A Multi-center, Randomized, Placebo- and Active-controlled, Parallel-group, 24-week Proof of Concept and Dose-finding Study to Evaluate Efficacy, Safety, and Tolerability of XXB750 in Patients With Heart Failure
Phase: PHASE2
Conditions: Heart Failure
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
Clinical Trial Protocol Title: 
A multi-center, randomized, placebo- and active-controlled, 
parallel-group, 24-week proof of concept and dose-finding 
study to evaluate efficacy, safety, and tolerability of 
XXB750 in patients with heart failure 
Clinical Trial Protocol Number: CXXB750A12201 / NCT06142383
Version Number: 02 (Amended Protocol) (Clean)  
Compound: XXB750 
Brief Title: A proof of concept and dose-finding study of XXB750 in patients with 
heart failure 
Study Phase: II 
Sponsor Name: Novartis 
Regulatory Agency Identifier Number(s): EU-CT Number 2023-504678-39-00 
Approval Date: 23-Feb-2024  
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 5.0 dated 14-Jan-2022 

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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 7 
Amendment 02 (23-Feb-2024) ............................................................................................ 8 
Amendment 01 (06-Feb-2024) ............................................................................................ 9 
1 
Protocol summary .............................................................................................................. 11 
1.1 
Summary ................................................................................................................ 11 
1.2 
Schema ................................................................................................................... 15 
1.3 
Schedule of activities (SoA) .................................................................................. 15 
2 
Introduction ....................................................................................................................... 19 
2.1 
Study rationale ....................................................................................................... 19 
2.2 
Background ............................................................................................................ 19 
2.3 
Benefit/Risk assessment ........................................................................................ 21 
3 
Objectives, endpoints, and estimands ................................................................................ 23 
3.1 
Primary estimands ................................................................................................. 24 
3.2 
Secondary estimands ............................................................................................. 25 
4 
Study design ...................................................................................................................... 26 
4.1 
Overall design ........................................................................................................ 26 
4.1.1 
Screening Period ................................................................................... 26 
4.1.2 
Randomized Treatment Period .............................................................. 27 
4.1.3 
Safety Follow-up Period ....................................................................... 28 
4.2 
Scientific rationale for study design ...................................................................... 29 
4.2.1 
Rationale for target study population .................................................... 30 
4.2.2 
Rationale for the primary endpoint ....................................................... 31 
4.3 
Justification for dose .............................................................................................. 31 
4.3.1 
Rationale for choice of background therapy ......................................... 32 
4.4 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 32 
4.5 
Rationale for public health emergency mitigation procedures .............................. 33 
4.6 
Purpose and timing of interim analyses/design adaptations .................................. 33 
4.7 
End of study definition .......................................................................................... 35 
5 
Study population ................................................................................................................ 35 
5.1 
Inclusion criteria .................................................................................................... 36 
5.2 
Exclusion criteria ................................................................................................... 36 
5.3 
Screen failures ....................................................................................................... 38 
5.3.1 
Replacement policy ............................................................................... 39 

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5.3.2 
Participant numbering ........................................................................... 39 
6 
Study treatment(s) and concomitant therapy ..................................................................... 39 
6.1 
Study treatment(s) .................................................................................................. 39 
6.1.1 
Additional study treatments .................................................................. 40 
6.1.2 
Treatment arms/group ........................................................................... 40 
6.1.3 
Treatment duration ................................................................................ 41 
6.2 
Preparation, handling, storage, and accountability ................................................ 41 
6.2.1 
Handling of study treatment .................................................................. 42 
6.2.2 
Handling of other treatment .................................................................. 43 
6.2.3 
Instruction for prescribing and taking study treatment ......................... 43 
6.3 
Measures to minimize bias: randomization and blinding ...................................... 44 
6.3.1 
Treatment assignment, randomization .................................................. 44 
6.3.2 
Treatment blinding ................................................................................ 44 
6.3.3 
Emergency breaking of assigned treatment code .................................. 46 
6.4 
Study treatment compliance .................................................................................. 47 
6.4.1 
Recommended treatment of adverse events .......................................... 47 
6.5 
Dose modification .................................................................................................. 47 
6.5.1 
Definitions of dose limiting toxicities (DLTs) ...................................... 48 
6.5.2 
Follow-up for toxicities ......................................................................... 49 
6.6 
Continued access to study treatment after the end of the study ............................. 50 
6.6.1 
Post trial access ..................................................................................... 50 
6.7 
Treatment of overdose ........................................................................................... 50 
6.7.1 
Reporting of study treatment errors including misuse/abuse ................ 51 
6.8 
Concomitant and other therapy .............................................................................. 51 
6.8.1 
Concomitant therapy ............................................................................. 51 
6.8.2 
Prohibited medication ........................................................................... 52 
6.8.3 
Rescue medicine .................................................................................... 53 
7 
Discontinuation of study treatment and participant discontinuation/withdrawal .............. 53 
7.1 
Discontinuation of study treatment ........................................................................ 53 
7.2 
Participant discontinuation from the study ............................................................ 54 
7.3 
Withdrawal of informed consent and exercise of participants’ data privacy 
rights ...................................................................................................................... 54 
7.4 
Lost to follow-up ................................................................................................... 55 
7.5 
Early study termination by the Sponsor ................................................................. 55 
8 
Study Assessments and Procedures ................................................................................... 55 
8.1 
Screening ............................................................................................................... 55 

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8.2 
Participant demographics/other baseline characteristics ....................................... 56 
8.3 
Efficacy assessments ............................................................................................. 56 
8.3.1 
NT-proBNP ........................................................................................... 56 
8.3.2 
Secondary efficacy assessments ............................................................ 57 
8.3.3 
Appropriateness of efficacy assessments .............................................. 57 
8.4 
Safety assessments ................................................................................................. 57 
8.4.1 
Physical examinations ........................................................................... 57 
8.4.2 
Vital signs.............................................................................................. 57 
8.4.3 
Height and weight ................................................................................. 58 
8.4.4 
Electrocardiograms ............................................................................... 58 
8.4.5 
Clinical safety laboratory tests .............................................................. 58 
8.4.6 
Pregnancy testing .................................................................................. 59 
8.4.7 
Other safety evaluations ........................................................................ 60 
8.4.8 
Appropriateness of safety measurements .............................................. 61 
8.5 
Additional assessments .......................................................................................... 61 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 61 
8.5.2 
Other assessments ................................................................................. 62 
8.6 
Adverse events (AEs), serious adverse events (SAEs), and other safety 
reporting ................................................................................................................. 63 
8.6.1 
Adverse events ...................................................................................... 63 
8.6.2 
Serious adverse events .......................................................................... 66 
8.6.3 
SAE reporting........................................................................................ 67 
8.6.4 
Pregnancy .............................................................................................. 69 
8.6.5 
Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs .................................................................... 69 
8.6.6 
Adverse events of special interest ......................................................... 70 
8.7 
Pharmacokinetics ................................................................................................... 70 
8.8 
Biomarkers ............................................................................................................. 70 
8.9 
Immunogenicity assessments ................................................................................. 72 
8.10 
Medical resource utilization and health economics ............................................... 72 
9 
Statistical considerations ................................................................................................... 72 
9.1 
Analysis sets .......................................................................................................... 72 
9.2 
Statistical analyses ................................................................................................. 73 
9.2.1 
General considerations .......................................................................... 73 
9.2.2 
Participant demographics and other baseline characteristics ................ 73 
9.2.3 
Treatments ............................................................................................. 74 
9.3 
Primary endpoint(s)/estimand(s) analysis .............................................................. 74 

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9.3.1 
Definition of primary endpoint(s) ......................................................... 74 
9.3.2 
Statistical model, hypothesis, and method of analysis .......................... 74 
9.3.3 
Handling of intercurrent events of primary estimand (if applicable) .... 76 
9.3.4 
Handling of missing values not related to intercurrent event ............... 77 
9.3.5 
Multiplicity adjustment (if applicable) .................................................. 77 
9.3.6 
Sensitivity analyses ............................................................................... 77 
9.3.7 
Supplementary analysis ......................................................................... 77 
9.4 
Secondary endpoint(s)/estimand(s) analysis .......................................................... 78 
9.4.1 
Efficacy and/or pharmacodynamic endpoint(s) .................................... 78 
9.4.2 
Safety endpoints .................................................................................... 79 
9.5 
Exploratory endpoint(s)/estimand(s) analysis ....................................................... 80 
9.5.1 
Exploratory variables ............................................................................ 81 
9.5.2 
Analysis methods .................................................................................. 81 
9.5.3 
Pharmacokinetics .................................................................................. 83 
9.5.4 
Biomarkers ............................................................................................ 84 
9.5.5 
Immunogenicity .................................................................................... 84 
9.5.6 
Patient reported outcomes ..................................................................... 84 
9.6 
Other safety analyses ............................................................................................. 84 
9.7 
Other analyses ........................................................................................................ 84 
9.7.1 
Subgroup analyses ................................................................................. 84 
9.7.2 
DNA ...................................................................................................... 85 
9.8 
Interim analysis ...................................................................................................... 85 
9.9 
Sample size determination ..................................................................................... 85 
9.9.1 
Primary endpoint(s) ............................................................................... 86 
9.9.2 
Secondary endpoint(s) ........................................................................... 86 
10 Supporting documentation and operational considerations ............................................... 86 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations ................... 86 
10.1.1 
Regulatory and ethical considerations .................................................. 86 
10.1.2 
Informed consent process ...................................................................... 88 
10.1.3 
Data protection ...................................................................................... 89 
10.1.4 
Committees structure ............................................................................ 90 
10.1.5 
Data quality assurance ........................................................................... 90 
10.1.6 
Source documents ................................................................................. 92 
10.1.7 
Publication policy.................................................................................. 92 
10.1.8 
Protocol adherence and protocol amendments ...................................... 93 
10.2 
Appendix 2: Abbreviations and definitions ........................................................... 94 

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10.2.1 
List of abbreviations .............................................................................. 94 
10.2.2 
Definitions ............................................................................................. 97 
10.3 
Appendix 3: Clinical laboratory tests .................................................................. 100 
10.3.1 
Clinically notable laboratory values and vital signs ........................... 100 
10.4 
Appendix 4: Participant Engagement .................................................................. 102 
10.5 
Appendix 5: Liver safety monitoring .................................................................. 103 
10.5.1 
Liver event and laboratory trigger definitions & follow-up 
requirements ........................................................................................ 103 
10.6 
Appendix 6: Renal safety monitoring .................................................................. 106 
10.6.1 
Specific Renal Alert Criteria and Actions and Event Follow-up ........ 106 
10.7 
Appendix 7: Managing hypotension .................................................................... 107 
10.8 
Appendix 8: Managing hyperkalemia ................................................................. 109 
11 References ....................................................................................................................... 111 
 
List of tables 
Table 1-1 
Assessment Schedule ............................................................................ 17 
Table 3-1 
Objectives and related endpoints .......................................................... 23 
Table 4-1 
Minimum required pre-study daily doses of ACEIs and ARBs ............ 27 
Table 4-2 
Overview of the planned staggered enrollment strategy ....................... 34 
Table 6-1 
Investigational and control drug ............................................................ 39 
Table 6-2 
Auxiliary treatments .............................................................................. 40 
Table 6-3 
Treatment arms, dose levels, and planned doses administered at 
dispensing visits during the Randomized treatment period .................. 41 
Table 6-4 
Blinding and unblinding plan ................................................................ 45 
Table 6-5 
Diagnostic assessments to determine alternative causes of observed 
LFT abnormalities ................................................................................. 49 
Table 8-1 
Clinical Safety Laboratory Tests ........................................................... 59 
Table 8-2 
MedDRA PT related to the underlying heart failure ............................. 68 
Table 9-1 
Selecting a winner based on combination of change of KCCQ CSS 
and change of NYHA class ................................................................... 82 
Table 10-1 
Clinically notable hematology abnormalities ...................................... 100 
Table 10-2 
Clinically notable blood chemistry abnormalities............................... 100 
Table 10-3 
Liver event and laboratory trigger definitions .................................... 103 
Table 10-4 
Follow up requirements for liver laboratory triggers - ALT, AST, 
TBL ..................................................................................................... 104 
Table 10-5 
Follow-up requirements for liver laboratory triggers based on 
isolated elevations in TBL .................................................................. 105 

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Table 10-6 
Renal event criteria and corresponding actions to be taken upon 
their occurrence ................................................................................... 106 
 
List of figures 
Figure 1-1 
Study design .......................................................................................... 15 
Figure 6-1 
Modification of injectable study medication ......................................... 48 
Figure 9-1 
Dose-response curve of candidate models ............................................ 75 
Figure 10-1 
Flow chart for managing hypotension ................................................. 108 
 

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Amended Protocol Version No. 02 (Clean) 
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Amendment 02 (23-Feb-2024) 
Amendment rationale 
The purpose of this amendment is to make minor editorial modifications to the protocol. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough red font for deletions and red underline for insertions. 
List of changes to the protocol are listed below: 
Section 3.2 Secondary estimands 
• The formatting of the paragraph describing the treatment of interest of the second 
secondary estimand was corrected to match the formatting of the original protocol. 
Section 5.2 Exclusion criteria 
• The formatting for Exclusion criterion #26 was corrected to clarify that each subpoint 
is a component of the main criterion rather than a stand-alone one. 
IRB/IEC 
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities.  
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 

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Amended Protocol Version No. 02 (Clean) 
Protocol No. CXXB750A12201 
 
Amendment 01 (06-Feb-2024) 
Amendment rationale 
The purpose of this amendment is to make modifications to the protocol that were requested by 
the EU Health Authorities.  
In addition, minor editorial changes are made to correct typographical errors, to make some 
clarifications, and to resolve some minor inconsistencies in various sections of the protocol.  
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough red font for deletions and red underline for insertions. 
List of changes to the protocol are listed below: 
Section 1.1 Summary 
• A footnote was added to table ‘Objectives, Endpoints, and Estimands’ to clarify that if 
the treatment arms 4a and 4b are eliminated (see Section 4.6), the second secondary 
objective will evaluate only the 120 mg XXB750 arm to sacubitril/valsartan. 
• The inclusion criterion was modified to require that other evidence-based therapy for 
heart failure should also be considered e.g., cardiac resynchronization therapy and 
implantable cardioverter-defibrillator in selected patients, as recommended by 
guidelines in selecting patients for the study. 
• The exclusion criterion was updated to exclude patients with previous intolerability to 
any ARB (as per the investigator’s judgement). 
Section 3 Objectives, endpoints and estimands 
• Table 3-1 was updated to include a footnote clarifying that in the event treatment 
arms 4a and 4b are eliminated (see Section 4.6), the second secondary objective will 
evaluate only the 120 mg XXB750 arm to sacubitril/valsartan. 
Section 3.2 Secondary estimands 
• This section was updated to reflect the estimand of the second secondary endpoint in 
the event treatment arms 4a and 4b are eliminated. 
Section 4.1.2 Randomized Treatment Period 
• This section was modified to clarify the distribution of participants across the 
different treatment arms according to their background anti-RAS treatment (i.e., 
ACEI/ARB vs. ARNI). 
Section 4.6 Purpose and timing of interim analyses/design adaptations  
• This section was modified to clarify that in case of elimination of treatment arms 4a 
and 4b, 180 participants will be allocated to treatment arm 3 from Group 2 for a 
total/overall sample size of 300 participants in this arm. 
• A statement was added to confirm that the sponsor will inform the local health 
authorities as per the local regulations in case of any adaptations to study design 
based on feedback from the DMC. 

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Section 5.1 Inclusion criteria  
• Inclusion criterion #7 was modified to require that other evidence-based therapy for 
heart failure should also be considered, e.g., cardiac resynchronization therapy and 
implantable cardioverter-defibrillator in selected patients, as recommended by 
guidelines in selecting patients for the study. Also, it was clarified that guideline 
recommended HF medications should be stable in dose for at least 4 weeks before 
screening. 
Section 5.2 Exclusion criteria  
• Exclusion criterion #6 was updated to exclude patients with previous intolerability to 
any ARB (as per the investigator’s judgment). Exclusion criterion #13 was updated to 
exclude patients with known right ventricular dysfunction that is deemed to increase 
susceptibility to the hypotensive effects of therapy in the opinion of the investigator. 
Exclusion criterion #15 was updated to exclude patients with CRT implantation 
within 3 months of screening. Exclusion criterion #18 was updated to exclude patients 
with planned/anticipated major cardiac surgery during the involvement of the 
participant in the study. 
Section 6.1.1 Additional study treatments 
• Table 6-2 Auxillary treatments was updated to delete the statement “Each packaging 
will be labeled as per country requirements” since none of the participating countries 
have such requirements. 
Section 9.4.1 Efficacy and/or pharmacodynamic endpoint(s) 
• This section was updated to note that in the event treatment arms 4a and 4b are 
eliminated, the comparison made in the second secondary endpoint will be between 
only the 120 mg XXB750 and the sacubitril/valsartan arms. 
Section 9.9.1 Primary endpoint(s) 
• This section was updated to note the sample size and statistical power for evaluating 
the primary endpoint in the event treatment arms 4a and 4b are eliminated. 
Section 9.9.2 Secondary endpoint(s)  
• This section was updated to note the sample size and statistical power for evaluating 
the first and second secondary endpoints in the event treatment arms 4a and 4b are 
eliminated.  
Miscellaneous corrections of typographical errors were made throughout the protocol. 
IRB/IEC 
A copy of this amended protocol will be sent to the Institutional Review Boards 
(IRBs)/Independent Ethics Committees (IECs) and Health Authorities.  
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 

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1 
Protocol summary 
1.1 
Summary 
Protocol Title: 
A multicenter, randomized, placebo- and active-controlled, parallel-group, 24-week proof-of-
concept and dose-finding study to evaluate efficacy, safety, and tolerability of XXB750 in 
patients with heart failure 
Brief Title: 
A proof-of-concept and dose-finding study of XXB750 in patients with heart failure 
Purpose: 
The purpose of this phase 2 study is to investigate the efficacy, safety, and tolerability of 
different doses of XXB750 given in different dosing regimens compared to placebo in heart 
failure (HF) patients with New York Heart Association classification II-III (NYHA class II-III) 
with left ventricular ejection fraction (LVEF) < 50% receiving standard of care (SoC) therapy. 
This study will also compare different dose levels of XXB750 versus a conversion to 
sacubitril/valsartan for the same outcomes. The results of this study will provide information 
needed for designing the XXB750 phase 3 HF program. 
Study Indication /Medical Condition: 
Heart failure 
Treatment type: 
Biological 
Study type: 
Interventional 
Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primary 
 
● To evaluate the efficacy and dose-response 
relationship of three XXB750 target dose levels 
compared to placebo in reducing N-terminal 
prohormone B-type natriuretic peptide (NT-proBNP) 
from baseline to Week 16 in symptomatic HF patients 
with LVEF < 50% treated with standard of care, 
including ACEI/ARB or sacubitril/valsartan. 
The primary clinical question of interest is: Is there a 
dose-response signal, and if so, to characterize the 
dose-response relationship of three XXB750 target 
dose levels versus placebo in reducing NT-proBNP 
from baseline to Week 16 in participants with heart 
● Change in log NT-proBNP from baseline to Week 
16 

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failure (NYHA classes II-III) with LVEF <50% 
regardless of type of baseline background HF 
therapy, discontinuation from study treatment, change 
in the dose of concomitant medications and use of 
prohibited concomitant medication. 
Secondary 
 
● To evaluate the treatment effect of the highest 
XXB750 target dose level compared to placebo in 
reducing NT-proBNP from baseline to Week 16 in 
symptomatic HF patients with LVEF < 50% treated 
with standard of care, including ACEI/ARB or 
sacubitril/valsartan. 
The estimand of this first secondary objective will 
further demonstrate the efficacy of highest XXB750 
target dose level compared with placebo, regardless 
of type of baseline background HF therapy, 
discontinuation from study treatment, change in the 
dose of background HF medications and use of 
prohibited concomitant medication; it will provide an 
estimate with a p-value in a hierarchical hypothesis 
testing procedure with overall type I error control after 
a dose-response signal is established in the primary 
objective. 
● To evaluate the treatment effect of combined two 
highest XXB750 target dose levels administered in 
addition to a background of ACEI/ARB versus 
conversion from ACEI/ARB to sacubitril/valsartan, in 
reducing NT-proBNP from baseline to Week 16.* 
● To evaluate the safety and tolerability of XXB750 
up-titration regimens and dose levels. 
● Change in log NT-proBNP from baseline to Week 
16 
● Adverse events, safety laboratory parameters, 
and vital signs from baseline to end of study (EOS) 
*In the event treatment arms 4a and 4b are eliminated (see Section 4.6), the second secondary 
objective will evaluate only the 120 mg XXB750 arm to sacubitril/valsartan arm. 
Trial Design: 
Study CXXB750A12201 is a multicenter, randomized, placebo- and active-controlled, parallel-
group study which is comprised of three periods: 
• A 7-days screening period 
• A 16-week parallel-group randomized treatment period, on either  
i) double-blind placebo-controlled treatment (XXB750 vs. placebo) or  
ii) open-label treatment (sacubitril/valsartan) 
• An 8-week safety follow-up period 
The study will enroll participants with HF (NYHA class II-III), elevated NT-proBNP levels and 
LVEF < 50% receiving SoC HF therapy. 
Brief Summary: 
The purpose of this study is to assess the efficacy and safety of different target doses of XXB750 
given in different up-titration regimens on NT-proBNP change from baseline at week 
16 compared to placebo and to sacubitril/valsartan in participants with symptomatic HF with 
LVEF < 50%. 

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XXB750 is a fully human monoclonal antibody with potent agonistic activity at the natriuretic 
peptide receptor 1 (NPR1). NPR1 catalyzes cyclic guanosine monophosphate (cGMP) 
synthesis, thereby enhancing natriuresis, diuresis and vasodilation as well as protecting from 
cardiac fibrosis. Consistent with its mechanism of action, XXB750 was shown to decrease 
cardiac hypertrophy and NT-proBNP levels in mice lacking atrial natriuretic peptide. 
Patients with symptomatic HF (NYHA class II-III), elevated NT-proBNP levels and a LVEF < 
50% despite receiving an ACEI, an ARB, or an angiotensin receptor neprilysin inhibitor 
(ARNI), and other guideline-recommended therapies for HFrEF and HFmrEF, will be recruited 
into the study. Participants must be on ACEI/ARB doses equivalent to enalapril 10 mg/day or 
higher (see Table 4-1) or sacubitril/valsartan doses of 49/51 mg twice daily (bid) or higher. 
Participants who successfully complete the Screening period are planned to be randomized to 
one of three target dose levels of XXB750 (60 mg, 120 mg or 240 mg) or matching placebo. In 
addition, a cohort of patients receiving an ACEI/ARB will be randomly selected to be converted 
to receive open-label sacubitril/valsartan in the randomized treatment period, replacing their 
pre-study ACEI/ARB. Participants who receive an ACEI and are randomized to receive open-
label sacubitril/valsartan must undergo a 36-hr ACEI-free wash-out period before starting to 
take the randomized treatment (open-label sacubitril/valsartan) to minimize the risk of 
occurrence of angioedema. All patients will continue to receive their other background HF 
medication. Overall, a total of approximately 720 participants will be randomized into this 
study. 
The randomized treatment period will last 16 weeks. Participants randomized to XXB750 or its 
matching placebo will receive 1 subcutaneous injection every 4 weeks, with a total of 4 
injections during the 16-week treatment period. Participants randomized to conversion to 
sacubitril/valsartan will receive sacubitril/valsartan for 16 weeks. At the end of the 16-week 
randomized treatment period, all assigned study treatments will be discontinued and the 
participants will enter an 8-week safety follow-up period during which they will be treated 
according to the investigator's clinical judgment. Assessment of NT-proBNP will occur at 
baseline, week 4, week 8, week 12, week 16 (timepoint of primary endpoint), week 20 and week 
24. Safety, efficacy and/or pharmacokinetic assessments will be performed serially throughout 
all three study periods. 
Study Duration: 
24 weeks 
Treatment Duration: 
16 weeks 
Visit Frequency: 
Every 1-4 weeks 
Treatment of Interest 
XXB750 target dose levels of 60 mg, 120 mg, and 240 mg or matching placebo or 
sacubitril/valsartan. Adaptive design features of the protocol may impact the planned target 
dose levels (Section 4.6). 

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Treatment Groups 
Participants will be randomized to be treated during a 16-week randomized treatment period 
with: 
• Placebo matching XXB750 
• XXB750 60 mg target dose 
• XXB750 120 mg target dose 
• XXB750 240 mg target dose in one of two up-titration regimens 
• Sacubitril/valsartan at target doses of 97/103 mg bid (only participants previously treated 
with ACEI/ARB) 
Treatment groups may be modified per adaptive design feature of the study design (Section 4.6). 
Number of Participants: 
720 participants female or male participants aged 18 years or older with symptomatic HF and 
LVEF < 50% will be randomized to study intervention. Participants with LVEF > 40% will be 
limited to approximately 25% of the total randomized participants. 
Key Inclusion Criteria 
• Written informed consent must be obtained before any assessment is performed. 
• Male and female outpatients who are ≥ 18 years old. 
• Symptom(s) of HF NYHA class II-III at Screening. 
• LVEF < 50% (most recent local measurement, made within 6 months prior to or during 
Screening using echocardiography, MUGA, CT scanning, MRI or ventricular angiography 
is acceptable, provided no subsequent measurement ≥ 50%). 
• NT-proBNP ≥ 600 pg/ml if in sinus rhythm or  
NT-proBNP ≥ 900 pg/ml if in atrial fibrillation/flutter at Screening. 
• Receiving an ACEI or an ARB at a stable dose of at least enalapril 10 mg/d or equivalent 
for at least 4 weeks before Screening or receiving sacubitril/valsartan at a stable dose of at 
least 49/51 mg bid for at least 4 weeks before Screening. 
• Receiving other guideline recommended HF therapies as deemed appropriate by the 
investigator and that are stable in dose for at least 4 weeks before Screening, unless 
contraindicated, not tolerated, or not available to patient. Other evidence-based therapy for 
heart failure should also be considered, e.g., cardiac resynchronization therapy and an 
implantable cardioverter-defibrillator in selected patients, as recommended by guidelines. 
Key Exclusion Criteria 
• Current acute decompensated HF (exacerbation of chronic HF manifested by signs and 
symptoms that may require intravenous therapy) or hospitalization for HF within 3 months 
prior to screening. 
• Office systolic blood pressure (SBP) ≥ 180 mmHg or < 105 mmHg at screening or at 
randomization. 

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• In subjects with ACEI/ARB medication at screening, previous inability to tolerate any dose 
of sacubitril/valsartan or any ARB (as per the investigator's judgment). 
• Serum potassium > 5.4 mmol/L at screening. 
• Estimated GFR (eGFR) < 30 mL/min/1.73m2 at screening as measured by the CKD-EPI 
formula. 
• Known history of angioedema. 
Data Monitoring/Other Committee: 
Yes (see Section 10.1.4 Committees Structure) 
Key words 
Heart failure, randomized, double-blind, dose finding, XXB750 
1.2 
Schema 
Figure 1-1 
Study design 
 
Sac/Val: Open-label sacubitril/valsartan. *May be modified per adaptive design feature of the study (Section 4.6). 
Doses of Sac/Val, ACEI or ARB in arms 1-4 equal to dose at randomization. 
1.3 
Schedule of activities (SoA) 
Table 1-1 lists all scheduled assessments throughout the study. In addition to the protocol-
required visits, participants may be seen at any time throughout the study at the discretion of 
the investigator to follow-up on any new laboratory abnormalities or adverse events (AEs). 
Participants should be seen for all visits/assessments as outlined in the SoA or as close to the 
designated day/time as possible. Day 1 will be considered the reference visit for all study visits 
during the randomized treatment period, regardless of occurrence of any unscheduled visits. If 
one visit is missed, postponed, or brought forward, it should not result in the next visit being 
postponed or brought forward. For details on administration of injectable study medication in 

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this situation, please see Section 6.1.2. The next visit, if at all possible, should adhere to the 
original time schedule. 
Participants who discontinue from study treatment are to complete the end of treatment visit as 
soon as possible, and continue to attend the follow-up visits as indicated in the SoA. 
Participants who discontinue from the study should be scheduled for a final evaluation visit if 
they agree, as soon as possible, at which time all the assessments listed for the final visit of the 
randomized treatment period will be performed. At this final visit, all dispensed study treatment 
should be reconciled, and the adverse events and concomitant medications not previously 
reported must be recorded on the appropriate CRF. 
Patient Reported Outcome (PRO) measure(s) must be completed by the participant before any 
assessments are performed at any given visit. 
Throughout the randomized treatment and safety follow-up periods, participants will undergo 
safety and biomarker laboratory assessments as well as pharmacokinetic (PK) sampling per the 
schedule shown in Table 1-1. After randomization, all laboratory evaluations for planned visits 
will be performed through the central laboratory or other authorized laboratory. Unscheduled 
laboratory assessments can be performed locally as necessary or as permitted by the protocol. 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e., pandemic, epidemic or natural disaster that limits or prevents on-site study visits, alternative 
methods of providing continuing care may be implemented by the Investigator as the situation 
dictates. If allowable by a local health authority, national and local regulations and depending 
on operational capabilities, phone calls, virtual contacts (e.g., tele consultation) or visits by site 
staff/off-site healthcare professional(s) staff to the participant´s home, can replace certain 
protocol assessments, for the duration of the disruption until it is safe for the participant to visit 
the site again. If the Investigator delegates tasks to an off-site healthcare professional, the 
Investigator must ensure the individual(s) is/are qualified and appropriately trained to perform 
assigned duties. The Investigator must oversee their conduct and remains responsible for the 
evaluation of the data collected.

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Table 1-1 
Assessment Schedule 
Epoch Screening 
Randomized Treatment 
Safety Follow-up 
Visit Name Screening Randomization Day 2 
Call 
Week 
2 
Week 
4 
Day 30 
Call 
Week 
8 
Day 58 
Call 
Week 
12 
Day 86 
Call 
Week 16 
EOT 
Week 
20 
Week 24 
EOS 
Visit Numbers1 
10 
101 
102 
103 
104 
105 
106 
107 
108 
109 
9998 
201 
202 
Days 
-7 to 1 
1 
2 
14 
28 
30 
56 
58 
84 
86 
112 
140 
168 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Genetic consent (optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/current 
medical conditions 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol and smoking history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete Physical 
Examination 
S 
 
 
 
 
 
 
 
 
 
S 
 
S 
Abbreviated physical 
examination 
 
S 
 
S 
S 
 
S 
 
S 
 
 
S 
 
Body Height (H) and Weight 
(W) 
H/W 
W 
 
W 
W 
 
W 
 
W 
 
W 
W 
W 
Electrocardiogram (ECG) 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Echocardiogram (optional) 
S 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Central lab blood chemistry 
X 
 
 
X2 
X2 
 
X2 
 
X2 
 
X 
X2 
X 
Hematology 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
Coagulation Panel 
X 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
NT-proBNP 
X 
X 
 
 
X3 
 
X3 
 
X3 
 
X 
X 
X 
NYHA classification (HF 
signs and symptoms) 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
X 
X 
IWRS/IRT Registration  
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
Study drug 
dispensation/administration4 
 
X 
 
X 
X 
 
X 
 
X 
 
 
 
 
Study medication 
compliance5 
 
 
 
S 
S 
 
S 
 
S 
 
S 
 
 

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Epoch Screening 
Randomized Treatment 
Safety Follow-up 
Visit Name Screening Randomization Day 2 
Call 
Week 
2 
Week 
4 
Day 30 
Call 
Week 
8 
Day 58 
Call 
Week 
12 
Day 86 
Call 
Week 16 
EOT 
Week 
20 
Week 24 
EOS 
Visit Numbers1 
10 
101 
102 
103 
104 
105 
106 
107 
108 
109 
9998 
201 
202 
Days 
-7 to 1 
1 
2 
14 
28 
30 
56 
58 
84 
86 
112 
140 
168 
Adverse Events 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker urine collection 
  
X3 
  
  
  
  
X3 
  
X3 
  
X 
  
  
Biomarker blood collection 
  
X3,6 
  
  
  
  
X3 
  
X3 
  
X 
  
  
PK blood collection7 
  
X8 
  
  
X3,8 
  
  
  
X3,8 
  
X 
  
X 
Anti-drug antibody7 
  
X3 
  
  
X3 
  
  
  
X3 
  
X 
  
X 
Exploratory DNA Sampling 
(optional)9 
  
X 
  
  
  
  
  
  
  
  
  
  
  
Urinalysis 
X 
X 
  
X 
X 
  
X 
  
X 
  
X 
X 
X 
Assessment of fertility 
S 
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy Test (serum) 
X 
  
  
  
  
  
  
  
  
  
X 
  
X 
Pregnancy Test (urine) 
  
S 
  
  
S 
  
S 
  
S 
  
  
S 
  
KCCQ questionnaire 
  
X 
  
  
  
  
  
  
  
  
X 
  
  
Study period completion 
information 
X 
  
  
  
  
  
  
  
  
  
X 
  
X 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
1 Visit structure given for internal programming purpose only 
2 Abbreviated safety panel (Please refer to Table 8-1) 
3 Samples must be taken prior to study drug administration. 
4 For participants on ACEI and randomized to treatment arm 5, a 36-hour washout period must be observed: Open-label sacubitril/valsartan to be started in evening of 
Day 2. Dispensing visit at Week 2 is for only patients randomized to receive open-label sacubitril/valsartan, which can be used as a dose titration visit. 
5 Only applicable to participants randomized to conversion to open-label sacubitril/valsartan (treatment arm 5) 
6 Additional collection with P100 tube. Please refer to Section 8.8. 
7 Not applicable to participants randomized to conversion to open-label sacubitril/valsartan (treatment arm 5) 
8 Sample to be collected 2-4h post dose. 
9 To be collected only for participants signing optional DNA consent.  

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2 
Introduction 
2.1 
Study rationale 
The purpose of this study is to investigate the efficacy, safety, and tolerability of three dose 
levels of XXB750 in HF patients (NYHA class II-III) with LVEF < 50% receiving standard of 
care (SoC) HF therapies. This study will provide evidence to understand the dose-response 
relationship of XXB750 in reducing NT-proBNP, a prognostic biomarker of HF clinical 
outcomes, and to choose the optimal dosing regimen to investigate in future phase 3 studies. In 
addition, this study will help to assess the benefit of XXB750 relative to placebo when given 
on top of SoC HF therapy, as well as its benefit in ACEI/ARB treated patients compared to 
converting them to sacubitril/valsartan (i.e., direct comparison of XXB750 vs 
sacubitril/valsartan). 
2.2 
Background 
Heart failure (HF) is a major public health problem associated with a high mortality rate, 
frequent hospitalizations, and poor quality of life (QoL). Worldwide, an estimated 64.3 million 
people were living with heart failure in 2017, with a prevalence between 1-3% of the general 
adult population in developed countries (Groenewegen et al 2020, Savarese et al 2022). In the 
United States, the prevalence of HF is 6 million individuals, which is approximately 1.8% of 
the total US population (Roger 2021). Heart failure is associated with frequent hospitalizations, 
with 
30-40% 
of 
patients 
having 
a 
history 
of 
hospitalization 
for 
HF (Crespo-Leiro et al 2016) and 22% of patients being re-admitted for HF within 1 year of 
their initial diagnosis (Lawson et al 2019). 
Heart failure is a complex clinical syndrome that most commonly causes structural or functional 
impairment of ventricular filling or emptying, ultimately resulting in the heart's inability to meet 
the body's need for adequate supplies of oxygenated blood. The natural course of HF includes 
deterioration in symptoms, often leading to repeated hospitalizations for acute 
decompensations, and eventually death most frequently due to arrythmia (i.e., sudden death) or 
progressive pump failure (Desai et al 2015). 
Heart failure with reduced left ventricular ejection fraction (HFrEF) is regarded as a common 
type of HF and is characterized by an LVEF ≤ 40%; it is the best studied type of HF. The current 
standard of care of pharmacologic treatment for HFrEF is comprised of four main drug classes: 
blockers of the renin angiotensin system (RAS) with either angiotensin converting enzyme 
inhibitors (ACEI), anangiotensin II receptor blockers (ARB), or angiotensin receptor neprilysin 
inhibitor (ARNI), β-blockers, mineralocorticoid receptor antagonists (MRAs) and sodium-
glucose cotransporter 2 (SGLT2) inhibitors. These four classes have been shown to reduce 
morbidity and mortality in patients with HFrEF and are recommended as standard-of-care 
treatment 
as 
per 
recently 
published 
guidelines 
for 
the 
treatment 
of 
HF 
(McDonagh et al 2021, Heidenreich et al 2022). Adjacently situated to HFrEF on the LVEF 
spectrum is heart failure with mildly reduced ejection fraction (HFmrEF), which is 
characterized by an LVEF > 40% but < 50%. 
Evidence based on analyses of large outcome trials suggests that drug classes effective in HFrEF 
may also be effective in HFmrEF patients, thereby supporting recommendations for using them 

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Amended Protocol Version No.02 (Clean)  
Protocol No. CXXB750A12201 
 
 
doses ≥ 120 mg) were of greater magnitude than what was seen with sacubitril in healthy 
volunteers. Also, single 120 mg SC doses of XXB750 have been tested in HF patients with 
ACEI/ARB and other background HF medications. XXB750 was found to have an acceptable 
safety and tolerability profile. This data, together with evidence of the beneficial effects of ANP 
and other ANP mimetics in heart failure patients, provides a scientific rationale to develop 
XXB750 for the treatment of heart failure. Refer to the XXB750 investigator's brochure for 
more detailed information on the safety, pharmacokinetics, and pharmacodynamic biomarker 
data available on this biologic. 
The current study is a combined phase 2a/2b study which aims to establish proof-of-concept 
and dose range relationship for XXB750 in reducing NT-proBNP levels in HF patients (NYHA 
class II-III) with LVEF < 50%, to inform the dose regimen of XXB750 to be tested in Phase 3, 
and to further characterize the benefit-risk profile of XXB750 in patients with HF. 
2.3 
Benefit/Risk assessment 
Participants are expected to benefit from extensive monitoring of their HF condition and 
symptoms during the course of the study. Participants will continue to receive their background 
standard of care HF medications, including ACEIs/ARBs or ARNI, during the duration of the 
study. Some patients treated with ACEIs will be randomly assigned to receive open-label the 
ARNI sacubitril/valsartan, which is considered by international HF treatment guidelines to be 
preferred over ACEIs in HFrEF due to improved efficacy in reducing long-term morbidity and 
mortality 
(Fiuzat et al 2022, Heidenreich et al 2022, McDonagh et al 2021). 
Participants 
randomized to the investigational treatment XXB750 may potentially benefit from improved 
augmentation of the natriuretic peptide system. 
During the total study duration of 24 weeks, a total of 8 in-person visits will be conducted at 
the site, with 3 of the visits lasting up to several hours. Study visit procedures include blood 
draws to obtain blood samples totally approximately 183 mL to 207 mL over the duration of 
the study, depending on which sub-studies the patient participates in. Patients included in this 
study are expected to have no background illnesses that will prevent them from producing 
sufficient new blood to compensate for the blood obtained for the study over its duration. Some 
patients may experience bruising from the phlebotomy needed in obtaining the blood samples. 
Study participants may also experience some discomfort associated with some study 
procedures, such as blood pressure measurements and urine sample collection. 
Due to the mode of action of XXB750 and other background medications the patient may be 
taking for HF and other comorbidities, there is a risk of occurrence of hypotension and 
hypotension-related symptoms, such as dizziness, lightheadedness, orthostasis, postural 
symptoms, pre-syncope or syncope. Reflex rise in heart rate has also been reported with 
XXB750. In patients randomized to XXB750 the risk of symptomatic hypotension is greatest 
in the first few days after dosing but can potentially happen at any time during the study. 
Participants will receive a blood-pressure monitoring device to enable BP assessments at home 
as needed and per the investigator’s request in the event they experience potential hypotension-
related AEs. Additionally, participants will be contacted 2-3 days after each dose administration 
via a scheduled telephone call to monitor their tolerability and inquire about their general well-
being. The current protocol includes a guidance on how to address symptomatic hypotension in 
the context of this study (Section 10.7). 

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All injections of XXB750 and its matching placebo will be administered during site visits as 
single SC injections of 1.6 mL, which may cause injection site reactions or bruising. Like many 
monoclonal antibodies, XXB750 may result in formation of anti-drug antibodies (ADA). 
Although available data on ADA formation do not indicate that they result in any safety 
problems or interfere with the PK or PD of XXB750, they will be studied carefully in this study 
and other ongoing XXB750 studies to better understand their significance. Hypersensitivity 
reactions are a potential risk for XXB750, although it has not been observed so far in XXB750 
clinical studies. Hypersensitivity occurrence and its clinical significance will be monitored 
during the current the study. Participants will be monitored at the site for a minimum of 20 
minutes after each injection. For additional information on XXB750 and its available safety 
information, please refer to the latest edition of the XXB750 investigator’s brochure. 
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study, they must adhere to the contraception requirements outlined in the 
exclusion criteria. If there is any question that the participant will not reliably comply with the 
recommendations of contraception, they should not be entered or continue in the study. In 
general, the levels of a monoclonal antibody (mAb) in semen are expected to be low, and 
therefore, the subsequent levels in a female partner would be negligible. Based on this principle, 
the probability that XXB750 would cause teratogenicity is very low. Therefore, no restrictions 
will be placed on male participants with regard to sexual activity or condom use. 
Patients randomized to receive open-label sacubitril/valsartan in place of their background 
ACEI/ARB may experience hypotension/hypotension-related side effects. They may also 
experience renal dysfunction and hyperkalemia, although the latest published evidence 
indicates that sacubitril/valsartan results in a lower incidence of these side effects that 
ACEIs/ARBs. Angioedema has also been reported with sacubitril/valsartan. The risk of 
angioedema will be minimized by observing a 36-hour ACEI- and sacubitril/valsartan-free 
washout period whenever patients are switched from an ACEI to open-label sacubitril/valsartan 
(such as at the start of the randomized treatment period and the start of the safety follow-up 
period, as applicable). Also, patients with history of angioedema will be excluded from the trial. 
For more potential information and side effects of sacubitril/valsartan, please refer to your 
locally approved sacubitril/valsartan label. 
The risk to participants in the study will be minimized by compliance with the eligibility criteria, 
close clinical monitoring, including home BP measurement and a follow-up call after each 
injection of study drug. Eligible participants with eGFR ≥ 30 ml/min/1.73m2 will enter the 
study with close monitoring of renal function and serum potassium at every scheduled study 
site visit to ensure their safety. All participants will be carefully monitored by the investigators 
for satisfactory risk-to-benefit ratio. 
A periodic review of the safety data by an independent Data Monitoring Committee (DMC) will 
further enhance safety for the study participants. Additionally, enrollment of participants to 
treatment arms with doses of XXB750 higher than 120 mg will only start after the benefit-risk 
balance of XXB750 administration is deemed to be acceptable by the DMC. This will be 
evaluated in an interim safety analysis that includes data of the lower dose arms from this study 
along with additional data from the ongoing phase 1b study administrating XXB750 up to 
240 mg in patients with HF. 

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Protocol No. CXXB750A12201 
 
 
Should a participant develop clinically significant AEs during the course of the study, the 
blinded study treatment may, as per the investigator's discretion, be temporarily or permanently 
discontinued to minimize the risk to participants, and they will be managed by the treating 
physicians according to local standard of care. 
Given the close monitoring, criteria for patient selection, and the known safety and tolerability 
profile of the drug in humans, it is considered that overall risks for participants in this study are 
acceptable. 
3 
Objectives, endpoints, and estimands 
Table 3-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
● To evaluate the efficacy and dose-response relationship 
of three XXB750 target dose levels compared to placebo in 
reducing NT-proBNP from baseline to Week 16 in 
symptomatic HF patients with LVEF < 50% treated with 
standard of care, including ACEI/ARB or sacubitril/valsartan. 
● Change in log NT-proBNP from baseline to 
Week 16 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
● To evaluate the treatment effect of the highest XXB750 
target dose level compared to placebo in reducing NT-
proBNP from baseline to Week 16 in symptomatic HF 
patients with LVEF < 50% treated with standard of care, 
including ACEI/ARB or sacubitril/valsartan. 
● Change in log NT-proBNP from baseline to 
Week 16 
● To evaluate the treatment effect of combined two highest 
XXB750 target dose levels administered in addition to a 
background of ACEI/ARB versus conversion from 
ACEI/ARB to sacubitril/valsartan, in reducing NT-proBNP 
from baseline to Week 16.* 
● Change in log NT-proBNP from baseline to 
Week 16 
● To evaluate the safety and tolerability of XXB750 up-
titration regimens and dose levels. 
● Adverse events (incidence and severity, 
including but not limited to, hypotension, 
tachycardia, bradycardia, hypersensitivity and 
injection site reactions), vital signs (blood 
pressure, pulse), safety laboratory tests, and 
ECG parameters from baseline to end of study 
(EOS). 
Exploratory objective(s) 
Endpoint(s) for exploratory objective(s) 
● To evaluate the effects of highest XXB750 target dose 
level compared to placebo in improving a composite 
hierarchical outcome of: 1) time to all-cause death, 2) 
number of HF hospitalizations, 3) Kansas City 
Cardiomyopathy Questionnaire (KCCQ) clinical summary 
score (CSS) categorical change, 4) NYHA class change , 5) 
relative change in NT-proBNP levels between baseline and 
Week 16. 
● Hierarchically ordered composite consisting 
of: 1) time to all-cause death up to Week 16; 2) 
number of HF hospitalizations up to Week 16; 
3) categorical KCCQ CSS change from 
baseline to Week 16; 4) NYHA class change 
from baseline to Week 16; 5) relative change in 
NT-proBNP levels from baseline to Week 16. 
● To evaluate changes in each domain of the KCCQ, 
including clinical summary score (CSS) and overall summary 
score (OSS), from baseline to Week 16. 
● Change in all domains of the KCCQ from 
baseline to Week 16. 
● To evaluate the effects of XXB750 on slowing the rate of 
decline in estimated glomerular filtration rate (eGFR) from 
baseline to Week 16. 
● Estimated glomerular filtration rate (eGFR) 
at scheduled assessment visits. 

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Objective(s) 
Endpoint(s) 
● To evaluate the change in biomarkers related to heart 
failure, cardiovascular disease and renal function from 
baseline to Week 8 and to Week 16. 
● Change from baseline in biomarkers 
including, but not limited to, plasma and urinary 
cGMP, urinary cGMP-to-creatinine ratio, 
urinary albumin-to-creatinine ratio, BNP and 
hs-Troponin, at Week 8 and Week 16. 
● To evaluate the change in NYHA class and in signs and 
symptoms of heart failure from baseline to Week 16. 
● Change in NYHA class and signs and 
symptoms of HF from baseline to Week 16. 
● To explore the population pharmacokinetic (PK) 
properties of XXB750 in HF patients. 
● Population PK analysis results including 
mathematic models and parameters. 
● To evaluate immunogenicity (IG) of XXB750. 
● Detection of immune response markers, 
including anti-drug antibodies. 
*In the event treatment arms 4a and 4b are eliminated (see Section 4.6), the second secondary 
objective will evaluate only the 120 mg XXB750 arm to sacubitril/valsartan arm. 
3.1 
Primary estimands 
The primary clinical question of interest is: 
Is there a dose-response signal, and if so, what is the dose-response relationship among three 
XXB750 target dose levels and placebo in reducing NT-proBNP from baseline to Week 16 in 
participants with HF (NYHA classes II-III) and LVEF < 50%, treated with standard of care, 
including ACEI/ARB or sacubitril/valsartan, regardless of type of baseline background HF 
therapy, discontinuation from the study treatment, change in the dose of concomitant 
medications and receiving prohibited concomitant medication? 
The justification for the primary estimand is that it will capture both the effects of XXB750 and 
the effects of changes in other HF medications. This will provide a clear assessment of the 
XXB750 treatment effect in clinical practice versus placebo. 
The primary estimand is described by the following attributes: 
1. Population: participants with HFrEF and HFmrEF (LVEF < 50%), NYHA classes II-III 
and elevated NT-proBNP levels at screening while taking optimal guideline-directed HF 
therapy. 
2. Variable: change in log NT-proBNP from baseline to 16 weeks 
3. Treatment of interest: Treatment groups with three XXB750 target dose levels, and 
placebo all administered on top of ACEI/ARB or sacubitril/valsartan and other guideline-
recommended standard of care therapy for HF. 
Handling of intercurrent events: 
• Discontinuation of study treatment: ignore (treatment policy strategy) 
• Change in concomitant medications: ignore (treatment policy strategy) 
• Receiving prohibited concomitant medication: ignore (treatment policy strategy) 
4. The summary measure: difference in variable means between treatments. Since the 
variable in attribute 2 is equivalent to the log of ratio of Week 16 NT-proBNP over 
baseline NT-proBNP, and the difference in variable means between 2 treatment groups is 
the log of ratio of ratio to baseline of the 2 groups, therefore, the summary measure can be 

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back-transformed by exponentiation and expressed as ratio of geometric mean of ratio to 
baseline of the 2 treatment groups. 
3.2 
Secondary estimands 
Treatment effect of the highest XXB750 target dose level compared to placebo 
in reducing NT-proBNP from baseline at Week 16 in HF patients treated with 
standard of care, including ACEI/ARB or sacubitril/valsartan 
The first secondary clinical question of interest is: 
What is the effect of the highest XXB750 dose level versus placebo in reducing NT-proBNP 
level from baseline to Week 16 in participants with heart failure (NYHA classes II-III) and 
LVEF < 50%, treated with standard of care, including ACEI/ARB or sacubitril/valsartan, 
regardless of type of baseline background HF therapy, discontinuation from study treatment, 
change in the dose of concomitant medications, and receiving prohibited concomitant 
medication? 
The justification for the first secondary estimand is that it will capture both the effects of study 
medication and the effects of changes in guideline-directed concomitant medications. This will 
provide a clear assessment of the XXB750 treatment effect in clinical practice versus placebo. 
The attributes and handling of intercurrent events are the same as those described in primary 
estimand except that the treatment of interest being the highest XXB750 dose level and placebo, 
instead of all XXB750 dose levels as described below: 
Highest XXB750 dose level versus placebo in combination with guideline-recommended 
standard of care therapy for HF. 
Treatment effect of combined two highest XXB750 target dose levels in 
addition to a background of ACEI/ARB versus conversion from ACEI/ARB to 
sacubitril/valsartan, in reducing NT-proBNP from baseline to Week 16 
The clinical question of interest for this objective is: 
What is the effect of combined two highest XXB750 dose groups in addition to a background 
of ACEI/ARB versus conversion from ACEI/ARB to sacubitril/valsartan in reducing NT-
proBNP level from baseline to Week 16 in participants with heart failure (NYHA classes II-III) 
and LVEF < 50% regardless of type of baseline background HF therapy, discontinuation from 
the study treatment, change in the dose of concomitant medications and receiving prohibited 
concomitant medication? 
The attributes and handling of intercurrent events are the same as those described in primary 
estimand except that: 
• Population: participants with HFrEF and HFmrEF (LVEF < 50%), NYHA classes II-III 
and elevated NT-proBNP levels and on ACEI/ARB at screening while taking other 
guideline-directed HF therapy. 
• Treatment of interest: two highest XXB750 dose levels in addition to ACEI/ARB 
background medication versus conversion from ACEI/ARB to sacubitril/valsartan in 

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combination with guideline-recommended standard of care therapy for HF. In the event 
treatment arms 4a and 4b are eliminated (see Section 4.6), treatment of interest will be only 
the 120 mg dose XXB750 dose level in addition to ACEI/ARB background medication 
versus conversion from ACEI/ARB to sacubitril/valsartan in combination with guideline-
recommended standard of care therapy of HF. 
Evaluation of the safety and tolerability of XXB750 up-titration regimens and 
target dose levels 
Adverse events (AEs) and serious AEs, laboratory parameters and vital signs will be evaluated 
and summarized in each treatment group for different treatment periods (randomized treatment 
period and safety follow-up period). Please refer to Section 9.4.2 for analysis details. 
4 
Study design 
4.1 
Overall design 
Study CXXB750A12201 is a multicenter, randomized, placebo- and active-controlled, parallel-
group phase 2 study which is comprised of three periods (Figure 1-1): 
• A screening period of approximately 7 days 
• A 16-week parallel-group randomized treatment period on either 
i) double-blind placebo-controlled treatment (XXB750 vs. placebo) or 
ii) open-label treatment (sacubitril/valsartan) 
• An 8-week safety follow-up period 
The study will randomize adult participants with LVEF < 50% receiving ACEI/ARB/ARNI and 
guideline-recommended HF therapies for HFrEF or HFmrEF to three XXB750 target dose 
levels; a cohort of patients treated with ACEI/ARB before the study will be randomized to be 
converted to open-label sacubitril/valsartan in place of their pre-study ACEI/ARB. The study 
will randomize a total of approximately 720 patients. The percentage of patients with LVEF > 
40% will be limited to approximately 25% of the total sample. 
Refer to Figure 1-1 for an overview of study design, and to Section 6.1.2 for details on the 
administered doses in the different treatment arms. 
A staggered approach to enrollment will be followed in this protocol. The first group of 300 
participants will be randomized to placebo (treatment arm 1), XXB750 60 mg target dose 
(treatment arm 2), XXB750 120 mg target dose (treatment arm 3), and conversion to 
sacubitril/valsartan (treatment arm 5). The independent Data monitoring Committee will 
complete a safety analysis of the XXB750 doses tested and if it is safe to allow the dosing of 
patients with XXB750 planned top dose of 240 mg (i.e., allowing enrollment in arms 4a and 4b 
as planned). See Section 4.6 for details on planned interim analyses and adaptive design 
features. 
4.1.1 
Screening Period 
The purpose of the screening period is to assess participants' eligibility to enter into the 
randomized treatment period of the study. At the Screening visit, participants will be asked to 

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review and sign the inform consent form (ICF) before performing any study-related 
assessments. The inclusion and exclusion criteria will be assessed to verify the candidate’s 
eligibility for enrollment into the study. 
HF, cardiovascular (CV) and other medical history will be collected. An ECG will be 
performed. Protocol-specified biochemical criteria, including the required eGFR, potassium, 
and NT-proBNP levels will be assessed using a central laboratory. The sample obtained to 
assess NT-proBNP for study eligibility must be collected on the same day as performing the 
ECG. Concomitant medications will be recorded. In order to be eligible, participants are 
required to receive sacubitril/valsartan or ACEI/ARB for their HF at study entry, with minimum 
doses of sacubitril/valsartan 49/51 mg bid or an ACEI/ARB equivalent to enalapril 10 mg/day 
that have been stable/unchanged for at least 4 weeks. Table 4-1 lists total daily doses of 
commonly used ACEIs and ARBs with doses considered equivalent to enalapril 10 mg/day for 
the purpose of eligibility. 
Table 4-1 
Minimum required pre-study daily doses of ACEIs and ARBs 
ACEIs 
Minimum daily dose 
ARBs 
Minimum daily dose 
Enalapril 
10 mg 
Valsartan 
160 mg 
Lisinopril 
10 mg 
Candesartan 
16 mg 
Benazepril 
20 mg 
Azilsartan 
40 mg 
Captopril 
100 mg 
Eprosartan 
400 mg 
Cilazapril 
2.5 mg 
Fimasartan 
60 mg 
Delapril 
15 mg 
Irbesartan 
150 mg 
Fosinopril 
20 mg 
Losartan 
50 mg 
Imidapril 
10 mg 
Olmesartan 
10 mg 
Moexipril 
7.5 mg 
Telmisartan 
40 mg 
Perindopril 
4 mg 
 
 
Quinapril 
20 mg 
 
 
Ramipril 
5 mg 
 
 
Temocapril 
2 mg 
 
 
Trandolapril 
2 mg 
 
 
Zofenopril 
30 mg 
 
 
Other HF medication and their doses will be recorded. If the participant is not taking other 
classes of HF medications that are recommended per locally applicable guidelines and available 
locally such as beta-blockers, MRAs and/or SGLT2 inhibitors, the investigator must provide a 
qualifying reason for that on the appropriate electronic case report form (eCRF). The participant 
will continue his/her therapy, including his/her HF medications with no change during the 
screening period. 
Refer to Table 1-1 and Section 8.1 for a full list and details of screening procedures, 
respectively. 
4.1.2 
Randomized Treatment Period 
Only participants who successfully complete the screening period by meeting all inclusion 
criteria and none of the exclusion criteria (refer to Section 5 for a full list of inclusion and 

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judgment and local and international HF treatment guidelines and according to locally approved 
medication label. If at the start of the safety follow-up period the investigator wishes to place 
patients who were previously randomized to open-label sacubitril/valsartan on an ACEI, a 36 
hour sacubitril/valsartan-free washout period must be observed before the patient begins to take 
the ACEI in order to minimize the likelihood of occurrence of angioedema. For example, if a 
participant's last dose of open-label study sacubitril/valsartan is on Wednesday evening, the first 
dose of the ACEI should be taken on Friday morning. 
Two study visits will be conducted to collect safety data, NT-proBNP, and PK laboratory 
assessments and to monitor the participant’s overall health status (i.e., Week 20 and Week 24 
visits). 
Participants who prematurely discontinue the study medication should complete similar safety 
follow-up procedures, which should be scheduled 8 and 12 weeks after the last dose 
administration of XXB750 or its matching placebo, respectively. 
4.2 
Scientific rationale for study design 
The current study aims to investigate several aspects of the efficacy and safety of XXB750 in 
HF patients with LVEF < 50%. The primary objective of the study aims to characterize the 
dose-response pattern of XXB750 when added to treatment with ACEI/ARB or 
sacubitril/valsartan in patients with LVEF < 50%. A secondary objective of the study aims to 
determine the relative efficacy of modulating the NP system via NPR1 agonism compared to 
modulating it via neprilysin inhibition in reducing NT-proBNP in this patient population. 
Moreover, since XXB750 is the first injectable long-acting NPR1 agonist, the study aims to 
identify an optimal dosing regimen that best balances risks with benefits of XXB750. 
With all the above in mind, the current study design is considered to be optimal for 
accomplishing its objectives and for arriving to sound and reliable answers to the scientific 
questions of the study, while minimizing the burden to the participants and to the investigators 
and ensuring patient safety. Regarding the primary objective, i.e., the dose-response finding 
(DRF) aspect of the study, this is a randomized, double-blind, and placebo-controlled study. 
This design is typical for DRF studies as it compares the effects of three doses of XXB750 to 
placebo (all given SC every 4 weeks) to help form a dose-response curve with change in NT-
proBNP level as the endpoint. Patients will be randomized to receive XXB750 or its matching 
placebo in a blinded manner on top of other background guideline-direct HF therapy. As a 
result, this design maximizes the chances of producing reliable and internally and externally 
valid results to support sound conclusions about the efficacy and safety of the experimental 
treatment (i.e., XXB750 in this study). A multicenter setting has been chosen to ensure adequate 
enrollment into the study and to include an internationally representative sample that accounts 
for regional and local differences in practice norms. 
Based on extrapolation from data established for sacubitril/valsartan, it is expected that the full 
effect of NT-proBNP reduction will be achieved in all treatment groups after 8 weeks of study 
treatment at target dose levels. Thus, considering that target dose levels are reached at Week 8 
in all treatment arms, the 16-week duration of the randomized treatment period is expected to 
be sufficient to examine the effect of each target dose level of XXB750 to lower NT-proBNP. 

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The current design is also adequate for assessing the relative effect of the investigational 
modality of NP modulation, i.e., NPR1 agonism with XXB750, compared to the NP modulation 
mechanism currently available in clinical practice, i.e., neprilysin inhibition using sacubitril, in 
reducing NT-proBNP. Because the only available neprilysin inhibitor is commercially delivered 
via a compound with valsartan, the study is designed to include sufficient ACEI/ARB-treated 
participants who will be randomized to receive either XXB750 at different target dose levels 
(i.e., NPR1 agonist + ACEI/ARB cohort) or be converted to receive open-label 
sacubitril/valsartan at the approved target dose in place of their ACEI/ARB (i.e., neprilysin 
inhibitor + ARB cohort). The open-label design of the sacubitril/valsartan cohort optimally 
balances the degree of burden to patients and complexity of the study, while ensuring the 
conclusions based on this cohort are scientifically robust. Indeed, the primary endpoint of the 
study is change in NT-proBNP, which is an objective measure. 
To better explore the safety profile of XXB750 and the most optimal regimen of its 
administration, patients assigned to the highest XXB750 target dose will be further assigned to 
one of two up-titration regimens to be administered in a blinded manner. The regimens differ 
in the initial starting dose and will allow for understanding whether a slower, more gradual 
dosing regimen will result in improved tolerability and higher adherence rate to the target dose 
than a more condensed regimen that requires fewer up-titration steps. 
4.2.1 
Rationale for target study population 
The current study will include subjects with symptomatic HF (NYHA class II-III) with LVEF 
< 50%, i.e., HFrEF and HFmrEF subjects, who are being treated with guideline-directed 
therapy. The percentage of patients with LVEF > 40% will be limited to approximately 25% of 
the total sample, which is in line with the reported relative prevalence of HFrEF and 
HFmrEF (McDonagh et al 2021). This population was chosen because it is a population that 
continues to have a projected unacceptably high rate of morbidity and mortality despite the 
latest approved treatment modalities. 
Despite recently introduced recommendations for a quadruple pharmacological therapy for the 
treatment of HFrEF, including ARNI, beta-blockers, MRA and SGLT2 inhibitors 
(McDonagh et al 2021, Heidenreich et al 2022), outcomes on this comprehensive therapy are 
projected 
to 
leave 
significant 
room 
for 
improvement 
(Vaduganathan et al 2020, Tromp et al 2022). Thus, there remains an unmet need for further 
therapies improving mortality and morbidity in patients with HFrEF. 
Treatment options for HFmrEF patients are less well-studied and, until relatively recently, 
recommendations for treatment of patients with HFmrEF were mostly based on post-hoc and 
subset 
analyses 
from 
HFrEF 
and 
HFpEF 
trials 
including 
patients 
with 
HFmrEF (Heidenreich et al 2022). More recently, the approved labels of the ARNI 
sacubitril/valsartan as well as of the SGLT2 inhibitors dapagliflozin and empagliflozin were 
expanded to include treatment of HFmrEF patients in some regions of the world. Nonetheless, 
a need for identifying novel treatments that will lower morbidity and mortality in HFmrEF 
patients remains unmet. Given that medications thought to be beneficial in HFrEF tend to also 
be beneficial in HFmrEF, it is deemed appropriate to study XXB750 in a combined sample of 
HFrEF and HFmrEF patients. Moreover, given that sacubitril/valsartan and XXB750 are both 
NP modulators, albeit via differing mechanisms with differing potencies, it is reasonable to 

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expect that XXB750 may also provide benefit in HFmrEF patients. This provides a strong 
rationale for the choice of studying the effects of XXB750 in patients with LVEF up to 50%. 
The study will include patients who have been already treated with guideline-direct HF therapy 
so that the incremental benefit of the investigational treatment XXB750 will be clearly 
measured to better project the extent of improvements it can provide on top of the current 
standard of care. All eligible participants must be receiving an anti-RAS agent, i.e., an ACEI, 
ARB, or the ARNI sacubitril/valsartan. Participants should also be receiving beta blockers 
MRAs and SGLT2 inhibitors, unless contraindicated, not tolerated, not available to the patient 
or not recommended per local practice standards. 
4.2.2 
Rationale for the primary endpoint 
The primary endpoint of this study is the change in log NT-proBNP from baseline to Week 16. 
Aggregate clinical data has demonstrated that NT-proBNP not only provides value for the 
diagnosis, and helps the management of patients with HF, but also predicts clinical outcome 
(mortality and morbidity). Studies suggest that NT-proBNP levels strongly correlate with 
adverse clinical outcomes in HF patients including death and hospital admission for chronic HF 
(Zile et al 2016, Januzzi et al 2021, Schmitt et al 2021). 
More 
importantly, 
changes 
in 
natriuretic peptides were significantly associated with treatment effects on HF hospitalization 
across contemporary HF trials evaluating RAS inhibition (Vaduganathan et al 2018). With 
regard to ARNI, in a landmark analysis based on the PARADIGM-HF trial data, adjusted for 
baseline values, a 50% reduction in NT-proBNP levels was associated with approximately 32% 
reduction in the composite of CV death or HF hospitalization (Zile et al 2016). 
In view of XXB750's mode of action, change of NT-proBNP is thus considered an appropriate 
surrogate endpoint for clinical outcomes of HF in this short-term study in patients with HF. The 
results will be used to determine the projected benefit of XXB750 on long-term HF outcomes 
when added to SoC guideline-directed HF therapy. 
4.3 
Justification for dose 
Doses and administration regimens of XXB750 were selected based on the safety, tolerability, 
and pharmacodynamic profile observed in first interpretable results (FIR) from the FIH trial of 
XXB750 (study CXXB750A02101) and data observed in a phase 1b study in patients with 
HFrEF/HFmrEF (study CXXB750A12101). 
Study CXXB750A02101 investigated the safety, tolerability, PK, and pharmacodynamics of 
single SC doses of XXB750 ranging from 1 mg to 600 mg in healthy volunteers without (1 mg, 
3 mg, 10 mg, 30 mg, 60 mg, 120 mg, and 240 mg) and with elevated blood pressure (450 mg 
and 600 mg). The highest single tolerated dose was found to be 450 mg. There was no observed 
distinguishable effect on plasma cGMP or BP at doses of 1 mg, 3 mg, and 10 mg and placebo 
injection. XXB750 showed cGMP elevation and BP lowering effect at doses of ≥ 30 mg, which 
appeared to be greater than the effect of a placebo injection. For these doses, plasma cGMP 
elevation reached its maximum at day 2 post-dose, while it was lower than peak effect but still 
elevated compared to placebo at day 28 post-dose. Blood pressure lowering achieved maximum 
effect by day 3 and showed a gradual decline over the following weeks. At day 28 post-dose, 
the BP lowering effect was still present with doses ≥ 120 mg (SBP change from baseline of 

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~7 mmHg and ~5 mmHg for 120 mg and 240 mg dose cohorts, respectively). In the phase 1b 
study in HF patients with LVEF <50% receiving ACEI/ARBs and other background HF 
medications (cohort 1), a single XXB750 SC dose of 120 mg resulted in a maximum decrease 
in SBP of 7 mmHg, which occurred on day 2 post-dosing and was found to be well tolerated. 
Please refer to the XXB750 investigators brochure for detailed data on studies 
CXXB750A02101 and CXXB750A12101). 
Given the sustained cGMP elevation and acceptable safety and tolerability profile, the 120 mg 
dose has been selected as the highest starting dose to be tested in this study. Based on 
pharmacometric modeling of the data from study CXXB750A02101, XXB750 doses of 60 mg, 
120 mg and 240 mg are selected to be evaluated as target dose levels, to further investigate 
efficacy and safety of XXB750 in HF patients, and to support its use in subsequent studies as a 
once every 4 weeks SC administration regimen. 
In the open-label sacubitril/valsartan cohort the target dose will be 97/103 mg bid, which is the 
target dose shown to be effective in reducing morbidity and mortality in HFrEF patients 
(McMurray et al 2014). The effectiveness of this dose extends to HF patients with higher LVEF 
with the greatest benefit occurring in patients with LVEF below normal, including patients with 
HFmrEF (Solomon et al 2020). 
For more information about studies CXXB750A02101 and CXXB750A12101, please refer to 
the XXB750 Investigator’s Brochure. 
4.3.1 
Rationale for choice of background therapy 
The current study aims that all participants are treated with guideline-directed heart failure 
therapy 
as 
recommended 
per 
recently 
published 
guidelines 
(McDonagh et al 2021, Heidenreich et al 2022). To reduce variability across the studied sample 
and to ensure patients are treated with reasonably effective doses of background anti-RAS 
therapy, eligible patients must be receiving approximately half the target dose of their pre-study 
ACEI/ARB/ARNI or higher per international treatment guidelines and locally approved labels. 
Other components of guideline-directed therapies for HFrEF and HFmrEF are recommended 
as background therapy at individually optimized doses, unless not tolerated or not available to 
patients. 
Overall, these requirements will ensure that participants are treated according to current 
guideline recommendations including sacubitril/valsartan or an ACEI/ARB. 
To avoid an influence of dose adjustments on baseline NT-proBNP levels, all background heart 
failure therapy must be given at a stable dose for at least 4 weeks prior to screening. 
4.4 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
The primary objective of this study is to evaluate the dose-response effect of three dose levels 
of XXB750 on lowering NT-proBNP when administered on top of standard of care therapy 
recommended for patients with HFrEF (McDonagh et al 2021, Heidenreich et al 2022). As 
such, a placebo is considered the appropriate control for achieving this objective. A placebo 

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comparator is also appropriate for evaluating the safety and tolerability of XXB750 when given 
at the three dose levels. 
Another objective of this study is to assess the benefit of NPR1 agonism with XXB750 on 
reduction in NT-proBNP relative to neprilysin inhibition. Thus, sacubitril/valsartan, a 
compound that delivers neprilysin inhibition and angiotensin receptor blockade, is the only 
clinically available and appropriate control. To ensure this objective is properly achieved, a 
sufficient number of ACEI/ARB treated participants will be randomized to either receive 
XXB750 while continuing to take their ACEI/ARB (i.e., receive NPR1 agonism + anti-RAS 
treatment in treatment arms 2, 3, 4a and 4b) or stop their pre-study ACEI/ARB and be converted 
to sacubitril/valsartan (i.e., receive neprilysin inhibition + anti-RAS treatment in treatment arm 
5). 
4.5 
Rationale for public health emergency mitigation procedures 
During a public health emergency as declared by local or regional authorities e.g., pandemic, 
epidemic, or natural disaster, mitigation procedures to ensure participant safety and trial 
integrity may be implemented. Notification of the public health emergency as declared by local 
or regional authorities should be discussed among investigators and Novartis. All procedures 
adapted to the situation must be submitted, if required as per local regulations, through a 
protocol amendment for approval by local or regional Health Authorities and Ethics 
Committees prior to implementation of mitigation procedures. 
4.6 
Purpose and timing of interim analyses/design adaptations 
Limited safety data is currently available for XXB750, and it is thus prudent to dose the 
medication cautiously in participants until more is learned about its side effects. 
Staggered enrollment and the safety interim analysis 
To help guard the safety of study participants, randomization will initially exclude the planned 
highest target dose of XXB750 (i.e., arms 4a and 4b) until an interim analysis is conducted to 
evaluate the safety of the lower two target doses and that a sufficient safety margin exists to 
allow patients to be dosed with the highest target dose arms. 
The randomized participant sample will be divided into two groups. Group 1 will consist of the 
first approximately 300 participants who will be randomized to receive placebo, XXB750 target 
dose of 60 mg every 4 weeks, XXB750 target dose of 120 mg every 4 weeks, or 
sacubitril/valsartan at a target dose of 97/103 mg bid in a 1:1:2:1 ratio (see Table 4-2 ). 
Group 2 will consist of the remaining approximately 420 participants who are planned to be 
randomized to receive placebo, XXB750 target dose of 60 mg q 4 weeks, XXB750 target dose 
of 120 mg q 4 weeks, XXB750 target dose of 240 mg q 4 weeks at a starting dose of 60 mg, 
XXB750 target dose of 240 mg at a starting dose of 120 mg, or sacubitril/valsartan 97/103 mg 
bid in a 2:2:2:3:3:2 ratio (see Table 4-2). 
The DMC will conduct an early safety interim analysis of the data of Group 1 when 
approximately 85 participants have completed at least 9 weeks of randomized treatment to 
assess the safety profile of repeat doses of XXB750 up to 120 mg in the study participants. 

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Additionally, safety data from cohort 2 of the ongoing XXB750 phase 1b study 
CXXB750A12101 (i.e., safety profile of two XXB750 120 mg doses followed by one 240 mg 
dose all given 4 weeks apart and followed for 12 weeks after the last dose) will be reviewed to 
provide further insight into the tolerability of the planned 240 mg dose of XXB750 in HF 
patients. If the totality of available safety evidence is deemed acceptable by the DMC to allow 
for dosing of XXB750 at doses of 240 mg, enrollment of Group 2 will start once Group 1 
enrollment is completed. 
In addition to the planned interim safety analysis summarized above, there will be safety data 
reviews conducted regularly by the DMC approximately twice annually. Refer 
to Section 10.1.4 for more information about the role of the DMC in this study. 
Table 4-2 
Overview of the planned staggered enrollment strategy 
Treatment arm 
Target dose, up-
titration scheme 
Group 1 
n 
Group 2 
n 
Total 
n 
1 
Placebo 
60 
60 
120 
2 
XXB750 60 mg 
60 
60 
120 
3 
XXB750 120 mg 
120 
60 
180 
4a* 
XXB750 240 mg, 
initial dose 60 mg 
0 
90 
90 
4b* 
XXB750 240 mg, 
initial dose 120 mg 
0 
90 
90 
5 
Sacubitril/valsartan 
97/103 mg bid 
60 
60 
120 
Total 
300 
420 
720 
*Highest target XXB750 dose may potentially be changed to be 180 mg. Refer to the adaptive design features 
section below for details. 
Adaptive design features 
If at the DMC early safety review described above, it is deemed inappropriate or unadvisable 
to continue the study as planned, i.e., to allow patients to be randomized to as planned into 
groups 4a and 4b at a target dose of 240 mg every 4 weeks, one of the following adaptations to 
the design of the study may be implemented per the recommendation of the DMC: 
1. Change the highest target dose in the study from the planned XXB750 240 mg every 4 
weeks to 180 mg every 4 weeks.  
In Group 2, participants randomized to treatment arm 4a will receive XXB750 60 mg SC 
at the Randomization followed by XXB750 120 mg SC at Week 4 and XXB750 180 mg 
SC at Week 8 and Week 12. Participants randomized to treatment arm 4b will receive 
XXB750 120 mg SC at the Randomization followed by XXB750 180 mg SC at Week 4, 
Week 8, and Week 12. The planned dosing schedule of all other treatment arms will 
remain unmodified. The sample size allotted to all treatment arms will remain unchanged. 
2. Eliminate treatment arm 4b (top dose either XXB750 240 mg or 180 mg every 4 weeks). 
In this case the highest target dose will be reached after a starting dose of 60 mg 
(treatment arm 4a). In Group 2, all participants previously allocated to treatment arm 4b 
will be reallocated to treatment 4a. Thus, the 420 participants in Group 2 will be 
randomized to receive placebo, XXB750 target dose of 60 mg every 4 weeks, XXB750 
target dose of 120 mg every 4 weeks, XXB750 target dose of 240 mg (or 180 mg) every 4 

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weeks at a starting dose of 60 mg, or sacubitril/valsartan 97/103 mg bid in a 1:1:1:3:1 
ratio. 
3. Eliminate treatment arms 4a and 4b. 
In this case the highest target dose in the study will be XXB750 120 mg every 4 weeks 
(treatment arm 3) and 180 participants will be allocated to treatment arm 3 from Group 2 
for a total/overall sample size of 300 participants in this arm. Thus, Group 2 will include 
360 participants who will be randomized to receive placebo, XXB750 target dose of 
60 mg every 4 weeks, XXB750 target dose of 120 mg every 4 weeks, or 
sacubitril/valsartan 97/103 mg bid in a 1:1:3:1 ratio. The planned dosing schedule of these 
treatment arms will remain unmodified. In this case the total sample size of the study will 
be approximately 660 participants. 
Participating investigators will be informed promptly of any of the adaptations to the design 
of the study shown above that are to be implemented in consultation with the DMC, so that 
they can inform the participants and ethics committees/IRBs as required by local regulations. 
The sponsor will inform the local health authorities as per local regulations. 
Administrative interim analysis informing other programs 
An additional administrative interim analysis to inform other development programs and studies 
may be conducted when approximately 430 participants are randomized into the study (at 
least 40 participants in each of arms 1-4) and are followed for at least 16 weeks. The results of 
this administrative interim analysis will not lead to any changes in this study and its results will 
be kept blinded for anyone who is directly involved in the conduct of this study. More details 
about the DMC review process and how unblinding will be handled in the context of DMC 
reviews will be provided in the DMC charter. 
4.7 
End of study definition 
The end of the study is defined as the date of the last visit of the last participant in the study 
globally. 
Study completion is defined as when the last participant finishes his/her Week 16 visit and any 
repeat assessments associated with this study visit have been documented and followed-up 
appropriately by the Investigator. 
All randomized participants will have a safety follow-up after last administration of study 
treatment as outlined in Section 1.3 SoA and Section 4.1.3. Serious adverse event (SAE) 
reporting continues during this time period as described in Section 8.6.3. Documentation of 
attempts to contact the participant are required to be recorded in the source documentation. 
5 
Study population 
The study population will consist of male and female participants 18 years old or older with 
symptomatic HFrEF or HFmrEF as defined in the inclusion criteria. A total of approximately 
720 participants will be randomized into this study. The percentage of patients with LVEF > 
40% will be limited to approximately 25% of the total sample. 

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5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study. 
2. Male and female outpatients who are ≥ 18 years old at screening. 
3. Current symptom(s) of HF NYHA class II-III. 
4. LVEF < 50% (any local measurement, made within the past 6 months prior to or during 
screening using echocardiography, MUGA, CT scanning, MRI or ventricular angiography 
is acceptable, provided there is no subsequent measurement ≥ 50%). 
5. NT-proBNP ≥ 600 pg/mL if in sinus rhythm or 
NT-proBNP ≥ 900 pg/ml if in atrial fibrillation/flutter at screening. 
6. Receiving an ACEI or an ARB at a stable dose of at least enalapril 10 mg/d or equivalent 
for at least 4 weeks before screening or receiving sacubitril/valsartan at a stable dose of at 
least 49/51 mg bid for at least 4 weeks before screening. 
7. Receiving other guideline recommended HF therapies as deemed appropriate by the 
investigator and that are stable in dose for at least 4 weeks before screening, unless 
contraindicated, not tolerated, or not available to patient. Other evidence-based therapy for 
heart failure should also be considered, e.g., cardiac resynchronization therapy (CRT) and 
an implantable cardioverter-defibrillator in selected patients, as recommended by 
guidelines.  
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and 
symptoms that may require intravenous therapy) or hospitalization for HF within 3 months 
prior to screening. 
2. Current symptomatic hypotension (for example dizziness/presyncope). 
3. Office systolic blood pressure (SBP) ≥ 180 mmHg or < 105 mmHg at screening or at 
randomization. 
4. History of hypersensitivity to XXB750, sacubitril/valsartan, or any of the study drug's 
excipients or to any other biological drugs. 
5. Received a monoclonal antibody or immunoglobulin-based agent within 1 year of 
screening. 
6. In subjects with ACEI/ARB medication at screening, previous inability to tolerate any 
dose of sacubitril/valsartan or any ARB (as per the investigator's judgment). 
7. Known history of angioedema (as per the investigator's judgment). 
8. Serum potassium > 5.4 mmol/L (or equivalent plasma potassium value) at screening. 
9. Estimated GFR < 30 mL/min/1.73m2 as measured by the CKD-EPI formula at screening. 
10. Presence of known functionally significant bilateral renal artery stenosis at screening. 
11. Evidence of urinary obstruction, or difficulty in voiding at screening, or of congenital 
renal abnormalities with known effect on renal function. 
12. Clinically significant congenital heart disease that could be the cause of the patient’s 
symptoms and signs of HF. 

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13. Presence of hemodynamically significant valvular heart disease other than functional 
mitral insufficiency or known right ventricular dysfunction that is deemed to increase 
susceptibility to the hypotensive effects of therapy in the opinion of the investigator. 
14. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), high-grade atrio-
ventricular (AV) block (e.g., Mobitz type II and third-degree AV block in the absence of a 
pacemaker) or symptomatic bradycardia within 6 months of screening according to the 
investigator's judgement. 
15. Acute myocardial infarction (AMI) or unstable angina, any history of ischemic or 
hemorrhagic stroke, or any percutaneous coronary intervention (PCI) or coronary artery 
bypass graft (CABG) within 6 months of screening, or CRT implantation within 3 months 
of screening. 
16. History or current diagnosis of severe pulmonary disease (e.g. COPD) requiring chronic 
supplemental oxygen, corticosteroid, or nebulizer therapy or pulmonary arterial 
hypertension (WHO group 1 or 4) requiring pharmacology treatment at screening. 
17. At screening, symptomatic anemia or hemoglobin < 10 g/dL in male subjects or < 9 g/dL 
in female subjects. 
18. Prior major organ transplant, intention to transplant (i.e. on transplant list) or 
planned/anticipated major cardiac surgery during the involvement of the participant in the 
study. 
19. History or presence of any other disease where the life expectancy is less than 3 years. 
20. History of malignancy of any organ system (other than localized basal or squamous cell 
carcinoma of the skin or localized prostate cancer), treated or untreated, within the past 3 
years, regardless of whether there is evidence of local recurrence or metastases. 
21. Evidence of hepatic disease as determined by any one of the following: aspartate 
aminotransferase (AST; serum glutamic-oxaloacetic transaminase, SGOT) or alanine 
aminotransferase (ALT; serum glutamic-pyruvic transaminase, SGPT) values exceeding 
3x the upper limit of normal (ULN), or total bilirubin (TBL) > 1.5 mg/dL at screening. 
22. History or current diagnosis of drug abuse or alcohol dependency. 
23. Lacking the ability to comprehend or follow instructions, or for any reason in the opinion 
of the investigator, a patient that would be unlikely or unable to comply with study 
protocol. 
24. Concurrent enrollment in any other investigational drug or device trial (participation in 
non-interventional registries is acceptable). 
25. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-
lives of enrollment, whichever is longer. 
26. Pregnant, nursing or planning to become pregnant (documented negative pregnancy test 
required within a maximum of 7 days prior to enrollment of all women of childbearing 
potential). Documentation of highly effective contraception is also required for women of 
childbearing potential (see below). 
Women of child-bearing potential are defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception while 
taking study treatment and for 3 months after last double-blind injectable study treatment 

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or for 7 days after the last dose of oral study treatment (if randomized to receive open-
label sacubitril/valsartan). Highly effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g. calendar, ovulation, symptom-thermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy, total hysterectomy, bilateral salpingectomy, or bilateral tubal ligation) 
at least six weeks before taking study treatment. In case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow-up hormone 
level assessment. 
• Male sterilization (vasectomy) of the male partner(s) of the female participant (at least 
6 months prior to screening). For female participants on the study, the vasectomized 
male partner(s) should be the sole partner(s) for that participant. 
• Use of oral, (estrogen and progesterone), injected, or implanted hormonal methods of 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS), or other forms of hormonal contraception that have comparable efficacy (failure 
rate < 1%), for example hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g., age-appropriate 
history of vasomotor symptoms). Women are considered not of childbearing potential if 
they are post-menopausal or have had surgical bilateral oophorectomy (with or without 
hysterectomy), total hysterectomy, bilateral salpingectomy or bilateral tubal ligation at 
least six weeks before enrollment on study. In the case of oophorectomy alone, only when 
the reproductive status of the woman has been confirmed by follow up hormone level 
assessment is not she considered to be of childbearing potential. 
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF. 
5.3 
Screen failures 
A screen failure occurs when a participant who consents to participate in the clinical study is 
subsequently found to be ineligible and therefore does not enter the Randomized treatment 
period of the study. A minimal set of screen failure information is required to ensure transparent 
reporting of screen failure participants to meet the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, reason(s) for screen failure, eligibility criteria, 
adverse events related to AxMPs and any SAE. 
The reason for screen failure should be recorded on the appropriate CRF. The demographic 
information, informed consent, and inclusion/exclusion pages must also be completed for 
screen failure participants. Screening laboratory assessments will also be collected and entered 
into the clinical database. No other data will be entered into the clinical database for participants 
who are screen failures, unless the participant experienced a serious adverse event during the 

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screening period (see Section 8.6.3 for SAE reporting details). If the participant fails to be 
randomized, the IWRT (Interactive Web Response Technology)/IRT (Interactive Response 
Technology) system must be updated with the screen fail that the participant will not be 
randomized. Data and samples collected from participants prior to screen failure may still be 
analyzed. 
Individuals who do not meet the criteria for participation in this study (screen failure), will have 
one opportunity to be re-screened again for this study, ≥ 2 weeks after the original screening 
date. 
5.3.1 
Replacement policy 
Not applicable. 
5.3.2 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. The Participant No. consists of the Site Number 
(Site No.) (as assigned by Novartis to the investigative site) with a sequential participant 
number suffixed to it, so that each participant’s participation is numbered uniquely across the 
entire database. Upon signing the informed consent form, the participant is assigned to the next 
sequential Participant No. available. 
A new ICF must be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant Number. 
Additional details regarding Screening are provided in Section 8.1. 
6 
Study treatment(s) and concomitant therapy 
6.1 
Study treatment(s) 
Study treatment includes investigational drugs XXB750, its matching placebo, and 
sacubitril/valsartan. 
Oral study medication refers to sacubitril/valsartan as investigational/control drug. 
XXB750 or matching placebo will be administered as a SC injection every 4 weeks during the 
randomized treatment period (Randomization, Week 4, Week 8 and Week 12). Table 6-1 lists 
investigational and control drug. 
Table 6-1 
Investigational and control drug 
Treatment Title 
XXB750 150 mg/mL 
XXB750 0 mg/mL 
(placebo) 
Sacubitril/valsartan 
Treatment Description 
Liquid in Vial 
Liquid in Vial 
Solid 
Type 
Biologic 
Placebo 
Drug 
Dose Formulation 
Concentrate for solution 
for injection 
Solution for injection 
Tablet 
Unit Dose Strength(s) 
150 mg/ml 
0 mg/ml 
97/103 mg, 49/51 mg 
and 24/26 mg 

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Dosage Level(s) 
as per Table 6-3 
as per Table 6-3 
as per Table 6-3 
Route of 
Administration 
Subcutaneous use 
Subcutaneous use 
Oral 
Use 
Experimental 
Placebo 
Active comparator 
IMP 
Yes 
Yes 
Yes 
Sourcing 
Novartis (global) 
Novartis (global) 
Provided locally 
Packaging and 
Labeling 
Study treatment will be 
provided in vials. Each 
vial will be labeled as per 
country requirement. 
Open-label packs 
Study treatment will be 
provided in vials. Each 
vial will be labeled as per 
country requirement. 
Open-label packs 
As per local packaging. 
Each package will be 
labeled as per country 
requirement. Open-label 
packs 
6.1.1 
Additional study treatments 
Auxiliary medicinal products (under EU CTR) in this trial are ACEI, ARB and 
sacubitril/valsartan. When participants enter the randomized treatment period, they will remain 
on the same background ACEI or ARB or on sacubitril/valsartan (as applicable) they had been 
receiving for their usual care before randomization without change in dose, source, or type of 
ACEI/ARB/ARNI (per local requirements). Exception is made to those participants that are 
randomized to arm 5, who will be switched from their pre-study ACEI or ARB to open-label 
sacubitril/valsartan, which will be provided by Novartis during the 16 weeks randomized 
treatment period. 
Table 6-2 
Auxiliary treatments 
Treatment Title 
ACEI 
ARB 
Sacubitril/valsartan 
Treatment Description 
Once or twice daily 
Once or twice daily 
Twice daily 
Type 
Drug 
Drug 
Drug 
Dose Formulation 
Tablet 
Tablet 
Tablet 
Route of Administration 
Oral 
Oral 
Oral 
Use 
Background medication 
Background medication 
Background medication 
Authorization status of 
the AMP in EEA 
Yes 
Yes 
Yes 
Sourcing 
Provided locally as per 
country requirement 
Provided locally as per 
country requirement 
Provided locally as per 
country requirement 
Packaging and 
Labeling 
Auxiliary treatment will be 
provided in commercially 
available packaging. 
Auxiliary treatment will be 
provided in commercially 
available packaging.  
Auxiliary treatment will be 
provided in commercially 
available packaging.  
6.1.2 
Treatment arms/group 
Table 6-3 summarizes planned study treatment arms and their dosing schedule. Please refer 
to Section 4.6 for potential adaptive design features that may potentially affect the treatment 
arms at the DMC early safety review. 

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Table 6-3 
Treatment arms, dose levels, and planned doses administered at 
dispensing visits during the Randomized treatment period 
Treatment 
arm 
Target dose level 
Titration 
scheme 
Rando-
mization 
Week 2 
Week 4 
Week 8 
Week 12 
Arm 1 
XXB750 placebo 
 
Placebo 
 
Placebo 
Placebo 
Placebo 
Arm 2 
XXB750 60 mg 
 
60 mg 
 
60 mg 
60 mg 
60 mg 
Arm 3 
XXB750 120 mg 
 
60 mg 
 
120 mg 
120 mg 
120 mg 
Arm 4 
XXB750 240 mg* 
4a 
60 mg 
 
120 mg 
240 mg* 
240 mg* 
4b 
120 mg 
 
240 mg* 
Arm 5 
Sacubitril/valsartan 
open-label, 
97/103 mg bid 
Starting 
dose as per 
label and 
investigator's 
judgment 
49/51 
mg bid 
49/51  
mg bid 
97/103  
mg bid 
97/103  
mg bid 
97/103  
mg bid 
24/26  
mg bid 
* May be lowered to a target dose of 180 mg, determined after interim safety analysis 
In treatment arms 1 through 4, all patients will receive SC injections of XXB750 or matching 
placebo. Refer to Section 6.5 for instructions on adjusting the dose of XXB750 in the context 
of management of adverse events. 
In treatment arm 5, restricted to patients on ACEI/ARB, the pre-study ACEI/ARB medication 
will be discontinued and replaced by open-label sacubitril/valsartan. Participants on pre-study 
ACEIs must be instructed to observe an ACEI-free washout wash-out period of 36 hours is 
mandatory prior to the first dose of open-label sacubitril/valsartan to minimize the potential risk 
of angioedema. Refer to Section 4.1.2 for a description of how to implement the ACEI-free 
washout. 
Patients randomized to open-label sacubitril/valsartan may be initiated on 24/26 mg to 49/51 
mg bid per the investigator’s clinical judgment (taking into account the pre-study ACEI/ARB 
dose) and must be gradually force-titrated to the target dose of 97/103 mg bid by Week 4. Every 
attempt should be made to maximize the dose of the study open-label sacubitril/valsartan by 
modifying other background medications, such as diuretics, nitrates, and calcium channel 
blockers, as per the investigator’s clinical judgment. The dose of open-label sacubitril/valsartan 
may be down-titrated if the participant experiences dose-limiting side effects that cannot be 
managed by modifications of the patient's concomitant medications. 
6.1.3 
Treatment duration 
The planned duration of randomized treatment is 16 weeks. After the 16-week randomized 
treatment period, participants will enter an 8-week safety follow-up period in which participants 
may be treated at the discretion of the investigator taking into account that their heart failure 
clinical status may still be affected by the study treatment for some time after its discontinuation. 
6.2 
Preparation, handling, storage, and accountability 
Each 
study 
site 
will 
be 
supplied 
with 
study 
treatment 
as 
described 
under Section 6.1 in Table 6-1 (investigational and control drugs). 
A unique medication number is printed on the study medication label (applicable only for 
globally sourced investigational and control drug, i.e. XXB750 or matching placebo). 

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Unblinded qualified and properly trained members of the study team at the site will identify the 
IMP kits to be administered or be dispensed to the participants by contacting the IRT system 
and obtaining the medication number(s). Drug accountability and reconciliation data are 
recorded in the IRT system. 
For locally sourced open-label oral study medication, according to the treatment assigned to the 
participant, Investigator staff will select the study medication to be dispensed to the participant. 
Site personnel will record the locally sourced supply dispensation into the participant's source 
document. 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, delivery 
of injectable IMP directly to a participant's home is not possible because XXB750 is to be 
administered subcutaneously by a trained and certified personnel or nurse, and because other 
essential assessments and PK sampling etc. requires the patient to be on site. 
Supply, preparation, dispensation and return of IMP will be described in the Pharmacy Manual. 
6.2.1 
Handling of study treatment 
Study treatment must be received by the unblinded person at the study site, handled and stored 
safely and properly and kept in a secured location which only designated site personnel have 
access to. Upon receipt, all study treatment must be stored according to the instructions 
specified in the product information(s) and in the Investigator's Brochure and in accordance 
with Good Manufacturing Practice (GMP) and Good Clinical Practice (GCP) procedures. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization Quality Assurance. 
The subcutaneous study treatment of XXB750 or respective placebo needs to be prepared by 
unblinded qualified site personnel (in accordance with local regulations, e.g. pharmacist) in 
order to ensure treatment blinding. Details about handling, storage and administration will be 
provided in a separate Pharmacy Manual. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The designated site staff must maintain an accurate record of the shipment and dispensing of 
IMP in the IRT drug accountability log. Monitoring of drug accountability will be performed 
by field monitors during site or remote monitoring visits, and at the completion of the trial. The 
investigator must provide accountability also for locally sourced study materials/treatment used 
for administration (e.g. i.v. syringes). 
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging, as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to 
the Novartis monitor or to the Novartis address provided in the investigator folder at each site. 

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Oral study medication (i.e. open-label sacubitril/valsartan as active comparator) will be 
dispensed in an open-label fashion at scheduled site visits. Participants will be asked to return 
all unused oral study medication and packaging at each site visit or at the time of discontinuation 
of oral study medication. Site personnel will record the locally sourced supply dispensation into 
the participant's source document. 
6.2.2 
Handling of other treatment 
The participant's use of other medications will be monitored (dose, dose changes and reasons for 
changes) throughout the whole duration of the study by documentation of all medications at 
each visit. 
6.2.3 
Instruction for prescribing and taking study treatment 
All study medications will be administered in addition to other background medications the 
participant is taking, including other background HF medications. 
Table 6-3 shows how the study treatments should be prescribed at each dispensing visit during 
the randomized treatment period. Please refer to Section 6.5 for dose modification algorithm to 
manage adverse events that may be contributed to the injectable study medication. 
All kits of study treatment assigned by IRT will be recorded in the IRT system. 
XXB750 Injectable Study Medication 
Participants in treatment arms 1-4 will receive an SC injection of XXB750/matching placebo 
according to the participant’s randomized treatment assignment. The unblinded, qualified site 
personnel will prepare the study drug for injection in a blinded way according to the Pharmacy 
Manual; qualified blinded study staff will inject the study drug subcutaneously in the upper arm 
or abdomen. Injections should not be given into areas of active skin disease or injury such as 
sunburns, skin rashes, inflammation, or skin infections. After injection, the participant will be 
observed for potential hypersensitivity reactions for ≥20 minutes, before he/she can leave the 
site. 
Only the unblinded qualified site personnel in charge of preparing the study medication will be 
aware of the contents of the administered injectable study medication. Refer to Section 6.2.1 for 
more details regarding the preparation of the study medications for dispensing. 
Oral Study Medication 
At every dispensing visit during the randomized treatment period, the open-label 
sacubitril/valsartan oral study medication will be dispensed to participants in treatment arm 5 
in 
sufficient 
quantities 
to 
last 
until 
the 
next 
scheduled 
visit 
(Section 6.1.2, Table 6-1, and Table 6-3). 
• Participants should be instructed to take the oral open-label sacubitril/valsartan study 
medication twice daily at approximately the same times of each day except for study site 
visit days. On these days, participants should bring their oral study medication to the site 
and take it after blood sampling for this visit has been performed. 

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• Participants should take the oral study medication without regard to food. Each dose may 
be taken with a glass of water. 
• If vomiting occurs during the course of treatment, participants should not take the oral 
study treatment again before the next scheduled dose. 
• If the patient misses taking any study drug dose, he/she should take it as soon as possible, 
unless if it is almost time for the following scheduled dose. In this case, the patient should 
skip the missed dose and return back to his/her regular study drug administration schedule. 
6.3 
Measures to minimize bias: randomization and blinding 
6.3.1 
Treatment assignment, randomization 
At the randomization visit, all eligible participants will be randomized via IRT to one of the 
treatment arms (see Section 1.2 and Table 6-3). The investigator or his/her delegate will contact 
the IRT after confirming that the participant fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the participant, which will be used to link the participant 
to a treatment arm and will specify a unique medication number for the injectable product to be 
dispensed to the participant. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant numbers to randomization numbers. These 
randomization numbers are linked to the different treatment arms, which in turn are linked to 
medication numbers. A separate medication list will be produced by or under the responsibility 
of Novartis Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the investigational product. 
Randomization will be stratified by region, and ACEI/ARB or sacubitril/valsartan background 
medication, respectively. Stratification will serve to prevent a potential imbalance of regions 
and ACEI/ARB or sacubitril/valsartan background medication, across the arms. In addition, 
stratified randomization will make sure that arms 1-4 will have 1:2 ratio of participants on 
ACEI/ARB or sacubitril/valsartan background medication, respectively, and arm 5 will include 
only participants on prior ACEI/ARB background medication. The randomization scheme for 
participants will be reviewed and approved by a member of the Randomization Office. 
6.3.2 
Treatment blinding 
Participants, investigator staff, persons performing the assessments, and the Novartis Clinical 
Trial Team (CTT) will remain blinded to the identity of the treatment from the time of 
randomization until database lock. 
The following methods will be used to maintain the blind: 
1. Randomization data will be kept strictly confidential until the time of final database lock 
and will not be accessible by anyone else involved in the study with the following 
exceptions: 

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• Unblinded staff (i.e. pharmacist/nurse) or other designated qualified site personnel 
who prepare the double-blind study medication doses at the study site and unblinded 
CRA monitoring the sites who will monitor study medication preparation at the site. 
• The bioanalyst for PK analyses (to avoid the unnecessary analysis of samples 
belonging to participants randomized to placebo treatment) 
• The DMC and an external independent analysis team who need to prepare efficacy 
interim and safety monitoring analysis reports for the DMC. For details on the DMC, 
please refer to Section 10.1.4.1. 
These personnel will not be involved in any other trial activities. 
2. The identity of the treatments will be concealed by the use of study treatments that are all 
identical in packaging, labeling, schedule of administration, and appearance. All 
XXB750/matching placebo injections will be prepared such that they will all have the 
same injection volumes regardless of dose to maintain the blinding. Blinded label supply 
(also mention respective drug name) will be provided at sites to the unblinded site 
pharmacist to prepare study drug and to conceal treatment code from participants and the 
investigator staff administering the study injections/dispensing the study medications and 
performing the assessments. 
3. Data with unblinding potential, such as PK concentrations and immunogenicity data 
collected after the randomization visit, will be kept blinded to all personnel included in 
study conduct activities until the time of final database lock. 
4. Sponsor staff responsible for decision making at the clinical program development level 
(the Novartis decision making team) will receive the aggregated unblinded results at the 
treatment group level at the time of the administrative interim analysis informing other 
programs, as outlined in Table 6-4. The team will not have access to the individual 
participant treatment codes. 
The DMC will review unblinded data reports created by an external independent analysis team. 
More details about the DMC review process and how unblinding will be handled in the context 
of DMC reviews will be provided in the DMC charter. 
Table 6-4 
Blinding and unblinding plan 
Role 
Time or Event 
 
 
Randomizatio
n list 
generated 
Treatmen
t 
allocatio
n & 
dosing 
Safety 
event 
(single 
subject 
unblinded
) 
Safety 
monitorin
g review 
IA for 
safet
y 
Administrativ
e IA to inform 
other 
programs 
 
Participants 
B 
B 
UI 
B 
B 
B 
 
Site staff 
B 
B 
UI 
B 
B 
B 
 
Unblinded site 
personnel involved 
in dose preparation 
B 
UI 
B 
B 
B 
B 
 
Global Clinical 
Supply 
UG/UI 
UG/UI 
UG/UI 
UG/UI 
B 
B 
 
Randomization 
Office 
UI 
UI 
UI 
UI 
UI 
UI 
 

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Role 
Time or Event 
 
 
Randomizatio
n list 
generated 
Treatmen
t 
allocatio
n & 
dosing 
Safety 
event 
(single 
subject 
unblinded
) 
Safety 
monitorin
g review 
IA for 
safet
y 
Administrativ
e IA to inform 
other 
programs 
 
Unblinded Sponsor 
staff, e.g., for study 
treatment re-
supply, unblinded 
monitor(s), sample 
analyst(s) 
UG 
UI 
B 
UG 
B 
B 
 
Unblinded 
Pharmacovigilance 
Sponsor staff 
B 
B 
UI 
B 
B 
B 
 
DMC 
UI 
UI 
UI 
UI 
UI 
UI 
 
External 
independent 
Statistician/statistic
al programmer/ 
data analysts 
UI 
UI 
UI 
UI 
UI 
UI 
 
Biomarker analyst 
B 
B 
B 
B 
B 
B 
 
PK analyst 
UI 
UI 
B 
UI 
B 
B 
 
Sponsor CTT 
B 
B 
B 
B 
B 
B 
 
Novartis decision 
making team for 
IAs 
B 
B 
B 
B 
B 
UG 
 
All other Sponsor 
staff not identified 
above (i.e. 
management, 
support functions) 
B 
B 
B 
B 
B 
B 
 
B: Complete blinded 
UG: Unblinded at the group level (i.e. has access to unblinded group level summary results,  
but not to the individual participant treatment codes) 
UI: Unblinded to individual participant treatment codes 
 
6.3.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat the 
participant safely. 
Most often, discontinuation from study treatment and knowledge of the possible treatment 
assignments are sufficient to treat a study participant who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
Investigator contacts the system to break a treatment code for a participant, he/she must provide 
the requested participant identifying information and confirm the necessity to break the 
treatment code for the participant. The Investigator will then receive details of the 
investigational drug treatment for the specified participant and a fax or email confirming this 
information. The system will automatically inform the Novartis monitor for the site and the 
study team that the code has been broken. 

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It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The Investigator 
will provide: 
• protocol number 
• participant number 
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time. 
In case of emergency unblinding, the participants should be discontinued from study treatment 
and continue with the study visit as scheduled without study medication administration. 
6.4 
Study treatment compliance 
Injections of XXB750 or matching placebo will be administered at the site. All study treatment 
administered, dispensed and returned must be recorded in the Drug Accountability and Returns 
Management functionality in the IRT system. The dispensed and returned data recorded 
electronically in the IRT database will be considered the source record. 
For participants randomized to arm 5, the investigator must promote adherence to treatment by 
instructing the participant to take the study medication exactly as prescribed and by stating that 
compliance is necessary for the participant’s safety and the validity of the study. The participant 
must also be instructed to contact the investigator if he/she is unable for any reason to take the 
study treatment as prescribed. Compliance will be assessed by the investigator and/or study 
personnel at each visit using information provided by the participant. This information should 
be captured in the source document at each visit. 
Pharmacokinetic parameters (measures of treatment exposure) will be determined in all 
participants treated with XXB750, as detailed in Section 8.7. 
6.4.1 
Recommended treatment of adverse events 
Recommendations for handling liver events are described in Appendix 5. 
Recommendations for handling potential drug induced liver injury (DILI) cases are described 
in Section 6.5.2.1. 
Recommendations for handling hypotension are described in Appendix 7. 
Recommendations for handling hyperkalemia are described in Appendix 8. 
Recommendations for handling renal events are described in Section 10.6.1. 
Medication used to treat adverse events (AEs) must be recorded on the appropriate CRF. 
6.5 
Dose modification 
For participants who do not tolerate the protocol-specified dosing schedule, dose adaptations 
are recommended in order to allow participants to continue the study treatment. 
In general, every effort should be made to resolve AEs that may be attributed to study 
medication and/or foundational background HF treatments before the next dose of study 

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medication can be administered. Detailed recommendations for dose modifications of 
concomitant non-HF treatments, diuretics, and foundational background HF treatments 
(i.e., ACEI/ARB, sacubitril/valsartan, MRA, SGLT2 inhibitor and/or beta-blocker) in case of 
hypotension or hyperkalemia are provided in Appendix 7 (Section 10.7, Figure 10-1) and 
Appendix 8 (Section 10.8), respectively. 
For dosing of the injectable study medication, the patient should be evaluated at the scheduled 
study visit when the study medication is due to be administered. The flow chart 
in Figure 6-1 shows how to evaluate the participant based on the following principles: 
• If by the next dosing visit the participant's foundational background HF treatments are 
fully resumed at pre-study doses, the injectable study medication will be administered as 
planned. 
• If the dose of at least one foundational background HF treatment is still required to be 
reduced relative to the pre-study dose, the injectable study medication will be 
administered at the same dose as at the previous visit (i.e., no dose escalation). 
• If one of the foundational background HF treatments had been stopped and cannot be 
resumed due to the AE not being resolved, the injectable study medication dose should be 
skipped and administered at the next dosing visit at the same dose level as previously 
administered to the participant if the patient has been able to resume taking the 
foundational background HF treatment previously stopped. 
Figure 6-1 
Modification of injectable study medication 
 
*Figure 10-1 
Evaluate foundational background HF treatments (i.e., ACEI/ARB/ARNI, MRA, SGLT2i, beta blocker) relative to 
baseline with respect to type of drug and dose. Adverse events, especially events indicative of symptomatic 
hypotension, should be evaluated and potentially require action as outlined in the respective appendix. For the 
evaluation of planned study drug administration, only AEs related to study drug or foundational background HF 
treatments should be considered. 
Safety criteria determining dose interruption or discontinuation based on liver or renal events 
are listed in Appendix 5 (Section 10.5) and Appendix 6 (Section 10.6), respectively. 
All dose changes must be recorded on the appropriate CRF. 
6.5.1 
Definitions of dose limiting toxicities (DLTs) 
Not applicable. 

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6.5.2 
Follow-up for toxicities 
Refer to Appendix 5 (Section 10.5) for the follow-up of liver events and Appendix 6 
(Section 10.6) for the follow-up of renal events. 
6.5.2.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Transaminase increases combined with total bilirubin increases may be indicative of potentially 
severe DILI and should be considered as clinically important events and assessed appropriately 
to establish the diagnosis. The required clinical information, as detailed below, should be sought 
to obtain the medical diagnosis of the most likely cause of the observed laboratory 
abnormalities. 
The threshold for potential DILI may depend on the participant’s baseline aspartate 
aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (TBL) values; 
participants meeting any of the following criteria will require further follow-up as outlined 
below: 
• For participants with normal AST and ALT and TBL values at baseline: AST or 
ALT > 3.0 x ULN combined with TBL > 2.0 x ULN 
• For participants with elevated AST or ALT or TBL values at baseline: [AST or ALT > 2 x 
baseline level] OR [AST or ALT > 300 U/L] (whichever occurs first) combined with 
[TBL > 2 x baseline level AND > 2.0 x ULN] 
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should be 
considered and their role clarified before DILI is assumed to be the cause of liver injury. 
A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected. 
Laboratory tests should include AST, ALT, TBL, direct and indirect bilirubin, gamma-glutamyl 
transferase (GGT), prothrombin time (PT)/international normalized ratio (INR), alkaline 
phosphatase, albumin, and creatine kinase. If available, testing of glutamate dehydrogenase 
(GLDH) is additionally recommended. Refer to Section 10.5.1 for further guidance. 
Perform 
relevant 
examinations 
(ultrasound 
or 
MRI, 
endoscopic 
retrograde 
cholangiopancreatography [ERCP]) as appropriate, to rule out an extrahepatic cause of 
cholestasis. 
Table 6-5 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed liver function test (LFT) 
abnormalities. 
Table 6-5 
Diagnostic assessments to determine alternative causes of observed 
LFT abnormalities 
Disease 
Assessment 
Hepatitis A, B, C, E 
● IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV 
DNA; anti-HCV, HCV RNA, IgM & IgG anti-HEV, HEV 
RNA 
CMV, HSV, EBV infection 
● IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & 
IgG anti-EBV 

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Disease 
Assessment 
Autoimmune hepatitis 
● Antinuclear Antibodies (ANA) & Anti-Smooth 
Muscle Antibody (ASMA) titers, total IgM, IgG, IgE, 
IgA 
Alcoholic hepatitis 
● Ethanol history, GGT, MCV, CD-transferrin 
Nonalcoholic steatohepatitis 
● Ultrasound or MRI 
Hypoxic/ischemic hepatopathy 
● Medical history: acute or chronic congestive heart 
failure, hypotension, hypoxia, hepatic venous 
occlusion. Ultrasound or MRI 
Biliary tract disease 
● Ultrasound or MRI, ERCP as appropriate 
Wilson disease (if < 40 years old) 
● Cæruloplasmin 
Hemochromatosis 
● Ferritin, transferrin 
Alpha-1-antitrypsin deficiency 
● Alpha-1-antitrypsin 
MCV: mean corpuscular volume; ERCP: Endoscopic retrograde cholangiopancreatography; HAV: hepatitis A 
virus; HBV: hepatitis B virus; HCV: hepatitis C virus; HEV: hepatitis E virus; CMV: cytomegalovirus; EBV: 
Epstein Barr virus; CD-transferrin: carbohydrate-deficient transferrin; MRI: magnetic resonance imaging; 
HBsAg: Hepatitis B virus surface antigen; HSV: Herpes simplex virus 
Other causes should also be considered based upon participants’ medical history such as 
hyperthyroidism (causing thyrotoxic hepatitis where T3, T4 and thyroid-stimulating hormone 
[TSH] should be tested), CV disease (causing ischemic hepatitis where an ECG could be 
performed, and the history of prior hypotensive episodes should be inquired), and Type 1 
diabetes mellitus (causing glycogenic hepatitis). 
Obtain PK sample to determine exposure to study treatment and metabolites. 
Following the appropriate causality assessments, as outlined above, the causality of the 
treatment is estimated as “probable” (i.e. > 50% likely), if it appears greater than all other 
possible causes of liver injury combined. The term “treatment-induced” indicates probably 
caused by the treatment, not by something else, and only such a case can be considered a DILI 
case and should be reported as an SAE. 
All cases confirmed by repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified, should be considered as “medically 
significant” and thus, meet the definition of SAE and should be reported as a SAE using the 
term “potential treatment-induced liver injury.” All events should be followed-up with the 
outcome clearly documented. 
6.6 
Continued access to study treatment after the end of the study 
After Week 16, regular standard of care for heart failure should be provided to the participant 
by the investigator and/or referring physician as per the local standard of care and applicable 
guidelines. 
6.6.1 
Post trial access 
No post-trial access program is planned for this trial. Participants who complete or prematurely 
discontinue participation in this trial will switch to standard of care treatment. 
6.7 
Treatment of overdose 
In the event of an overdose, the investigator should: 

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• Contact the medical monitor immediately. 
• Evaluate the participant to determine, in consultation with the medical monitor, whether 
study treatment should be interrupted or whether the dose should be reduced. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities as required 
according to the pharmacodynamic and pharmacokinetic characteristics of the drug 
concerned. 
• Obtain a plasma sample for PK analysis within 6 days from the date of the last dose of 
injectable study treatment if requested by the medical monitor (determined on a case-by-
case basis). 
• Document the quantity of the excess dose as well as the duration of the overdose. 
• Follow the recommendations of the approved product label about overdose in case this 
involves sacubitril/valsartan study medication. 
6.7.1 
Reporting of study treatment errors including misuse/abuse 
Study treatment errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of study treatment. 
Study treatment misuse refers to situations where the study treatment is intentionally and 
inappropriately used not in accordance with the protocol. 
Study treatment abuse corresponds to the persistent or sporadic, intentional excessive use of 
study treatment, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol, including misuse or 
abuse, must be reported on the AE (or SAE, if the event meets the definition of an SAE) CRF. 
6.8 
Concomitant and other therapy 
6.8.1 
Concomitant therapy 
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant entered the study must be recorded on the 
appropriate CRFs. 
Each concomitant drug must be regularly assessed, based on the locally applicable label, against 
all entry criteria, prohibited medication and comparator reference labels (i.e. labels selected as 
Reference Safety Information). If in doubt, the investigator should contact the Novartis medical 
monitor before randomizing a participant or allowing a new medication to be started. If the 
participant is already enrolled, contact Novartis to determine if the participant should continue 
participation in the study. The participant should be instructed and encouraged to report any 
new medications/therapies he/she takes at any point in the study. 
Heart failure therapy 
As described in earlier sections of the protocol, all participants will receive the study medication 
on top of the guideline-directed background heart failure therapy in arms 1-4 or as a replacement 
of ACEI/ARB therapy in arm 5. Once the participants enters the study, every effort should be 

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made to avoid dose modifications of all heart failure therapy components, unless absolutely 
necessary to manage AEs. 
If the participant experiences AEs and non-pharmacological interventions were not effective in 
relieving these AEs, the investigator can down-titrate or stop concomitant medications or oral 
study medications to rectify the situation, per his/her clinical judgment and reflecting the nature 
of the AE. 
Before adjustment(s) are made to doses of foundational background HF treatments (i.e., 
ACEI/ARB/ARNI, MRA, beta blocker, and SGLT2 inhibitor), consideration should be given 
to modifications of other medications (e.g., in the case of hypotension, to adjust diuretics, 
calcium channel blockers (CCBs), alpha-blockers or nitrates). 
If adjustment of background heart failure treatments are considered the only possibility to 
manage AEs or tolerability, the investigator should down-titrate or temporarily stop these 
medications (i.e. ACEI/ARB, sacubitril/valsartan, beta-blocker, MRA or SGLT2 inhibitor) or 
sacubitril/valsartan if this is the randomized study medication (i.e., participant randomized to 
arm 5) as per his/her clinical judgment. Background HF treatments should be reinstated at their 
pre-study dose as soon as possible to ensure proper care per the investigator’s judgment. 
Please refer to Section 10.7 pertaining to hypotension and to Section 10.8 pertaining to 
hyperkalemia for instructions on the steps to be taken to address these if they occur. 
6.8.1.1 
Permitted concomitant therapy requiring caution and/or action 
Anti-hypertensive medication 
Anti-hypertensive medication not directly targeting the RAS (including but not limited to 
CCBs, alpha-blockers, centrally acting agents, etc.) should be used with caution during 
screening and randomized treatment periods due to the theoretically increased possibility of 
occurrence of hypotension. 
Phosphodiesterase-5 (PDE-5) inhibitors, oral nitrates and vericiguat 
PDE-5 inhibitors, oral nitrates and vericiguat should be used with caution during screening and 
randomized treatment periods due to the increased possibility of the occurrence of hypotension. 
Intravenous (IV) nitrates, nesiritide and carperitide 
The concomitant administration of XXB750 with IV nitrates, nesiritide, and carperitide has not 
been studied. In the event a study participant requires the concomitant administration of one of 
these IV medications with the study medications, the investigator should consider starting them 
at a low dose or a slow infusion rate while monitoring the participant’s BP carefully. 
6.8.2 
Prohibited medication 
Other than the guideline-directed heart failure treatment mandated in the study, use of the 
treatments described below are not allowed during the randomized treatment period. 
For participants in treatment arm 5, the concomitant use of an ACEI/ARB is strictly prohibited 
while the patient is receiving study medication during the randomized treatment period. If the 

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investigator believes that treatment with an ACEI/ARB is necessary, the open-label 
sacubitril/valsartan study drug must be discontinued. Study medication should be stopped 36 
hours prior to the first dose of an ACEI. Similarly, if study medication (i.e. sacubitril/valsartan) 
is to be restarted, the background treatment with an ACEI should be discontinued 36 hours prior 
to resuming the open-label sacubitril/valsartan study medication. 
6.8.3 
Rescue medicine 
Not applicable. 
7 
Discontinuation of study treatment and participant 
discontinuation/withdrawal 
7.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a participant occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study treatment administration, if 
any) and can be initiated by either the participant or the Investigator. 
The Investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Discontinuation from study treatment is required under the following circumstances : 
• Participant/guardian decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment section 
• Any situation in which continued study participation might result in a safety risk to the 
participant 
• Following emergency unblinding 
If discontinuation from study treatment occurs, the Investigator should make a reasonable effort 
to understand the primary reason for the participant’s discontinuation from study treatment and 
record this information. 
Participants who discontinue from study treatment agree to return for the end of treatment and 
follow-up visits and undergo all study procedures indicated in Section 1.3 Schedule of 
Activities. Thus, discontinuation of study medication does not imply discontinuation from the 
study as a whole, unless the participant withdraws his/her consent for participation. If the 
participant cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the participant, or with a person pre-designated by the participant. This 
telephone contact should preferably be done according to the study visit schedule. 
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• Adverse Events / Serious Adverse Events 

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The Investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
7.2 
Participant discontinuation from the study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be made as detailed in Section 1.3 Schedule of Activities. 
7.3 
Withdrawal of informed consent and exercise of participants’ 
data privacy rights 
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant: 
• Explicitly requests to stop use of their data 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be as per local regulations (e.g. in writing) and recorded in the source 
documentation. 
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g. to respond to data queries) and potentially other country-specific restrictions. It is therefore 
very important to ensure accurate recording of withdrawal vs. discontinuation based on the 
protocol definitions of these terms. 
In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw their 
consent/exercise data privacy rights and record this information. The Investigator shall clearly 
document if the participant has withdrawn his/her consent for the use of data in addition to a 
study discontinuation. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made as detailed in Section 1.3 Schedule of 
Activities. 
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form. 

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7.4 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent (or exercise other participants’ 
data privacy rights), the Investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the participant, e.g. dates of telephone calls, registered letters, 
etc. A participant should not be considered as lost to follow-up until due diligence has been 
completed. 
7.5 
Early study termination by the Sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination (but not limited to) : 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study. 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study treatment development 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued from study treatment. Participants should be invited for EOT 
visit and Investigator should ensure the participant will be appropriately switched to standard 
of care therapy. The Investigator may be informed of additional procedures to be followed in 
order to ensure that adequate consideration is given to the protection of the participant’s 
interests. The Investigator or Novartis depending on local regulation will be responsible for 
informing IRBs/IECs of the early termination of the trial. 
8 
Study Assessments and Procedures 
The Assessment Schedule (Table 1-1) lists all the assessments and when they are performed. 
All data obtained from these assessments must be supported in the participant’s source 
documentation. Adherence to the study design requirements, including those specified in the 
Assessment Schedule, are essential and required for study conduct. 
8.1 
Screening 
Once the participant has signed the informed consent form, the participant may enter the 
screening period. 
The initial screening period can last approximately 7 days. Upon verification of eligibility 
inclusion/exclusion criteria, the participant will be eligible to enter the randomized treatment 
period. Concomitant medication information will be collected to ensure patient's eligibility for 
the trial. No changes in the patient's background anti-RAS treatment should be made after 
screening. 
LVEF measurements required for eligibility will be based on the most recent locally obtained 
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tomographic angiography (CTA), magnetic resonance imaging (MRI), or ventricular 
angiographies performed within the last 6 months provided that no subsequent measurements 
were ≥ 50%. If an LVEF measurement from the last 6 months is not available, the patient may 
enter the trial based on a LVEF < 50% obtained during the screening period, i.e., before 
assigning any study medication. If a patient has an implanted cardiac resynchronization therapy 
device or a myocardial infarction, the LVEF value used to qualify for the study must be obtained 
at least three months after the implantation of that device or the reference myocardial infarction. 
Blood samples obtained for assessing eligibility NT-proBNP must be obtained on the same day 
as the screening ECG. In the case where a safety laboratory assessment at screening is outside 
of the allowed range specified in the eligibility criteria, the assessment may be repeated once 
per the investigator’s discretion to confirm the patient’s eligibility for continuing in the study. 
If the repeat value remains outside of the specified range, the participant must be screen failed. 
Refer to Section 5.3 (Screen failures) for further details. 
8.2 
Participant demographics/other baseline characteristics 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
Participant demographics: full date (only if required and permitted) or year of birth or age, sex, 
race/predominant ethnicity (if permitted) and relevant medical history/current medical 
conditions (until date of signature of informed consent) will be recorded in the eCRF. Where 
possible, the diagnosis and not symptoms should be recorded. Participant race/ethnicity data 
are collected and analyzed to assess the degree of diversity of the study population as required 
by Health Authorities and to identify any differences in the safety and/or efficacy profile of the 
treatment due to these characteristics. 
All prescription medications, over-the-counter drugs and significant non-drug therapies used 
within 30 days before the start of the study must be documented. See the 
protocol Section 6.8 for further details on what information must be recorded on the appropriate 
page of the eCRF. 
8.3 
Efficacy assessments 
Planned time points for all efficacy assessments are provided in the Assessment Schedule 
(Section 1.3). 
8.3.1 
NT-proBNP 
NT-proBNP will be assessed in all participants by using the central laboratory at the screening 
visit to determine eligibility for the trial and at time points outlined in the Schedule of 
Assessments (see Table 1-1). These samples will be obtained before participants take their 
morning study drug dose (if applicable per assignment to treatment arm 5). 
Only the screening NT-proBNP value will be reported to the investigator for the purpose of 
determining eligibility for inclusion in the study. Samples collected for determining NT-
proBNP levels at Randomization and thereafter will be analyzed in batches to ensure uniformity 
of analytical processes and reagents. Post-Screening NT-proBNP values will not be reported to 
investigators to avoid the potential introduction of bias. Moreover, investigators are encouraged 

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to avoid assessing NT-proBNP levels from local laboratories as much as feasible to avoid 
introduction of bias. 
8.3.2 
Secondary efficacy assessments 
Not applicable. 
8.3.3 
Appropriateness of efficacy assessments 
NT-proBNP is considered the best available surrogate marker when evaluating NP system 
modulation in heart failure and thus used to assess efficacy in this study. Reduction in NT-
proBNP levels has been linked to improved risk of long-term HF outcomes. Refer 
to Section 4.2.2 for more details. 
8.4 
Safety assessments 
Safety assessments are specified below with Section 1.3 Schedule of Activities detailing when 
each assessment is to be performed. 
For details on AE collection and reporting, refer to Section 8.6. 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, regular 
phone or virtual calls can occur for safety monitoring and discussion of the participant´s health 
status until it is safe for the participant to visit the site again. 
8.4.1 
Physical examinations 
Physical examinations will be performed by the investigator or his/her designee who are 
qualified to do so per local regulations/standards. Information about all physical examinations 
performed must be included in the source documentation at the study site. Clinically relevant 
findings that are present before signing informed consent must be recorded on the appropriate 
CRF page that captures medical history. Significant findings made after signing informed 
consent which meet the definition of an AE must be recorded as an AE. 
A complete physical examination will include examination of the general appearance, vital 
signs (blood pressure [SBP and DBP] and pulse), skin, neck (including thyroid), eyes, ears, 
nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, the vascular, and the 
neurological systems. If indicated based on medical history and/or symptoms, rectal, external 
genitalia, breast, and pelvic exams will be performed. 
An abbreviated physical examination will include examination of the general appearance and 
vital signs (blood pressure [SBP and DBP] and pulse). 
Refer to Assessment Schedule Table 1-1 for details of the type and frequency of the physical 
examination. 
8.4.2 
Vital signs 
Vital signs include BP and pulse measurements. BP will be measured in the sitting position 
after 5 minutes of rest using an automated validated device (e.g., OMRON) or a standard 

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sphygmomanometer with an appropriately sized cuff on the non-dominant arm. 
Guidelines for the management of hypotension are provided in Section 10.7. 
8.4.3 
Height and weight 
Height in centimeters (cm) will be measured at screening. 
Body weight (to the nearest 0.1 kilogram (kg) in indoor clothing without shoes) will be 
measured at screening, randomization and every visit thereafter. 
8.4.4 
Electrocardiograms 
Single local 12-lead ECGs will be collected at Screening, Week 16 and Week 24 visits. 
ECGs will be locally collected and evaluated. Interpretation of the tracing must be made by a 
qualified physician and documented in source and on the appropriate CRF. Each ECG tracing 
should be labeled with the study number, participant initials (where regulations permit), 
participant number, date and kept in the source documents at the study site. Clinically 
significant abnormalities present at randomization should be documented as medical 
history/current medical conditions on the appropriate CRF. New or worsened clinically 
significant findings occurring after entering the randomized treatment period must be recorded 
as adverse events. 
The original ECGs on non-heat-sensitive paper or a certified copy on non-heat sensitive paper, 
appropriately signed, must be archived at the study site. 
Additionally, unscheduled safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. For any ECGs that raises a safety concern, two 
additional ECGs must be performed to confirm the safety finding. ECG safety monitoring, or a 
review process (as per the investigator's discretion), should be in place for clinically significant 
ECG findings at baseline before administration of study treatment and during the study. 
8.4.5 
Clinical safety laboratory tests 
A central laboratory will be used for analysis of all specimens collected. Details on the 
collection, shipment of samples and reporting of results by the central laboratory are provided 
to investigators in the laboratory manual. Please refer to Table 1-1. 
If participants cannot visit the site for safety lab assessments conducted through central labs 
during a public health emergency as declared by local or regional authorities, i.e., pandemic, 
epidemic or natural disaster, that limits or prevents on-site study visits or as deemed appropriate 
by the investigator in the course of study conduct, an alternative (local) lab collection site may 
be used. 
For China, POCT (e.g. urinalysis, urine pregnancy) is to be analyzed at local laboratories. When 
study-required testing is not available at a local site, a central lab could be used. 
Clinically notable laboratory findings are defined in Section 10.3.1. Clinically significant 
abnormalities must be recorded as either medical history/current medical conditions or adverse 
events as appropriate. 

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Table 8-1 lists the clinical safety laboratory tests performed during the study. The tests with an 
asterisk (*) beside their names are part of the abbreviated panel of clinical safety laboratory 
tests. 
Table 8-1 
Clinical Safety Laboratory Tests 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Mean Corpuscular 
Hemoglobin, Mean Corpuscular HGB Concentration, 
Mean Corpuscular Volume, Platelets, Erythrocytes, 
Leukocytes, Differential (% Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils), Hemoglobin 
A1c 
Chemistry 
Albumin*, Alkaline phosphatase*, ALT*, AST*, 
Gamma-glutamyl-transferase (GGT)*, Lactate 
Dehydrogenase (LDH), Calcium*, Magnesium, 
Phosphate, Chloride, Sodium*, Potassium*, 
Creatinine (enzymatic)*, Creatine Kinase*, Direct 
Bilirubin*, Total Bilirubin, Lipid Panel (Total 
Cholesterol, LDL Cholesterol, High-density lipoprotein 
[HDL] Cholesterol, Triglycerides [random]), Total 
Protein, Blood Urea Nitrogen (BUN)*, eGFR*, Uric 
Acid, Amylase, Lipase, Glucose (random) 
Urinalysis 
Macroscopic (Dipstick) Panel* (Color, Bilirubin, Occult 
Blood, Macroscopic Blood, Glucose, Ketones, 
Leukocyte Esterase, Nitrite, pH, Protein, Specific 
Gravity, Urobilinogen) 
Microscopic Panel** (Erythrocytes, Leukocytes, 
Casts, Crystals, Bacteria, Epithelial cells) 
Coagulation 
Prothrombin Time/INR* 
Pregnancy Test 
Highly sensitive serum or urine human chorionic 
gonadotropin (hCG) pregnancy test (as needed for 
women of childbearing potential) 
Assessments of Fertility 
Follicle-stimulating hormone and estradiol (as needed 
in women of non-child bearing potential only) 
*Test is part of the abbreviated panel of clinical safety laboratory tests 
**Microscopic Panel only to be tested in the event that the Macroscopic (Dipstick) results were positive 
8.4.6 
Pregnancy testing 
All women of childbearing potential will undergo pregnancy testing. Additional pregnancy 
testing might be performed if requested by local requirements. 
Serum pregnancy testing with beta-human chorionic gonadotropin (β-hCG) must be done at 
screening, at Week 16 (EOT) visit and at Week 24 (EOS) visit. Urine pregnancy test should be 
performed at randomization visit (before randomization), at Week 4, Week 8, Week 12, and 
Week 20. A negative Screening serum pregnancy test result (not older than 7 days) and a 
negative Randomization urine pregnancy test result, must be available before the subject is 
randomized. A positive urine pregnancy test must be confirmed with a serum pregnancy test. If 
the latter is also positive, the participant must be discontinued from study treatment. 
As per Section 4.5, during a public health emergency as declared by local or regional 
authorities' i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study 

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visits, if participants cannot visit the site to have serum pregnancy tests, urine pregnancy test 
kits may be used. Relevant participants can perform the urine pregnancy test at home and report 
the result to the site. It is important that participants are instructed to perform the urine 
pregnancy test first and only if the test result is negative proceed with the administration of the 
study treatment. A communication process should be established with the participant so that the 
site is informed and can verify the pregnancy test results (e.g. following country specific 
measures). 
In general, the levels of a mAb like XXB750 in semen are expected to be low; therefore, the 
subsequent levels in female partner would be negligible. Based on this principle, the probability 
that XXB750 would cause teratogenicity is very low. Therefore, no restrictions will be placed 
on male participants with regard to sexual activity or condom use. 
Assessments of fertility 
Assessment of fertility must be performed at screening. A woman is considered of childbearing 
potential from menarche and until becoming post-menopausal unless permanently sterile. 
Permanent sterilization methods include hysterectomy, bilateral tubal ligation, bilateral 
salpingectomy and bilateral oophorectomy. In the case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow-up hormone level assessment 
is she considered to be not of child-bearing potential. Medical documentation of permanent 
method of sterilization must be retained as source documents. 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause and an appropriate clinical profile. 
In absence of the medical documentation confirming permanent sterilization, or if the post-
menopausal status is not clear, the investigator should use his medical judgment to appropriately 
evaluate the fertility state of the woman and document it in the source document. Also, in these 
cases, follicle-stimulating hormone (FSH) testing is required, at screening, for any female 
participant regardless of reported reproductive/menopausal status. 
8.4.7 
Other safety evaluations 
8.4.7.1 
Liver safety monitoring 
To ensure participant 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. 
Please refer to Table 10-1 in Section 10.5.1 for complete definitions of liver laboratory triggers. 
Once a participant is exposed to study treatment, every liver event defined in Table 10-1 should 
be followed up by the investigator or designated personnel at the trial site, as summarized 
below. Additional details on actions required in case of liver events are outlined 
in Table 10-2 and Table 10-3. Repeat liver chemistry tests (i.e., SGOT, SGPT, total bilirubin 
(TBL), PT/INR, alkaline phosphatase (ALP) and GGT) should be done to confirm elevation. 
These liver chemistry repeats will be performed using the central laboratory. If results will not 
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laboratory to monitor the safety of the participant. If a liver event is subsequently reported, any 
local liver chemistry tests previously conducted that are associated with this event should have 
results recorded on the appropriate CRF. 
If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
If a liver AE is reported that corresponds to these liver events, an assessment of the causal role 
of each study medication in the origin of the liver AE must be provided. 
The following actions should be considered: 
• Discontinuation of the investigational drug (refer to the discontinuation of study 
treatment, Section 7.1), if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include, as per the Investigator's discretion: 
obtaining more details on the history of the liver event (including its symptoms), as well 
as on prior and concurrent diseases, concomitant drug use, serology tests, imaging and 
pathology assessments, hepatologist's consultancy, ruling out any underlying liver disease. 
In addition, the follow-up actions described in Section 6.5.2.1 should be performed. All follow-
up information and findings from consultations and procedures must be recorded as appropriate 
in the CRFs. 
8.4.7.2 
Renal safety monitoring 
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events 
should be monitored and followed up by the investigator or designated trial staff as summarized 
in Section 10.6.1. 
8.4.7.3 
Immunogenicity 
Immunogenicity testing will be performed on each participant. The results will be analyzed to 
determine, among others, any impact of anti-drug antibodies (ADA) on the efficacy of XXB750 
and on the occurrence of adverse events. Refer to Section 8.9 for more details on 
immunogenicity testing. 
8.4.8 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/participant population. PK 
sampling and immunogenicity assessments performed periodically during the study will allow 
to determine relationships between drug blood concentrations, existence of ADA (neutralizing 
or not) and the occurrence of certain adverse events. 
8.5 
Additional assessments 
8.5.1 
Clinical Outcome Assessments (COAs) 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, COA data 

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may be collected remotely (e.g. web portal, telephone interviews) depending on local 
regulations, technical capabilities, and following any applicable training in the required process. 
Patient reported outcomes (PRO) 
The participant should be made aware that completed measure(s) are not reviewed by the 
investigator/study personnel. 
The KCCQ is a self-administered questionnaire and requires, on average, 4-6 minutes to 
complete. It contains 23 items, covering physical function, clinical symptoms, social function, 
self-efficacy and knowledge, and Quality of Life (QoL), each with different Likert scaling 
wording, including limitations, frequency, bother, change in condition, understanding, levels of 
enjoyment and satisfaction. A change of 5 points on the scale scores, either as a group mean 
difference or an intra-individual change appears to be clinically significant, based on 
comparisons of changes in the scale scores to clinical indicators and patient global reports of 
change. The KCCQ is a valid, reliable and responsive health status measure for patients with 
CHF and may serve as a clinically meaningful outcome in CV clinical research, patient 
management and quality assessment (Green et al 2000). 
The HF symptoms and physical limitation domains scores show the best correlation for 
improvements following a CHF exacerbation (Green et al 2000). Thus, the clinical summary 
score based on the HF symptoms and physical limitation domains scores of the KCCQ will be 
one exploratory endpoint next to the overall summary score when the instruments will be 
evaluated as a whole. 
The KCCQ questionnaire will be completed at randomization and Week 16 visits, before any 
other study procedures and regardless of discontinuation of study treatment. 
The KCCQ is available in a number of validated translations. However, participants in whose 
language a validated translation of the KCCQ is not available will be exempt from completing 
this instrument. 
8.5.2 
Other assessments 
8.5.2.1 
Estimated glomerular filtration rate (eGFR) 
The eGFR to determine eligibility of the patient for screening into the trial will be calculated at 
screening from the serum creatinine concentration which will be measured centrally. The eGFR 
will be further measured as part of the abbreviated safety laboratory samples at each visit to 
guide the investigator to take any appropriate action as necessary (e.g., stopping study 
treatment) in case of eGFR decrease. 
Estimated GFR will only be calculated using the following version of the CKD-EPI formula 
(Inker et al 2021): 
eGFRcr = 142 x min(Scr/κ, 1)α x max(Scr/κ, 1)-1.200 x 0.9938Age x 1.012 [if female] 
where κ = 0.7 (female) or 0.9 (male) and α = -0.241 (female) or -0.302 (male) 
 

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8.5.2.2 
Urinary cGMP to creatinine ratio 
Urinary cGMP as a measure of XXB750's engagement with its target NPR1 will be assessed in 
spot urine samples at visits as outlined in Table 1-1. To allow indexing of urinary biomarkers, 
creatinine in spot urine will also be measured. Samples will be obtained before taking the 
morning study medication (as applicable per patient's treatment assignment). 
8.5.2.3 
Urine albumin to creatinine ratio (UACR) 
Spot urine samples will be collected before taking the morning study drug dose (as applicable 
per assigned study medication) at the visits indicated in Table 1-1 for analysis of urinary 
albumin and creatinine (measured as UACR). 
8.6 
Adverse events (AEs), serious adverse events (SAEs), and other 
safety reporting 
The definitions of adverse events (AEs) and serious adverse events (SAEs) can be found 
in Section 8.6. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs (see Section 7). 
For the investigational product, information about adverse drug reactions and how to manage 
them can be found in the Investigator's Brochure (IB) or equivalent documentation. Information 
about adverse drug reactions can also be found in the product information for marketed 
products. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 8.6.3. 
8.6.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any occurrence of unfavorable 
and unintended sign(s), symptom(s) or medical condition, including abnormal laboratory 
findings, or worsening of any pre-existing sign(s), symptom(s) or medical condition) in a 
participant after providing written informed consent for participation in the study. Therefore, 
an AE may or may not be temporally or causally associated with the use of any treatment used 
in this study. This includes events reported by the participant (or, when appropriate, by a 
caregiver, surrogate, or the participant’s legally authorized representative).  
Abnormal laboratory values or test results constitute AEs 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 

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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 considered to be non-typical in participant with the 
underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Section 10.3.1. 
The Investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial-related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments, excluding Patient-Reported Outcomes (which are related to 
the underlying heart failure). 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer 
to Section 8.6.2): 
1. The severity grade. 
• Mild: A type of AE that is usually transient and may require only minimal treatment 
or therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
• Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
• Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention 
2. Causality 
• The investigator is obligated to assess the relationship between any treatment used in 
the study (study treatment, AxMP(s)) and each occurrence of each AE. The 
investigator will use clinical judgment to determine the relationship. A reasonable 
possibility of a relationship conveys that there are facts, evidence, and/or arguments 
to suggest a causal relationship, rather than a relationship cannot be ruled out. 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration, will be considered and investigated. For causality assessment, the 
investigator will also consult the IB and/or product information, for marketed 
products. The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 
3. Its duration (start and end dates or ongoing) and the outcome must be reported. 
4. Whether it constitutes a SAE (see Section 8.6.2 for definition of SAE) and which 
seriousness criteria have been met. 

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5. Action taken regarding with study treatment. All adverse events must be treated 
appropriately. Treatment may include one or more of the following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/permanently discontinued 
6. Its outcome 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued at least until Visit Week 24 (EOS) or until 3 
months after the last dose of injectable study medication, whichever is longer. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be not recovered/not resolved (e.g. continuing at the end of the study), and assessment must be 
made at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
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 participant 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Section 10.3. 
Reporting of AEs related to AxMP(s) 
All AEs related to any authorized AxMP used in this study must be reported to Novartis. 
In assessing causality, the investigators will use the points above. 
If a suspicion that a medical occurrence could be related to study treatment (and/or interaction 
with study treatment) cannot be ruled out, the reporting rules for study treatment apply. 
Handling of AEs 
All adverse events must be treated appropriately. More information about how to manage AEs 
can be found in the IB. Information about adverse drug reactions can also be found in product 
information for marketed products. 

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Once an AE is detected, the Investigator must pro-actively followed up the participant, until 
resolution of the AE, or until it is judged to be not recovered/not resolved (e.g., continuing at 
the end of the study), or until stabilization, or until the participant is lost to follow-up. Any 
change in severity or suspected relationship to study treatment must be assessed at each visit 
(or more frequently, if necessary). 
8.6.2 
Serious adverse events 
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: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the participant 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 the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect, fetal death or a congenital abnormality or 
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 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• 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 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
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 participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” 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 the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 

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All reports of intentional misuse and abuse of the product are also considered serious adverse 
events irrespective of whether a clinical event has occurred. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
8.6.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until End of Study visit must be reported to Novartis safety 
immediately, without undue delay, but under no circumstances later than within 24 hours of 
obtaining knowledge of the events (Note: If more stringent, local regulations regarding 
reporting timelines prevail). Detailed instructions regarding the submission process and 
requirements are to be found in the Investigator folder provided to each site. Information about 
all SAEs is collected and recorded on the electronic Serious Adverse Event Report Form with 
paper backup (as further detailed in the CRF Completion Guideline). All applicable sections of 
the form must be completed in order to provide a clinically thorough report. 
SAE occurring between the time the participant has provided informed consent until either EOS 
visit or until 3 months after the last dose of injectable study medication (whichever is longer) 
must be reported to Novartis. Any SAE experienced by participants who discontinue study 
treatment prematurely but remain in the study for follow-up, should continue to be reported 
until either EOS visit or until 3 months after the last dose of injectable study medication 
(whichever is longer). 
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 
immediately, without undue delay, but under no circumstances later than within 24 hours of the 
Investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). 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. 
Any SAEs experienced after the EOS visit or 3 months after the last dose of injectable study 
medication (whichever is longer) should only be reported to Novartis Safety if the Investigator 
suspects a causal relationship to study treatment, unless otherwise specified by local 
law/regulations. 
The investigator must review and provide an assessment of causality for each SAE. There may 
be situations in which an SAE has occurred, and the investigator has minimal information to 
include in the initial report to Novartis. However, it is very important that the investigator 
always makes an assessment of causality for every event before the initial transmission of the 
SAE data to Novartis. The investigator may change his/her opinion of causality in light of 
follow-up information and send an SAE follow-up report with the updated causality assessment. 
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) 
If a SAE is not previously documented in the IB or product information for marketed products 
and is thought to be related to any study treatment, Novartis may urgently require further 
information from the investigator for HA reporting. Novartis may need to issue an Investigator 

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Notification (IN) to inform all investigators involved in any study with the same study 
treatment. SUSARs will be reported to the competent authorities and relevant ethics committees 
in accordance with national regulatory requirements in participating countries, including EU 
Clinical Trial Regulation 536/2014. 
Study-specific unblinding rules for suspected unexpected serious adverse 
reactions (SUSARs) that are disease-related 
In clinical trials evaluating treatments for high morbidity and/or high mortality disease states, 
SAEs that are known consequences of the underlying disease or condition under investigation, 
or events common in the study population, are anticipated to occur with some frequency during 
the course of the trial, regardless of drug exposure. While the investigator must still report all 
SAEs according to the instructions provided in Section 8.6.2 and Section 8.6.3, SUSARs 
containing terms that are considered consistent with the MedDRA Preferred Terms listed 
in Table 8-2 will not be unblinded and will not be reported in an expedited timeframe to 
regulatory agencies, ethic committees or investigators during the course of the study 
(FDA 2021). Investigator notifications will not be issued for these reports. An external 
independent DMC will review data of the ongoing trial on a regular basis (Section 10.1.4.1). 
The opinion and the recommendations of the DMC will be notified by Novartis as soon as 
possible to the competent authorities and the EC's where they qualify for expedited reporting. 
If specifically requested by a local Health Authority (HA), SUSARs reporting the terms 
in Table 8-2 will be expedited to this Health Authority as blinded reports and Investigator 
notifications will not be issued for these events. Alternatively, if specifically requested by a 
local HA, SUSARs reporting the terms in Table 8-2 that occur in participants under the 
jurisdiction of the requesting HA will be expedited to that HA as unblinded reports and 
investigator notifications will be issued for these events to investigators under the jurisdiction 
of this HA. These events will be presented in the clinical study report at the end of the study. 
Any other SUSAR not reporting any term included in Table 8-2 will be unblinded and reported 
to the competent authorities and relevant ECs. In these cases, IN will be issued when applicable. 
Table 8-2 
MedDRA PT related to the underlying heart failure 
Cardiac output 
decreased 
Pulmonary arterial 
wedge pressure 
increased 
Cardiogenic 
shock 
Ventricular failure 
Pulmonary 
oedema 
Left ventricular end-
diastolic pressure 
decreased 
Pulmonary arterial 
wedge pressure 
abnormal 
Cardiac failure high 
output 
Low cardiac output 
syndrome 
Left ventricular 
failure 
Ejection fraction 
abnormal 
Cardiac failure 
Cardiac failure 
congestive 
Cardio-respiratory 
distress 
Acute left 
ventricular failure 
Ejection fraction 
decreased 
Cardiac failure 
acute 
Cardiac failure 
chronic 
Acute pulmonary 
oedema 
 
Reporting of SAEs related to AxMP(s) 
All SAEs related to any AxMP (whether authorized or not) used in this study must be reported 
to Novartis within 24 hours of the site becoming aware of it. In assessing causality, the 
investigators will use the points above. If a suspicion that the medical occurrence could be 

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related to study treatment (or and interaction with study treatment) cannot be ruled out, the 
reporting rules for study treatment apply. 
8.6.4 
Pregnancy 
• Details of all pregnancies in female participants will be collected after the start of study 
treatment and until 3 months after the last dose of injectable study medication . 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE or 
SAE. 
• Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs and will be reported as 
such. 
• Any post study pregnancy-related SAE considered reasonably related to the study 
treatment by the Investigator will be reported to Novartis as described in Section 8.6.3. 
While the Investigator is not obligated to actively seek this information in former study 
participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study treatment. This participant may stay in the study and follow the 
assessments, if she wishes to do so. All assessments that are considered as a risk during 
pregnancy must not be performed. The participant may continue all other protocol 
assessments. 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the Investigator to collect and report information regarding the pregnancy. 
To ensure participant 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 should be recorded and reported by the Investigator to the Novartis PS&PV 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment of any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. Post-natal follow-up should occur at 1, 3 and 12 months after delivery. 
8.6.5 
Disease-related events and/or disease-related outcomes not qualifying 
as AEs or SAEs 
No disease-related events not qualifying as AEs or SAEs are specified in this study. 

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8.6.6 
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events which are of scientific and 
medical interest specific to Novartis’s product or program, for which ongoing monitoring may 
be appropriate. Such events may require further investigation in order to characterize and 
understand them. AESI are defined on the basis of potential safety risks for the product, class 
effects, and data from preclinical studies. The following are currently defined as AESI for 
XXB750 in this study: serious hypotension (i.e., meeting any of the seriousness criteria listed 
in Section 8.6.2), serious hypersensitivity reactions (including, but not limited to, allergic 
reactions, anaphylaxis or anaphylactoid reactions, cytokine release syndrome, serum sickness 
or serum sickness-like reactions), serious injection site reactions, severe tachycardia, severe 
acute bradycardia and serious presyncope/syncope. 
8.7 
Pharmacokinetics 
A population pharmacokinetics (PK) sub-study will be conducted in approximately 200 
participants who are randomized to either XXB750 or matching placebo. Pharmacokinetics 
samples will be collected in these participants at the visits defined in the assessment schedule 
at randomization (2-4 hours post dose), Week 4 (prior to AND 2-4 hours post dose), Week 12 
(prior to AND 2-4 hours post dose), Week 16 and Week 24. Follow instructions outlined in the 
laboratory manual regarding sample collection, numbering, processing and shipment. In order 
to better define the PK profile, the timing of the PK sample collection may be altered based on 
emergent data. The number of samples/blood draws and total blood volume collected will not 
exceed those stated in the protocol. 
Pharmacokinetic samples will be obtained in all eligible participants enrolled at sites 
participating in this sub-study, but evaluated only in participants treated with XXB750. 
XXB750 concentration will be determined by a validated method; the anticipated Lower Limit 
of Quantification (LLOQ) is 50 ng/mL. Concentrations will be expressed in mass per volume 
units. Concentrations below the LLOQ will be reported as “zero” and missing data will be 
labeled as such in the Bioanalytical Data Report. The individual data will be listed. Population 
PK analysis of XXB750 will be conducted and the results of this analysis will be reported 
separately. 
8.8 
Biomarkers 
As described in the Assessment Schedule (Table 1-1), blood and urine will be collected for 
biomarker assessments from all participants (where feasible). The sample collection 
information, including the exact time and date of collection, must be entered on the appropriate 
sample collection eCRF page(s). 
Biomarkers related to heart failure and/or XXB750 mechanism of action or treatment effect will 
be analyzed. In addition to NT-proBNP, plasma and urine cGMP, BNP and hs-Troponin will 
be analyzed. Biomarkers related to the renin-angiotensin-aldosterone system may also be tested 
using biobanked samples. ANP will be tested at baseline to determine if ANP levels at the start 
of XXB750 treatment modify its NT-proBNP effect. Urine creatinine will be analyzed to allow 
indexing of urine cGMP and other urine biomarkers. Proteins (via SomaScan profiling) or 

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metabolites that may be associated with heart failure development or progression, study drug 
treatment response or predict response to treatment will also be analyzed. 
Due to both posture and time of collection affecting levels of several of the planned biomarkers, 
the laboratory manual will include instructions for: 1) participants to be calm and seated for 15 
minutes prior to blood biomarker sampling and 2) urine and blood biomarker samples be 
collected in the morning with no greater than a 1-hour difference between collection times at 
the post-randomization visits compared to the time at the randomization visit. For a detailed 
description regarding sample collection, numbering, processing, and shipment, please refer to 
the instructions provided in the laboratory manual. 
Biobank samples (where permitted) will be collected to allow the list of biomarkers to 
change during the study due to new assay availability, technical issues or as more relevant 
biomarkers/proteins are determined during conduct of the XXB750 program or clinical research 
in heart failure. Thus, additional biomarkers related to XXB750 or heart failure, may be tested 
during the study or after study completion. Additional biomarkers may include those related to 
fibrosis such as soluble ST2 or collagen synthesis or degradation biomarkers. Except for NT-
proBNP levels at screening, biomarker results will remain blinded and will not be available to 
investigators or the Novartis study team during the study. The Novartis biomarker bioanalyst, 
who is not involved in study management, will have access to unblinded biomarker data to 
assess for the need of re-analyzing samples due to suspected technical issue. The Novartis 
biomarker bioanalyst will remain blinded to the patient level and group level treatment 
assignments during the entire study. 
While the goal of the biomarker assessments is to provide supportive data for the clinical study, 
there may be circumstances when a decision is made to stop a collection, or to not perform or 
discontinue an analysis due to either practical or strategic reasons (e.g., inadequate sample 
number, issues related to the quality of the sample or issues related to the assay that preclude 
analysis, impossibility to perform correlative analyses, etc.). Therefore, depending on the 
results obtained during the study, sample analysis for specific biomarkers or specific 
participants may be omitted at the discretion of Novartis. 
Exploratory DNA sampling 
The study includes an optional genetic research component which requires a separate informed 
consent signature if the participant agrees to participate. As permitted by local governing 
regulations and by IRB/EC, it is required as part of this protocol that the investigator presents 
these options to the participant. 
The optional DNA sample is to be collected at randomization or later, as described in 
Assessment Schedule (Table 1-1). Instructions for sample collection and shipment will be 
provided in the laboratory manual. The sample will be sent to the Central Lab for DNA 
extraction and stored by the Central Lab or Novartis until genetic analyses are performed during 
the study or after the study end. 
The purpose of genetic research may be to better understand the safety and efficacy of XXB750, 
to learn more about human diseases, or to help develop ways to detect, monitor and treat 
diseases. As technology changes over time, the most appropriate technology will be used at the 

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time the exploratory genetic research is performed. This may include the study of the entire 
genome. 
The use of DNA to search for biomarkers of disease and drug action is exploratory. Any results 
from this DNA study will not be placed in the participant’s medical records. To maximize 
confidentiality, all samples will be double-coded to prevent the exposure of the participant’s 
information and identity. This double-coding process allows Novartis to go back and destroy 
the sample at the participant’s request. In addition, sample information is stored in one secured 
database while genetic data is stored in an independent secured database. 
8.9 
Immunogenicity assessments 
Anti-drug antibody (ADA) samples will be obtained in participants randomized to injectable 
study medication (i.e. treatment arms 1-4) according to Section 1.3 Schedule of Activities. A 
validated ligand binding assay (i.e. ELISA, MSD, etc.) will be used for the detection of potential 
anti-XXB750 antibodies. Confirmed immunogenicity positive samples may be further analyzed 
for presence of neutralizing antibodies using a validated method. 
In case of a suspected allergic hypersensitivity reaction, samples to measure ADA and a panel 
of immunoglobulins (IGs), as well as samples to measure tryptase (if sampling occurs within 4 
hours following a suspected hypersensitivity reaction), are also to be collected. 
If the hypersensitivity reaction is observed at the site following study drug administration, 
samples for ADA, the IG panel, and tryptase, should be collected as soon as possible after the 
reaction (and no longer than 4 hours after the reaction commenced). In the event the reaction 
occurs off-site, the ADA and IG panel samples should be collected at the time of the next site 
visit. Additionally, the ADA and IG panel samples should also be collected at the final visit 
from participants who discontinued study treatment or were withdrawn from the study. IG panel 
testing 
is 
planned 
for 
drug-specific 
IgE 
and 
other 
immunoglobulins 
(e.g. 
IgA/IgG1/IgG2/IgG3/IgG4/IgM). Depending on the results of the IG panel, antibody epitope 
mapping, immunogenicity profiling, and serological profiling may also be performed using 
backup IG panel and backup pre-dose PK samples. 
Follow instructions outlined in the Laboratory Manual regarding sample collection, numbering, 
processing, and shipment. 
The detailed methods for immunogenicity assessment will be described in the Bioanalytical 
Data Report. 
8.10 
Medical resource utilization and health economics 
Medical resource utilization and health economics parameters are not evaluated in this study. 
9 
Statistical considerations 
9.1 
Analysis sets 
The following analysis sets will be defined for statistical analysis: 

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Screened Set (SCR) - All participants who signed the informed consent form. The SCR includes 
only unique screened participants, i.e., in the re-screened participants only the chronologically 
last screening data is counted. 
Randomized Analysis Set (RAS) - All randomized participants who received a randomization 
number, regardless of receiving trial medication. 
Full Analysis Set (FAS) - All participants to whom study treatment has been assigned by 
randomization and who are not mis-randomized. Mis-randomized participants are those who 
have not been qualified for randomization, have been inadvertently randomized into the study 
and did not receive any double-blind study medication. According to the intent to treat principle, 
participants will be analyzed according to the treatment they have been assigned to during the 
randomization procedure. 
Safety Set (SAF) - All randomized participants who received at least one dose of study 
treatment. Participants will be analyzed according to the study treatment received, where 
treatment received is defined as the randomized/assigned treatment if the participant took at 
least one dose of that treatment or the first treatment received if the randomized/assigned 
treatment was never received. 
PK Analysis Set (PKS) - All randomized participants with at least one available valid (i.e., not 
flagged for exclusion) PK concentration measurement, who received any study XXB750 
treatment. 
Immunogenicity Prevalence Set (IPS) - All participants in the safety set with a non-missing 
baseline ADA sample or at least one non-missing post-baseline ADA sample. 
Immunogenicity Incidence Set (IIS) - All participants in the safety set with a non-missing 
baseline ADA sample and at least one non-missing post-baseline ADA sample. 
9.2 
Statistical analyses 
9.2.1 
General considerations 
Data analyses are described in Section 9 of the study protocol with more details available in 
statistical analysis plan (SAP). 
Unless specified otherwise, baseline is defined as the measurement obtained at the 
randomization visit, or the measurement obtained at an earlier visit (scheduled or unscheduled) 
which was closest to the randomization visit, if the randomization visit measurement is missing. 
All efficacy analyses will be based on FAS and all safety analyses will be based on SAF unless 
specified otherwise. In descriptive summaries, continuous variables will be summarized using 
n, mean, standard deviation (SD), median, minimum, 25th percentile (Q1), 75th percentile (Q3), 
and maximum; categorical variables will be summarized using frequency and percentage. 
9.2.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease history and standard background 
medications will be summarized descriptively by treatment group. 

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Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group. 
9.2.3 
Treatments 
The duration of exposure in day(s) to XXB750/matching placebo and sacubitril/valsartan as 
well as the dose intensity (computed as the ratio of actual cumulative dose received and actual 
duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity 
and planned dose intensity) will be summarized by means of descriptive statistics and treatment 
group using the safety set. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized, by treatment group. 
9.3 
Primary endpoint(s)/estimand(s) analysis 
Primary estimands are described in Section 3.1. The primary endpoint and statistical analysis 
will be described in this Section. 
9.3.1 
Definition of primary endpoint(s) 
The primary efficacy variable is change in log NT-proBNP from baseline to Week 16, which is 
equivalent to the log of ratio of Week 16 NT-proBNP over baseline NT-proBNP. 
Missing values at Week 16 will be imputed as described in Section 9.3.3 and Section 9.3.4. 
9.3.2 
Statistical model, hypothesis, and method of analysis 
The primary objective of determination of a dose-response signal and to characterize the dose-
response relationship in XXB750 doses compared to placebo will be evaluated using an 
optimally weighted contrast test following the Multiple Comparison Procedure-Modeling 
(MCP-MOD) methodology described in Pinheiro et al 2006 and Pinheiro et al 2014. 
A candidate model set is defined corresponding to the range of the expected mean response in 
each of the dose groups. The candidate model set is used to generate a set of weights for the 
calculation of optimal contrasts between the responses in the studied dose groups and the 
placebo group. A statistical test comparing all doses in the different dose groups simultaneously 
to the placebo is used, hence a multiplicity adjustment is applied that accounts for the multiple 
possible dose response behavior considered as well as the common placebo between dose 
groups. A critical value is derived from a multivariate t-distribution using the correlation matrix 
induced by the correlations between the weights corresponding to the candidate sets as well as 
the correlation between the tests of shapes in the dosing groups to the placebo group. 
Test of the dose response signal 
The null hypothesis of a flat dose-response relationship for the change from baseline in 
logarithm NT-proBNP compared to placebo will be tested at a 1-sided significance level of 
2.5% against the alternative hypothesis of a dose-response relationship leading to a significant 
reduction in the NT-proBNP. 
Hence, the following null and alternative hypotheses will be tested: 

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• H10: there is no dose-response relationship for XXB750 (i.e. the dose response 
relationship is flat). 
• H11: there is a dose-response relationship for XXB750 (i.e. there is more reduction in NT-
proBNP in XXB750 doses based on the assumed candidate models). 
There are five candidate models to capture the shape of the dose-response relationship for 
XXB750 at the Week 16 endpoint, as depicted in Figure 9-1. The candidate models generating 
the contrast weights are described below: 
• Model 1: Emax with ED50 at 15 mg dose level 
• Model 2: Emax with ED50 at 120 mg dose level 
• Model 3: Sigmoid Emax with ED50 at 60 mg dose level and hill parameter h=3 
• Model 4: Sigmoid Emax with ED50 at 120 mg dose level and hill parameter h=3 
• Model 5: Beta-model with delta1=0.2, delta2=0.3 and scale=288 
Figure 9-1 
Dose-response curve of candidate models 
 
The analysis to derive the test statistics is based on an analysis of covariance (ANCOVA) model 
with the change from baseline logarithm of NT-proBNP to Week 16 as response variable, 
treatment (placebo and XXB750 dose groups), LVEF (≤ 40%, > 40%), background medication 
stratification factor (ACEI/ARB, sacubitril/valsartan), and region stratification factor as factors, 
and baseline logarithm of NT-proBNP as a covariate. 
The response variable of the change in logarithm NT-proBNP from baseline at Week 16 used 
in the above ANCOVA model is from an imputed dataset, where a missing Week 16 NT-
proBNP is imputed using the multiple imputation method as described in Section 9.3.3 
and Section 9.3.4. In order to account for the imputation uncertainty, this ANCOVA model will 
be repeated for each imputed dataset, which results in a set of least squares (LS) mean estimate 
for all treatment groups and the related covariance matrices. Rubin's rule will be used to 
combine the multiple sets of LS mean estimates and the related covariance matrices to a single 

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set of LS mean estimates of change of NT-proBNP at Week 16 for all treatment groups and the 
related covariance matrix. 
The optimal contrasts derived from the candidate model sets will be applied to the combined 
estimated dose means and covariance matrix to obtain t-statistics for each candidate model and 
the common critical value C0.025. C0.025 is the common critical value derived from the reference 
multivariate t-distribution with the 5x5 correlation matrix induced by test the candidate dose 
response models with respect to comparing all XXB750 dose groups to placebo. 
The H10 will be rejected and the statistical significance of dose-response in NT-proBNP 
reduction is established if the max (t1, t2,..., t5) ≥ C0.025. 
Model averaging to obtain the dose response 
The response data in each imputed dataset, including relevant covariates, will be used to fit the 
models in the candidate set. The estimated dose-response will be derived by using model 
averaging methods on a subset of candidate models, for which the associated contrast tests are 
statistically significant. If there are more than three candidate models that are statistically 
significant, the top three models with largest t-statistics as calculated above will be selected as 
basis for the model averaging. 
Model averaging will be carried out for each imputed dataset, and the resulting mean efficacy 
estimates and confidence intervals will be derived using the combination variance that accounts 
for the uncertainty of the imputed data using Rubin's rules. Comparisons between XXB750 
doses and placebo will be simultaneously derived for the model averaged estimates together 
with confidence intervals reflecting the imputation procedure applied. 
Selection of the optimal dose will be based on the model averaged dose response estimates of 
NT-proBNP reduction of XXB750 over the dose range studied. 
Summaries of absolute values and change from baseline in NT-proBNP by treatment group and 
visit will be presented using statistics as described in Section 9.2.1 additionally with geometric 
mean and coefficient of variation. Figures will be produced to visually show the mean NT-
proBNP level by visit over study period (randomized treatment period and safety follow-up 
period) for each treatment group. 
The FAS will be used for the above analyses. 
9.3.3 
Handling of intercurrent events of primary estimand (if applicable) 
Intercurrent events for the primary endpoint are defined in Section 3.1 and the strategy for 
handling of intercurrent events in the primary analysis is described below: 
1. Discontinuation of study treatment: NT-proBNP data collected after discontinuation of 
study treatment will be used in the analysis (treatment policy strategy). 
2. Unforeseen change in the dose of allowed concomitant medications: NT-proBNP data 
collected after unforeseen change in the dose of allowed concomitant medication will be 
used in the analysis (treatment policy strategy). 
3. Receiving prohibited concomitant medication: NT-proBNP data collected after receiving 
prohibited concomitant medication will be used in the analysis (treatment policy strategy). 

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If a missing primary endpoint occurs after intercurrent event(s), it will be imputed based on 
participants with observed endpoint after same type of intercurrent event(s) in the respective 
treatment group. If there is no or very limited participants with observed endpoint after 
intercurrent event(s) in the respective treatment group, then the missing primary endpoint will 
be imputed based on the respective treatment group combined with lower dose group(s). if there 
are still very limited participants with observed endpoint after intercurrent event(s), then 
missing will be imputed based on those with observed endpoint in the placebo group. 
9.3.4 
Handling of missing values not related to intercurrent event 
Missing data for the primary endpoint will be imputed using a multiple imputation approach 
assuming that missingness mechanism can be retrieved from observed data (missing at random 
(MAR)). The imputation model will include the longitudinal sequence of NT-proBNP data 
collected at randomization, Week 4, Week 8, Week 12, and Week 16 visits, LVEF factor 
(≤ 40%, > 40%), background medication stratification factor (ACEI/ARB, sacubitril/valsartan), 
region stratification factor, and other baseline variables as appropriate, imputing for each 
treatment group separately. 
The full detailed information about the multiple imputation algorithms will be specified in a 
separate statistical analysis plan. 
9.3.5 
Multiplicity adjustment (if applicable) 
Please refer to Section 9.3.2 for primary analysis of MCP-MOD for multiplicity adjustment 
with respect to testing for a dose response signal across multiple candidate shapes. The 
secondary hypotheses included in the order of the hierarchical testing procedure are an 
evaluation and demonstration of: (1) treatment effect of highest XXB750 target dose level 
versus placebo; (2) combined two highest XXB750 target dose levels versus conversion to 
sacubitril/valsartan in participants receiving ACEI/ARB background medication. The 
secondary hypotheses will be tested in the order described above and statistical inference will 
be made only if the primary hypothesis is rejected. 
9.3.6 
Sensitivity analyses 
The primary analysis for which missing data imputation is based on missing at random or 
retrieve dropouts would favor the XXB750 treatment groups when early treatment/study 
discontinuation is due to XXB750 related adverse events or if the participant dies. Placebo 
multiple imputation method will be performed, when participants randomized to XXB750 
treatment groups are assumed to be similar to placebo treated participants after above mentioned 
events. 
9.3.7 
Supplementary analysis 
Supportive analyses for the primary analysis results are listed below: 
1. Results based on the single best dose response model fit will also be reported. 
2. The mixed model for repeated measure (MMRM) analysis of covariance (ANCOVA) with 
treatment, LVEF (≤40%, >40%), background medication stratification factor (ACEI/ARB, 
sacubitril/valsartan), and region stratification factor, visit (Week 4, Week 8, Week 12, or 
Week 16), and treatment-by-visit as factors, and baseline logarithm NT-proBNP as a 

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covariate, with a common unstructured covariance matrix among visits will be used. 
Treatment comparisons at Week 16 will be provided. The analysis will be based on all 
available data up to Week 16 in the FAS and based on likelihood method with an 
assumption of missing at random for missing data. 
3. In addition to treatment policy strategy to handle the intercurrent events in the primary 
analysis, a supplemental analysis based on a hypothetical strategy will be also used to 
handle the intercurrent events. This strategy assumes that premature discontinuations of 
study treatment, change in the dose of allowed concomitant medication, receiving 
prohibited concomitant medication or lost to follow-up/discontinue study would not have 
occurred in the participants. This analysis uses partial data available up to the occurrence 
of the intercurrent events, and missing data after the intercurrent events will be imputed as 
based on the pattern of other participants who do not have intercurrent events (missing at 
random). The imputation steps are same as described in Section 9.3.4 and the newly 
imputed data will be used in the analysis as described in Section 9.3.2. 
4. Analysis based on the while on-treatment strategy to handle the intercurrent of premature 
discontinuations of study treatment will be performed. This analysis uses the data taken at 
the end of treatment visit as the Week 16 assessment and repeat the analysis described 
in Section 9.3.2. 
5. Treatment grouping is based on highest dose received and repeat the analysis described 
in Section 9.3.2. 
6. Subgroup analyses will be performed for the primary analysis. The analysis will be done 
using the analysis specified in Section 9.3.2 at individual subgroup level separately. Please 
see Section 9.7 for subgroup details. 
Summary statistics for NT-proBNP and change from baseline will be summarized by treatment 
group for observed and imputed values. Figures will be produced to visually show the observed 
and the imputed mean changes by visit over 16 weeks randomized treatment epoch for each 
treatment group. FAS will be used for the analyses. 
9.4 
Secondary endpoint(s)/estimand(s) analysis 
The secondary efficacy endpoints are described in Section 9.4.1 and are part of the hierarchical 
testing strategy. Analyses related to safety endpoints are described in Section 9.4.2. 
9.4.1 
Efficacy and/or pharmacodynamic endpoint(s) 
There are two efficacy secondary objectives: 
1. To evaluate the treatment effect of the highest XXB750 target dose level compared to 
placebo in reducing NT-proBNP from baseline at Week 16 in HF patients treated with 
standard of care, including ACEI/ARB or sacubitril/valsartan. 
2. To evaluate the treatment effect of combined two highest XXB750 target dose levels in 
addition to a background of ACEI/ARB versus conversion from ACEI/ARB to 
sacubitril/valsartan, in reducing NT-proBNP from baseline to Week 16. 
The efficacy variable in secondary objective 1 is the change from baseline at Week 16 in 
logarithm of NT-proBNP and will be analyzed using a repeated measures ANCOVA model 
with treatment (highest XXB750 target dose level or placebo), LVEF (≤40%, >40%), 

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background medication stratification (ACEI/ARB, sacubitril/valsartan), and region 
stratification factor, visit (Week 4, Week 8, Week 12, or Week 16), and treatment-by-visit as 
factors, and baseline logarithm of NT-proBNP as a covariate, with a common unstructured 
covariance matrix among visits. Within treatment estimates and between treatment comparisons 
at Week 16 will be provided. Please refer to Section 3.2 and Section 9.3.3 for the intercurrent 
events and its handling strategy and Section 9.3.4 for handling missing data not related to 
intercurrent event. The analysis will be run on each of the imputed datasets as described 
in Section 9.3.2. Overall results are obtained by applying Rubin's rules on the estimates 
obtained from imputed datasets. 
The efficacy variable in secondary objective 2 and analysis model is the same as those 
described above in secondary objective 1, except that treatments being compared are combined 
two highest XXB750 target dose levels with background medication of ACEI/ARB stratum 
versus conversion from ACEI/ARB to sacubitril/valsartan. In the event treatment arms 4a and 
4b are eliminated, the comparison will be between only the 120 mg XXB750 and the 
sacubitril/valsartan treatment arms. 
9.4.2 
Safety endpoints 
For all safety analyses, the safety set will be used unless specified otherwise. All listings and 
tables will be presented by treatment group. 
Adverse events 
All information obtained on adverse events will be displayed by treatment group and 
participant. 
The number (and percentage) of participants with treatment emergent adverse events (events 
started after the first dose of study medication or events present prior to start of double-blind 
treatment but increased in severity based on preferred term) will be summarized in the following 
ways: 
• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation, and adverse events 
leading to dose adjustment. 
The number (and proportion) of participants with adverse events of special interest and related 
to potential risks (as per the Investigator's Brochure) will be summarized by treatment. 
A participant with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. 
Adverse events which will be counted for a specific treatment period are those which are 
treatment emergent. These events are those with an onset after the start of the treatment period, 
or which were present prior to the start of the treatment period but increased in severity, changed 

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from being not suspected to being suspected of study treatment relationship, or developed into 
SAEs after the start of the treatment period. 
Vital signs 
Summary statistics will be provided by treatment and visit for all vital signs, as well as for the 
proportion of participants presenting with clinically notable abnormal values. Graphical 
displays of the values of selected vital signs over time may be provided by treatment group. 
More details on the analysis of vital signs will be described in the Statistical Analysis Plan 
(SAP). 
12-lead ECG 
A standard 12 lead ECG will be performed at Randomization, Week 16, and Week 24. 
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
section of the CRF. Each ECG tracing should be labeled with the study and subject number, 
date, and kept in the source documents at the study site. Clinically significant abnormalities 
should also be recorded on the Medical History/AE CRF page. 
Summary Statistics for continuous data and number and percentage of participants for 
categorical data (e.g. interpretation) will be provided by treatment and visit. 
More details on the analysis of ECG parameters will be described in the SAP. 
Clinical laboratory evaluations 
Laboratory data collected during the study will be summarized by presenting shift tables using 
extended normal ranges (baseline to most extreme post-baseline value), summary statistics of 
raw data and change from baseline by treatment and visit. The number of participants meeting 
pre-defined clinically notably laboratory values and percent changes will also be summarized 
by treatment. 
Immunogenicity 
All immunogenicity results including (the incidence of ADA and/or neutralizing antibodies) 
will be summarized by treatment and listed by treatment group, participant, and visit/time. IPS 
and IIS will be used for analyses. 
More details on the analysis of immunogenicity parameters will be described in the SAP. 
9.5 
Exploratory endpoint(s)/estimand(s) analysis 
Exploratory objectives are defined in Section 3. 
Analyses of the exploratory efficacy variables will be based on the Full Analysis Set 
(FAS). Summary statistics by treatment group will be performed for the baseline values, the 
post-baseline values, and the change from baseline, with baseline defined as the randomization 
visit (or the measurement obtained at an earlier visit (scheduled or unscheduled) which is closest 
to the randomization visit, if the randomization visit measurement is missing). At each post 
baseline visit, only participants with a value at both baseline and that post-baseline visit will be 

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included in the change from baseline summary and missing post-baseline values will not be 
imputed. 
9.5.1 
Exploratory variables 
Below are the variables for the exploratory analysis: 
1. Number of winners based on the hierarchically ordered composite endpoint consisting of: 
1) time to all-cause death; 2) number of HF hospitalizations; 3) categorical KCCQ CSS 
change; 4) NYHA class change; 5) relative change in NT-proBNP levels from baseline to 
Week 16; 
2. Rate of change in eGFR (eGFR slope) from baseline to Week 16; 
3. Change from baseline at assessment visits in biomarkers (details are provided 
in Section 9.5.4); 
4. Change in NYHA class from baseline to Week 16; 
5. Changes in HF signs and symptoms from baseline to Week 16; 
6. Change in all domains of the Kansas City Cardiomyopathy Questionnaire from baseline to 
Week 16; 
7. Population PK analysis results including mathematic models and parameters (details are 
provided in Section 9.5.3); 
8. Incidence of anti-XXB750 antibodies (details are provided in Section 9.5.5). 
9.5.2 
Analysis methods 
In general, exploratory variables will be analyzed in the FAS unless specified otherwise. 
Statistical tests will be performed at the two-sided significance level of 0.05. To better satisfy 
the normality assumption, the log-transformation will be taken on each biomarker prior to 
statistical analysis. There will be no multiplicity adjustment for any analysis of exploratory 
variables. 
Win ratio analysis 
The hierarchical ordered composite endpoint will be analyzed using the win ratio approach 
(Pocock et al 2012), with treatment as fixed-effect factor and stratified by region and 
background medication (ACEI/ARB, sacubitril/valsartan) (Dong et al 2018). Every participant 
in the highest XXB750 target dose level group will be compared to every participant in the 
placebo group within each stratum in the following order: 
1. all pairs will be compared first by time to all-cause death; if there is no winner, then 
2. they will be compared for the number of HF hospitalizations; if there is no winner, then 
3. they will be compared according to the combination of change in KCCQ CSS and change 
in NYHA class from baseline to Week 16; if still there is no winner, then 
4. they will be compared according to reduction in NT-proBNP levels from baseline to Week 
16. 
5. If the comparison between changes in NT-proBNP levels does not result in a winner, the 
respective pairwise comparison is tied. 

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When comparing the time to all-cause death and number of HF hospitalizations between two 
participants and at least one of the times is censored, the comparison is only performed up to 
the censoring time. Three categories are defined for the change of KCCQ CSS: worsened 
(decrease of 5 points or more), improved (increase of 5 points or more), or unchanged (neither 
worsened nor improved). The comparison of KCCQ CSS categorical change is in favor of the 
participant in the highest XXB750 arm if the category of the participant is better compared to 
that in placebo arm. Similarly, three categories are defined for the change of NYHA class, 
worsened, improved, or unchanged; and the comparison of NYHA class change is in favor of 
the participant in the highest XXB750 arm if the class change of the participant is better 
compared to that in the placebo arm. Please refer to Table 9-1 for the example of combination 
of change in KCCQ CSS and change in NYHA class. 
Table 9-1 
Selecting a winner based on combination of change of KCCQ CSS and 
change of NYHA class 
Example 
Participant A 
Participant B 
Result of 
comparison 
Change of 
KCCQ CSS 
from baseline 
to Week 16 
Change of 
NYHA Class 
from baseline 
to Week 16 
Change of 
KCCQ CSS 
from baseline 
to Week 16 
Change of 
NYHA Class 
from baseline 
to Week 16 
1 
Improved 
Improved 
Improved 
Improved 
Tie 
2 
Improved 
Worsened 
Worsened 
Improved 
Tie 
3 
Worsened 
Unchanged 
Worsened 
Worsened 
A wins 
4 
Worsened 
Worsened 
Worsened 
Improved 
B wins 
The comparison of NT-proBNP is performed based on the relative change between baseline 
and Week 16 and takes into account that relative changes within ±25% are considered medically 
irrelevant; in detail, let μXXB750 and μplacebo be the relative changes of participants in the highest 
XXB750 and the placebo arm, respectively. Then, a comparison of NT-proBNP is in favor of 
the participant in the highest XXB750 arm if μXXB750 < 0.75 μplacebo. On the other hand, the 
comparison is in favor of the participant in the placebo arm if μplacebo < 0.75 μXXB750. 
The win ratio is estimated by the ratio of the number of winners in the highest XXB750 
treatment group and the number of winners in the placebo group with weights defined as the 
reciprocal of the stratum sample size. 
 
where nXXB750(m) and nplacebo(m) are the total of wins in the mth stratum for the highest XXB750 
and placebo treatment groups, respectively; w(m)=1/N(m) and N(m) is the total sample size in the 
mth stratum. 
The estimated win ratio and the corresponding 2-sided 95% CI will be provided. The 
contribution to the number of winners of each component of the win ratio will be summarized. 

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Analysis of continuous variables 
Continuous variables, which are assumed to be normally distributed, are: 
• Rate of change (slope) in eGFR from baseline at Week 16; 
• Change in KCCQ from baseline at Week 16. 
For the rate change in eGFR, the eGFR slope will be estimated from a repeated measures 
ANCOVA model including treatment, LVEF (≤40%, >40%), background medication 
stratification factor (ACEI/ARB, sacubitril/valsartan), region stratification factor, time (when 
the eGFR is assessed in weeks), and treatment-by-time as fixed effects with random intercept 
and slope (time) and a common unstructured covariance. The least-square means of slopes for 
within and between treatment groups, and the corresponding two-sided 95% confidence interval 
will be provided. 
Changes from baseline in KCCQ scores will be analyzed based on an ANCOVA model in which 
treatment, LVEF (≤40%, >40%), background medication stratification factor (ACEI/ARB, 
sacubitril/valsartan) and region stratification factor will be included as factors and baseline 
value as a covariate. Treatment comparisons and effect size estimates at Week 16 will be 
provided. The analysis will be performed based on all available data up to Week 16 in the FAS. 
Analysis of ordinal variables 
The ordinal variables include 
• Change in NYHA class from baseline; 
• Changes in HF signs and symptoms from baseline. 
The ordinal variables will be analyzed, at Week 4, Week 8, Week 12, and Week 16, using a 
repeated measures proportional cumulative odds model. The model will include patient as a 
random effect and the respective baseline category, treatment, LVEF (≤40%, >40%), 
background medication stratification factor (ACEI/ARB, sacubitril/valsartan), region 
stratification factor, visit (all available post-randomization visits) and treatment-by-visit 
interaction as fixed effect factors. This model assumes that the treatment effect sizes across 
measurement categories are the same. The visit-wise effect size estimates and their 95% 
confidence intervals will also be provided. The analysis will be based on all available data in 
the FAS and likelihood method with an assumption of missing at random for missing data. 
For population PK analysis and incidence of anti-XXB750 antibodies, please refer 
to Section 9.5.3 and Section 9.5.5, respectively. 
Analysis methods for biomarkers are described in Section 9.5.4 with more details available in 
the statistical analysis plan (SAP). 
All exploratory endpoints will be summarized over 16 weeks randomized treatment epoch for 
each treatment group. Additional summary over safety follow-up will be provided as 
appropriate. FAS will be used for analyses. 
9.5.3 
Pharmacokinetics 
Sparse PK samples are collected for population PK analysis. Results will be reported separately. 
Individual drug concentration will be listed in Clinical Study Report (CSR). 

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9.5.4 
Biomarkers 
Both blood and urine samles will be collected at all sites where geographically feasible at 
Randomization, Week 8, Week 12, and Week 16 as described in Table 1-1. Biomarkers to be 
analyzed may include, but are not necessarily limited to: cyclic GMP (plasma and urine), 
urinary cGMP-to-creatinine ratio, urinary albumin-to-creatinine ratio, BNP and hs-Troponin (in 
addition to primary endpoint NT-proBNP). 
The change from baseline to a pre-defined time-point in logarithmic scale will be analyzed 
using a repeated measures ANCOVA model with treatment, LVEF (≤40%, >40%), background 
medication stratification factor (ACEI/ARB, sacubitril/valsartan), and region stratification 
factor, visit (Week 8, Week 12, or Week 16), and treatment-by-visit as factors, and respective 
baseline in logarithm scale as a covariate, with a common unstructured covariance matrix 
among visits will be used. Estimates of treatment difference and their two-sided 95% confidence 
intervals will be provided. These estimates and confidence intervals will be back-transformed 
for presentation. 
In addition, biomarker data will be summarized by treatment and time point. Further displays 
of biomarker data may be considered and will be described separately in the Statistical Analysis 
Plan (SAP). 
9.5.5 
Immunogenicity 
All immunogenicity results including the incidence of ADA and/or neutralizing antibodies will 
be summarized by treatment and listed by treatment group, participant, and visit/time. IPS and 
IIS will be used for analyses. 
More details on the analysis of immunogenicity parameters will be described in the SAP. 
9.5.6 
Patient reported outcomes 
The change in HF symptoms and physical limitation scores assessed by the clinical summary 
score of the KCCQ and the change in other domains of KCCQ is one of the exploratory efficacy 
endpoints. Please refer to Section 9.5.2 for the analysis method. 
9.6 
Other safety analyses 
Please refer to statistical analysis plan for details. 
9.7 
Other analyses 
9.7.1 
Subgroup analyses 
The subgroups of interest for primary analysis and selected secondary/exploratory analyses 
include but are not limited to: 
• Age (< 65, ≥ 65) 
• Sex (female, male) 
• Region 
• LVEF (≤ 40%, > 40%) 

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• Type of RAS inhibition (ACEI/ARB, sacubitril/valsartan) 
• Dose level of ACEI/ARB or sacubitril/valsartan at randomization. 
Please refer to statistical analysis plan for more details. 
9.7.2 
DNA 
Exploratory DNA studies are designed to investigate the association between genetic factors 
(genotypes) and clinical assessments (phenotypes) which are collected during the clinical trial. 
Without prior evidence of a strong association, a number of possible associations are evaluated 
with exploratory analyses. A range of statistical tests are used for the analyses. Additional data, 
from other clinical trials, are often needed to confirm associations. Alternatively, if the number 
of participants enrolled in the study is too small to complete proper statistical analyses, the data 
may be combined, as appropriate, with those from other studies to enlarge the dataset for 
analysis. 
Data generated on hypothesis-free platforms will be reported separately outside of CSR. 
9.8 
Interim analysis 
One safety interim analysis will be conducted when data from the ongoing XXB750 phase 1b 
study CXXB750A12101 becomes available. This analysis will include all available data of the 
study CXXB750A12101 and treatment arms 1-3 and 5 of the current study to assess the need 
for adapting the design of the current study. 
An additional administrative interim analysis informing other programs may be conducted 
when approximately 430 participants are randomized into the study (approximately 40 
participants each in arms 1-4) and are followed for 16 weeks to help the planning of another 
trial in a different development program. The results of this interim analysis will not lead to any 
changes in this study and will be kept blinded to anyone directly involved in the conduct of the 
study. More details about the DMC review process and how unblinding will be handled in the 
context of DMC reviews will be provided in the DMC charter. 
No alpha adjustment will be made for the interim safety analysis, safety data monitoring, and 
the administrative interim analysis. All interim analyses and safety data monitoring will be 
performed by an independent statistician who will not be involved in the trial conduct. The 
results will be reviewed by the independent DMC. 
The primary analysis will be performed after all participants have completed Week 16 (or 
discontinued prior to Week 16). A final analysis will be performed after all participants 
completed Week 24 (or discontinued prior to Week 24). Formal testing of the primary endpoint 
with full level alpha of 0.025 (1-sided) will be performed at the primary analysis time point. 
Regular safety data monitoring, including the safety interim analysis and the administrative 
interim analysis, is planned as specified in Section 4.6. 
9.9 
Sample size determination 
The study is planned to randomize 720 participants in total. 

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9.9.1 
Primary endpoint(s) 
For the primary endpoint analysis, 600 participants allocated in the ratio of 2:2:3:3 to placebo, 
XXB750 60 mg dose level, XXB750 120 mg dose level, and highest XXB750 dose level, 
respectively. 
Assuming a common standard deviation of 0.67 for log NT-proBNP change from baseline and 
a one-sided 2.5% significance level (with adjustments for multiple comparisons using MCP-
MOD), a sample size of 600 participants (120 in placebo, 120 in XXB750 60 mg dose level, 
180 in XXB750 120 mg dose level, and total of 180 in highest XXB750 dose level) or, in the 
event treatment arms 4a and 4b are eliminated (see Section 4.6), a sample size of 540 
participants (120 in placebo, 120 in XXB750 60 mg dose level, and 300 in XXB750 120 mg 
dose level) will provide a power of at least 90% if the underlying true maximum NT-proBNP 
reduction on XXB750 vs. placebo is 23%.  
9.9.2 
Secondary endpoint(s) 
A common standard deviation of 0.67 for log NT-proBNP change from baseline and a one-
sided 2.5% significance level is assumed for all sample size determinations relating to 
secondary endpoints. 
For the first secondary endpoint, a sample size of 120 participants in placebo and 180 
participants in XXB750 optimal dose level, respectively, will provide a minimum power of 90% 
if the true NT-proBNP reduction on XXB750 vs. placebo is 23%. In the case of when treatment 
arms 4a and 4b are eliminated after safety interim analysis, a sample size of 120 participants in 
placebo and 300 participants in XXB750 120 mg dose level will provide a power of 
approximately 95% if the true NT-proBNP reduction on XXB750 vs. placebo is 23%.  
For the second secondary endpoint, in participants with ACEI/ARB background medication 
converted to sacubitril/valsartan, a sample size of 120 participants in a group combining the 
two highest XXB750 target dose levels and 120 participants in sacubitril/valsartan conversion 
arm will provide approximately 80% power if the underlying true maximum NT-proBNP 
reduction with adding XXB750 vs. conversion to sacubitril/valsartan is 22%. In the case when 
treatment arms 4a and 4b are eliminated, a sample size of 100 participants in XXB750 120 mg 
dose level and 120 participants in sacubitril/valsartan conversion arm will provide 
approximately 77% power if the underlying true maximum NT-proBNP reduction with adding 
XXB750 vs. conversion to sacubitril/valsartan is 22%.  
10 
Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 

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• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) international ethical guidelines 
• Applicable ICH Good Clinical Practice (GCP) guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator’s Brochure, [IDFU], and other relevant 
documents (e.g. advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments/modifications to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The Investigator will be responsible for the following: 
Signing a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, 
auditors, Novartis Quality 
Assurance 
representatives, 
designated 
agents 
of Novartis, 
IRBs/IECs, and regulatory authorities as required 
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by the 
IRB/IEC 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC 
procedures 
Providing oversight of the conduct of the study at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations 
Inform Novartis immediately if an inspection of the clinical site is requested by a regulatory 
authority. 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC or European Clinical Trial 
Regulation 536/2014, US CFR 21), and with the ethical principles laid down in the Declaration 
of Helsinki. 

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10.1.2 
Informed consent process 
The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the patient or their legally authorized representative and answer all questions 
regarding the study. 
Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data protection 
requirements, where applicable, and the IRB/IEC or study center. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent must also sign the ICF. 
A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative. 
Patients who are re-screened are required to sign a new ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional additional research, e.g. genetic analysis. The Investigator or authorized designee 
will explain to each participant the objectives of the additional research. Participants will be 
told that they are free to refuse to participate and may withdraw their consent at any time and 
for any reason during the storage period. A separate signature will be required to document a 
participant’s agreement to allow any remaining specimens to be used for additional research. 
Participants who decline to participate in this optional additional research will document this. 
Eligible patients may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her level of understanding. If the participant is capable of doing so, he/she 
must indicate agreement by personally signing and dating the written informed consent 
document. 
Information about common side effects already known about the investigational treatment can 
be found in the Investigator's Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant upon obtaining consent and also 
during the study as needed. Any new information regarding the safety profile of the 
investigational drug 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 then must be discussed with the participant. 
The following informed consents are included in this study: 
• Main study consent, which also included: 

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• A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study 
• Optional consent for activities that may be done outside of the study site 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants or the 
female partners of any male participants who took study treatment 
• Patient information sheet for female partners of any male participants who took study 
treatment 
• Optional Genetics Consent to provide a sample for exploratory DNA studies 
The study includes an optional sub-study/ DNA component which requires a separate signature 
if the participant agrees to participate. It is required as part of this protocol that the Investigator 
presents this option to the participants, as permitted by local governing regulations. The process 
for obtaining consent should be exactly the same as described above for the main informed 
consent. 
Declining to participate in these optional assessments (DNA) will in no way affect the 
participant’s ability to join the main research study. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that may challenge the ability to obtain a standard 
written informed consent due to limits that prevent an on-site visit, Investigator may conduct 
the informed consent discussion remotely (e.g. telephone, videoconference) if allowable by a 
local health authority. 
Guidance issued by local regulatory bodies on this aspect prevail and must be implemented and 
appropriately documented (e.g. the presence of an impartial witness, sign/dating separate ICFs 
by trial participant and person obtaining informed consent, etc.). 
10.1.3 
Data protection 
Participants will be assigned a unique identifier by Novartis. Any participant records or datasets 
that are transferred to Novartis will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used 
by Novartis in accordance with local data protection law. The level of disclosure must also be 
explained to the participant who will be required to give consent for their data to be used as 
described in the informed consent. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by Novartis, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities. 
Novartishas appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws. 

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10.1.4 
Committees structure 
In this study, an Executive Committee will support development and conduct of the study, while 
an independent, program-wide Data Monitoring Committee will oversee patient safety and 
frequently review patient safety data as outlined below. 
10.1.4.1 Data Monitoring Committee 
This study will include a data monitoring committee (DMC) which will function independently 
of all other individuals associated with the conduct of this clinical trial, including the site 
investigators participating in the study. The DMC will assess at defined intervals the progress 
of a clinical trial, safety data, and critical efficacy variables and recommend to Novartis whether 
to continue, modify, or terminate a trial. 
At the time of the interim analysis for safety in order to open enrollment into treatment arms 4a 
and 4b (see Section 4.6), the DMC will have 3 options to recommend based on the safety 
profile: 
• To continue the study as per protocol (i.e. to open enrollment into both arms 4a and 4b as 
planned). 
• To not open both treatment arms 4a and 4b, or to not open treatment arm 4b. 
• To replace the originally planned 240 mg target dose with a 180 mg target dose as the 
highest target dose (at either low and high starting dose or only a low starting dose). 
The DMC may also conduct a planned administrative interim analysis to inform other programs. 
Details on the DMC early safety interim analysis and the administrative interim analysis to 
inform other programs are described in Section 4.6 and Section 9.8. 
More details regarding composition, responsibilities, data monitoring, and meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in a 
separate charter that is established between Novartis and the DMC. 
10.1.4.2 Executive Committee 
The Executive Committee (EC) will be established comprising of outside medical experts i.e. 
not being members of the DMC and Novartis representatives from the Clinical Trial Team. 
The EC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The EC will review 
protocol amendments as appropriate. Together with the clinical trial team, the EC will also 
develop recommendations for publications of study results including authorship rules. 
10.1.5 
Data quality assurance 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g. risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques (central, 
remote, or on-site monitoring) are provided in the monitoring plan. 

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Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during the 
retention period without the written approval of Novartis. No records may be transferred to 
another location or party without written notification to Novartis. 
10.1.5.1 Data collection 
Designated Investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements. Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the Investigator staff. 
The Investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the Investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
10.1.5.2 Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated Investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis (or a designated CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. The 
code break functionality will remain available until study shut down or upon request 
of Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 

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available for data analysis for the CSR at the conclusion of the study. Any changes to the 
database after that time can only be made after written agreement by Novartis development 
management. 
10.1.6 
Source documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
The Investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. The Investigator must also keep the original 
informed consent form signed by the participant (a signed copy is given to the participant). 
Definition of what constitutes source data and its origin can be found in monitoring guidelines. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. Study monitors will perform ongoing source data verification 
to confirm that data entered into the CRF by authorized site personnel are accurate, complete, 
and verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory requirements. 
Key study personnel must be available to assist the field monitor during all visits. Continuous 
remote monitoring of each site’s data may be performed by a centralized Novartis / CRA 
organization. Additionally, a central analytics organization may analyze data & identify risks 
& trends for site operational parameters, and provide reports to Novartis clinical teams to assist 
with trial oversight. 
10.1.7 
Publication policy 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT . In addition, after study completion and finalization of the study report 
the results of this trial will be submitted for publication and posted in a publicly accessible 
database of clinical trial results, such as the Novartis clinical trial results website and all 
required health authority websites (e.g. Clinicaltrials.gov, EudraCT etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to 
the Novartis publication policy training materials that were provided to you at the trial 
Investigator meetings. 
Any data analysis carried out independently by the Investigator should be submitted 
to Novartis before publication or presentation. 
Summary results of primary and secondary endpoints will be disclosed based upon the global 
Last Participant Last Visit (LPLV) date, since multinational studies are locked and reported 
based upon the global LPLV. 

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10.1.8 
Protocol adherence and protocol amendments 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an Investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the Investigator shall immediately disclose it 
to Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
Investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by 
Novartis and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 
10.1.8.1 Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the Investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 

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10.2 
Appendix 2: Abbreviations and definitions 
10.2.1 
List of abbreviations 
ACEI(s) 
Angiotensin converting enzyme inhibitor(s) 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANA 
Antinuclear Antibodies 
ANCOVA 
Analysis of covariance 
ARB(s) 
Angiotensin receptor blocker(s) 
ARNI 
Angiotensin receptor neprilysin inhibitor 
ASCT 
Autologous Stem Cell Transplant 
ASMA 
Anti-smooth muscle antibody 
AST 
Aspartate Aminotransferase 
AV 
Atrio-ventricular 
AxMP 
Auxiliary Medicinal Product 
bid 
bis in die/twice a day 
BLRM 
Bayesian Logistic Regression Model 
BMA 
Bone Modifying Agents 
BMI 
Body Mass Index 
BP 
Blood pressure 
BUN 
Blood Urea Nitrogen 
CABG 
Coronary artery bypass graft 
CDS 
Core Data Sheet 
cGMP 
Cyclic guanosine monophosphate 
CK 
Creatine Kinase 
CO 
Country Organization 
COA 
Clinical Outcome Assessment 
CQA 
Clinical Quality Assurance 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CRT 
Cardiac resynchronization therapy 
CSR 
Clinical study report 
CTT 
Clinical Trial Team 
CV 
Cardiovascular 
DBP 
Diastolic Blood Pressure 
DIN 
Drug Inducted Nephrotoxicity 
DLT 
Dose Limiting Toxicity 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of study 
EOT 
End of treatment 

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ERCP 
Endoscopic retrograde cholangiopancreatography 
eSAE 
Electronic Serious Adverse Event 
eSource 
Electronic Source 
FDA 
Food and Drug Administration 
FIH 
First in Human 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate Dehydrogenase 
GMP 
Good Manufacturing Practice 
h 
Hour 
HBsAg 
Hepatitis B virus surface antigen 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HED 
Human Equivalent Dose 
HF 
Heart failure 
HFmrEF 
Heart failure with mildly reduced ejection fraction 
HFrEF 
Heart failure with reduced ejection fraction 
HSCT 
Hematopoietic Stem Cell Transplant 
i.v. 
intravenous 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use 
IDFU 
Investigational directions for use 
IEC 
Independent Ethics Committee 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
KCCQ 
Kansa City Cardiomyopathy Questionnaire 
LCZ696 
Sacubitril/valsartan 
LDH 
lactate dehydrogenase 
LFT 
Liver function test 
LLN 
lower limit of normal 
LLOQ 
lower limit of quantification 
LVEF 
Left ventricular ejection fraction 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
mL 
milliliter(s) 
MRA(s) 
Mineralcorticoid receptor antagonist(s) 
Nab 
Neutralizing antibody 
NCDS 
Novartis Clinical Data Standards 
NP(s) 
Natriuretic petide(s) 
NPR1 
Natriuretic Peptide Receptor 1 

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NT-
proBNP 
N-terminal prohormone B-type natriuretic peptide 
NYHA 
New York Heart Association 
OHP 
Off-site Healthcare Professional 
p.o. 
Oral(ly) 
PA 
Posteroanterior 
PCI 
Percutaneous coronary intervention 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PKS 
PK analysis set 
POCT 
Point of Care Testing 
PRO 
Patient Reported Outcomes 
PS&PV 
Patient Safety and Pharmacovigilance 
PSD 
Premature Subject Discontinuation 
PT 
prothrombin time 
q4w 
Every 4 weeks 
QD 
Once a day 
QoL 
Quality of life 
R Value 
ALT/ALP x ULN 
RAAS 
Renin-angiotensin-aldosterone system 
RD 
Recommended Dose 
RU 
Resource Utilization 
s.c. 
subcutaneous 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
standard deviation 
SGLT2I(s) 
Sodium Glucose Co-transporter-2 Inhibitor(s) 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SoA 
Schedule of Activities 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBL 
Total bilirubin level 
ULN 
upper limit of normal 
WHO 
World Health Organization 

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10.2.2 
Definitions 
Additional treatment 
Medicinal products that may be used during the clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. any background 
therapy) 
Assessment 
A procedure used to generate data required by the study 
Auxiliary medicinal 
product 
Medicinal product used for the needs of a clinical trial as described in the protocol, 
but not as an investigational medicinal product (e.g. rescue medication, challenge 
agents, background treatment or medicinal products used to assess end-points in the 
clinical trial). 
Concomitant therapy is not considered as AMP. 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study participant 
Clinical Outcome 
Assessment (COA) 
A measure that describes or reflects how a participant feels, functions, or survives 
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting of all clinical 
trial activities. Examples of team members include the Study Lead, Medical Monitor, 
Trial Statistician etc. 
Coded Data 
Personal Data which has been de-identified by the investigative center team by 
replacing personal identifiers with a code. 
Discontinuation from 
study 
Point/time when the participant permanently stops receiving the study treatment and 
further protocol required assessments or follow-up, for any reason. No specific 
request is made to stop the use of their samples or data. 
Discontinuation from 
study treatment 
Point/time when the participant permanently stops receiving the study treatment for 
any reason (prior to the planned completion of study intervention administration, if 
any). Participant agrees to the other protocol required assessments including follow-
up. No specific request is made to stop the use of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg once a 
day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study data using 
data collection systems, such as Web-based applications, interactive voice response 
systems and clinical laboratory interfaces. EDC includes the use of Electronic Case 
Report Forms (eCRFs) which are used to capture data transcribed from source 
data/documents used at the point of care 
End of the clinical trial 
The end of the clinical trial is defined as the last visit of the last participant. 
Enrollment 
Point/time of participant entry into the study at which informed consent must be 
obtained. The action of enrolling one or more participants 
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines source 
documents and case report forms (eCRFs) into one application, allowing for the real 
time collection of clinical trial information to Novartis and other oversight authorities, 
as appropriate 
Estimand 
As defined in the ICH E9(R1) addendum, estimand is a precise description of the 
treatment effect reflecting the clinical question posed by the trial objective. It 
summarizes at a population-level what the outcomes would be in the same 
participants under different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and treatment of interest, as 
well as the specification of how the remaining intercurrent events are addressed and 
a population-level summary for the variable. 
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest. 
Investigational drug/ 
treatment 
The drug whose properties are being tested in the study 
Investigational 
Product/ 
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference (such as an active comparator) in a clinical trial, including a product with a 

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Investigational 
Medicinal product 
marketing authorization when used or assembled (formulated or packaged) in a way 
different from the approved form, or when used for an unapproved indication, or when 
used to gain further information about an approved use. 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for randomization and 
who did not take study treatment, but have been inadvertently randomized into the 
study or the participant allocated to an invalid stratification factor 
Off-site 
Describes trial activities that are performed at remote location by an off-site 
healthcare professional, such as procedures performed at the participant's home. 
Off-site healthcare 
Professional (OHP) 
A qualified healthcare professional, who performs certain protocol procedures for the 
participant in an off-site location such as a participant's home. 
Orthostatic 
hypotension 
A reduction in SBP of ≥20 mmHg or in DBP of ≥10 mmHg within 3 min of standing 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study (i.e. 
concomitant or rescue therapy) 
Part 
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple 
dose part, or a part in participants with established disease and in those with newly-
diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient). "Participant" terminology is 
used in the protocol whereas term "Subject" is used in data collection 
Participant number 
A unique number assigned to each participant upon signing the informed consent. 
This number is the definitive, unique identifier for the participant and should be used 
to identify the participant throughout the study for all data collected, sample labels, 
etc. 
Patient-Reported 
Outcome (PRO) 
A measurement based on a report that comes directly from the participant about the 
status of a participant's health condition without amendment or interpretation of the 
participant's report by a clinician or anyone else 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical 
trial database setup and eventually in analysis 
Perpetrator drug 
A drug which affects the pharmacokinetics of the other drug 
Personal data 
Participant information collected by the Investigator that is coded and transferred to 
Novartis/Sponsors for the purpose of the clinical trial. This data includes participant 
identifier information, study information and biological samples. 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the assignments in 
order to reduce bias. 
Randomization 
number 
A unique identifier assigned to each randomized participant 
Remote 
Describes any trial activities performed at a location that is not the investigative site. 
Rescreening 
If a participant fails the initial screening and is considered as a Screen Failure, he/she 
can be invited once for a new Screening visit after medical judgment and as specified 
by the protocol 
Screen Failure 
A participant who did not meet one or more criteria that were required for participation 
in the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from where data 
comes. The data source can be a database, a dataset, a spreadsheet or even hard-
coded data, such as paper or eSource 
Start of the clinical trial 
The start of the clinical trial is defined as the signature of the informed consent by the 
first participant. 
Study treatment 
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational drug(s), 
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Tele-visit 
Procedures or communications conducted using technology such as telephone or 
video-conference, whereby the participant is not at the investigative site where the 
Investigator will conduct the trial. 
Treatment arm/group 
A treatment arm/group defines the dose and regimen or the combination, and may 
consist of 1 or more cohorts. 
Treatment of interest 
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations of 
interventions administered concurrently, e.g. as add-on to standard of care, or might 
consist of an overall regimen involving a complex sequence of interventions. This is 
the treatment of interest used in describing the related clinical question of interest, 
which might or might not be the same as the study treatment. 
Variable (or endpoint) 
The variable (or endpoint) to be obtained for each participant that is required to 
address the clinical question. The specification of the variable might include whether 
the participant experiences an intercurrent event. 
Withdrawal of consent 
Withdrawal of consent from the study occurs when the participant explicitly requests 
to stop use of their data and/or biological samples AND no longer wishes to receive 
study treatment, AND does not agree to further protocol required assessments. This 
request should be in writing (depending on local regulations) and recorded in the 
source documentation. 
This request should be distinguished from a request to discontinue the study. Other 
study participant's privacy rights are described in the corresponding informed consent 
form. 

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10.3 
Appendix 3: Clinical laboratory tests 
10.3.1 
Clinically notable laboratory values and vital signs 
Clinically notable laboratory abnormalities for selected tests performed by Central Laboratory 
(based on: 1) proportional or absolute changes from baseline; 2) the limit of the normal range 
established by the Central Laboratory; 3) cut-off values used to define Grade 3 as established 
by the Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0 
(US Department of Health and Human Services 2017) or higher). 
Hematology 
Table 10-1 
Clinically notable hematology abnormalities 
Parameter 
Shift 
Criteria 
Red blood cell count 
Increase 
> 50% increase AND value > ULN 
 
Decrease 
> 30% decrease AND value < LLN 
Hemoglobin 
Increase 
> 50% increase AND value > ULN 
 
Decrease 
either (> 30% decrease AND value 
< LLN) OR value < 8.0 g/dL 
Hematocrit 
Increase 
> 50% increase AND value > ULN 
 
Decrease 
> 30% decrease AND value < LLN 
White blood cell count 
Increase 
value > 100,000 cells/mm3 
 
Decrease 
value < 2000 cells/mm3 
Platelet count 
Decrease 
value < 50,000 platelets/mm3 
ULN: upper limit of the normal range; LLN: lower limit of the normal range 
Blood chemistry 
Table 10-2 
Clinically notable blood chemistry abnormalities 
Parameter 
Shift 
Criteria 
Alkaline phosphatase 
Increase 
value > 5 x ULN if baseline was 
normal OR value > 5 x baseline if 
baseline was abnormal 
ALT (SGPT) 
Increase 
value > 5 x ULN if baseline was 
normal OR value > 5 x baseline if 
baseline was abnormal 
AST (SGOT) 
Increase 
value > 5 x ULN if baseline was 
normal OR value > 5 x baseline if 
baseline was abnormal 
Total bilirubin 
Increase 
value > 3 x ULN if baseline was 
normal OR value > 3 x baseline if 
baseline was abnormal 
BUN 
Increase 
≥ 50% increase 
Creatinine 
Increase 
≥ 50% increase 
Potassium 
Increase 
value > 6.0 mmol/L 
 
Decrease 
value < 3.0 mmol/L 
Chloride 
Increase 
> 115 mEq/L 
 
Decrease 
< 90 mEq/L 

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Parameter 
Shift 
Criteria 
Calcium 
Increase 
corrected serum calcium > 
3.1 mmol/L 
 
Decrease 
corrected serum calcium < 
1.75 mmol/L 
Uric acid 
Increase 
> 50% increase 
Plasma glucose 
Increase 
> 25% increase 
 
Decrease 
value < 40 mg/dL 
ULN: upper limit of the normal range 
Along with investigators, the clinical trial team from Novartis will receive alerts for clinically 
notable values via fax/e-portal (or appropriate means agreed with central labs and Novartis). 

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10.4 
Appendix 4: Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the time points indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis. 
• Thank You letter 
• Plain language trial summary - after CSR publication 

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10.5 
Appendix 5: Liver safety monitoring 
10.5.1 
Liver event and laboratory trigger definitions & follow-up requirements 
Table 10-3 
Liver event and laboratory trigger definitions 
 
Definition/threshold 
If ALT or AST normal at baseline 
 
Liver laboratory triggers 
· 3 x ULN < ALT or AST ≤ 5 x ULN 
· TBL > ULN* 
Liver events 
· ALT or AST > 5 × ULN 
· ALP > 2 × ULN (in the absence of known bone 
pathology) 
· Total bilirubin > 3 × ULN (in the absence of known 
Gilbert syndrome) 
· ALT or AST > 3 × ULN AND (TBL > 2 x ULN OR 
INR > 1.5) 
· Potential Hy’s Law cases (defined as ALT or AST > 
3 × ULN and Total bilirubin > 2 × ULN [mainly 
conjugated fraction] without notable increase in ALP 
to > 2 × ULN) 
· Any clinical event of jaundice (or equivalent term) 
· ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, nausea, or vomiting, 
or rash with eosinophilia 
· Any adverse event potentially indicative of a liver 
toxicity 
If ALT or AST elevated at baseline: 
 
Liver laboratory triggers 
· ALT or AST > 2 x baseline or > 200 U/L (whichever 
occurs first) 
· TBL > ULN* 
Liver events 
· ALT or AST > 3 x baseline or > 300 U/L (whichever 
occurs first) 
· (ALT or AST > 2 × baseline or > 200 U/L [whichever 
occurs first]) AND (TBL > 2 x ULN OR INR > 1.5) 
· ALT or AST > 5 × ULN 
· ALP > 2 × ULN (in the absence of known bone 
pathology) 
· Total bilirubin > 3 × ULN (in the absence of known 
Gilbert syndrome) 
· Potential Hy’s Law cases (defined as ALT or AST > 
3 × ULN and Total bilirubin > 2 × ULN [mainly 
conjugated fraction] without notable increase in ALP 
to > 2 × ULN) 
· Any clinical event of jaundice (or equivalent term) 
· (ALT or AST > 2 × baseline or > 200 U/L [whichever 
occurs first]) accompanied by (general) malaise, 
fatigue, abdominal pain, nausea, or vomiting, or rash 
with eosinophilia 
· Any adverse event potentially indicative of a liver 
toxicity 
* Fractionate bilirubin, evaluate for cholestatic liver injury (ALP) or alternative causes of bilirubin elevation. 
Treat alternative causes according to local institutional guidelines 

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Table 10-4 
Follow up requirements for liver laboratory triggers - ALT, AST, TBL 
 
ALT 
TBL 
Liver Symptoms 
Action 
ALT increase without bilirubin increase: 
 
 
If normal at 
baseline: 
ALT > 3 x ULN 
Normal 
For 
participants with 
Gilbert’s syndrome: 
No change in 
baseline TBL 
None 
● No change to 
study treatment 
● Measure ALT, 
AST, ALP, GGT, 
TBL, INR, albumin, 
CK, and GLDH in 
48-72 hours. 
● Follow-up for 
symptoms. 
If elevated at 
baseline: 
ALT > 2 x baseline 
or > 200 U/L 
(whichever occurs 
ﬁrst) 
 
If normal at 
baseline: 
ALT > 5 x ULN for 
more than two 
weeks 
Normal 
For 
participants with 
Gilbert’s syndrome: 
No change in 
baseline TBL 
None 
● Interrupt study 
treatment 
● Measure ALT, 
AST, ALP, GGT, 
TBL, INR, albumin, 
CK, and GLDH in 
48-72 hours. 
● Follow-up for 
symptoms. 
● Initiate close 
monitoring and 
workup for 
competing 
etiologies. 
● Study treatment 
can be restarted 
only if another 
etiology is identiﬁed 
and liver enzymes 
return to baseline. 
If elevated at 
baseline: 
ALT > 3 x baseline 
or > 300 U/L 
(whichever occurs 
ﬁrst) for more than 
two weeks 
 
If normal at 
baseline: 
ALT > 8 x ULN 
Normal 
None 
ALT increase with bilirubin increase: 
 
If normal at 
baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN (or 
INR > 1.5) 
For participants 
with Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at 
baseline: 
ALT > 2 x baseline 
or > 200 U/L 
(whichever occurs 
ﬁrst) 
 
If normal at 
baseline: 
ALT > 3 x ULN 
Normal or elevated 
Severe fatigue, 
nausea, vomiting, 
right upper 
quadrant pain 
If elevated at 
baseline: 
ALT > 2 x baseline 
or > 200 U/L 
(whichever occurs 
ﬁrst) 

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Table 10-5 
Follow-up requirements for liver laboratory triggers based on isolated 
elevations in TBL 
Criterion 
Actions required 
Follow-up monitoring 
Total Bilirubin (isolated) 
 
 
Any elevation > ULN 
Fractionate bilirubin, evaluate for 
cholestatic liver injury (ALP) or 
alternative causes of bilirubin 
elevation. Treat alternative causes 
according to local institutional 
guidelines 
As shown below according to the 
degree of elevation 
>1.5 – 3.0 ULN 
● Maintain treatment 
● Repeat LFTs within 48-72 
hours 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline 
> 3 - 10 × ULN (in the absence of 
known Gilbert syndrome) 
● Interrupt treatment 
● Repeat LFT within 48-72 hours 
● Hospitalize if clinically 
appropriate 
● Establish causality 
● Record the AE and contributing 
factors (e.g. concomitant 
medications, medical history, lab 
test) in the appropriate CRF 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline (ALT, AST, total bilirubin, 
Alb, PT/INR, ALP and GGT) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 
> 10 x ULN 
● Discontinue the study 
treatment immediately after all 
other alternative causes are ruled 
out 
● Record the AE and contributing 
factors(e.g. concomitant 
medications, medical history, lab 
test)in the appropriate CRF 
Monitor ALT, AST, total bilirubin, 
Alb, PT/INR, ALP and GGT until 
resolution (frequency at 
investigator discretion) 
Any AE potentially indicative of a 
liver toxicity 
● Consider study treatment 
interruption or discontinuation 
● Hospitalization if clinically 
appropriate 
● Establish causality 
● Record the AE and contributing 
factors(e.g. concomitant 
medications, medical history, lab 
test)in the appropriate CRF 
Investigator discretion 

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10.6 
Appendix 6: Renal safety monitoring 
10.6.1 
Specific Renal Alert Criteria and Actions and Event Follow-up 
Table 10-6 
Renal event criteria and corresponding actions to be taken upon their 
occurrence 
Renal event 
Actions 
Confirmed serum creatinine increase of 
25 – 49% from baseline 
● Consider causes and possible interventions 
● Follow-up within 2-5 days 
Confirmed serum creatinine increase ≥ 50% from 
baseline (corresponds to KDIGO criterion for acute 
kidney injury) 
● Consider causes and possible interventions 
● Repeat assessment within 24-48h if possible 
● Consider drug interruption or 
discontinuation unless other causes are diagnosed 
and corrected 
● Consider participant hospitalization 
and specialized treatment 
New onset dipstick proteinuria ≥ 300 mg/dL 
OR 
Protein-creatinine ratio (PCR) ≥ 1g/g Cr (or mg/mmol 
equivalent as converted by the measuring laboratory) 
● Consider causes and possible interventions 
● Assess serum albumin and serum total protein 
● Repeat assessment to confirm 
● Consider drug interruption or discontinuation 
unless other causes are diagnosed and corrected 
New onset of hematuria ≥ 1 mg/dL on urine dipstick 
● Repeat assessment to confirm 
● Distinguish hemoglobinuria from hematuria 
● Urine sediment microscopy 
● Assess serum creatinine 
● Exclude infection, trauma, bleeding from the distal 
urinary tract or bladder, menstruation 
● Consider bleeding disorder 
FOLLOW-UP OF RENAL EVENTS 
Assess, document and record in CRF: 
• Urine dipstick and sediment microscopy evidence of drug-induced nephrotoxicity (DIN): 
crystals, red blood cells (dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), 
white blood cells, tubular epithelial cells 
• Blood pressure and body weight 
• Serum creatinine, BUN, electrolytes (sodium, potassium, phosphate, calcium) and uric 
acid 
• Urine output 
Review and record possible contributing factors to the renal event (co-medications, other co-
morbid conditions) and additional diagnostic procedures (MRI etc.) in the CRF 
Monitor participant regularly (frequency at investigator’s discretion) until: 
• Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr) 
or 
• Event stabilization: sCr level with ±10% variability over last 6 months or protein-
creatinine ratio stabilization at a new level with ±50% variability over last 6 months. 
• Analysis of urine markers in samples collected over the course of the DIN event 

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Figure 10-1 
Flow chart for managing hypotension 
 

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10.8 
Appendix 8: Managing hyperkalemia 
General principles 
Elevation of potassium levels above the cut-off values defined below should be repeated and 
confirmed before any action is taken. 
Any participant who presents with a potassium level > 5.4 mmol/L at screening, confirmed by 
repeat testing, should be considered a screen failure. Any participant with a serum potassium > 
5.3 mmol/L after randomization requires regular, repeated checks of potassium concentration 
(beyond that required in the protocol) until it is clear that the potassium concentration is stable 
and not rising into the range of concern (≥ 5.5 and < 6.0 mmol/L) or of potential danger 
(≥ 6.0 mmol/L). Participants with an elevated potassium value should be managed according to 
the corrective actions outlined below. Hyperkalemia should be followed until resolution. 
Corrective action for management of hyperkalemia 
Serum potassium > 5.3 mmol/L and ≤ 5.5 mmol/L 
• Confirm potassium concentration in a non-hemolyzed sample 
• Reinforce low potassium diet and restriction of food/drinks with high potassium content 
(e.g. orange juice, melon, bananas, low-salt substitutes, etc.) 
• Review medical regimen (including dietary supplements and over-the-counter 
medications) for agents known to cause hyperkalemia 
• Consider reduction in dose or discontinuation of the following non-disease modifying 
agents: 
• Potassium-sparing diuretics (e.g., amiloride and triamterene) including when in 
combination products with thiazide or loop diuretics 
• Potassium supplements, e.g., potassium chloride 
• Salt substitutes 
• Trimethoprim and trimethoprim-containing combination products, such as Bactrim® 
and Septra® (trimethoprim/sulfamethoxazole fixed combination) 
• Non-steroidal anti-inflammatory drugs (NSAIDs) 
• Cyclo-oxygenase-2 (COX-2) inhibitors 
• Herbal Supplements: For example, Noni juice, alfalfa (Medicagosativa), dandelion 
(Taraxacum officinale), horsetail (Equisetum arvense), nettle (Urtica dioica), 
milkweed, lily of the valley, Siberian ginseng, hawthorn berries 
• Consider down-titration of background HF agents: 
• Aldosterone antagonists (if they are believed to be the most likely cause of 
hyperkalemia) 
• Sacubitril/valsartan or ACEI/ARB, according to the investigator’s medical judgment 
• Repeat serum potassium measurement within 3 to 5 days 
• If serum potassium remains > 5.3 and ≤ 5.5 mmol/L, regularly monitor serum 
potassium levels to ensure stability (suggested once monthly) 

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Serum potassium > 5.5 and < 6.0 mmol/L 
• Confirm potassium concentration in a non-hemolyzed sample 
• Apply all measures outlined for serum potassium > 5.3 and ≤ 5.5 mmol/L 
• Consider down-titration or discontinuation of background HF agents according to the 
investigator's medical judgment: 
• Aldosterone antagonists (if they are believed to be the most likely cause of 
hyperkalemia) 
• Sacubitril/valsartan or ACEI/ARB 
• Repeat serum potassium measurement after 2-3 days 
• If serum potassium < 5.5 mmol/L, consider resumption of background HF agent at a lower 
dose and repeat potassium measurement within 5 days 
Serum potassium ≥ 6.0 mmol/L 
• Immediately hold further administration of all non-disease modifying and disease-
modifying medications known to cause hyperkalemia as listed above. 
• Confirm potassium concentration in a non-hemolyzed sample 
• Urgently evaluate patient and treat hyperkalemia as clinically indicated 
• Apply all measures outlined for serum potassium > 5.3 and < 6.0 mmol/L 
Discontinued background HF agents or study drug must not be resumed without individualized 
case discussion with, and permission from, Novartis medical monitor or his/her designee. In 
general, discontinued non-disease modifying agents known to cause hyperkalemia should not 
be resumed during the duration of the study. 

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11 
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