A Multi-center, Randomized, Double-blind, Parallel-group, 20-week Dose-finding Study to Evaluate Efficacy, Safety, and Tolerability of XXB750 in Patients With Resistant Hypertension
Phase: PHASE2
Conditions: Resistant Hypertension
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
Clinical Trial Protocol Title: 
A multi-center, randomized, double-blind, parallel-group, 
20-week dose-finding study to evaluate efficacy, safety, 
and tolerability of XXB750 in patients with resistant
hypertension 
Clinical Trial Protocol Number: CXXB750B12201/ NCT05562934
Version Number: 02 (Clean) 
Compound: XXB750 
Brief Title: An efficacy, safety, tolerability and dose finding study of XXB750 in 
resistant hypertension patients 
Study Phase: II 
Sponsor Name: Novartis 
Regulatory 
Agency 
Identifier 
Number(s): 
EUDRACT: 
2021-005738-41; 
IND: 147562 
Approval Date: 05-Mar-2024 (content final) 
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 2 (05-Mar-2024) ............................................................................................. 8 
Amendment 1 (07-Jun-2023) ............................................................................................ 10 
1 
Protocol summary .............................................................................................................. 13 
1.1 
Summary ................................................................................................................ 13 
1.2 
Schema ................................................................................................................... 18 
1.3 
Schedule of activities (SoA) .................................................................................. 18 
2 
Introduction ....................................................................................................................... 23 
2.1 
Study rationale ....................................................................................................... 23 
2.2 
Background ............................................................................................................ 23 
2.3 
Benefit/Risk assessment ........................................................................................ 26 
3 
Objectives, endpoints, and estimands ................................................................................ 28 
3.1 
Primary estimands ................................................................................................. 30 
3.2 
Secondary estimands ............................................................................................. 30 
4 
Study design ...................................................................................................................... 32 
4.1 
Overall design ........................................................................................................ 32 
4.2 
Scientific rationale for study design ...................................................................... 36 
4.2.1 
Participant input into design .................................................................. 39 
4.3 
Justification for dose .............................................................................................. 39 
4.3.1 
Rationale for choice of background therapy ......................................... 39 
4.4 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 40 
4.5 
Rationale for public health emergency mitigation procedures .............................. 40 
4.6 
Purpose and timing of interim analyses/design adaptations .................................. 40 
4.7 
End of study definition .......................................................................................... 41 
5 
Study population ................................................................................................................ 41 
5.1 
Inclusion criteria .................................................................................................... 41 
5.2 
Exclusion criteria ................................................................................................... 41 
5.3 
Screen failures ....................................................................................................... 43 
5.3.1 
Replacement policy ............................................................................... 44 
5.3.2 
Participant numbering ........................................................................... 44 
6 
Study treatment(s) and concomitant therapy ..................................................................... 44 
6.1 
Study treatment(s) .................................................................................................. 44 
6.1.1 
Additional study treatments .................................................................. 45 

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6.1.2 
Treatment arms/group ........................................................................... 45 
6.1.3 
Treatment duration ................................................................................ 45 
6.1.4 
Medical devices ..................................................................................... 45 
6.2 
Preparation, handling, storage, and accountability ................................................ 45 
6.2.1 
Handling of study treatment .................................................................. 46 
6.2.2 
Handling of other treatment .................................................................. 47 
6.2.3 
Instruction for prescribing and taking study treatment ......................... 47 
6.3 
Measures to minimize bias: randomization and blinding ...................................... 47 
6.3.1 
Treatment assignment, randomization .................................................. 47 
6.3.2 
Treatment blinding ................................................................................ 48 
6.3.3 
Emergency breaking of assigned treatment code .................................. 50 
6.4 
Study treatment compliance .................................................................................. 50 
6.4.1 
Recommended treatment of potential anticipated adverse events ........ 51 
6.5 
Dose modification .................................................................................................. 51 
6.5.1 
Dose escalation guidelines .................................................................... 51 
6.5.2 
Definitions of dose limiting toxicities (DLTs) ...................................... 51 
6.5.3 
Dose modifications ................................................................................ 52 
6.5.4 
Follow-up for toxicities ......................................................................... 52 
6.5.5 
Retreatment criteria ............................................................................... 54 
6.6 
Continued access to study treatment after the end of the study ............................. 54 
6.6.1 
Post trial access ..................................................................................... 54 
6.7 
Treatment of overdose ........................................................................................... 54 
6.7.1 
Reporting of study treatment errors including misuse/abuse ................ 54 
6.8 
Concomitant and other therapy .............................................................................. 55 
6.8.1 
Concomitant therapy ............................................................................. 55 
6.8.2 
Prohibited medication ........................................................................... 56 
6.8.3 
Rescue medicine.................................................................................... 57 
7 
Discontinuation of study treatment and participant discontinuation/withdrawal .............. 57 
7.1 
Discontinuation of study treatment ........................................................................ 57 
7.2 
Participant discontinuation from the study ............................................................ 58 
7.3 
Withdrawal of informed consent and exercise of participants’ data privacy 
rights ...................................................................................................................... 58 
7.4 
Lost to follow-up ................................................................................................... 59 
7.5 
Early study termination by the Sponsor................................................................. 59 
8 
Study Assessments and Procedures ................................................................................... 60 
8.1 
Screening ............................................................................................................... 60 

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8.2 
Participant demographics/other baseline characteristics ....................................... 61 
8.3 
Efficacy assessments ............................................................................................. 61 
8.3.1 
Ambulatory blood pressure monitoring ................................................ 61 
 
 62 
 
 63 
8.3.4 
Appropriateness of efficacy assessments .............................................. 64 
8.4 
Safety assessments ................................................................................................. 64 
8.4.1 
Physical examinations ........................................................................... 64 
8.4.2 
Vital signs.............................................................................................. 64 
8.4.3 
Electrocardiograms ............................................................................... 64 
8.4.4 
Clinical safety laboratory tests .............................................................. 65 
8.4.5 
Pregnancy testing .................................................................................. 66 
8.4.6 
Other safety evaluations ........................................................................ 67 
8.4.7 
Appropriateness of safety measurements .............................................. 68 
8.5 
Additional assessments .......................................................................................... 68 
8.6 
Adverse events (AEs), serious adverse events (SAEs), and other safety 
reporting ................................................................................................................. 68 
8.6.1 
Adverse events ...................................................................................... 68 
8.6.2 
Serious adverse events .......................................................................... 70 
8.6.3 
SAE reporting........................................................................................ 71 
8.6.4 
Pregnancy .............................................................................................. 72 
8.6.5 
Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs .................................................................... 73 
8.6.6 
Adverse events of special interest ......................................................... 73 
 
 73 
 
 74 
 
 75 
 
 75 
 
 75 
8.10 
Health economics OR Medical resource utilization and health economics .......... 75 
9 
Statistical considerations ................................................................................................... 75 
9.1 
Analysis sets .......................................................................................................... 75 
9.2 
Statistical analyses ................................................................................................. 76 
9.2.1 
General considerations .......................................................................... 76 
9.2.2 
Participant demographics and other baseline characteristics ................ 76 
9.2.3 
Treatments ............................................................................................. 76 
9.3 
Primary endpoint(s)/estimand(s) analysis.............................................................. 77 

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9.3.1 
Definition of primary endpoint(s) ......................................................... 77 
9.3.2 
Statistical model, hypothesis, and method of analysis .......................... 77 
9.3.3 
Handling of intercurrent events of primary estimand (if applicable) .... 79 
9.3.4 
Handling of missing values not related to intercurrent event ............... 80 
9.3.5 
Multiplicity adjustment (if applicable).................................................. 80 
9.3.6 
Sensitivity analyses ............................................................................... 80 
9.3.7 
Supplementary analysis ......................................................................... 80 
9.4 
Secondary endpoint(s)/estimand(s) analysis.......................................................... 81 
9.4.1 
Efficacy endpoints ................................................................................. 81 
9.4.2 
Safety endpoints .................................................................................... 84 
 
 85 
 
 85 
 
 86 
 
 88 
 
 88 
 
 88 
 
 88 
9.6 
(Other) Safety analyses .......................................................................................... 88 
9.7 
Other analyses ........................................................................................................ 89 
9.8 
Interim analysis ...................................................................................................... 89 
9.9 
Sample size determination ..................................................................................... 89 
9.9.1 
Primary endpoint(s) ............................................................................... 89 
9.9.2 
Secondary endpoint(s) ........................................................................... 90 
10 Supporting documentation and operational considerations ............................................... 91 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations................... 91 
10.1.1 
Regulatory and ethical considerations .................................................. 91 
10.1.2 
Informed consent process ...................................................................... 92 
10.1.3 
Data protection ...................................................................................... 93 
10.1.4 
Committees structure ............................................................................ 94 
10.1.5 
Data quality assurance ........................................................................... 94 
10.1.6 
Source documents ................................................................................. 95 
10.1.7 
Publication policy.................................................................................. 96 
10.1.8 
Protocol adherence and protocol amendments ...................................... 96 
10.2 
Appendix 2: Abbreviations and definitions ........................................................... 98 
10.2.1 
List of abbreviations .............................................................................. 98 
10.2.2 
Definitions ............................................................................................. 99 

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10.3 
Appendix 3: Clinical laboratory tests .................................................................. 102 
10.3.1 
Clinically notable laboratory values and vital signs ........................... 102 
10.4 
Appendix 4: Participant Engagement .................................................................. 104 
10.5 
Appendix 5: Liver safety monitoring .................................................................. 105 
10.5.1 
Liver event and laboratory trigger definitions & follow-up 
requirements ........................................................................................ 105 
10.6 
Appendix 6: Renal safety monitoring .................................................................. 108 
10.6.1 
Specific Renal Alert Criteria and Actions and Event Follow-up ........ 108 
10.7 
Appendix 7: Managing hypotension .................................................................... 109 
10.8 
Appendix 8: Recommended minimum doses of background medication ........... 110 
11 References ....................................................................................................................... 112 
List of tables 
Table 1-1 
Primary and secondary objectives, endpoints and estimands ............... 13 
Table 1-2 
Assessment Schedule ............................................................................ 20 
Table 3-1 
Objectives and related endpoints .......................................................... 28 
Table 4-1 
Overview of staggered enrollment strategy .......................................... 32 
Table 6-1 
Investigational and control drug ............................................................ 45 
Table 6-2 
Study Drug/Control Drug ...................................................................... 47 
Table 6-3 
Blinding and unblinding plan ................................................................ 49 
Table 6-4 
XXB750 dose levels evaluated during this trial .................................... 51 
Table 6-5 
Diagnostic assessments to determine alternative causes of observed 
LFT abnormalities ................................................................................. 53 
Table 6-6 
Prohibited medication ........................................................................... 56 
 63 
Table 8-2 
Clinical safety laboratory tests .............................................................. 65 
Table 10-1 
Clinically notable hematology abnormalities ...................................... 102 
Table 10-2 
Clinically notable blood chemistry abnormalities ............................... 102 
Table 10-3 
Liver event and laboratory trigger definitions .................................... 105 
Table 10-4 
Follow-up requirements for liver triggers (based on ALT, AST and 
TBL values) ......................................................................................... 106 
Table 10-5 
Follow-up requirements for liver laboratory triggers based on 
isolated elevations in TBL .................................................................. 107 
Table 10-6 
Renal event criteria and corresponding actions to be taken upon their 
occurrence ........................................................................................... 108 
Table 10-7 
Thiazide or thiazide-like diuretics ....................................................... 110 
Table 10-8 
Long-acting dihydropyridine calcium channel blockers (CCBs) ........ 110 
Table 10-9 
Angiotensin converting enzyme inhibitors ......................................... 110 

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Table 10-10 
Angiotensin receptor blockers............................................................. 111 
List of figures 
Figure 1-1 
Study Design ......................................................................................... 18 
Figure 9-1 
Dose-response curve of candidate models ............................................ 78 
Figure 9-2 
Dose-response curve of candidate models for proportion of 
participants with BP control .................................................................. 82 
Figure 9-3 
Sequentially rejective multiple testing procedure ................................. 83 

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Amended Protocol Version 02 (Clean) 
 
Protocol No. CXXB750B12201 
 
Amendment 1 (07-Jun-2023) 
Amendment rationale 
The main aim of the CXXB750B12201 study is evaluate the safety and efficacy of various 
doses of XXB750 in patients with treatment resistant hypertension (rHTN) as defined by 
various major clinical practice guidelines across the world. Accordingly, the inclusion/ 
exclusion criteria were chosen with the intent to identify and recruit patients that are reflective 
of the commonly accepted definition of rHTN, i.e., patients who remain hypertensive despite 
being treated with maximally tolerated doses of the first three lines of antihypertensive 
medication classes recommended by international guidelines, specifically a thiazide/thiazide-
like diuretic, an ACEI or an ARB, and a long acting dihydropyridine CCB. The protocol also 
stipulates that patients should be treated with maximally tolerated doses of those medication 
classes, but also requires specific minimum doses of triple background antihypertensive 
medications that the patients must be taking to qualify for enrollment. It also disallows use of 
any other medications for the purpose of treating hypertension, including beta blockers. 
However, international guidelines specifically refer to optimal and maximally or best-tolerated 
doses. Further, experience to date suggests that the incorporation of guideline directed medical 
therapy into clinical practice varies considerably across regions. Given the subtle differences in 
local guidelines, it became apparent that clinical practice in some regions is not reflective of 
some of the stringent criteria set out in the study protocol. As many of the patients have 
significant other cardiovascular morbidities such as ischemic heart disease, beta blockers are 
commonly prescribed in these patients and in most instances, these are chosen as drug of choice 
to serve both the purposes of treating hypertension as well as the comorbidities. Feedback from 
participating investigators suggests that the doses of background antihypertensive medications 
considered optimal in individual patients and patient groups differ amongst regions. 
A universal protocol mandate requiring all patients to be on a set minimum dose of background 
antihypertensive medications is proving to be unpragmatic and inconsistent with global clinical 
practice. 
Therefore, in order to ensure enrollment of patients with relevant clinical characteristics into 
the study and taking into consideration the clinical profile of patients with rHTN across several 
countries, an amendment to some of the inclusion/exclusion criteria are made in the protocol. 
These changes will allow for investigators’ best clinical judgement taking into account 
participants’ comorbidities in drug and dose selection across countries and yet remain consistent 
with various international guideline recommendations. Recruitment in study CXXB50B12201 
began on 08-Nov-2022 and as of 23-May-2023 39 patients were randomized in the study. None 
of the changes made in the amendment are expected to have a major impact on the target 
population intended for the study, the analysis of the objectives, or the scientific integrity of the 
study. Key changes to the protocol are summarized in the ‘changes to the protocol’ section. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 

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List of major changes to protocol are below: 
• Section 1.1 Summary section updated to reflect all the major changes of this protocol 
amendment. 
• Table 1-2 Footnote #2 updated to add a pregnancy test assessment in WoCBP prior to 
randomization. 
• Table 1-2 - Screening: updated msSBP from 145 to 140, changed to optimal 3 or 4 
antihypertensive drugs; single blind period: changed to optimal or maximum tolerated dose 
of 3 or 4 antihypertensive drugs. 
• Section 3 Multiple updates as the second secondary objective is replaced with "To evaluate 
the treatment effect of the highest XXB750 dose versus placebo in the dosing interval 
average of ambulatory SBP as assessed by average of mean 24hr SBP measured at week 9 
and week 12." 
• Section 4.1 and Section 4.2 
• Multiple changes to match with the updated inclusion/exclusion criteria 
• Clarified the need to witness intake of the background medication during the visits as 
well as when to take the medicine during the visits where ABPM is attached. 
• Removed time requirement for rescreening. 
• Section 4.1Corrected the error in the total number of enrollment in Group 2 (68 instead of 
136). 
• Section 5 Study Population - 25% limit of beta blocker treated participants was removed. 
• Section 5.2 Updated inclusion criteria 3 to "Apparent rHTN at screening (Visit 1) defined 
as uncontrolled BP with an office msSBP ≥ 140 mmHg despite treatment with stable (i.e., 
unchanged for ≥4 weeks), optimal or maximally tolerated doses of three or four 
antihypertensive drugs of different classes, including an ACEI/ARB, a long-acting 
dihydropyridine CCB, and a thiazide or thiazide-like diuretic. Refer to Section 10.8 for 
recommended minimum doses of some commonly prescribed drugs in those classes. 
Participant with documented intolerance to any doses of CCBs may be eligible if receiving 
another class of antihypertensive medication at an optimal or maximally tolerated dose. An 
optimal dose is defined as the highest dose taking into account participant's documented 
comorbidities and tolerability per investigator's clinical judgment. " 
• Section 5.2 
• Updated exclusion criteria 1 to remove minimum SBP requirement at Visit 30. 
• Updated exclusion criteria 5 adding Sacubitril/Valtarsan 
• Updated exclusion criteria 11 to increase mid-arm circumference to 44cm. 
• Updated exclusion criteria 12 "Patients with history of hospitalization for hypertensive 
emergencies characterized by severe hypertension (usually grade 3) associated with 
funduscopic changes (flame hemorrhages and/or papilloedema), microangiopathy, 
disseminated intravascular coagulation, encephalopathy, acute aortic dissection, acute 
myocardial ischemia, or acute heart failure any time prior to screening or 
hospitalization for non-emergent/non-urgent uncontrolled hypertension without target 
organ damage within 3 months prior to screening" 

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• Replaced exclusion criteria 13 with "Receiving more than 4 antihypertensive 
medications." 
• Updated exclusion criteria 22 to specify the acceptable dose of aspirin. 
• Added exclusion criteria 24 "History of hypersensitivity to any of the study drugs, 
excipients or drugs of similar class." 
• Section 5.3, Section 8.1 and Section 10.2.2. Re-screening only after 4 weeks was removed; 
Clarified participant can be re screened if a fails the initial screening or prior to 
administration of single blind study medication 
• Section 6 - Multiply changes: triple before background medication and specifying LCMS 
compliance test refers to End of Run in. 
• Section 6.3.2 added wording to precise blinded team: pharmacist or delegated qualified 
personnel 
• Section 7.1: Rephrasing change 
• Section 8.3.1 Text modified to: ABPM assessment will be performed at Visit 30 (End of 
Run-in) and after the participant has met office BP criterion (i.e. msSBP < 180 mmHg and 
msDBP <110 mmHg);Precised: Patients should take their background medications in the 
clinic witnessed by the investigator or designee (and study medication when applicable) 
prior to attaching the ABPM device. 
• 
 
• Section 8.3.3 - typo correction 
• Section 9 Multiple updates to statistical section support new secondary objective and other 
changes related to inclusion of patients receiving 3 or 4 background antihypertensive 
medications with removal of the limitation on patients receiving beta blockers. 
• Section 10.6.1 Updated the units of the cut-off values defining renal events 
• Section 10.8 Updated title to "Recommended minimum doses of background medications". 
• Section 11 Ref. Guideline on Missing Data in Confirmatory Clinical Trials removed 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein do NOT affect the Informed Consent. 

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Protocol No. CXXB750B12201 
 
1 
Protocol summary 
1.1 
Summary 
Protocol Title: 
A multi-center, randomized, double-blind, parallel-group, 20-week dose-finding study to 
evaluate efficacy, safety, and tolerability of XXB750 in patients with resistant hypertension 
Brief Title: 
An efficacy, safety, tolerability and dose finding study of XXB750 in resistant hypertension 
patients 
Purpose 
The purpose of this 20-week randomized double-blind study in patients with resistant 
hypertension (rHTN) is to evaluate the efficacy, safety, and tolerability, of four doses of 
XXB750 (30 mg, 60 mg, 120 mg and 240 mg) administered once every 4 weeks (q4w) as 
subcutaneous (SC) injections, compared to placebo. Since all study participants will be patients 
with rHTN, all study treatments will be given on top of optimal or maximally tolerated 
background antihypertensive therapy recommended by international guidelines for treatment of 
HTN (i.e., a thiazide or a thiazide-like diuretic, an angiotensin converting enzyme inhibitor 
(ACEI) or an angiotensin receptor blocker (ARB), and a long-acting dihydropyridine calcium 
channel blocker (CCB). 
Study Indication /Medical Condition: 
Resistant Hypertension 
Treatment type 
Biological 
Study type 
Interventional 
Objectives, Endpoints, and Estimands: 
Table 1-1 
Primary and secondary objectives, endpoints and estimands 
Objectives 
Endpoints 
Primary 
 
To 
evaluate 
the 
efficacy 
and 
dose-response 
relationship of XXB750 30 mg SC q4w, 60 mg SC q4w, 
120 mg SC q4w, and 240 mg SC q4w compared to 
placebo in reducing the mean 24hr ambulatory systolic 
blood pressure (mean 24hr SBP) from baseline to 
Week 12. 
• 
Change from baseline in mean 24hr SBP at Week 
12 

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The primary clinical question of interest is: Is there a 
dose-response signal, and if so, to characterize the 
dose-response relationship of XXB750 30 mg SC q4w, 
60 mg SC q4w, 120 mg SC q4w, and 240 mg SC q4w 
versus placebo in reducing the mean 24hr SBP at 
Week 12 from randomization in participants with rHTN, 
regardless of discontinuation from study treatment, 
change 
in 
the 
dose 
of 
allowed 
background 
antihypertensive medications and receiving prohibited 
concomitant medication? 
Secondary 
 
• 
To evaluate the treatment effect of the highest 
XXB750 dose versus placebo in reducing the 
mean 24hr SBP from baseline to Week 12. 
The estimand of this objective will further demonstrate 
the efficacy of XX750 highest dose group compared 
with placebo, regardless of discontinuation from study 
treatment, change in the dose of allowed background 
antihypertensive medications and receiving prohibited 
concomitant medication, and 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 the highest 
XXB750 dose versus placebo in the dosing 
interval average of ambulatory SBP as assessed 
by average of mean 24hr SBP measured at week 
9 and week 12 . 
The estimand of the second secondary objective in 
terms of attributes are the same as described for the 
primary estimand (Section 3.1) except for (1) the 
treatment of interest which is restricted to the highest 
XXB750 dose group and placebo only; and (2) for 
variable which is average change from baseline in 
mean 24hr SBP at Week 9 and at Week 12. This 
estimand will demonstrate the overall efficacy of 
XXB750 highest dose group compared with placebo in 
terms of average change from baseline at Week 9 
(approximate peak state) and at Week 12 (approximate 
trough state) and provide an estimate with a p-value in 
a hierarchical hypothesis testing procedure with overall 
type I error control after efficacy in primary and first 
secondary objectives are established. 
• 
To evaluate the proportions of participants 
achieving BP (Blood Pressure) control by 
ambulatory blood pressure monitoring - ABPM 
(i.e., mean 24hr SBP <130 mmHg and 24-hour 
mean ambulatory diastolic blood pressure (mean 
24hr DBP) <80 mmHg) and dose-response 
relationship in the four XXB750 dose level groups 
compared to placebo at week 12. 
The third secondary question of interest is: What is the 
dose-response 
signal 
and 
the 
dose-response 
relationship of XXB750 30 mg SC q4w, 60 mg SC q4w, 
120 mg SC q4w, and 240 mg SC q4w versus placebo 
with respect to the proportion of participants achieving 
BP control at Week 12 in patients with rHTN without 
any premature discontinuation from study treatment 
• 
Change from baseline in mean 24hr SBP at Week 
12 
• 
Average of changes from baseline in mean 24hr 
SBP at Week 9 and at Week 12 
• 
The proportions of participants achieving blood 
pressure control defined as mean 24hr SBP <130 
mmHg and mean 24hr DBP <80 mmHg at Week 
12 
• 
Adverse events, safety laboratory parameters, 
and vital signs through end of treatment/study 
(EOT/EOS) 

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. Participants will be followed to monitor their safety for an additional 
8 weeks during which time no active study medication will be given. 
Each of the first approximately 68 randomized participants will be assigned to receive one of 
the three lower doses of XXB750 or placebo (17 participants per arm). A DMC will review the 
safety and tolerability data of those participants when the first 40 participants have completed 
at least 5 weeks of the study and, contingent upon DMC’s findings of their safety and 
tolerability experience, the highest XXB750 dose of 240 mg will be introduced in the remaining 
approximately 102 participants. 
Study Duration: 
20 weeks 
Treatment Duration: 
12 weeks 
Visit Frequency: 
Every 1-4 weeks 
Treatment of interest 
The investigational treatment XXB750/placebo. 
Number of Participants: 
A total of approximately 170 participants will be randomized into the study. 
Key Inclusion criteria 
• Male and female participants who are ≥18 years old. 
• Signed informed consent prior to participation in the study. 
• Apparent rHTN at screening (Visit 1) defined as uncontrolled BP with an office msSBP ≥ 
140 mmHg despite treatment with stable (i.e., unchanged for ≥4 weeks), optimal or 
maximally tolerated doses of three or four antihypertensive drugs of different classes, 
including an ACEI/ARB, a long-acting dihydropyridine CCB, and a thiazide or thiazide-
like diuretic. Refer to Section 10.8 for recommended minimum doses of some commonly 
prescribed drugs in those classes. Participant with documented intolerance to any doses of 
CCBs may be eligible if receiving another class of antihypertensive medication at an 
optimal or maximally tolerated dose. An optimal dose is defined as the highest dose taking 
into account participant's documented comorbidities and tolerability per investigator's 
clinical judgment. 
• Mean 24hr SBP ≥135 mmHg (measured by ABPM) at the end-of Run-in-Visit (Visit 30) on 
treatment with optimal or maximally tolerated doses of an ACEI/ARB, a long-acting 
dihydropyridine CCB (or a suitable alternative in case of intolerance per inclusion criterion 
above), and a thiazide or thiazide-like diuretic. 

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Key Exclusion criteria 
• Subjects with the following blood pressures at the specified time points: 
• Office msSBP <140 mmHg at Visit 20 OR 
• Office msSBP ≥180 mmHg or office msDBP ≥110 mmHg at the end-of-run-in visit 
(Visit 30) OR 
• 24h mean SBP >170 mmHg or 24h mean DBP >105mmHg measured by ABPM at the 
end of the run-in (Visit 30). 
• Known history of secondary hypertension (moderate-to-severe obstructive sleep apnea 
without receiving CPAP therapy (either face mask or nasal device), renovascular 
hypertension, primary aldosteronism, pheochromocytoma, Cushing syndrome, aortic 
coarctation or other cause of secondary hypertension). 
• Estimated GFR <30 mL/min/1.73m2 using CKD-Epi equation at screening (Visit 1) or at 
end-of-run-in visit (Visit 30) 
• Serum potassium >5.0 mmol/L (or equivalent plasma potassium value) at screening or end-
of-run-in visit (Visit 30) 
• Current therapy with a mineralocorticoid receptor antagonist (MRA) or sacubitril/valsartan, 
received an MRA or sacubitril/valsartan within the 4 weeks prior to screening 
• Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), high-grade AV 
block (e.g., Mobitz type II and third-degree AV block in absence of a pacemaker) within 6 
months of screening according to investigator's judgement. 
• Receiving more than 4 antihypertensive medications 
Treatment Groups: 
Participants will be randomly assigned to one of the following five treatment arms targeting a 
final ratio of 1:1:1:1:1 at the end of the trial. 
Placebo SC every 4 weeks for 12 weeks 
XXB750 30 mg SC every 4 weeks for 12 weeks (dose level1) 
XXB750 60 mg SC every 4 weeks for 12 weeks (dose level 2) 
XXB750 120 mg SC every 4 weeks for 12 weeks (dose level 3) 
XXB750 120 mg SC at the Randomization visit followed by 240 mg SC at Week 4 and Week 
8 (dose level 4) 
Data Monitoring/Other Committee: 
Yes (see Section 10.1.4 Committees Structure) 
Key words 
Resistant hypertension, randomized, double-blind, dose finding, XXB750. 

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1.2 
Schema 
Figure 1-1 
Study Design 
 
ABPM = ambulatory blood pressure monitoring; mean 24hr SBP = mean ambulatory systolic blood 
pressure (based on 24hr ambulatory blood pressure monitoring); msSBP = mean sitting systolic blood 
pressure (based on office assessment); SC = subcutaneously; WOCBP = women of childbearing 
potential. 
1.3 
Schedule of activities (SoA) 
The Assessment Schedule (Table 1-2) lists all of the assessments and when they are performed. 
All data obtained from these assessments must be supported in the participant’s source 
documentation. The “X” in the table denotes the assessments to be recorded in the clinical 
database or received electronically from a vendor. The “S” in the table denotes the assessments 
that are only in the participant’s source documentation and do not need to be recorded in the 
clinical database. 
Participants should be seen for all visits/assessments as outlined in the Assessment Schedule or 
as close to the designated day/time as possible. Missed or rescheduled visits should not lead to 
automatic discontinuation or to a change in the timing of the next scheduled visit (if applicable). 
Participants who discontinue from study treatment are to complete the end of treatment visit 
(Visit 170) procedures as soon as possible, and attend the follow-up visits as indicated in the 
Assessment Schedule. 
Participants who discontinue from study should be scheduled for a final evaluation visit if they 
agree, as soon as possible, at which time all of the assessments listed for the final visit (Visit 
1999) will be performed. At this final visit, all dispensed investigational product should be 
reconciled, and the adverse events and concomitant medications not previously reported must 
be recorded on the CRF. 
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 

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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 remain responsible for the 
evaluation of the data collected. 

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Table 1-2 
Assessment Schedule 
Period 
Screening Placebo Run-in 
Randomized Treatment 
Safety Follow-up 
Visit Name 
Screening Run-
In 
End of Run-
in 
Baseline Week 1 
Call 
Week 
2 
Week 
4 
Week 5 
Call 
Week 
8 
Week 9 Week 12 
EOT 
Week 
16 
Week 20 
EOS 
Visit Numbers1 
1 
20 
30 
100 
110 
120 
130 
140 
150 
160 
170 
180 
1999 
Days 
-21 to -15 -14 
-1 to 0 
0 
3 
14 
28 
31 
56 
59 to 63 84 
112 
140 
Informed consent 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / Exclusion criteria X 
X 
X2 
  
  
  
  
  
  
  
  
  
  
Physical Examination 
X 
X3 
X 
  
  
X3 
X3 
  
X3 
X3 
X 
X3 
X 
Body Weight 
  
  
X 
  
  
  
X 
  
X 
  
X 
X 
X 
Body Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Medical history/current 
medical conditions 
X 
  
  
  
  
  
  
  
  
  
  
  
  
Vital Signs/Office BP 
X 
24-hr Ambulatory BP 
Monitor 
  
  
X 
  
  
  
  
  
  
X 
X 
  
  
Electrocardiogram (ECG) 
X 
  
X 
  
  
  
  
  
  
  
X 
  
X 
Pregnancy Test (serum)5 
X 
  
X 
  
  
  
  
  
  
  
X 
  
X 
Pregnancy test (urine)5 
  
  
  
  
  
  
S 
  
S 
  
  
S 
  
Assessment of fertility 
S 
  
  
  
  
  
  
  
  
  
  
  
  
Urinalysis 
X 
  
X 
  
  
X 
X 
  
X 
  
X 
X 
X 
Urine background 
medication screening 
sample collection 
  
  
X 
  
  
  
  
  
  
  
X 
  
  
Laboratory evaluations6 
X 
  
X 
  
  
X7 
X7 
  
X7 
  
X 
X7 
X 

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Period 
Screening Placebo Run-in 
Randomized Treatment 
Safety Follow-up 
Visit Name 
Screening Run-
In 
End of Run-
in 
Baseline Week 1 
Call 
Week 
2 
Week 
4 
Week 5 
Call 
Week 
8 
Week 9 Week 12 
EOT 
Week 
16 
Week 20 
EOS 
Visit Numbers1 
1 
20 
30 
100 
110 
120 
130 
140 
150 
160 
170 
180 
1999 
Days 
-21 to -15 -14 
-1 to 0 
0 
3 
14 
28 
31 
56 
59 to 63 84 
112 
140 
IWRS/IRT Randomization  
  
  
  
X 
  
  
  
  
  
  
  
  
  
IWRS/IRT Registration  
X 
X 
X 
  
  
X 
X 
  
X 
X 
X 
X 
X 
Study drug 
dispensation/administration 
  
X 
  
X 
  
  
X 
  
X 
  
  
  
  
Background medication 
compliance 
  
S 
S 
S 
  
S 
S 
  
S 
  
S 
  
  
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior/Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study period completion 
information 
  
  
X 
  
  
  
  
  
  
  
X 
  
X 

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2 
Introduction 
2.1 
Study rationale 
The design features of this phase 2 trial are intended to support its purpose as stated in Study 
Design (Section 4). The results of this study will help describe the dose-response relationship 
of XXB750 and how it compares in its safety and efficacy to placebo. In addition, this study 
will provide needed insight on XXB750 dose(s) to be studied further in the development 
program in patients with rHTN. 
2.2 
Background 
Hypertension (HTN) is a key risk factor for heart disease and strokes across the world 
contributing significantly to cardiovascular (CV) mortality and morbidity and other end organ 
damage such as retinopathy and nephropathy. Data from the National Health and Nutrition 
Examination Survey (NHANES) and the International Society of Hypertension suggest that an 
estimated 50% of deaths from coronary heart disease (CHD) and stroke were attributable to 
HTN (Lawes et al 2008, Ford 2011). Hypertension is also a leading cause contributing to a third 
of incident end-stage renal disease (ESRD) among patients with kidney disease 
(Johansen et al 2021). 
The prevalence of HTN is rising globally due to ageing of the population and increases in 
lifestyle risk factors, such as unhealthy diets, obesity and lack of physical activity. It is estimated 
that more than 30% of the world’s adult population has hypertension and its prevalence seems 
to continue to increase in the low and middle income countries (Mills et al 2016). Despite it 
being one of the most important modifiable risk factors of cardiovascular morbidity and 
mortality, control of HTN in a substantial proportion of patients remains inadequate. It is 
estimated that nearly half the patients with HTN do not have adequate blood pressure control 
(Whelton et al 2018). Consequently, the use of multiple antihypertensive medications from 
different therapeutic classes is not uncommon in treating HTN. Several payor and patient-
related factors appear to contribute to inadequate control of blood pressure in hypertensive 
patients, including excessive reliance on monotherapy, reluctance to increase drug doses or to 
add more antihypertensive drugs, non-adherence to prescribed medication, drug side effects, 
and the cost of medications (Elliott 2008). 
Despite of the availability of many effective antihypertensive medications with several 
mechanisms of action, a significant proportion of hypertensive patients experience treatment 
resistant HTN (rHTN). Based on population studies, this category of hypertension affects 
approximately 
12% 
to 
15% 
of 
patients 
treated 
for 
HTN 
(Egan et al 2011, Persell 2011, Tanner et al 2013) and approaches a prevalence of 20% in 
clinic-based 
studies 
(de la Sierra et al 2011, Egan et al 2013, Borghi et al 2016, Thomas et al 2016). 
Resistant 
HTN has been formally defined by international medical societies as blood pressure that 
remains above goal despite the concurrent use of three antihypertensive agents of different 
classes at optimal or maximally tolerated doses. Generally, these antihypertensive classes 
include a long-acting calcium channel blocker (CCB), an angiotensin receptor blocker (ARB) 
or 
an 
angiotensin 
converting 
enzyme 
inhibitor 
(ACEI), 
and 
a 
diuretic 

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(Whelton et al 2018, Carey et al 2018). Resistant HTN is often associated with chronic kidney 
disease (CKD), black race, diabetes, obesity, and atherosclerotic disease, as well as older age 
(Williams et al 2018). Patients with rHTN are at a particularly high risk of experiencing adverse 
cardiorenal outcomes compared to other hypertensive patients. Compared to patients with 
controlled HTN, patients with rHTN are 27% more likely to experience the composite endpoint 
of non-fatal myocardial infarction, non-fatal stroke, or all-cause death and 47% more likely to 
experience (cardiovascular) death (multivariate-adjusted model) (Smith et al 2014). Moreover, 
rHTN patients are 32% more likely to reach ESRD than other hypertensive patients 
(Sim et al 2015). 
International guidelines recommend spironolactone 25-50 mg per day for the treatment of 
patients with rHTN (on top of background antihypertensive therapy that includes a 
thiazide/thiazide-like diuretic, an ACEI or an ARB, and a long-acting dihydropyridine CCB). 
This is based on the results of randomized clinical trials, such as ASPIRANT and PATHWAY-
2 (Václavík et al 2011, Williams et al 2015). The PATHWAY-2 trial demonstrated that 
spironolactone dosed at 25-50 mg per day was more effective than the beta blocker bisoprolol 
dosed at 5-10 mg per day and the alpha blocker doxazosin dosed at 4-8 mg per day 
(Williams et al 2015). However, spironolactone is not well tolerated in many patients due to a 
significantly increased risk of hyperkalemia or hormonal abnormalities that cause 
gynecomastia, erectile dysfunction or menstrual disorders (Williams et al 2018). This is 
particularly relevant for patients on background therapy of renin-aldosterone-angiotensin 
system (RAAS) blockers or in patients who have reduced glomerular filtration rates (GFR) 
associated with CKD or diabetes mellitus, which are all conditions that are commonly present 
in rHTN patients (Whelton et al 2018). Thus, while beta blockers and alpha blockers can be 
used in place of spironolactone as they have been shown to have antihypertensive efficacy in 
rHTN (Williams et al 2015), they are significantly less efficacious than spironolactone. 
Nonetheless, the use of these therapeutic classes is limited by increased risks of metabolic 
abnormalities, fatigue, and bradycardia (particularly at higher doses) and orthostatic 
hypotension. Hydralazine and minoxidil, which are direct vasodilators, have been used in 
rHTN, but they may cause significant tachycardia and fluid retention. Thus, regardless of which 
currently available therapeutic drug class is used to treat this complicated subgroup of 
hypertensive patients, adverse effects and worsening of the significant polypharmacy that rHTN 
patients already experience limit compliance with treatment, thereby limiting its success in 
maintaining lower blood pressure in those patients. Thus, there remains a significant unmet 
need for developing new classes of antihypertensive medications with improved efficacy over 
the existing therapeutic modalities, preferably minimizing the impact on the polypharmacy in 
these patients or perhaps even reversing it. 
One physiological system that contributes to blood pressure maintenance is the natriuretic 
peptide (NP) system. It is an endocrine, autocrine and paracrine system, consisting primarily of 
three genetically distinct, but structurally related peptides including atrial natriuretic peptide 
(ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). Natriuretic 
peptides interact with three different types of NP receptors, NPR-1, (or NPR-A), NPR-2 (or 
NPR-B), and NPR-3 (or NPR-C). ANP and BNP activate the transmembrane guanylyl cyclase, 
NPR-1 whereas CNP activates NPR-2. Both receptors catalyze the synthesis of cyclic guanosine 
monophosphate (cGMP), which mediates most known effects of natriuretic peptides, including 
vasodilatation, natriuresis, and diuresis. NPR-3 clears natriuretic peptides from the circulation 

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through receptor-mediated internalization and degradation (Potter et al 2009). Binding of ANP 
or BNP to NPR1 activates membrane bound particulate guanylate cyclase and stimulates 
intracellular cGMP- dependent second messenger signaling cascade, which mediates their 
physiological actions. ANP and BNP play a pivotal role in the maintenance of blood pressure 
(BP) and intravascular volume. The action on BP effects is likely to be via the regulation of 
vascular tone, caused by a direct relaxation effect of NPs on vascular smooth muscle cells. 
Furthermore, NPs help to regulate BP by suppressing the RAAS, reducing sympathetic tone 
and inhibiting secretion of the vasoconstrictor endothelin-1 (ET-1) (Nishikimi et al 2006). 
Therefore, augmentation of NP system can be a potential therapeutic target in the management 
of hypertensive patients. 
One mechanism that has been used to upregulate the NP system to lower BP is via the inhibition 
of neprilysin (also known as neutral endopeptidase 24.11; NEP), an enzyme that breaks down 
NPs with greater affinity for metabolizing ANP. Exploiting this mechanism in lowering blood 
pressure necessitates the simultaneous inhibition of the activity of angiotensin II because 
neprilysin also metabolizes this potent vasoconstrictor. Two therapeutic classes have been 
investigated in lowering blood pressure by simultaneously inhibiting neprilysin and the activity 
of angiotensin II: vasopeptidase inhibitors and angiotensin receptor neprilysin inhibitors 
(ARNIs). Omapatrilat was a vasopeptidase inhibitor which was found to be effective in 
lowering blood pressure by simultaneously inhibiting ACE and neprilysin. However, this 
compound resulted in unacceptably high rates of severe angioedema, particularly in African-
American patients, a potentially life-threatening adverse effect, because it also inhibited 
aminopeptidase-P, which, along with ACE and neprilysin, is responsible for metabolism of 
bradykinin, the key vasoactive peptide thought to be the culprit in angioedema 
(Kostis et al 2004). As a result, omapatrilat was not approved by regulators despite its efficacy. 
Although neprilysin inhibition is an innovative mechanism to lower BP via NP system 
modulation, it has several drawbacks that may limit its efficacy and use in rHTN. First, 
neprilysin inhibition blocks only one pathway of NP degradation; other NP degradation 
pathways, including via insulin-degradation enzyme, exist and limit the effectiveness of this 
pharmacological pathway. Second, currently available neprilysin inhibitors cannot be 
administered alone and must be combined with angiotensin receptor blockade to counteract the 
reduced metabolism of angiotensin II, thereby exposing the patient to potential side effects of 
two medications instead of one. Finally, because neprilysin inhibitors increase bradykinin 
levels, they cannot be co-administered with ACEIs, which also increase bradykinin levels, as 
combined use of these two therapeutic classes may lead to an unacceptably high risk of 
angioedema. Consequently, switching from an ACEi to an ARNI (or vice versa) require an 
ACEI/ARNI-free washout of at least 36 hours between stopping one medication and initiating 
the other. Thus, new modalities to modulate the NP system are needed to exploit its potential 
more fully and more effectively to safely lower BP in rHTN patients. 
One way to efficiently modulate the NP system is by direct NPR-1 agonism. This mechanism 
has the advantage of specificity. It also does not interfere with the metabolism of bradykinin, 
and, therefore, is unlikely to increase the incidence of angioedema. Unlike neprilysin inhibition, 
directly activating NPR-1 does not require co-administration of other medications to counteract 
off-target effects, which provides much more flexibility in treating patients. In a recently 
published first-in-human study, the NPR-1 agonist M-atrial natriuretic peptide (MANP), an 

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analog of human ANP, was shown to increase cGMP levels and natriuresis and to lower 
aldosterone levels and BP when administered subcutaneously (SC) to hypertensive patients 
(Chen et al 2021). Although, most of its effect dissipated within 24 hours, the demonstrated 
effects of MANP in this study provide proof-of-concept for NPR-1 agonism as a potentially 
effective modality in reducing blood pressure in hypertensive patients. 
XXB750 is a long-acting fully human monoclonal IgG1 antibody agonist of NPR-1 with a half-
life of approximately 
 in humans (Section 4.3). The prolonged half-life allows for once-
a-month SC dosing compared to daily dosing of other antihypertensive agents and earlier 
analogs of ANP. Pre-clinical studies with XXB750 have shown 15-20 mmHg SBP reduction in 
normal rats and normal monkeys and ~80 mmHg SBP reduction in hypertensive rats. In the 
ongoing first-in-human (FIH) study in healthy volunteers, XXB750 has been administered as a 
single SC injection at doses up to 240 mg. XXB750 resulted in plasma cGMP elevations and 
BP lowering effect up to a placebo-adjusted maximum SBP reduction of ~18 mmHg at peak 
effect with the 240 mg dose. Cyclic GMP and BP effects trended back to pre-dose values over 
the weeks after dosing but were still present 4 weeks post-dose (see Section 4.3 and the 
Investigator Brochure for details on preliminary results from the FIH study). 
Given its mechanism of action, its long half-life, its significant BP lowering effects seen in its 
preclinical trials as well as in healthy volunteers, XXB750 promises to be an innovative and 
important therapeutic option in the management of patients with rHTN by overcoming several 
challenges including the hormonal and metabolic side effects of spironolactone and other 
currently available therapeutics. Moreover, with its expected once monthly SC administration 
regimen, XXB750 may offer a significant advantage by improving medication adherence in this 
population in which polypharmacy is common. 
The current study is a phase 2 study which aims to establish proof-of-concept of blood pressure 
lowering by NPR1 agonism using XXB750, identify its optimal dose(s) to study in phase 3, and 
to characterize its benefit-risk profile in patients with rHTN..  
2.3 
Benefit/Risk assessment 
All study participants are expected to benefit from intensive monitoring of their blood pressure 
and overall health while receiving the optimal or maximally tolerated triple background 
antihypertensive therapy for their rHTN. Eighty percent of participants are planned to be treated 
with an additional antihypertensive agent (XXB750) in an effort to better control their blood 
pressure. The remaining participants will be treated with placebo and the duration of their 
treatment with placebo will be kept to a minimum, to accomplish the scientific purpose of the 
study. Nonetheless, the extent of this potential benefit is unknown at this time and is the primary 
reason for conducting this study. 
As all participants are required to continue with their existing background antihypertensive 
medications the risk of developing severe uncontrolled hypertension during the study is 
expected to be minimal. Participants with a baseline office systolic blood pressure of SBP >180 
mmHg are excluded from the study. Participants who develop severe uncontrolled hypertension 
during the study and whose SBP remains or who develop SBP >180 mmHg will be withdrawn 
from the study and will be managed using conventional therapies. In addition to minimize the 
risk due to uncontrolled hypertension participants who have experienced any significant 

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Participation in the study and undergoing routine study procedures may cause discomfort 
associated with sample collection and study drug administration. XXB750 will be administered 
as single 1.6 mL subcutaneous injection to the study participants. While injection site reaction 
is a potential local adverse event, subcutaneous injections are well tolerated in the single 
ascending dose study. Therefore, the risk to the participants in this study is expected to be 
minimal. Participants will be monitored closely for local injection site reactions and through 
adverse event collection. Blood samples will be taken on multiple occasions during the course 
of the study which may be associated with bleeding or bruising and rarely fainting and infection. 
However, such events are very rare and the risk to the participants in this study is expected to 
be minimal. 
Women of child-bearing potential will 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, they 
should not be entered or continue in the study. In general, the levels of a mAb in semen are 
expected to be low, and 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. 
Given the close monitoring, criteria for participant selection and the known safety and 
tolerability profile of the drug in human volunteers it is considered that overall potential benefits 
outweigh the risks for participants in this study. 
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 XXB750 30 mg SC q4w, 60 mg SC q4w, 120 mg SC 
q4w, and 240 mg SC q4w compared to placebo in 
reducing the mean 24hr ambulatory systolic blood 
pressure (mean 24hr SBP) from baseline at Week 12. 
• 
Change from baseline in mean 24hr SBP 
at Week 12 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To evaluate the treatment effect of the highest XXB750 
dose versus placebo in reducing the mean 24hr SBP from 
baseline to Week 12. 
• 
Change from baseline in mean 24hr SBP 
at Week 12 
• 
To evaluate the treatment effect of the highest XXB750 
dose versus placebo in the dosing interval average of 
ambulatory SBP as assessed by average of mean 24hr 
SBP measured at week 9 and week 12. 
• 
 Average of changes from baseline in 
mean 24hr SBP at Week 9 and at Week 
12 
• 
To evaluate the proportions of participants achieving 
ambulatory BP control (i.e., mean 24hr SBP < 130 mmHg 
and mean 24hr DBP < 80 mmHg) with respect to the 
dose-response relationship of the four XXB750 dose level 
groups compared to placebo at week 12. 
• 
The proportions of participants achieving 
blood pressure control defined as mean 
24hr SBP <130 mmHg and mean 24hr 
DBP <80 mmHg at Week 12 

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Objective(s) 
Endpoint(s) 
• 
To evaluate the safety and tolerability of the XXB750 
regimens over 12 weeks of treatment and over the 20-
week study period including safety follow-up. 
• 
Adverse events, safety laboratory 
parameters, and vital signs through end 
of treatment/study (EOT/EOS) 

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3.1 
Primary estimands 
The primary clinical question of interest is: Is there a dose-response signal with respect to the 
dose-response relationship of XXB750 30 mg SC q4w, 60 mg SC q4w, 120 mg SC q4w, and 
240 mg SC q4w versus placebo in reducing the mean 24hr SBP at Week 12 from randomization 
in participants with rHTN, regardless of discontinuation from study treatment, regardless of 
change in the dose of allowed background antihypertensive medications and regardless of 
receiving prohibited concomitant medication? 
The justification for the primary estimand is that it will capture both the effect of the tested 
treatments and the effect of additional standard concomitant medications, mirroring the 
conditions in clinical practice. 
The primary estimand is described by the following attributes: 
1. Population: participants with rHTN receiving allowed concomitant medications defined in 
study population (Section 5). 
2. Variable: change from baseline in mean 24hr SBP at Week 12. 
3. Treatment of interest: the randomized treatments (XXB750 30 mg SC q4w, 60 mg SC q4w, 
120 mg SC q4w, 240 mg SC q4w or placebo) with allowed antihypertensive concomitant 
medications. 
Handling of remaining intercurrent events: 
1. Discontinuation of study treatment: ignore (treatment policy strategy). 
2. Unforeseen change in the dose of allowed concomitant medications: ignore (treatment 
policy strategy). 
3. Receiving prohibited concomitant medication: ignore (treatment policy strategy). 
The summary measure is the difference in variable means between treatments. 
3.2 
Secondary estimands 
Difference between highest XXB750 dose group versus placebo in change from 
baseline in mean 24-hour SBP at Week 12 
The estimand of the first secondary objective in terms of attributes will be the same as described 
for the primary estimand (Section 3.1) except for the treatment of interest, which is restricted 
to the highest XXB750 dose group and placebo only. 
This estimand will further demonstrate the efficacy of XXB750 highest dose group compared 
with placebo and 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. 
Difference between highest XXB750 dose group versus placebo in average of 
changes from baseline in mean 24-hour SBP at Week 9 and at Week 12 
The estimand of the second secondary objective in terms of attributes are the same as described 
for the primary estimand (Section 3.1) except for (1) the treatment of interest which is restricted 
to the highest XXB750 dose group and placebo only; and (2) for variable which is average 
change from baseline in mean 24hr SBP at Week 9 and at Week 12. 

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This estimand will demonstrate the overall efficacy of XXB750 highest dose group compared 
with placebo in terms of average change from baseline at Week 9 (approximate peak state) and 
at Week 12 (approximate trough state) and provide an estimate with a p-value in a hierarchical 
hypothesis testing procedure with overall type I error control after efficacy in primary and first 
secondary objectives are established. 
Dose-response signal and dose-response relationship of XXB750 dose groups 
versus placebo with respect to the proportion of participants achieving blood 
pressure (BP) control at Week 12 
The third secondary question of interest is: What is dose-response signal and assess the dose-
response relationship of XXB750 30 mg SC q4w, 60 mg SC q4w, 120 mg SC q4w, and 240 mg 
SC q4w versus placebo with respect to the proportion of participants achieving BP control at 
Week 12 in patients with rHTN without any premature discontinuation from study treatment 
and without any increase in the dose of allowed background antihypertensive medications nor 
receiving any prohibited medications. 
The key secondary estimand is described by the following attributes: 
1. Population: participants with rHTN receiving allowed concomitant medications defined in 
study population (Section 5). 
2. Variable: participant's achievement of blood pressure control defined as mean 24hr SBP 
<130 mmHg and mean 24hr DBP <80 mmHg at Week 12. 
3. Treatment of interest: the randomized treatment XXB750 30 mg SC q4w, 60 mg SC q4w, 
120 mg SC q4w, 240 mg SC q4w or placebo. 
Handling of remaining intercurrent events: 
1. Discontinuation of study treatment: imputed as not achieving BP control (composite 
strategy). 
2. Unforeseen increase in the dose of allowed concomitant medications: imputed as not 
achieving BP control (composite strategy). 
3. Receiving prohibited concomitant medication: imputed as not achieving BP control 
(composite strategy). 
The summary measure is the difference in proportions between treatments. 
Evaluating the safety and tolerability of XXB750 regimens over 12 weeks of 
treatment and up to 20 weeks of follow-up 
Adverse events (AEs) and serious AEs, laboratory parameters and vital signs will be evaluated 
and summarized in each treatment group for different treatment periods (run-in, randomized 
treatment period and post-treatment safety follow-up). Please refer to Section 9.4.2 for analysis 
details. 

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4 
Study design 
4.1 
Overall design 
Study XXB750B12201 is a multicenter, randomized, double-blind, placebo-controlled, 
parallel-group phase 2 study which is comprised of four periods (Figure 1-1): 
• A screening period (approximately 7 days) 
• A single-blind placebo run-in period lasting approximately 2 weeks 
• A 12-week double-blind, placebo-controlled, parallel-group treatment period 
• An 8-week safety follow-up period 
The study will enroll participants with rHTN defined as patients with uncontrolled BP despite 
treatment with optimal or maximally tolerated doses of 3 or 4 antihypertensive drugs of different 
classes, specifically a thiazide/thiazide-like diuretic, an ACEI or an ARB, and a long acting 
dihydropyridine CCB. Approximately 170 participants will be randomized to receive placebo, 
XXB750 30 mg, 60 mg, 120 mg, or 240 mg SC every 4 weeks, at an overall final ratio of 
1:1:1:1:1. The overall design of the study is depicted in Figure 1-1. 
A staggered approach to enrollment will be followed in this protocol. As summarized 
in Table 4-1, the randomized participant sample will be divided into two groups, which will 
vary in terms of the ratio of allocation to the treatment arms. Group 1 will consist of 
approximately 68 participants who will be randomized to either placebo, XXB750 30 mg SC 
every 4 weeks (dose level 1), XXB750 60 mg SC every 4 weeks (dose level 2), or XXB750 120 
mg SC every 4 weeks (dose level 3) in a 1:1:1:1 ratio. The Data Monitoring Committee (DMC) 
will review the safety data of the Group 1 participants when approximately 40 participants have 
completed at least the first 5 weeks of randomized treatment. If the safety profile of XXB750 
dose levels 1, 2 and 3 is deemed acceptable by the DMC, Group 2 enrolment will start upon full 
completion of Group 1 enrollment. Group 2 will consist of approximately 102 participants who 
will be randomized to either placebo, XXB750 dose level 1, XXB750 dose level 2, XXB750 
dose level 3, or XXB750 120 mg SC for one injection followed by 240 mg SC every 4 weeks 
for two injections beginning 4 weeks after the first dose (dose level 4) in a 1:1:1:1:2 ratio. All 
participants will be followed for 8 additional weeks after end of dosing of the study medications 
to monitor their safety. 
In the event that the DMC recommends that participants should not be exposed to XXB750 240 
mg dose, the study will continue without it, and dose level 4 will be eliminated from the study. 
In this case, the Group 2 enrollment will consist of approximately 68 participants randomized 
to either placebo, XXB750 dose level 1, XXB750 dose level 2, or XXB750 dose level 3 in a 
1:1:1:1 ratio. 
Table 4-1 
Overview of staggered enrollment strategy 
Treatment arm 
Group 1 
Group 2 
(adjusted*) 
Total 
(adjusted*) 
Placebo 
n = 17 
n = 17 
N = 34 
XXB750 30mg SC every 
4 weeks 
n = 17 
n = 17 
N = 34 

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Treatment arm 
Group 1 
Group 2 
(adjusted*) 
Total 
(adjusted*) 
XXB750 60mg SC every 
4 weeks 
n = 17 
n = 17 
N = 34 
XXB750 120mg SC every 
4 weeks 
n = 17 
n = 17 
N = 34 
XXB750 120mg SC x 1 
dose, 
then 
XXB750 
240mg every 4 weeks 
n = 0 
n = 34 (0*) 
N = 34 (0*) 
Total 
N = 68 
N = 102 (68*) 
N = 170 (136*) 
* Adjusted numbers are applicable if DMC recommends against administration of dose level 4 in the Group 2 
enrollment. 
Refer to Section 1.2 Schema for study design figure. 
The following is an overview of the study procedure plan. All office visits should be conducted 
at approximately the same time throughout the study, which should be approximately between 
07:00am and 11:00am. The participant should be instructed not to take any of the background 
antihypertensive therapy medications prior to the scheduled office visit, but bring their 
antihypertensive medications to the study site so they can take them after all of the office study 
assessments are complete witnessed by the investigator or designee . At clinic visits when re 
ABPM assessment is scheduled, patients should not take their triple background 
antihypertensive medications until after all office assessments are complete and immediately 
before attaching the ABPM device.  
Screening 
The purpose of the Screening Period, which begins at Visit 1 and continues for approximately 
one week, is to assess participants' eligibility to continue into the run-in period of the study. 
During the Screening Visit, participants will be asked to review and provide informed consent 
prior to undergoing any screening procedures. After signing the informed consent form (ICF), 
inclusion and exclusion criteria will be assessed to verify the study candidate’s eligibility for 
enrollment into the study. This will include assessment of blood pressure in the investigator’s 
office and stability of ongoing regimens of background antihypertensive therapy. Every effort 
should be made to maintain patients at the highest tolerated doses of the background 
antihypertensive therapy components which include ACEI/ARB, long acting CCB and a 
thiazide diuretic. If the participant is not taking maximum doses of these medications per their 
local approved label or local guidelines, the investigator must provide a qualifying reason for 
that in the participant’s electronic case report form (eCRF. Protocol-specified biochemical 
criteria will be assessed using a central laboratory. The participant will continue his/her therapy, 
including his/her antihypertensive medications with no change during the Screening Period. 
Once the participant’s Screening central lab results become available, he/she will be informed 
by the investigator or his/her designee of whether he/she is eligible to continue in the study. 
Only participants who meet all the inclusion criteria and none of the exclusion criteria will be 
asked to return to Visit 20 to begin the Run-in Period. Per the investigator’s discretion, 
participants who have failed the screening period (screen failures) or have failed prior to 
administration of single blind study treatment are allowed to be rescreened once,. 

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The 12-week duration of the double-blind treatment period is sufficient to examine the BP 
lowering effect of each dose of XXB750 as compared to placebo. It is expected that after 4-6 
weeks of study treatment, the full BP lowering effect would have been reached in all treatment 
groups. 
Limited safety data are currently available for XXB750 and it would be prudent to dose the 
medication cautiously in participants until more is learned about its side effect profile. To help 
guard the safety of study participants, a staggered enrollment approach is utilized in the early 
part of the study (Section 4.1, Table 4-1). Participants will be exposed to the highest dose of 
XXB750 only after the independent DMC evaluates early safety data of the three lower 
XXB750 doses and deems their safety profile to be acceptable. Moreover, participants assigned 
to the highest dose level of XXB750 (240 mg) will first be dosed with 120 mg and then up 
titrated to 240 mg four weeks later to reach the target dose. This gradual up-titration is expected 
to help avoid potential tolerability issues related to the top XXB750 dose. 
Target study population 
The protocol utilizes a rigorous process and entry criteria to ensure that only participants who 
truly have rHTN are randomized into the study. All major international guidelines for the 
diagnosis and treatment of hypertension define rHTN based on two key aspects of the patient’s 
blood pressure status: (1) treatment with three or more antihypertensives (one of which should 
be a diuretic) given at optimal or maximally tolerated doses, and (2) patient continues to present 
with 
blood 
pressure 
above 
the 
target 
values 
(Whelton et al 2018, Williams et al 2018, Unger et al 2020). 
The current study requires all participants to be treated with optimal or maximally tolerated 
doses of a thiazide or thiazide-like diuretic, an ACEI or an ARB, and a long-acting 
dihydropyridine CCB, which are the three therapeutic classes of choice recommended by 
international guidelines for treating most hypertensive patients. These three classes of 
antihypertensives are commonly available and exploit different complementary mechanisms for 
lowering BP. Per international guidelines for diagnosis and treatment of hypertension, patients 
treated with optimal or maximally tolerated doses of medications from these three therapeutic 
classes and remain with uncontrolled blood pressure are considered to have rHTN 
(Williams et al 2018). 
International guidelines differ in the blood pressure measurement values used to define 
hypertension and in the way they categorize it. However, they all agree that office msSBP ≥140 
mmHg is considered hypertension that should be treated to lower the risk of cardiovascular 
outcomes 
(Whelton et al 2018, Williams et al 2018, Unger et al 2020). 
In 
this 
study, 
participants will be required to have an office msSBP ≥ 140 mmHg at Screening to qualify for 
inclusion. These initial SBP inclusion criteria are in line with international guidelines definition 
of hypertension, while allowing a small margin of BP lowering that can occur during the Single-
blind Placebo Run-in Period and still remain within the definition of uncontrolled 
hypertension. In addition, at the end of the Single-blind placebo Run-in Period participants must 
have a mean 24hr SBP ≥135 mmHg based on ABPM, a BP monitoring procedure that can rule 
out white coat hypertension. This is above international guidelines for ABPM-based definition 
of hypertension (mean 24hr SBP ≥130 mmHg) (Unger et al 2020), as it is expected to allow for 
a primary endpoint baseline value that will help to more clearly demonstrate the differences in 

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optimal or maximally tolerated doses of medications from these three therapeutic classes and 
remain with uncontrolled blood pressure are considered to have rHTN (Williams et al 2018). 
4.4 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
The primary objective of the study is to assess the true BP lowering effect of various doses of 
XXB750. Therefore, placebo is chosen as the primary comparator in Stage 1 of this study as it 
serves as a good reference standard without any relevant pharmacological activity in the disease 
under study. Placebo as a comparator allows for better characterization of BP lowering 
responses of various doses of the study drug and for evaluation of the dose-response 
relationship. Since it is widely known that some patients may show a favorable response to 
treatment with placebo in clinical trials, a placebo-adjusted evaluation of treatment response 
still provides a clearer assessment of response as opposed to active comparators which have 
varying degrees of pharmacological effects in the population under study. Hence placebo will 
be the primary comparator to assess drug dose response in this study. From a safety perspective, 
the use of placebo as a control allows for the least possible confounded interpretation of the 
nature, the causality and the rate of adverse events observed in the overall study population. 
4.5 
Rationale for public health emergency mitigation procedures 
In the event of a public health emergency as declared by local or regional authorities (i.e. 
pandemic, epidemic or natural disaster), mitigation procedures may be required to ensure 
participant safety and trial integrity and are listed in relevant sections of the study protocol. 
Notification of the public health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures, and permitted/approved by local or regional health 
authorities and ethics committees as appropriate. 
4.6 
Purpose and timing of interim analyses/design adaptations 
A staggered approach is planned to generate safety data in the target rHTN population with the 
three lower doses of XXB750 before enrolling participants to receive the highest dose. The 
staggered enrollment will follow the strategy outlined in Section 4.1 Table 4-1. In this strategy, 
17 participants will be exposed to each of the lower doses of XXB750 (dose level 1, dose level 
2 and dose level 3), and 17 participants will be exposed to placebo. The DMC will conduct an 
interim safety analysis on data of approximately 40 participants who complete at least 5 weeks 
of double-blind treatment. If the safety profile of the 3 lower XXB750 doses is acceptable, 
approximately 102 additional participants will be randomized and exposed to study medications 
(17 on XXB750 dose levels 1, 2, 3 and placebo and 34 participants on XXB750 dose level 4). 
In addition to the planned early interim safety analysis, there will be safety data reviews 
conducted regularly by the DMC. Refer to Section 10.1.4 for more information about the role 
of the DMC in this study. 
The primary analysis will be performed after all participants have completed Week 12 (or 
discontinued prior to Week 12). A final analysis will be performed after all participants have 
completed Week 20 (or discontinued prior to Week 20). Please see Section 9.8 for more details. 

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4.7 
End of study definition 
Study completion is defined as when the last participant completes Week 20/EOS visit 
assessments as defined in Section 1.3 of the protocol. 
5 
Study population 
The study population will consist of male and female participants 18 years old or older with 
apparent resistant hypertension as defined in the inclusion criteria. A total of approximately 170 
participants will be randomized into this dose-response finding study.  
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Male and female participants who are ≥ 18 years old. 
2. Signed informed consent prior to participation in the study. 
3.  Apparent rHTN at screening (Visit 1) defined as uncontrolled BP with an office msSBP ≥ 
140 mmHg despite treatment with stable (i.e., unchanged for ≥4 weeks), optimal or 
maximally tolerated doses of three or four antihypertensive drugs of different classes, 
including an ACEI/ARB, a long-acting dihydropyridine CCB, and a thiazide or thiazide-
like diuretic. Participant with documented intolerance to any doses of CCBs may be eligible 
if receiving another class of antihypertensive medication at an optimal or maximally 
tolerated dose (referred to as triple background antihypertensive therapy. An optimal dose 
is defined as the highest dose taking in to account participant's documented comorbidities 
and tolerability per investigator's clinical judgment. Refer to Section 10.8 for recommended 
minimum doses of some commonly prescribed ACEI/ARBs, long acting dihydropyridine 
calcium channel blockers and thiazide diuretics. 
4. Mean 24hr SBP ≥135 mmHg (measured by ABPM) at the end-of Run-in-Visit (Visit 30) on 
treatment with optimal or maximally tolerated doses of an ACEI/ARB, a long-acting 
dihydropyridine CCB (or a suitable alternative in case of intolerance per inclusion criterion 
above), and a thiazide or thiazide-like diuretic. 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Subjects with the following blood pressures at the specified time points are not eligible to 
participate in the study: 
a. Office msSBP <140 mmHg at Visit 20 OR 
b. Office msSBP ≥180 mmHg or office msDBP ≥110 mmHg at the end-of-run-in visit 
(Visit 30) OR 
c. 24h mean SBP >170 mmHg or 24h mean DBP >105mmHg measured by ABPM at 
the end of the run-in (Visit 30). 
2. Known history of secondary hypertension (moderate-to-severe obstructive sleep apnea 
without receiving CPAP therapy (either face mask or nasal device), renovascular 
hypertension, primary aldosteronism, pheochromocytoma, Cushing syndrome, aortic 
coarctation or other cause of secondary hypertension). 

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3. Estimated GFR <30 mL/min/1.73m2 using CKD-Epi equation at screening (Visit 1) or at 
end-of-run-in visit (Visit 30). 
4. Serum potassium >5.0 mmol/L (or equivalent plasma potassium value) at screening or end-
of-run-in visit (Visit 30). 
5. Current therapy with a mineralocorticoid receptor antagonist (MRA) or sacubitril/valsartan 
or received an MRA or sacubitril/valsartan within the 4 weeks prior to screening. 
6. Type I diabetes mellitus or uncontrolled Type II diabetes (defined as a plasma HbA1c ≥9%) 
7. Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), high-grade AV 
block (e.g., Mobitz type II and third-degree AV block in absence of a pacemaker) within 6 
months of screening according to investigator's judgement. 
8. Chronic non-paroxysmal atrial fibrillation. 
9. Acute myocardial infarction (AMI) or unstable angina, or any history of ischemic or 
hemorrhagic stroke within 12 months of screening; or any percutaneous coronary 
intervention (PCI) or coronary artery bypass graft (CABG) within 12 months of screening 
10. History of a renal denervation procedure. 
11. Mid-arm circumference ≥ 44 cm. The cuff should snugly fit on the arm without the margins 
of cuff overhanging arm musculature. 
12.  Patients with history of hospitalization for hypertensive emergencies characterized by 
severe hypertension (usually grade 3) associated with funduscopic changes (flame 
haemorrhages and/or papilloedema), microangiopathy, disseminated intravascular 
coagulation, encephalopathy, acute aortic dissection, acute myocardial ischaemia, or acute 
heart failure any time prior to screening or hospitalization for non-emergent/non-urgent 
uncontrolled hypertension without target organ damage within 3 months prior to screening.  
13. Receiving more than 4 antihypertensive medications. 
14. Night shift workers. 
15. History of presence of any other disease where the life expectancy is less than 3 years. 
16. 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. 
17. Evidence of hepatic disease as determined by any one of the following: SGOT (AST) or 
SGPT (ALT) values exceeding 3x the upper limit of normal (ULN), or bilirubin >1.5 mg/dl 
at Visit 1. 
18. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-
lives of enrollment, whichever is longer. 
19. History of drug abuse or alcohol dependency. 
20. Lacking the ability to comprehend or follow instructions, or for any reason in the opinion 
of the investigator, a participant that would be unlikely or unable to comply with study 
protocol. 
21. Concurrent enrollment in any other investigational drug or device trial (participation in non-
interventional registries is acceptable). 
22. Requiring prolonged/regular use of NSAIDs except for prophylactic use of low dose aspirin 
up to 325 mg QD or other prohibited medications during the study (i.e., required use for 
longer than 1 week). 

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23. 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, 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 stopping medication. 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, 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 (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner 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 or bilateral tubal ligation at least six weeks ago. 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 not of child bearing 
potential. 
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF. 
24. History of hypersensitivity to any of the study drugs, excipients or drugs of similar class. 
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 into the Run-in 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, screen failure details (including clinical laboratory results if 
available), eligibility criteria, and any serious adverse event (SAE). 

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The reason for screen failure should be recorded on the appropriate Case Report Form. 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 (SAE) during the 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) must be notified within 2 days of the 
screen fail that the participant will not be randomized. Data and samples collected from 
participants prior to screen failure may still be analyzed. 
In the case where a safety laboratory assessment at screening is outside of the range specified 
in the eligibility criteria, the assessment may be repeated per the investigator’s discretion to 
confirm the participant’s eligibility for continuing in the study. If the repeat value remains 
outside of the specified range, the participant must be screen failed. 
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. 
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 signs the ICF and is screened. This Participant No. is retained for 
the participant throughout his/her participation in the trial. A new Participant No. will be 
assigned at every subsequent enrollment if the participant is rescreened. 
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 number available. 
A new ICF will need to be signed if the Investigator chooses to rescreen the participant after 
he/she has screen failed, and the participant will be assigned a new Participant number. 
6 
Study treatment(s) and concomitant therapy 
6.1 
Study treatment(s) 
XXB750 dose level 1 (30 mg), dose level 2 (60 mg), dose level 3 (120 mg), and dose level 4 
(240 mg) or matching placebo will be administered as SC injection every 4 weeks during the 
Randomized Treatment Period (Baseline, Week 4 and Week 8). Table 6-1 lists the 
investigational agents used in the study, including the control drug. 

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Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
(Name 
and 
Strength) 
Pharmaceutical 
Dosage Form 
Route 
of 
Administration 
Presentation 
Sponsor (global or 
local) 
XXB750 150 mg/mL 
Concentration 
for 
solution for injection 
Subcutaneous 
Open label patient 
specific, Vials 
Sponsor (global) 
Placebo 0 mg/mL 
Solution for injection 
Subcutaneous 
Open label patient 
specific, Vials 
Sponsor (global) 
6.1.1 
Additional study treatments 
No other treatment beyond investigational drug and control drug are included in this trial. 
6.1.2 
Treatment arms/group 
At Visit 100 participants will be randomly assigned to one of the following five treatment arms 
targeting a final ratio of 1:1:1:1:1 at the end of the trial. 
Placebo SC every 4 weeks for x 3 doses. 
XXB750 30 mg SC every 4 weeks x 3 doses (dose level 1). 
XXB750 60 mg SC every 4 weeks x 3 doses (dose level 2). 
XXB750 120 mg SC every 4 weeks x 3 doses (dose level 3). 
XXB750 120 mg SC at the Randomization visit followed by 240 mg SC at Week 4 and Week 
8 (dose level 4). 
6.1.3 
Treatment duration 
The planned duration of treatment is 12 weeks per participant. Participants may be discontinued 
from treatment earlier due to unacceptable adverse events, disease progression and/or if 
treatment is discontinued at the discretion of the investigator or the participant. Following the 
conclusion of the 12-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 blood pressure may still be affected by the study 
treatment for some time after its discontinuation, especially those who were randomized to 
XXB750. 
6.1.4 
Medical devices 
Not Applicable 
6.2 
Preparation, handling, storage, and accountability 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section. It will contain XXB750 or placebo in vials for preparation by 
unblinded pharmacist or other qualified study site personnel. 
A unique medication number is printed on the study medication label. 

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Investigator staff will identify the study medication kits to use in preparing the 
XXB750/matching placebo injectable dose for the participant by contacting the IRT and 
obtaining the medication number(s) of the required vial(s). Unblinded qualified and properly 
trained members of the study team at the site will prepare the study drug injection in a blinded 
way for study staff for injection. Immediately before dispensing the medication kit injection to 
the site personnel in charge of injecting the participant, site personnel preparing the study 
medication or his/her designee will detach the outer part of the label from the packaging of the 
vial(s) used for preparing the study medication dose and affix it to the source document. The 
instructions of how to prepare the injections of XXB750 and its matching placebo will be 
provided in a separate pharmacist manual. 
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 IMP (Investigational Medicinal Product) directly to a participant's home may be 
permitted (if allowed by Local or Regional Health Authorities and Ethics Committees as 
appropriate) in the event the Investigator has decided that an on-site visit by the participant is 
no longer appropriate or possible, and that it is in the interest of the participant's health to 
administer the study treatment even without performing an on-site visit. The dispatch of IMP 
from the site to the participant’s home remains under the accountability of the Investigator. 
Supply, preparation, IRT registration, dispensation and return of IMP will be described in 
Pharmacist Manual. 
6.2.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the Investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified in the Investigator's Brochure. 
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. 
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 Investigator or designated site staff (blinded or unblinded, as applicable) must maintain an 
accurate record of the shipment and dispensing of study treatment in a 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 materials 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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The treatment for administration will be handled and shipped in line with the pharmacy manual 
and required procedures for shipping. 
6.2.2 
Handling of other treatment 
Components of the background antihypertensive therapy, which includes the thiazide or 
thiazide-like diuretic, the ACEI/ARB, and the long-acting dihydropyridine CCB that the 
participant was taking since screening will be monitored. Those medications will be monitored 
for compliance through whole duration of the study by asking participant about compliance and 
by obtaining urine samples for future chemical adherence testing as required. 
6.2.3 
Instruction for prescribing and taking study treatment 
Table 6-2 shows how the study medications should be prescribed at each dispensing visit. 
During the Single-blind Run-in Period participants will receive a single SC injection of placebo 
matching XXB750 in a single blinded fashion to ensure that the participant is unaware of the 
content of the medication. 
A double-blind design is employed during the Randomized Treatment Period. Per Table 6-2, at 
every dispensing visit of the Randomized Treatment period all participants will receive a SC 
injection of XXB750/matching placebo according to the participant’s randomized treatment 
assignment. Only the unblinded pharmacist or other qualified site personnel in charge of 
preparing the study medication will be aware of the contents of the dispensed/administered 
study medication. Refer to Section 6.2 for more details regarding the preparation of the study 
medications for dispensing. 
Table 6-2 
Study Drug/Control Drug  
Visit 
Medication 
Dose 
Frequency and/or 
Regimen 
20 
Placebo 
n/a 
SC once 
100 
XXB750 
30 
mg/60 
mg/120 
mg/matching placebo 
SC once 
130 and 150 
XXB750 
30 mg/60 mg/120 mg/240 
mg/matching placebo 
SC every 4 weeks for two 
doses 
The XXB750/matching placebo injections will be administered subcutaneously to participants 
by a qualified study site team member at the site in the upper arm. All kits of study treatment 
assigned by the IRT will be recorded in the IRT system. 
6.3 
Measures to minimize bias: randomization and blinding 
6.3.1 
Treatment assignment, randomization 
At visit 100, all eligible participants will be randomized via Interactive Response Technology 
(IRT) to one of the allowed treatment arms per design (Figure 1-1). 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 first package of study treatment to be dispensed to the participant. 

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Role 
Time or Event 
  
Randomization 
list generated 
Treatment 
allocation 
& dosing 
Safety 
event 
(single 
subject 
unblinded) 
Interim 
Analysis/ dose 
escalation/ 
safety review 
conducted by 
DMC 
Primary analysis 
All other Sponsor 
staff not identified 
above (i.e. project 
team, management 
& decision boards, 
support functions) 
B 
B 
UI 
B 
UI  
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. 
It is the Investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT 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 participant should be discontinued from study treatment 
and continue with the study visits as scheduled without study medication administration. 
6.4 
Study treatment compliance 
The investigator must promote adherence to treatment by instructing the participant to take the 
antihypertensive background therapy exactly as prescribed and by stating that compliance is 
necessary for the participant’s safety and the validity of the study results. This information 

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6.5.3 
Dose modifications 
Except for force up-titration of study medications outlined in Section 6.5.1.1, Investigational 
study treatment dose adjustments and/or interruptions are not permitted. Participants who are 
considered to be intolerant to study medications should discontinue study treatment. 
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. Deviations 
from mandatory dose interruptions and/or reductions are not allowed. 
If the participant experiences severe hypertension (defined as SBP >180 mmHg confirmed by 
3 readings 5 minutes apart), consider discontinuing all study medication and starting the subject 
on open label treatment accompanied by monitoring of BP as per local standard of care until 
the doses of the new medications are stable and BP is under control. 
Dose modifications of background therapy 
Dose adjustments of any component(s) of the background antihypertensive therapy medications 
and study medication due to hypotension are listed in Section 10.7. 
6.5.4 
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. 
6.5.4.1 
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 AST/ALT and total 
bilirubin value; participants meeting any of the following criteria will require further follow-up 
as outlined below: 
• For participants with normal ALT and AST and total bilirubin value at baseline: AST or 
ALT > 3.0 x ULN combined with total bilirubin > 2.0 x ULN 
• For participants with elevated AST or ALT or total bilirubin value at baseline: [AST or 
ALT > 2 x baseline level] OR [AST or ALT > 300 U/L] (whichever occurs first) combined 
with [total bilirubin > 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 ALT, AST, total bilirubin, direct and indirect bilirubin, 
Gamma-glutamyl transferase (GGT), prothrombin time (PT)/ International normalized ratio 

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(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 
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 yrs 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, 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). 
. 
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. 

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All cases confirmed on 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. 
6.5.5 
Retreatment criteria 
Not Applicable 
6.6 
Continued access to study treatment after the end of the study 
After the end of study continued care should be provided to the participant by the Investigator 
and/or referring physician as per the local Standard of Care. 
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: 
• 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 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 local label about overdose in case this involves any 
component of the background therapy 
6.7.1 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE. Study treatment 

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errors and uses outside of what is foreseen in the protocol, misuse or abuse will be collected 
and reported in the safety database irrespective of it being associated with an AE/SAE within 
24 hours of Investigator’s awareness. For more information on AE and SAE definition and 
reporting requirements, please see the respective sections. 
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 was enrolled into the study must be 
recorded on the appropriate Case Report Forms. 
Each concomitant drug must be individually assessed against all exclusion criteria and 
prohibited medication. 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 s/he takes at any point in the study. 
Dose modifications of beta blockers and prostate-specific alpha blockers in patients taking these 
drugs for non-hypertension indications or benign prostatic hypertrophy, respectively, should be 
avoided until the completion of the Double-blind Treatment period. 
Triple background antihypertensive therapy 
As described in earlier sections of the protocol, all participants will receive the study medication 
on top of the optimal or maximally tolerated doses of their antihypertensive triple background 
therapy, which includes a thiazide/thiazide-like diuretic, an ACEI/ARB, and a long-acting 
dihydropyridine CCB Although participants will enter the run-in based on their optimal or 
maximally tolerated pre-study triple background and any other antihypertensive therapy they 
were taking for at least 4 weeks prior to screening, they may still experience adverse events 
(AEs) related to one or more of its components as they begin to take these medications under 
study conditions. This may be due to improved compliance, placebo effect, or other reasons. If, 
per the clinical judgment of the investigator, these AEs could be relieved by modifying the dose 
of the appropriate component of the background antihypertensive therapy during the run-in, the 
participant should not be randomized. Once the participants are randomized, every effort should 
be made to avoid dose modifications of the background antihypertensive therapy components 
for the 12-week duration of the Randomized Treatment Period, unless absolutely necessary to 
manage hypotension. Up titration of antihypertensive background therapy is not allowed. 
If the participant experiences AEs of hypotension and non-pharmacological interventions were 
not effective in relieving these AEs, thereby necessitating a modification in the component(s) 
of the antihypertensive background therapy, please refer to Section 10.7 for instructions on the 
steps to be taken. 
If the investigator decides that, as a last resort for treating the participant it is required to increase 
the doses of background antihypertensive therapy or to add other antihypertensive medications 
to a participant’s regimen at some point during the 12-week Randomized Treatment Period, an 

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End of Treatment Visit will be conducted, including a 24-hr ABPM procedure. After that, the 
study medications can be terminated to allow for introduction of open label antihypertensive 
therapy according to local standard of care. The participant will continue to attend all remaining 
study visits as scheduled until the end of the study. 
Patients should not take their background antihypertensive medications on the day of clinic 
visits. Instead they should bring them to the clinic and take them at the appropriate time 
witnessed by the study staff.  
6.8.1.1 
Permitted concomitant therapy requiring caution and/or action 
Phosphodiesterase-5 (PDE-5) inhibitors 
PDE-5 inhibitors should be used with caution while the participant is receiving study 
medication due to the increased possibility of the occurrence of hypotension. 
Neseritide and intravenous (IV) nitrates 
The concomitant administration of XXB750 with neseritide and IV nitrates has not been 
studied. In the event a study participant requires the concomitant administration of neseritide 
and/or IV nitrates 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 
Use of the treatments displayed in Table 6-6 are not allowed after start of single-blind placebo 
Run-in Period. 
Table 6-6 
Prohibited medication 
Medication 
Prohibition period 
Action taken 
Any antihypertensive 
treatment that is not part of 
the antihypertensive 
background therapy, 
including any new ACEi 
inhibitors, ARBs, DRIs, 
CCBs, or thiazide/thiazide-
like diuretics or potassium-
sparing diuretics, MRAs, β-
blockers`, non-prostate-
specific α-blockers, centrally 
acting agents, vasodilators, 
etc 
Run-in and Double-blind 
Periods until Week 12 
(while on study 
medication); any time 
within 48 hours prior to 
any study visit. 
If use of prohibited medication can not be 
stopped, permanently discontinue study drug. 
Sacubitril/valsartan 
Run-in and Double-blind 
Periods until Week 12 
(while on study 
medication) 
Temporarily discontinue study drug if 
sacubitril/valsartan must be taken, and resume 
study treatment as soon as possible and as 
judged by the Investigator. 
NSAIDs (prophylactic use of 
low dose aspirin up to 325 
mg QD; 
paracetamol/acetaminophen 
are allowed*) 
Use for greater than 3 
consecutive days in the 
Run-in or 5 consecutive 
days in the Double-blind 
until Week 12 (while on 
study medication) 
NSAIDs should be discontinued immediately and 
site personnel must be notified. 

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Medication 
Prohibition period 
Action taken 
Sympathomimetic drugs, 
such as pseudoephedrine, 
phenylephrine, and other 
ephedrine derivatives, often 
found in oral/nasal 
decongestants, diet aids, 
attention deficit hyperactivity 
disorder**  
>3 days per week during 
the Run-in and 
Randomized Treatment 
Period; any time within 48 
hours prior to any study 
visit. 
Discontinue the prohibited medication as soon as 
possible. If not possible, discontinue the study 
medication. 
*Administration of paracetamol/acetaminophen (no more than 650 mg in a single dose and no more than 1300 
mg per day) or topical NSAID preparations is acceptable but must be documented. 
**Regular use of bronchodilators for asthma/COPD is acceptable but must be documented. 
6.8.3 
Rescue medicine 
After completing the Double-Blind Treatment Period when the double-blind medication will be 
discontinued, the investigator will monitor the participant’s health status and blood pressure to 
determine the need for modification of the participant’s medication regimen. At this point, the 
investigator may make any modifications to the participant’s medication regimen he/she deems 
necessary, including changes to the participant’s antihypertensive regimen. 
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) 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 
• Participants who develop severe uncontrolled hypertension during the study and whose SBP 
remains >180 mmHg. 
• Any situation in which continued study participation might result in an unacceptable safety 
risk to the participant. This includes adverse events, liver (Section 10.5) and renal 
(Section 10.6) events as described in the corresponding sections, as well as intolerance to 
investigational study drugs. 
• Following emergency unblinding 
The reasons for discontinuation from study treatment must be collected. 

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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 indicated in Section 1.3 Schedule of Assessment. 
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 all efforts should be made to continue follow-up as 
per study design; 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 
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 consented 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. 

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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. 
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 or until the end of the study. 
7.5 
Early study termination by the Sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination (may include, but are 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 rHTN. 
• Changes in XXB750 development program that renders continuation of the study 
unnecessary. 
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 into 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 

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informing IRBs (Institutional Review Board) /IECs (Independent Ethics Committee) of the 
early termination of the trial. 
8 
Study Assessments and Procedures 
The Assessment Schedule (Table 1-2) lists all the assessments and when they are performed. 
All data obtained from these assessments must be supported in the participant’s source 
documentation. 
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 1-2) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. 
Unscheduled visits can be performed by the site at the discretion of the investigator, in order to 
perform a safety evaluation or to retry assessments which were not completed at scheduled 
visits. 
Visit 100 will be considered the reference visit for all study visits during the Randomized 
Treatment Period and Safety Follow-up Period. Regardless of the occurrence of any 
unscheduled visits, scheduled visits should be performed within the specified timeframe in 
relation to Visit 100 as outlined in Table 1-2. If a visit is completed earlier than scheduled or 
postponed, it should not result in the next visit being brought forward or postponed. 
Participants who discontinue from study treatment are to return for the end of treatment visit as 
soon as possible and continue to attend any visits as indicated in the Assessment Schedule. 
Participants who discontinue from study or withdraw their consent/oppose the use of their 
data/biological samples should be scheduled for a final evaluation visit if they agree, as soon as 
possible, when all the assessments listed for the final visit will be performed. At this final visit, 
all dispensed investigational product should be reconciled, and any adverse events and 
concomitant medications not previously reported must be recorded on the CRF. 
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 and depending on operational 
capabilities, phone calls, virtual contacts (e.g. tele consult) or visits by site staff/ home nursing 
staff to the participant´s home, can replace on-site study visits, for the duration of the disruption 
until it is safe for the participant to visit the site again. 
8.1 
Screening 
Once the participant has signed the informed consent form, the participant may enter the 
screening period. 
An initial screening period can last approximately 7 days. Upon verification of eligibility 
inclusion/exclusion criteria, the participant will enter the Run-in Period. The Run-in Period will 
last up to approximately 2 weeks. 
Participants who successfully complete the Run-in Period will be randomized and enter the 
Randomized Treatment Period and receive 3 months of study treatment. 

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Participants can be re-screened once if she/he fails initial screening. 
In the case where a safety laboratory assessment at screening is outside of the allowed range 
specified in the entry criteria, a single retest to address any transient issues is allowed per the 
investigator's clinical decision. 
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 
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 
8.3.1 
Ambulatory blood pressure monitoring 
The first 24-hour ABPM assessment will be performed at Visit 30 (End of Run-in) and after the 
participant has met office BP criteria (i.e. msSBP < 180 mmHg and msDBP <110 mmHg). The 
second and third ABPM assessments will be performed at weeks 9 and week 12 (visit 160 and 
visit 170/EOT respectively), or earlier in the case of premature permanent discontinuation of 
blinded study drugs. ABPM assessments may be repeated at any of the visits listed above if 
there is a quality control finding. 
ABPM Procedures 
Patients should take their background medications in the clinic witnessed by the investigator or 
designee (and study medication when applicable) prior to attaching the ABPM device. The 
ABPM device should be attached to the non-dominant arm of the participant. The 
application/verification procedures consist of taking several readings using manual prompts to 
verify that the ABPM device is functioning properly and that no error codes are obtained during 
the application process. The verification process is not intended for comparison to the clinic 
reading but rather for confirming that the unit is working properly before prompting the 24-
hour period to begin. Following the completion of the verification readings, the investigator or 
his/her staff would prompt an additional reading to identify the “Beginning of Test” time. 
The ABPM unit will be automatically set to measure and record BP every 20 minutes during 
the day and every 30 minutes during the night. 

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8.3.4 
Appropriateness of efficacy assessments 
The efficacy of an antihypertensive drug is generally assessed by blood pressure change before 
and after starting the treatment with the drug. Blood pressure can be measured with automated 
devices for 24-hour BP monitoring and/or office BP measurement. The methodology for BP 
measurement and efficacy variables described in this protocol are appropriate and in line with 
guidelines for the treatment of hypertension and the evaluation of antihypertensive agents per 
international health authorities. 
8.4 
Safety assessments 
Safety assessments are specified below with the assessment schedule 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 (every 4 weeks or more frequently if needed) 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. A complete physical examination will include 
the 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. 
A short physical exam will include the examination of the general appearance and vital signs 
(blood pressure [SBP and DBP] and pulse). Refer to Table 1-2 for details of the type and 
frequency of the physical examination. 
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 
Adverse Event must be recorded as an adverse event. 
8.4.2 
Vital signs 
Vital signs include BP and pulse measurements. 
 
 
8.4.3 
Electrocardiograms 
Local 12 lead ECGs will be collected at Visits 1, 30, 170 and 1999. 

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ECGs will be locally collected and evaluated. Interpretation of the tracing must be made by a 
qualified physician and documented 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 screening should be reported on the appropriate CRF. Clinically 
significant findings must be discussed with Novartis prior to enrolling the participant in the 
study. New or worsened clinically significant findings occurring after informed consent must 
be recorded as adverse events. 
The original ECGs appropriately signed, must be archived at the study site. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. For any ECGs with participant safety concerns, 
two additional ECGs must be performed to confirm the safety finding. 
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events as appropriate. 
8.4.4 
Clinical safety laboratory tests 
Safety samples that can be collected remotely will be collected and analyzed in line with the 
study laboratory manual. 
If participants cannot visit the site for safety lab assessments conducted through central labs, 
local lab collection may be used 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. 
Moreover, if it will minimize the inconvenience to the subject, local laboratories may be used 
to assess eGFR and potassium levels at the end of run-in visit to assess the subject’s eligibility 
for randomization more quickly. In such case, an additional blood sample will be obtained at 
the same time to send to the central laboratory; results of the central laboratory need not confirm 
the results of the local laboratory. Results of local laboratory assessments should be recorded 
in the appropriate CRF along with their corresponding reference range. 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. 
Investigator may repeat safety tests once if results are unexpectedly out-of-range per his/her 
clinical judgement. 
Table 8-2 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 8-2 
Clinical safety laboratory tests 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Ery. Mean Corpuscular 
Hemoglobin, 
Ery. 
Mean 
Corpuscular 
HGB 
Concentration, Ery. Mean Corpuscular Volume, 
Platelets, Erythrocytes, Leukocytes, Differential (% 
Basophils, Eosinophils, Lymphocytes, Monocytes, 
Neutrophils), hemoglobin A1C 

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Test Category 
Test Name 
Chemistry 
Albumin*, Alkaline phosphatase*, ALT* , AST* , 
Gamma-glutamyl-transferase 
(GGT)*, 
Lactate 
dehydrogenase 
(LDH), 
Calcium*, 
Magnesium, 
Phosphate, 
Chloride, 
Sodium*, 
Potassium*, 
Creatinine*, Creatine kinase*, Direct Bilirubin*, Total 
Bilirubin, Fasting Lipid Panel (Total Cholesterol, LDL 
Cholesterol, 
High-density 
lipoprotein 
[HDL] 
Cholesterol, Triglycerides), Total Protein, Blood urea 
nitrogen (BUN)*, eGFR*, Uric Acid, Amylase, Lipase, 
Glucose (random) 
Urinalysis 
Microscopic Panel (Erythrocytes, Leukocytes, Casts, 
Crystals, Bacteria, Epithelial cells) 
Macroscopic Panel* (Dipstick) (Color, Bilirubin, Occult 
Blood, 
Macroscopic 
Blood, 
Glucose, 
Ketones, 
Leukocytes esterase, Nitrite, pH, Protein, Specific 
Gravity, Urobilinogen) 
Coagulation 
Prothrombin time/INR* 
Pregnancy Test 
Serum / Urine pregnancy test 
* test is part of the abbreviated panel of clinical safety laboratory tests 
8.4.5 
Pregnancy testing 
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, 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). 
All pre-menopausal women who are not surgically sterile 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 visit 30 (before randomization), Visit 170 (EOT) and Visit 1999 (EOS). Urine 
pregnancy test should be performed at Visits 130, 150 and 180. In case the urine pregnancy test 
is positive, the participant must contact and report to the investigator immediately. 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. 
If participants cannot visit the site to have serum pregnancy tests 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, urine pregnancy test may be used at home 
as described above. 
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. 

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Assessments of fertility 
Assessment of fertility must be performed at Screening. Medical documentation of 
oophorectomy, hysterectomy, or tubal ligation must be retained as source documents. 
Subsequent hormone level assessment to confirm the woman is not of child-bearing potential 
must also be available as source documentation in the following cases: 
1. Surgical bilateral oophorectomy without a hysterectomy 
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile. 
In the absence of the above medical documentation, Follicle-stimulating hormone (FSH) testing 
is required of any female participant regardless of reported reproductive/menopausal status at 
screening or baseline. 
8.4.6 
Other safety evaluations 
8.4.6.1 
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 and Table 10-3 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 10-3 and Table 10-5 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 10-4 and Table 10-5. Repeat liver chemistry tests (i.e., ALT, AST, 
total bilirubin (TBL), PT/INR, Alkaline phosphatase [ALP] and GGT) to confirm elevation. 
These liver chemistry repeats will be performed using the central laboratory. If results will not 
be available from the central laboratory, then the repeats can also be performed at a local 
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 
As well, the follow-up actions described in Section 6.5.4.1 should be performed. All follow-up 
information and findings from consultations and procedures must be recorded as appropriate in 
the CRFs. 

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by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
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, as follows: 
• mild: usually transient in nature and generally not interfering with normal activities 
• moderate: sufficiently discomforting to interfere with normal activities 
• severe: prevents normal activities 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e., progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
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 
5. Action taken 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 1999 or until 3 months after 
the last dose of injectable study drug, 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: 

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• 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 participants 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Section 10.3. 
After an AE is reported by the Investigator, Novartis may require additional information from 
the investigator on that AE. 
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 

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do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
Treatment-emergent elevations in AST or ALT (>3x ULN) in combination with total 
bilirubin >2x ULN or jaundice in the absence of cholestasis (defined as ALP < 2 ULN) or other 
causes of hyperbilirubinemia can be an indicator of severe drug induced liver injury (Hy’s Law). 
For this reason, a potential Hy’s Law case requires expedited reporting, and will be handled as 
a serious unexpected adverse event (assessing it as medically significant in the absence of any 
other seriousness criteria). It must be reported as an SAE to the sponsor promptly (i.e., even 
before all other possible causes of liver injury have been excluded). Reporting should include 
all available information, especially that needed for evaluating the diagnosis, severity and 
likelihood that the study treatment caused the reaction. For patient monitoring and to better 
understand potential etiologies, the investigator must initiate a close follow-up until complete 
resolution of the problem and completion of all attempts to obtain supplementary data. 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
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 eSAE (electronic Serious Adverse Event) with paper 
backup (as further detailed in the CRF Completion Guideline). Serious Adverse Event Report 
Form: all applicable sections of the form must be completed in order to provide a clinically 
thorough report. SAE reported after the EOS visit must be collected and reported to Novartis 
using the paper SAE form provided to the site. 
Screen failures 
SAEs occurring after the participant has provided informed consent until the time the participant 
is deemed a Screen Failure must be reported to Novartis. 
Run-in or Baseline failures 
SAEs collected between the time the participant has provided informed consent until time that 
participant is determined to be a run-in failure or a baseline failure must be reported to Novartis. 

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Randomized participants 
SAEs 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 drug (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 drug (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. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the Investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification (IN) to inform all 
Investigators involved in any study with the same study treatment that this SAE has been 
reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the EOS visit or after 3 months after the last dose of injectable 
study drug (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. 
8.6.4 
Pregnancy 
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. Any female participant that becomes pregnant after signing the 
informed consent remain in the study and continue to attend scheduled study visits unless they 
withdraw informed consent 
Pregnancy should be recorded and reported by the Investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 

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Number and percentage of participants on different antihypertensive medications as well as the 
doses will be summarized by treatment at baseline, Week 4, Week 8 and Week 12 during the 
randomized treatment period, and at Week 16 and Week 20 during safety follow-up period. The 
FAS and SAF will be used for these analyses. 
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 from baseline in mean 24 hr SBP at Week 12. 
Missing values at Week 12 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, 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. 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 mean 
24-hour ambulatory systolic blood pressure (mean 24 hr SBP) 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 mean 24 hr SBP. 
Hence, the following null and alternative hypotheses will be tested: 
• H10: there is no dose-response relationship for XXB750 (i.e. all dose groups have the same 
response mean as the placebo group). 
• H11: there is a dose-response relationship for XXB750 (i.e. at least one dose-groups has a 
response mean different from the placebo group). 
There are five candidate models to capture the shape of the dose-response relationship for 
XXB750 at Week 12 endpoint, as depicted in Figure 9-1. The candidate models generating the 
contrast weights are described below: 
• Model 1: Emax with ED50 at 30 mg SC q4w 

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• Model 2: Emax with ED50 at 60 mg SC q4w 
• Model 3: sigmoid Emax with ED50 at 30 mg SC q4w and hill parameter h=3 
• Model 4: sigmoid Emax with ED50 at 120 mg SC q4w 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 mean 24 hr SBP at Week 12 as response variable, treatment 
(placebo and XXB750 dose groups), number of antihypertensive medications ( 3 or >3), and 
region as factors, and the baseline mean 24 hr SBP as a covariate. 
The response variable of the change in mean 24 hr SBP from baseline at Week 12 used in the 
above ANCOVA model is from an imputed dataset, where missing Week 12 mean 24 hr SBP 
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 set of LS mean estimates of change of mean 24 hr SBP at Week 12 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 mean 24hr SBP 
reduction is established if the max(t1, t2,..., t5) ≥C0.025. 

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Model averaging to obtain the dose response 
A parametric bootstrap-based model averaging approach (Pinheiro et al 2014) will be 
implemented to obtain the dose response estimates according to the following steps: 
1. The parametric bootstrap procedure will draw a sample of changes of mean 24 hr SBP from 
baseline to Week 12 for all doses (including placebo) from a multivariate normal 
distribution, with mean and covariance matrix was determined using Rubin’s rule, as 
described earlier. This sample corresponds to the mean response for each dose (including 
placebo). 
2. Model selection will be performed as follows: general dose-response models as specified 
will be fit to this bootstrap sample, i.e. Emax, Sigmoid Emax and β-model will be fit to 
mean response data from placebo and XXB750 doses. The best model based on the gAIC 
criterion will be selected. 
3. The dose response estimate will be calculated for each dose group, including placebo, using 
this selected model. The difference in estimated dose response between each dose and 
placebo will also be calculated.  
4. The above procedure (steps 1-3) will be repeated 5,000 times. The mean dose-response 
estimates by dose group and mean differences of dose-response estimates between each 
XXB750 dose and placebo, the target doses of interest, as well as their 95% confidence 
intervals will be calculated based on the quantiles (median, 2.5th and 97.5th percentiles) of 
these multiple sets of dose-response and target dose estimates generated in step 3. In 
addition, the bootstrapping model-based medians over the range from 0 mg (placebo) to 240 
mg with 95% point-wise confidence interval (2.5th and 97.5th percentiles) will be displayed 
in a figure. 
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: mean 24hr SBP 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: mean 24hr SBP 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: mean 24hr SBP data collected after receiving 
prohibited concomitant medication will be used in the analysis (treatment policy strategy). 
If missing data for 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 missing 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. 

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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 mean 24hr SBP data 
collected at baseline, Week 9 and Week 12 visits, number of background antihypertensive 
medications ( 3 or >3), region, 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 hierarchical testing procedure are: (1) evaluate 
and demonstrate treatment effect of highest XXB750 dose group versus placebo in reducing the 
mean 24hr SBP from baseline to Week 12, (2) , evaluate and demonstrate treatment effect of 
highest XXB750 dose group versus placebo in reducing the average of mean 24hr SBP from 
baseline to Week 9 and Week 12 and (3) dose-response relationship in terms of proportions of 
participants achieving BP control among XXB750 dose groups and placebo. 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 using retrieved dropouts or missing at random (MAR) approaches for 
missing values after early treatment/ study discontinuation due to adverse event(s) or death may 
assign values in the XXB750 dose groups that are too favorable. Therefore, a sensitivity analysis 
will be performed where missing values after early treatment/study discontinuation due to AE 
or death will be multiply imputed based on results from similar patients in the placebo group. 
Placebo multiple imputation method will be performed, where participants randomized to 
XXB750 dose groups are assumed to be similar to placebo treated participants after drop-out. 
9.3.7 
Supplementary analysis 
The 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, number of background antihypertensive medications (3 or >3), region, visit 
(Week 9 or Week 12), and treatment-by-visit as factors, and baseline mean 24hr SBP as a 
covariate, with a common unstructured covariance matrix among visits will be used. 
Treatment comparisons at Week 12 will be provided. The analysis will be based on all 
available data up to Week 12 in the FAS and based on likelihood method with an assumption 
of missing at random for missing data. 

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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 12 assessment and repeat the analysis described 
in Section 9.3.2. 
5. 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 mean 24hr SBP and change from baseline will be summarized by 
treatment group for observed and imputed values. Figures will be produced to visually show 
the raw and the imputed mean changes by visit over 12 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 endpoints 
There are three efficacy secondary objectives: 
1. Between treatment comparison of XXB750 highest dose versus placebo in reducing the 
mean 24hr SBP from baseline at Week 12. 
2. Between treatment comparison of XXB750 highest dose versus placebo in reducing the 
average of the mean 24hr SBP from baseline at Week 9 and at Week 12 
3. To determine a dose-response signal and to characterize the dose-response relationship in 
XXB750 doses and placebo with respect to the proportion of participants achieving 
BP control at week 12. 
The efficacy variable in secondary objective 1 is the change from baseline at Week 12 in the 
mean 24hr SBP and will be analyzed using a repeated measures ANCOVA model with 
treatment, number of background antihypertensive medications ( 3 or >3), region, visit (Week 
9 or Week 12), and treatment-by-visit as factors, and baseline mean 24hr SBP as a covariate, 
with a common unstructured covariance matrix among visits. The analysis time point for the 
treatment comparisons is at Week 12. 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 

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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 is the average change from baseline at Week 
9 and Week 12 in the mean 24hr SBP and will be analyzed using an analysis of covariance 
(ANCOVA) model including treatment, number of background antihypertensive medications 
(3 or >3), and region as fixed-effect factors and baseline mean 24hr SBP as covariate. Within 
treatment and between treatment comparisons 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 3 is the achievement of BP control by ABPM 
(i.e., mean 24hr SBP <130 mmHg and 24-hour mean ambulatory diastolic blood pressure (mean 
24hr DBP) <80 mmHg) at Week 12. 
There are five candidate models to capture the shape of the dose-response relationship for 
XXB750 with respect to the proportion of participants with BP control at Week 12, as depicted 
in Figure 9-2. The candidate models generating the contrast weights are described below: 
• Model 1: Emax with ED50 at 30 mg SC q4w 
• Model 2: Emax with ED50 at 60 mg SC q4w 
• Model 3: sigmoid Emax with ED50 at 30 mg SC q4w and hill parameter h=3 
• Model 4: sigmoid Emax with ED50 at 120 mg SC q4w and hill parameter h=3 
• Model 5: Beta-model with delta1=0.2, delta2=0.3 and scale=288 
Figure 9-2 
Dose-response curve of candidate models for proportion of 
participants with BP control 
 

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The analysis method of generalized MCP-Mod for binary data is similar as the primary analysis 
described in Section 9.3.2, but with the response for participant i in treatment k, Yki, follows a 
Bernoulli(pk), where pk is the probability of participants achieving BP control in treatment group 
k. And logit(pk) will be estimated using a logistic regression with treatment (placebo and 
XXB750 dose groups), number of background antihypertensive medications( 3 or >3), and 
region as factors, and the baseline mean 24hr SBP and mean 24hr DBP as covariates. The 
intercurrent events and corresponding handling strategy are described in Section 3.2, and the 
handling of missing not related to intercurrent events in Section 9.3.2 and Section 9.3.4 so that 
achievement of BP control will be based on imputed mean 24hr SBP and mean 24hr DBP at 
Week 12. Participants with intercurrent events will be imputed as not having BP control in the 
analysis. 
The statistical testing procedure described below will be carried out for the multiple treatment 
comparisons in the primary and secondary efficacy objectives to ensure that the overall 
significance level for the multiple hypotheses to be tested is controlled at the one-sided 0.025 
level (i.e. two-sided 0.05). 
The testing hypotheses associated with secondary efficacy objectives are described below: 
• H20: No difference in the change of mean 24hr SBP from baseline at Week 12 between 
highest XXB750 dose versus placebo. 
• H30: No difference in average change of mean 24hr SBP from baseline at Week 9 and at 
Week 12 between highest XXB750 dose versus placebo. 
• H40: There is no dose-response relationship for XXB750 (i.e. all dose groups have the same 
response as the placebo group) in terms of proportions of participants achieving blood 
pressure control at Week 12. 
The testing procedure is to be based on the sequentially rejective multiple test procedure pre-
specified in controlling overall type I error (Bretz et al 2009) and H10 of the primary hypothesis 
will be initially test first at the one-sided 0.025 significance level. If the primary hypothesis can 
be rejected, the relocation of its significance level with a weight of 1 to the other hypotheses is 
specified in Figure 9-3 below. The sequentially rejective multiple test procedure is completed 
until no more hypothesis can be further rejected. 
Figure 9-3 
Sequentially rejective multiple testing procedure 
 
Number and percentage of participants with ambulatory BP control will be summarized by 
treatment group for observed and imputed values. Figures will be produced to visually show 
the raw and the imputed ambulatory BP control by visit over 12 weeks randomized treatment 
epoch for each treatment group. FAS will be used for the analyses. 

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9.4.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings, figures and tables will be 
presented by treatment group. 
Adverse events 
All information obtained on adverse events will be displayed by treatment group. 
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 Medical Dictionary for Regulatory Activities (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 
from being not suspected to being suspected of study treatment relationship, or developed into 
SAEs after the start of the treatment period. 
More details on the analysis of AE will be described in the Statistical Analysis Plan (SAP). 
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 Visit 1, visit 30, visit 170 and visit 1999. 
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 

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9.7 
Other analyses 
Subgroup analyses 
The subgroups of interest for primary endpoint and selected secondary endpoints include but 
are not limited to: 
• Age (<60, >=60 years) 
• Age (<=median, > median) 
• Sex (male, female) 
• Region 
• Number of background antihypertensive medications (3, >3) 
• eGFR (<60, >=60 mL/min/1.73m2) 
Please refer to statistical analysis plan for details. 
9.8 
Interim analysis 
One interim safety analysis will be conducted when approximately first 40 participants 
complete at least 5 weeks of double-blind treatment. Regular safety data monitoring is planned 
as specified in Section 4.6. No alpha adjustment will be made for the interim safety analysis 
and safety data monitoring. Interim safety analysis 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 12 (or 
discontinued prior to Week 12). A final analysis will be performed after all participants have 
completed Week 20 (or discontinued prior to Week 20). Formal testing of the primary endpoint 
with full level alpha of 0.025 (1-sided) will be performed at the primary analysis timepoint. 
9.9 
Sample size determination 
9.9.1 
Primary endpoint(s) 
The study is planned to randomize 170 participants including approximately 10% lost to follow-
up, allocated in the ratio of 1:1:1:1:1 to placebo, XXB750 30 mg SC q4w, 60 mg SC q4w, 
XXB750 120 mg SC q4w and XXB750 240 mg SC q4w, respectively. 
Assuming a common standard deviation of 12 mmHg for mean 24hr SBP change from baseline 
and a one-sided 2.5% significance level (with adjustments for multiple comparisons using 
MCP-MOD), a sample size of 150 participants (30 each in placebo, XXB750 30 SC q4w, 
XXB750 60 mg SC q4W, and XXB750 120 mg SC q4w, and XXB750 240 mg SC q4w) will 
provide a minimum power of 92% if the underlying true maximum mean 24hr SBP reduction 
on XXB750 vs placebo is 10 mmHg. 

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9.9.2 
Secondary endpoint(s) 
Assuming a common standard deviation of 12 mmHg for mean 24hr SBP change from baseline 
and a one-sided 2.5% significance level, a sample size of 30 participants in placebo and in 
XXB750 highest dose, respectively, will provide approximately 89% power if the true mean 
24hr SBP reduction on XXB750 vs placebo is 10 mmHg. 
Secondly, same assumption as first secondary endpoint is used for the average change from 
baseline in mean 24hr SBP at Week 9 and at Week 12 and a one-sided 2.5% significance level , 
a sample size of 30 participants in placebo and in XXB750 highest dose, respectively, will 
provide approximately 89% power if the true mean 24hr SBP reduction on XXB750 vs placebo 
is 10 mmHg.  
Lastly, assuming a one-sided 2.5% significance level (with adjustments for multiple 
comparisons using MCP-MOD), a sample size of 150 participants (30 each in placebo, XXB750 
30 mg SC q4w, XXB750 60 mg SC q4W, XXB750 120 mg SC q4w, and in XXB750 240 mg 
SC q4w) will provide a minimum power of 76% if the underlying true BP control achievement 
in placebo and XXB750 doses range from 10% to 45%, respectively. 

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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: 
• 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, Investigational directions for 
use (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. 

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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. 
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 participant or their legally authorized representative) and answer all 
questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants 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. Participants who are rescreened 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. 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 participants 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) and Core Data Sheet for marketed drugs. 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 

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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: 
• 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  
• Optional Genetics Consent to provide a sample for 
 
The study includes an optional sub studies/ 
 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 
 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. 
The study includes the option for the participant to have certain study procedures performed 
off-site by an off-site healthcare professional instead of at the study site, for which a separate 
signature is required if the participant agrees. It is required as part of this protocol that the 
Investigator presents this option to the participant, as permitted by national and local governing 
regulations. The process for obtaining consent should be exactly the same as described above 
for the main informed consent. 
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. 

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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. 
Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws. 
10.1.4 
Committees structure 
The study will have support of a Data Monitoring Committee and an Executive Committee. 
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 the clinical trial, safety data, and critical efficacy variables as needed and recommend 
to Novartis whether to continue, modify, or terminate the trial. 
Specific details regarding composition, responsibilities, data monitoring, 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 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. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 25 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-

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enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC (Electronic Data Capture) 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-Contract Research Organization) 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 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. 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. 

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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 these 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 (defined as last participant last visit) 
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). 
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. 
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, 

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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 
ABPM 
Ambulatory Blood Pressure Monitoring 
ACEi 
Angiotensin Converting Enzyme Inhibitor 
 
 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANA 
Antinuclear Antibodies 
ANCOVA 
Analysis of covariance 
ANP 
Atrial Natriuretic Peptide 
ARB 
Angiotensin Receptor Blocker 
ARNI 
Angiotensin Receptor Neprilysin Inhibitor 
AST 
Aspartate Aminotransferase 
AUC 
Area Under Curve 
BNP 
B-type natriuretic peptide 
BP 
Blood Pressure 
BUN 
Blood Urea Nitrogen 
CCB 
Calcium Channel Blocker 
cGMP 
cyclic guanosine monophosphate 
CKD 
Chronic Kidney Disease 
CMV 
cytomegalovirus 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CV 
Cardiovascular 
DBP 
Diastolic Blood Pressure 
DILI 
Drug Induced Liver Injury 
DMC 
Data Monitoring Committee 
EBV 
Epstein Barr virus 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
estimated Glomerular Filtration Rate 
EOS 
End of Study 
EOT 
End of Treatment 
ESRD 
End-Stage Renal Disease 
FAS 
Full Analytical Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLDH 
Glutamate Dehydrogenase 
 
 
hr 
Hour 
HSV 
Herpes simplex virus 
HTN 
Hypertension 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human 
Use 
IEC 
Independent Ethics Committee 

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IMP 
Investigational Medicinal Product 
IN 
Investigator Notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IV 
Intravenous (IV) 
IWRS 
Interactive Web Response System 
LCMS 
Liquid Chromatography tandem Mass Spectrometry 
LFT 
Liver function test 
MAR 
Missing at random 
MCP-
MOD 
Multiple Comparison Procedure- Modeling 
mg 
milligram(s) 
mL 
milliliter(s) 
MRA 
Mineralocorticoid Receptor Antagonist 
msDBP 
mean sitting Diastolic Blood Pressure 
msSBP 
mean sitting Systolic Blood Pressure 
mwSBP 
mean weekly Systolic Blood Pressure 
NP 
Natriuretic Peptide 
NPR 
Natriuretic peptide receptor 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
PDE-5 
Phosphodiesterase-5 
PK 
Pharmacokinetic(s) 
PT 
prothrombin time 
q4w 
once every 4 weeks 
QA 
Quality Assurance 
RAAS 
Renin Aldosterone Angiotensin System 
RAS 
Randomized Analysis Set 
rHTN 
Resistant Hypertension 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SC 
Subcutaneous 
SCR 
Screened Set 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SoA 
Schedule of Activities 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBL 
Total Bilirubin 
ULN 
upper limit of normal 
10.2.2 
Definitions 
Assessment 
A procedure used to generate data required by the study 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, urine, 
stool, etc. taken from a study participant 
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. 

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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. 
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 
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 
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. 
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. 
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 
Personal data 
Participant information collected by the Investigator that is coded and transferred to 
Novartis 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 or prior to administration of single blind study 
medication 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 
Run-in Failure 
A participant who is screened but not randomized/treated after the run-in period (where 
run-in period requires adjustment to participant's intervention or other treatment) 
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 

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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), control(s) or 
background therapy 
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. 

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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] (CTCAE) v 5.0 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 abnormally high. 
ALT (SGPT) 
Increase 
value > 5 x ULN if baseline was 
normal OR value > 5 x baseline if 
baseline was abnormally high. 
AST (SGOT) 
Increase 
value > 5 x ULN if baseline was 
normal OR value > 5 x baseline if 
baseline was abnormally high. 
Total bilirubin 
Increase 
value > 3 x ULN if baseline was 
normal OR value > 3 x baseline if 
baseline was abnormally high. 
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 
Not applicable. 

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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 
† Please, consult Section 8.6.2 on reporting requirements of potential Hy's Law cases 

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Table 10-4 
Follow-up requirements for liver triggers (based on ALT, AST and TBL 
values) 
 
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, 
TBIL, 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 
drug 
· Measure ALT, 
AST, ALP, GGT, 
TBIL, INR, albumin, 
CK, and GLDH in 
48-72 hours. 
· Follow-up for 
symptoms. 
· Initiate close 
monitoring and 
workup for 
competing 
etiologies. 
· Study drug 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 x 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., conmeds, med hx, 
lab)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), bicarbonate 
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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10.8 
Appendix 8: Recommended minimum doses of background 
medication 
Table 10-7, Table 10-8, Table 10-9, Table 10-10 list the minimum doses of commonly 
prescribed thiazide/thiazide-like diuretics, long-acting dihydropyridine CCBs, ACEIs, and 
ARBs the participant is recommended be on . 
If the participant is not receiving the maximum dose per locally approved label and/or treatment 
guideline, the reason for that must be properly documented in the participant’s eCRF. 
Table 10-7 
Thiazide or thiazide-like diuretics 
Medication name 
Minimum daily dose 
Chlorthalidone 
12.5 mg 
Hydrochlorothiazide 
25 mg 
Metolazone 
2.5 mg (or 0.5 mg SR) 
Indapamide 
2.5 mg (or 1.25 mg XL) 
Bendroflumethiazide 
2.5 mg 
Hydroflumethiazide 
25 mg 
Trichlormethiazide 
2 mg 
Xipamide  
20 mg 
 Potassium sparing diuretics (excluding MRAs such as spironolactone and eplerenone) either in combination or 
in addition to Thiazide / thiazide like diuretics are allowed. 
Table 10-8 
Long-acting dihydropyridine calcium channel blockers (CCBs) 
Drug name 
Minimum daily dose 
Amlodipine 
5 mg 
Nifedipine (extended release) 
60 mg 
Felodipine (extended release) 
5 mg 
Lercanidipine 
20 mg 
Nitrendipine 
20 mg OD (long acting) 
Table 10-9 
Angiotensin converting enzyme inhibitors 
Drug name 
Minimum daily dose 
Benazepril 
20 mg 
Captopril 
100 mg (50 mg BID) 
Cilazapril 
5 mg 
Enalapril 
20 mg 
Fosinopril 
40 mg 
Imidapril 
10 mg 
Lisinopril 
20 mg 
Moxepril 
15 mg 
Perindopril 
4 mg 
Quinapril 
20 mg 
Ramipril 
10 mg 
Trandolapril 
4 mg 
Zofenopril 
60 mg 

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Table 10-10 
Angiotensin receptor blockers 
Drug name 
Minimum daily dose 
Losartan 
100 mg 
Candesartan 
16 mg 
Eprosartan 
600 mg 
Irbesartan 
150 mg 
Telmisartan 
40 mg 
Olmesartan 
20 mg 
Azilsartan medoximil 
40 mg 
Valsartan 
160 mg 

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11 
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