................................................................................................................... 50 
13.5 
Assessment of compliance ..................................................................................................................... 51 
13.6 
Overdose of study treatment ................................................................................................................ 51 
13.7 
Permitted study drug dose adjustment and interruptions ................................................................... 52 
13.8 
Study drug restart after temporary treatment interruption ................................................................ 52 
13.9 
Study drug discontinuation and premature withdrawal of subjects .................................................... 53 
13.10 
Emergency unblinding of treatment assignment ............................................................................. 54 
13.11 
Definition of end-of-trial ................................................................................................................... 54 
14. 
SAFETY REPORTING ................................................................................................................................ 55 
14.1 
Definitions .............................................................................................................................................. 55 
14.2 
Adverse event assessment ..................................................................................................................... 57 
14.3 
Emergency unblinding procedures ........................................................................................................ 58 
14.4 
Follow up of adverse events .................................................................................................................. 58 
14.5 
Documentation of adverse events by the Investigator ......................................................................... 59 
14.6 
Reporting procedures for SAEs to the Sponsor ..................................................................................... 60 
14.7 
Reporting procedures for SUSARs to the EC and Regulatory authorities ............................................. 60 
14.8 
SAE reporting to Novartis ...................................................................................................................... 61 
14.9 
Annual reports and line listings ............................................................................................................. 62 
15. 
PROTOCOL ADHERENCE ......................................................................................................................... 62 
15.1 
Protocol Amendments ........................................................................................................................... 62 
16. 
STATISTICS .............................................................................................................................................. 63 
16.1 
Description of statistical methods ......................................................................................................... 63 
16.2 
Determination of sample size ................................................................................................................ 63 
17. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................................................. 64 
18. 
DATA HANDLING AND RECORD KEEPING .............................................................................................. 64 
18.1 
Data collection, source documents and case report forms (CRFs) ....................................................... 64 
18.2 
Data reporting ........................................................................................................................................ 65 
19. 
RETENTION OF ESSENTIAL DOCUMENTS ............................................................................................... 65 
20. 
QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES ............................................................. 65 

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20.1 
Before the study ..................................................................................................................................... 65 
20.2 
During the study ..................................................................................................................................... 65 
21. 
AUDITS AND INSPECTIONS ..................................................................................................................... 67 
22. 
ETHICAL CONSIDERATIONS .................................................................................................................... 67 
22.1 
Ethical conduct of the study .................................................................................................................. 67 
22.2 
Declaration of Helsinki ........................................................................................................................... 68 
22.3 
Good Clinical Practice ............................................................................................................................ 68 
22.4 
Approvals ............................................................................................................................................... 68 
22.5 
Informed consent ................................................................................................................................... 68 
22.6 
Subject confidentiality ........................................................................................................................... 70 
23. 
FINANCING AND INSURANCE/INDEMNITY ............................................................................................ 70 
24. 
CLINICAL STUDY REPORT AND PUBLICATION POLICY ........................................................................... 70 
24.1 
Clinical study report ............................................................................................................................... 70 
24.2 
Publication policy ................................................................................................................................... 70 
25. 
STUDY PLANNING AND SCHEDULE ........................................................................................................ 71 
25.1 
Timelines and study duration ................................................................................................................ 71 
26. 
APPENDICES ........................................................................................................................................... 72 
Appendix 1. Montreal Cognitive Assessment (MoCA) ....................................................................................... 72 
Appendix 2. Standardised Mini-Mental State Examination SMMSE) ................................................................ 72 
Appendix 3. EuroQoL (EQ-5D-5L) Health Questionnaire .................................................................................... 73 
Appendix 4. Montreal Cognitive Assessment (MoCA) Version 3. Administration and Scoring Instructions .... 75 
Appendix 5. Adverse Event Handling. Investigator Responsibilities. Flow Diagram ......................................... 79 
Appendix 6. Adverse Event Handling. Sponsor Responsibilities. Flow Diagram ............................................... 80 
Appendix 7. Clinically notable laboratory values and vital signs ....................................................................... 81 
Appendix 8. Treatment guidelines ...................................................................................................................... 82 
REFERENCES ......................................................................................................................................................... 86 
 
 
 

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6. DOCUMENT HISTORY 
 
Document 
Approval 
date 
Summary of Change 
Version 
1.0 
27 
August 
2015 
New document 
Version 
2.0 
16 
October 
2015 
Protocol has been updated to reflect the recommendations/queries of 
the HPRA and EC review of the initial CTA. The changes are as 
follows: 
Exclusion criteria to include women of childbearing potential not using 
adequate contraception. Definition of postmenopausal added. 
Contraception must be continued for one week following 
discontinuation of study drug. 
A pregnancy test (urinary dipstick) will be carried out in women of 
childbearing potential at all timepoints  
Exclusion criteria has been extended to exclude patients with SBP 
<100mmHg 
MMSE and MoCA questionnaires previously referred to as QOL 
questionnaires. This has been updated to refer to them as cognitive 
assessments. 
MMSE and MoCA will also be administered at 5 years 
Concomitant medication section (12.4.18) has been updated with 
details of furosemide, PDE inhibitors, metformin and statin 
interactions 
Details of SAE reporting to Novartis has been updated (Appendix 8 
and Section 14.8) 
Section 22.5 (Informed Consent) updated to include IC for biobanking 
blood samples 
Appendix 10 has been updated with more precise instruction for 
hypotension management 
Section 12.4.17 updated to state that if a patient had a cMRI in the 
past 6 weeks there is no need to repeat the MRI at baseline. 
Reference to Blackrock Clinic is Section 12.4.17 has been removed. 
Section 14.2 updated to cross-reference to the section of the IB that 
should be used to evaluate expectedness of an adverse reaction. 
Section 12.4.19 updated to state that any illnesses identified following 
the administration of a questionnaire should be managed 
appropriately. 
 
 

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Version 3.0 
22 Jan 2016 
(Substantial 
amendment) 
Reference to the Blood Pressure Unit has been changed to the STOP-
HF Service throughout the document. 
Section 11.2.2. Exclusion criteria no 11 updated to ‘malignancy or 
presence of any other disease with a life expectancy of < 2 years 
Section 12.2. LCZ696 and valsartan administration. ‘Twice daily’ 
inserted. 
Table 2 updated. Glucose monitoring deleted; cGMP measurement at 
4/52 and 3/12 also 
Section 12.4.1. Glucose testing deleted. 
Section 12.4.3. Additional two time points added for cGMP at 4/52 and 
3/12 
Section 12.4.5. NT-proBNP will be measured by St Vincent’s Hospital 
Group laboratory as per standard hospital policy and not using a point-of-
care assay. 
Section 12.4.12. Description of how to measure waist/hip ratio inserted. 
Section 12.4.19. Standardised MMSE used instead of MMSE 
Section 13. Reference to HBT-GCP-SOP-17 ‘Study Drug Management 
for the PARABLE Study’ inserted. Reference to the distribution company 
Almac inserted. Reference to clinical trials pharmacist replaced by 
investigator site. 
Section 13.10. Reference to HBT-GCP-SOP-17 ‘Study Drug 
Management for the PARABLE Study’ inserted which describes the 
unblinding process 
Section 25.1. Timelines updated 
Appendix 2. Standardised MMSE inserted 
Version 4.0 
10 May 2016 
(Substantial 
amendment).  
Section 7.0 and section 11.2.1. NP cut-off values for inclusion criteria 
have been amended as follows: 
Elevated NP: BNP between 35 and 280pg/ml or NT-proBNP values 
between >125 pg/ml and 1,000 pg/ml within 6 months prior to screening 
Section 11.2.1, 12.1, 12.4.5 and Table 2. An elevated NP level in the six 
month period prior to screening is acceptable. 
Section 11.1, 12.1, 12.2, Figure 1a and 1b.  Requirement for a 36 hour 
washout period for patients on current ARB therapy is not required. The 
requirement for 36 hour washout period for an ACEI remains the same. 
Section 12.1 and 22.5. Informed consent may only be taken by a 
qualified medical doctor. 
Table 2. Requirement for measurement of alk phos at baseline has been 
removed. 
Section 12.4.3 and Table 2. Measurement of cGMP changed from 4 
week timepoint to 6 week timepoint. 
Section 12.1. Patients may also contact the STOP-HF clinic directly in 
response to an advertisement. Patients may also be referred from other 
clinics, hospital departments or healthcare professionals. 

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Table 2. Additional row added for Natriuretic peptide (previously included 
with biomarkers) 
Table 2. Biomarker measurement at 2 weeks and 4 weeks has been 
removed. 
Version 5.0 
01 Nov 2016  
Substantial amendments (HPRA approval: 19 Dec 2016; EC approval: 08 Dec 2016 
Section 11.2.1. Key Exclusion Criteria updated with new BNP and NT-proBNP cut-offs as follows: 
Elevated NP: BNP between 20 and 280pg/ml or NT-proBNP values between 100 pg/ml and 1,000 pg/ml 
within 6 months prior to screening. 
Asymptomatic left ventricular systolic dysfunction defined as LVEF <50% on most recent measurement. 
Non-substantial amendments 
Section 7.0. Eligibility criteria No 3. Added ‘or at screening’  
Section 11.1. Added ‘discontinuation of ARB (no washout necessary)’. 
Section 11.2.1. Inclusion criteria.  
Change to BNP and NT-proBNP cut-offs 
Added ‘or at screening’ to criteria no 3. 
Section 12.1. Screening visit 
Added that initial contact with patient must be documented in the medical notes. Updated NP cut-off 
values. 
Section 12.2. Changes made to the titration dosages. 
Clarification that a 36h washout is needed for ACEI only. 
Section 12.3. Clarified that a ‘paper’ CRF is being used. 
Table 2. Randomisation changed from Visit 1 to visit 2. 
Column added ‘Where to record source data’ 
Row added to allow for visit ‘windows’ 
Section 12.4.1. Added reference to Laboratory SOP 
Section 12.4.5. Added ‘or at screening’ 
Section 13. Added ‘LCZ696, Valsartan and matching placebos are provided by Novartis Ireland Ltd to the 
distributor company, Almac’. Clarified scope of SOP-17. 
Section 13.2. Added that the investigator will notify sponsor when stocks of study drug are running low 
and that it is the responsibility of the sponsor (not investigator) to re-order study drug. Study drug will be 
delivered directly to STOP-HF service, and not pharmacy department. 
Section 13.3. Replaced ‘drug accountability ledger’ with HBT-GCP-FM-22; ‘Study Drug Inventory and 
Subject Assignment Log’. 
Added that ‘All patient returns should be recorded in the CRF and in the Study Drug Returns Log (HBT-
GCP-FM-23)’. 
Section 13.4. Added that study drug is provided to the site labelled. Added that dispensing records should 
be maintained in the drug accountability log (HBT-GCP-FM-22; ‘Study Drug Inventory and Subject 
Assignment Log’ 
Section 13.10. Added that the CTPM should be contacted in the event of an unblinding requested, and 
WebEz Helpdesk as a backup. 

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Section 13.11. Changed ‘Chief’ investigator to ‘Principal investigator’. 
Section 14. The Adverse Event Report Form is no longer an appendix in this protocol. Therefore, 
reference is made to the Form in the CRF and not appendix 5.  
Update made to the location of the EMA IME list. 
The Serious Adverse Event Report Form is no longer an appendix in this protocol. Therefore, reference is 
made to the QMS number of the form.  
Section 14.2. Causality should be made assuming study drug is LCZ696. 
Terms for causality modified slightly to reflect terminology used in AE Form (Possible and Probably instead 
of possibly and probably). 
Added ‘SmPC for valsartan’ to the assessment of expectedness section. 
Changes made to the ‘action taken’ terminology to reflect terminology in SAE form.  
Section 14.6. No need to notify the sponsor immediately of an SAE.  
Responsible Person for Pharmacovigilance replaced with Clinical Trial Project Manager. 
Section 14.7. Back-up measure to SUSAR reporting during periods of non-availability of CTPM added 
(i.e. direct reporting to HPRA) 
Section 14.9. Email address for Novartis notification of SAEs updated. 
Section 15. SOP on Deviation and Protocol Violation referenced. 
Section 22.5. Last paragraphs added to state that the informed consent process must be documented in 
the patients’ medical notes. 
Section 25.1. Timelines of study updated. 
Appendices: 
Adverse Event Report Form removed from Appendix. 
Serious Adverse Event Report Form removed from Appendix. 
Appendix 5. Immediate reporting to sponsor removed. Medical sign-off of SAE form added. 
Version 6.0 
Approval date: 04 Sept 2017. Effective date: 31 Oct 2017 
Substantial amendments  
Section 10.1. Safety has been removed as an exploratory objective and added as a secondary objective. 
Section 10.2. Safety has been removed as an exploratory endpoint and added as a secondary endpoint. 
Section 10.2. The first endpoint (relating to cMRI LAVI and 9 months) has been removed. 
Section 10.2. The second endpoint (relating to cMRI parameters of left ventricular structure and function) 
has been adjusted to remove assessment at 9 months. 
Section 10.2. Secondary endpoint to also include change in BNP. 
Section 12.4.17. MRI will only be performed at baseline and 18 months (9 month MRI removed). 
Section 12.4.17. St Vincent’s University Hospital has been added as a site for cMRI. 
Section 12.4.17. ‘Use of gadolinium containing contrast’ has been removed and reference to gadolinium 
has been deleted. 
Non-substantial amendments 
Section 12.1. The following text was deleted as it does not relate to the screening visit ‘If the patients is 
taking an ACE inhibitor, they will be instructed to stop taking this medication 36 hours before visit 2)’. 

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Table 2. The ‘Where to record source data’ column was updated (to reflect that the CRF can be used as 
the source document for some data). 
Table 2. Footnote added ‘Baseline echo must be performed within 90 days prior to baseline’. 
Section 12.4.4. The speed, duration and temperature settings on the centrifuge were updated. 
Section 12.4.16. Text added ‘A baseline echo must be performed within 90 days prior to baseline visit’. 
Section 13.10. The WebEz Helpdesk must be contacted with a request for emergency unblinding 
(previously the clinical trial project manager could be contacted). 
Section 14.1. The following text was added ‘Abnormal signs and symptoms identified during the physical 
and cardiac exam may also constitute an adverse event it they were not present at baseline’. 
Section 14.1. The note to refer to the EMA IME list for adverse event assessment of seriousness was 
deleted. 
Section 14.8. The email address of the Novartis pharmacovigilance department was updated. 
Section 15. All deviations will now be recorded in a Deviation Log according to SOP (GBT-GCP-FM-28). 
Section 25.1. The study timelines were updated. 
Version 7.0 
Approval date: 27 November 2018. Effective date: 01 March 2019 
Substantial amendments  
Section 10.1. Secondary objectives. The following objective was added:   
To assess response to LVZ696 based on genetic variants of the NPPB, NPRA and NPRC genes (e.g. 
rs5068, rs198389). 
Section 10.1. Exploratory objectives. The following objectives were added:   
To assess the difference between groups in terms of atrial fibrillation measured non-invasively over 5-7 
days using Holter monitoring 
To assess response of immune cells to sacubitril/valsartan 
Section 10.2. Secondary endpoints.  
The following was added to bullet point 4. e.g. ejection fraction, Lateral/medial e’ and 
lateral/medial/average E/e’.  
The following were added as secondary endpoints:  
Response to sacubitril/valsartan based on genetic variants of the NPPB, NPRA and NPRC genes (e.g. 
rs5068, rs198389);  
Change in the numbers of patients with progression of left ventricular dysfunction, defined as: ejection 
fraction <50% with change of >5%; and/or lateral E/e’ >13 or average E/e’ >14 (with change >2); and/or 
lateral e’<9, with reduction >2. 
Section 10.2. Exploratory endpoints: The following were added:   
Difference between groups in terms of immune system response, e.g. CD14+, CD16+/- monocyte RNA 
expression profile;  
Difference between groups in terms of atrial fibrillation measured non-invasively over 2-7 days using Holter 
monitoring. 
Section 11.2.2. Exclusion criteria No. 14 amended so that raised LFTs are limited to AST and ALT. 
Section 16.1. Description of statistical methods. The tests to be used to analyse continuous variables are 
described depending on their ability to be transformed or not. A plan for missing data is included. A 
description of how demographic and clinical characteristics will be presented is outlined. Further detail is 

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given on how to analyse primary and secondary outcomes and the variables to be considered when 
adjusting.   
Section 16.2. Determination of sample size. The following was added: In a review of the expected effect 
size, once blinded echocardiography was available for 125 patients at the 9-month time point, it was 
noted that the actual standard deviation of baseline to 9-month change scores was 4.7. This means an 
expected effect size of at least (2.0/5.0) = 0.40. An effect size of 0.4 would require 96 patients in each 
group, suggesting that the study is adequately powered on LAVI assessed by echocardiography. In 
addition, the study has at least 80% power with a two-tailed alpha = 5% to detect a 6 g/m2 difference in 
LVMI change by CMRi, a 2.5 mL/m2 in LAVI change by CMRi, a 2-unit difference in E/e’ or e’ using 
Tissue Doppler measurements. 
Section 25.1. Timelines and study duration. The LPFV and LPLV dates were updated. 
Section 7.0. Synopsis. Updated to reflect the changes to the various sections of the protocol. 
Non-substantial amendments  
Section 4.0. Signatures. Affiliation added to KMD and ML positions. ML title changed. 
Section 9.2. Background. The full meaning of the STOPHF acronym was included. The AHA guideline was 
updated from 2014 to 2017. The following was added “In the STOP-HF follow up study, we show that the 
minor C allele of genetic variant rs198389 of the Nppb gene is associated with sustained elevated 
circulating levels of BNP and reduced incidence of left ventricular dysfunction over a five year follow up 
period”. 
Section 9.3. Rationale. Added ‘This may be mediated through impacts on the innate immune system and 
monocyte-derived-macrophage phenotypes in the myocardium’. 
Section 12.1. Screening visit. The interval between the screening visit and baseline visit has been clarified 
and wording changed to “An appointment for Visit 2 is scheduled for up to two weeks later”. 
Section 12.4.11. Vital signs. Clarification that the cuff BP (and not 24h ABPM) will be used to confirm 
eligibility and inform dosing decisions. 
Section 16.2. Determination of sample size. A reference for the sample size was added.  
Table 2. The second column from the left (Where to record source data) was deleted as there is a Source 
Documentation SOP that details this information. 
Version 8.0 
Approval date: 17 April 2019. Effective date: 01 July 2019 
Substantial amendments (9-month follow-up study) 
Table 2. An additional column was added for the 9-month follow-up visit (visit 12) 
Appendix 9 added. Details of sub-study described 
Minor amendments 
Amend typographical error from “To assess response to LVZ696 based on genetic variants of the NPPB, 
NPRA and NPRC genes (e.g. rs5068, rs198389)”  in Protocol Version 7.0 Summary, page 13, and 
Objectives section, page 23, to reflect the endpoint defined in Protocol Version 7.0: i.e. “To assess 
response to LVZ696 based on genetic variants associated with the expression and metabolism of BNP 
(e.g.  neprilysin, Nppb, Npra and Nprc genes).” 
 
 

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Version 9.0 
Approval date: 06 October 2020. Effective date: 06 October 2020 
Substantial amendments  
Section 9 ‘Background’. Inserted new publication (reference 6) supporting the study hypothesis showing 
potential benefit of NP augmentation on atrial electrophysiology, structure and function. 
Section 10.2 ‘Endpoints’. Final changes, clarifications and additions to secondary and exploratory 
endpoints, linked to new publication (reference 6) have been made in this section of the protocol prior to 
completion of the study.  
Section 12.4.4. The list of blood biomarkers of fibrosis, inflammation, metabolism, platelet function and 
coagulation have been updated.  
The following biomarkers have been added to the table in this section: Col1A1, MMP-3, TIMP-4, PRA, 
aldosterone, IL-1R1, IL-R2, IL-2RA, IL-6RA, ANP, IL-17, GP6, uPAR, TR-AP, CD163, E/P-Selectins, 
uPA, vWF, TRAP, Cystatin B, PON3, TR-P1. 
Sections 12.4.6 (MMP2 and TIMP-1) and 12.5.7 (other biomarkers) were deleted. These sections 
described in detail the assays to be used to analyse the biomarkers. This was replaced with the following 
statement: [Biosamples]…will be transported on dry ice to the Conway Institute, University College Dublin 
for simultaneous analysis of selected biomarkers from the table below using validated analytical 
techniques.  
Version 10.0 
Approval date: 17/02/2021. Effective date: 18/02/2021 
Substantial amendments  
Section 10.1 ‘Objectives’ amended as follows: 
The list of objectives has been numbered (previously bullet points were used). The following changes 
were made to the list of secondary objectives: 
• 
Secondary objective #2 was added “To assess the impact of LCZ696 versus valsartan therapy on 
cardiovascular and non-cardiovascular adverse events, including prior to and post onset of 
Covid19 pandemic”.  
o 
Justification: The impact of the interventions on clinical adverse events has previously 
been designated a secondary endpoint measure. Furthermore, the overall cardiovascular 
adverse clinical event rate per participant/year is 4 times higher in PARABLE than the 
original STOP-HF study, justifying its separate evaluation. Finally, it is important to 
evaluate adverse clinical events prior to the onset of Covid19 and post-onset of Covid19. 
Exploratory objectives: 
• 
Exploratory objective #2 updated to include any atrial or ventricular arrythmia (and not just atrial 
fibrillation) 
• 
Exploratory objective #4 was removed to avoid duplication as this is now incorporated into 
secondary objective #2. 
• 
Exploratory objective  #4 added to evaluate if the treatment effects observed during the 18-month 
period persist nine-months after study drug discontinuation (9 month follow-up substudy) 
Section 10.2 ‘Endpoints’ (EP) amended as follows: 
The list of EPs has been numbered (previously bullet points were used).   
The following secondary endpoints were updated:  
 
Secondary endpoints:  
• 
EP #1 order updated: Left ventricular function using Doppler Echocardiography (average E/e’) 
between baseline and 18 months 

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• 
EP #2 order updated: Left atrial volume index (Doppler Echocardiography LAV)/BSA* between 
baseline and 9 months 
• 
EP #3 order updated: Left atrial function measured as total cMRI LAEF ((LAVimax-
LAVimin)/LAVimax) over 18 months 
• 
EP #4 order updated Left atrial function measured as cMRI left atrial stroke volume index 
(LAVmax-LAVmin)/BSA*, or LAVimax-LAVimin over 18 months  
• 
EP #5 order updated Left ventricular structure (cMRI LVMi indexed to BSA*) over 18 months 
• 
EP #6 order updated Left ventricular function (cMRI LVEF) over 18 months 
• 
EP #7 updated Measures of vascular compliance (ABPM pulse pressure) between baseline and 
18 months 
• 
EP #8 order updated Change in log transformed NT-proBNP between baseline and 18 months 
• 
EP #9 updated Time to first all cardiovascular death and major adverse cardiac events (MACE) 
requiring hospitalisation over 18 months. MACE includes arrthymia (including atrial 
fibrillation/flutter), transient ischaemic attack, stroke, valvular heart disease, myocardial 
infarction, peripheral or pulmonary thrombosis/embolus or heart failure 
• 
EP #10 added primary endpoint analysed per protocol  
 
The following exploratory endpoints were updated/reordered:  
Exploratory endpoints:  
• 
EP #11 added to include left atrial function measured as left atrial cardiac index (LAVimax-
LAVimin) x heart rate 
• 
EP #12 updated Left atrial function as cMRI myocardial strain measured using feature tracking 
between baseline and 18 months 
• 
EP #13 added Left ventricular structure (as cMRI LVESV, LVEDV, Fractal Analysis), all indexed 
to BSA* between baseline and 18 months 
• 
EP#14  Left ventricular function, measured as cMRI left ventricular stroke volume index 
(LVESVi-LVEDVi) between baseline and 18 months 
• 
EP#15  Left ventricular function, measured as cMRI left ventricular cardiac index ((LVESVi-
LVEDVi) x heart rate) between baseline and 18 months 
• 
EP#16  Left ventricular function as cMRI myocardial strain using feature tracking between 
baseline and 18 months 
• 
EP#17  Left ventricular function as cMRI e’ 
• 
EP#18  Evaluation of treatment effects on cMRI measures of right atrial and structure and 
function (RAVI, RAEF, RVEF, SV, CI, E’, E/e’)  
• 
EP#19  Left atrial function using Doppler Echocardiography (E/A ratio) 
• 
EP#20  Left ventricular structure using Doppler Echocardiography (LVMI, LVESVI, LVEDVI)  
• 
EP#21  Left ventricular function using Doppler Echocardiography (LVEF, stroke volume (SV), 
cardiac index (CI), Lateral or medial e’ and lateral or medial E/e’)  
• 
EP#22  Change in log transformed BNP, NTproBNP/BNP ratio and other related peptides, e.g. 
ANP, urinary cGMP between baseline and 9 months and baseline and 18 months 
• 
EP#23  Change in the following parameters of 24-hour ABPM between baseline and 9 months 
and baseline and 18 months: Systolic blood pressure, diastolic blood pressure and heart rate 
• 
EP#24  Change in resting (clinic measured) systolic blood pressure, diastolic blood pressure and 
heart rate between baseline and 9 months and baseline and 18 months. 
• 
EP#25  Incidence of all cardiovascular death and MACE requiring hospitalisation over 18 
months. 
• 
EP#26  Incidence of all cardiovascular related serious adverse events (SAEs) over 18 months 
• 
EP#27  Incidence of all-cause death and SAEs requiring hospitalisation over 18 months 
• 
EP#28  Incidence of all SAEs over 18 months 
• 
EP#29  Incidence of all-cause adverse events (AEs) by system organ class over 18 months 

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• 
EP#30  Time to first event analysis using Kaplan Meier survival curves for cardiovascular death 
or MACE requiring hospitalisation, cardiovascular-related SAEs, death or all-cause emergency 
hospitalisations, all-cause SAE. 
• 
EP #33. Impact of LCZ696 on endpoints dependent on BNP above or below 50pg/ml has been 
added  to this endpoint which already includes median BNP, NTproBNP and NTproBNP/BNP 
ratio at baseline 
• 
EP #34. Correlations between Echo and MRI measures of atrial and ventricular structure and 
function added 
• 
EP #36. CES, CYP2C9, NPRA and NPRB added to the list of genetic variants 
• 
EP #37. Additional biomarkers of inflammation added  
• 
EP #38. Change in creatinine, albumin creatinine ratio and cGMP added to list of urinary 
biomarkers 
• 
EP #39. Two additional correlations added to this section: Measures of left atrial and structure and 
function (LAVI, LAEF, LVEF, SV, CI, E’, E/e’) and pericardial and epicardial fat; Measures of right 
atrial and structure and function (RAVI, RAEF, RVEF, SV, CI, E’, E/e’) and pericardial and 
epicardial fat. 
• 
EP #40,41 added (MoCA, MMSE and EuroQol data separated out into three separate EPs) 
• 
EP #45. Atrial fibrillation/flutter, paroxysmal supraventricular tachycardia and other atrial or 
ventricular arrthymias added to this EP instead of paroxysmal atrial fibrillation and atrial 
tachycardia (clarification of language) 
• 
EP #46. Polygenic risk score of atrial fibrillation and atrial dilatation added to this EP. KLKB1 
added to the list of gene variants 
• 
EP #47. Sub-group analyses prespecified 
• 
EP #48. Use of circulating metabolomics to identify responders to LCZ696 added 
• 
EP #50. An endpoint was added to evaluate all primary and secondary endpoints in the total follow-
up period and prior to Covid19 restrictions implemented (13 March 2020). 
• 
EP #52. An endpoint to capture health economics (cost-benefit and cost-effectiveness analysis) 
added 
Section 12.4.3. ANP added to cGMP in this section on urinary biomarkers. 
Section 25.1. Study end date updated 
Appendix 9. This list of endpoints for the 9-month follow-up study have been deleted and replaced with a 
reference to the objectives and endpoints outlined in Section 10.1 and 10.2 of the protocol. 
 
 

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7. SYNOPSIS 
 
Title of study 
Personalised prospective comparison of ARni with ArB in patients with 
natriuretic peptide eLEvation (PARABLE) 
 
Name of Sponsor 
The Heartbeat Trust 
Phase of 
development 
Phase II 
Hypothesis 
We hypothesise that, in a phase II study design, the relative impact of 
LCZ696 and valsartan on left atrial volume index will be different in at-risk, 
asymptomatic patients with elevated natriuretic peptide over 18 months.  
 
Objectives 
Primary: 
To assess the impact of LCZ696 versus angiotensin II receptor blocker 
(ARB) (valsartan) on left ventricular diastolic function over 18 months. 
 
Secondary: 
1. To assess the impact of LCZ696 versus valsartan therapy on atrial 
and ventricular structure and function over 9 and 18 months.  
2. To assess the impact of LCZ696 versus valsartan therapy on 
cardiovascular and non-cardiovascular adverse events, including 
prior to and post onset of Covid19 pandemic. 
3. To assess the impact of LCZ696 versus valsartan on biochemical 
markers of fibro-inflammation and myocardial damage at 9 and 18 
months.  
4. To assess the response to LCZ696 based on genetic variants of 
associated with the expression and metabolism of BNP (e.g.  
neprilysin, Nppb, Npra and Nprc genes) 
5. To assess the impact of LCZ696 versus valsartan on biochemical 
markers of renal function. 
6. To correlate the impact on left ventricular dysfunction and 
biochemical markers in order to understand the mechanism of 
benefit of LCZ696 versus ARB therapy in modulating fibro-
inflammation, myocardial damage, and cardiac function. 
7. To provide further information in the target population on the safety 
and tolerability of LCZ696 versus valsartan.  
  
Exploratory: 
1. To assess the impact of LCZ696 versus valsartan on Health-
Related Quality of Life and cognitive function in the target 
population. 
2. To assess the response to therapy in terms of atrial and ventricular 
arrthymia measured non-invasively over 5-7 days using Holter 
monitoring 
3. To assess the response of immune cells to sacubitril/valsartan 
4. To evaluate if the treatment effects observed during the 18-month 
PARABLE 
study 
persist 
nine-months 
after 
study 
drug 
discontinuation 
Trial design 
This is a single centre, parallel design, randomised, double blind, double 
dummy, phase II trial in asymptomatic patients at risk of heart failure with 
elevated levels of natriuretic peptide. 

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Key inclusion 
criteria 
To be eligible for inclusion, each subject must meet the following criteria 
at the screening visit: 
1. Age > 40yrs with cardiovascular risk factor(s) including at least one 
of: 
a. History of hypertension (medicated for greater than one month); 
b. History of diabetes; 
2. Elevated NP: BNP between 20 and 280pg/ml or NT-proBNP values 
between 100 pg/ml and 1,000 pg/ml within 6 months prior to 
screening or at screening 
3. LAVI > 28 mL/m2 obtained during Doppler Echocardiography within 
6 months prior to screening or at screening 
4. Subjects must give written informed consent to participate in the 
study and before any study related assessments are performed. 
Key exclusion 
criteria 
1. A history of heart failure 
2. Asymptomatic left ventricular systolic dysfunction defined as LVEF 
<50% on most recent measurement 
3. Systolic blood pressure <100mmHg 
4. Persistent atrial fibrillation  
5. Subjects’ with a history of hypersensitivity, allergy or intolerance to 
LCZ696, ARB or neprilysin therapy or to any of the excipients or 
other contraindication to their use 
6. Previous history of intolerance to recommended target doses for 
ARBs 
7. Subjects who require treatment with both an ACE inhibitor and an 
ARB 
8. Presence of haemodynamically significant mitral and /or aortic 
valve disease 
9. Presence of hemodynamically significant obstructive lesions of left 
ventricular outflow tract, including aortic stenosis 
10. Conditions that are expected to compromise survival over the study 
period 
11. Serum potassium level > 5.2 mmol/L  
12. Severe renal insufficiency (eGFR <30 mL per minute per 1.73 m2). 
13. Hepatic dysfunction (AST or ALT values exceeding 3 x Upper Limit 
of Normal (ULN)]  
14. Concomitant use of aliskiren  
15. History of angioedema 
16. History or evidence of drug or alcohol abuse within the last 12 
months 
17. Malignancy or presence of any other disease with a life expectancy 
of < 2 years 
18. Women who are pregnant, breast-feeding, or women of 
childbearing potential not using estro-progestative oral or intra-
uterine contraception or implants, or women using estro-
progestative oral or intra-uterine contraception or implants but who 
consider stopping it during the planned duration of the study. A 
postmenopausal state is defined as no menses for 12 months 
without an alternative medical cause. (Contraception must be 
continued for one week following discontinuation of study drug). 
19. Concomitant participation in other interventional clinical trials 
20. Participation in any investigational drug trial within one month of 
visit 1 
21. Refusal to provide informed consent 
22. Subjects with contraindications to MRI  

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23. Any surgical or medical condition which might significantly alter the 
pharmacokinetics of study drugs 
Number of 
subjects 
Planned: A total of 250 subjects are to be included in the treatment period 
Test product, 
dose and mode of 
administration 
Included subjects will be randomised into one of two groups: 
• 
LCZ696 (and matching placebo) 
• 
Valsartan (and matching placebo) 
 
All treatments will be administered in tablet form, orally, twice daily 
Duration of 
treatment 
18 months 
Statistical 
methods 
If continuous variables are transformable to normal, they will be power-
transformed and independent, two sample t-tests will be used for analysis 
of continuous variables. If data are not transformable to normal, non-
parametric t-test equivalents (e.g. Wilcoxon signed rank and rank sum test, 
Mann-Whitney test and analysis of covariance (ANCOVA)) will be used. 
Chi-squared (or Fisher Exact) analyses will be used to compare categorical 
variables. If required, missing data will be addressed using multiple 
imputation using chained equations as previously described (Ledwidge et 
al. JAMA. 2013;310(1):66-74) and results will be presented (primary and 
secondary end points) as pooled results from the multiple imputed data sets 
using a last-observation carried-forward analysis. 
 
Demographics and clinical characteristics will be summarized with 
descriptive statistics (counts and percentages for categorical variables, or 
mean value ± the standard deviation for normally distributed continuous 
variables, or medians and interquartile ranges for non-normally distributed 
continuous variables). Repeated marker changes from baseline to 18 
months will be analysed using ANOVA with repeated measures models. 
 
Primary and secondary outcome measures will be performed both with and 
without adjustment for the effects of age, sex, diabetes, hypertension, 
obesity, and vascular disease. Further models will include adjustment for 
baseline measures of the outcome of interest (e.g. LAVI, BNP).  Categorical 
endpoints will be analyzed using generalized linear modeling with a 
binomial outcome distribution for prevalence and a Poisson outcome 
distribution for incidence rate (adjusted for patient-years). The multivariable 
models will include both prespecified covariates (age, sex, diabetes, 
hypertension, obesity, and vascular disease) and those variables with 
univariate P values ≤ 0.25. The likelihood ratio test and the Nagelkerke R 
Square will be used to identify independent variables with low explanatory 
power and to assess the fit of each specification of the multiple regression 
models.  
 
Sample size 
Based on the endpoint of change in LAVI over 18 months, the PARABLE 
trial aims to recruit 250 subjects (125 per arm). Sample size estimates were 
calculated from the current STOP-HF subject database (n=1499). A 
subsample of subjects with BNP > 50 pg/mL, LAVI> 28 mL/m2, with normal 
ejection fraction (≥ 50%) and in normal sinus rhythm was drawn. This 
resulted in a population of 163 (11%) of the total with a population BNP of 
125 pg/mL and a baseline mean LAVI of 36.2 mL/m2 (standard deviation of 
6.9 mL/m2) determined by Doppler Echocardiography. This LAVI is 
reassuringly similar to the baseline level observed by Solomon et al. 
(Lancet 2012; 380: 1387–95) in the PARAMOUNT study, which observed 
a 36-week drop in LAVI of 2.6 mL/m2.  Assuming the control group-shows 
no decrease in LAVI (as in Solomon et al. 2012 paper), the expected effect 
size in a similar study is 2.6/6.5 = 0.38. Setting alpha = 5% (two-tailed), 

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beta = 20% and using an independent t-test to assess the change in LAVI 
over follow-up, the required number of subjects to detect this effect is 222 
(111 per study arm), or 248 after accounting for a 10% dropout rate. 
 
In a review of the expected effect size, once blinded echocardiography was 
available for 125 patients at the 9-month time point, it was noted that the 
actual standard deviation of baseline to 9-month change scores was 4.7. 
This means an expected effect size of at least (2.0/5.0) = 0.40. An effect 
size of 0.4 would require 96 patients in each group, suggesting that the 
study is adequately powered on LAVI assessed by echocardiography. In 
addition, the study has at least 80% power with a two-tailed alpha = 5% to 
detect a 6 g/m2 difference in LVMI change by CMRi, a 2.5 mL/m2 in LAVI 
difference by CMRi, a 2-unit difference in E/e’ or e’ using Tissue Doppler 
measurements.  
 

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8. ABBREVIATIONS 
 
ABPM 
Ambulatory Blood Pressure Monitoring  
AC 
Atrial Cardiomyopathy 
ACE 
Angiotensin Converting Enzyme 
AE 
Adverse Event 
ALVDD 
Asymptomatic Left Ventricular Diastolic Dysfunction 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
ARB 
Angiotensin Receptor Blocker 
ARNI 
Angiotensin Receptor Neprilysin Inhibitor  
BID 
Twice Daily 
BNP 
 Brain Type Natriuretic Peptide 
BP 
Blood Pressure 
cGMP 
Cyclic Guanosine Monophosphate 
CRF 
Case Report Form 
EC 
Ethics Committee 
ECG 
Electrocardiography 
ECM 
Extracellular Matrix 
eGFR 
Estimated Glomerular Filtration Rate 
ELISA 
Enzyme-Linked Immunosorbent Assay 
EOS 
End of Study 
EQ-5D 
EuroQOL-5D 
EVCTM 
EudraVigilance Clinical Trial Module 
FBC 
Full Blood count 
FPFV 
First Patient First Visit 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HPRA 
Health Products Regulatory Authority 
IL 
Interleukins 
IME 
Important Medical Events 
LAVI 
Left Atrial Volume Index 
LFT 
Liver Function Test 
LV 
Left Ventricular 
LVEF 
Left Ventricular Ejection Fraction 
MCP 
Monocyte Chemoattractant Protein 
MMP 
Matrix Metalloproteinase 
SMMSE 
Standardised Mini Mental State Examination 
MoCA 
Montreal Cognitive Assessment 
MRI 
Magnetic Resonance Imaging 
NP 
Natriuretic Peptide 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
NT-proBNP 
N-terminal of the prohormone brain natriuretic peptide 
PICP 
Procollagen Type 1 Carboxy-Terminal Propeptide 

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PIIINP 
Procollagen III N-Terminal Propeptide  
PINP 
Procollagen Type I N-terminal Propeptide 
POC 
Point of Care 
RAAS 
Renin Angiotensin Aldosterone System 
SAE 
Serious Adverse Event 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SPSS 
Statistical Package for the Social Sciences 
SSAR 
Suspected Serious Adverse Reactions 
STOP-HF 
St Vincent’s Screening TO Prevent Heart Failure 
SUSAR 
Serious Unexpected Serious Adverse Reaction 
TIMP 
Tissue Inhibitor of Matrix Metalloproteinase 
TNF 
Tumour Necrosis Factor 
U&E 
Urea and Creatinine 
ULN 
Upper Limit of Normal 
 
 
 

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9. INTRODUCTION 
9.1 Overview and hypothesis 
Elevated natriuretic peptide (NP) in asymptomatic patients is a protective, diuretic, 
natriuretic and anti-fibrotic response in patients with left ventricular dysfunction. The 
St Vincent’s Screening TO Prevent Heart Failure (STOP-HF) study showed that NP 
screening and collaborative primary-secondary care can prevent cardiovascular 
diseases amongst at-risk patients. However, the intensification of pharmacological 
therapy applied in the STOP-HF study was largely focused on renin-angiotensin-
aldosterone-system (RAAS) blockade and was non-specific to NP elevation. 
 
LCZ696 (sacubitril/valsartan), is a first-in-class angiotensin receptor neprilysin inhibitor 
(ARNI). In addition to RAAS blockade, LCZ696 inhibits neprilysin resulting in reduced 
degradation of biologically active NPs. Previous work over 36 weeks has shown that 
LCZ696 in comparison with valsartan can provide greater reduction in left atrial volume 
index (LAVI), a continuous imaging surrogate of left ventricular diastolic dysfunction, 
when given to patients with heart failure.  
 
We hypothesise that, in a phase II study design, the relative impact of LCZ696 and 
valsartan on LAVI will be different in at-risk, asymptomatic patients with elevated NP 
over 18 months.  
 
9.2 Background information 
An effective prevention strategy is critical if we are to curb the established epidemic of 
heart failure and cardiovascular disease. This is particularly important in the context 
of increasing community prevalence of left ventricular diastolic abnormalities 
associated with hypertension and diabetes and requires community diagnostics and 
targeted preventative therapies. New data demonstrate that grading risk beyond the 
presence of established risk factors can be individualized with NP assessment. 
Elevated NP in a population with established cardiovascular disease defines a group 
more prone to ventricular dysfunction, heart failure and other cardiovascular events 
and can be used to risk stratify asymptomatic populations, targeting those most likely 
to need intensive intervention and follow-up.  
We have demonstrated in a prospective, randomised trial that NP-based screening 
and collaborative care with general practice can help target cardiovascular prevention 
and improve outcome in the St Vincent’s Screening TO Prevent Heart Failure (STOP-
HF) study [1]. This multi-faceted intervention involved community NP screening, 
improved use of RAAS modifying therapy, collaborative care with general practice and 
cardiovascular coaching to encourage adherence and attention to risk factor 
management. It demonstrated reduced development of left ventricular dysfunction, 
heart failure and other cardiovascular events requiring hospitalisation. This first of type 
study indicated that a biomarker driven strategy based on NP screening for heart 
failure prevention is feasible and has an impact across the wider expression of 
cardiovascular disease and has been incorporated into 2017 American Heart 
Association/American College of Cardiology guidelines.   

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As a unique, biomarker directed strategy for prevention of cardiovascular disease in 
patients without heart failure, the STOP-HF approach was ambitious and successful. 
It has been followed by a smaller, supportive study in diabetes [2]. New data from the 
study show that the intervention is cost-effective, potentially providing an important 
public health impetus for the STOP-HF biomarker driven approach to prevention.  
However, while successful, the STOP-HF biomarker strategy lacks a specific 
pharmacological intervention linked to the screening biomarker, NP. In the STOP-HF 
follow up study, we show that the minor C allele of genetic variant rs198389 of the 
Nppb gene is associated with sustained elevated circulating levels of BNP and 
reduced incidence of left ventricular dysfunction over a five year follow up period. 
These promising data support the use of LCZ696, a first in class angiotensin receptor 
neprilysin inhibitor, to pharmacologically raise BNP and provide cardioprotection in at-
risk patients. As neprilysin degrades biologically active NP, LCZ696 increases 
myocardial cyclic guanosine monophosphate (cGMP) while reducing myocardial 
stiffness and hypertrophy. NPs also stimulate natriuresis, diuresis, vasodilation and 
have been shown to have anti-fibrotic and anti-sympathetic benefits which could 
augment the STOP-HF preventative strategy [1, 3-5]. New data from our unit show 
that atrial tissue gene expression of BNP is strongly associated with atrial fibrosis, 
procollagen expression and presence of M2 monocyte-derived-macrophage marker 
CD163 [6]. Data from the STOP-HF follow-up study show that BNP strongly associates 
with the presence of atrial cardiomyopathy, which in turn is independently predictive 
of new onset major adverse cardiovascular events. Taken together, these data support 
the study hypothesis and a role for sacubitril/valsartan versus valsartan alone in 
favourably modulating progression of atrial cardiomyopathy, including left atrial 
volume index (LAVI), electrophysiological measures and fibrosis [6]. If left atrial 
structure and function is also associated with new onset major adverse cardiovascular 
events, the intervention could modulate propensity for thrombosis, which will be 
assessed using biomarkers. Finally, new CMRI imaging measures of atrial and 
ventricular structure and function, such as CMR e’ will allow full characterisation of the 
cardiovascular impact of the intervention.   
 
9.3 Rational for the study 
Elevated NP in an at-risk population independently identifies cardiovascular risk, which 
can be specifically targeted by LCZ696. In a small number of patients (4%) with 
cardiovascular risk factors and elevated NP, significant asymptomatic LV systolic 
dysfunction will be present and for these RAAS modifying therapy is mandated.  
However, there is a larger group of patients with elevated NP who have normal systolic 
function of the left ventricle but who have significant isolated diastolic dysfunction. 
These patients have asymptomatic left ventricular diastolic dysfunction (ALVDD), atrial 
cardiomyopathy (AC) or both and are at heightened risk for heart failure and other 
cardiovascular events[6].  

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The increase in NP in ALVDD is likely a fibro-inflammatory signal, which in-turn is 
contributing to tissue remodelling, vascular disease, myocardial stiffening and left 
ventricular dysfunction.  For example, hypertension, a common risk factor for ALVDD, 
is associated with an adverse accumulation of fibrous tissue[6-8] and studies have 
demonstrated a strong relationship between ventricular stiffness, myocardial collagen 
content and plasma levels of myocardial collagen turnover markers[7, 8]. 
Moreover, there is a larger group of patients with elevated NP who have normal 
systolic function of the left ventricle but who have significant isolated diastolic 
dysfunction. These are at heightened risk for heart failure and other cardiovascular 
events. We, and others, have shown that cardiac inflammation, fibrosis and 
hypertrophy drive the pathophysiology [6,9]. Importantly, there is currently no specific 
therapy for these patients, beyond conventional risk factor control.  
Since the increase in NP in this cohort reflects haemodynamic abnormalities and a 
fibro-inflammatory signal, which in turn is contributing to inflammation, tissue 
remodelling, vascular disease, myocardial stiffening, hypertrophy as well as left atrial 
and ventricular dysfunction,[3] interrupting this pathophysiological process at an early 
stage before the development of ventricular dysfunction, may prevent/slow 
development to heart failure and also have an impact on the development of other 
cardiovascular events driven by this pathophysiological process. Accordingly, 
suppressing the RAAS will reduce the pro-fibrotic impact of angiotensin II. Addition of 
LCZ696, which reduces degradation of endogenous, cardio-protective NPs, will 
augment the beneficial anti-inflammatory and anti-fibrotic effects of NPs beyond 
conventional RAAS modifying therapy. This may be mediated through impacts on the 
innate immune system and monocyte-derived-macrophage phenotypes in the 
myocardium. Therefore, we hypothesise that the ARNI compound, LCZ696, will 
demonstrate superior cardio-protection in this at-risk patient cohort and provide 
a novel way to modify cardiovascular risks at an earlier stage in the natural course of 
disease, in a targeted and individualized manner. 
Collagen is a stable protein and its balanced turnover is estimated to be in the order 
of 80 to120 days. Alteration of collagen turnover balance by various mechanisms can 
lead to adverse accumulation of collagen in the myocardial interstitium leading to 
fibrosis, increased tissue stiffness and reduced myocardial compliance. As a result, 
diastolic function can become impaired and left ventricular atrial volume increases. 
Several studies have shown that the interplay between the myocardium and 
extracellular matrix (ECM) can now be evaluated via analysis of serum samples of 
markers of collagen turnover.[8, 9] The enzymatic steps involved in ECM metabolism 
present therapeutic opportunities to modulate myocardial remodelling in order to 
prevent the progression from ALVDD to heart failure, elevated serum levels of CITP, 
matrix metalloproteinase (MMP)-2 and MMP-9 suggest increased degradation of 
myocardial collagen and other components of the ECM. Associated elevated levels of 
PICP, PIIINP and a trend towards an increase in PINP levels also indicate increased 
collagen synthesis in diastolic heart failure[10] [11]. 
 

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Other biomarkers of cardiac structure and function of relevance in AC/ALVDD include 
cardiac Troponin, a biomarker of cardiac damage, Galectin3 and ST-2, biomarkers of 
cardiac remodelling and tissue fibrosis. Finally, cGMP, which blunts activation 
pathways, diminishes hypertrophy, fibrosis, cellular toxicity, and maladaptive 
remodelling in the myocardium.  
 
Importantly, there is currently no specific therapy for AC/ALVDD, beyond conventional 
cardiovascular risk factor control. Interrupting this pathophysiological process at an 
early stage before the development of ventricular dysfunction, may prevent/slow 
development to heart failure and also have an impact on the development of other 
cardiovascular events driven by this pathophysiological process. This represents a 
novel way to modify risks at an earlier stage in the natural course of cardiovascular 
disease, in a targeted and individualized manner. It is known that suppressing the 
RAAS will reduce the pro-fibrotic impact of angiotensin II. Addition of neprilysin 
inhibitor sacubitril in LCZ696, will reduce degradation of endogenous, cardio-
protective, biologically active NPs and cGMP and will augment the beneficial impact 
on fibro-inflammation beyond conventional RAAS modifying therapy. 
 
There are a number of emerging biochemical and imaging surrogates of left ventricular 
dysfunction, which can be evaluated in a relatively small population over a short time 
frame in a prospective, phase II study design. Of these, one of the most reliable, 
continuous markers of diastolic function in the heart is LAVI.  There was a dramatic 
impact of LCZ696 on LAVI in comparison with valsartan in the PARAMOUNT study 
[12]. The reduction of 2.6 mL/m2 with LCZ696 compared with an increase of 0.3 mL/m2 
with valsartan (p=0.007 for difference) from a baseline of 36 mL/m2 over 36 weeks is 
clinically meaningful. Furthermore, this endpoint can be precisely defined using 
cardiac magnetic resonance imaging (cMRI) in a phase II design. We will collect 
Doppler Echocardiographic images to correlate with cMRI images. Doppler 
Echocardiography will be more feasible in follow on studies with larger populations.  
In summary, it has been demonstrated that asymptomatic patients with elevated NP 
levels are at higher risk of heart failure and other cardiovascular events. At-risk 
patients with C allele of genetic variant rs198389 of the Nppb gene have sustained 
elevated BNP. Elevated NP in this setting represents a protective, endogenous 
response to fibro-inflammation and is associated with beneficial effects on progression 
of left ventricular dysfunction. The predominant cardiac abnormality in these patients 
is ALVDD, which can be tracked using LAVI. We hypothesise that augmenting this 
protective fibro-inflammatory response pharmacologically with LCZ696 could 
demonstrate superiority over the current state of art therapy in patients with 
hypertension or diabetes and elevated NP in a phase II study design and, in doing so, 
PARABLE may deliver a major clinical innovation in the prevention of cardiovascular 
disease.[3] 
 
 

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10. OBJECTIVES AND ENDPOINTS 
The overall purpose of the PARABLE trial is to assess the impact of LCZ696 on 
functional, structural and biochemical abnormalities as surrogates of cardiovascular 
disease in an asymptomatic cohort with cardiovascular risk factors and elevated NP 
(brain type natriuretic peptide (BNP) and N-terminal of the prohormone BNP (NT-
proBNP). 
 
10.1 
Objectives 
Primary objective:  
1. To assess the impact of LCZ696 (sacubitril/valsartan) versus angiotensin II 
receptor blocker (ARB) (valsartan) on left ventricular diastolic function over 18 
months. 
 
Secondary objectives:  
1. To assess the impact of LCZ696 versus valsartan therapy on atrial and 
ventricular structure and function over 9 and 18 months.   
2. To assess the impact of LCZ696 versus valsartan therapy on cardiovascular 
and non-cardiovascular adverse events, including prior to and post onset of 
Covid19 pandemic. 
 
Exploratory objectives:  
1. To assess response to LCZ696 based on genetic variants associated with the 
expression and metabolism of BNP (e.g.  neprilysin, Nppb, Npra and Nprc 
genes).  
2. To assess the impact of LCZ696 versus valsartan on biochemical markers of 
fibro-inflammation and myocardial damage at 9 and 18 months.  
3. To assess the impact of LCZ696 versus valsartan on biochemical markers of 
renal function  
4. To correlate the impact on left ventricular dysfunction and biochemical markers 
in order to understand the mechanism of benefit of LCZ696 versus ARB therapy 
in modulating fibro-inflammation, myocardial damage, and cardiac function.  
5. To provide further information in the target subject population on the safety and 
tolerability of LCZ696 versus valsartan.  
6. To assess the impact of LCZ696 versus valsartan on Health-Related Quality of 
Life and cognitive function (through the administration of questionnaires) in the 
target subject population. 
7. To assess the difference between groups in terms of atrial and ventricular 
arrthymia measured non-invasively over 5-7 days using Holter monitoring  
8. To assess response of immune cells to sacubitril/valsartan  
9. To evaluate if the treatment effects observed during the 18-month PARABLE 
study persist nine-months after study drug discontinuation 
 

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10.2 
Endpoints 
Primary endpoint:  
Change in left atrial volume index (LAVI) measured by cMRI over 18 months.  
 
Secondary endpoints:  
1. Left ventricular function using Doppler Echocardiography (average E/e’) 
between baseline and 18 months 
 
2. Left atrial volume index (Doppler Echocardiography LAV)/BSA* between 
baseline and 9 months 
 
3. Left 
atrial 
function 
measured 
as 
total 
cMRI 
LAEF 
((LAVimax-
LAVimin)/LAVimax) over 18 months 
 
4. Left atrial function measured as cMRI left atrial stroke volume index (LAVmax-
LAVmin)/BSA*, or LAVimax-LAVimin over 18 months  
 
5. Left ventricular structure (cMRI LVMi indexed to BSA*) over 18 months 
 
6. Left ventricular function (cMRI LVEF) over 18 months 
 
7. Measures of vascular compliance (ABPM pulse pressure) between baseline 
and 18 months 
 
8. Change in log transformed NT-proBNP between baseline and 18 months 
 
9. Time to first all cardiovascular death and major adverse cardiac events (MACE) 
requiring hospitalisation over 18 months. MACE includes arrythmia (including 
atrial fibrillation/flutter), transient ischaemic attack, stroke, valvular heart 
disease, myocardial infarction, peripheral or pulmonary thrombosis/embolus or 
heart failure 
 
10. Primary endpoint analysed per protocol. 
 
*BSA calculated using the DuBois formula 
 
Exploratory endpoints:  
11. Left atrial function measured as cMRI left atrial cardiac index ((LAVimax-
LAVimin) x heart rate) between baseline and 18 months 
 

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12. Left atrial function as cMRI myocardial strain measured using feature tracking 
 
13. Left ventricular structure (as cMRI LVESV, LVEDV, Fractal Analysis), all 
indexed to BSA* between baseline and 18 months 
 
14. Left ventricular function, measured as cMRI left ventricular stroke volume index 
(LVESVi-LVEDVi) between baseline and 18 months 
 
15. Left ventricular function, measured as cMRI left ventricular cardiac index 
((LVESVi-LVEDVi) x heart rate) between baseline and 18 months 
 
16. Left ventricular function as cMRI myocardial strain using feature tracking 
between baseline and 18 months 
 
17. Left ventricular function as cMRI e’ 
 
18. Evaluation of treatment effects on cMRI measures of right atrial and structure 
and function (RAVI, RAEF, RVEF, SV, CI, E’, E/e’)  
 
19. Left atrial function using Doppler Echocardiography (E/A ratio) 
 
20. Left ventricular structure using Doppler Echocardiography (LVMI, LVESVI, 
LVEDVI)  
 
21. Left ventricular function using Doppler Echocardiography (LVEF, stroke volume 
(SV), cardiac index (CI), Lateral or medial e’ and lateral or medial E/e’)  
 
22. Change in log transformed BNP, NTproBNP/BNP ratio and other related 
peptides, e.g. ANP, urinary cGMP between baseline and 9 months and baseline 
and 18 months 
 
23. Change in the following parameters of 24-hour ABPM between baseline and 9 
months and baseline and 18 months: Systolic blood pressure, diastolic blood 
pressure and heart rate  
 
24. Change in resting (clinic measured) systolic blood pressure, diastolic blood 
pressure and heart rate between baseline and 9 months and baseline and 18 
months  
 
25. Incidence of all cardiovascular death and MACE requiring hospitalisation over 
18 months 
 
26. Incidence of all cardiovascular related serious adverse events (SAEs) over 18 
months 
 
27. Incidence of all-cause death and SAEs requiring hospitalisation over 18 months 

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28. Incidence of all SAEs over 18 months 
 
29. Incidence of all-cause adverse events (AEs) by system organ class over 18 
months 
 
30. Time to first event analysis using Kaplan Meier survival curves for 
cardiovascular death or MACE requiring hospitalisation, cardiovascular-related 
SAEs, death or all-cause emergency hospitalisations, all-cause SAE 
 
31. Impact of LCZ696 on endpoints in a subset of patients with or without baseline 
atrial cardiomyopathy, using EHRA/HRS/APHRS/SOLAECE 2016 consensus 
definition; a complex of electrophysiological (e.g. atrial fibrillation, atrial flutter), 
structural/architectural (e.g. LAVI >34ml/m2) or contractile (e.g. LAEF, elevated 
E/A ratio) on cMRI or Doppler Echocardiography, at 9 and 18 months 
 
32. Impact of LCZ696 on prevalent and new onset atrial cardiomyopathy using 
EHRA/HRS/APHRS/SOLAECE 2016 consensus definition (defined as a 
complex of electrophysiological (e.g. atrial fibrillation, atrial flutter), 
structural/architectural (e.g. LAVI >34ml/m2) or contractile (e.g. LAEF, elevated 
E/A ratio) on cMRI or Doppler Echocardiography)  at 9 and 18 months 
 
33. Impact of LCZ696 on primary and secondary endpoints, at 9 and 18 months 
dependent on BNP above or below 50pg/mL, median BNP, NTproBNP and 
NTproBNP/BNP ratio at baseline  
 
34. Correlation between Doppler Echocardiography and cMRI measures of the 
following at baseline and 18 months: 
• Left atrial structure and function (LAVi, LAEF) 
• Left ventricular structure and function (e.g. LVMi, LVSVi, LVCi, LVEF, e’) 
• Correlation of cMRI-e’ with left atrial and left ventricular feature tracking 
analysis 
 
35. Change in the numbers of patients with progression of left ventricular 
dysfunction, defined using Doppler Echocardiography as: ejection fraction 
<50% with change of >5%; and/or lateral E/e’ >13 or average E/e’ >14 (with 
change >2); and/or lateral e’<9, with reduction >2 over 9 and 18 months  
 
36. Pharmacogenetic response to therapy (i.e. change in primary and secondary 
endpoints) dependent on status of common genetic variants (or proxies in high 
linkage disequilibrium) associated with the expression and metabolism of 
natriuretic peptide, sacubitril and valsartan (e.g.  CES, CYP2C9, NPRA, NPRB, 
NPPB, NPPA, NPRC (NPR3), MME, FURIN, CLCN, DPP4) at 9 and 18 months  
 

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37. Change in blood biomarkers of collagen turnover (e.g. Col1A1, PICP, PIIINP), 
ECM turnover (e.g. MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-4), myocardial 
damage (hsTroponin), fibrosis (e.g. Galectin-3, sST-2), inflammation (e.g. IL-
1R1, IL-R2, IL-2RA, IL-6RA, IL-6, TNF-αR1/R2, MCP1, CT1, GDF15 and RAAS 
(e.g. PRA, aldosterone), GP6, creatinine, ANP, uPAR, CD163, uPA, PON3, TR-
AP, E/P-selectins, vWF, cystatin B, TF-PI between baseline and 18 months 
 
38. Change in eGFR, creatinine, albumin creatinine ratio and urinary biomarkers of 
natriuretic peptide (e.g. cGMP, ANP) between baseline and 9 months and 
baseline and 18 months 
 
39. Correlation between Doppler Echocardiography and cMRI measures of the 
following: 
• Left atrial structure and function (LAVI, LAEF, LVEF, SV, CI, E’, E/e’) 
and blood/urinary biomarkers 
• Left atrial and structure and function (LAVI, LAEF, LVEF, SV, CI, E’, E/e’) 
and pericardial and epicardial fat. 
• Right atrial and structure and function (RAVI, RAEF, RVEF, SV, CI, E’, 
E/e’) and pericardial and epicardial fat. 
 
40. Change in cognitive function as measured by the Standardised Mini-Mental 
State Examination (MMSE) between baseline and 9 months and baseline and 
18 months 
 
41. Change in cognitive function as measured by the Montreal Cognitive 
Assessment tool (MoCA) between baseline and 9 months and baseline and 18 
months 
 
42. Change in quality of life as measured using the EuroQoL-5D-5L instrument 
(overall summary score and individual domain score) between baseline and 9 
months and baseline and 18 months 
 
43. Difference between groups in terms of CD14+, CD16+/- monocyte RNA 
expression profile, in a sub-set of subjects, between baseline and 9 months and 
baseline and 18 months 
 
44. Impact of LCZ696 on biomarkers of angiogenesis, hypoxia, cardiac 
remodelling, cell adhesion, platelet activation, coagulation, chemotaxis, 
catabolic stress, inflammation and fibrosis which will be assessed using Olink 
CVIII proseek panel, between baseline and 18 months 
 
45. Difference between treatment groups in incidence of atrial fibrillation/flutter, 
paroxysmal supraventricular tachycardia and other atrial or ventricular 
arrthymias  measured non-invasively in a sub-set of subjects over 5-7 days 
using continuous ECG monitoring  

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46. Pharmacogenetic responses to therapy dependent on polygenic risk score of 
blood pressure, atrial fibrillation, atrial dilatation associated gene variants and 
established pharmacogenetic gene variants of natriuretic peptide pathway and 
sacubitril (e.g. NPPB, NPPA, NPRC (NPR3), MME, FURIN, CLCN, DPP4, 
KLKB1, CES1 gene variants) at 18 months  
 
47. Subgroup analyses on primary outcome and secondary endpoints (pre-
specified subgroups include above and below median age and BMI, eGFR 
(above and below 90mls/min); gender, obesity, vascular disease, hypertension, 
diabetes, atrial fibrillation/flutter, valve disease)  
 
48. Use of circulating metabolomics profile to identify responders to LCZ696 (based 
on primary and secondary endpoints) 
 
49. Evaluation of secondary and exploratory endpoints in a sub-set of subjects, 9 
months after completing therapy with IMP (extension analysis/9 months follow-
up sub-study) 
 
50. Evaluation of primary and secondary endpoints in total follow up period and 
prior to Covid19 restrictions implemented (13 March 2020) 
 
51. Additional novel and established biomarkers outlined above measured in 
serum, plasma, or urine profiling using proteomic, transcriptomic, epigenomic, 
and metabolomic approaches 
 
52.  Evaluation of health economic analysis using cost-benefit analysis and cost-
benefit analysis. 
 
 
 
 

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11. TRIAL DESIGN 
11.1 
General considerations 
PARABLE is a proof of concept, randomised, double-blind, double-dummy, phase II, 
parallel group, controlled trial. It will enrol 250 patients with cardiovascular risk factors, 
elevated NP and LAVI above 28 mL/m2. 
 
Standard dosing regimen: Following selection, discontinuation of existing angiotensin 
converting enzyme (ACE) inhibitor and a washout period of 36 hours, or angiotensin 
receptor blocker (ARB) (no washout necessary), PARABLE will randomly assign 
subjects to LCZ696 100mg twice daily titrated to LCZ696 200mg twice daily or 
valsartan 80mg twice daily titrated to valsartan 160 mg twice daily for 18 months (see 
Figure 1a). 
 
Lower dosing regimen: A starting dose of LCZ696 50 mg twice daily or valsartan 40mg 
twice daily will be used for subjects not currently taking an ACE inhibitor or an ARB, 
and for subjects previously taking low doses of these agents (as per Investigator 
judgement). A lower dosing regimen should also be used for subjects with a systolic 
BP of ≥100mm to 110mmHg at screening or baseline. The dose of LCZ696 and 
valsartan will be doubled every 2 to four weeks to the target dose of 200mg and 160mg 
twice daily for LCZ696 and valsartan respectively, as tolerated by the subject. (See 
Figure 1b) 
 
(LCZ696 200mg twice daily delivers similar exposure of valsartan (assessed by AUC) 
as Diovan 160mg twice daily. This dose delivers approximately 90% of its maximal 
neprilysin inhibition (Novartis Company Information)). 
 
 
Figure 1a. Study design for subjects titrated with the standard starting dose of study drug  
 
 
Discontinue  
ACEi  

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Figure 1b. Study design for subjects titrated with the lower starting dose of study drug  
 
 
 
11.2 
Selection of study population 
Eligible patients will be male or female, over 40 years old, with cardiovascular risk 
factors, elevated NP and LAVI above 28 mL/m2. 
 
11.2.1 Inclusion criteria 
To be eligible for inclusion, each patient must meet each of the following criteria 
at screening (Visit 1) and must continue to fulfil these criteria at baseline (Visit 2).  
1. Age > 40yrs with cardiovascular risk factor(s) including at least one of: 
a. History of hypertension (medicated for greater than one month); 
b. History of diabetes;  
2. Elevated NP: Elevated NP: BNP between 20 and 280pg/ml or NT-proBNP 
values between 100 pg/ml and 1,000 pg/ml within 6 months prior to screening or 
at screening 
3. LAVI > 28 mL/m2 obtained during Doppler Echocardiography within 6 months 
prior to screening or at screening 
4. Subjects must give written informed consent to participate in the study and 
before any study related assessments are performed. 
 
 
 
Discontinue  
ACEi  

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11.2.2 Exclusion criteria 
1. A history of heart failure. 
2. Asymptomatic left ventricular systolic dysfunction defined as LVEF <50% on 
most recent measurement. 
3. Systolic blood pressure <100mmHg 
4. Persistent atrial fibrillation.  
5. History of hypersensitivity, allergy or intolerance to LCZ696, ARB or neprilysin 
therapy or to any of the excipients or other contraindication to their use. 
6. Previous history of intolerance to recommended target doses for ARBs 
7. Subjects who require treatment with both an ACE inhibitor and an ARB 
8. Presence of haemodynamically significant mitral and /or aortic valve disease. 
9. Presence of hemodynamically significant obstructive lesions of left ventricular 
outflow tract, including aortic stenosis. 
10. Conditions that are expected to compromise survival over the study period. 
11. Serum potassium level > 5.2 mmol/L at screening. 
12. Severe renal insufficiency (eGFR <30 mL per minute per 1.73 m2). 
13. Hepatic dysfunction (AST or ALT values exceeding 3x ULN) 
14. Concomitant use of aliskiren  
15. History of angioedema. 
16. History or evidence of drug or alcohol abuse within the last 12 months 
17. Malignancy or presence of any other disease with a life expectancy of < 2 years 
18. Women who are pregnant, breast-feeding, or women of child bearing potential 
not using estro-progestative oral or intra-uterine contraception or implants, or 
women using estro-progestative oral or intra-uterine contraception or implants 
but who consider stopping it during the planned duration of the study. A 
postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. (Contraception must be continued for one week 
following discontinuation of study drug). 
19. Concomitant participation in other intervention trials 
20. Participation in any investigational drug trial within one month of visit 1. 
21. Refusal to provide informed consent 
22. Subjects with contraindications to MRI  
a) Brain aneurysm clip  
b) Implanted neural stimulator  
c) Implanted cardiac pacemaker or defibrillator  
d) Cochlear implant  
e) Ocular foreign body (e.g. metal shavings)  
f) Other implanted medical devices: (e.g. Swan-Ganz catheter)  
g) Insulin pump  
h) Metal shrapnel or bullet.  
23. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of study drugs, including but not limited to 
any of the following:  
a) History of major gastrointestinal tract surgery including gastrectomy, 
gastroenterostomy, or bowel resection.  
b) Inflammatory bowel disease during the 12 months prior to Visit 1.  

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c) Any history of pancreatic injury, pancreatitis or evidence of impaired 
pancreatic function/injury as indicated by abnormal lipase or amylase.  
d) Evidence of hepatic disease as determined by any one of the following: 
SGOT or SGPT values exceeding 3 x ULN at Visit 1, a history of hepatic 
encephalopathy, a history of oesophageal varices, or a history of 
portocaval shunt.  
No additional exclusions may be applied by the Investigator in order to ensure that 
the study population will be representative of all eligible patients. 
 
12. STUDY ASSESSMENTS AND PROCEDURES  
Informed consent will be obtained prior to any study-related procedures being 
undertaken. 
 
12.1 
Screening visit (Visit 1) 
Prior to Visit 1, the Investigator shall perform a ‘pre-screening’ exercise and review the 
STOP-HF 
database 
to 
identify 
subjects 
that 
may 
potentially 
meet 
the 
inclusion/exclusion criteria (e.g. age, risk factors for heart failure and other co-
morbidities).  
The Investigator shall contact those subjects that meet the inclusion and exclusion 
criteria based on the information available in the STOP-HF database and provide 
information to them about the clinical trial and ascertain their interest in participating 
in the trial. (Prior to any contact, www.rip.ie  should be checked to identify deceased 
patients).  This contact must be documented in the patients’ medical notes. Patients 
may also contact the STOP-HF clinic directly in response to an advertisement. 
Patients may also be referred from other clinics, hospital departments or healthcare 
professionals. 
If the subject expresses interest in participating in the trial, they will be invited to attend 
a screening visit (Visit 1). They will be given a Subject Information Leaflet and Informed 
Consent Form. They will be given sufficient time to consider their participation in the 
study and to ask any questions concerning the study (See section 22.5 for further 
information on the informed consent process). Informed consent must be received 
before any study related procedures are carried out. Only a qualified medical doctor 
may obtain informed consent. 
Following informed consent, various clinical laboratory assessments will be carried out 
to assess/confirm eligibility (e.g. potassium, liver function, eGFR). The Investigator 
should review the subject’s medical history to confirm that no other exclusion criteria 
related to the study or contraindications to study medication are known. For NP, any 
elevated value (BNP >20pg/ml or NT-proBNP >100 pg/ml) obtained in the previous 6 
months is acceptable. For LAVI, any elevated value (> 28 mL/m2) obtained in the 
previous six months is acceptable.   
An appointment for Visit 2 is scheduled for up to two weeks later. 

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Following Visit 1 and following a review of laboratory assessment to confirm eligibility, 
patient randomisation will take place. The patient will be assigned to one of the two 
treatment arms in accordance with the randomisation scheme. 
 
Table 1. Study interventions  
Treatment 
arm 
# of subjects 
randomised 
Type  
Compound 
Min 
dose 
Max dose 
(target dose) 
Frequency 
Route 
Arm 1 
~125 
Active  
LCZ696 
50 mg* 
200 mg  
Twice daily 
Oral 
Arm 2 
~125 
Comparator 
Valsartan 
40 mg* 
160 mg  
Twice daily 
Oral 
 
12.2 
Baseline visit (Visit 2) 
Eligible patients will undergo a 36-hour washout period if they were previously taking 
an ACE inhibitor† and be randomized to one of two arms for 18 months: 
[1] Intervention arm: LCZ696 100mg twice daily, titrated after two weeks to 200mg 
twice daily on top of usual medical care or  
[2] Control arm: ARB (valsartan) 80mg twice daily, titrated after two weeks to 160 twice 
daily on top of usual medical care.  
†LCZ696 must not be initiated until 36 hours after taking the last dose of ACE inhibitor.  
*A starting dose of LCZ696 50mg twice daily or valsartan 40mg twice daily will be used 
for subjects not currently taking an ACE inhibitor or an ARB, and/or for subjects 
previously taking low doses of these agents (as per Investigator judgement). A lower 
dosing regimen should also be used for subjects with a systolic BP of ≥100mm to 
110mmHg at screening or baseline. The dose of LCZ696 and valsartan will be doubled 
every 2 to four weeks to the target dose of 200mg and 160mg twice daily for LCZ696 
and valsartan respectively, as tolerated by the subject.  
All subjects will be reviewed two weeks after dose titration for tolerability issues (e.g. 
symptomatic hypotension, hyperkalaemia, renal dysfunction). In cases of poor 
tolerability, temporary down-titration of study drug, co-medication or discontinuation 
will be considered (see Appendix 10). 
Additional medications or interventions will be administered at the discretion of the 
attending physician. The use of an ACE inhibitor an ARB concomitantly with the study 
drug after randomisation is strictly prohibited. 
The Investigator shall complete a ‘Wallet Card’ for each patient. Patients will be 
advised to carry the card with them at all times and to present the card to medical 
personnel should they require any medical care outside the study while participating 
in the study.  
 
 

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12.3 
Follow up visits (Visits 3-11) 
Table 2 outlines the schedule of clinical assessments, blood sampling, imaging and 
follow-up that will apply in PARABLE. Follow-up visits will take place in the STOP-HF 
Service, St Michael’s Hospital, Dun Laoghaire. 
 
A follow-up visit will also take place two weeks after each dose titration (i.e. at week 
two and four and six.   
 
If any subject refuses to return for these assessments or is unable to do so, every 
effort should be made to contact him/her by telephone and these attempts should be 
recorded in the subject’s paper case report form (pCRF). If one visit is postponed or 
brought forward, it should not result in the next visit being postponed or brought 
forward. The next visit, if at all possible, should adhere to the original time schedule. 
 

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Table 2. Study assessments and procedures 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
Assessment 
Wk-2 
Screening 
D0  
Baseline 
Wk 2 
Wk 4 
Wk 6 
Wk 13 / 
Mth 3 
Wk 26 / 
Mth 6 
Wk 39 /  
/ Mth 9 
Wk 52 / 
Mth 12 
Wk 65 /  
Mth 15 
Wk 78 / 
Mth 18 (EOS) 
Mth 27 
(Optional 
sub-study) 
± 3d 
± 3d 
± 3d 
± 7d 
± 7d 
± 7d 
± 7d 
± 7d 
± 7d 
± 28 
Assessment of eligibility 
x 
 
 
 
 
 
 
 
 
 
 
x 
Pregnancy test (WOCBP) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
x 
Randomisation 
 
x 
 
 
 
 
 
 
 
 
 
 
Medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
Physical exam 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height (H) and weight (W) 
 
H/W 
 
 
 
 
 
W 
 
 
W 
H/W 
Waist/hip circumference 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
Vital signs (BP and pulse) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Natriuretic peptide 
 
 
X# 
 
  x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Biomarkers 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
U&E, LFT, Alk phos 
x (no alk 
phos) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Haematology 
x 
x 
 
 
 
 
 
x 
 
 
x 
x 
eGFR 
x 
x 
 
 
 
 
 
x 
 
 
x 
x 
HbA1c, lipid profile, iron studies 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
cGMP (urinary) 
 
x 
 
 
x 
x 
 
x 
 
 
x 
x 
ABPM 
  
x 
 
 
 
 
 
x 
 
 
x 
x 
Electrocardiography (ECG) 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
Doppler echocardiography 
X¥  
x† 
 
 
 
 
 
x 
 
 
x 
x 
Cardiac MRIƵ 
  
x 
 
 
 
 
 
 
 
 
x 
 
Questionnaires** 
 
x 
 
 
 
 
 
x 
 
 
x 
x 
Concomitant medications  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Adverse events 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Dispense medication 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Drug accountability  
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Holter monitor (optional) 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 

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*Source: results of these assessments may be filed in the Subject Study File on the original source document (questionnaires) or a copy of the source document (e.g. laboratory report, Echo report, 
ECG (this must be a copy of the original), ABPM printout etc.) 
¥ Echo may be needed at Visit 1 if one hasn’t been performed in the previous six months. 
† If an Echo is performed at screening, it does not have to be repeated at baseline, unless the investigator decides otherwise. Baseline echo must be performed within 90 days prior to baseline. 
** The   SMMSE and MoCA cognitive assessment questionnaire will also be administered five years after the patient’s end of study visit. 
Ƶ If the patient had an MRI in the previous six weeks, then there is no need for a repeat MRI at baseline 
#  NP levels may be needed at Visit 1 if one hasn’t been performed in the previous six months.

               
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12.4 
Assessments  
12.4.1 Laboratory parameters 
Peripheral venous blood samples will be drawn at the timelines shown in Table 2. 
Laboratory examinations are analysed in St Michael’s Hospital laboratory or St 
Vincent’s Hospital laboratory. Methods for sampling and handling are detailed in the 
PARABLE laboratory manual (HBT-GCP-SOP-16 ‘Handling Laboratory Samples for 
the PARABLE Study’). Evaluations will include the following: 
• Biochemistry 
o Urea & Electrolytes (U&E) 
o Liver Function Tests (LFT) 
o Alkaline Phosphatase 
o Lipid profile 
o HbA1c 
o Iron studies 
• Haematology 
o Full blood count 
 
Sample processing and analysis will be done as per local standard operating 
procedures. The local hospital laboratory should provide the report to the Investigator 
who is responsible for the clinical assessment of the results. Any abnormality should 
be assessed for its clinical significance. Any clinically significant value should be 
recorded as an AE in the CRF and followed up.  
 
12.4.2 eGFR assessments 
The eGFR to determine eligibility of the subject for screening into the trial will be 
calculated at Visit 1 (screening) from the serum creatinine concentration. The eGFR 
will be further measured at Visit 8 (month 9) and Visit 11 (EOS).  
eGFR will only be calculated using the following formula: eGFR (mL/min/1.73 m2) = 
175 × (standardized SCr in mg/dL)-1.154 × (age in years)-0.203 × (0.742 if female) × 
(1.212 if black), where SCr is the standardized serum creatinine value. 
 
12.4.3 Urinary biomarkers 
A spot office urine sample (random sample) will be collected from subjects at Visit 2 
(baseline), Visit 5 (week 6), Visit 6 (month 3), Visit 8 (month 9) and Visit 11 (EOS/18 
month) for assessment of cGMP and atrial natriuretic peptide (ANP).  
 
12.4.4 Biomarkers  
Peripheral blood samples and plasma for biomarker analysis will be drawn at the 
timelines shown in Table 2. Samples will undergo immediate serum separation by 
centrifuge at 1500 rcf (relative centrifugal force) for 15 minutes at 21°C. The serum 
and plasma will then be separated into aliquots and stored at -80°C. They will be 

               
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transported on dry ice to the Conway Institute, University College Dublin for 
simultaneous analysis of selected biomarkers from the Table below using validated 
analytical techniques:  
 
• Col1A1 
• Aldosterone 
• PICP  
• Creatinine 
• PIIINP  
• IL-6 
• MMP-2  
• IL-1R1 
• MMP-3 
• IL-R2 
• MMP-9  
• IL-2RA 
• TIMP-1  
• IL-6RA 
• TIMP-4 
• IL-17RA 
• GP6 
• TNF-alpha R1/R2 
• sST-2 
• ANP 
• hsTroponin 
• MCP1  
• Galectin-3 
• CT1  
• PRA 
• GDF15 
• uPAR 
• TR-AP 
• CD163 
• E/P-Selectins 
• uPA 
• vWF 
•  
• Cystatin B 
• PON3 
• TF-P1 
 
12.4.5 Serum BNP and NT-proBNP 
NP measurements required for eligibility will be based on levels measured within the 
last 6 months or at screening.  
 
Serum BNP from the peripheral circulation will be measured using the Alere Triage® 
BNP test, a POC fluorescence immunoassay. Several drops of EDTA anticoagulated 
whole blood or plasma is added to the sample port of the test device which is then 
inserted in to the meter. The concentration of BNP in the specimen is directly 
proportional to the fluorescence detected. The results are displayed on the meter 
screen approximately 15 minutes from the addition of the specimen. 
 
Serum NT-proBNP from the peripheral circulation will be measured by the St Vincent’s 
Healthcare Group Laboratory according to standard hospital policy.  
 
  
12.4.6 Medical history 
The subject’s medical history will be recorded at the screening visit. 
 
12.4.7 Demographics 
The subject’s date of birth, gender and race will be recorded at the screening visit. 

               
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12.4.8 Physical exam 
A short physical exam will include the examination of general appearance and a 
cardiac exam at every visit. Information will be recorded in the CRF. Significant 
findings that are present prior to the start of study drug must be included in the relevant 
section of the subject’s CRF. Significant findings made after the start of study drug 
which meet the definition of an AE must be recorded on an AE form in the subject’s 
CRF. 
 
12.4.9 Vital signs 
Vital signs will be assessed at every visit. This will include BP and pulse 
measurements. BP will be measured by using a standard sphygmomanometer with 
an appropriate size cuff and the non-dominant arm in the sitting position after 5 
minutes of rest. This BP (and not 24h ABPM) will be used to confirm eligibility and 
inform dosing decisions. 
 
12.4.10 
Height, weight and waist/hip circumference 
Height in centimetres (cm) will be measured at Visit 2 (baseline). Body weight (to the 
nearest 0.1 kilogram [kg] in indoor clothing without shoes) and waist/hip circumference 
(at natural waistline, which is located above the belly button and below the rib cage; 
start at one hip and wrap the tape measure around the rear, making sure the tape is 
over the largest part of the buttocks) (to the nearest centimetre [cm] in indoor clothing) 
will be measured at Visit 2 (baseline), Visit 8 (month 9) and Visit 11 (EOS).  
 
12.4.11 
Ambulatory blood pressure monitoring (ABPM) 
ABPM will be measured at Visit 2 (baseline), Visit 8 (month 9) and Visit 11 (EOS).  
The device employed for ABPM analysis will be the SpaceLab 90207 oscillometric 
device. Depending on arm circumference, two standard cuff sizes will be used with 
application to the non-dominant arm. Subjects will be instructed to go about their usual 
activities with minimal restrictions. The systolic blood pressure (BP), diastolic BP, and 
heart rate of each subject will be automatically measured every 30 minutes for 24 
consecutive hours with a properly calibrated SpaceLab 90207 device. The device will 
be fitted and removed by a cardiovascular technician/nurse blinded to study treatment 
allocation. If quality criteria are not met, one repeat measurement will be allowed 
during the following 1–2 month period. Nocturnal dipping is defined as subjects with a 
more than 10% fall in nocturnal BP relative to daytime values. Non-dipping is defined 
as a less than 10% nocturnal fall in BP. 
 
12.4.12 
Pregnancy test 

               
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A dipstick urinary pregnancy test will be carried out on all women of childbearing 
potential at each study visit. 
 
12.4.13 
Electrocardiography (ECG) 
A standard 12-lead ECG (after 5 minutes rest) will be performed (at Visit 2 (baseline), 
Visit 8 (month 9) and Visit 11 (EOS)) using appropriate procedures (i.e. paper speed 
25 mm/sec, amplitude 10 mm/mV, at least 10 seconds recording available for 
measurement) and the use of an automatic recorder with the capacity for digital signal 
processing.  The heart rate will be measured, and relevant abnormalities regarding 
cardiac rhythm, conduction and repolarisation parameters such as QT prolongation or 
atrio-ventricular block, will be recorded. A copy of the print-out will be kept in the 
subjects study file.  The results will be assessed within the CRF as within normal limits, 
abnormal but not clinically significant or abnormal and clinically significant.  
 
 
12.4.14 
Echo-Doppler studies 
Echocardiography will be performed at Visit 2 (baseline), 8 (month 9) and 11 (EOS) to 
assess myocardial function. This will be performed by a designated experienced 
echocardiographer who will be blinded as to treatment assignment.  
LAVI measurements required for eligibility (LAVI >28 mL/m2) will be based on 
echocardiograms performed within the last 6 months. If a LAVI measurement from the 
last six months is not available, an additional echocardiography may be performed at 
the screening visit. If an echo is performed at the screening visit, this can be used for 
the baseline visit (unless using clinical judgement, the investigator decides that 
another echo is necessary). A baseline echo must be performed within 90 days prior 
to baseline visit. 
The following parameters will be reported: 
- Left ventricular ejection fraction  
- LAVI 
- E/A ratio  
- E wave deceleration time 
- E/E’ 
- Isovolumetric relaxation time  
- Pulmonary venous flow analysis  
- Tissue Doppler studies 
 
Standard two-dimensional, targeted M-Mode and Doppler Echocardiographic 
measurements will be obtained with the subject lying in the left lateral position. M-
mode measurements will be taken according to the guidelines from the American 
Society of Echocardiography. Left ventricular ejection fraction will be calculated using 
the Simpson’s biplane method. The following pulsed Doppler measurements from 3 
consecutive cardiac cycles will be obtained in the apical view with a cursor at mitral 

               
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valve inflow: maximal early (E) and late (A) transmitral velocities in diastole and E 
wave deceleration time. Isovolumetric relaxation time will be measured in the apical 
four chamber view by continuous wave Doppler placed between the mitral inflow area 
and left ventricular outflow tract. Left ventricular filling pressures were noninvasively 
assessed through analysis of the ratio of peak E-wave (E) to maximum velocity of 
lateral mitral valve annulus (E’) ratio (E’/E) measured at the lateral mitral valve 
annulus. An experienced sonographer blinded to treatment allocation will carry out all 
echocardiography imaging and reporting. 
 
Tissue Doppler imaging will be used to record longitudinal velocities of the mitral 
anulus. The velocities will be recorded from the apical four-chamber view by placing a 
2-5mm sample volume of the lateral portion of the mitral anulus. The E' velocity will be 
recorded and the ratio between E and E' (E/E') calculated. 
 
In assessing changes over 18 months of left ventricular structure and function as part 
of the secondary objectives of the study, a E/E'> 15 is taken as evidence of diastolic 
dysfunction. An E/E' < 8 excludes the diagnosis. An E/E' ratio ranging from 8 to 15 is 
considered suggestive but non-diagnostic evidence of left ventricular diastolic 
dysfunction and needs other imaging evidence of diastolic dysfunction. These can 
consist of blood flow Doppler of mitral valve or pulmonary veins, echo measures of LV 
mass index or left atrial volume index, electrocardiographic evidence of atrial 
fibrillation. 
 
12.4.15 
Cardiac magnetic resonance imaging (cMRI) 
Overview of cMRI in PARABLE 
MRI imaging will be performed at baseline and 18 months of the study to assess 
myocardial structure and function. Measures of interest will include LAVI, left 
ventricular mass index, ejection fraction and aortic distensibility.  (If the patient had an 
MRI in the previous six weeks, then there is no need for a repeat MRI at baseline).   
Changes in cMRI measures of LAVI will comprise the primary endpoint of the study. 
Imaging will be carried out in St Vincent’s Private Hospital. See ‘Cardiac MRI for the 
PARABLE study’ Work Instruction (HBT-GCP-WI-01) for details on how to refer 
subjects.  cMRI analysis will be performed by a designated radiologist assigned to this 
study who will be blinded to the treatment assignment.  
  
 
Image acquisition and analysis 
Imaging will be performed using a Phillips 1.5T scanner or a Siemens Avanto 1.5 T 
scanner equipped with a phased-array coil placed over the praecordium.  Patients will 
be scanned in the supine position, and after localizing scans, ECG-gated steady state 
free precession (SSFP) cine images of the heart will be acquired at end expiration in 
three standard long planes (vertical and horizontal long axes and 3 chamber view). 
Subsequently, multiple short-axis (SA) slices will be acquired from the base to the 
apex of the heart, with slice thickness of 8 mm and interslice gap of 2 mm, creating 
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Images will be analysed offline by an experienced operator familiar with clinical CMR 
& with the analysis methods described.  Analysis will be performed on each scan using 
CMR tools (Cardiovascular Imaging Solutions, London, UK) or Argus Syngo MR 
software (Siemens Medical Imaging, Erlangen, Germany) as follows: 
 
The multislice, short-axis cine datasets will be analysed to calculate LV, LA and right 
ventricular (RV) volumes and masses. Endo- and epicardial borders will be traced 
manually on end-diastolic and end-systolic frames in contiguous short-axis slices. Left 
ventricular end-diastolic (EDV) and end-systolic volumes will be calculated using 
summation of area × (slice thickness + interslice gap) for each slice (Simpson’s 
method), which will allow calculation of LVEF and LV mass. The end systolic frame is 
considered to be the frame in which the LV cavity visually appears smallest.  At the 
base of the heart, slices are considered to be within the LV at end diastole and end 
systole if the cavity is surrounded by 50% or more of ventricular myocardium. If the 
basal slice contains both ventricular and atrial myocardium, contours will be drawn up 
to the junction and joined by a curved line through the blood pool. Papillary muscles 
will be excluded from LV volume measurements and included in mass calculations. 
The inter-ventricular septum is considered part of the LV. Left atrial and right 
ventricular volumes, mass, and EF will be calculated in a similar fashion.  All 
measurements will be indexed to body surface area.  
 
Further analysis of the left atrium will be performed in the long axis views. Left atrial 
maximum volume (the frame just before mitral valve opening) and minimum volume 
(the frame just after mitral valve closure) will be measured in both two- and four-
chamber views by manually tracing the LA endocardial border. The anterior border is 
at the mitral annular plane and the posterior border at the ostia of the pulmonary veins, 
excluding the LA appendage. Left atrial volumes will be calculated using the area–
length method (volume ¼ 0.85 × area2/length) and LA emptying function (LAEF) will 
be calculated using the formula: [(LA max - LA min)/LA max] × 100%.  We will also 
calculate LA total emptying volume (reservoir function) using (LA max - LA min) and 
LA conduit volume using (LV stroke volume – LA total emptying volume).   
 
The imaging process will be synchronised with the R wave of the ECG. Images will 
be acquired during each heartbeat in mid-diastole during breath hold. A non-selective 
inversion prepulse will be used in order to accentuate the difference between T1 
images in normal and abnormal myocardium. Segmented T1 weighted fast gradient 
echo sequence images will be conducted after inversion delay time.  LV long axis and 
contiguous short axis slices is acquired using an inversion delay time of 200-
380ms. Images will be analysed for the presence of abnormal enhancement by an 
experienced operator. A Radiology Report will be provided to the Investigator for filing 
in the Subject Study File. 
 
 
12.4.16 
Concomitant medications. Potential drug interactions with LCZ696 
and/or valsartan therapy 
At every visit the Investigator should question the study subject on any changes in 
concomitant medications (new medications or changes in dose of existing 

               
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medications). The following is a list of medications that have the potential to interact 
with LCZ696 and/or valsartan: 
• ACE Inhibitors. Due to the risk of angioedema, LCZ696 or valsartan should not 
be used concomitantly with an ACE inhibitor. LCZ696 must not be initiated until 
36 hours after taking the last dose of ACE inhibitor therapy. If LCZ696 is 
stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last 
dose of LCZ696.  
• Angiotensin receptor blocker: LCZ696 should be not co-administered with an 
ARB due to the angiotensin II receptor blocking activity of LCZ696.  
• Aliskiren: LCZ696 or valsartan must not be administered with aliskiren  
• Lithium: Reversible increases in serum lithium concentrations and toxicity have 
been reported during concurrent use of ACE inhibitors. Due to the lack of 
experience with concomitant use of valsartan and LCZ696 and lithium, this 
combination is not recommended. If the combination proves necessary, careful 
monitoring of serum lithium levels is recommended 
• Antihypertensive agents: LCZ696 and valsartan may increase the effects of 
other agents with antihypertensive properties (e.g. guanethidine, methyldopa, 
vasodilators, ACE inhibitors, beta-blockers, calcium channel blockers, diuretics 
and direct renin inhibitors). 
• Pressor amines (e.g. noradrenaline, adrenaline). Possible decreased response 
to pressor amines.  
• Non-steroidal anti-inflammatory drugs (NSAIDs): In elderly subjects, volume 
depleted subjects (including those on diuretic therapy), or subjects with 
compromised renal function, concomitant use of LCZ696/valsartan and 
NSAIDs including selective cyclooxygenase 2 (COX-2) inhibitors, may lead to 
an increased risk of worsening of renal function. Concomitant use of valsartan 
and NSAIDs may also lead to an increase in serum potassium.   Therefore, 
monitoring of renal function is recommended when initiating or modifying 
treatment in subjects in LCZ696 or valsartan who are taking NSAID 
concomitantly. Co-administration of valsartan and NSAIDs may attenuate the 
antihypertensive effect of valsartan.  
• Medications known to raise potassium levels: Potassium-sparing diuretics (e.g., 
spironolactone, triamterene, amiloride), potassium supplements, aldosterone 
antagonists, salt substitutes containing potassium and other substances that 
may increase potassium levels (heparin etc.) should be used with caution due 
to the increased risk of hyperkalaemia. If a medicinal product that affects 
potassium levels is considered necessary, monitoring of potassium plasma 
levels is advised. 
• Bile acid sequestering agents (e.g. cholestyramine and colestipol): use is 
prohibited to avoid interference with study drug absorption 

               
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• Phosphodiesterase inhibitors: Due to more than additive BP reduction, caution 
is recommended when co-administering LCZ696 with sildenafil or other PDE-5 
inhibitors (tadalafil, vardenafil etc). 
• Statins: Concomitant administration of LCZ696 and atorvastatin may increase 
the plasma concentration of atorvastatin due to the OATP1B1 and OATP1B3 
inhibitory properties of sacubitril (following concomitant administration of 
LCZ696 and atorvastatin, the AUC of atorvastatin and its active metabolites, o-
hydroxyatorvastatin and p-hydroxyatorvastatin was increased by up to 34%). 
Caution is recommended when co-administering LCZ696 with atorvastatin or 
other statins that are substrates of OATP1B1 and OATP1B3, such as 
simvastatin, pravastatin and/or pitavastatin. Monitor the patient carefully for 
adverse effects of statin therapy (e.g. muscular side-effects (e.g. myopathy, 
myositis, myalgia), GI disturbances, altered LFTs, sleep disturbance, headache, 
dizziness). 
• Furosemide: LCZ696 may reduce the plasma levels of furosemide which may 
result in a reduced diuretic response. Monitor patient carefully.  
• Nitrates: Co-administration of LCZ696 with nitroglycerine may be associated 
with an increased reduction in heart rate compared to the administration of 
nitroglycerine alone. In general, no dose adjustment is needed. 
• Metformin: LCZ696 may reduce the plasma concentrations of metformin. The 
clinical relevance of this finding is unknown. Therefore, when initiating therapy 
with LCZ696 in patients receiving metformin, the clinical status of the patients 
sould be evaluated. 
• Other: Co-administration of rifampicin, ciclosporin, tenofovir, cidofovir or 
ritonavir may increase the systemic exposure of these drugs to valsartan. 
Exercise appropriate care when initiating or ending concomitant treatment with 
such drugs. 
 
 

               
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12.4.17 
Questionnaires 
1. EuroQOL-5D (EQ-5D): EQ-5D is an instrument used to assess the current 
health status of subjects. It consists of five domains and one visual analogue 
scale. This instrument assesses morbidity, self-care, usual activity, pain and 
anxiety and depression of subjects. It is administered in less than 5 minutes 
(See Appendix 3).  
2. Standardised Mini-Mental State Examination (SMMSE): The purpose of the 
SMMSE-2 is to screen for cognitive impairment. It is a 30 point test, 
administered in approximately 10 minutes, and measures various domains of 
cognitive function including orientation to time and place; registration; 
concentration; short-term recall; naming familiar items; repeating a common 
expression; and the ability to read and follow written instructions, write a 
sentence, construct a diagram, and follow a three-step verbal command.(See 
Appendix 2).  
3. Montreal Cognitive Assessment (MoCA) (Version 7.3): MoCA is a 30 point test, 
administered in approximately 10 minutes to assess several cognitive domains 
including short-term memory recall, visuospatial abilities, executive functions, 
attention, concentration and working memory, language, orientation and place 
(See Appendix 1). The administration and scoring instructions are outlined in 
appendix 4). 
All three questionnaires will be completed at Visit 2 (baseline), Visit 8 (month 9) and 
Visit 11 (EOS). The SMMSE and MoCA questionnaires shall also be administered five 
years after the end of study visit for each patient. A record shall be made in the clinic 
database to ensure follow-up of this requirement. Any illnesses identified following the 
administration of a questionnaire should be managed appropriately. Questionnaires 
are available in English only. Subjects who are not capable of completing the 
questionnaire in English are exempt from completing the questionnaires.  
 
13. STUDY DRUG 
LCZ696, valsartan and matching placebos are provided by Novartis Ireland Ltd to 
the distributor company, Almac. HBT-GCP-SOP-17 ‘Study Drug Management for the 
PARABLE Study’ outlines the procedure for the allocation/dispensing of the study 
drug.  
13.1 
Blinding 
LCZ696, valsartan and matching placebos are provided by Novartis (via the distributor 
company, Almac). All tablets (LCZ696 50mg, 100mg and 200mg) and valsartan 
(40mg, 80mg and 160mg) have different shapes and colours. Therefore, this study is 
a double-blind, double dummy to ensure the blinding of patients and investigators 
during the entire course of the study. To maintain the blinding, subjects will be required 
to take their assigned active treatment tablet along with placebo matching the opposite 

               
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treatment twice daily (morning and evening) in addition to their conventional 
concomitant therapy (except for ACE inhibitor or ARB, which will be substituted with 
study drug). 
 
The following are provided by Novartis (via Almac): 
 
• Phase 1 
o LCZ696 50mg film-coated tablets (LCZ696 Phase 1) 
o Placebo to match LCZ696 50mg film-coated tablets (placebo matching 
LCZ696 Phase1)  
o Valsartan 40mg film-coated tablets (Valsartan Phase 1) 
o Placebo to match Valsartan 40mg film-coated tablets (placebo matching 
LCZ696 Phase 1)  
 
• Phase 2 
o LCZ696 100mg film-coated tablets (LCZ696 Phase 2) 
o Placebo to match LCZ696 100mg film-coated tablets (placebo matching 
LCZ696 Phase 2)  
o Valsartan 80mg film-coated tablets (Valsartan Phase 2) 
o Placebo to match Valsartan 80mg film-coated tablets (placebo matching 
LCZ696 Phase 2)  
 
• Phase 3 
o LCZ696 200mg film-coated tablets (LCZ696 Phase 3) 
o Placebo to match LCZ696 200mg film-coated tablets (placebo matching 
LCZ696 Phase 3) 
o Valsartan 160mg film-coated tablets (Valsartan Phase 3) 
o Placebo to match Valsartan 160mg film-coated tablets (placebo 
matching LCZ696 Phase 3)  
 
13.2 
Study drug supply and storage  
The study drug and matching placebo are supplied by Novartis using Almac as the 
distributor. The investigators will monitor the stock of study drug and notify the sponsor 
when stocks are running low. It is the responsibility of the sponsor to re-order supplies 
from Almac when required. Study drug will be delivered directly to the investigator site 
(The STOP-HF Service) at a pre-arranged time.   
 
The study drug will be stored in a secure, temperature monitored cabinet in the STOP-
HF Service. It is the responsibility of the investigator staff to ensure the study drug is 
stored securely and correctly. Investigational products are for investigational use only 
are to be used only within the context of this study. 
 
 

               
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13.3 
Accountability of the study drug 
The investigator site will maintain an accurate record of the shipment and dispensing 
of each study drug in a drug accountability log (HBT-GCP-FM-22; ‘Study Drug 
Inventory and Subject Assignment Log’). Monitoring of drug accountability will be 
performed by the monitor during site visits and at the completion of the trial. Subjects 
will be asked to return any unused study drug and packaging at each visit, at the time 
of study drug discontinuation and at the end of the study. All patient returns should be 
recorded in the CRF and in the Study Drug Returns Log (HBT-GCP-FM-23)  
 
At the conclusion of the study, and as appropriate during the course of the study, the 
Investigator will return all unused study drug, including opened and unopened 
packaging, and a copy of the completed Study Drug Returns Log to the sponsor 
according to the instructions provided by them. 
 
13.4 
Dispensing the study drug 
All study drug is provided to the investigator site labelled. Medication labels are in 
English and comply with the legal requirements for clinical trials in Ireland.  
 
At each visit, study subjects will be provided with two medication ‘kits’; one containing 
the study drug (LCZ696 or valsartan) and one containing placebo drug corresponding 
to their assigned treatment arms and dose level, sufficient to last until the next 
scheduled visit. Records of each dispensing shall be maintained using a drug 
accountability log (HBT-GCP-FM-22; ‘Study Drug Inventory and Subject Assignment 
Log’).  
 
Table 2 and 3 below summarises the study drug that will be dispensed at the various 
clinic visits for subject on the standard dosing schedule and the lower dosing schedule 
respectively. (A lower starting dose of LCZ696 50mg twice daily or valsartan 40mg 
twice daily will be used for subjects not currently taking an ACE inhibitor or ARB, for 
subjects previously taking low doses of these agents (as per Investigator judgement) 
and for subjects with a systolic BP of ≥100mm to 110mmHg at screening or baseline).  
 
The procedure for the dispensing/allocation of medication pack is described in HBT-
GCP-SOP-17 ‘Study Drug Management for the PARABLE Study’. 
 
Subjects will be required to take the study drug and matching placebo twice a day 
(morning and evening) for the duration of the study. Patients will be instructed to take 
their morning dose at approximately 08.00 and their evening dose at approximately 
19.00. The medications should be taken with a glass of water with or without food. If 
the subject misses a dose, he/she should take it as soon as possible, unless if it is 
almost time for the following scheduled dose. In this case, the subject should skip the 
missed dose and return back to his/her regular study drug administration schedule. 
The patient should be instructed to contact the Investigator if he/she is unable to take 
the study drug as proscribed for any reason. 
 
 
 

               
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Table 2. Study drug dispensed (standard dosing schedule) 
Visit # 
Dose 
level 
LCZ696 
Valsartan 
1 
(screening) 
- 
- 
- 
 
2 
(Day 0  
/baseline) 
 
2 
• 
LCZ696 100mg tablets  
• 
Placebo to match 
Valsartan 80mg tablets 
• 
Valsartan 80mg tablets  
• 
Placebo to match LCZ696 
100mg tablets  
3-11 
(Day 14-
EOS) 
3 
• 
LCZ696 200mg tablets  
• 
Placebo to match 
Valsartan 160mg tablets  
• 
Valsartan 160mg tablets  
• 
Placebo to match LCZ696 
200mg tablets 
 
Table 3. Study drug dispensed (lower dosing schedule) 
Visit # 
Dose 
level 
LCZ696 
Valsartan 
1 
(screening) 
- 
- 
- 
 
2 
(Day 0 / 
baseline) 
 
1 
• 
LCZ696 50mg tablets  
• 
Placebo to match 
Valsartan 40mg tablets  
• 
Valsartan 40mg tablets  
• 
Placebo to match LCZ696 
50mg tablets  
3 
(Day 14) 
2 
• 
LCZ696 100mg tablets  
• 
Placebo to match 
Valsartan 80mg tablets  
• 
Valsartan 80mg tablets  
• 
Placebo to match LCZ696 
100mg tablets 
4-11 
(Day 28-
EOS) 
3 
• 
LCZ696 200mg tablets  
• 
Placebo to match 
Valsartan 160mg tablets  
 
• 
Valsartan 160mg tablets  
• 
Placebo to match LCZ696 
200mg tablets 
 
 
 
13.5 
Assessment of compliance 
Compliance will be assessed by the Investigator at each visit using pill counts and 
information provided subject and recorded in the CRF. The Investigator will counsel 
the subject if compliance is below 80%.  
 
13.6 
Overdose of study treatment 
Any accidental overdose with the study drug by a study subject or a person in his/her 
family must be notified to the Sponsor, whether or not it has medical consequences 
(serious or non-serious AE, or absence of signs and symptoms).  
 
 

               
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13.7 
Permitted study drug dose adjustment and interruptions 
Every attempt should be made to maintain subjects on the target dose level (i.e. 
LCZ696 200mg and Valsartan 160mg) for as long a duration as possible throughout 
the trial. If, however, in the opinion of the Investigator, the subject does not tolerate 
the target dose of study drug (Phase 3), the Investigator should consider whether non-
disease-modifying medication (e.g., calcium channel blockers, diuretics, nitrates, 
alpha blockers) can be reduced, before considering reducing the dose of the study 
drug to the next lower dose phase.  
 
If down titration is necessary, the subject should be down-titrated to the next lower 
dose phase. The subject may continue receiving the lower dose phase for a 
recommended period of 1 to 4 weeks before re-challenging the subject with the next 
higher dose phase. For example, a subject who encounters tolerability problems at the 
target dose level (dose phase 3), should receive the study drug at dose phase 2 for 1 
to 4 weeks. Then, he/she should be re-challenged with up-titration back to dose phase 
3. If the tolerability issues are not alleviated despite down-titration by one dose phase, 
the Investigator may lower the study drug dose further to the next lower phase for 1 to 
4 weeks, up to temporary withdrawal of the study drug. Again, once stable, the subject 
should be rechallenged with up-titration to the next higher dose phase every 1 to 4 
weeks in an attempt to bring back the subject gradually to the target study drug dose 
level (dose phase 3). The Investigator may choose the next dose phase for down- or 
up-titration according to his or her judgment. Dose phase 1 or 2 could be maintained 
if the Investigator considers that the subjects condition would not allow any further up-
titration to the target dose of study medication (phase 3). In this case it would be 
acceptable to maintain the subject at dose phase 1 or phase 2, whichever is the higher 
and tolerated dose phase by the subject. 
 
If needed, the study drug may be stopped completely, but the subject should continue 
to attend the study visits and be followed until the completion of the study. Ultimately 
the goal is to keep the subject on the highest study drug dose possible for as long as 
possible and to follow the subject in the study as long as possible. Study drug dose 
level adjustments should mainly be based on overall safety and tolerability with special 
focus on a) hyperkalaemia; b) symptomatic hypotension; and c) clinically significant 
decrease in eGFR/increase in serum creatinine (see Appendices 7-10 for treatment 
guidelines for hyperkalaemia, management of BP, and renal dysfunction). All dosage 
adjustments should be recorded in the subjects CRF. 
 
13.8 
Study drug restart after temporary treatment interruption 
Study drug should be reintroduced in those who temporarily discontinue it as soon as 
medically justified in the opinion of the Investigator and at the most appropriate and 
allowable dose level per his/her medical judgment. Should the subject not tolerate the 
re-start study drug dose level, he/she may be down-titrated again (if appropriate) or 
discontinue the study medication again and a new attempt to up-titrate or reintroduce 
the study drug could be considered by the Investigator as soon as medically justified 
in his/her medical judgment. 
 
 

               
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13.9 
Study drug discontinuation and premature withdrawal of subjects 
After randomisation, study drug discontinuation for any reason does not constitute 
withdrawal from the study and should not lead to the subject being withdrawn from the 
entire study. On the contrary, even subjects who have stopped taking study drug are 
expected to attend all the protocol specified study visits and perform all assessments 
as stipulated in the visit schedule (Table 2).  If the subject does not attend the study 
visits, follow-up should continue according to the specified schedule by telephone to 
determine if any of the health events/endpoint prespecified in the protocol has 
occurred, except in the case that the subject specifically refuses such follow-up and 
withdraws his/her consent.  The emergence of the following circumstances will require 
study drug discontinuation:  
 
• Subject wishes to withdraw from study with or without stated reason 
• Pregnancy 
• Investigator thinks that continuation would be detrimental to the subject’s well-
being   
• Suspected occurrence of angioedema  
 
Study medication may be discontinued at the Investigator’s discretion if any of the 
following occurs:  
 
• Any subject who experiences an AE may be withdrawn at any time from the 
study at the discretion of the Investigator. However, the following AE warrants 
immediate withdrawal;   
o Angioedema: if angioedema (including swelling of the larynx and glottis, 
causing airway obstruction and/or swelling of the face, lips, pharynx, 
and/or tongue) 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. 
Study drug must not be re-administered. 
o Serious hypersensitivity reactions  
• Depending on the serum potassium, blood pressure, or eGFR, subjects may 
need to have their study drug dose or the dose of another concomitant 
medication reduced or discontinued, or, if appropriate, have potentially 
contributing agents adjusted. Please refer to Appendices 7-10 for treatment 
guidelines for hyperkalaemia, hypotension, or renal dysfunction.  
 
In the case of study drug discontinuation, the subject should continue to complete all 
scheduled study visits and procedures. If the subject refuses, he/she should be 
contacted by telephone in place of protocol-specified visits unless the subject 
expressly refuses such contacts. A record of all attempts to contact the subject should 
be recorded in the Telephone Contact Log in the CRF.  
 
If a subject is withdrawn from the study due to an AE, the AE should be noted on the 
appropriate CRF and the subject’s progress should be followed until the AE is 
resolved. This follow-up may occur by phone. 
 
 

               
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13.10 
Emergency unblinding of treatment assignment 
Emergency unblinding should only be undertaken if knowledge of the subject's trial 
treatment affects the immediate, urgent medical treatment of the subject. Most often, 
study drug discontinuation and knowledge of the possible treatment assignments are 
sufficient to treat a study subject who presents with an emergency condition.  
 
If the treatment allocation needs to be revealed, contact the WebEz Helpdesk as per 
the process outlined in the SOP ‘Unblinding of the Study Drug during PARABLE by 
the Investigator’ (HBT-GCP-SOP-12) 
 
Study drug must be discontinued after emergency unblinding. Study drug also must 
be discontinued for any subject whose treatment code has been broken inadvertently 
or for any non-emergency reason and the investigator becomes aware of the treatment 
allocation.  
 
13.11 
Definition of end-of-trial 
 
The end-of-trial is the date of the last visit of the last subject enrolled in the 9-month 
follow-up sub-study.  
 
Other end of study considerations 
The Sponsor or Principle Investigator has the right at any time to terminate the study 
for clinical or administrative reasons. In terminating the study, the Sponsor and the 
Principle Investigator will ensure that adequate consideration is given to the protection 
of the best interests of the participants. 
 
The end of the study will be reported to the Ethics Committee (EC) and Regulatory 
Authority within 90 days, or 15 days if the study is terminated prematurely.  The 
Investigators will inform subjects and ensure that the appropriate follow-up is arranged 
for all involved. 
 
A summary report of the study will be provided to the sponsor (Novartis), the EC and 
HPRA within 12 months of the end of the study. This is a legal requirement. The final 
study report shall include a full summary of safety and efficacy information from the 
study and shall comply with the established principles and standards for the 
corresponding format according to ICH-GCP.  
 
 

               
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14. SAFETY REPORTING 
The safety and tolerability of the study drugs will be evaluated starting from the 
administration of the study drug (Visit 2) through to EOS visit.   Information regarding 
all AEs will be collected at each study visit based on information provided 
spontaneously by the subject and/or through questioning of the subject. 
 
14.1 
Definitions 
Adverse event (AE) 
Any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign (including 
an abnormal laboratory finding, for example), symptom or disease temporally 
associated with the use of a medicinal product, whether or not considered related to 
the medicinal product.  
Worsening of a pre-existing medical condition (e.g., cancer, diabetes, migraine 
headaches, gout) should be considered and AE if there is either an increase in 
severity, frequency, or duration of the condition or an association with significantly 
worse outcomes.  Abnormal signs and symptoms identified during the physical and 
cardiac exam may also constitute an adverse event if they were not present at 
baseline. Interventions for pre-treatment conditions (e.g., elective cosmetic surgery) 
or medical procedures that were planned before study enrolment are not considered 
AEs.  
The Investigator is responsible for reviewing laboratory test results and determining 
whether an abnormal value in an individual study subject represents a change from 
values before the study. In general, abnormal laboratory findings without clinical 
significance (based on the Investigator’s judgment) should not be recorded as AEs; 
however, laboratory value changes requiring therapy or adjustment in prior therapy 
are considered AEs. 
All AEs are recorded in the CRF and on the Adverse Event Report Form within the 
CRF.  
 
Adverse reaction (AR) 
All untoward and unintended responses to a medicinal product related to any dose. The 
phrase ‘responses to a medicinal product’ means that a causal relationship between a 
study 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 study medication qualify as adverse reactions.   
All ARs are recorded in the CRF and on the Adverse Event Report Form within the 
CRF.  

               
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Serious adverse event (SAE) 
Any untoward medical occurrence or affect that at any dose:  
- 
results in death,  
- 
is life-threatening* 
- 
requires hospitalisation¥ or prolongation of existing hospitalisation 
- 
results in persistent or significant disability or incapacity 
- 
is a congenital anomaly or birth defect 
- 
important medical events** 
 
¥ A hospitalisation meeting the regulatory definition for “serious” is any inpatient hospital admission that 
includes a minimum of an overnight stay in a health care facility. Any AE that does not meet one of the 
definitions of serious (e.g., A & E visit, outpatient surgery, or requires urgent investigation) may be 
considered by the Investigator to meet the “other significant medical hazard” criterion for classification 
as a serious adverse event.  
*Regarding a life-threatening event, this refers to an event in which the subject was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe.  
 
**Some medical events may jeopardise the subject or may require an intervention to prevent one of the 
above characteristics/consequences. Such events (hereinafter referred to as ‘important medical events’) 
should also be considered as ‘serious’ in accordance with the definition.  
 
All SAEs are recorded in the patients’ medical notes, the CRF, on the Adverse Event 
Report Form within the CRF and on a Serious Adverse Event Report Form (HBT-GCP-
FM-21).  
 
Severe adverse events 
The term ‘severity’ is used here to describe the intensity of a specific event. This has to 
be distinguished from the term ‘serious’.  
 
The severity of the AE should be graded according to the following definitions: 
o Mild: An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities 
o Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities 
o Severe: An event that prevents normal everyday activities 
 
Suspected unexpected serious adverse reactions (SUSAR) 
An adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g. Investigator’s brochure for an unauthorised investigational 
medicinal product or summary of product characteristics (SmPC) for an authorised 
medicinal product. 
 
 
 

               
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14.2 
Adverse event assessment 
Assessment of seriousness 
The Investigator should make an assessment of seriousness (see definition of 
seriousness in section 14.1). 
 
Assessment of casualty 
All adverse events judged by either the Investigator or the Sponsor as having a 
reasonable suspected causal relationship to an investigational medicinal product 
qualify as adverse reactions. 
 
As the PARABLE study is blinded, the case should be assessed for causality 
assuming that the study drug under investigation caused the reaction (i.e. LCZ696).  
 
The causality assessment given by the Investigator should not be downgraded by the 
Sponsor. 
 
The Investigator/Sponsor must make an assessment of whether the AE/SAE is likely 
to be related to treatment according to the following definitions: 
 
• Unrelated: Where an event is not considered to be related to the study 
medication. 
 
• Possible: Although a relationship to the study medication cannot be completely 
ruled out, the nature of the event, the underlying disease, concomitant 
medication or temporal relationship make other explanations possible. 
 
• Probable: The temporal relationship and absence of a more likely explanation 
suggest the event could be related to the study medication. 
 
All AEs/SAEs judged as having a reasonable suspected causal relationship (e.g. 
possible, probable) to the study medication will be considered as ARs/SARs. 
 
All AEs/SAEs judged as being related (e.g. possibly, probably) to an interaction 
between the study medication and another medication will also be considered to be 
ARs/SAR. 
 
Alternative causes such as natural history of the underlying disease, concomitant 
therapy, other risk factors and the temporal relationship of the event to the treatment 
should be considered. 
 
 
 
 
 
 
 

               
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Assessment of severity 
The Investigator will make an assessment of severity for each AE/SAE and record this 
on the Adverse Event Report Form according to one of the following categories: 
 
• Mild: An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with every day activities. 
 
• Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities. 
 
• Severe: An event that prevents normal everyday activities. 
 
Assessment of expectedness 
The expectedness of an adverse reaction will be determined by the Sponsor according 
to the reference document which in this study is the Investigator's brochure for LCZ696 
and the SmPC for valsartan.  
 
14.3 
Emergency unblinding procedures 
See section 13.10.  
 
14.4 
Follow up of adverse events 
It will be left to the Investigators clinical judgement whether or not an AE is of sufficient 
severity to require the subject’s removal from treatment. A subject may also voluntarily 
withdraw from treatment due to what he or she perceives as an intolerable AE. If either 
occurs, the subject must undergo an EOS assessment and be given appropriate care 
under medical supervision until symptoms cease or the condition becomes stable. 
All SAEs that are encountered during the reporting period will be followed to their 
resolutions, until the Investigator assesses them as stable. 
AEs considered related to the study medication as judged by the Investigator or 
Sponsor will be followed until resolution or until the subject/event is considered stable.  
All related AEs that result in a subject’s withdrawal from the study or are present at the 
end of the study, should be followed up until a satisfactory resolution occurs. 
Any pregnancy occurring during the clinical study and the outcome of the pregnancy 
should be recorded and followed-up for congenital abnormality or birth defect. 
 
 
 
 

               
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14.5 
Documentation of adverse events by the Investigator 
All AEs occurring during the study, observed by the Investigator or reported by the 
subject, whether or not attributed to the study medication are recorded in the 
appropriate section of the CRF. 
All AEs are also recorded on an Adverse Event Report Form within the CRF.  
In addition to recording the AE in the CRF and on an Adverse Event Report Form, all 
SAEs must be recorded on a Serious Adverse Event Report Form (HBT-GCP-FM-21). 
and in the patients’ medical file. 
The following information shall be recorded on the Adverse Event Report Form. 
• AE event term 
• Whenever possible, recognized medical terms will be used to describe 
AEs rather than colloquialisms (for example, “influenza” rather than “flu”) 
and abbreviations will be avoided. 
• A description of the event  
• Dates of onset and resolution  
• The maximum severity of the AE (i.e. mild, moderate or severe) 
• The relationship (causality) of the event to the study drug should be determined 
by the Investigator (Unrelated, possibly related, probably related) 
• Any drug action taken by the Investigator to resolve the event: 
o None  
o Dose reduced  
o Dose increased  
o Withdrawn permanently  
o Withdrawn temporarily 
o Unknown  
o Other (which can include concomitant medication given, non-drug 
therapy given or hospitalized etc).   
 
• Event outcome at resolution or time of last follow-up will be recorded as: 
o Recovered without sequelae  
o Recovered with sequelae  
o Not yet recovered  
o Unknown  
o Fatal  
 
• Seriousness. AEs shall be assessed as serious or non-serious according to 
the definition in section 14.1.   
AEs occurring secondary to other AEs (e.g. sequelae or complications) will be 
identified by the primary cause. A primary AE if clearly identifiable, generally 

               
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represents the most accurate clinical term to record. The Investigator will provide 
his/her opinion of which is the primary AE. 
 
14.6 
Reporting procedures for SAEs to the Sponsor 
See Appendix 7 for an overview of this procedure. 
All SAE information must be recorded on an SAE Report form and forwarded (by fax, 
email or in person) to the sponsor (Clinical Trial Project Manager) within 24 hours. 
Under no circumstances should this exceed 24 hours following knowledge of the SAE.  
Additional information received for a case (follow-up or corrections to the original case) 
need to be detailed on a new SAE form and sent expeditiously to the Sponsor. 
The Sponsor will keep detailed records of all adverse events which are reported to him 
by the Investigator or Investigators and perform an evaluation with respect to 
seriousness, causality and expectedness. If the Sponsor disagrees with the 
Investigators assessment, both the opinion of the Investigator and the Sponsor should 
be provided with the report. The Sponsor should NEVER downgrade any assessment 
made by the Investigator.  
 
14.7 
Reporting procedures for SUSARs to the EC and Regulatory 
authorities 
The Sponsor will report all SUSARs in parallel to both the competent authorities (the 
Health Products Regulatory Authority (HPRA) in Ireland) and the Clinical Trials module 
of the EudraVigilance database (EVCTM) and to the EC(s) concerned.  For HPRA 
reporting, an electronic transmission will be sent via EudraVigilance. 
 As a back-up measure during times of non-availability of the clinical trials project 
manager, the reporter shall report the SUSAR to the HPRA directly using the online 
report form at the following address: 
https://www.hpra.ie/homepage/about-us/report-an-issue/form2 
This arrangement has been agreed with the Pharmacovigilance Department of the 
HPRA. They have requested that all SUSARs be transmitted to them in a timely 
manner in order to facilitate internal HPRA review and onward reporting by the HPRA 
to EudraVigilance. The following timelines therefore, must be adhered to:  
• Any fatal/life threatening reports must reach the HPRA by Day 2.  
• All other SUSARs by Day 7.  
During any planned absences, the CTPM shall confirm in writing to the Principal 
Investigator and the Investigator team the process to be followed, including who to 
contact to carry out an assessment of expectedness. During any unplanned absences, 
the Research Director of the Heartbeat Trust should be contacted. 
For EC reporting to the St Vincent’s EC, a copy of the SAE Report Form along with a 
cover letter should be emailed to joan.mcdonnell@ucd.ie. 

               
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Timelines for reporting 
• Fatal or life-threatening SUSARs must be reported within 7 days.  
• SUSARs which are not fatal and not life-threatening are to be reported 
within 15 days.  
The Sponsor will also inform all Investigators concerned of relevant information about 
SUSARs that could adversely affect the safety of subjects. 
If the initial report is incomplete, e.g. if the Sponsor has not provided all the 
information/assessment within seven days, the Sponsor will submit a completed report 
based on the initial information within an additional eight days. 
If significant new information on an already reported case is received by the Sponsor, 
the clock starts again at day zero, i.e. the date of receipt of new information. This 
information will be reported as a follow-up report within 15 days. 
 
14.8 
SAE reporting to Novartis 
See Appendix 8 for an overview of this procedure. 
The Sponsor shall provide to Novartis details of all SAEs irrespective of causality 
within 24 hours of first notification of the SAE or subsequent follow-up information to 
the Sponsor.   
Initial and follow-up reports shall be emailed or faxed directly to the Novartis Safety 
Desk in Ireland: 
 
 
 
 
 
 
 
 
To facilitate Novartis’ compliance with the regulatory requirements, all suspected 
unexpected SAEs will be unblinded for regulatory reporting. 
The Sponsor shall support Novartis in the following-up of all SAEs. The Sponsor shall 
perform SAE reconciliation according to Novartis SOPs and processes on an ongoing 
basis throughout the study. 
SAEs will be reviewed on an ongoing basis by the Sponsor or its designee, with a 
summary included in the annual reports to regulatory agencies and analysis will be 
provided in the final study report. 
Novartis Ireland Limited 
Drug Safety and Epidemiology 
The Vista Building, Elm Park Business Park, 
Merrion Road, 
Dublin 4, D04, A9N6 
Tel: +353 1 2601255 
Fax: +353 1 2838777 
Email:  
CC: ct_processing.gbfr@novartis.com 
 

               
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14.9 
Annual reports and line listings  
In addition to the expedited reporting above, the Sponsor shall submit once a year 
throughout the clinical trial or on request, a safety report to the competent authority 
(the HPRA in Ireland) and EC. The annual safety report will be presented in the DSUR 
format as per ICH guideline E2F - Note for guidance on development safety update 
reports. This is a legal requirement. (See also SOP: HBT-GCP-SOP-09) 
The Sponsor shall provide the St Vincent’s EC with six monthly line listings of all SAEs 
(whether suspected or not, or unexpected or not) which have occurred over the reporting 
period. 
Line listings are not routinely required by the HPRA. However, it should be noted that 
copies of these line listings may be requested and, as such, should be made available 
to the HPRA when required. 
 
15. PROTOCOL ADHERENCE  
Investigators ascertain they will apply due diligence to avoid protocol deviations.  
If the Investigator feels a protocol deviation would improve the conduct of the study 
this must be considered a protocol amendment, and unless such an amendment is 
agreed upon by the Sponsor and approved by the applicable Health Authorities and 
EC, it cannot be implemented. Therefore, all suggested protocol deviations must be 
communicated to the Sponsor who will decide whether or not to submit an amendment 
to the protocol.  
Once identified, the investigator shall record the deviation in the Deviation Log (HBT-
GCP-FM-28) as per SOP HBT-GCP-SOP-05; ‘Deviation Management’.  
 
 
15.1 
Protocol Amendments  
Any change or addition to the protocol can only be made in a written protocol 
amendment that must be approved by the Sponsor, Health Authorities and EC. Only 
amendments that are required for subject safety may be implemented prior to 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
Investigator is expected to take any immediate action required for the safety of any 
subject included in this study, even if this action represents a deviation from the 
protocol. In such cases, the Sponsor should be notified of this action and the EC 
informed within 10 working days. 
 
 

               
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16. STATISTICS 
16.1 
Description of statistical methods 
If continuous variables are transformable to normal, they will be power-transformed 
and independent, two sample t-tests will be used for analysis of continuous variables. 
If data are not transformable to normal, non-parametric t-test equivalents (e.g. 
Wilcoxon signed rank and rank sum test, Mann-Whitney test and analysis of 
covariance (ANCOVA)) will be used. Chi-squared (or Fisher Exact) analyses will be 
used to compare categorical variables. Two-sided p values <0.05 will denote 
significance, with adjustment for multiplicity using Holm procedure. If required, missing 
data will be addressed using multiple imputation using chained equations as 
previously described (Ledwidge et al. JAMA. 2013;310(1):66-74) and results will be 
presented (primary and secondary end points) as pooled results from the multiple 
imputed data sets using a last-observation carried-forward analysis. 
 
Demographics and clinical characteristics will be summarized with descriptive 
statistics (counts and percentages for categorical variables, or mean value ± the 
standard deviation for normally distributed continuous variables, or medians and 
interquartile ranges for non-normally distributed continuous variables).Repeated 
marker changes from baseline to 18 months will be analysed using ANOVA with 
repeated measures models. 
 
Primary and secondary outcome measures will be performed both with and without 
adjustment for the effects of age, sex, diabetes, hypertension, obesity, and vascular 
disease. Further models will include adjustment for baseline measures of the outcome 
of interest (e.g. LAVI, BNP).  Categorical endpoints will be analyzed using generalized 
linear modeling with a binomial outcome distribution for prevalence and a Poisson 
outcome distribution for incidence rate (adjusted for patient-years). The multivariable 
models will include both prespecified covariates (age, sex, diabetes, hypertension, 
obesity, and vascular disease) and those variables with univariate P values ≤ 0.25. 
The likelihood ratio test and the Nagelkerke R Square will be used to identify 
independent variables with low explanatory power and to assess the fit of each 
specification of the multiple regression models.  
 
16.2 
Determination of sample size   
Based on the endpoint of change in LAVI over 18 months, the PARABLE trial aims to 
recruit 250 subjects (125 per arm). The current STOP-HF database includes 1499 
subjects with cardiovascular risk factors. An additional cohort of just under 1000 
subjects has been recruited from the STOP-HF outreach service and is available for 
screening and recruitment into the study. The STOP-HF Investigators are also working 
with other clinical trial units and can incorporate additional centres if required to 
achieve timely recruitment.  
 
Sample size estimates were calculated from the current STOP-HF subject database 
(n=1499). A subsample of subjects with BNP > 50 pg/mL, LAVI > 28 mL/m2, with 
normal EF (≥ 50%) and in normal sinus rhythm was drawn. This resulted in a 
population of 163 (11%) of the total with a population BNP of 125 pg/mL and a baseline 
mean LAVI of 36.2 mL/m2 (standard deviation of 6.9 mL/m2) determined by Doppler 

               
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Echocardiography. This LAVI is reassuringly similar to the baseline level observed by 
Solomon et al. (Lancet 2012; 380: 1387–95) in the PARAMOUNT study, which 
observed a 36-week drop in LAVI of 2.6 mL/m2, and assuming the control group-shows 
no decrease in LAVI (as in Solomon et al. 2012 paper), the expected effect size in a 
similar study is 2.6/6.5 = 0.38. Setting alpha = 5% (two-tailed), beta = 20% and using 
an independent t-test to assess the change in LAVI over follow-up, the required 
number of subjects to detect this effect is 222 (111 per study arm), or 248 after 
accounting for a 10% dropout rate. 
 
In a review of the expected effect size, once blinded echocardiography was available 
for 125 patients at the 9-month time point, it was noted that the actual standard 
deviation of baseline to 9-month change scores was 4.7. This means an expected 
effect size of at least (2.0/5.0) = 0.40. An effect size of 0.4 would require 96 patients 
in each group, suggesting that the study is adequately powered on LAVI assessed by 
echocardiography. In addition, the study has at least 80% power with a two-tailed 
alpha = 5% to detect a 6 g/m2 difference in LVMI change by CMRi, a 2.5 mL/m2 in 
LAVI change by CMRi, a 2-unit difference in E/e’ or e’ using Tissue Doppler 
measurements. 
 
17. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
Direct access will be granted to authorised representatives from the Sponsor, host 
institution and the regulatory authorities to permit trial-related monitoring, audits and 
inspections. 
 
18. DATA HANDLING AND RECORD KEEPING  
18.1 
Data collection, source documents and case report forms (CRFs) 
Source documents for this study will include hospital records, procedure reports and 
data collection forms (e.g. questionnaires). These documents will be used to enter 
data on the CRFs.  
A paper CRF will be used for this study. All data entered on CRFs must be entered 
legibly. If an error is made, the error will be crossed through with a single line in such 
a way that the original entry can still be read. The correct entry will then be clearly 
inserted and the alterations will be initialled and dated by the Investigator. 
Data reported on the CRF that are derived from source documents must be consistent 
with the source documents or the discrepancies must be explained. In some instances 
it is acceptable to file a copy of the source document (e.g. blood report, ABPM read-
out) in the study file and to cross-reference to the source document in the CRF. 
The monitor must make certain that all data are completed on the CRF. After 
comparing the data to the source documents, the monitor will request 
correction/clarification from the Investigator. 
After the last visit of the subject, the Investigator must attest the authenticity of the 
data collected in the CRF by signing the appropriate section of the CRF. 

               
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All documents will be stored safely in a confidential manner. On all study-specific 
documents, other than informed consent, the subject will be referred to by the subject 
study number/code. 
 
18.2 
Data reporting 
Subjects will be identified by a study specific subject number in the database. The 
name and any other identifying detail will not be included in any study data electronic 
file.  
 
19. RETENTION OF ESSENTIAL DOCUMENTS 
Essential documents will be retained until at least 15 years after the publication of the 
clinical study report. These documents will be retained for a longer period however, if 
required by the applicable regulatory requirements or by agreement with the Sponsor. 
The Investigator should retain the trial-related essential documents as required by the 
applicable regulatory requirements and until the Sponsor informs the Investigator 
these documents are no longer necessary. 
 
20. QUALITY CONTROL AND QUALITY ASSURANCE PROCEDURES 
The study will be conducted in accordance with the current approved protocol, ICH 
good clinical practice (GCP), relevant regulations and applicable SOPs.   
20.1 
Before the study 
The Investigator will allow the monitor to visit the site and facilities where the study 
will take place in order to ensure compliance with the protocol requirements. 
Training sessions will be organised for the Investigators/study team on the study 
protocol. 
20.2 
During the study 
For all participants who give informed consent, regardless of whether or not they 
receive any study drug, the Investigator designee will record participant identification 
data in the "Participant Identification List" (full name, initials, date of birth, participant 
identification code) or other similar list. The participant identification list will allow for 
the definite identification of any research participant that takes part in the study. A 
statement acknowledging the participation of a research participant in this clinical 
study will be also documented in the participant's medical file/notes.  
To protect the research participant's identity a unique identification code 
(randomisation number/study ID) will be assigned by WebEz to each study participant 
and used in lieu of the participant's name when AEs and/or other study-related data 
are reported. This coded form of identification, instead of the participant’s name, will 
appear on all documents/databases and will be cross-referenced by the participant's 

               
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date of birth. Documents not for submission to Sponsor, such as the confidential 
participant identification list and the signed Informed Consent Forms, will be kept in 
strict confidence on site and will not be removed from site.  
Personal information will be treated as confidential but may need to be reviewed by 
authorised representatives of the Sponsor - such as monitors and auditor/inspector 
from the ECs and the regulatory authorities. The participant's consent to direct access 
to his/her original medical records for data verification purposes will be obtained, via 
the informed consent process prior to that participant’s participation in the study.  
The Investigator will permit the Sponsor, authorised agents of the Sponsor (such as 
monitors, auditors, etc.), the Contract Research Organization, and regulatory agency 
employees to enter and inspect any site where the drug or records pertaining to the 
drug are held, and to inspect and copy all records relating to an investigation, including 
research participant records.  
The Investigator will make available all CRFs for review by the Sponsor, study monitor, 
and the regulatory agencies as necessary. To ensure the accuracy of data submitted, 
it is mandatory that representatives of the Sponsor and of the regulatory agencies 
have access to source documents (i.e. participant medical records or notes, charts, 
laboratory reports, etc.). Participant confidentiality will be protected at all times. The 
Investigator will allow the monitor to:  
• inspect the site, the facilities and the material used for the study  
• meet all members of his/her team involved in the study  
• consult all of the documents relevant to the study  
• have access to the CRFs  
• check that the CRFs have been filled out correctly  
• directly access source documents for comparison of data therein with 
the data in the CRFs  
• verify that the study is carried out in compliance with the protocol and 
local regulatory requirements  
The study Investigators will adhere to hospital protocols pertaining to healthcare 
record use and storage. The Investigators and authorised designees will ensure that 
the confidentiality of the participants’ data is preserved. On CRFs or any other 
documents submitted to the Sponsor’s designee, the participant will be identified not 
by their names, but by their coded form of identification.  
 
 

               
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21. AUDITS AND INSPECTIONS 
The trial may be subject to internal or external auditing or inspection procedure to 
ensure adherence to GCP. Access to all trial-related documents will be given at that 
time. 
A quality assurance audit may be conducted by the Sponsor or its agent at any time 
during, or shortly after, the study. The Investigator will permit an independent audit by 
an auditor mandated by Sponsor, after reasonable notice. The purpose of an audit is 
to confirm that the study is conducted as per protocol, GCP and applicable regulatory 
requirements, that the rights and well-being of the patients enrolled have been 
protected, and that the data relevant for the evaluation of the IMP have been captured, 
processed and reported in compliance with the planned arrangements. The 
Investigator will permit direct access to all study documents, drug accountability 
records, medical records and source data.   
Regulatory authorities may perform an inspection of the study up to several years after 
its completion. If an inspection is announced the Sponsor will be informed immediately. 
 
22. ETHICAL CONSIDERATIONS  
22.1 
Ethical conduct of the study 
This study will be carried out in compliance with the Study Protocol and in accordance 
with the Sponsors SOPs.  These are designed to ensure adherence to GCP 
guidelines, as described in:  
• International Conference on Harmonization (ICH) of Technical Requirements 
for Registration of Pharmaceuticals for Human Use Harmonized Tripartite 
Guidelines for Good Clinical Practice 1996  
• EU CT Directive 2001/20/EC  
• GCP Commission Directive 2005/28/EC  
• Declaration of Helsinki, concerning medical research in humans (1964) 
including all amendments up to and including the 2013 revision  
• National laws  
The Investigator agrees, when signing the study protocol, to adhere to the instructions 
and procedures described in it and to the principles of GCP to which it conforms. The 
regulatory permission to perform the study will be obtained in accordance with 
applicable regulatory requirements. All ethical and regulatory approvals must be 
available before a patient is exposed to any study-related procedure, including 
screening tests to determine eligibility.  
 
 
 
 

               
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22.2 
Declaration of Helsinki  
The Sponsor will ensure that this study is conducted in accordance with the ethical 
principles that have their origins in the Declaration of Helsinki.   
  
22.3 
Good Clinical Practice  
This study will be conducted in accordance with GCP, as defined by the ICH and in 
accordance with the ethical principles underlying EU Directive 2001/20/EC and 
2005/28/EC.  
22.4 
Approvals  
Before initiating this study, the protocol, SmPC, Investigators Brochure, Patient 
Information Leaflet and Informed Consent Form, and any other written information to 
be given to participants will be reviewed and approved by the competent authority and 
the EC.    
A signed and dated statement that all documents submitted for review have been 
approved by the EC will be given to the Sponsor or designee before the study can 
commence at a site. The membership and the constitution of the EC who approved 
the documents will be also supplied to the Sponsor or designee.  
The Sponsor/designee will submit and obtain approval from the above parties for 
substantial amendments to the original approved documents.  
Modifications of the signed protocol are only possible by approved protocol 
amendments and with the agreement of all responsible persons. The procedure for 
approval of a protocol amendment is identical to that for approval of the protocol. All 
substantial protocol amendment must be submitted to the Regulatory Authority and 
EC for approval. The changes in the protocol must not be instituted until the 
amendment and the revised informed consent (if appropriate) has been reviewed and 
received approval / favourable response from both the Regulatory Authority and EC. 
A protocol amendment intended to eliminate an apparent immediate hazard to 
participants may be implemented immediately providing that both the Regulatory 
Authority and EC are notified as soon as possible, and an approval is requested. Non-
substantial protocol amendments may be implemented immediately.  
 
22.5 
Informed consent 
The Investigator or his/her designee shall obtain written informed consent from each 
participant before his/her participation in the study and before any study related 
procedure is undertaken. Therefore, informed consent shall be obtained at Visit 1 
before any study related procedure is performed. Prior to this, the Investigator or 
his/her delegate must inform each participant of the objectives, benefits, risks and 
requirements imposed by the study, as well as the nature of the study drugs.  Informed 
consent must also be obtained for each patient to allow biobanking of blood samples. 

               
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A separate signature page is included on the Participant Information and Consent 
Form for this purpose. Only a qualified medical doctor may obtain informed consent. 
The participant will be provided with an information and consent form in clear, simple 
language. He/she must be allowed ample time to inquire about details of the study and 
to decide whether or not to participate in the study. The Investigator shall answer all 
questions the patient may have about the study. 
Two original information and consent forms must be completed, dated and signed 
personally by the participant and by the person responsible for collecting the informed 
consent. The participant will be given one signed original information and consent 
form, the second original will be kept by the Investigator.  
Any change to the information and consent form constitutes an amendment to this 
document and must be submitted for approval to the EC, and if applicable to the 
Regulatory Authorities. Such amendments may only be implemented after written 
approval of the EC has been obtained and compliance with the local regulatory 
requirements, with the exception of an amendment required to eliminate an immediate 
risk to the study participants.  
Each participant affected by the amendment or an independent witness must 
complete, date and sign two originals of the new version of the information and consent 
form together with the person who conducted the informed consent discussion. He/she 
will receive one signed original amendment to the information and consent form.  
The obtaining of informed consent and any pre-consent discussions should be 
documented in the patients’ medical notes. The following should be recorded in the 
subject’s medical file:  
• The date that the Informed Consent Form was given to the subject 
• The date written informed consent was obtained  
• The name of the person obtaining informed consent   
• Any other relevant information regarding the consent process 
For every patient recruited into the PARABLE clinical trial, a notification should be 
placed on the inside of the front cover of the patients’ medical notes in order to identify 
the clinical trial.  (The notification should record the study name, patients study ID, 
consent date, the ‘end of patient participation date’ which should be completed at visit 
11, the name of the Principal Investigator and contact number of the research team). 
 
 
 
 
 
 

               
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22.6 
Subject confidentiality  
The trial staff will ensure that the participants’ anonymity is maintained. The 
participants will be identified only by initials and a subject’s identification number on 
the CRF and any database. All documents will be stored securely. The study will 
comply with the Data Protection Act.  
 
23. FINANCING AND INSURANCE/INDEMNITY  
The Heartbeat Trust is the Sponsor and it will ensure that every Investigator is covered 
by a Clinical Trial Insurance, which shall remain in effect for the duration of the 
Agreement. All Investigators are qualified and practicing physicians and are thus 
insured by the clinical indemnity scheme.   
 
24. CLINICAL STUDY REPORT AND PUBLICATION POLICY  
24.1 
Clinical study report 
The study report will be drafted by the Clinical Trials Manager of the HBT in compliance 
with the Sponsor’s SOP.   
The Sponsor and the Chief Investigator must mutually agree on the final version. One 
copy of the final report must be dated and signed by the Chief Investigator and the 
Legal Representative of the Sponsor.  
 
24.2 
Publication policy  
The results of this study will be published in a high-quality clinical journal. The results 
of this study may provide the impetus for further research into the management of 
asymptomatic patients with risk factors for heart failure with LCZ696.   
The responsibility for publication of the data obtained from this study lies with the 
Investigator. Neither the Sponsor, nor any of the study funders, will have any 
involvement in data collection, data review, data analysis or preparation of the 
publication manuscript or in the decision to submit for publication. Submission of any 
publication manuscript may take place only with the permission of Prof. Kenneth 
McDonald, Consultant Cardiologist, and Dr Mark Ledwidge, Director of Research, St. 
Vincent’s University Hospital, Dublin 4. 
 
 

               
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25. STUDY PLANNING AND SCHEDULE  
The project milestones are as follows:  
 
1. Clinical trial application to the HPRA 
2. St Vincent’s University Hospital Ethics application 
3. Selection of suitable subjects from the STOP-HF data base and STOP-HF 
Service in St Michael’s Hospital 
4. Informed consent from subjects  
5. Recruitment of patients and inclusion in the study 
6. Final evaluation 
7. Data analyses 
8. Manuscript preparation 
9. Publication and presentation of results 
 
25.1 
Timelines and study duration 
Start date: FPFV: 16 December 2015 
 
End date:  
• 18-month treatment period: LPFV: December 2018. FPLV: Oct 2017 and 
LPLV: December 2020  
• 9- month follow-up (regression) substudy: FPFV: July 2019; LPLV: May 2021 
 
Study Report date: CSR to be made available within 12 months after study 
completion. 
 
 

               
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26. APPENDICES 
 
Appendix 1. Montreal Cognitive Assessment (MoCA)  
 
 
 
Appendix 2. Standardised Mini-Mental State Examination SMMSE) 
 
 
Montreal Cognitive Assessment Basic_MoCA.pdf
Standardised MMSE.pdf

               
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Appendix 3. EuroQoL (EQ-5D-5L) Health Questionnaire 
 
Subject study ID:  
 
Subject initials:          
Date of test: 
 
 
 
Visit number: 
¨Baseline 
                                            ¨9 months 
                                     ¨18 months 
 
Under each heading, please tick the ONE box that best describes your 
health TODAY. 
MOBILITY 
 
I have no problems in walking about 
q 
I have slight problems in walking about 
q 
I have moderate problems in walking about 
q 
I have severe problems in walking about 
q 
I am unable to walk about 
q 
SELF-CARE 
 
I have no problems washing or dressing myself 
q 
I have slight problems washing or dressing myself 
q 
I have moderate problems washing or dressing myself 
q 
I have severe problems washing or dressing myself 
q 
I am unable to wash or dress myself 
q 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure activities) 
I have no problems doing my usual activities 
q 
I have slight problems doing my usual activities 
q 
I have moderate problems doing my usual activities 
q 
I have severe problems doing my usual activities 
q 
I am unable to do my usual activities 
q 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
q 
I have slight pain or discomfort 
q 
I have moderate pain or discomfort 
q 
I have severe pain or discomfort 
q 

               
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I have extreme pain or discomfort 
q 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
q 
I am slightly anxious or depressed 
q 
I am moderately anxious or depressed 
q 
I am severely anxious or depressed 
q 
I am extremely anxious or depressed 
q 
 
• We would like to know how good or bad your health is TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your health is TODAY. 
• Now, please write the number you marked on the scale in the box 
below. 
 
 
 
 
 
 
 
YOUR HEALTH 
TODAY = 
 
 
10 
0 
20 
30 
40 
50 
60 
80 
70 
90 
100 
5 
15 
25 
35 
45 
55 
75 
65 
85 
95 
The worst health            
you can imagine 
The best health              
you can imagine 
 

               
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Appendix 4. Montreal Cognitive Assessment (MoCA) Version 3. 
Administration and Scoring Instructions 
The Montreal Cognitive Assessment (MoCA) was designed as a rapid screening instrument for mild 
cognitive dysfunction. It assesses different cognitive domains: attention and concentration, executive 
functions, memory, language, visuoconstructional skills, conceptual thinking, calculations, and 
orientation.  
Time to administer the MoCA is approximately 10 minutes.  
The total possible score is 30 points; a score of 26 or above is considered normal.  
1. Alternating Trail Making:  
Administration: The examiner instructs the subject: "Please draw a line, going from a number to a 
letter in ascending order. Begin here [point to (1)] and draw a line from 1 then to A then to 2 and so 
on. End here [point to (E)]."  
Scoring: Allocate one point if the subject successfully draws the following pattern: 1 −A- 2- B- 3- C- 
4- D- 5- E, without drawing any lines that cross. Any error that is not immediately self-corrected 
earns a score of 0.  
2. Visuoconstructional Skills (Cylinder):  
Administration: The examiner gives the following instructions, pointing to the cylinder: “Copy this 
drawing as accurately as you can, in the space below”.  
Scoring: One point is allocated for a correctly executed drawing.  
• 
Drawing must be three-dimensional  
• 
All lines/ovals are drawn  
• 
No line is added  
• 
The horizontal lines are relatively parallel.  
• 
The objects at the end must be ovals rather than circles.  
• 
The horizontal lines must touch the top/bottom of the ovals.  
A point is not assigned if any of the above-criteria are not met.  
3. Visuoconstructional Skills (Clock):  
Administration: Indicate the right third of the space and give the following instructions: “Draw a 
clock. Put in all the numbers and set the time to ten past nine”.  
Scoring: One point is allocated for each of the following three criteria:  
• 
Contour (1 pt.): the clock face must be a circle with only minor distortion acceptable (e.g., slight 
imperfection on closing the circle);  
• 
Numbers (1 pt.): all clock numbers must be present with no additional numbers; numbers must 
be in the correct order and placed in the approximate quadrants on the clock face; Roman 
numerals are acceptable; numbers can be placed outside the circle contour;  
• 
Hands (1 pt.): there must be two hands jointly indicating the correct time; the hour hand must 
be clearly shorter than the minute hand; hands must be centred within the clock face with their 
junction close to the clock centre.  
A point is not assigned for a given element if any of the above-criteria are not met.  

               
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4. Naming:  
Administration: Beginning on the left, point to each figure and say: “Tell me the name of this animal”.  
Scoring: One point each is given for the following responses: (1) donkey (or mule); (2) pig (or hog); 
(3) kangaroo.  
5. Memory:  
Administration: The examiner reads a list of 5 words at a rate of one per second, giving the following 
instructions: “This is a memory test. I am going to read a list of words that you will have to remember 
now and later on. Listen carefully. When I am through, tell me as many words as you can remember. 
It doesn’t matter in what order you say them.”  
Mark a check in the allocated space for each word the subject produces on this first trial. When the 
subject indicates that (s)he has finished (has recalled all words), or can recall no more words, read 
the list a second time with the following instructions: “I am going to read the same list for a second 
time. Try to remember and tell me as many words as you can, including words you said the first time.”  
Put a check in the allocated space for each word the subject recalls after the second trial. At the end 
of the second trial, inform the subject that (s)he will be asked to recall these words again by saying, 
“I will ask you to recall those words again at the end of the test.”  
Scoring: No points are given for Trials One and Two. Scoring is based on the delayed recall trial.  
6. Attention:  
Forward Digit Span: Administration: Give the following instruction: “I am going to say some numbers 
and when I am through, repeat them to me exactly as I said them”. Read the five number sequence 
at a rate of one digit per second.  
Backward Digit Span: Administration: Give the following instruction: “Now I am going to say some 
more numbers, but when I am through you must repeat them to me in the backwards order.” Read 
the three number sequence at a rate of one digit per second. 
Scoring: Allocate one point for each sequence correctly repeated, (N.B.: the correct response for the 
backwards trial is 4-7-1).  
7. Vigilance:  
Administration: The examiner reads the list of letters at a rate of one per second, after giving the 
following instruction: “I am going to read a sequence of letters. Every time I say the letter A, tap your 
hand once. If I say a different letter, do not tap your hand”.  
Scoring: Give one point if there is zero to one errors (an error is a tap on a wrong letter or a failure 
to tap on letter A).  
8. Serial 7s:  
Administration: The examiner gives the following instruction: “Now, I will ask you to count by 
subtracting 7 from 80, and then, keep subtracting 7 from your answer until I tell you to stop.” Give 
this instruction twice if necessary.  

               
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Scoring: This item is scored out of 3 points. Give no (0) points for no correct subtractions, 1 point 
for one correction subtraction, 2 points for two-to-three correct subtractions, and 3 points if the 
participant successfully makes four or five correct subtractions.  
Count each correct subtraction of 7 beginning at 80. Each subtraction is evaluated independently; 
that is, if the participant responds with an incorrect number but continues to correctly subtract 7 
from it, give a point for each correct subtraction. For example, a participant may respond “72 – 65 
– 58 – 51 – 44” where the “72” is incorrect, but all subsequent numbers are subtracted correctly. 
This is one error and the item would be given a score of 3.  
9. Sentence repetition:  
Administration: The examiner gives the following instructions: “I am going to read you a sentence. 
Repeat it after me, exactly as I say it [pause]: She heard his lawyer was the one to sue after the 
accident.”  
Following the response, say: “Now I am going to read you another sentence. Repeat it after me, exactly 
as I say it [pause]: The little girls who were given too much candy got stomach aches.”  
Scoring: Allocate 1 point for each sentence correctly repeated. Repetition must be exact. Be alert 
for errors that are omissions (e.g., omitting "too much") and substitutions/additions (e.g., " . . . his 
lawyer sued after . . .”; “the girls”), altering plurals, etc.).  
10. Verbal fluency:  
Administration: The examiner gives the following instruction: “Tell me as many words as you can 
think of that begin with a certain letter of the alphabet that I will tell you in a moment. You can say 
any kind of word you want, except for proper nouns (like Peter or Paris), numbers, or words that begin 
with the same sound but have a different suffix, for example, love, lover, loving. I will tell you to stop 
after one minute. Are you ready? [Pause] Now, tell me as many words as you can think of that begin 
with the letter B. [time for 60 sec]. Stop.”  
Scoring: Allocate one point if the subject generates 11 words or more in 60 sec. Record the subject’s 
response in the bottom or side margins.  
11. Abstraction:  
Administration: The examiner asks the subject to explain what each pair of words has in common, 
starting with the example: “Tell me how an orange and a banana are alike”. If the subject answers in 
a concrete manner, then say only one additional time: “Tell me another way in which those items 
are alike”. If the subject does not give the appropriate response (fruit), say, “Yes, and they are also 
both fruit.” Do not give any additional instructions or clarification. After the practice trial, say: “Now, 
tell me how an eye and an ear are alike”.  
Following the response, administer the second trial, saying: “Now tell me how a trumpet and a piano 
are alike”. Do not give any additional instructions or prompts.  
Scoring: Only the last two item pairs are scored. Give 1 point to each item pair correctly answered. 
The following responses are acceptable:  
• 
eye-ear = sensory organs, parts of the head, parts of the body;  
• 
trumpet-piano = musical instruments, you can play them.  
The following responses are not acceptable: eye-ear = parts of the face.  

               
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12. Delayed recall:  
Administration: The examiner gives the following instruction: “I read some words to you earlier, which 
I asked you to remember. Tell me as many of those words as you can remember.” Make a check mark 
( √ ) for each of the words correctly recalled spontaneously without any cues, in the allocated space.  
Scoring: Allocate 1 point for each word recalled freely without any cues.  
 
13. Orientation:  
Administration: The examiner gives the following instructions: “Tell me the date today”. If the subject 
does not give a complete answer, then prompt accordingly by saying: “Tell me the [year, month, 
exact date, and day of the week].” Then say: “Now, tell me the name of this place, and which city it is 
in.”  
Scoring: Give one point for each item correctly answered. The subject must tell the exact date and 
the exact place (name of hospital, clinic, unit). No points are allocated if subject makes an error of 
one day for the day and date.  
TOTAL SCORE: Sum all sub-scores listed on the right-hand side. Add one point for an individual 
who has 12 years or fewer of formal education, for a possible maximum of 30 points. A final total 
score of 26 and above is considered normal. 

               
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Appendix 5. Adverse Event Handling. Investigator Responsibilities. Flow 
Diagram  
 
 

               
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Appendix 6. Adverse Event Handling. Sponsor Responsibilities. Flow 
Diagram 
 
 
 

               
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Appendix 7. Clinically notable laboratory values and vital signs  
Clinically notable laboratory abnormalities for selected tests based on a percent 
change from baseline:  
 
Haematology  
RBC count    
 
>50% increase  
>20% decrease  
Haemoglobin  
 
 >50% increase  
>20% decrease  
Haematocrit   
 
>50% increase  
>20% decrease  
WBC count    
 
>50% increase  
>50% decrease  
Platelet count   
 
>75% increase  
>50% decrease  
 
Blood Chemistry  
ALT (SGPT)   
 
>150% increase  
AST (SGOT)  
 
>150% increase  
BUN    
 
 
>50% increase  
Creatinine    
 
>50% increase  
Total bilirubin   
 
>100% increase  
CPK     
 
 
>300% increase  
Alkaline phosphatase  
>100% increase  
Sodium   
 
 
>5% decrease  
Potassium    
 
>20% increase  
>20% decrease  
Chloride  >10% increase,   
 
 
>10% decrease  
Calcium  >10% increase,   
 
 
>10% decrease  
Uric acid  >50% increase  
 
 
 

               
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Appendix 8. Treatment guidelines  
Treatment guidelines for hyperkalaemia (serum K+ > 5.2 mEq/L)   
General principles: It is recommended that any subject with a serum K+ > 5.2 mEq/L 
following randomization may require frequent checks of potassium concentration 
until it is clear that the potassium concentration is stable and not rising into the range 
of concern (> 5.5 and < 6.0 mEq/L) or potential danger (> 6.0 mEq/L).   
Investigators should not randomize a subject with a serum K+ > 5.2 mEq/L at Visit 1 
(screening) and follow the other measures outlined below if K+ increases to values > 
5.2 mEq/L after randomization.  
Corrective action recommended for management of hyperkalaemia  
K+ > 5.2 and ≤ 5.5 mEq/L  
• If necessary, confirm potassium concentration was obtained in a non-
haemolysed sampled. If it is confirmed that questionable results were obtained 
from haemolysed specimen, redraw blood sample for K+ measurement and 
caution should be taken to minimize the incidence of haemolysis by proper 
blood sample collection and handling  
• 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 Confirm that potassium-sparing diuretics and potassium supplements 
aren’t being used  
o Salt substitutes   
o Non-steroidal anti-inflammatory drugs (NSAIDs)  
o Cyclo-oxygenase-2 (COX-2) inhibitors  
o Trimethoprim and trimethoprim-containing combination products such 
as trimethoprim/sulfamethoxazole   
o Herbal Supplements: (for xample, Noni juice, alfalfa (Medicago sativa), 
dandelion (Taraxacum officinale), horsetail (Equisetum arvense), nettle 
(Urtica dioica), milkweed, lily of the valley, Siberian ginseng, hawthorn 
berries) 
K+ > 5.5 and ≤ 6.0 mEq/L   
• If necessary, confirm potassium concentration was obtained in a non-
hemolyzed sample   
• Apply all measures outlined for K+ 5.2 and ≤ 5.5 mEq/L   
• Repeat K+ measurement after 1-3 days  
• Discontinue the study drug if a repeated K+ > 5.5 mEq/L   
 

               
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K+ > 6.0 mEq/L  
• Immediately discontinue study drug  
• Confirm potassium concentration in a non-haemolysed sample  
• Urgently evaluate subject and treat hyperkalaemia as clinically indicated   
• Apply all measures outlined for K+ > 5.2 and ≤ 6.0 mEq/L  
 
Guidelines for the management of hypotension  
1. Treatment should not be initiated if systolic BP <100mmHg at screening or 
baseline. A lower starting dose (Level 1) should be considered for patients with 
systolic BP ≥100 to 110mmHg.  
2. Investigator should monitor blood pressure closely throughout the study 
3. If systolic BP falls to ≤95mmHg (or symptomatic hypotension occurs at any BP):  
• Correct any treatable cause, e.g. hypovolemia  
• If symptomatic hypotension persists, consider down titrating or stopping other 
hypotensive medications, and/or study drug as appropriate.   
• If symptomatic hypotension persists during two consecutive office visits or as 
judged by the Investigator, discontinue the study drug.   
 
Guidelines for the management of renal dysfunction   
General principles: Some subjects may develop renal dysfunction after study drug 
administration. Two types of response to serum creatinine increase are described:  
Surveillance situation   
If, at any moment after recruitment, serum creatinine increases by ≥50% from baseline 
(Visit 1), the Investigator will check for potentially reversible cases of renal dysfunction 
such as:  
• NSAID intake, diuretics, antibiotics, or other treatments known to affect 
creatinine 
• Volume decrease  
• Urinary infection  
• Urinary tract obstruction  
• Study medication  
The Investigator should consider discontinuing any medication known to affect the 
renal function and should repeat the serum creatinine after 5-7 days.  
Action situation   
If serum creatinine >3.0 mg/dL or increases by ≥100% from baseline (Visit 1), the 
Investigator will discontinue study drug and check for potentially reversible causes of 
renal dysfunction (see above). Thereafter, serum creatinine should be monitored until 
its resolution.  

               
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Appendix 9. PARABLE. Nine-month follow-up study  
1. Objectives and endpoints 
The overall objective of the nine-month follow-up study is to evaluate if the treatment 
effects observed during the 18-month PARABLE study persist nine-months after 
study drug discontinuation (see Exploratory Objective No 4 in Section 10.1).  
Secondary and exploratory endpoints shall be evaluated in this sub-set of subjects 
(see Exploratory Endpoint No 10 Section 10.2).  
 
2. Eligibility criteria 
All PARABLE participants that completed the 18-month follow-up period, and did not 
discontinue the study drug prematurely, will be eligible for inclusion in the follow-up 
study. 
3. Informed Consent 
The procedure for obtaining informed consent is outlined in Section 22.5 of the main 
PARABLE protocol. Informed consent shall be obtained from the participant prior to 
any study related assessment or procedure been conducted using the Participant 
Information Leaflet and Informed Consent Form for the follow-up study (HBT-GCP-
FM-39). 
 
4. Assessments and procedures 
The following assessments and procedures will be carried out at the nine-month 
follow-up visit in the same manner they were conducted during the main 
PARABLE study (see section 12.4) of the study protocol). 
• Physical exam 
o Vital size (BP and pulse, height, weight and waist/hip circumference) 
o Biochemistry 
§ Urea & Electrolytes (U&E) including eGFR 
§ Liver Function Tests (LFT) 
§ Alkaline Phosphatase 
§ Lipid profile 
§ HbA1c 
§ Iron studies 
o Haematology 
§ Full blood count 
 
• Urine for second messenger cGMP and ANP* 
• Blood for biomarkers*  
• Serum BNP and NT-proBNP 
• Ambulatory blood pressure monitoring 
• 12-lead ECG 
• Echo-Doppler studies 

               
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• QOL questionnaire (EuroQol) and two cognitive function assessment tools 
 
*cryovials will be labelled with the following information: 
• 
PAR-XXXX (where XXXX is the participants PARABLE study ID) 
• 
The date the sample was taken 
• 
The type of sample (e.g. whole blood, lithium heparin, urine etc) 
• 
Timepoint: 9M-FU  
 
 
 
 

               
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