Conditions: Heart Failure
Keywords: Heart failure with reduced left ventricular ejection fraction LVEF Cardiac dysfunction Heart muscle dysfunction Left ventricular (LV) dilation Left ventricular hypertrophy HF AHF CHF CCF acute heart failure chronic heart failure congestive heart failure congestive cardiac failure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 55
Healthy volunteers: no

Brief summary:
This is a phase IV, prospective, randomized, double-blind, double-dummy, parallel-group study.

The study assessed the effects of 6 weeks of stable sacubitril/valsartan therapy, as compared with valsartan therapy, on the efficiency of cardiac work in patients with NYHA II-III heart failure (HF) and reduced systolic function using 11C-acetate positron emission tomography (PET) and echocardiography.

Detailed description:
Subjects were randomized into valsartan or sacubitril/valsartan arms in a 1:1 ratio. Regardless of the treatment arm a subject is in, the study drug was up-titrated to the highest tolerated dose level during the scheduled study visits. The different strengths of the two study drugs were not identical in appearance so the possible dose modification(s) during the treatment period could not be performed in a blinded manner. Subjects started on valsartan 80 mg BID or sacubitril/valsartan 100 mg BID dose and there was only one scheduled up-titration visit after the randomization. Exception for this were the subjects that were on valsartan 160 mg BID dose during the run-in phase. These subjects were randomized directly to valsartan 160 mg BID or sacubitril/valsartan 100 mg BID. Subjects that were randomized to valsartan arm had similar visit after which they continued on the same dose. For subjects that were randomized from valsartan 160 mg BID to sacubitril/valsartan 100 mg BID the dose was up-titrated to 200 mg BID if clinically possible.

The total duration for each patient was planned to be about 14 weeks but could be longer if required for scheduling purposes . The longest participation, from signing of ICF until end of study, was 26 weeks.

Arms:
arm 1: subjects received sacubitril/valsartan 100 mg orally twice daily (BID). The dose was then up-titrated to 200 mg BID (or maintained at the starting dose level, if up-titration was not possible). arm 2: subjects received 80 mg orally twice daily (BID). The dose was then up-titrated to 160 mg BID (or maintained at the starting level, if up-titration was not possible)

Interventions: intervention 1: sacubitril/valsatran intervention 2: valsartan intervention 3: placebo to valsartan intervention 4: placebo to sacubitril/valsartan
Intervention descriptions: intervention 1: sacubitril/valsatran 100 or 200 mg BID intervention 2: Valsartan 80 or 160 mg BID intervention 3: placebo to valsartan 80 or 160 BID intervention 4: placebo to sacubitril/valsartan 100 or 200 mg BID

Protocol document:
Prot_000.pdf: 


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SIGNATURES 
 
 
 
 
Principal Investigator: __________________________ 
Date: ______/_____/_______ 
 
 
 
 
 
 
 
Representative of 
the Sponsor:  
 __________________________ 
Date: _____/_____/________ 
 
 
 
 
 
 
 
 
 
 
Representative of 
the Sponsor:  
 __________________________ 
Date: _____/_____/________ 
 
 
 
 
 
 
 
 




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TABLE OF CONTENTS 
 
 
LIST OF TABLES 
7 
LIST OF FIGURES 
7 
SYNOPSIS 
8 
ABBREVIATIONS AND DEFINITION OF TERMS 
12 
 
1 
AMENDMENTS AND UPDATES 
14 
1.1 
The possibility to perform screening visit 2 and visit 2 as remote visits 
14 
1.2 
Safety blood samples may be collected 1-2 business day(s) before the 
scheduled study visits 
14 
1.3 
Primary endpoint clarification 
15 
1.4 
Physical examination clarification 
15 
2 
INTRODUCTION 
17 
2.1 
Background 
17 
2.2 
Valsartan 
19 
2.3 
Sacubitril/valsartan 
20 
2.4 
11C-acetate 
22 
2.5 
Rationale of the study 
22 
2.6 
Risk assessment 
23 
3 
STUDY OBJECTIVES AND ENDPOINTS 
25 
3.1 
Primary objective and endpoint 
25 
3.2 
Exploratory objectives and endpoints 
25 
4 
STUDY DESIGN 
25 
4.1 
Type and design of the study 
25 
4.2 
Randomization and blinding 
26 
4.3 
General study outline 
27 
5 
SUBJECTS 
31 
5.1 
Source population 
31 
5.2 
Number of subjects 
31 
5.3 
Inclusion criteria 
32 
5.4 
Exclusion criteria 
32 
5.5 
Recruitment 
33 
5.6 
Study subject screening log and identification log 
34 
5.7 
Instructions concerning lifestyle and concomitant treatments 
34 
5.8 
Withdrawal of subjects 
34 
5.9 
Information to be collected on screening failures 
35 
6 
TREATMENTS 
35 
6.1 
Investigational treatment sacubitril/valsartan 
35 
6.2 
Control treatment 
38 
6.3 
PET-tracer 11C-acetate 
38 
6.4 
Handling of the study products 
39 
6.5 
Prior and concomitant treatments 
39 
6.5.1 Prohibited treatments during the study 
39 
6.5.2 Permitted treatments during the study 
40 
6.6 
Emergencies and treatment of adverse events 
40 
6.7 
Procedures for monitoring subject compliance 
40 
7 
VISIT SCHEDULE 
41 
7.1 
Screening/run-in period 
41 
7.2 
Treatment period 
42 
7.3 
Unscheduled visits 
44 
8 
ASSESSMENTS 
44 
8.1 
Screening data 
44 
8.1.1 Demographic and other baseline information 
44 


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8.1.2 Screening laboratory determinations 
45 
8.2 
Assessment of efficacy 
45 
8.2.1 
11C-acetate PET- scan 
45 
8.2.2 Echocardiography 
45 
8.2.3 Biomarkers 
46 
8.3 
Assessment of safety 
46 
8.3.1. Physical examination 
46 
8.3.2 Blood pressure and heart rate 
46 
8.3.3 Laboratory safety assessments 
47 
8.3.4 Adverse events 
47 
8.3.4.1 Serious adverse events 
49 
8.3.4.1.1 Definition of SAE 
49 
8.3.4.1.2 SAE reporting 
50 
8.3.4.2. Liver safety monitoring 
51 
8.3.4.3 Renal safety monitoring 
51 
8.3.4.4 Reporting of study treatment errors including misuse/abuse 
51 
8.3.4.5 Pregnancy reporting 
52 
8.3.4.6. Serious adverse event reporting 
52 
9 
STATISTICS 
54 
9.1 
Estimation of sample size 
54 
9.2 
Statistical methods 
54 
9.2.1 Statistical Analysis Plan 
54 
9.2.2 Statistical hypotheses 
54 
9.2.3 Data sets to be analyzed 
55 
9.2.4 General statistical considerations 
55 
9.2.5 Demographic and baseline characteristics 
55 
9.2.6 Analysis of efficacy variables 
56 
9.2.7 Analysis of safety variables 
56 
9.2.7.1 Evaluation of adverse events 
56 
9.2.7.2 Clinical safety evaluations 
57 
9.2.7.3 Clinical safety laboratory evaluations 
57 
9.3 
Interim analyses 
57 
9.4 
Software 
57 
10 
DATA MANAGEMENT 
58 
10.1 
Database design 
58 
10.2 
Data entry 
58 
10.3 
Data validation and query management 
58 
10.4 
Medical encoding 
58 
10.5 
Data lock 
59 
10.6 
Database closure 
59 
10.7 
Software 
59 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
59 
12 
ETHICAL CONSIDERATIONS 
60 
13 
DATA HANDLING AND RECORD KEEPING 
61 
13.1 
Case report forms 
61 
13.2 
Source data 
61 
13.3 
Deviations 
62 
13.4 
Amendments 
62 
14 
STUDY SCHEDULE 
62 
15 
CRITERIA FOR PREMATURE STUDY TERMINATION 
62 
16 
FINANCING AND INSURANCE 
63 
17 
STUDY REPORT AND PUBLISHING 
63 
18 
ARCHIVING 
63 
19 
REFERENCES 
64 
20 
APPENDICES 
70 


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LIST OF TABLES 
 
Table 1 Substantial study protocol amendments and updates .........................................14 
Table 2. NYHA classes and associated symptoms ..........................................................17 
Table 3. General study outline .........................................................................................30 
Table 4. Guidance for capturing the study treatment errors including misuse/abuse ........52 
 
 
LIST OF FIGURES 
 
Figure 1. General study design 
29 
Figure 2. Study treatment during the double-blind treatment period with 
sacubitril/valsartan. 
36 
Figure 3. Study treatment during the double-blind treatment period with valsartan. 
37 
 
 


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SYNOPSIS 
 
Name of the Sponsor/Company: 
Novartis Finland Oy 
 
 
Name of the active ingredient: 
Sacubitril/valsartan 
Study code: 
CLCZ696BFI03 (Sponsor) / C605 
, EudraCT 2017-002113-64 
Study title: 
Controlled trial on the short-term effects of sacubitril/valsartan therapy on cardiac oxygen 
consumption and efficiency of cardiac work in patients with NYHA II-III heart failure and 
reduced systolic function using 
11C-acetate positron emission tomography and 
echocardiography 
Investigators and study centres: 
 (Principal Investigator), MD, PhD.
 
, Finland 
Development phase: 
IV 
Objectives: 
Primary objective: The primary objective of the study is to evaluate the effects of 6 weeks 
of stable sacubitril/valsartan therapy, as compared with valsartan therapy, on the 
efficiency of cardiac work in patients with NYHA II-III heart failure (HF) and reduced 
systolic function using 11C-acetate and echocardiography.  
Exploratory objective: The exploratory objective of the study is to evaluate the effects of 
6 weeks of stable sacubitril/valsartan therapy, as compared with valsartan therapy, on 
myocardial oxygen consumption and cardiac and systemic hemodynamics. 
Methodology: 
This is a phase IV, prospective, randomized, double-blind, double-dummy, parallel-group 
study performed at a single center. The subjects enrolled into the study will be patients 
with chronic HF, NYHA II-III symptoms and reduced ejection fraction (EF) who fulfill all of 
the inclusion criteria and none of the exclusion criteria. No more than 50% of the study 
subjects are allowed to have diabetes. The study will have two treatment arms, the 
sacubitril/valsartan treatment arm and the valsartan treatment arm, and the subjects will 
be randomized into these arms in a 1:1 ratio. The study will be performed in a double-
blinded manner in regards to the treatment. As the sacubitril/valsartan and valsartan 
tablets are not similar in appearance, the study will be performed in a double-dummy 
manner in order to maintain blinding. Regardless of the treatment arm a subject is in, the 
study drug will be up-titrated to the highest tolerated dose level during the scheduled study 
visits. The different strengths of the two study drugs are not identical in appearance so 
the possible dose modification(s) during the treatment period cannot be performed in a 
blinded manner. The subjects will start on valsartan (80 mg twice a day [BID] or 160 mg 
twice a day) or sacubitril/valsartan (100 mg BID) dose and there will be only one 
scheduled up-titration visit after the randomization. If clinically indicated, dose modification 
(up- or down-titration) will be allowed once after the randomization outside the scheduled 
study visits. In order to be eligible for the final study assessments on visit 3 (i.e. the 11C-
acetate positron emission tomography [PET] scan and echocardiography), the subjects 
have to be on a stable dose for at least 6 weeks on one of the following treatment options: 
valsartan 80 mg BID or 160 mg BID or sacubitril/valsartan 100 mg BID or 200 mg BID. 


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Study treatment will be dispensed by an unblinded member of the study team during the 
treatment period. 
The total duration of the study is planned to be approximately 14 weeks for each subject, 
but it may be longer if required for scheduling purposes. During the study, the subjects 
will have 5-6 study visits. Two of these visits, screening visit 2 and visit 2, may performed 
as a remote visit (i.e. telephone contact), if deemed sufficient by the investigator. In 
addition, unscheduled visits may occur at any time, if considered necessary for subject 
safety. The study includes a screening/run-in period (up to 6 weeks) and a treatment 
period (approximately 8 weeks). Both the screening/run-in and the treatment period may 
be longer, if necessary. Efficacy assessments, i.e. 
11C-acetate PET-scan and 
echocardiography, will be performed twice during the study. The first assessments will be 
done at the baseline visit, after the subject has been on a stable valsartan treatment for a 
minimum of 4 weeks, and then repeated at the last visit, when the subject has been on a 
stable sacubitril/valsartan or valsartan treatment for a minimum of 6 weeks. Subject safety 
will be monitored throughout the study by evaluating the subject’s clinical status, blood 
pressure (BP), heart rate (HR) and safety laboratory assessments. Specific safety-related 
withdrawal criteria are given in section 5.8.  
Sample size: 
The planned number of enrolled study subjects is 60 (30 subjects/treatment arm). The 
aim is that at least 27 subjects/treatment arm finish the study according to the protocol. If 
discontinuations occur, the need of recruiting additional subjects to reach the targeted 
total number of subjects will be considered and carried out as appropriate. Thus, in case 
of discontinuations during the study, the number of enrolled study subjects may be larger 
than 60. 
Main eligibility criteria: 
Patients with 40-80 years of age and chronic HF with reduced EF (left ventricle EF 25-
35%) and NYHA class II-III symptoms; estimated glomerular filtration rate (eGFR) ≥ 45 
ml/min; serum potassium <5.2 mmol/l and creatinine <1.5 x ULN (upper limit of normal) 
at the screening visits; systolic BP 110-160 mmHg at the randomization visit; optimal 
standard HF therapy according to European Society of Cardiology (ESC) guidelines at a 
stable dose for at least 4 weeks before the screening visit. The subjects must fulfill all of 
the inclusion criteria and none of the exclusion criteria.  
Investigational drug, dose and mode of administration: 
The investigational drug will be sacubitril/valsartan (Entresto™). It will be taken orally BID. 
Two strengths will be available for use after randomization, 49 mg sacubitril/51 mg 
valsartan and 97 mg sacubitril/103 mg valsartan. After randomization, subjects will receive 
either sacubitril/valsartan 100 mg BID or valsartan 80 mg BID or 160 mg BID (depending 
on the screening/run-in dose). The dose will be then up-titrated to the highest tolerated 
dose (or maintained at the starting dose level, if up-titration is not possible). In case of 
sacubitril/valsartan, the dose will be either up-titrated to 200 mg BID or maintained at 100 
mg BID. In order to be eligible for the final assessments, the subject has to tolerate the 
100 mg BID dose at the minimum (i.e. subjects who do not tolerate the change to 
sacubitril/valsartan 100 mg BID will be withdrawn from the study).  
Comparative drug(s)/placebo, dose and mode of administration: 
Valsartan 80 mg and 160 mg tablets will be used as comparative drugs, taken orally BID. 
At screening visit 1, the subjects will be switched to valsartan treatment that will replace 
their previously used angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II 


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receptor blocker (ARB) treatment during the screening/run-in period. The starting dose of 
valsartan is 80 mg BID or if a subject is already on a dose of 160 mg BID or equivalent 
the dose will be maintained on that level. Subjects will be maintained at a stable dose of 
80 mg BID or 160 mg BID of valsartan for at least 4 weeks before randomization. After 
randomization, subjects that were on 80 mg BID valsartan dose during the run-in will 
receive either sacubitril/valsartan 100 mg BID or valsartan 80 mg BID. Subjects that were 
on 160 mg BID valsartan during the run-in will be randomized to either valsartan 160 mg 
BID or sacubitril/valsartan 100 mg BID. The dose in both treatment arms will be then up-
titrated to the highest tolerated dose (or maintained at the starting dose level, if up-titration 
is not possible). In order to be eligible for the final assessments, the subject has to tolerate 
the 80 mg BID dose of valsartan at the minimum. 
Duration of treatment:  
The subjects will receive valsartan treatment during the screening/run-in period. The 
screening/run-in period can last for up to 6 weeks (may be longer, if needed) and the 
valsartan dose has to be stable for at least 4 weeks prior to randomization. After 
randomization, 
subjects 
will 
receive 
study 
treatment 
(either 
valsartan 
or 
sacubitril/valsartan) for approximately 8 weeks; during the first 2 weeks, the dose of the 
study drug will be up-titrated to the highest tolerated dose level (or the starting dose will 
be maintained, if up-titration is not possible on clinical bases or if the subject is already on 
the highest dose level), and then the highest tolerated dose will be administered for 6 
weeks at a stable dose prior to the final efficacy assessments.  
Assessments:  
Efficacy assessments: 11C-acetate PET scan, echocardiography and biomarkers 
In order to assess cardiac efficiency and hemodynamics, PET imaging and 
echocardiography will be performed before randomization (after a minimum of 4 weeks 
on stable dose of 80 mg BID or 160 mg BID of valsartan) and repeated after 6 weeks on 
a stable dose of either 80 mg BID or 160 mg BID of valsartan or 100 mg BID or 200 mg 
BID of sacubitril/valsartan. 
11C-acetate PET: Myocardial resting perfusion and oxygen consumption will be evaluated 
by 11C-acetate PET as tracer uptake (k1) and a mono-exponential clearance rate of 11C-
acetate (kmono). Efficiency of left ventricle (LV) mechanical work will be calculated as 
follows: Efficiency = (LV work/gram of tissue) / oxygen consumption. 
Echocardiography: Comprehensive echocardiographic evaluation of cardiac structure, 
systolic and diastolic function will be performed using 2D and 3D imaging, strain imaging 
and Doppler. LV mechanical work will be calculated as follows: LV work/gram of tissue= 
(SBP x SV x HR) / LV mass; where SBP is systolic blood pressure, SV is stroke volume 
and HR is heart rate. 
Biomarkers: Biomarkers (N-terminal prohormone brain natriuretic peptide [NT-proBNP], 
hs-troponin and creatinine) will be measured to understand the possible mechanisms of 
the potential changes in myocardial efficiency.  
Safety: Seated BP and HR will be measured at all site visits for safety assessment. BP 
and HR will be monitored also during the imaging sessions. All subjects will undergo blood 
laboratory tests, including serum potassium and creatinine, during the screening/run-in 
period on screening visits 1 and 2. The same laboratory assessments will be performed 
during the treatment period on visits 1-3, and also on unscheduled visits, if clinically 
indicated. If necessary to assess subject safety, more laboratory tests may be performed 
at any visit. 


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The decision to modify (up- or down-titrate) the dose level of a subject’s study drug (either 
valsartan or sacubitril/valsartan) during the study may be done without the knowledge of 
the laboratory results; however, the results must be available and reviewed as soon as 
possible to ensure subject safety. Adverse events (AEs) and changes in concomitant 
medication(s) will be reported and documented throughout the study. 
Statistical methods:  
The study hypothesis is that short-term therapy with sacubitril/valsartan added on 
standard HF therapy improves cardiac efficiency in patients with systolic HF. Analysis of 
covariance (ANCOVA) will be used for statistical analysis, when appropriate. Other 
statistical analyses may also be implemented, as described in the statistical analysis plan 
(SAP).  
Efficacy: The difference in the primary (cardiac efficiency) and exploratory efficacy 
parameters will be evaluated by comparing change from baseline at visit 3 between 
treatment groups. Change from baseline will be analysed using an ANCOVA, adjusting 
for treatment, strata, and baseline. From this model the treatment difference will be 
estimated with a 95% confidence interval (CI). In addition, treatment by stratification 
interaction analyses will be performed for the primary efficacy parameters in order to 
estimate within stratification group differences. 
Safety: AEs reported during the study will be classified by system organ class (SOC) and 
preferred terms (PT) using the MedDRA coding system. The number and proportion (%) 
of subjects’ AEs will be presented by treatment and dose level and the severity and 
causality will be tabulated with subject and event counts. Systolic and diastolic BP and 
HR and laboratory safety variables and their changes from the baseline values will be 
evaluated and summarized using descriptive statistics by treatment and dose level. The 
laboratory values tabulated as low, normal or high according to their reference ranges 
and clinically significant laboratory abnormalities will be listed. 


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ABBREVIATIONS AND DEFINITION OF TERMS 
 
ACE 
 
Angiotensin-converting enzyme 
ACEI  
Angiotensin-converting enzyme inhibitor 
ADL 
 
Activities of daily living 
ADR  
Adverse drug reaction 
AE 
 
Adverse event 
ANCOVA 
Analysis of covariance 
AngII  
Angiotensin II 
ANP 
 
Atrial natriuretic peptide 
ARB 
 
Angiotensin II receptor blocker 
ARNI  
Angiotensin receptor/neprilysin inhibitor 
ATR 
 
Angiotensin receptor 
AUC  
Area under the concentration-time curve 
BID 
 
Twice a day 
BP 
 
Blood pressure 
CA 
 
Competent authority 
cGMP  
cyclic Guanosine monophosphate 
CI 
 
Confidence interval 
Cmax 
 
Peak plasma concentration 
CRF 
 
Case report form 
CRO  
Contract research organization 
CT 
 
Computed tomography 
CV 
 
Cardiovascular 
CV%  
Coefficient of variation 
DM 
 
Data management 
DMP  
Data management plan 
EC 
 
Ethics committee 
ECG  
Electrocardiogram 
(e)CRF 
(electronic) Case report form 
EDC  
Electronic data capture 
EF 
 
Ejection fraction 
eGFR  
estimated Glomerular filtration rate 
EMA  
European Medicines Agency 
EPAR  
European public assessment report 
ESC 
 
European Society of Cardiology 
FAS 
 
Full analysis set 
FDA 
 
Food and Drug Administration 
GCP  
Good Clinical Practice 
GFR  
Glomerular filtration rate 
GMP  
Good Manufacturing Practice 
HF 
 
Heart failure 
HR 
 
Heart rate 
IB 
 
Investigator’s Brochure 
IC 
 
Informed consent 
ICF  
 
Informed consent form 
ICH 
 
International Conference on Harmonization 
IMP  
 
Investigational medicinal product 
ISF 
 
Investigator’s study file 
iv. 
 
intravenous 
LSLV  
Last subject last visit 
LV 
 
Left ventricle 
LVIDD  
Left ventricular internal diastolic diameter 
LVOT  
Left ventricle outflow tract 
MedDRA 
Medical Dictionary for Regulatory Activities 


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MRA  
Mineralocorticoid receptor antagonists 
MR-proANP Mid-regional pro-atrial natriuretic peptide 
NCI 
 
National Coordinating Investigator 
NEP 
 
Neutral endopeptidase 
NHANES 
National Health and Nutrition Examination Survey 
NP 
 
Natriuretic peptide 
NSAID  
Non-steroidal anti-inflammatory drug 
NT-proBNP 
N-terminal prohormone brain natriuretic peptide 
NYHA  
New York Heart Association 
PET 
 
Positron emission tomography 
PPS 
 
Per protocol set 
PT 
 
Preferred term 
RAAS  
Renin-angiotensin-aldosterone system 
SAE 
 
Serious adverse event 
SAP 
 
Statistical analysis plan 
SBP 
 
Systolic blood pressure 
SOC  
System organ class 
SOP  
Standard operating procedure 
SPC 
 
Summary of Product Characteristics 
SUSAR 
Suspected unexpected serious adverse drug reaction 
SV 
 
Stroke volume 
SVR 
 
Systemic vascular resistance 
TCA 
 
Tricarboxylic acid cycle 
TMF 
 
Trial master file 
ULN 
 
Upper limit of normal 
WHO DD 
World Health Organization Drug Dictionary 
 
 
 
 


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1 
AMENDMENTS AND UPDATES 
 
Table 1 Substantial study protocol amendments and updates 
Number 
Date 
Section of 
study protocol 
Amendment or 
update 
Reason 
1.1 
04JAN2019 
Synopsis, 4.3, 
6.7, 7.1, 7.2 
The possibility to 
perform screening 
visit 2 and visit 2 as 
remote visits 
Reduce the number of 
site visits and thus the 
burden caused by the 
study on the subjects 
1.5 
24JUNE2020 
Synopsis, 5.3 
Changing the upper 
age limit of the 
eligible patients from 
75 to 80 years 
Improvement of 
recruitment rate. Several 
eligible study candidates 
have been aged between 
75 and 80 years. 
 
 
 
 
 
 
 
1.1 
The possibility to perform screening visit 2 and visit 2 as remote visits 
Date/version of change: 04JAN2019, protocol version 2.0 (amendment 1) 
Section: 
Synopsis; 4.3 General study outline; 6.7 Procedures for monitoring 
subject compliance; 7.1. Screening/run-in period; 7.2 Treatment period; 
Was:  
NA; updates to the protocol were done throughout the protocol text to 
reflect the changes described in Item 1.1. 
Should be: 
With protocol amendment 1, the possibility to perform screening visit 
2 and visit 2 as remote visits (with the exception of safety laboratory assessments) 
was added. As a result of this, the number of visits during the study altogether and 
during the treatment period was updated. Updates were made also to the general 
study design (Figure 1.) and general study outline (Table 3.).  
Reason: 
In order to reduce the number of site visits and thus the burden 
caused by the study on the subjects, screening visit 2 during the screening/run-in 
period and visit 2 during the treatment period may be performed as remote visits, if 
deemed sufficient by the investigator. It is of note that even if these visits are 
performed as remote visits, the protocol-specified safety laboratory tests have to be 
performed for each visit to ensure subject safety. Aside from the laboratory tests, 
other protocol-specified assessments for these visits may be performed remotely 
(e.g. adverse event and concomitant medication check) or omitted altogether (e.g. 
blood pressure measurement at site). This change, by reducing subject burden, is 
expected to have a favorable impact on subject recruitment and retention. Subject 
safety is not expected to be affected by this amendment as laboratory tests are still 
performed at each visit and the decision of remote/site visits is done by the 
investigator based on the laboratory results and overall clinical status of the subject. 
Subjects will be contacted by the study personnel via telephone or other method if 
the screening visit 2 and/or visit 2 are performed remotely so the subject will have 
an opportunity to report any subjective feelings/symptoms and ask questions, if 
necessary. 
 
1.2 
Safety blood samples may be collected 1-2 business day(s) before the scheduled 
study visits 
Date/version of change: 04JAN2019, protocol version 2.0 (amendment 1) 


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Section: 
4.3 General study outline; 7.2 Treatment period; 8.3.3 Laboratory 
safety assessments 
Was:  
NA; new text added to serve as clarification. 
Should be: 
It was added that safety blood samples may be collected 1-2 business 
day(s) before the scheduled study visits (with the exception of screening visit 1). 
Reason: 
This update was made to clarify the timing of safety blood samples. 
The timing of safety blood samples was not specified clearly in the previous protocol 
version (final version 1.0, 28Aug2017). With this clarification, the protocol text is now 
in line with the normal procedures of the study site and with the intent of the protocol. 
 
1.3 
Primary endpoint clarification 
Date/version of change: 04JAN2019, protocol version 2.0 (amendment 1) 
Section: 
3.1 Primary objective and endpoint 
Was:  
NA, 
additional 
text 
added 
to 
serve 
as 
clarification. 
Should be: 
Clarification on how the difference in cardiac efficiency will be 
evaluated. 
Reason: 
This update was made to clarify the primary endpoint of the study. 
The primary endpoint has not changed. The primary endpoint was not clearly stated 
in the previous version of the protocol (final version 1.0, 28Aug2017). With this 
clarification, the protocol text is now in line with how this calculation is described 
elsewhere in the protocol (section 9.2.6 Analysis of efficacy variables). 
 
1.4 
Physical examination clarification 
Date/version of change: 04JAN2019, protocol version 2.0 (amendment 1) 
Section:  
Table 3, 8.3.1 Physical examination 
Was:   
NA, new text added to serve as clarification 
Should be:  The procedure of the physical examination, i.e. examination of 
general appearance, as well as the cardio-vascular system as seen relevant by the 
investigator, for example lungs, heart and extremities, as well how this is reported, 
i.e. in the source documentation at site, has been added. 
Reason:  
This update was made to clarify the procedure of the physical 
examination, which was not clearly stated in the previous version of the protocol 
(final version 1.0, 28Aug2017). With this clarification, the protocol text is now in line 
with the normal procedures of the study site and with the intent of the protocol. 
 
 
 
In addition to the above mentioned changes, typographical errors, table and section 
numbers were also corrected in the protocol text. 
 
1.5 
Change of the inclusion criteria: the upper age limit of the eligible patients from 75 
to 80 years 
Date/version of change: 24JUNE2020, protocol version 3.0 (amendment 2) 
Section:  
Synopsis, 5.3 Inclusion criteria 


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Was:   
Age limits in the Inclusion criteria were ≥40 to ≤75 
Should be:  The upper age limit was changed throughout the protocol to ≤80 
Reason:  
As heart failure is a disease of the elderly, the site has noticed that 
many of the patients fulfill the other inclusion criteria but are aged between 75 and 
80 years. The investigators estimate that incresing the upper age limit of eligible 
patients to 80 years will decrease the recruitment time up to 4 months. 
 
 
 
 


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2 
INTRODUCTION 
2.1 
Background 
Heart failure (HF) is a clinical syndrome characterized by typical signs and 
symptoms caused by structural and/or functional cardiac abnormality and resulting 
in reduced cardiac output and/or elevated intracardiac pressures at rest or during 
stress. According to the European Society of Cardiology (ESC) guidelines published 
in 2016, the prevalence of HF is approximately 1–2% of the adult population in 
developed countries, rising to ≥10% among people >70 years of age (Ponikowski 
2016, Mosterd 2007, Redfield 2003, Ceia 2002). Based on data from National Health 
and Nutrition Examination Survey (NHANES) 2009 to 2012, an estimated 5.7 million 
Americans ≥20 years of age suffer from HF and projections show that the prevalence 
of HF will increase 46% from 2012 to 2030, resulting in > 8 million people ≥18 years 
of age with HF. In the USA, each year more than 550,000 new HF cases are 
diagnosed. Data from the Framingham Heart Study indicate that at the age of 40 
years, remaining lifetime risk of developing HF for both men and women is 1 in 5, 
while at 80 years of age, the remaining lifetime risk for development of new HF 
remains at 20% even with the shorter life expectancy. (Mozaffarian 2015, Hunt 
2009). In the Rotterdam Heart Study, the lifetime risk of HF at the age of 55 was 
33% for men and 29% for women (Bleumink 2004). The etiology of HF is diverse 
and may include different cardiovascular (CV) and/or non-cardiovascular 
pathologies (e.g. ischemic heart disease, toxic, metabolic and inflammatory damage 
to the heart). 
The symptoms of HF are most widely graded according to the New York Heart 
Association (NYHA) functional classification that is used to describe the severity of 
symptoms and exercise intolerance (The Criteria Committee of the New York Heart 
Association. (1994). Nomenclature and Criteria for Diagnosis of Diseases of the 
Heart and Great Vessels. (9th ed.). Boston: Little, Brown & Co. pp. 253–256.). The 
NYHA classes and the associated symptoms are presented in Table 2 below.  
 
 
Table 2. NYHA classes and associated symptoms 
 
NYHA 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary 
physical activity, e.g. no shortness of breath when walking, climbing 
stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight 
limitation during ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-
ordinary activity, e.g. walking short distances (20–100 m). 
Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly 
bedbound patients. 
 


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The diagnosis of HF includes evaluation of cardiac function by patient interview and 
examination, laboratory tests and different imaging modalities. The typical signs and 
symptoms of HF include e.g. breathlessness, ankle swelling, reduced exercise 
tolerance and fatigue, elevated jugular venous pressure, pulmonary crackles, gallop 
rhythm and peripheral oedema. The plasma concentration of natriuretic peptides 
(NPs) is usually used as an initial diagnostic test in HF. Electrocardiogram (ECG) is 
also often recorded and an abnormal ECG increases the likelihood of the diagnosis 
of HF, even though ECG has low specificity (van Riet 2014, Kelder 2011, Davie 
1996, Thomas 2002). Some abnormalities on the ECG however may provide 
information on etiology (e.g. myocardial infarction) and indications for therapy (e.g. 
anticoagulation for atrial fibrillation, need for a pacemaker).  
Among the imaging modalities, echocardiography is the most useful and widely 
available test in patients with suspected HF to establish the diagnosis. It provides 
immediate information on chamber volumes, ventricular systolic and diastolic 
function, wall thickness, valve function and pulmonary hypertension (Paulus 2007, 
Marwick 2010, Dokainish 2011, Kirkpatrick 2007, Nagueh 2011, Caballero 2015, 
Garbi 2015, Lang 2015, Gimelli 2014, Voigt 2015). This information is crucial in 
establishing the diagnosis and in determining appropriate treatment. Other cardiac 
imaging modalities that may help diagnosis or provide information on the etiology, 
include 
e.g. 
chest 
X-ray, 
transesophageal 
echocardiography, 
stress 
echocardiography, magnetic resonance imaging, computed tomography (CT), 
coronary angiography, single-photon emission CT and positron emission 
tomography (PET). (Ponikowski 2016). 
Over the last 30 years, improvements in the treatments and in their implementation 
have improved survival and reduced the rate of hospitalization in patients with HF 
with reduced ejection fraction (EF) (Hubers 2016, Maggioni 2013). According to the 
guidelines for the diagnosis and treatment of acute and chronic heart failure 
published by the ESC in 2016, the pharmacological treatments indicated in patients 
with symptomatic (NYHA class II-IV) HF with reduced EF include the following: 
angiotensin-converting 
enzyme 
inhibitor 
(ACEI), 
beta-blockers 
and 
mineralocorticoid receptor antagonists (MRA). In selected HF patients, also the 
following treatments may be indicated: diuretics to reduce the signs and symptoms 
of congestion; angiotensin II receptor blockers (ARB) in patients who do not tolerate 
ACEI; angiotensin receptor/neprilysin inhibitor (ARNI) to replace ACEI or ARB in 
patients that are still symptomatic. (Ponikowski 2016). Recent European data (ESC-
HF pilot study) demonstrate that 12-month all-cause mortality rates for hospitalized 
and stable/ambulatory HF patients were 17% and 7%, respectively, and the 12-
month hospitalization rates were 44% and 32%, respectively (Maggioni 2013). In 
patients with HF (both hospitalized and ambulatory), most deaths are due to CV 
causes, mainly sudden death and worsening HF. All-cause mortality is generally 
higher in HF with reduced EF than with preserved EF. (Ponikowski 2016, Maggioni 
2013, Pocock 2013). 
 


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2.2 
Valsartan 
The following information on the indication and pharmacodynamics and –kinetics of 
valsartan is based on the European public assessment reports (EPAR) – product 
information, annex 1. 
Valsartan is an orally active, potent and specific angiotensin II (Ang II) receptor 
antagonist. It acts selectively on the AT1 receptor subtype, which is responsible for 
the known CV actions of Ang II. Blocking the AT1 receptor prevents sustained 
activation of the renin-angiotensin-aldosterone system (RAAS) that would result in 
vasoconstriction, renal sodium and fluid retention, activation of cellular growth and 
proliferation, and subsequent maladaptive CV remodeling. Valsartan has a much 
greater affinity (about 20,000 fold) for the AT1 receptor than for the AT2 receptor but 
the increased plasma levels of Ang II following AT1 receptor blockade may stimulate 
the unblocked AT2 receptor. Valsartan is not known to bind to or block other 
hormone receptors or ion channels known to be important in CV regulation nor does 
it inhibit the angiotensin converting enzyme (ACE). Therapeutic indications of 
valsartan include hypertension, recent myocardial infarction and HF. (Burnier 2001, 
Hubers 2016). 
In the Val-HeFT clinical trial valsartan was compared with placebo on morbidity and 
mortality in over 5000 NYHA class II (62%), III (36%) and IV (2%) HF patients 
receiving standard therapy. The mean duration of follow-up in this trial was nearly 
two years and the mean daily dose of valsartan was 254 mg. All-cause mortality was 
similar (p=not significant) in the valsartan (19.7%) and placebo (19.4%) groups. The 
primary benefit was a 27.5% (95% confidence interval [CI]: 17 to 37%) reduction in 
risk for time to first HF hospitalization (13.9% vs. 18.5%). In a subgroup of patients 
not receiving ACEI at baseline (n=366), the morbidity benefits were the greatest. In 
this subgroup all-cause mortality was significantly reduced (by 33%, 95% CI: –6% 
to 58%) with valsartan compared to placebo (17.3% valsartan vs. 27.1% placebo) 
and the composite mortality and morbidity risk was significantly reduced by 44% 
(24.9% valsartan vs. 42.5% placebo). In the overall Val-HeFT population, valsartan 
treated patients showed significant improvement in NYHA class and HF signs and 
symptoms, including dyspnea, fatigue, oedema and rales, compared to placebo. 
Patients treated with valsartan had a better quality of life as demonstrated by change 
in the Minnesota Living with Heart Failure Quality of Life score. EF was also 
significantly increased and left ventricular internal diastolic diameter (LVIDD) 
significantly reduced from baseline in valsartan treated patients. (Maggioni 2002, 
Cohn 2001, Cohn 2000, Cohn 1999). 
For HF indication, the recommended starting dose of valsartan is 40 mg BID. Up-
titration to 80 mg and 160 mg BID (to the highest dose tolerated by the patient) is 
usually done at intervals of at least two weeks. The maximum daily dose 
administered in clinical trials has been 320 mg in divided doses. Valsartan may be 
administered with other HF therapies. 
According to the information given in the EPAR – product information (annex 1) on 
the pharmacokinetics of valsartan, following oral administration of valsartan alone, 
peak plasma concentrations (Cmax) are reached in 2–4 hours. The mean absolute 
bioavailability of valsartan is approximately 23%. Food decreases exposure (as 


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measured by the area under concentration-time curve [AUC]) by about 40% and 
Cmax by about 50%. This reduction in AUC is not, however, accompanied by a 
clinically significant reduction in the therapeutic effect. AUC and Cmax values are 
almost proportional with increasing dose over the clinical dosing range (40 to 160 
mg twice a day [BID]). Valsartan is highly bound to serum proteins (94–97%), mainly 
to serum albumin. Valsartan is not biotransformed to a high extent; only about 20% 
of dose is recovered as metabolites. Valsartan is primarily eliminated by biliary 
excretion in feces (about 83% of dose) and renally in urine (about 13% of dose), 
mainly as unchanged drug. No dosage adjustment is required for patients with a 
creatinine clearance >10 ml/min. The elimination half-life of valsartan is 
approximately 6 hours. The average time to peak concentration and elimination half-
life of valsartan in HF patients are similar to those observed in healthy volunteers. 
(Burnier 2001). 
 
2.3 
Sacubitril/valsartan 
The following information on the indication and pharmacodynamics and –kinetics of 
sacubitril/valsartan is based on the EPAR – product information, annex 1. 
Sacubitril/valsartan (LCZ696) is a sodium salt complex that comprises of two active 
components, sacubitril and valsartan, and is marketed under the name Entresto™. 
It exhibits the mechanism of action of an ARNI by simultaneously inhibiting neprilysin 
(neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug 
sacubitril, and by blocking the AT1 receptor via valsartan. The complementary CV 
benefits of sacubitril/valsartan in HF patients are attributed to the enhancement of 
peptides that are degraded by neprilysin, such as NPs, and the simultaneous 
inhibition of the effects of Ang II. NPs exert their effects by activating membrane-
bound guanylyl cyclase-coupled receptors, resulting in increased concentrations of 
the second messenger cyclic guanosine monophosphate (cGMP), which can result 
in vasodilation, natriuresis and diuresis, increased glomerular filtration rate (GFR) 
and renal blood flow, inhibition of renin and aldosterone release, reduction of 
sympathetic activity, and anti-hypertrophic and anti-fibrotic effects. (Hubers 2016, 
Gu 2010, Volpe 2014). For valsartan’s mechanism of action, please refer to Section 
2.2. 
Sacubitril/valsartan is indicated in adult patients for treatment of symptomatic 
chronic HF with reduced EF. The pharmacodynamic effects of sacubitril/valsartan 
were evaluated after single and multiple dose administrations in healthy subjects 
and in patients with HF, and are consistent with simultaneous neprilysin inhibition 
and RAAS blockade (Gu 2010). In a 7-day valsartan-controlled study in HF patients 
with reduced EF, administration of sacubitril/valsartan resulted in an initial increase 
in natriuresis, increased urine cGMP, and decreased plasma levels of mid-regional 
pro-atrial natriuretic peptide (MR-proANP) and N-terminal prohormone brain 
natriuretic peptide (NT-proBNP) compared to valsartan. In a 21-day study in HF 
patients with reduced EF, sacubitril/valsartan significantly increased urine atrial 
natriuretic peptide (ANP) and cGMP and plasma cGMP, and decreased plasma NT-
proBNP, aldosterone and endothelin 1 compared to baseline. The AT1-receptor was 


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also blocked as evidenced by increased plasma renin activity and plasma renin 
concentrations. (Kobalava 2016). 
In the large phase III PARADIGM-HF study, sacubitril/valsartan decreased plasma 
NT-proBNP and increased plasma BNP and urine cGMP compared with enalapril. 
PARADIGM-HF was a multinational, randomized, double-blind study of over 8400 
patients comparing sacubitril/valsartan to enalapril, both given to adult patients with 
chronic HF, NYHA class II-IV and reduced EF (≤40%, amended later to ≤35%), in 
addition to standard HF therapy. During the double-blinded period of the study, the 
subjects received either sacubitril/valsartan 200 mg or enalapril 10 mg BID 
[sacubitril/valsartan (n=4209); enalapril (n=4233)]. In the study, sacubitril/valsartan 
was superior to enalapril in reducing the risk of CV death or HF hospitalizations to 
21.8% compared to 26.5% for enalapril treated patients. The absolute risk 
reductions were 4.7% for the composite of the CV death or HF hospitalization, 3.1% 
for CV death alone, and 2.8% for first HF hospitalization alone. The relative risk 
reduction was 20% versus enalapril. This effect was observed early and was 
sustained throughout the duration of the study. The risk reduction was consistently 
observed across subgroups including gender, age, race, geography, NYHA class 
(II/III), EF, renal function, history of diabetes or hypertension, prior HF therapy, and 
atrial fibrillation. Sacubitril/valsartan improved survival with a significant reduction in 
all-cause mortality of 2.8% (sacubitril/valsartan, 17%, enalapril, 19.8%). The relative 
risk reduction was 16% compared with enalapril. PARADIGM-HF trial was stopped 
early at the third interim analysis because the pre-specified stopping boundary for 
an overwhelming benefit of sacubitril/valsartan had been crossed. (Hubers 2016, 
McMurray 2014 /N Engl J Med, McMurray 2014 /Eur J Heart Fail, McMurray 2013). 
The recommended starting dose of sacubitril/valsartan is one tablet of 49 mg/51 mg 
BID. The dose should be doubled at 2-4 weeks to the target dose of one tablet of 97 
mg/103 mg BID, as tolerated by the patient. According to current recommendations 
found in the Summary of Product Characteristics (SPC) of sacubitril/valsartan, if 
patients experience tolerability issues (systolic blood pressure [BP[ ≤95 mmHg, 
symptomatic hypotension, hyperkalemia, renal dysfunction), adjustment of 
concomitant medications or temporary down–titration or discontinuation of 
sacubitril/valsartan is recommended. No dose adjustment is required in patients with 
mild renal impairment (estimated GFR [eGFR] 60-90 ml/min/1.73 m2) while a starting 
dose of 24 mg/26 mg twice daily is recommended in patients with moderate renal 
impairment (eGFR 30-60 ml/min/1.73 m2). 
According to the information given in the EPAR – product information (annex 1) on 
the pharmacokinetics of sacubitril/valsartan, following oral administration, 
sacubitril/valsartan dissociates into valsartan and the prodrug sacubitril. Sacubitril is 
further metabolized to the active metabolite LBQ657 by carboxylesterases 1b and 
1c. Sacubitril and LBQ657 reach peak plasma concentrations in 1 hour and 2 hours, 
respectively. They are highly bound to plasma proteins (94-97%). LBQ657 is not 
further metabolized to a significant extent. Approximately 50-70% of sacubitril 
(primarily as LBQ657) is excreted in urine and 30-50% in feces. Sacubitril, LBQ657 
and valsartan are eliminated from plasma with a mean elimination half-life of 
approximately 1.4 hours, 11.5 hours, and 9.9 hours, respectively. The 
pharmacokinetics of sacubitril, LBQ657 and valsartan are approximately linear over 


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a sacubitril/valsartan dose range of 24 mg sacubitril/26 mg valsartan to 97 mg 
sacubitril/103 mg valsartan. The valsartan contained within sacubitril/valsartan is 
more bioavailable than the valsartan in other marketed tablet formulations; 26 mg, 
51 mg, and 103 mg of valsartan in sacubitril/valsartan are equivalent to 40 mg, 80 
mg and 160 mg of valsartan, respectively. (Gu 2010, Hubers 2016). 
 
2.4 
11C-acetate 
11C-acetate is mainly used for quantification of oxidative metabolism and perfusion. 
Acetate is quickly metabolized into acetyl-CoA in living tissues. Acetyl-CoA can then 
either enter into the Krebs cycle (tricarboxylic acid or TCA cycle) which is the main 
route in the myocardium, or it can enter into structural lipids, mainly in tumours. 
(Grassi 2012).  
After intravenous (iv.) injection of 11C-acetate, the build-up phase of radioactivity in 
the tissue is related (but not linearly) to tissue perfusion. Washout of the radiolabel 
represents the formation of 11C-CO2 in tissue, and is therefore related to oxygen 
consumption (Buck 1991; Klein 2001). Uptake at later time points may represent the 
rate of fatty acid synthesis (Lewis 2014). 
Clearance of 11C-acetate from the myocardium has been found to be bi-exponential 
(Brown 1988, Brown 1989, Armbrecht 1989). The k1 from bi-exponential and kmono 
from mono-exponential clearance estimation are correlated to myocardial oxygen 
consumption (Buxton 1989, Armbrecht 1989, Sun 1998, Ukkonen 2001, Wong 
2013). Parametric kmono images can be computed and presented as polar maps 
(Kotzerke 1990, Miller 1990). 
Several compartmental models have been presented to estimate myocardial oxygen 
consumption, as reviewed by Klein et al. in 2001. One-tissue compartment model 
analysis of 11C-acetate data allows also quantification of myocardial perfusion at rest 
as well as under stress conditions (van den Hoff 2001, Sciacca 2001, Sörensen 
2010). This model is a simplification of previous five-compartment model (van den 
Hoff 1996), and performed best in comparison to three other models (Timmer 2010). 
It was found to provide myocardial blood flow values in fairly good agreement with 
actual perfusion values in both healthy individuals and patients with hypertrophic 
cardiomyopathy over physiological ﬂow ranges under baseline conditions (Timmer 
2010), and a reliable index (k2) of oxygen consumption (Wong 2013). Arterial blood 
curve is extracted from left ventricular region, and corrected for metabolism using 
population-based function. The most common method of analyzing myocardial 
oxygen consumption is based on mono-exponential fitting of clearance rate (kmono) 
(Armbrecht 1989). 
 
2.5 
Rationale of the study 
Even though proven effective in terms of clinical outcomes, mechanistic data about 
the effects of the novel ARNI sacubitril/valsartan are needed in patients with HF and 
reduced EF. The clinical benefits of sacubitril/valsartan (reduced hospitalizations 
and improvement of symptoms) can be seen within 30 days after the onset of 


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therapy, but the underlying functional mechanisms are not known (Hubers 2016, 
McMurray 2014 /N Engl J Med).  
Mechanical efficiency of the heart is defined as the ratio of useful energy produced 
(i.e. stroke work) to the amount of oxygen consumed. Excessive oxygen 
consumption in relation to mechanical work, i.e. reduced efficiency of forward work, 
is a typical feature of the failing heart. (Knaapen 2008). Previous studies have shown 
that cardiac efficiency can be improved by therapies that improve symptoms and 
clinical outcomes in HF, including cardiac resynchronization therapy, inhibition of 
beta-adrenergic system and inhibition of the RAAS (Knaapen 2007). ACEIs reduce 
mean aortic pressure and systemic vascular resistance (SVR) (Burnier 2001). 
Because of the related reduction in the LV load, there is an immediate increase in 
stroke volume and stroke work while myocardial oxygen consumption is lowered, 
thereby augmenting mechanical efficiency. Decreased degradation of NPs with 
sacubitril/valsartan encounters natriuretic resistance in HF resulting in improved 
endothelial function, vasodilatation and natriuresis (Hubers 2016). However, it is not 
known whether these beneficial hemodynamic effects result in improved efficiency 
of the LV work.  
Cardiac oxidative metabolism can be measured non-invasively using 11C-acetate 
PET. Changes in cardiac efficiency can be seen faster (days-to-weeks) than 
structural changes in LV volume (months-to-years) (Knaapen 2007, Tuunanen 
2008). Our hypothesis is that short-term therapy with sacubitril/valsartan added on 
standard HF therapy improves cardiac efficiency in patients with systolic HF. 
 
2.6 
Risk assessment 
Based on the information presented in the SPC of valsartan, in controlled clinical 
studies with valsartan in patients with hypertension, the overall incidence of adverse 
drug reactions (ADRs) was comparable with placebo and was consistent with the 
pharmacology of valsartan. The safety profile seen in controlled clinical studies in 
patients with post-myocardial infarction and/or HF varied somewhat from the overall 
safety profile seen in hypertensive patients. This was speculated to be related to the 
patients’ underlying disease. Renal failure and renal impairment are described as a 
common (≥ 1/100 to < 1/10) ADRs with valsartan. (Cohn 2001).  
The most commonly reported adverse reactions during sacubitril/valsartan 
treatment are hypotension, hyperkalemia and renal impairment. Angioedema, but 
not airway compromise, has also been reported in patients treated with 
sacubitril/valsartan. The safety of sacubitril/valsartan in patients with chronic HF was 
evaluated in the study PARADIGM-HF. Hyperkalemia and serum potassium 
concentrations 
>5.4 
mmol/l 
were 
reported 
in 
11.6% 
and 
19.7% 
of 
sacubitril/valsartan-treated patients and in 14.0% and 21.1% of enalapril-treated 
patients, respectively, whereas hypotension and clinically relevant low systolic BP 
(<90 mmHg and decrease from baseline of >20 mmHg) were reported in 17.6% and 
4.76% of sacubitril/valsartan-treated patients compared with 11.9% and 2.67% of 
enalapril-treated patients, respectively. Discontinuation of therapy due to an adverse 
reaction in the double-blind period of the study occurred in 450 sacubitril/valsartan-
treated patients (10.7%) and 516 enalapril-treated patients (12.2%). Based on the 


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information presented in the SPC of sacubitril/valsartan, other very common (≥1/10) 
and common (≥1/100 to <1/10) adverse reactions during sacubitril/valsartan 
treatment include e.g. anemia, hypokalemia, hypoglycemia, headache, cough, 
diarrhea, nausea, gastritis, fatigue and asthenia. (Hubers 2016, McMurray 2014 /N 
Engl J Med). 
Marked hypotension is the most likely symptom of overdose with both valsartan and 
sacubitril/valsartan, due to their BP lowering effects (Hubers 2016, McMurray 2014 
/N Engl J Med, Cohn 2001). Marked hypotension can lead to depressed level of 
consciousness, circulatory collapse and/or shock. In cases of marked hypotension, 
symptomatic treatment should be provided. 
Regarding other concomitant medications that may be used by the study subjects, 
the following possible interactions have to be considered: according to the SPC, 
concomitant use of valsartan is not recommended with potassium-sparing diuretics, 
potassium supplements, salt substitutes containing potassium and other substances 
that may increase potassium levels. Caution is required when valsartan is used 
concomitantly with non-steroidal anti-inflammatory medicines (NSAIDs), including 
selective COX-2 inhibitors and acetylsalicylic acid >3 g/day. 
In vitro data indicate that sacubitril inhibits organic anion-transporting polypeptide 
OATP1B1 and OATP1B3 transporters. Sacubitril/valsartan may therefore increase 
the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins and 
caution should be exercised when co-administering these medications. (Hubers 
2016). Other drugs that may have possible interactions with sacubitril/valsartan 
include NSAIDs, potassium containing or elevating drugs, lithium, furosemide and 
nitrates.  
This study involves two PET-scans with 11C-acetate. These scans cause exposure 
to ionizing radiation, which is harmful to living organisms. The total radiation dose 
from two up to 500 MBq 11C-acetate PET tracer injections and low-dose CT scans 
for attenuation correction will be 7.5 mSv.  
The current study with its design, including specific inclusion and exclusion criteria 
and study schedule and procedures, is aimed to minimize the risks (e.g. previously 
described possible adverse reactions and possible drug interactions) on subjects 
while participating in this study. Subject safety will be monitored throughout the study 
and the investigators will have the option to down-titrate the dose of the study 
medication or discontinue the subject’s participation in the trial altogether, if they 
think that continuation would be detrimental to the subject’s well-being. Subjects will 
be advised to contact the study site if they have new/worsening symptoms they feel 
may be due to the study treatment and/or instability of their HF therapy. During the 
scheduled visits, subject safety will be monitored with BP measurements (at site 
visits) and laboratory tests (including serum potassium and creatinine). 
Unscheduled visits may be performed at any time, if required, based on the 
investigator’s clinical judgement.  
 
 


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3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Primary objective and endpoint 
The primary objective of the study is to evaluate the effects of 6 weeks of stable 
sacubitril/valsartan therapy, as compared with valsartan therapy, on the efficiency 
of cardiac work in patients with NYHA II-III HF and reduced systolic function using 
11C-acetate and echocardiography.  
In order to do this, the difference in cardiac efficiency will be evaluated by comparing 
the results obtained after 6 weeks of stable treatment to the results from the baseline 
visit. 
 
3.2 
Exploratory objectives and endpoints 
The exploratory objective of the study is to evaluate the effects of 6 weeks of stable 
sacubitril/valsartan therapy, as compared with valsartan therapy, on myocardial 
oxygen consumption and cardiac and systemic hemodynamics.  
In order to do this, the difference in the following cardiac and systemic hemodynamic 
parameters will be evaluated as exploratory endpoints: EF, NT-proBNP, systemic 
BP, SVR, coronary vascular resistance and cardiac oxygen consumption. 
 
 
4 
STUDY DESIGN 
4.1 
Type and design of the study 
This is a phase IV, prospective, randomized, double-blind, double-dummy, parallel-
group study performed at a single center that is formed by 
 
. The subjects enrolled into this study 
will be patients with chronic HF who fulfill all of the inclusion criteria and none of the 
exclusion criteria. No more than 50% of the study subjects are allowed to have 
diabetes. The study will have two treatment arms, the sacubitril/valsartan treatment 
arm and the valsartan treatment arm, and the subjects will be randomized into these 
arms in a 1:1 ratio. The study will be performed in a double-blind manner in regards 
to the treatment the subjects receive during the treatment period. As the 
sacubitril/valsartan and valsartan tablets are not similar in appearance, the study will 
be performed in a double-dummy manner in order to maintain blinding, i.e. the 
subjects will take 2 tablets BID, either active valsartan + placebo for 
sacubitril/valsartan or active sacubitril/valsartan + placebo for valsartan. Regardless 
of the treatment arm a subject is in, the study drug will be up-titrated to the highest 
tolerated dose level during the scheduled study visits. The different strengths of the 
two study drugs are not identical in appearance so the possible dose modification(s) 
during the treatment period cannot be performed in a blinded manner. Subjects will 
start on valsartan 80 mg BID or sacubitril/valsartan 100 mg BID dose and there will 
be only one scheduled up-titration visit after the randomization. Exception for this 
are the subjects that are on valsartan 160 mg BID dose during the run-in phase. 


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These subjects will be randomized directly to valsartan 160 mg BID or 
sacubitril/valsartan 100 mg BID. Subjects that are randomized to valsartan arm will 
have similar visit after which they will continue on the same dose. For subjects that 
were randomized from valsartan 160 mg BID to sacubitril/valsartan 100 mg BID the 
dose will be up-titrated to 200 mg BID if clinically possible. If clinically indicated, dose 
alterations will be allowed up to week 4 after randomization. In order to be eligible 
for the final study assessments on visit 3 (i.e. the 11C-acetate PET-scan and 
echocardiography), the subjects have to be on a stable dose for at least 6 weeks on 
one of the following treatment options: valsartan 80 mg BID or 160 mg BID or 
sacubitril/valsartan 100 mg BID or 200 mg BID. Study drug dispensing during the 
treatment period will be performed by an unblinded member of the study team and 
the study drugs will be self-administered by the subjects at home. To achieve similar 
groups, the number of subjects with renal insufficiency (GFR 45-60 or >60 
mL/min/1.73m2) and/or diabetes mellitus (on insulin or oral glucose-lowering 
therapy) will be balanced in the treatment arms by stratified randomisation. The 
baseline HF therapy (the number of subjects that are on valsartan 160 mg BID at 
the time of randomization) will be also balanced between the treatment arms.  
 
4.2 
Randomization and blinding 
The subjects will be randomized in a 1:1 ratio to one of the two treatment arms, 
either the sacubitril/valsartan treatment arm or the valsartan treatment arm. 
Stratified randomization will be used to achieve similar groups in terms of patients 
with renal insufficiency (GFR 45-60 or >60 mL/min/1.73m2) and/or diabetes mellitus 
(on insulin or oral glucose-lowering therapy, no more than 50 % of patients in the 
study are allowed to be diabetic). The baseline HF therapy (the number of subjects 
that are on valsartan 160 mg BID at the time of randomization) will also be taken 
into account during randomization. 
Study drug packages will be provided from Novartis with removable labels stating 
the treatment. Treatment allocation will be done by an un-blinded member of the 
study team who will remove the labels stating the treatment before distributing the 
study drug packages to the subjects. 
The randomization will be generated by an independent statistician at 
 using 
SAS®. 
Sealed envelopes containing the individual treatment codes (randomization number 
and the corresponding treatment) will be stored adjacent to the investigational 
medicinal products (IMPs) until the end of the trial. In case of an emergency requiring 
immediate knowledge of the treatment administered, the code of an individual 
subject may be opened. The reasons for opening the code have to be documented 
and the subject has to be discontinued from the study. The study monitor and the 
sponsor should be immediately informed about breaking of the treatment code.  
This study will be conducted in a double-blinded fashion regarding the treatment (i.e. 
sacubitril/valsartan or valsartan). As the sacubitril/valsartan and valsartan tablets 
differ in appearance, the study has to be performed in a double-dummy manner with 
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strengths of the two study drugs are not identical in appearance so the possible dose 
modification(s) during the treatment period cannot be performed in a blinded 
manner. However, the up-titration step will be aligned in both treatment arms – the 
subjects will start on valsartan (80 mg BID or 160 mg BID) or sacubitril/valsartan 
(100 mg BID) and there will be only one scheduled up-titration visit after the 
randomization. The subjects that start from valsartan 160 mg BID will have similar 
scheduled visit but will stay on the same dose. 
Valsartan used in the screening/run-in period will be taken from local commercial 
stock and will be labelled by Tamro. Study drugs for the treatment period of this 
study are manufactured by Novartis, in accordance with Good Manufacturing 
Practice (GMP) guidelines. Supplies for the study will be packed and labelled in 
compliance with GMP regulations and then released at Novartis. The different 
strengths of the study drugs and the corresponding placebo tablets will be packed 
in separate study drug packages and an appropriate number of these study drug 
packages will be provided to the study site. The study drug packages containing the 
different strengths of the specific treatment (i.e. sacubitril/valsartan or valsartan) and 
placebo will be labelled in a way that does not reveal the treatment arm; the 
removable labels stating the treatment will be removed before dispensing the 
packages to the subjects. The possible up-titration of the study drug dose will be 
decided by the investigator based on the subject’s clinical status and safety 
assessments. A schematic figure on the treatment arms and the possible doses is 
given in Section 6.1 (Figure 2 and 3). 
At screening visit 1, subjects who have signed the Informed Consent form (ICF) will 
be given screening numbers beginning from 1-1001. Once enrollment has been 
confirmed, subjects will receive randomization numbers from the stratum-specific list 
and will be allocated to the treatment assigned to each randomization number as 
indicated by the randomization lists. If an enrolled subject discontinues the study, 
the investigator (after consulting with the sponsor) will decide on a case-by-case 
basis about including an additional subject into the study.  
 
4.3 
General study outline 
The total duration of the study is planned to be about 14 weeks for each subject, but 
it may be longer if required for scheduling purposes (e.g. availability of PET slots, 
subject’s schedule). During the study, the subjects will have 5-6 study visits, 
depending on the need for safety visits (visit 2; see Table 3). Two of these visits, 
screening visit 2 and visit 2, may performed as a remote visit (i.e. telephone contact), 
if deemed sufficient by the investigator. In addition, unscheduled visits may occur at 
any time, if considered necessary for subject safety. The study includes a 
screening/run-in period (up to 6 weeks) and a treatment period (approximately 8 
weeks). Both the screening/run-in and the treatment period may be longer, if 
necessary (see Section 7.1 for further details). 
The subjects who sign the ICF will enter the screening/run-in period of the study. All 
study-related procedures will be performed only after the ICF has been signed. 
During the first study visit, the investigator will consider the subject’s eligibility based 
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these considerations, the subject is found to be likely to fulfill all of the inclusion 
criteria and none of the exclusion criteria, the subject will be switched to valsartan 
treatment and it will replace his/her previously used ACEI or ARB treatment during 
the screening/run-in period. The starting dose of valsartan will be 80 mg BID or if 
the dose of previous RAAS blockage medication has been higher, the valsartan 
dose will be 160 mg BID to ensure that the subjects’ medication level is not down-
titrated in the beginning of the screening/run-in period. Approximately one week after 
the screening visit 1, screening visit 2 will be scheduled in order to evaluate the 
safety and efficacy of the ongoing valsartan treatment. If deemed sufficient by the 
investigator, screening visit 2 can be performed remotely. If so, safety blood 
sampling, eligibility criteria review, adverse events and concomitant medication must 
be assessed. Only subjects who tolerate 80 mg BID or 160 mg BID of valsartan and 
can maintain a stable dose for at least 4 weeks will be eligible to enter into the 
treatment period.  
After the screening evaluations and confirmation of eligibility, the subjects will be 
allocated randomization numbers and randomized to receive the treatment assigned 
to each number in a blinded manner. Study drugs will be dispensed by an unblinded 
member of the study team member during the treatment period while the study 
personnel directly involved in the clinical assessments will remain blinded 
throughout the study. The starting dose for each subject in the sacubitril/valsartan 
arm will be 100 mg BID and in the valsartan arm 80 mg BID or 160 mg BID (see 
Figures 2 and 3). The study subjects will return to the study center 2-3 times during 
the treatment period at the following time points: approximately 2 weeks (visit 1), 3 
weeks (visit 2) and 8 weeks (visit 3) after the start of the treatment period. 
During visit 1, treatment tolerability will be evaluated and possible dose up-titration 
will be considered. Every subject should be attempted to be up-titrated to the next 
dose level (sacubitril/valsartan 200 mg or valsartan 160 mg, if the latter needed), if 
clinically possible. If up-titration is not possible, the starting dose should be 
maintained. The intent of visit 2 (week 3) is to confirm subject safety on the dose 
level that is likely to be maintained for the rest of the study. If deemed sufficient by 
the investigator, visit 2 can be performed remotely. If so, safety blood sampling, 
adverse events and concomitant medication must be assessed. 
After visit 2, if clinically indicated, the dose of the study treatment may be modified 
(up- or down-titrated) up to week 4. If study drug dose is modified within this time, 
an unscheduled visit should be performed to assess subject safety on the new dose 
level. During the treatment period, the subjects will self-administer two tablets from 
two study drug packages BID (one tablet from the study drug package containing 
the active treatment and one tablet from the study drug package containing the 
placebo). The last study visit will include the final efficacy assessments, i.e. the 11C-
acetate PET-scan and the echocardiography. 
The general study design is presented in Figure 1 and the study outline is presented 
in Table 3. The methods and timing of assessments and recording of efficacy, safety, 
tolerability and other measures are described in detail in Section 8.  
 
 
 


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Figure 1. General study design 
 
 
Screening visit 2 and visit 2 are marked with (x) as they may be performed remotely, if 
deemed sufficient by the investigator. In addition, visit 2 may be omitted altogether, if 
no dose modification was made on the previous visit (visit 1). 
 
 
 




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R – If deemed sufficient by the investigator, screening visit 2 and visit 2 can be 
performed remotely (i.e. by telephone). If so, safety blood sampling, (eligibility 
criteria for screening visit 2 only), adverse events and concomitant medication must 
be assessed. If the visit is performed as a remote visit, assessments marked with 
“*” do not need to be performed. 
1 Visit 2 is a safety visit to be performed only for subjects whose dose was modified 
on visit 1 and/or if clinically indicated based on the investigator’s decision. For 
subjects whose dose is not up-titrated on visit 1, visit 2 may be omitted. 
2 Visit 3 will be performed after the study treatment has been on a stable dose for a 
minimum of 6 weeks. It may be performed before or after 8 weeks, based on when 
the last dose modification was performed. 
3 Physical examination is part of clinical assessment and will take place on every site 
visit. 
4 Blood pressure and heart rate will be measured in a seated position, after at least 
5 min of rest. 
5 Safety blood samples may be collected 1-2 business day(s) before the scheduled 
visit (with the exception of screening visit 1). 
6 For female subjects of childbearing potential. 
7 Study drugs will be dispensed by an unblinded member of the study team during 
the double-blinded treatment period. Valsartan may be dispensed by any member 
of the study team during the screening/run-in period.  
8 Instructions on drug intake have to be given at the start of each period and 
thereafter only if clinically indicated or significant non-compliance is detected. 
9 These study events include both the valsartan treatment during the screening/run-
in period and the double-blinded study drug treatment during the treatment period. 
 
 
5 
SUBJECTS 
5.1 
Source population 
The subjects participating in this study will be patients with chronic HF, reduced EF 
and NYHA class II-III symptoms who fulfill all of the inclusion criteria and none of the 
exclusion criteria. The results of the screening evaluations will determine whether a 
subject can be included in the study or not. 
 
5.2 
Number of subjects 
The planned number of enrolled study subjects is 60 (30 subjects/treatment arm). 
The aim is that at least 27 subjects/treatment arm finish the study according to the 
protocol. If discontinuations occur, the need of recruiting additional subjects to reach 
the targeted total number of subjects will be considered and carried out as 
appropriate. Thus, in case of discontinuations during the study, the number of 
enrolled study subjects may be larger than 60. 
For justification of sample size, see Section 9.1.  
 


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5.3 
Inclusion criteria 
Subjects have to fulfill all of the following inclusion criteria to be eligible for inclusion 
in this study.  
1. Voluntary, valid written informed consent (IC) obtained before any study-related 
assessment is performed. 
2. Sufficient command of the Finnish or Swedish language to be able to fully 
understand the ICF and other study information and to be able to communicate with 
the study personnel. 
3. Male and female subjects ≥40 and ≤80 years of age. 
4. Documented chronic HF with left ventricle EF 25-35% and NYHA class II-III 
symptoms. 
5. Systolic BP 110-160 mmHg at the time of randomization. 
6. Optimal standard HF therapy according to ESC guidelines, including at a minimum 
beta-blockers in all subjects, at a stable dose for at least 4 weeks before the first 
screening visit. 
7. Valsartan treatment tolerated at a dose of 80 mg or 160 mg BID for at least 4 weeks 
during the screening/run-in period. 
 
5.4 
Exclusion criteria 
Subjects fulfilling any of the following exclusion criteria are not eligible for inclusion 
in this study. 
1. Predicted poor compliance or inability to communicate well with the investigator or 
the study center personnel. 
2. Current acute or subacute decompensated HF. 
3. Presence of acute coronary syndrome, stroke, transient ischemic attack or other 
major cardiovascular event or cardiovascular procedure within 3 months before 
screening.  
4. Coronary or carotid artery disease likely to require surgical or percutaneous 
intervention within the 6 months after randomization.  
5. Evidence of clinically significant renal, hepatic, hematological, gastrointestinal, 
pulmonary, metabolic-endocrine, neurological, urogenital or psychiatric disease that 
may constitute a health risk for the subject and/or would interfere with the evaluation 
of the results, as judged by the investigator. 
6. Symptomatic hypotension that persists even after modification of concomitant 
medication(s), at any time during the screening/run-in period.  
7. Estimated glomerular filtration rate (eGFR) < 45 ml/min at any time during the 
screening/run-in period that persists even after modification of concomitant 
medication(s). 
8. Serum potassium >5.2 mmol/l at any time during the screening/run-in period that 
persists even after modification of concomitant medication(s). 
9. Serum creatinine > 1.5 x ULN (upper limit of normal) at any time during the 
screening/run-in period that persists even after modification of concomitant 
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10. Contraindication to neprilysin inhibitor or ARB (such as previous angioedema or 
known intolerance). 
11. Susceptibility to severe allergic reactions or known hypersensitivity to the active 
substances or to any of the excipients. 
12. Intake of any medication that could affect the outcome of the study, interfere with 
the evaluation of the results or constitute a health risk for the study subject, as 
judged by the investigator. 
13. Positive serology to human immunodeficiency virus antibodies (HIVAgAb), hepatitis 
C virus antibodies (HCVAb) or hepatitis B surface antigen (HBsAg) in medical 
history. 
14. Unwillingness to use adequate methods of contraception while participating in the 
study and for 3 months after the last administration of the PET tracer. 
15. Participation in another clinical drug study within 3 months prior to the first study 
treatment administration of this study. 
16. Prior participation in an investigational PET study or other medical or occupational 
exposure to significant doses of ionizing radiation, as judged by the investigator. 
 
5.5 
Recruitment 
The subjects will be recruited from the patient population of the hospital district of 
Southwest Finland. A description of the possible means of subject recruitment is 
included in the submission to the Ethics Committee (EC). The recruitment of 
subjects will start after approvals have been received from the EC and Competent 
Authority (CA).  
The investigator or an appropriate designee will look over the medical records of the 
patients treated in the hospital district of Southwest Finland. If needed, colleagues 
of the investigator may be informed about the study to aid in recruitment. Possibly 
suitable subjects will be contacted and the person responsible for subject 
recruitment will first shortly brief the potential subjects about the study in layman’s 
language. This first study-related contact may be performed also in person, if the 
subject candidate is on site. The main inclusion and exclusion criteria will be 
checked during telephone contact or face-to-face conversation. If an inclusion 
criterion is not fulfilled, or an exclusion criterion is fulfilled, this is immediately told to 
the subject, and the interview is terminated. If, according to this preliminary 
evaluation, the subject candidate might be eligible for the study, the procedures for 
providing the written subject information are discussed. The subject information 
leaflet and the ICF are handed over to the subject or delivered to him by post, e-mail 
or another method. The next steps in the recruitment process will be agreed upon, 
as convenient to the subject and as defined in the protocol. Upon the subject 
candidate’s wish, a screening visit may be booked or performed on-site after signing 
the ICF (all study-related assessments will be performed after signing the ICF).  
The subjects will be told what personal information of them will be collected and how 
it will be stored and processed. The collection of personal information is described 
in a Description of the Personal Data Register, which is kept in the Investigator’s 
Study File (ISF) and is made available to the subjects, if they wish. 
 


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5.6 
Study subject screening log and identification log 
The investigator will keep a subject identification list in the ISF. The list includes 
information to link all study-related records to a subject, i.e. randomization list, case 
report forms (CRFs) and source data. Furthermore, a subject screening log of all 
subjects screened for the study will be maintained. The identity of the subject 
(screening number, the subject’s first name, last name and personal identity 
number), date of IC, date of entry or date of exclusion and the reason for exclusion, 
if applicable, for those recruited for screening but not fulfilling the criteria and 
therefore excluded, should be recorded on the list.  
 
5.7 
Instructions concerning lifestyle and concomitant treatments  
The subjects are instructed to keep their usual dietary and exercise habits during 
their participation in the study. Blood donation is not allowed during the study. 
Female subjects of childbearing potential and male subjects with female partners of 
childbearing potential should be instructed to use adequate methods of 
contraception while participating in the study and for 3 months after the last 
administration of the PET tracer. Urine pregnancy tests will be performed for females 
of childbearing potential prior to each PET scan. Use of alcohol and caffeine-
containing beverages is forbidden for 12 h before each PET-scan. In addition, a 
study subject shall not participate concurrently or have participated in any other 
clinical drug trial within 3 months prior to entry into this study. Instructions regarding 
concomitant treatments can be found in Section 6.5. 
 
5.8 
Withdrawal of subjects 
Study subjects are free to withdraw from the study at any time without providing a 
reason. However, the investigator should try to find out the reason and document it 
on the corresponding CRF page. A subject may also be withdrawn from the study if 
his/her adherence to the study protocol is not acceptable. A study subject needs to 
discontinue the study if the investigator considers that continuation in the study 
would be detrimental to the subjects well-being. The following situations should 
result in the withdrawal of the subject, unless the investigator considers it safe for 
the subject to continue in the study, possibly after dose modifications of the study 
drug or other concomitant medication:  
- 
persistent symptomatic hypotension after randomization; 
- 
serum potassium > 5.2 mmol/l after randomization; 
- 
serum creatinine > 1.5 x ULN after randomization. 
If the subject continues in the study, the investigator has to document his/her 
decision in the source documents and verify continuous subject safety with e.g. 
repeat BP surveillance and/or laboratory safety measurements during unscheduled 
visit(s). 
Irrespective of the reason for discontinuation, discontinued study subjects should be 
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assessments (incl. BP, safety laboratory tests and possibly other tests judged 
necessary by the investigator). The CRFs should be as complete as possible. 
If discontinuations occur, the need of recruiting additional subjects to reach the 
targeted total number of subjects will be considered and carried out as appropriate. 
Discontinued study subjects are not allowed to re-enter the study.  
 
5.9 
Information to be collected on screening failures 
From subjects screened but not included in the study, the following data will be 
collected on CRFs: date of IC, demography (year of birth, sex and race), the 
inclusion/exclusion criterion/criteria causing the exclusion and the date of the 
decision of exclusion. 
 
 
6 
TREATMENTS 
6.1 
Investigational treatment sacubitril/valsartan 
The IMP, sacubitril/valsartan, will be provided in appropriately labelled study drug 
packages of the different strengths of the active drug. Also, corresponding placebo 
tablets that are similar in appearance to the active sacubitril/valsartan will be 
provided. The following strengths of sacubitril/valsartan will be available: 
- 
sacubitril/valsartan 100 mg: containing 49 mg sacubitril/51 mg valsartan,  
- 
sacubitril/valsartan 200 mg: containing 97 mg sacubitril/103 mg valsartan. 
The IMP is manufactured by Novartis in accordance with GMP guidelines. The 
labelling will be also done in compliance with GMP regulations after which the study 
drug will be released at Novartis. The sacubitril/valsartan will be stored in the Heart 
Center in locked cabinets according to the instructions provided in the SPC. The 
subjects will receive their study treatment according to the randomization list which 
contains randomization numbers and allocated treatments. The study drugs will be 
dispensed by an unblinded member of the study team and the subjects will take the 
study drugs and corresponding matching placebo tablets at home BID. After the 
randomization, 50% of the subjects will start in the sacubitril/valsartan treatment arm 
on a starting dose of 100 mg BID (see Figure 2). There is one visit scheduled for 
possible up-titration of the dose (visit 1) and during this visit every subject should be 
attempted to be up-titrated to the next dose level (sacubitril/valsartan 200 mg or 
valsartan 160 mg), if clinically possible and if the latter needed. If up-titration is not 
clinically possible, the starting dose should be maintained. During the treatment 
period, subjects will receive new study drug packages (active drug and placebo) 
from the unblinded drug dispenser, as applicable.  
The study subjects and all investigators and other study personnel participating in 
the assessments will be kept blinded to the treatments but not the dose level. 
A schematic figure about the possible treatments and doses is shown in Figures 2 
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6.2 
Control treatment 
Valsartan will be used as control treatment during the study. Its use aims to 
standardize background therapy for efficacy and hemodynamic effects in order to 
assess the incremental effects of combined angiotensin receptor (ATR) inhibition 
and neprilysin inhibition therapy as compared to ATR inhibition alone. Valsartan will 
replace previously used ACEI or ARB in all subjects during the screening/run-in 
period on a dose of 80 mg BID or 160 mg BID, if the dose of previous RAAS blockade 
was higher than 80 mg BID or equivalent. In order to be eligible for the study, a 
minimum dose of valsartan 80 mg BID has to be tolerated by the subject.  
Valsartan will be provided in appropriately labelled study drug packages of the 
different strengths of the active drug. Also, corresponding placebo tablets that are 
similar in appearance to the active valsartan will be provided. The following strengths 
of valsartan will be available: 
- 
valsartan 80 mg (used in both the screening/run-in period – not blinded – 
and also after randomization in a blinded manner), 
- 
valsartan 160 mg (used in both the screening/run-in period – not blinded – 
and also after randomization in a blinded manner). 
For the screening/run-in period, valsartan will be taken from local commercial stock 
and subsequently labelled as a research drug by Tamro. During the screening/run-
in period, valsartan can be dispensed by any member of the study team. For the 
treatment period, valsartan is manufactured by Novartis in accordance with GMP 
guidelines. The labelling will be also done in compliance with GMP regulations after 
which the study drug will be released at Novartis. Valsartan will be stored in the 
Heart Center in locked cabinets according to instructions provided in the SPC. The 
subjects will receive their study treatment according to the randomization list which 
contains randomization numbers and allocated treatments. During the treatment 
period, the study drugs will be dispensed by an unblinded member of the study team 
and the subjects will take the study drugs and corresponding matching placebo 
tablets at home BID. After the randomization, 50% of the subjects will continue in 
the valsartan treatment arm, on a starting dose of 80 mg BID or 160 mg BID if they 
were on this dose during the screening/run-in (see Figure 3). There is one visit 
scheduled for possible up-titration of the dose (visit 1) and during this visit every 
subject should be attempted to be up-titrated to the next dose level 
(sacubitril/valsartan 200 mg or valsartan 160 mg, if the latter needed), if clinically 
possible. If up-titration is not clinically possible, the starting dose should be 
maintained. During the treatment period, subjects will receive new study drug 
packages (active drug and placebo) from the unblinded drug dispenser, as 
applicable.  
 
6.3 
PET-tracer 11C-acetate 
PET-tracer synthesis will be done according to the standard operating procedures 
(SOPs) of 
. 11C-acetate is synthesized by reaction of 11C-carbon 
dioxide with methylmagnesium bromide in diethyl ether. Labelling reaction is 
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phase extraction, formulated for iv. injection and filtered through sterile filter. The 
radioligand preparation will undergo quality control tests before each intravenous 
bolus administration. 
 
6.4 
Handling of the study products 
Study products will be kept in locked and temperature-monitored storage facilities at 
the Heart Center until dispensing to study subjects. Separate written instructions on 
the storage conditions are provided in the SPCs of valsartan and sacubitril/valsartan. 
The shelf-life and storage conditions will be available on the labels of the study drug 
packages. The study drugs, both sacubitril/valsartan and valsartan, will be tablets 
for oral administration provided in sealed study drug packages. Any member of the 
study team may dispense valsartan to the subjects during the screening/run-in 
period, but only an appointed unblinded member of the study team is allowed to 
dispense the study drugs (active drug and placebo) during the treatment period. 
Manufacturing, packaging and labelling of 11C-acetate will comply with GMP and 
standard practices at 
. 
 
6.5 
Prior and concomitant treatments 
The subjects must be on a stable and optimal standard HF therapy according to 
ESC guidelines prior to participation in the study. The therapy must be at a stable 
dose for at least 4 weeks before the first screening visit and must include at a 
minimum beta-blocker and ACEI or ARB in all subjects. Valsartan will replace 
previously used ACEI or ARB on a dose of 80 mg BID or 160 mg BID if the dose of 
previous ACEI or ARB was higher than equivalent to 160 mg BID valsartan. The use 
of spironolactone is allowed, if at a stable dose for at least 4 weeks before the first 
screening visit. Dose reduction of loop diuretics is allowed during the study at all 
times to prevent hypotension. The HF therapy should otherwise remain unchanged 
throughout the whole study (i.e. until visit 3). 
Concomitant medication(s) required for treatment of subjects’ concurrent diseases 
are allowed during the study, with the exception of medication(s) that could affect 
the outcome of the study, interfere with the evaluation of the results or constitute a 
health risk for the study subject, as judged by the investigator. These include e.g. 
vasoactive supporting medication(s) that have known effects on cardiac efficiency. 
All concomitant treatments administered during the study must be recorded on the 
CRF page for concomitant treatments. No other investigational treatment is allowed 
to be used during the study. A study subject must not participate concurrently or 
have participated in any other clinical drug study within 3 months prior to the first 
study treatment administration of this study. 
 
6.5.1 Prohibited treatments during the study 
Concomitant medication(s) that could affect the outcome of the study, interfere with the 
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the investigator. These include e.g. vasoactive supporting medication(s) that have 
known effects on cardiac efficiency. 
 
6.5.2 Permitted treatments during the study 
Optimal standard HF therapy and other concomitant medication(s) needed for 
treatment of possible concurrent diseases are allowed. 
 
6.6 
Emergencies and treatment of adverse events 
Emergencies will be treated according to the decision of the physician in charge or 
the investigator when available. The treatment of possible AEs will be primarily 
symptomatic.  
Any relevant control or follow-up examinations may be initiated at any time by the 
investigator. In case of any clinically significant abnormalities, medical assistance is 
assured until complete resolution or stabilization. 
 
6.7 
Procedures for monitoring subject compliance 
During the screening/run-in period, the subjects will take one tablet of valsartan twice 
a day at home. During the treatment period, the subjects will take one tablet of active 
drug and one placebo tablet twice a day at home. They will be instructed to take 
valsartan (during the run-in) and the study drugs (active and placebo) in the morning 
and in the evening. In case a subject forgets to take the tablet(s) in the morning or 
in the evening, he/she is instructed to take the next one at the next scheduled drug 
intake time. At each administration time during the treatment period, the subjects 
are instructed to take one tablet from each of the two study drug packages they were 
provided with at a previous site visit. Two study drug packages (one containing the 
active drug and one containing the placebo) will be dispensed to the subjects at the 
baseline visit and at visit 1 by an unblinded member of the study team. In case the 
dose of the study drug is down-titrated during the treatment period, new study drug 
packages may be dispensed after visit 1. The subjects will be asked to return the 
study drug packages at each site visit, with all of the unused tablets, both during the 
screening/run-in and treatment period. Study personnel will do a valsartan and study 
drug/placebo accountability check and record this when applicable (i.e. at baseline 
visit and visits 1 and 3; also at screening visit 2 and visit 2, if they are performed as 
site visits). Valsartan accountability check during the screening/run-in period may be 
performed by any member of the study team, whereas study drug/placebo 
accountability check during the treatment period has to be performed by the 
unblinded member of the study team. 
Drug accountability records will be kept. The investigator or his/her delegate must 
maintain accurate written records demonstrating the date and amount of study drugs 
received at the site, to whom and by whom dispensed (drug dispensing list) and 
accounts of drugs accidentally or deliberately destroyed. Unused study drugs will be 
recorded and returned to the sponsor or disposed of, on the sponsor’s consent. Any 


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discrepancies between the returned and expected returned study drugs should be 
explained. 
 
 
7 
VISIT SCHEDULE 
7.1 
Screening/run-in period 
The screening/run-in period can last up to 6 weeks, but is not intended to last over 
4 weeks, before the first study drug administration in the double-blinded treatment 
period. In certain cases, if clinically indicated (e.g. tolerability issues) or necessary 
for other reasons (e.g. scheduling), the screening/run-in period may last longer than 
6 weeks. Screening/run-in period extensions (over 6 weeks) must be justified by the 
investigator and the reasons documented. Screening/run-in safety assessments 
should be repeated, based on investigator’s judgement and/or if necessary, so that 
the laboratory results and the latest BP values are no older than 6 weeks.  
During the first screening visit, a potential study subject will receive both written and 
verbal information on the study and will have an opportunity to ask questions and 
sufficient time to make up his/her mind concerning participation in the study. A 
signed and dated written IC will be obtained. All study-related assessments will be 
performed after the ICF has been signed. 
At the first screening visit, subjects who have signed the ICF will receive screening 
numbers starting from 1-1001, and after assessment of inclusion and exclusion 
criteria, enrolled subjects will receive randomization numbers from the stratum 
specific list. During the screening/run-in period, the subjects will be interviewed for 
their relevant medical and surgical history and their prior and current use of 
medications. Demographic data will be also collected. This information may also be 
obtained from the subject’s medical records, if available. If medical charts are used, 
relevant medical history events and concomitant medications should be verified with 
the subject (in order to ensure the subject does not use any medication not in his/her 
medical records). BP will be measured and safety laboratory tests will be performed 
at the first screening visit. If the investigator considers the subject to be eligible for 
the study based on these initial investigations, the subject may continue in the 
screening/run-in period.  
During the screening/run-in period, the subjects will receive valsartan treatment that 
will replace their previous ACEI or ARB HF therapy. Valsartan during the 
screening/run-in period may be dispensed by any member of the study team. The 
screening/run-in dose of valsartan (80 mg BID or 160 mg BID) will be decided by 
the investigator based on the subject’s clinical status, prior HF therapy and 
concomitant medications. The subjects will have a scheduled safety and efficacy 
assessment visit during the screening/run-in period (screening visit 2 in the study 
schedule, Table 3). If deemed sufficient by the investigator, screening visit 2 can be 
performed remotely. If so, safety blood sampling, eligibility criteria review, adverse 
events and concomitant medication must be assessed. 
 


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Dose reduction of a loop diuretic is allowed during the screening/run-in to prevent 
hypotension. Unscheduled visits may be performed at any time during the 
screening/run-in period. Study visit should be performed as close proximity to the 
stated day in the study schedule (Table 3) as possible. 
The subject has to tolerate at the minimum 80 mg BID valsartan at a stable dose for 
minimum of 4 weeks in order to be eligible for the treatment period. Before the PET-
scan, a urine pregnancy test should be performed for female subjects of childbearing 
potential. During the baseline visit, PET-scan and echocardiography will be done 
and blood samples for biomarker assessment will be drawn. After all other study 
procedures are performed at the baseline visit and the subject is deemed eligible for 
the study, he/she will be randomized and start the double-blinded treatment period. 
The results for the laboratory tests taken during the on-site screening visits do not 
need to be available before decision-making (i.e. starting valsartan treatment), but 
they have to be reviewed as soon as possible after they become available in order 
to ensure subject safety. All screening/run-in period laboratory results must be 
available and reviewed before randomization, except the results of the laboratory 
tests taken on the baseline visit, as randomization is performed on the same day as 
the baseline visit.  
Adverse events and changes in concomitant medications will be recorded 
throughout the screening/run-in period. 
A subject will be entered into the study at the time of randomization, after the 
baseline PET-scan and echocardiography have been performed, if all inclusion 
criteria and none of the exclusion criteria are met. 
For a detailed description on the information to be recorded during the 
screening/run-in period, please refer to Section 8.1. 
 
7.2 
Treatment period 
The treatment period will last for approximately 8 weeks for each subject (it may be 
longer if required for clinical and/or scheduling purposes). During this time, the 
subjects will receive either sacubitril/valsartan or they will continue in the valsartan 
treatment arm. The subjects will be randomized into one of these two treatment arms 
in a 1:1 ratio. Study drugs during the treatment period will be dispensed by an 
unblinded member of the study team. As the different treatments, valsartan and 
sacubitril/valsartan, and the different strengths of these treatments are not similar in 
appearance, the study will be performed in a double-dummy manner, i.e. the 
subjects will take two tablets BID throughout the treatment period. The following 
options are possible: 
- 
valsartan + placebo for sacubitril/valsartan, 
- 
sacubitril/valsartan + placebo for valsartan. 
The starting dose in the sacubitril/valsartan treatment arm will be 100 mg BID and 
in the valsartan treatment arm it will be 80 mg BID or 160 mg BID. A schematic figure 
about the possible treatments and doses is shown in Figures 2 and 3, Section 6.1. 
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highest tolerated dose, up to 160 mg BID (if needed) for valsartan and up to 200 mg 
BID for sacubitril/valsartan. There will be one visit scheduled for possible up-titration 
of the dose (visit 1) and during this visit every subject should be attempted to be up-
titrated to the next dose level (sacubitril/valsartan 200 mg or valsartan 160 mg, if 
needed), if clinically possible. If up-titration is not clinically possible, the starting dose 
should be maintained. At the minimum, 80 mg BID of valsartan or 100 mg BID of 
sacubitril/valsartan has to be tolerated by the subject in order to finish the study – if 
these doses are not tolerated, the subject has to be withdrawn from the study. The 
decision to up-titrate the dose will be done by the investigator during the study visits 
based on the subject’s clinical status and the safety assessments, incl. BP and 
safety laboratory tests. The laboratory results, if taken on the days of the on-site 
visits, do not need to be available before decision-making but they have to be 
reviewed as soon as possible to ensure subject safety. If the safety blood samples 
are collected 1-2 business day(s) before the scheduled visit, the laboratory results 
have to be available and reviewed before decision-making. Dose reduction of a loop 
diuretic is allowed during the up-titration to prevent hypotension. 
The day the subject starts taking the double-blind study medication is Day 1 (i.e. day 
of randomization) and the subsequent visits will take place on Day 14 (visit 1) and 
Day 21 (visit 2). Study visits should be performed as close proximity to the stated 
day in the study schedule (Table 3) as possible. Ideally, the last dose modification 
is done on visit 1. Visit 2 is a safety visit to be performed only for subjects for whom 
the treatment dose was modified on visit 1 and/or if it is clinically indicated based on 
the investigator’s decision. If deemed sufficient by the investigator, visit 2 can be 
performed remotely. If so, safety blood sampling, adverse events and concomitant 
medication must be assessed. For subjects whose dose is not up-titrated on visit 1, 
visit 2 may be omitted, based on investigator’s decision that has to be documented. 
Unscheduled visits may be performed at any time during the treatment period. Dose 
modifications, including up- and possible down-titrations are permitted during the 
first 4 weeks of the treatment period. Every effort should be made that the highest 
tolerated dose is reached on visit 1, at the latest, and only down-titrations are done 
after that, if clinically indicated. If dose is modified (down- and/or up-titrated) within 
the first 4 weeks, an unscheduled visit should be performed to assess subject safety 
on the new dose level. As dose modifications may be performed at any visit, the 
subjects will be asked to return their study medication at each site visit. They will be 
given new study drug packages or the same study drug packages will be returned 
to them, as applicable, according to the investigator’s decision on dose modification.  
The subjects will have to be on a stable dose of study treatment for a minimum of 6 
weeks before visit 3. Visit 3 will include safety assessments (BP and safety 
laboratory tests), blood samples will be obtained for biomarker analysis and PET-
scan and echocardiography will be performed. Before the PET-scan, a urine 
pregnancy test should be performed for female subjects of childbearing potential. 
The study ends for a subject after the last assessment is performed during visit 3; 
there will be no separate end-of-study visit. The subject will return the study 
medication to the site and he/she will continue his/her normal HF therapy, as advised 
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Adverse events and changes in concomitant medications will be recorded 
throughout the treatment period. Any possible serious adverse events (SAEs) or 
other clinically significant AEs, as judged by the investigator, will be followed up after 
the last study visit until resolution or until the event is considered chronic and/or 
stable. 
 
7.3 
Unscheduled visits 
Unscheduled visits may occur at any time during the study, if considered necessary 
by the investigator. The main purpose of an unscheduled visit will be to assess 
subject safety and any safety-related study assessment(s) may be performed during 
this visit, including BP and HR measurement and safety laboratory tests. In addition, 
AEs and concomitant medications may be reviewed by the investigator. If 
necessary, changes to the subject’s concomitant medication or study treatment (e.g. 
down-titration) may be performed.  
 
 
8 
ASSESSMENTS 
8.1 
Screening data 
Information to be recorded during the screening/run-in period includes demographic 
and other baseline information (Section 8.1.1) and safety laboratory determinations 
(Section 8.1.2). 
 
8.1.1 Demographic and other baseline information 
The following demographic and other baseline information will be collected: 
• 
subject’s name, address, contact information (not on CRF); 
• 
year of birth 
• 
race; 
• 
information on relevant previous diseases and current medical conditions; 
• 
information on previous and current medications; all treatments used 
(including prescription medications, over-the-counter medications, herbal 
remedies, trace elements and vitamins) within 4 weeks before the screening 
visit will be recorded; 
• 
information on previous participation in clinical trials; 
• 
systolic and diastolic BP and HR is recorded in a seated position after at 
least 5 min of rest; 
• 
blood samples are collected for safety laboratory determinations; 
• 
personal identity number is collected (not on CRF) due to laboratory logistics, 
on subject’s permission given in the ICF;  
 


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8.1.2 Screening laboratory determinations 
All subjects will undergo blood laboratory tests during the screening/run-in period on 
screening visits 1 and 2. The reference ranges of all laboratory determinations will 
be included in the ISF before study start and updated whenever necessary. The 
laboratory tests detailed below are taken during the screening visits:  
 
Chemistry: 
• 
Potassium 
• 
Creatinine 
Haematology: 
• 
Haemoglobin 
 
8.2 
Assessment of efficacy 
In order to assess cardiac efficiency and hemodynamics, PET imaging and 
echocardiography will be performed before randomization (after a minimum of 4 
weeks on stable dose of 80 mg BID or 160 mg BID of valsartan) and repeated after 
6 weeks on a stable dose of either 80 mg BID or 160 mg BID of valsartan or 100 mg 
BID or 200 mg BID of sacubitril/valsartan. 
 
8.2.1 
11C-acetate PET- scan 
Myocardial resting perfusion and oxygen consumption will be evaluated by 11C-
acetate PET as tracer uptake (k1) and a mono-exponential clearance rate of 11C-
acetate (kmono) before randomization and repeatedly on visit 3, after 6 weeks of 
stable sacubitril/valsartan or valsartan treatment. Resting perfusion (k1) will be used 
for calculation of myocardial vascular resistance. Efficiency of LV mechanical work 
will be calculated as follows: 
Efficiency = (LV work/gram of tissue) / Oxygen consumption 
 
PET-imaging will be performed using a PET scanner (GE Discovery 690PET/CT) at 
.  
 
8.2.2 Echocardiography 
Comprehensive echocardiographic evaluation of cardiac structure, systolic function, 
diastolic function using 2D and 3D imaging, strain imaging and Doppler will be done 
before randomization and repeatedly on visit 3, after 6 weeks of stable 
sacubitril/valsartan or valsartan treatment. Estimates of LV filling pressure will be 
used to assess hemodynamic effects of interventions. Measurements of LV mass 
(linear method), LV outflow tract (LVOT) area and cardiac output (Doppler flow 
velocity profiles in the LVOT or LV volumes) will be used for calculation of LV 
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LV work/gram of tissue= (SBP x SV x HR) / LV mass;  
where SBP is systolic blood pressure, SV is stroke volume and HR is heart rate. 
Echocardiography will be performed using a GE Vivid E9 ultrasound machine. 
Separate written instructions will be provided to the study team before the start of 
the clinical part of the study with detailed description on the PET procedure and 
echocardiography. 
 
8.2.3 Biomarkers 
Biomarkers will be measured to understand the potential mechanisms of how 
sacubitril/valsartan changes myocardial efficiency. Blood samples will be obtained 
for measurement of NT-proBNP, hs-troponin and creatinine to assess effects of 
interventions on hemodynamics before randomization and repeatedly on visit 3, 
after 6 weeks of stable sacubitril/valsartan or valsartan treatment. The biomarker 
analyses will be performed at 
, the accredited clinical laboratory of 
 
 
In addition, one blood sample will be taken and stored up to 15 years for possible 
future biomarker analysis. 
 
8.3 
Assessment of safety 
8.3.1. Physical examination 
Physical examination will include the examination of general appearance as well as 
the cardio-vascular system as seen relevant by the investigator, for example lungs, 
heart and extremities. 
Information for all physical examinations must be included in the source 
documentation at the study site. Significant findings that are present before signing 
the ICF must be included in the relevant medical history eCRF. Significant findings 
made after signing the ICF which meet the definition of an AE must be recorded in 
the Adverse Event eCRF. 
 
8.3.2 Blood pressure and heart rate 
BP and HR will be measured in a seated position after at least 5 min rest at all site 
visits for safety assessment. BP and HR will be monitored also during the imaging 
sessions according to separate written instructions. SVR will be calculated based on 
peripheral BP and cardiac output. 
In case of abnormal findings, additional control assessments may be performed 
according to investigator’s judgement.  
 


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8.3.3 Laboratory safety assessments 
Please refer to Section 8.1.2 for laboratory safety assessments to be performed 
during the screening visits. During the treatment period on visits 1-3, the same 
laboratory assessments will be performed, and also on unscheduled visits, if 
clinically indicated. Safety blood samples may be collected 1-2 business day(s) 
before the scheduled visits (with the exception of screening visit 1). If necessary to 
assess subject safety, more laboratory tests may be performed at any visit. In this 
study, the maximum volume of blood drawn from a subject for safety laboratory 
assessments during scheduled visits will not exceed 50 ml. If control blood samples 
are needed for subject safety, the blood volume may exceed 50 ml. The analyses of 
clinical chemistry will be performed at 
, the accredited clinical laboratory 
of 
. 
Urine pregnancy test will be performed for all female subjects with childbearing 
potential prior to the PET-scans. Urine pregnancy test will be performed at 
 
 using available commercial kits. 
The investigator will evaluate the clinical significance of the safety laboratory 
findings. In case of abnormal findings, additional control assessments may be 
performed according to investigator’s judgement. For specific laboratory values 
resulting in subject withdrawal, please refer to Section 5.8.  
 
8.3.4 Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable 
and unintended sign (including abnormal laboratory findings), symptom or disease) 
in a subject or clinical investigation subject after providing written informed consent 
for participation in the study until the end of study. Therefore, an AE may or may not 
be temporally or causally associated with the use of a medicinal (investigational) 
product. 
In addition, all reports of intentional misuse and abuse of the product are also 
considered an adverse event irrespective if a clinical event has occurred. 
The occurrence of adverse events must be sought by non-directive questioning of 
the patient at each visit during the study. Adverse events also may be detected when 
they are volunteered by the patient during or between visits or through physical 
examination findings, laboratory test findings, or other assessments. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill 
at least one of the following criteria: 
• 
they induce clinical signs or symptoms,  
• 
they are considered clinically significant,  
• 
they require therapy.  
Clinically significant abnormal laboratory values or test results must be identified 
through a review of values outside of normal ranges/clinically notable ranges, 
significant changes from baseline or the previous visit, or values which are 
considered to be non-typical in patient with underlying disease. Investigators have 


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the responsibility for managing the safety of individual patient and identifying 
adverse events.  
Adverse events must be recorded in the appropriate CRF capturing AEs under the 
signs, symptoms or diagnosis associated with them, accompanied by the following 
information: 
• 
the severity grade 
• 
mild: usually transient in nature and generally not interfering with normal 
activities 
• 
moderate: sufficiently discomforting to interfere with normal activities 
• 
severe: prevents normal activities 
• 
its relationship to the study treatment  
• 
its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported. 
• 
whether it constitutes a serious adverse event (SAE - See Section 8.3.3.1.1 for 
definition of SAE) and which seriousness criteria have been met. 
• 
action taken regarding [investigational] treatment  
All adverse events must be treated appropriately. Treatment may include one or 
more of the following:  
• 
no action taken (e.g. further observation only)  
• 
[investigational] treatment dosage increased/reduced 
• 
[investigational] treatment interrupted/withdrawn 
• 
concomitant medication or non-drug therapy given  
• 
non-drug therapy given  
• 
patient hospitalized/patient’s hospitalization prolonged (see Section 8.3.3.1.1 for 
definition of SAE) 
• 
its 
outcome 
(not 
recovered/not 
resolved; 
recovered/resolved; 
recovering/resolving, recovered/resolved with sequelae; fatal; or unknown) 
Once an adverse event is detected, it must be followed until its resolution or until it 
is judged to be permanent, and assessment must be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to 
the study drug, the interventions required to treat it, and the outcome. 
Information about common side effects already known about the investigational drug 
can be found in the Investigator Brochure (IB). This information will be included in 
the patient informed consent and should be discussed with the patient during the 
study as needed. Any new information regarding the safety profile of the medicinal 
product that is identified between IB updates will be communicated as appropriate, 
for example, via an Investigator Notification or an Aggregate Safety Finding. New 
information might require an update to the informed consent and has then to be 
discussed with the patient. 
The investigator must also instruct each patient to report any new adverse event 
(beyond the protocol observation period) that the patient, or the patient’s personal 
physician, believes might reasonably be related to study treatment. This information 


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must be recorded in the investigator’s source documents; however, if the AE meets 
the criteria of an SAE, it must be reported to Novartis. 
 
8.3.4.1 Serious adverse events 
8.3.4.1.1 Definition of SAE 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-
existing)] undesirable sign(s), symptom(s) or medical conditions(s)) which meets 
any one of the following criteria: 
• 
is fatal or life-threatening  
• 
results in persistent or significant disability/incapacity 
• 
constitutes a congenital anomaly/birth defect 
• 
requires inpatient hospitalization or prolongation of existing hospitalization, 
unless hospitalization is for: 
• 
routine treatment or monitoring of the studied indication, not associated with 
any deterioration in condition  
• 
elective or pre-planned treatment for a pre-existing condition that is unrelated 
to the indication under study and has not worsened since signing the 
informed consent 
• 
treatment on an emergency outpatient basis for an event not fulfilling any of 
the definitions of a SAE given above and not resulting in hospital admission  
• 
social reasons and respite care in the absence of any deterioration in the 
patient’s general condition 
• is medically significant, e.g. defined as an event that jeopardizes the patient or 
may require medical or surgical intervention. 
All malignant neoplasms will be assessed as serious under “medically significant” 
if other seriousness criteria are not met. 
Life-threatening in the context of a SAE refers to a reaction in which the patient was 
at risk of death at the time of the reaction; it does not refer to a reaction that 
hypothetically might have caused death if it were more severe (please refer to 
Annex IV, ICH-E2D Guideline). 
Medical and scientific judgment should be exercised in deciding whether other 
situations should be considered serious reactions, such as important medical events 
that might not be immediately life threatening or result in death or hospitalization but 
might jeopardize the patient or might require intervention to prevent one of the other 
outcomes listed above. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization or development of dependency or 
abuse (please refer to Annex IV, ICH-E2D Guideline). 
Any suspected transmission via a medicinal product of an infectious agent is also 
considered a serious adverse reaction. 
 


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8.3.4.1.2 SAE reporting 
IMPORTANT: To comply with regulations, all suspected, unexpected, serious 
adverse reactions (SUSARs) occurring in a clinical trial must be reported in an 
expedited timeframe (7 or 15 days) to competent authorities.  
To ensure patient safety, every SAE, regardless of causality, occurring after the 
patient has provided informed consent and until 30 days after the last study visit 
must be reported to Novartis safety within 24 hours of learning of its occurrence. 
Any SAEs experienced after the 30 day period after the last study visit should only 
be reported to Novartis safety if the investigator suspects a causal relationship to 
study treatment.  
All follow-up information for the SAE including information on complications, 
progression of the initial SAE and recurrent episodes must be reported as follow-up 
to the original episode within 24 hours of the investigator receiving the follow-up 
information. An SAE occurring at a different time interval or otherwise considered 
completely unrelated to a previously reported one must be reported separately as a 
new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event 
Report Form; all applicable sections of the form must be completed in order to 
provide a clinically thorough report. The investigator must assess the relationship of 
each SAE to each specific component of study treatment, (if study treatment 
consists of several components) complete the SAE Report Form in English, and 
submit the completed form within 24 hours to Novartis. Detailed instructions 
regarding the submission process and requirements for signature are to be found in 
the investigator folder provided to each site.  
Follow-up information is submitted as instructed in the investigator folder. Each re-
occurrence, complication, or progression of the original event must be reported as 
a follow-up to that event regardless of when it occurs. The follow-up information 
should describe whether the event has resolved or continues, if and how it was 
treated, whether the blind was broken or not, and whether the patient continued or 
withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package 
Insert (new occurrence) and is thought to be related to the study treatment a Patient 
Safety associate may urgently require further information from the investigator for 
health authority reporting. Novartis may need to issue an Investigator Notification 
(IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with EU Guidance 2011/C 172/01 and as 
per national regulatory requirements in Finland. 
Note: SAEs must be reported to Novartis within 24 hours of the investigator learning 
of its occurrence/receiving follow-up information. 
 


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8.3.4.2. Liver safety monitoring 
To ensure patient safety and enhance reliability in determining the hepatotoxic 
potential of an investigational drug, a standardized process for identification, 
monitoring and evaluation of liver events has to be followed.  
The following category of abnormalities / adverse events has to be considered 
during the course of the study (irrespective of whether classified/reported as (S)AE): 
• 
Liver events, which will require close observation, follow-up monitoring should be 
entered into the appropriate CRFs.  
For the liver events: 
• 
Repeating the LFT to confirm elevation as appropriate 
• 
Discontinuation of the investigational drug if appropriate 
• 
Hospitalization of the patient if appropriate 
• 
A causality assessment of the liver event via exclusion of alternative causes (e.g., 
disease, co-medications) 
• 
An investigation of the liver event which needs to be followed until resolution.  
These investigations can include serology tests, imaging and pathology 
assessments, hepatologist’s consultancy, based on investigator’s discretion. All 
follow-up information, and the procedures performed must be recorded on the 
appropriate CRFs. 
8.3.4.3 Renal safety monitoring 
The following category of abnormal renal laboratory value has to be considered 
during the course of the study: 
• 
Serum event: 
• 
confirmed (after ≥24h) increase in serum creatinine of ≥25% compared to 
baseline during normal hydration status 
 
8.3.4.4 Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, 
administration or monitoring of a medicine while under the control of a healthcare 
professional, patient or consumer (EMA definition). 
Medication errors are usually unintentional, although a patient can intentionally 
‘commit’ a medication error due to a lack of medical knowledge or sound judgment 
(e.g. intentionally removing drug from capsule and dissolving in juice) or there is an 
accidental drug omission by an HCP). 
Misuse refers to situations where the medicinal product is intentionally and 
inappropriately used not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a 
medicinal product, which is accompanied by harmful physical or psychological 
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Study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the appropriate CRF, irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will 
be collected and reported in the safety database irrespective of it being associated 
with an AE/SAE. 
 
 
Table 4. Guidance for capturing the study treatment errors including misuse/abuse 
Treatment error 
type 
Document in CRF 
(Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional 
study treatment 
error 
Yes 
Only if associated 
with an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes,  
Yes, even if not 
associated with a SAE 
 
8.3.4.5 Pregnancy reporting 
To ensure patient safety, each pregnancy occurring after signing the informed 
consent must be reported to Novartis within 24 hours of learning of its occurrence. 
The pregnancy should be followed up to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and 
reported by the investigator to the local Novartis Patient Safety. Pregnancy follow-
up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment. Pregnancy should be followed up until 
the child is born and until all relevant information related to the child’s condition has 
been received. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must 
be reported on a SAE form. 
 
8.3.4.6. Serious adverse event reporting  
In case of an SAE, the investigator will contact the Sponsor as soon as possible. 
SAEs must be reported to Novartis’ local Patient Safety within 24 hours of becoming 
aware of an SAE, regardless of the time that may have elapsed since the time the 
event occurred and regardless of the causal relationship of the study drug to the 
event. An initial SAE report will be submitted by the investigator to the Sponsor, and 
follow-up reports will be provided later, if indicated. Follow-up reports to an SAE 
should be prepared if any relevant change in the condition of the study subject 
occurs after the initial report. SAEs should be followed up until resolved or until the 
event is considered chronic and/or stable outcome.  
 
 
 




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9 
STATISTICS 
9.1 
Estimation of sample size 
In previous studies using the same techniques (i.e. 11C-acetate PET scan and 
echocardiography), beta-blockers in drug-naïve patients increased cardiac 
efficiency by 45% (Beanlands 2000). In later studies using e.g. new biventricular 
pacing techniques in previously medicated patients, the cardiac efficiency was 
improved by 20% (Sundell 2004). Therefore, we assume that the clinically significant 
change in cardiac efficiency in medicated patients would be about 20%. In our 
previous studies in patients with heart failure (Nesterov 2015, Tuunanen 2008), the 
same patients were studied twice in the interval of 3 months, the coefficient of 
variation (CV%) of Kmono in placebo group was 18.4% and in efficiency 19.7%. Based 
on sample size calculations, in order to detect a 15% change in cardiac efficiency, 
27 subjects would need to be included in each treatment arm (assuming α = 0.05 
and β = 0.2). Due to potential drop outs during the study, the target is to enroll 30 + 
30 subjects in the treatment arms. 
 
9.2 
Statistical methods 
A summary of the statistical methods is described below.  
 
9.2.1 Statistical Analysis Plan 
Before unblinding the study data a separate statistical analysis plan (SAP), which 
will provide the technical details of the statistical analysis outlined below, will be 
prepared by the biostatistics service provider, and approved. 
 
9.2.2 Statistical hypotheses 
The study hypothesis is that short-term therapy with sacubitril/valsartan added on 
standard HF therapy improves cardiac efficiency in patients with systolic HF. In order 
to test this, the null hypothesis is formulated as follows: 
 
 
H0 : µ1 = µ2 
which will be tested against the alternative hypothesis: 
HA : µ1 ≠ µ2 
 
where µ1 and µ2 are the mean values of change in cardiac efficiency in the two 
treatment arms, as measured by PET and echocardiography at visit 3. The null 
hypothesis will be tested based on a two-sided test and a significance level of 0.05. 
 


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9.2.3 Data sets to be analyzed 
The following analysis sets will be used for the statistical analysis and presentation 
of data:  
The safety set will consist of all randomised subjects who received at least one 
dose of the study medication in the treatment period, provided that there was at 
least one safety follow-up performed for the subject. 
The full analysis set (FAS) will consist of all randomised subjects who have 
received at least one dose of study medication in the treatment period and have 
at least one post-baseline assessment of any efficacy endpoints.  
The per protocol set (PPS) will consist of all subjects in the FAS who received at 
least 75% of the study drug doses, and do not have any other major protocol 
violations which will affect the assessment of efficacy. Major/important protocol 
violations may include, but are not limited to, the following: 
o Non-fulfillment of all inclusion criteria  
o Fulfillment of at least one exclusion criteria 
o Use of certain concomitant medications (this will be judged on a case 
to case basis, depending on extent of treatment) 
The final criteria for PPS, regarding which protocol deviations that warrant exclusions, 
will be determined when all data on protocol violations/deviations are available and 
before breaking the blind. The FAS is considered as the primary analysis dataset, and 
will be used for all primary and secondary efficacy analyses. The primary efficacy 
analysis will be repeated using the PPS. Any significant discrepancy between the 
results from the FAS and the PPS will be analysed and discussed. 
Baseline presentations will be based on the safety set.  
Safety presentations will be based on the safety set 
 
9.2.4 General statistical considerations 
All data will be analyzed using summary statistics and listed. Summary statistics will 
include at least the number of subjects, mean, standard deviation, median, minimum 
and maximum for continuous variables, and frequencies and percentages for 
categorical variables. Geometric mean, standard deviation and coefficient of 
variation will also be presented, when appropriate. All summary statistics will be 
presented by treatment and dose level. All data collected will be listed by subject 
and dose level. In addition, analysis of covariance (ANCOVA) will be used for 
statistical analysis, when appropriate. Other statistical analyses may also be 
implemented, as described in the SAP. 
 
9.2.5 Demographic and baseline characteristics 
All relevant demographic and baseline characteristics will be summarized using 
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will be listed and tabulated by treatment and dose level. Separate listings will be 
provided for subjects screened but not included in the study (screening failures). 
 
9.2.6 Analysis of efficacy variables 
All efficacy variables will be tabulated using summary statistics as described in 
section 9.2.4, including both statistics for observed levels by visit and changes from 
baseline. 
 
Primary Endpoint 
The primary endpoint, change from baseline in cardiac efficiency after 6 weeks on 
stable sacubitril/valsartan or valsartan therapy, will be analyzed by an ANCOVA 
including treatment and stratification as independent factors and covariate 
adjustment for baseline cardiac efficiency. From this model, the within treatment 
group (sacubitril/valsartan-valsartan) changes will be estimated by least square 
means and the corresponding treatment difference between treatments will be 
calculated with a 95% confidence interval and p-value. In addition, treatment by 
stratification interaction analyses will be performed for the primary efficacy 
parameters in order to estimate within stratification group differences. For both the 
baseline visit and visit 3, the results will be also summarized using descriptive 
statistics, with the visit 3 results to be summarized also by dose level and treatment 
arm. 
 
Exploratory Endpoints 
The changes in the following cardiac and systemic hemodynamics parameters will 
be evaluated as exploratory efficacy endpoints: EF, NT-proBNP, systemic BP, SVR, 
coronary vascular resistance and cardiac oxygen consumption. The change from 
baseline in these parameters after 6 weeks on stable sacubitril/valsartan or valsartan 
therapy will be analyzed by an ANCOVA including treatment and stratification as 
independent factors and covariate adjustment for baseline cardiac efficiency. From 
this model, the within treatment group (sacubitril/valsartan-valsartan) changes will 
be estimated by least square means and the corresponding treatment difference 
between treatments will be calculated with a 95% confidence interval and p-value. 
For both the baseline visit and visit 3, the results will be also summarized using 
descriptive statistics, with the visit 3 results to be summarized also by dose level and 
treatment arm. 
 
9.2.7 Analysis of safety variables 
9.2.7.1 Evaluation of adverse events 
AEs reported during the study will be classified by system organ class (SOC) and 
preferred terms (PT) using the MedDRA coding system. AEs will be displayed in a 
frequency table by dose level and treatment arm. The number and proportion (%) of 
subjects having each AE will be tabulated by SOC and PT and dose level. Severity 
of the AEs (mild, moderate, severe) and causality to the study treatment will be 


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tabulated with subject and event counts. SAEs and other significant AEs will be 
evaluated case by case. 
AEs occurring before and after the initiation of the double-blind treatment period will 
be reported separately. 
 
9.2.7.2 Clinical safety evaluations 
The actual values of systolic and diastolic BP and HR and their changes from 
baseline will be evaluated with descriptive statistics by dose level and treatment arm. 
There will be two separate baseline values defined for the BP and HR 
measurements: the first BP and HR baseline value will be the one taken on the first 
screening visit. The subsequent BP and HR measurements during the 
screening/run-in period will be compared to this. The second baseline value will be 
the one taken before randomization at the baseline visit. The subsequent BP and 
HR measurements during the double-blind treatment period will be compared to this. 
 
9.2.7.3 Clinical safety laboratory evaluations 
All laboratory safety variables and their changes from baseline will be evaluated and 
summarized using descriptive statistics by dose level and treatment arm. There will 
be two separate baseline values defined for the safety laboratory assessments: the 
first safety laboratory baseline values will be the ones taken on screening visit 1. 
The subsequent laboratory results obtained during the screening/run-in period will 
be compared to these. The second safety laboratory baseline values will be the ones 
taken at the baseline visit. The subsequent laboratory results obtained during the 
double-blind treatment period will be compared to these. Laboratory values will also 
be categorized into low, normal and high according to their reference ranges. 
Clinically significant laboratory abnormalities and any additional laboratory tests 
taken for subject safety will be listed and reported in the study report. 
 
9.3 
Interim analyses 
There will be no planned interim analyses during the study. The investigators and 
the sponsor will monitor subject safety and efficacy results on an ongoing basis.  
 
9.4 
Software 
Statistical analysis will be performed and tables and subject data listings will be 
prepared using SAS®. 
 
 


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10 
DATA MANAGEMENT 
Data management and handling of data will be conducted according to the study-
specific Data Management Plan (DMP) in line with ICH guidelines 
 standard 
operating procedures.  
 
10.1 
Database design 
The trial database and data entry screen design, as well as edit checks will be 
defined according to the corresponding eCRFs and the study protocol. 
 
10.2 
Data entry 
Flow of trial data and procedures regarding data handling will be described in detail 
in the DMP. Data will be collected on eCRFs specifically designed for this study. 
eCRF completion guidelines will be provided to enable accurate data entry.  
The investigator or designated study center personnel will enter subject data into the 
eCRFs. Only persons authorized by the investigator to make original eCRF entries 
will be allowed to make corrections. The eCRF will have an audit trail with 
appropriate functionality for data capture, tracking and documentation of any queries 
or changes. Electronic signatures will be used to lock the data and identify the 
person entering or changing the data.  
All eCRF entries should be verifiable from the study records. Definition of source 
data is agreed in a written source data agreement document before study start. 
Authorized persons will code medical history and current medical conditions, AEs 
and concomitant treatments using standard coding dictionaries. 
 
10.3 
Data validation and query management 
Data validation or data cleaning procedures will be designed to assure the validity 
and accuracy of the study data. A Data Validation Plan will specify the data checks 
that are performed on subject data to raise data discrepancies, and define the 
electronic edit checks, and data validation queries created for the trial. Validation 
and data queries will be handled by 
 DM team. All trial specific and standard 
data validation programming will be tested in a separate testing environment prior 
to use on production data.  
 
10.4 
Medical encoding 
AEs and medical history verbatim terms will be encoded using MedDRA, latest 
version available when approving the DMP. Concomitant Medications verbatim 
terms will be encoded using the World Health Organization Drug Dictionary (WHO 
DD), most recent version held by the DM vendor. 
 


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10.5 
Data lock 
Individual pages in the eCRFs may be locked on an ongoing basis during the study. 
A field may be locked after all necessary actions defined for that particular field have 
been completed. The fields may be unlocked if further updates are needed. 
 
10.6 
Database closure 
All data entry, verification, medical encoding and data validation activities will be 
finalized before final database lock. Quality control activities will be completed to 
acceptable error rates. All unnecessary user privileges to the study data will be 
removed, except for the Data Manager who will perform the database closure. 
Before database closure reconciliation will be performed between the SAEs entered 
in the Safety database and the study database. After database closure, the 
database will be exported as SAS® data sets. 
The locked database will be used in the final statistical analyses for study reporting. 
Any deviations, i.e. discrepancies and additions from the process defined in the 
DMP, will be described in a study specific Data Management Report.  
 
10.7 
Software 
TrialOnline will be used for DM. 
 
 
11 
QUALITY CONTROL AND QUALITY ASSURANCE 
The principles of GCP are followed throughout the study. During the PET scans, the 
SOPs of 
 are followed and for DM and statistics, the SOPs of
are followed. 
 
 Laboratory 
quality certificates will be available prior to study initiation and will be filed in the ISF 
and TMF. 
The study will be monitored by 
 The study monitor is allowed to monitor the 
study as frequently as necessary to ensure that data recording and protocol 
adherence are satisfactory. The CRFs and related source data will be reviewed in 
detail and source data verification will be performed according to the monitoring 
plan.  
The quality assurance personnel 
 and the Sponsor may conduct audits in 
any phase of the study. The study may also be inspected by CAs. 
A curriculum vitae in English will be obtained from all investigators who sign the 
protocol and from other relevant persons. 
 
 


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12 
ETHICAL CONSIDERATIONS 
This study will follow the relevant regulations and guidance for biomedical research 
involving human subjects, such as the Declaration of Helsinki, GCP, national laws 
and EU directives. Special emphasis will be put on the well-being of the study 
subjects. 
Prior to initiation of the study, the study protocol, the subject information leaflet and 
the ICF, the Description of the Study Data Register and the texts of any 
advertisements used for the recruitment of study subjects will be submitted to and 
approved by an independent EC. The EC will also be notified of any other materials 
to be given to the subjects (e.g. study subject diary, participant card). The study will 
be authorized by the CA (the Finnish Medicines Agency, Fimea) before its 
commencement.  
The study subject candidates will be provided with both verbal and written 
information on the study, its risks and benefits. They are encouraged to ask 
questions on the study. After having had enough time to consider their participation, 
they may sign the IC form. No study procedure will be implemented prior to obtaining 
written IC that is signed by the subject at the time of consent. A copy of the signed 
ICF will be given to the subject. The investigator will keep each subject’s signed ICF 
on file for inspection by a regulatory authority at any time. 
The subjects are told what information will be collected of them and how. The 
collection of study data and its confidential storage are described in the Description 
of the Personal Data Register, which is kept in the ISF and is available for inspection 
by the subjects. The investigator assures that the privacy of the subjects, including 
their personal identity and all medical information, will be maintained at all times.  
This study involves exposure to ionizing radiation, which is harmful to living 
organisms. The total radiation dose from two up to 500 MBq 11C-acetate PET tracer 
injections and low-dose CT scans for attenuation correction will be 7.5 mSv. The 
average annual radiation dose of a person living in Finland derived from the 
environment and from medical uses of radiation is approximately 3.2 mSv per year 
(Radiation and Nuclear Safety Authority of Finland). Therefore, the radiation 
exposure from this study will be approximately equivalent to 2 years and 4 months 
of background radiation in Finland. Despite the ionizing radiation exposure being 
low, any radiation dose may increase the risk of cancer. 
Other invasive procedures included in the study are the frequent blood samplings. 
The volume of blood drawn from each subject during the scheduled visits will not 
exceed 50 ml. This blood loss should not produce any adverse effects. 
Echocardiography is a non-invasive ultrasound-based imaging method used to 
assess cardiac function that is not associated with any known safety risks. 
The subjects are urged to report all AEs to the study personnel and they are given 
the phone numbers of the investigator and study nurse(s) whom they are instructed 
to call if they observe significant, possibly study drug related AEs, or in other urgent 
study-related issues. 
The subjects included to this study will have chronic HF, NYHA II-III symptoms and 
reduced EF. Their ongoing HF treatment will not be modified, with the exception of 


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changing their ACEI or ARB medication to valsartan during the screening/run-in 
period. The medication change and subsequent possible up-titration will be closely 
monitored by the study team to ensure subject safety at all times. During the double-
blind treatment period, subjects will receive either sacubitril/valsartan or valsartan 
and are expected to remain in a stable clinical condition. Also during this period, 
possible up-titration(s) will be closely monitored by the study team. In addition to the 
above mentioned medication changes, the study protocol allows for down-titration 
of a loop diuretic, if indicated based on clinical signs and/or symptoms. This study is 
designed so that the health and safety of the subjects can be monitored as closely 
as possible. 
Substantial changes to the final approved study protocol will be initiated only with 
the EC’s favorable opinion of a written amendment, except when necessary to 
eliminate immediate hazards to the study subjects. When a change involves only 
logistics or administration, it will be considered non-substantial, and needs not be 
submitted to the EC or the CA for approval. The CA will also be notified before 
adopting a substantial amendment. 
After the study has been completed and a Clinical Study Report prepared, the EC 
and CA will be notified as agreed by the Sponsor 
. 
 
 
13 
DATA HANDLING AND RECORD KEEPING 
13.1 
Case report forms 
Data to be collected according to the study protocol (and its amendments, if any) 
shall be recorded on study-specific eCRFs generated by 
 The data will be 
recorded with electronic data capture (EDC) using eCRFs at the study center. All 
data on the CRFs must be verifiable in the source data unless declared as source 
data in the monitoring plan. 
CRFs are required for each study subject. They will be completed in English by the 
investigator or other authorized study personnel. The investigator has to confirm the 
content of the CRF by an electronic signature. 
Corrections to the CRFs may be made by the investigator or other authorized study 
personnel. An audit trail within the system will track all changes/corrections made. 
Instructions and training for completing the CRFs will be provided. These 
instructions will cover the content and technical issues of the EDC system. 
 
13.2 
Source data 
Source data will recorded in the study subject’s medical records. Access to the 
source data revealing the identity of the study subjects is only to the study personnel 
and study monitor. The generated source data are stored at 
 
, 
. 


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The laboratory results of the blood safety determinations and biomarkers are stored 
as print-outs within the ISF and in the patient records of 
 
 the personnel of which is bound to professional secrecy.  
 
13.3 
Deviations 
In case the study monitor, the investigator, a study nurse or other authorized person 
involved in the study observes a protocol deviation or discrepancy, he/she should 
describe the issue as clearly as possible in a written memorandum. In addition to 
the date and signature of the writer, the investigator, the monitor or an authorized 
Sponsor’s representative will also sign the memorandum. Deviations concerning a 
single subject will be described in the corresponding CRF. 
 
13.4 
Amendments 
Minor changes (e.g., concerning logistics or administration) to the clinical study 
protocol can be clarified in a memorandum or in a non-substantial amendment, if the 
change has no effect on the safety of the subjects or on the scientific value of the 
study. The investigator will inform the Sponsor of such minor changes. All essential 
changes to the clinical study protocol are described in a substantial amendment, 
which is submitted for approval by the EC and CA before adopting the changes, 
except when necessary to eliminate immediate hazards to the study subjects. 
Amendments to the clinical study protocol are prepared as agreed by the parties 
involved in the study. 
 
 
14 
STUDY SCHEDULE 
The study is planned to be carried out Q3/2017 – Q2/2019. 
 
 
15 
CRITERIA FOR PREMATURE STUDY TERMINATION 
The study may be discontinued at the clinical site at the discretion of the Principal 
Investigator and/or the Sponsor based e.g. on the occurrence of the following: 
· 
ADRs unexpected to date in respect to their nature, severity, and duration or 
the unexpected incidence or severity of expected ADRs. 
· 
Medical or ethical reasons affecting the continued performance of the study. 
· 
Difficulties in the recruitment of subjects. 
· 
Significant deviations from the protocol. 
The investigator will inform the EC and the sponsor will inform the CA if the study is 
terminated prematurely. The Sponsor reserves the right to prematurely terminate 
the study for valid scientific or administrative reasons. In the case of premature 
termination of the study, the investigator will proceed to appropriate actions 
(described in a separate memorandum) concerning the study subjects. 


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FINANCING AND INSURANCE 
Financial matters related to the study are covered by an agreement between 
 
the Sponsor, and in appropriate agreements between any other relevant parties 
of the study. The Sponsor has an insurance policy covering damages caused by the 
investigational products administered during the study. The insurance statement will 
be provided in the ISF and TMF. In case of any injury caused by an incident that is 
related to the study procedures but is not causally related to the investigational 
products, study subjects will be covered by the patient insurance of 
 
.  
 
 
17 
STUDY REPORT AND PUBLISHING 
A final Clinical Study Report will be prepared after the study has been completed or 
prematurely terminated. The Sponsor may submit the report to another party. The 
EC will be notified by 
 while the CA will be notified by the sponsor about study 
completion according to applicable laws and regulations. The study report will be 
approved by the principal investigator and the Sponsor. The Sponsor remains the 
exclusive owner of the study data defined in the protocol. All involved parties agree 
that the study results should be published according to usual scientific practice. The 
eventual publication of the study results and authorship of the eventual publication(s) 
will be mutually agreed. Manuscripts will not be submitted for publication without 
prior approval of the Sponsor. 
 
 
18 
ARCHIVING 
The ISF (including e.g. source data, subject screening and identification logs, 
original signed ICFs, copies of CRFs, and drug accountability records) will be 
archived by study site to enable possible follow-up assessments or audits by the 
Sponsor, or inspections by regulatory authorities. The ISF is archived for at least 15 
years after the end of the study, unless specified otherwise by a written agreement 
between the Sponsor and study site. The study site may lend materials of this study 
to third parties on the Sponsor’s documented permission. 
The Sponsor will archive the TMF according to applicable laws and regulations. 
Information collected during the course of this study will be stored by the Sponsor 
and used in the further development and understanding of the study drug for as long 
as the information is relevant for patient care. Its use includes the transfer of data to 
regulatory authorities of the European Union or its member or affiliated states (i.e. 
non-EU countries belonging to the European Economic Area, EEA), the USA or 
other non-EU/EEA countries for the purpose of obtaining, maintaining and 
processing of marketing authorizations. All information is handled confidentially and 
according to the current laws and regulations. 
 


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19 
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Maggioni AP, Dahlström U, Filippatos G, Chioncel O, Leiro MC, Drozdz J, 
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OW, Zannad F, Tavazzi L. EURObservational Research Programme: regional 
differences and 1-year follow-up results of the Heart Failure Pilot Survey (ESC-HF 
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Maggioni AP, Anand I, Gottlieb SO, Latini R, Tognoni G, Cohn JN; Val-HeFT 
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mortality in patients with heart failure not receiving angiotensin-converting enzyme 
inhibitors. J Am Coll Cardiol. 2002 Oct 16;40(8):1414-21. 
Marwick TH, Raman SV, Carrio I, Bax JJ. Recent developments in heart failure 
imaging. JACC Cardiovasc Imaging 2010;3:429 – 439 
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz M, Rizkala AR, Rouleau 
JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF Committees 
Investigators. Baseline characteristics and treatment of patients in prospective 
comparison of ARNI with ACEI to determine impact on global mortality and morbidity 
in heart failure trial (PARADIGM-HF). Eur J Heart Fail. 2014 Jul;16(7):817-25.  
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, 
Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF 
Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in 
heart failure. N Engl J Med. 2014 Sep 11;371(11):993-1004.  
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, 
Rouleau J, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-HF 


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Committees and Investigators. Dual angiotensin receptor and neprilysin inhibition as 
an alternative to angiotensin-converting enzyme inhibition in patients with chronic 
systolic heart failure: rationale for and design of the Prospective comparison of ARNI 
with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure 
trial (PARADIGM-HF). Eur J Heart Fail. 2013 Sep;15(9):1062-73.  
Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 2007; 
93:1137 – 1146. 
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de 
Ferranti S, Després JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela 
BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, 
McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar 
RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, 
Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB; 
American Heart Association Statistics Committee and Stroke Statistics 
Subcommittee. Heart disease and stroke statistics--2015 update: a report from the 
American Heart Association. Circulation. 2015 Jan 27;131(4):e29-322.  
Nagueh SF, Bhatt R, Vivo RP, Krim SR, Sarvari SI, Russell K, Edvardsen T, 
Smiseth OA, Estep JD. Echocardiographic evaluation of hemodynamics in patients 
with  decompensated  systolic  heart  failure. Circ Cardiovasc Imaging 2011;4:220 – 
227. 
Nesterov SV, Turta O, Han C, Mäki M, Lisinen I, Tuunanen H, Knuuti J. C-11 
acetate has excellent reproducibility for quantification of myocardial oxidative 
metabolism. Eur Heart J Cardiovasc Imaging. 2015 May;16(5):500-6.  
Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, 
Rademakers FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF, Borbely 
A, Edes I, Handoko  ML,  Heymans  S,  Pezzali  N,  Pieske  B,  Dickstein  K,  Fraser  
AG, Brutsaert DL. How to diagnose diastolic heart failure: a consensus statement 
on the diagnosis of heart failure with normal left ventricular ejection fraction by the 
Heart Failure and Echocardiography Associations of the European Society of 
Cardiology. Eur Heart J 2007;28:2539 – 2550. 
Pocock SJ, Ariti CA, McMurray JJV, Maggioni A, Køber L, Squire IB, 
Swedberg K, Dobson J, Poppe KK, Whalley GA, Doughty RN. Predicting survival in 
heart failure: a risk score based on 39 372 patients from 30 studies. Eur Heart J 
2013; 34:1404 – 1413. 
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, 
González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, 
Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, 
Ruschitzka F, Rutten FH, van der Meer P; Authors/Task Force Members. 2016 ESC 
Guidelines for the diagnosis and treatment of acute and chronic heart failure: The 
Task Force for the diagnosis and treatment of acute and chronic heart failure of the 
European Society of Cardiology (ESC) Developed with the special contribution of 
the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016 Jul 
14;37(27):2129-200.  
Redfield MM, Jacobsen SJ, Burnett JC, Mahoney DW, Bailey KR, Rodeheffer 
RJ. Burden of systolic and diastolic ventricular dysfunction in the community: 
appreciating the scope of the heart failure epidemic. JAMA 2003; 289:194 – 202. 
Sciacca RR, Akinboboye O, Chou RL, Epstein S, Bergmann SR. 
Measurement of myocardial blood flow with PET using 1-11C-acetate. J Nucl Med. 
2001; 42(1): 63-70. 


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Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, Shi V, 
Bransford T, Takeuchi M, Gong J, Lefkowitz M, Packer M, McMurray JJ; Prospective 
comparison of ARNI with ARB on Management Of heart failUre with preserved 
ejectioN fracTion (PARAMOUNT) Investigators. The angiotensin receptor neprilysin 
inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-
blind randomised controlled trial. Lancet. 2012 Oct 20;380(9851):1387-95. doi: 
10.1016/S0140-6736(12)61227-6. Epub 2012 Aug 26. 
Sörensen, J, Valind S, Andersson LG. Simultaneous quantiﬁcation of 
myocardial perfusion, oxidative metabolism, cardiac efﬁciency and pump function at 
rest and during supine bicycle exercise using 1-11C-acetate PET - a pilot study. Clin 
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Sun KT, Yeatman A, Buxton DB, Chen K, Johnson JA, Huang S-C, Kofoed 
KF, Weismueller S, Czernin J, Phelps M, Schelbert HR. Simultaneous measurement 
of myocardial oxygen consumption and blood flow using [1-carbon-11]acetate. J 
Nucl Med. 1998; 39: 272–280. 
Sundell J, Engblom E, Koistinen J, Ylitalo A, Naum A, Stolen KQ, Kalliokoski 
R, Nekolla SG, Airaksinen KE, Bax JJ, Knuuti J. The effects of cardiac 
resynchronization therapy on left ventricular function, myocardial energetics, and 
metabolic reserve in patients with dilated cardiomyopathy and heart failure. J Am 
Coll Cardiol. 2004 Mar 17;43(6):1027-33 
Thomas JT, Kelly RF, Thomas SJ, Stamos TD, Albasha K, Parrillo JE, Calvin 
JE. Utility of history, physical examination, electrocardiogram, and chest radiograph 
for differentiating normal from decreased systolic function in patients with heart 
failure. Am J Med 2002;112:437 – 445. 
Timmer SA, Lubberink M, Germans T, Götte MJ, ten Berg JM, ten Cate FJ, 
van Rossum AC, Lammertsma AA, Knaapen P. Potential of [11C]acetate for 
measuring myocardial blood flow: Studies in normal subjects and patients with 
hypertrophic cardiomyopathy. J Nucl Cardiol. 2010; 17(2): 264-275. 
Tuunanen H, Engblom E, Naum A, Någren K, Scheinin M, Hesse B, Juhani 
Airaksinen KE, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J. Trimetazidine, a 
metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated 
cardiomyopathy. Circulation. 2008;118:1250- 8. 
Ukkonen H, Knuuti J, Katoh C, Iida H, Sipilä H, Lehikoinen P, Någren K, 
Voipio-Pulkki L-M. Use of [11C]acetate and [15O]O2 PET for the assessment of 
myocardial oxygen utilization in patients with chronic myocardial infarction. Eur J 
Nucl Med. 2001; 28(3): 334-339. 
van den Hoff J, Burchert W, Börner A-R, Fricke H, Kühnel G, Meyer GJ, Otto 
D, Weckesser E, Wolpers H-G, Knapp WH. [1-11C]-acetate as a quantitative 
perfusion tracer in myocardial PET. J Nucl Med 2001; 42: 1174-1182. 
van den Hoff J, Burchert W, Wolpers HG, Meyer GJ, Hundeshagen H. A kinetic 
model for cardiac PET with [1-carbon-11]-acetate. J Nucl Med. 1996; 37: 521-529. 
van Riet EES, Hoes AW, Limburg A, Landman MAJ, van der Hoeven H, Rutten 
FH. Prevalence of unrecognized heart failure in older persons with shortness of 
breath on exertion. Eur J Heart Fail 2014; 16:772 – 777. 
Voigt J-U, Pedrizzetti G, Lysyansky P, Marwick TH, Houle H, Baumann R, 
Pedri S, Ito Y, Abe Y, Metz S, Song JH, Hamilton J, Sengupta PP, Kolias TJ, 
d’Hooge J, Aurigemma GP, Thomas JD, Badano LP. Definitions for a common 
standard for 2D speckle tracking echocardiography: consensus document of the 


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EACVI/ASE/Industry Task Force to standardize deformation imaging. Eur Heart J 
Cardiovasc Imaging 2015;16:1 – 11. 
Volpe M. Natriuretic peptides and cardio-renal disease. Int J Cardiol. 2014 Oct 
20;176(3):630-9.  
Wong YY, Raijmakers P, van Campen J, van der Laarse WJ, Knaapen P, 
Lubberink M, Ruiter G, Vonk Noordegraaf A, Lammertsma AA. 11C-acetate 
clearance as an index of oxygen consumption of the right myocardium in idiopathic 
pulmonary arterial hypertension: a validation study using 15O-labeled tracers and 
PET. J Nucl Med. 2013; 54(8): 1258-1262. 


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20 
APPENDICES 
Appendix 1. Subject information sheet and Informed consent form 
Appendix 2. Signed consent of the investigator(s) 
 

SAP_001.pdf: 
Clinical Development 
Sacubitril/Valsartan (Entresto™). 
CLCZ696BFI03 / NCT03300427
Controlled trial on the short-term effects of sacubitril/valsartan 
therapy on cardiac oxygen consumption and efficiency of cardiac 
work in patients with NYHA II-III heart failure and reduced systolic 
function using 11C-acetate positron emission tomography and 
echocardiography 
Statistical Analysis Plan (SAP) 
Author: 
  
Document type: 
SAP Documentation 
Document status: 
Final 1.0 
Release date: 
25-April-2022
Number of pages: 
29 
Property of Novartis 
 Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 4.0, Effective from 25-Apr-2021 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
2022-
Apr-
25 
Prior 
to 
DB 
lock 
Creation of 
final 
version 
NA - First version 
NA 
 
 
 
 
 
 


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SIGNATURES
Name, Title, Affiliation
Signature & Date
Author
, 
Reviewing 
Statistician
Approved by 
Sponsor
, 
Novartis
Approved by 
PI
, 
Principal Investigator


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Table of contents 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design............................................................................................................. 6 
1.2 
Study objectives, endpoints and estimands ............................................................. 9 
1.2.1 
Primary Endpoint .................................................................................... 9 
1.2.2 
Secondary Endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 10 
2.2 
Analysis sets .......................................................................................................... 11 
2.2.1 
Subgroup of interest .............................................................................. 12 
2.3 
Subject disposition, demographics and other baseline characteristics .................. 12 
2.3.1 
Subject disposition ................................................................................ 12 
2.3.2 
Demographics and other baseline characteristics ................................. 12 
2.3.3 
Study treatment / compliance ................................................................ 12 
2.3.4 
Prior, concomitant and post therapies ................................................... 13 
2.4 
Analysis supporting primary objective(s) .............................................................. 14 
2.4.1 
Primary endpoint(s) ............................................................................... 14 
2.4.2 
Statistical hypothesis, model, and method of analysis .......................... 14 
2.4.3 
Handling of intercurrent events ............................................................. 15 
2.4.4 
Handling of missing values not related to intercurrent event ............... 15 
2.4.5 
Sensitivity analyses ............................................................................... 15 
2.4.6 
Supplementary analyses ........................................................................ 16 
2.5 
Analysis supporting secondary objectives ............................................................. 16 
2.5.1 
Secondary endpoint(s) ........................................................................... 16 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 16 
2.5.3 
Handling of intercurrent events ............................................................. 17 
2.5.4 
Handling of missing values not related to intercurrent event ............... 17 
2.5.5 
Sensitivity analyses ............................................................................... 17 
2.5.6 
Supplementary analyses ........................................................................ 17 
2.6 
Safety analyses ....................................................................................................... 17 
2.6.1 
Adverse events (AEs) ............................................................................ 17 
2.6.2 
Deaths .................................................................................................... 18 
2.6.3 
Laboratory data ..................................................................................... 18 


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2.6.4 
Other safety data ................................................................................... 18 
2.7 
Pharmacokinetic endpoints .................................................................................... 19 
2.8 
PD and PK/PD analyses......................................................................................... 19 
2.9 
Subject-reported outcomes .................................................................................... 19 
2.10 
Biomarkers ............................................................................................................. 19 
2.11 
Other Exploratory analyses .................................................................................... 19 
2.12 
Interim analysis ...................................................................................................... 19 
3 
Sample size calculation ..................................................................................................... 19 
4 
Change to protocol specified analyses .............................................................................. 20 
5 
An additional parameter, viable myocardium energetic efficiency, is added as a 
sensitivity analysis for the primary endpoint as described in section 2.4.5. Appendix ..... 20 
5.1 
Imputation rules ..................................................................................................... 20 
5.1.1 
Study drug ............................................................................................. 20 
5.1.2 
AE date imputation ............................................................................... 20 
5.1.3 
Concomitant medication date imputation ............................................. 20 
5.2 
AEs coding/grading ............................................................................................... 21 
5.3 
Laboratory parameters derivations ........................................................................ 21 
5.4 
Statistical models ................................................................................................... 21 
5.4.1 
Analysis supporting primary objective(s) ............................................. 22 
5.4.2 
Analysis supporting secondary objective(s).......................................... 22 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 22 
5.6 
Tables, Listings and Figures Overview ................................................................. 22 
6 
Reference ........................................................................................................................... 29 
 


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List of abbreviations 
AE 
Adverse Event 
ACEI 
Angiotensin Converting Enzyme Inhibitor 
ARB 
Angiotensin II type‐1 Receptor Blocker 
ATC 
Anatomical Therapeutic Chemical 
BID 
Twice a Day 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
DMS 
Document Management System 
DTS 
Data Transfer Specification 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
HF 
Heart Failure 
HR 
Heart Rate 
IA 
Interim Analyses 
IMP 
Investigational Medicinal Product 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
PT 
Preferred Term 
RAAS 
renin‐angiotensin‐aldosterone system 
RAP 
Reporting & Analysis Process 
SAE 
Serious Adverse Event 
SAF 
Safety analysis set 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 


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1 
Introduction 
 
The statistical aspects of this study is briefely described in the protocol. The purpose of this 
Statistical Analysis Plan (SAP) is ot provide a more detailed description of the analyses to be 
conducted in this study. This SAP is based on: 
 Clinical Study Protocol, Version 3, dated 24 June 2020 
 CRF version: 
_PET_CR5 (ver 1), dated 21 Sep 2020 
 
1.1 
Study design 
 
This is a phase IV, prospective, randomized, double-blind, double-dummy, parallel group 
study, performed at a single center that is formed by 
 
. The subjects enrolled into this study are subjects with chronic 
heart failure (HF) who fulfill all of the inclusion criteria and none of the exclusion criteria.  
 
This study consists of two parts, a screening/run-in period (up to 6 weeks) and a treatment 
period (approximately 8 weeks). The subjects who sign the ICF entered the screening/run-in 
period of the study.  
 
During the screening/run-in period the subject will be switched to valsartan treatment and this 
will replace his/her previously used ACEI or ARB treatment. The starting dose of valsartan 
will be 80 mg BID or if the dose of previous RAAS blockage medication has been higher, the 
valsartan dose will be 160 mg BID. Approximately one week after the screening visit 1, 
screening visit 2 will be scheduled in order to evaluate the safety and efficacy of the ongoing 
valsartan treatment. Only subjects who tolerate 80 mg BID or 160 mg BID of valsartan and 
can maintain a stable dose for at least 4 weeks will be eligible to enter into the treatment 
period. 
 
After the screening evaluations and confirmation of eligibility, the subjects will be 
randomized into the following two treatment arms in a 1:1 ratio:   
• 
the sacubitril/valsartan treatment arm  
• 
the valsartan treatment arm 
The randomization is generated by an independent statistician at 
 using SAS®. 
 
Study drugs will be dispensed by an unblinded member of the study team during the treatment 
period while the study personnel directly involved in the clinical assessments will remain 
blinded throughout the study. The starting dose for each subject in the sacubitril/valsartan arm 


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will be 100 mg BID and in the valsartan arm 80 mg BID or 160 mg BID. The study subjects 
will return to the study center 2-3 times during the treatment period at approximately 2 weeks 
(visit 1), 3 weeks (visit 2) and 8 weeks (visit 3) after the start of the treatment period. 
 
During visit 1, possible dose up-titration will be considered. Every subject should be 
attempted to be up-titrated to the next dose level (sacubitril/valsartan 200 mg or valsartan 160 
mg, if the latter needed), if clinically possible. If up-titration is not possible, the starting dose 
should be maintained. After visit 2, if clinically indicated, the dose of the study treatment may 
be modified (up- or down-titrated) up to week 4.  
 
During the treatment period, the subjects will self-administer two tablets from two study drug 
packages BID (one tablet from the study drug package containing the active treatment and one 
tablet from the study drug package containing the placebo). The last study visit will include 
the final efficacy assessments. 
No more than 50% of the study subjects are allowed to have diabetes. To achieve similar 
groups randomization was stratified by: 
 renal insufficiency (GFR 45-60 or >60 mL/min/1.73m2) and/or  
 diabetes mellitus (on insulin or oral glucose-lowering therapy)  
 baseline HF therapy (valsartan 160 mg BID at the time of randomization)  
 
The general study design is presented in Figure 1, and the titration patterns according to 
treatment arms are presented in Figure 2 and 3. 
 
 
Figure 1 Study design 


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Figure 2. Study treatment during the double-blind treatment period with sacubitril/valsartan. 
 
Figure 3. Study treatment during the double-blind treatment period with valsartan. 


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1.2 
Study objectives, endpoints and estimands  
This study was not designed with the estimand framework according to ICH E9(R1) taken 
into consideration. The primary analysis is based on FAS and the intention is to strive to 
correspond to a Treatment Policy approach to analysis of data based on this population. 
However, as intercurrent events may have lead to withdrawal of subjects from the study that 
would otherwise not have been withdrawn, had the treatment policy estimand framework been 
taken into consideration, the interpretation of the results may not fully correspond to a  
treatment policy approach. 
Primary objective  
The primary objective of the study is to evaluate the effects of 6 weeks of stable 
sacubitril/valsartan therapy, as compared with valsartan therapy, on the efficiency of cardiac 
work in subjects with NYHA II-III HF and reduced systolic function using 11C-acetate and 
echocardiography. 
Exploratory objectives and endpoints 
The exploratory objective of the study is to evaluate the effects of 6 weeks of stable 
sacubitril/valsartan therapy, as compared with valsartan therapy, on myocardial oxygen 
consumption and cardiac and systemic hemodynamics. 
1.2.1 
Primary Endpoint 
Difference in cardiac efficiency will be evaluated by comparing the results obtained after 6 
weeks of stable treatment to the results from the baseline visit. 
1.2.2 
Secondary Endpoints  
Difference in the following cardiac and systemic hemodynamic parameters will be evaluated 
as exploratory endpoints: 
 Ejection fraction (EF)  
 N-terminal prohormone brain natriuretic peptide (NT-proBNP), 
 Systemic BP,  
 Systemic vascular resistance (SVR), 
 Coronary Cascular Resistance 
 Cardiac Oxygen Consumption. 
 


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2 
Statistical methods 
2.1 
Data analysis general information 
The statistical analyses in this study will be conducted by the CRO
 
using SAS 9.4M3. At
the raw data generated by electronic data capture (EDC) system 
will be combined to applicable analysis data sets, as required, and statistical output will be 
generated based on these aggregated data sets.  
 
All data will be tabulated using summary statistics and/or listed. For continuous data both 
absolute values and the corresponding changes form baseline will be presented, and the 
following summary statistics will be included; number of observations, mean, standard 
deviation, minimum, first quartile, median, third quartile and maximum. In addition gemetric 
mean and coefficient of variation may be provided in the summaries of efficacy endpoints, as 
applicable.  
 
Categorical data will be presented as counts and percentages, i.e., n (xx.x%). Changes form 
baseline in categtorical data will be displayed in shift tables. Percentages will be based on the 
number of subjects in the analysis data set used.  
 
Summary statistics will be presented by randomized treatment group and in total, and by visit 
and assessment time, as applicable. In addition, summary statistics may be presented by final 
titrated dose group during run-in period and other stratification factor levels as described in 
the each section of this document. 
 
2.1.1 
General definitions  
 
Baseline 
Generally, a baseline measurement refers to the last non-missing 
assessment made before the first administration of randomized 
treatment (baseline visit). This is valid for, for example, vital signs 
and laboratory data, where a difference from baseline is derived.  
Relative day 
The relative day of an event with a start date is derived as: 
Relative day = (Start date) - (Baseline date) + 1 
For events occurring or starting before baseline the relative day is 
derived as: 
Relative day = (Start date) - (Baseline date) 
In this way, there will be no Day 0. Day 1 is the same day as 
baseline, and Day -1 is the day before. 
Date format 
All dates in analysis datasets and tables, listings and figures will be 
in the format YYYY-MM-DD 


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Treatment 
Emergent 
All Adverse Events occurring on, or after the day of randomization 
will be considered Treatment Emergent (TE)  
First drug date 
The first administration of randomized treatment is assumed to be 
on the same day as randomization 
Last drug date 
The last day of randomized treatment (treatment end date) is stated 
on the study termination page in CRF. 
By dose level 
In all cases where summaries are stated to be by dose level, then 
data will be summarized by the final titrated dose level during the 
run-in period, ie the stratification by dose. 
 
2.2 
Analysis sets  
 
The following analysis sets will be used for the statistical analysis and presentation 
of data: 
 
 The safety analysis set (SAF) will consist of all randomised subjects who received at 
least one dose of the study medication in the treatment period, provided that there was 
at least one safety follow-up performed for the subject. 
 
 The full analysis set (FAS) will consist of all randomised subjects who have 
received at least one dose of study medication in the treatment period and have 
at least one post-baseline assessment of any efficacy endpoints. 
 
 The per protocol set (PPS) will consist of all subjects in the FAS who received at 
least 75% of the study drug doses, and do not have any other major protocol 
violations which will affect the assessment of efficacy. Major/important protocol 
violations may include, but are not limited to, the following: 
o Non-fulfillment of all inclusion criteria 
o Fulfillment of at least one exclusion criteria 
o Use of certain concomitant medications (this will be judged on a case to case 
basis, depending on extent of treatment) 
 
The final criteria for PPS, regarding which protocol deviations that warrant exclusions, 
will be determined when all data on protocol violations/deviations are available and 
before breaking the blind. The decision of what protocol violations/deviations will lead to 
exclusion as well as the final classification of subjects according to analysis sets will be 
documented and signed off before breaking the blind. These decisions will be documented in 
a separate Pre-Analysis Review document. 
 
The FAS is considered as the primary analysis dataset, and will be used for all primary and 
secondary efficacy analyses. The primary efficacy analysis will be repeated using the PPS. 


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Any significant discrepancy between the results from the FAS and the PPS will be analysed 
and discussed. 
 
Baseline presentations will be based on the safety set. 
 
Safety presentations will be based on the safety set. 
2.2.1 
Subgroup of interest 
The study is stratified by : 
 renal insufficiency (GFR 45-60 or >60 mL/min/1.73m2) and/or  
 diabetes mellitus (on insulin or oral glucose-lowering therapy)  
 baseline HF therapy (valsartan 160 mg BID at the time of randomization)  
The number of subjects per stratum and combination of strata will be summarized. An 
analysis for primary endpoint, including the interaction between stratum and treatment will be 
conducted in order to estimate the stratum related treatment effects. 
2.3 
Subject disposition, demographics and other baseline 
characteristics 
2.3.1 
Subject disposition 
 
A subject disposition will be created including the total number of subjects screened, the 
number of subjects entering the run-in period, number of subjects completing and not 
completing the run-in period, the No. of subjects randomized and exposed in total and per 
treatment group, the No. of subjects completing not completing the treatment period in total 
and per treatment group. The subject disposition will also include the number of subjects 
included in each of the analysis sets, in total and by treatment group. In addition, a table will 
be created listing the number of subjects per reason for discontinuation.  
 
The number and reasons for withdrawals and discontinuations will be listed and tabulated by 
treatment. Separate listings will be provided for subjects screened but not included in the 
study (screening failures). 
A table will be made displaying the number of subjects by visit. 
2.3.2 
Demographics and other baseline characteristics 
 
The collected demographics include Age, Sex, and Race. These demographics will be 
summarized using descriptive statistics and will be listed. 
 


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Medical history will be coded using MedDRA version 20.1 and will be summarized by 
system organ class (SOC) and preferred term (PT). All Medical history will also be listed.  
 
2.3.3 
Study treatment / compliance 
Study drug compliance is assessed at site and recorded in the eCRF. This information will be 
used to evaluate the criterion of “at least 75% of the study drug doses received” for inclusion 
of subjects in the PPS as described in Section 2.2. The inclusion of subjects in PPS based on 
this criterion and other important criteria will be decided and documented as part of the pre-
analysis-review, prior to unblinding of data. 
The prescribed dose levels and titrated dose levels for both screening/run-in period and 
randomized treatment groups are captured in the eCRF. The number of subjects according to 
dose level will be summarized by visit. 
All drug accountability data will be listed. 
2.3.4 
Prior, concomitant and post therapies 
All concomitant treatments administered during the study must be recorded on the CRF page 
for concomitant treatments. No other investigational treatment is allowed to be used during 
the study. A study subject must not participate concurrently or have participated in any other 
clinical drug study within 3 months prior to the first study treatment administration of this 
study. 
 
All concomitant medications/therapies will be classified according to ATC level 3 group text 
and World Health Organization (WHO) Drug Dictionary preferred name. The medications 
will be classified into categories Prior, Concomitant and Post IMP based on start date and end 
date in relation to IMP exposure (randomized double-blinded treatment). 
 Prior medications are those were end dates of the medication/therapy are strictly 
before date of first administration of IMP. 
 Concomitant medications are those for which the period between their start dates and 
end dates coincide with exposure to study drug and can be further classified into:   
o Concomitant medications starting prior to first exposure of IMP having start 
dates strictly before first exposure of IMP and end dates on same date or after 
date of first administration of IMP or are ongoing. 
o Concomitant medications starting on the date of first administration of IMP or 
after but before or on the date of last administration of IMP 
 Post medications are those for which the start dates are strictly after date of last 
administration of IMP 
The concomitant medications will be presented in a summary table broken down on timing in 
relation to IMP (i.e., Prior, Concomitant and Post). Each subject will only be counted once for 
each medication and timing category, on a preferred name level in each period. 
 
 


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2.4 
Analysis supporting primary objective(s) 
2.4.1 
Primary endpoint(s) 
 
The primary endpoint is this study is change from baseline in cardiac efficiency at visit 3, 
after 6 weeks of stable sacubitril/valsartan or valsartan treatment.  
 
The definition of cardiac efficiency is (LV work/gram of tissue) / Oxygen consumtption. 
Where LV work/gram of tissue is obtained by Echocardiography as (SBP x SV x HR) / LV 
mass, and Oxygen consumtption is obtained by 11Cacetate PET as tracer as a mono 
exponential clearance rate of 11Cacetate (kmono) 
 
So, cardiac efficiency is calculated based on the following formula: 
 
Myocardial efficiency = ((SBP x SV x HR)/LV mass)/Kmono 
Where 
- 
SBP : Systolic blood pressure during PET  
- 
SV : Stroke volume (Echocardiography) 
- 
HR : Heart rate 
- 
Kmono: Mono-exponential clearance rate (11C-acetate PET- scan) 
- 
LV mass: Left ventricular mass 
 
2.4.2 
Statistical hypothesis, model, and method of analysis  
The study hypothesis is that short-term therapy with sacubitril/valsartan added on standard HF 
therapy improves cardiac efficiency in subjects with systolic HF. In order to test this, the null 
hypothesis is formulated as follows: 
H0 : μ1 = μ2 
which will be tested against the alternative hypothesis: 
HA : μ1 ≠μ2  
where μ1 and μ2 are the mean values of change in cardiac efficiency in the two treatment arms, 
as measured by PET and echocardiography at visit 3. The null hypothesis will be tested based 
on a two-sided test and a significance level of 0.05. 
 
The primary endpoint, change from baseline in cardiac efficiency after 6 weeks on stable 
sacubitril/valsartan or valsartan therapy, will be analyzed by an ANCOVA including 
treatment and stratification as independent factors and covariate adjustment for baseline 


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cardiac efficiency. From this model, the within treatment group changes from baseline will be 
estimated using least square means, and contrasts will be set up to estimate the corresponding 
treatment difference (sacubitril/valsartan-valsartan) with a 95% confidence interval and p-
value. 
 
Summary statistics will be prepared for the derived Myocardial energetic efficiency by visit 
and its change from baseline, using discriptive statistics. In addition, Box-plots will be 
constructed showing the distribution of changes from baseline by treatment group. 
2.4.3 
Handling of intercurrent events  
The protocol for this study did not define a primary estimand of interest and thus the 
implication for interpretation of study results related to the occurrence and type of intercurrent 
events was not considered prior to design of this study.  
Section 5.8 in the CSP describes criteria for withdrawal of subjects from the study. It is stated 
that subject may be withdrawn from the study if his/her adherence to the study protocol is not 
acceptable and the following situations should result in the withdrawal of the subject, unless 
the investigator considers it safe for the subject to continue in the study, possibly after dose 
modifications of the study drug or other concomitant medication: 
- persistent symptomatic hypotension after randomization; 
- serum potassium > 5.2 mmol/l after randomization; 
- serum creatinine > 1.5 x ULN after randomization. 
The CSP does not distinguish between withdrawal from study and withdrawal from treatment 
which would have been important for a strict treatment policy approach. 
However, the number of subjects actually withdrawing from the study is expected to be very 
limited, which would allow a treatment policy estimand interpreation to still be applicable. 
2.4.4 
Handling of missing values not related to intercurrent event 
In case of any missing response data for the primary analysis, then the missing data will be 
imputed using Multiple Imputation (MI). The missing data will be imputed based on the 
factors (treatment and stratification) and baseline as covariate as applied in the ANCOVA for 
the primary analysis.  
2.4.5 
Sensitivity analyses  
In addition to the derivation of the primary endpoint as stated in Section 2.4.1, an alternative 
formula will be used, where the viable myocardium energetic efficiency will be derived as: 
 
Viable myocardial energetic efficiency = ((SBP x SV x HR)/LV mass) / vKmono 
 
Where  
- 
vKmono : Viable myocardium clearance rate 
 


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This alternative parameter is included as a sensitivity analysis to exclude possible bias related 
to scar tissue in subjects with ischemic myopathy. Analyses for this parameter will be done 
using the same approach as is applied for the primary endpoint. 
 
2.4.6 
Supplementary analyses 
A Per-protocol analysis is planned for the primary endpoint.  
Under the assumption that the primary analysis, based on FAS which is aimed to be 
conducted according to the intention-to-treat (ITT) principle, would correspond approximately 
to a treatment policy estimand analysis, then an analysis based on the PPS, which may not be 
conservative and potentially biased, would be an analysis which is not reflecting the same 
estimand as the primary analysis and is therefore  considered a supplemental analysis.  
This analysis will be conducted using the same methods as applied for the analysis of the 
primary endpoint, although any result based on this will be considered highly exploratory. No 
imputations using multiple imputation will be done for the PPS analysis. 
The primary endpoint will in addition to overall be summarized by strata and an exploratory 
ANCOVA will be done where the treatment by strata interaction will be evaluated. Based on 
this model, the within stratum treatment difference will be estimated. 
2.5 
Analysis supporting secondary objectives  
2.5.1 
Secondary endpoint(s) 
 
The changes in the following cardiac and systemic hemodynamics parameters will be 
evaluated as exploratory secondary efficacy endpoints:  
 Ejection fraction (EF) 
 N-terminal prohormone brain natriuretic peptide (NT-proBNP) 
 Systemic BP, evaluated in relation to PET and Echocardiography 
 Systemic vascular resistance (SVR) 
 Coronary Vascular Resistance 
 Cardiac Oxygen Consumption (kmono) 
 
Systemic vascular resistance (SVR) will be derived as SBP/( SV x HR) and Coronary 
Vascular Resistance will be derived as SBP/myocardial perfusion (measured from acetate 
scan using K1). 
2.5.2 
Statistical hypothesis, model, and method of analysis 
 
The change from baseline in these parameters after 6 weeks on stable sacubitril/valsartan or 
valsartan therapy will be analyzed by an ANCOVA including treatment and stratification as 


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independent factors and covariate adjustment for baseline cardiac efficiency. From this model, 
the within treatment group changes will be estimated by least square means and the 
corresponding treatment difference (sacubitril/valsartan-valsartan) will be calculated with a 
95% confidence interval and p-value.  
 
Descriptive statistics will be provided for these secondary endpoints by treatment arm 
including levels at each visit and change from baseline.  
2.5.3 
Handling of intercurrent events  
The secondary endpoints are considered exploratory. In general, all available data in 
applicable analysis set will be used for the analyses of secondary endpoints, irrespective of if 
any intercurrent events have occurred. 
2.5.4 
Handling of missing values not related to intercurrent event 
No imputations will be done for any missing data related to secondary endpoints as these are 
considered exploratory. 
2.5.5 
Sensitivity analyses 
No sensitivity analysis will be conducted for secondary endpoints. 
2.5.6 
Supplementary analyses 
In addition to the secondary endpoints stated above, a number of additional parameters related 
to the PET and Echocardiography will be collected (see DTS). All of these parameters will be 
summarized using descriptive statistics including levels by visit and the corresponding 
changes from baseline. 
2.6 
Safety analyses 
Analyses of all safety endpoints will be based on the Safety set. 
2.6.1 
Adverse events (AEs) 
 
Adverse Events (AEs) will be coded using MedDRA and will be reported by system organ 
class (SOC) and preferred terms (PT). AEs will be considered treatment emergent if occurring 
on or after the date of randomization. All AE tables will be reported for treatment emergent 
events. Non treatment emergent, during run-in, will be listed separately. 
 
A summary table will be presented with number (No.) of subjects with Treatment Emergent 
Adverse Events (TEAEs), No. of subjects with serious TEAEs, No. of subjects with severe 
TEAEs, No. of subjects with related TEAEs, No. of subjects with at least one TEAE leading 
to discontinuation, and also the No.  of TEAEs, severe TEAEs, serious TEAEs. 
 
The total No. of subjects with at least one TEAE and the No. of TEAEs will be summarized in 
a table by SOC. PT. A similar table will be created for serious adverse events (SAEs). All 


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TEAEs will also be tabulated by severity (mild, moderate and severe) and causality  to the 
treatment (related, not related).  
 
In listings of AEs the relative day counted from first administration of IMP (Day 1) will be 
presented together with the relative day from the latest administration of IMP (the actual dates 
will also be included). 
 
2.6.1.1 
Adverse events of special interest / grouping of AEs 
 
There are no AEs of special interest defined in this study. 
2.6.2 
Deaths 
Deaths are expected to be rare in this study. In case any deaths are occurring, then these will be 
listed separately including detailed information of AE leading to death. 
2.6.3 
Laboratory data 
The following laboratory tests are performed at all site visits during the study: 
Chemistry: 
 Potassium 
 Creatinine 
Haematology: 
 Haemoglobin 
These laboratory variables and their changes from baseline will be evaluated and summarized 
using descriptive statistics by visit and treatment arm. There will be two separate baseline 
values defined for the safety laboratory assessments: the first safety laboratory baseline values 
will be the ones taken on screening visit 1. The subsequent laboratory results obtained during 
the screening/run-in period will be compared to these. The second safety laboratory baseline 
values will be the ones taken at the baseline visit. The subsequent laboratory results obtained 
during the double-blind treatment period will be compared to these. Laboratory values will 
also be categorized into low, normal and high according to their reference ranges, and shift 
tables will be constructed. The reference ranges of all laboratory determinations will be 
included in the ISF before study start and updated whenever necessary. 
Clinically significant laboratory abnormalities and any additional laboratory tests taken for 
subject safety will be listed and reported in the study report. 
Urine pregnancy test will be performed for all female subjects with childbearing potential 
prior to the PET-scans. 


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2.6.4 
Other safety data 
2.6.4.1 
Vital signs 
 
The actual values of systolic and diastolic blood presure (BP) and heart rate (HR) and their 
changes from baseline will be evaluated with descriptive statistics by treatment arm. There 
will be two separate baseline values defined for the BP and HR measurements: the first BP 
and HR baseline value will be the one taken on the first screening visit. The subsequent BP 
and HR measurements during the screening/run-in period will be compared to this. The 
second baseline value will be the one taken before randomization at the baseline visit. The 
subsequent BP and HR measurements during the double-blind treatment period will be 
compared to this.  
2.7 
Pharmacokinetic endpoints   
NA 
2.8 
PD and PK/PD analyses 
NA 
2.9 
Subject-reported outcomes 
NA 
2.10 
Biomarkers 
Biomarkers will be measured to understand the potential mechanisms of how 
sacubitril/valsartan changes myocardial efficiency. Blood samples will be obtained for 
measurement of NT-proBNP hs-troponin and creatinine to assess effects of interventions on 
hemodynamics before randomization and repeatedly on visit 3, after 6 weeks of stable 
sacubitril/valsartan or valsartan treatment. 
These biomarkers will be summarized using descriptive statistics including levels at baseline 
and Visit 3, and change from baseline at Visit 3. Creatinine is  collected as a safety laboratory 
parameter at all visits as described in Section 2.6.3, and will thus be summarized as part of 
safety laboratory. In addition NT-proBNP will be analysed by an ANCOVA according to 
description under secondary endpoints (Section 2.5.1).A shift table corresponding to those for 
safety lab will be provided. 
 
2.11 
Other Exploratory analyses 
NA  
2.12 
Interim analysis 
There are no interim analyses during the study. 


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3 
Sample size calculation 
 
In previous studies using the same techniques (i.e. 11C-acetate PET scan and 
echocardiography), beta-blockers in drug-naïve subjects increased cardiac efficiency by 45% 
(Beanlands 2000). In later studies using e.g. new biventricular pacing techniques in previously 
medicated subjects, the cardiac efficiency was improved by 20% (Sundell 2004). Therefore, 
we assume that the clinically significant change in cardiac efficiency in medicated subjects 
would be about 20%. In our previous studies in subjects with heart failure (Nesterov 2015, 
Tuunanen 2008), the same subjects were studied twice in the interval of 3 months, the 
coefficient of variation (CV%) of Kmono in placebo group was 18.4% and in efficiency 
19.7%. Based on sample size calculations, in order to detect a 15% change in cardiac 
efficiency, 27 subjects would need to be included in each treatment arm (assuming α = 0.05 
and β = 0.2). Due to potential drop outs during the study, the target is to enroll 30 + 30 
subjects in the treatment arms. 
4 
Change to protocol specified analyses 
An additional parameter, viable myocardium energetic efficiency, is added as a sensitivity 
analysis for the primary endpoint as described in section 2.4.5.  
In the protocol it was stated that all summary statistics will be done by dose level. Split of 
summary statistics by dose level, ie stratification factor, will be limited to the subject disposition, 
primary endpoint and overview of TEAEs.  
5 
Appendix 
5.1 
Imputation rules 
If the visit 3 assessment for the primary endpoint is missing for a subject then this will be 
imputed using a monotone regression approach including treatment and stratification as class 
variables. One hundred imputations will be done. Each replication of the data, including the 
imputed missing values, will then be analyzed using the ANCOVA used in the primary 
analysis, and estimates will be pooled using proc MIANALYZE SAS®. 
5.1.1 
Study drug 
Actual dates and time points of study drug adminstrations are not captured in the eCRF. The 
last drug date is recorded on the study termination page, the first drug date is assumedto be on 
the day of randomization. 
5.1.2 
 AE date imputation 
AEs with incomplete dates will be regarded as TEAEs if year and month are available and are 
the same as the date of first dose of randomized treatment or if only year is available and is the 
same year as the date of first dose of randomized treatment. 


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5.1.3 
Concomitant medication date imputation 
 
For medication and therapies with partial dates:  
o If start date is completely missing, it will be assumed that the medication started 
before date of first administration of randomized treatment. 
o If end date is completely missing and ongoing is not ticked, it will be assumed that the 
medication ended before date of first administration of randomized 
treatmenttreatment. 
o For medications/therapies where only partial dates are available, either only year or 
year and month, then this information will be used in analogy with how complete 
dates are used for classification. 
Relative day will not be calculated for medications with incomplete dates.  
5.1.3.1 
Other imputations 
NA  
5.2 
AEs coding/grading 
All AEs and medical history verbatim terms were encoded as SOC and PT using MedDRA, 
latest version available when approving the data management plan (DMP). Severity is graded 
as mild, moderate and severe. Relation to treatment is captured as related and not related. 
5.3 
Laboratory parameters derivations 
NA 
5.4 
Statistical models 
NA 
5.4.1 
Analysis supporting primary objective(s)  
See Section 2.4 
5.4.2 
Analysis supporting secondary objective(s) 
See Section 2.5 
5.5 
Rule of exclusion criteria of analysis sets  
 
The final criteria for PPS, regarding which protocol deviations and other criteria that warrant 
exclusions will be determined when all data on protocol deviations are available and before 
breaking the blind. Final classification of subjects according to study populations will be 
documented and included in a “pre-analysis review” document, which will be signed before 
unblinding.    


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5.6 
Tables, Listings and Figures Overview 
Tables to be Produced for the Clinical Study Report (Section 14 according to ICH 
E3) 
(Table numbers refer to section numbers in ICH E3.) 
 
14.1 Demography and Background Characteristics 
Table  
SAF 
FAS 
  PPS 
Subject disposition  
X 
 
Subject disposition by strata 
X 
 
 
Subject discontinuation 
X 
 
 
Subject discontinuation by strata 
X 
 
 
Demography  
X 
Demography by strata 
X 
 
 
Number of subjects by visit 
X 
 
 
Medical history  
X 
 
 
 


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14.2 EFFICACY DATA  
14.2.1 Primary Endpoint 
Table  
SAF 
FAS 
  PPS 
Summary of Myocardial energetic efficiency by visit and 
change from baseline  
X 
X 
Analysis of change from baseline in Myocardial 
energetic efficiency (ANCOVA) 
X 
X 
Boxplots of change from baseline in Myocardial 
energetic efficiency 
 
X 
X 
Summary of Myocardial energetic efficiency by visit and 
change from baseline by strata 
 
X 
X 
Analysis of change from baseline in Myocardial 
energetic efficiency (ANCOVA) including treatment by 
strata interaction 
 
X 
X 
Summary of Viable myocardium energetic efficiency by 
visit and change from baseline  
 
X 
X 
Analysis of change from baseline in Viable myocardium 
energetic efficiency (ANCOVA) 
 
X 
X 
Boxplots of change from baseline in Viable Myocardial 
energetic efficiency 
 
X 
X 
 
 
14.2.2 Secondary Endpoints 
Table  
SAF 
FAS 
  PPS 
Summary of  Ejection fraction (Echocardiography) by 
visit and change from baseline 
 
X 
 
Analysis of change from baseline in Ejection fraction 
(Echocardiography) (ANCOVA) 
 
X 
 
Summary of N-terminal prohormone brain natriuretic 
peptide (NT-proBNP) by visit and change from baseline 
 
X 
 
Analysis of change from baseline in N-terminal 
prohormone brain natriuretic peptide (NT-proBNP) 
(ANCOVA) 
 
X 
 
Summary Systemic BP during PET by visit and change 
from baseline  
 
X 
 


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Analysis of change from baseline in Systemic BP 
(ANCOVA) collected in relation to Echocardiograph 
and PET 
 
X 
 
Summary of Systemic vascular resistance (SVR)  by 
visit and change from baseline 
 
X 
 
Analysis of change from baseline in Systemic vascular 
resistance (SVR) (ANCOVA) 
 
X 
 
Summary of Coronary Vascular Resistance by visit and 
change from baseline 
 
X 
 
Analysis of change from baseline in Coronary Vascular 
Resistance (ANCOVA) 
 
X 
 
Summary of Cardiac Oxygen Consumption (kmono) by 
visit and change from baseline 
 
X 
 
Analysis of change from baseline in Cardiac Oxygen 
Consumption (kmono) (ANCOVA) 
 
X 
 
Summary of Resting perfusion (PET) by visit and 
change from baseline 
X 
 
Summary of Viable myocardiumResting  perfusion 
(PET) by visit and change from baseline  
 
X 
 
Summary of Viable myocardium clearance rate (PET) 
by visit and change from baseline 
 
X 
 
Summary of Left ventricle mass (Echocardiography) by 
visit and change from baseline 
 
X 
 
Summary of  Stroke volume (Echocardiography) by 
visit and change from baseline 
X 
 
Summary of  Cardiac output (Echocardiography) by 
visit and change from baseline 
 
X 
 
Summary of  Left ventricular mechanical work (SBP x 
SV x HR)/ LV mass (Echocardiography) by visit and 
change from baseline   
X 
 
Summary of  Global Longitudinal Strain 
(Echocardiography) by visit and change from baseline 
 
X 
 
Summary of  left ventricular systolic volume 
(Echocardiography) by visit and change from baseline 
 
X 
 
Summary of  left ventricular diastolic volume 
(Echocardiography) by visit and change from baseline 
 
X 
 
 


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14.3 SAFETY DATA  
14.3.1 Display of Adverse Events 
Item 
SAF 
FAS 
  PPS 
Summary of Treatment-Emergent Adverse Events 
X 
Summary of Treatment-Emergent Adverse Events by 
strata 
X 
 
 
Treatment-Emergent Adverse Events by System Organ 
Class and Preferred Term 
X 
Treatment-Emergent Adverse Events by Severity and 
System Organ Class and Preferred Term 
X 
 
 
Treatment-Emergent Adverse Events by Relation and 
System Organ Class and Preferred Term 
X 
 
 
 
14.3.2 Listings of Deaths, Other Serious Adverse Events, and Other Significant Adverse Events 
Item 
SAF 
FAS 
  PPS 
Listing of Serious Adverse Events  
X 
 
 
Adverse Events Leading to Death  
X 
Adverse Events Leading to Withdrawal 
X 
 
 
 
14.3.3 Reserved for narratives 
 
14.3.4 Laboratory Assessments 
Item 
SAF 
FAS 
  PPS 
Abnormal Laboratory Value Listing  
X 
Summary of Safety Laboratory Assessments 
X 
Safety Laboratory Assessments Shift Table  
X 
Summary of Laboratory Biomarker Assessments 
 
X 
 
Biomarker Laboratory Assessments Shift Table  
 
X 
 
 
14.3.5 Extent of Exposure 
Item 
SAF 
FAS 
  PPS 


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Exposure to Study Drug  
X 
Summary of subjects by dose group and visit 
X 
 
 
Compliance 
X 
 
 
 
14.3.6 Vital Signs 
Item 
SAF 
FAS 
  PPS 
Summary of Vital Signs  
X 
Vital Signs Shift Table  
X 
 
14.3.9 Concomitant Medication and Therapy  
Item 
SAF 
FAS 
  PPS 
Concomitant Medication and Therapy  
X 
 
 


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Listings of Individual Subject Data and Other Information to be Produced for the Clinical 
Study Report  
(Listing numbers refer to the relevant appendix number in ICH E3. CRF check questions/ 
reminders will not be listed.) 
 
16.1.7 Randomisation Scheme 
Listing 
SAF 
FAS 
  PPS 
Randomisation scheme  
X 
 
 
 
16.2.1 Discontinued Subjects, Reason for Discontinuation 
Listing 
SAF 
FAS 
  PPS 
Study discontinuation and reasons for withdrawal 
X 
 
 
Visit Dates and Other Important Dates 
X 
 
 
 
16.2.3 Subjects Excluded from the Efficacy Analysis (Evaluability, Reason for Evaluability 
Classification) 
Listing 
SAF 
FAS 
  PPS 
Subject disposition and analysis data sets and reasons for 
exclusion 
X 
 
 
 
16.2.4 Demographics and Other Background Characteristics 
Listing 
SAF 
FAS 
  PPS 
Demographics data 
X 
 
 
Medical history 
X 
 
 
 
16.2.5 Compliance and/or Drug Concentration Data 
Listing 
SAF 
FAS 
  PPS 
Compliance 
X 
 
 
Drug accountability 
X 
 
 
Titration data 
X 
 
 
 
 


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16.2.6 Individual Efficacy Response Data  
Listing 
SAF 
FAS 
  PPS 
Primary efficacy parameter  
X 
 
Secondary efficacy parameters for  PET-scan, 
Echocardiography 
X 
 
 
16.2.7 Adverse Events by Treatment, Subject, Relative Day or Week.  
Listing 
SAF 
FAS 
  PPS 
Adverse events by subject, relative day  
X 
 
 
Adverse events by SOC, PT and subject  
X 
 
 
Serious adverse events by subject, relative day  
X 
 
 
 
16.2.8 Laboratory parameters 
Listing 
SAF 
FAS 
  PPS 
Safety Laboratory Assessments  
X 
 
 
Laboratory Biomarker Assessments 
X 
 
 
Pregnancy test 
X 
 
 
Listing of reference ranges. 
 
 
 
 
16.2.9 Vital Signs  
Listing 
SAF 
FAS 
  PPS 
Vital Signs  
X 
 
 
 
16.2.10 Physical Examination 
Listing 
SAF 
FAS 
  PPS 
Physical Examination  
X 
 
 
 
16.2.11 Concomitant Medication and Therapy 
Listing 
SAF 
FAS 
  PPS 
Concomitant medication and therapy  
X 
 
 
 
 


Novartis 
Confidential 
Page 30 of 30 
SAP 
 
Study No. CLCZ696BFI03 
 
 
 
 
6 
Reference 
ICH E9(R1) Harmonized Guideline: addendum on estimands and sensitivity analysis in clinical 
trials to the guideline on statistical principles for clinical trials. Final version on 20 November 
2019.  
 
 
 


Page No
1 ( 6 )
ADDENDUM OF STATISTICAL ANALYSIS PLAN
ST_Form: Statistical Analysis Plan Addendum_03
Study Title:
Controlled trial on the short-term effects of sacubitril/valsartan 
therapy on cardiac oxygen consumption and efficiency of cardiac 
work in patients with NYHA II-III heart failure and reduced 
systolic function using 11C-acetate positron emission tomography 
and echocardiography
Investigational product:
Sacubitril/Valsartan
Sponsor:
Novartis Finland Oy
Sponsor Study Code:
CLCZ696BFI03
 Project Code: 
NOV1154
Date of approved SAP:
25/04/2022
Addendum 
no:
01
Date 
written:
04/07/2022
Author:
Review and Approval of SAP addendum:
Sponsor:
Date
Signature
Principal Investigator:
Date
Signature
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SAP addendum
Version: 1.0
Date: 04/07/2022
Sponsor: Novartis Finland Oy
Study Code: CLCZ696BFI03
NCT No.: 2017-002113-64
ST_Form: Statistical Analysis Plan Addendum_03
Reviewing Statistician:
Date
Signature
Author/Project Statistician:
Date
Signature
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
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SAP addendum 
Version: 1.0 
Date: 04/07/2022 
Sponsor: Novartis Finland Oy 
Study Code: CLCZ696BFI03 
NCT No.: 2017-002113-64 
 
ST_Form: Statistical Analysis Plan Addendum_03 
1.1 Amendment(s) of the SAP 
 
As SAP states: analyses for Viable myocardium energetic efficiency will be done using the same approach as 
is applied for the primary endpoint. For this reason, a summary statistic by strata and an ANCOVA model is 
added, where the treatment by strata interaction will be evaluated. Based on this model, the within stratum 
treatment difference will be estimated. 
 
 
Regarding secondary endpoints. The SAP did not include ANCOVA models for the following parameters: 
 
 
Resting perfusion (PET) 
 
Viable myocardium resting perfusion (PET) 
 
Viable myocardium clearance rate (PET) 
 
Left ventricle mass (Echocardiography) 
 
Stroke volume (Echocardiography) 
 
Cardiac output (Echocardiography) 
 
Left ventricular mechanical work (SBP echocardiography x SV x HR)/ LV mass (Echocardiography) 
 
Global Longitudinal Strain (Echocardiography) 
 
Left ventricular systolic volume (Echocardiography) 
 
Left ventricular diastolic volume (Echocardiography) 
 
Additional ANCOVA models will be added according to description under secondary endpoints: The change 
from baseline in these parameters after 6 weeks on stable sacubitril/valsartan or valsartan therapy will be 
analyzed by an ANCOVA including treatment and stratification as independent factors and covariate adjustment 
for baseline. From this model, the within treatment group changes will be estimated by least square means and 
the corresponding treatment difference (sacubitril/valsartan-valsartan) will be calculated with a 95% confidence 
interval and p-value.  
 
 
 
 
 
 
 


SAP addendum 
Version: 1.0 
Date: 04/07/2022 
Sponsor: Novartis Finland Oy 
Study Code: CLCZ696BFI03 
NCT No.: 2017-002113-64 
 
ST_Form: Statistical Analysis Plan Addendum_03 
1.2 Result 
 
The following tables highlighted in bold will be added 
 
14.2 EFFICACY DATA  
14.2.1 Primary Endpoint 
Table  
SAF 
FAS 
  PPS 
Summary of Myocardial energetic efficiency by visit and 
change from baseline  
X 
X 
Analysis of change from baseline in Myocardial 
energetic efficiency (ANCOVA) 
X 
X 
Boxplots of change from baseline in Myocardial 
energetic efficiency 
 
X 
X 
Summary of Myocardial energetic efficiency by visit and 
change from baseline by strata 
 
X 
X 
Analysis of change from baseline in Myocardial 
energetic efficiency (ANCOVA) including treatment by 
strata interaction 
 
X 
X 
Summary of Viable myocardium energetic efficiency by 
visit and change from baseline  
 
X 
X 
Analysis of change from baseline in Viable myocardium 
energetic efficiency (ANCOVA) 
 
X 
X 
Boxplots of change from baseline in Viable Myocardial 
energetic efficiency 
 
X 
X 
Summary of Viable Myocardial energetic efficiency 
by visit and change from baseline by strata 
 
X 
X 
Analysis of treatment by stratification interaction on 
change from baseline in Viable Myocardial energetic 
efficiency (ANCOVA) 
 
X 
X 
 
 
14.2.2 Secondary Endpoints 
Table  
SAF 
FAS 
  PPS 
Summary of Ejection fraction (Echocardiography) by 
visit and change from baseline 
 
X 
 
Analysis of change from baseline in Ejection fraction 
(Echocardiography) (ANCOVA) 
 
X 
 
Summary of N-terminal prohormone brain natriuretic 
peptide (NT-proBNP) by visit and change from baseline 
 
X 
 


SAP addendum 
Version: 1.0 
Date: 04/07/2022 
Sponsor: Novartis Finland Oy 
Study Code: CLCZ696BFI03 
NCT No.: 2017-002113-64 
 
ST_Form: Statistical Analysis Plan Addendum_03 
Analysis of change from baseline in N-terminal 
prohormone brain natriuretic peptide (NT-proBNP) 
(ANCOVA) 
 
X 
 
Summary Systemic BP during PET by visit and change 
from baseline  
 
X 
 
Analysis of change from baseline in Systemic BP 
(ANCOVA) collected in relation to Echocardiograph 
and PET 
 
X 
 
Summary of Systemic vascular resistance (SVR) by 
visit and change from baseline 
 
X 
 
Analysis of change from baseline in Systemic vascular 
resistance (SVR) (ANCOVA) 
 
X 
 
Summary of Coronary Vascular Resistance by visit and 
change from baseline 
 
X 
 
Analysis of change from baseline in Coronary Vascular 
Resistance (ANCOVA) 
 
X 
 
Summary of Cardiac Oxygen Consumption (kmono) by 
visit and change from baseline 
 
X 
 
Analysis of change from baseline in Cardiac Oxygen 
Consumption (kmono) (ANCOVA) 
 
X 
 
Summary of Resting perfusion (PET) by visit and 
change from baseline 
 
X 
 
Analysis of change from baseline in Resting 
perfusion (PET) (ANCOVA) 
 
X 
 
Summary of Viable myocardium Resting perfusion 
(PET) by visit and change from baseline  
X 
 
Analysis of change from baseline in Viable 
myocardium Resting perfusion (PET) (ANCOVA) 
 
X 
 
Summary of Viable myocardium clearance rate (PET) 
by visit and change from baseline 
 
X 
 
Analysis of change from baseline in Viable 
myocardium clearance rate (PET) (ANCOVA) 
 
X 
 
Summary of Left ventricle mass (Echocardiography) by 
visit and change from baseline 
 
X 
 
Analysis of change from baseline in Left ventricle 
mass (Echocardiography) (ANCOVA) 
 
X 
 
Summary of Stroke volume (Echocardiography) by visit 
and change from baseline 
X 
 
Analysis of change from baseline in Stroke volume 
(Echocardiography) (ANCOVA) 
 
X 
 


SAP addendum 
Version: 1.0 
Date: 04/07/2022 
Sponsor: Novartis Finland Oy 
Study Code: CLCZ696BFI03 
NCT No.: 2017-002113-64 
 
ST_Form: Statistical Analysis Plan Addendum_03 
Summary of Cardiac output (Echocardiography) by visit 
and change from baseline 
 
X 
 
Analysis of change from baseline in Cardiac output 
(Echocardiography) (ANCOVA) 
 
X 
 
Summary of Left ventricular mechanical work (SBP x 
SV x HR)/ LV mass (Echocardiography) by visit and 
change from baseline   
X 
 
Analysis of change from baseline in Left ventricular 
mechanical work (SBP x SV x HR)/ LV mass 
(Echocardiography) (ANCOVA) 
 
X 
 
Summary of Global Longitudinal Strain 
(Echocardiography) by visit and change from baseline 
 
X 
 
Analysis of change from baseline in Global 
Longitudinal Strain (Echocardiography) (ANCOVA) 
 
X 
 
Summary of left ventricular systolic volume 
(Echocardiography) by visit and change from baseline 
 
X 
 
Analysis of change from baseline in left ventricular 
systolic volume (Echocardiography) (ANCOVA) 
 
X 
 
Summary of left ventricular diastolic volume 
(Echocardiography) by visit and change from baseline 
 
X 
 
Analysis of change from baseline in left ventricular 
diastolic volume (Echocardiography) (ANCOVA) 
 
X