Clinical trial NCT05103332
Conditions: Hypertension
Keywords: High blood pressure Hypertension Hypertensive siRNA Angiotensinogen AGT
Sponsor: Alnylam Pharmaceuticals
Start date: 2021-11-05; Completion date: 2024-09-13
Enrollment: 663 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the effect of zilebesiran on systolic and diastolic blood pressure and to characterize the pharmacodynamic (PD) effects and safety of zilebesiran as add-on therapy.

Detailed description:

Arms: arm 1: Following a 4-week run-in treatment on indapamide, 2.5 milligrams (mg), orally, once daily (QD), eligible participants were randomized to receive placebo matched to zilebesiran as a subcutaneous (SC) injection on Day 1 of 6-month double-blind (DB) treatment period as add-on therapy to indapamide. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran once every 6 months (Q6M) during the open-label extension (OLE) period. Upon implementation of Amendment 3, the OLE period was closed. arm 2: Following a 4-week run-in treatment on indapamide, 2.5 mg, orally, QD, eligible participants were randomized to receive zilebesiran 600 mg, as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to indapamide. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran, Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed. arm 3: Following a 4-week run-in treatment on amlodipine, 5 mg, orally, QD, eligible participants were randomized to receive placebo matched to zilebesiran as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to amlodipine. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed. arm 4: Following a 4-week run-in treatment on amlodipine, 5 mg, orally, QD, eligible participants were randomized to receive zilebesiran 600 mg, as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to amlodipine. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran, Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed. arm 5: Following a 4-week run-in treatment on olmesartan, 40 mg, orally, QD, (or 20 mg, orally, QD for participants with creatinine clearance ≤60 milliliters per minute \[mL/min\] at screening enrolled at sites outside of the United States \[US\] consistent with local labeling), eligible participants were randomized to receive placebo matched to zilebesiran as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to olmesartan. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed. arm 6: Following a 4-week run-in treatment on olmesartan, 40 mg, orally, QD, (or 20 mg, orally, QD for participants with creatinine clearance ≤60 mL/min at screening enrolled at sites outside of the US consistent with local labeling), eligible participants were randomized to receive zilebesiran 600 mg, as a SC injection on Day 1 of 6-month DB treatment period as add-on therapy to olmesartan. Participants received protocol-assigned background medication for 6 months, after which it was discontinued. Thereafter, participants will receive zilebesiran, Q6M during the OLE period. Upon implementation of Amendment 3, the OLE period was closed.
Interventions: intervention 1: Indapamide intervention 2: Amlodipine intervention 3: Olmesartan intervention 4: Placebo intervention 5: Zilebesiran
Intervention descriptions: intervention 1: Indapamide administered orally intervention 2: Amlodipine administered orally intervention 3: Olmesartan administered orally intervention 4: Placebo administered by SC injection intervention 5: Zilebesiran administered by SC injection

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 3, 20 July 2023 
Alnylam Pharmaceuticals 
Confidential 
1 
 
CLINICAL STUDY PROTOCOL 
ALN-AGT01-003 
DATED 20 JULY 2023 
 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled, Multicenter 
Study to Evaluate the Efficacy and Safety of Zilebesiran Used as 
Add-on Therapy in Patients With Hypertension Not Adequately 
Controlled by a Standard of Care Antihypertensive Medication  
Short Title: 
Zilebesiran as Add-on Therapy in Patients With Hypertension Not 
Adequately Controlled by a Standard of Care Antihypertensive 
Medication (KARDIA-2)  
Study Drug: 
Zilebesiran (ALN-AGT01)  
EudraCT Number: 
2021-003776-13 
IND Number: 
143503 
Protocol Date: 
Original protocol, 25 August 2021 
Amendment 1, 22 March 2022 
Amendment 2, 22 September 2022 
Amendment 3, 20 July 2023 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Telephone: +1-617-551-8200 
Sponsor Contact:  
 
  
The concepts and information contained in this document or generated during the study are considered 
proprietary and may not be disclosed in whole or in part without expressed written authorization of 
Alnylam Pharmaceuticals, Inc. 
 
PPD
PPD


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 3, 20 July 2023 
Alnylam Pharmaceuticals 
Confidential 
2 
SPONSOR PROTOCOL APPROVAL 
 
I have read this protocol and I approve the design of this study. 
 
 
 
 
___________________________________________  
 
 
Alnylam Pharmaceuticals, Inc. 
 
 
___________________________________________  
Date 
PPD
PPD


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 3, 20 July 2023 
Alnylam Pharmaceuticals 
Confidential 
3 
INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-AGT01-003 protocol and agree to conduct the study in accordance with the 
protocol and all applicable regulations. I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol.  
 
___________________________________________  
Printed Name of Investigator 
 
___________________________________________  
Signature of Investigator 
 
___________________________________________  
Date 






Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 3, 20 July 2023 
Alnylam Pharmaceuticals 
Confidential 
6 
Study Design 
This is a Phase 2 randomized, double-blind (DB), placebo-controlled, multicenter study to 
evaluate the efficacy, safety, and pharmacodynamics (PD) of zilebesiran administered 
subcutaneously (SC) as an add-on therapy in patients with hypertension despite treatment with a 
standard of care antihypertensive medication. A schematic of the study design is provided in 
Figure 1. 
Patients who complete the Screening period and meet all inclusion/exclusion criteria for 
enrollment will be randomized to receive open-label therapy with olmesartan (40 mg orally once 
daily [or 20 mg orally once daily for patients with creatinine clearance ≤60 mL/min at screening 
enrolled at sites outside of the United States (US) or Australia, consistent with local labeling for 
olmesartan]), amlodipine (5 mg orally once daily), or indapamide (2.5 mg orally once daily) as 
their protocol-specified background antihypertensive medication during a Run-in period of at 
least 4 weeks. 
Patients who meet all inclusion/exclusion criteria after the Run-in period will be randomized 1:1 
to receive 600 mg zilebesiran SC or placebo SC on Day 1 of a 6-month DB treatment period as 
add-on therapy to their protocol-specified background antihypertensive medication.  
Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive 
medications”) may be added to the patient’s protocol-specified background antihypertensive 
medication per Investigator judgement for elevated blood pressure. 
After the 6-month DB period, protocol-specified background antihypertensive medications will 
be discontinued, and patients may have been eligible to participate in a separate zilebesiran 
open-label extension (OLE) study. If an individual patient reached Month 6 prior to availability 
of the separate OLE study, they may have received open-label zilebesiran at 600 mg SC once 
every 6 months for up to 30 additional months during the OLE period until the separate OLE 
study was open and then transition. Upon implementation of Amendment 3, the OLE period will 
be closed because a separate OLE study will not be conducted. Patients in the 6-month DB 
period will continue their planned visits through the end of the 6-month DB period and then enter 
the Safety Follow-up period. Patients will not receive a dose of study drug at Month 6. Patients 
who are already in the OLE period will not receive any additional doses of study drug. Patients 
should complete all planned assessments at Months 7, 8, and 9. For visits at Month 12 or later, 
patients should complete end of treatment (EOT) assessments in lieu of their scheduled visit 
assessments and enter the Safety Follow-up period. 
Number of Planned Patients 
The planned enrollment for this study is approximately 1800 patients to be randomized into the 
Run-in period and approximately 630 patients (300 patients in the olmesartan arm, 210 patients 
in the amlodipine arm, and 120 patients in the indapamide arm) to be randomized in the DB 
period. 
Diagnosis and Main Eligibility Criteria 
This study will include adults (18 to 75 years, inclusive, at time of initial informed consent) with 
untreated hypertension or on stable therapy with up to 2 antihypertensive medications. Patients 
should have a 24-hour mean systolic blood pressure (SBP) ≥130 mmHg and ≤160 mmHg by 
ambulatory blood pressure monitoring (ABPM) after at least 4 weeks of run-in on protocol-


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 3, 20 July 2023 
Alnylam Pharmaceuticals 
Confidential 
7 
specified background antihypertensive medication. Patients with secondary hypertension or 
orthostatic hypotension will be excluded. 
Study Drug, Dose, and Mode of Administration 
Zilebesiran is an SC administered N-acetylgalactosamine (GalNAc)-conjugated small interfering 
RNA (siRNA) targeting liver-expressed messenger RNA (mRNA) for angiotensinogen (AGT). 
Patients randomized to receive zilebesiran will be administered 600 mg SC once during the 6-
month DB treatment period. Before Amendment 3, patients who entered the OLE period 
received 600 mg zilebesiran SC at Month 6 after all predose assessments were conducted and 
once every 6 months during the OLE period. Upon implementation of Amendment 3, patients in 
the 6-month DB period will continue their planned visits through the end of the 6-month DB 
period but will not be eligible to enter the OLE period and receive a dose of study drug at 
Month 6. Patients in the OLE period will not receive any additional doses of study drug. 
Reference Treatment, Dose, and Mode of Administration 
Placebo (phosphate-buffered saline for SC administration) will be administered at the same 
dosing interval and volume as the study drug during the 6-month DB period. 
Protocol-specified Background Antihypertensive Medication, Dose, and Mode of 
Administration 
Patients will be randomized to 1 of the following protocol-specified background antihypertensive 
medications to be administered orally once daily during the Run-in and 6-month DB periods: 
• Olmesartan: 40 mg (or 20 mg for patients with creatinine clearance ≤60 mL/min at 
screening enrolled at sites outside of the US or Australia, consistent with local 
labeling). At the Investigator’s discretion, patients who are randomized to receive 40 
mg olmesartan once daily may initiate treatment at 20 mg once daily and then 
uptitrate to the full dose of 40 mg once daily after 1 to 2 weeks. 
• Amlodipine: 5 mg  
• Indapamide: 2.5 mg  
Duration of Treatment and Study Participation 
The duration of treatment with zilebesiran is up to 36 months. The estimated total time on study 
for each patient is up to approximately 45 months, including up to 75 days in the Screening and 
Run-in periods, up to 36 months of treatment, and up to 12 months after the last dose of study 
drug in the Safety Follow-up period. 
Statistical Methods 
The planned enrollment for this study is approximately 1800 patients to be randomized into the 
Run-in period and approximately 630 patients (300 patients in the olmesartan arm, 210 patients 
in the amlodipine arm, and 120 patients in the indapamide arm) to be randomized in the DB 
period. Randomization on Day 1 will be stratified by race (black or all other races), baseline 


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 3, 20 July 2023 
Alnylam Pharmaceuticals 
Confidential 
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blood pressure (24-hour mean SBP < or ≥145 mmHg), and screening estimated glomerular 
filtration rate (<60 or ≥60 mL/min/1.73m2). 
For the primary endpoint, assuming a standard deviation of 16 mmHg in change from baseline in 
24-hour mean SBP assessed by ABPM and 15% dropout rate from baseline to Month 3, with 2-
sided significance level of 0.05 for each of the comparisons (zilebesiran versus placebo as add-
on to olmesartan; zilebesiran versus placebo as add-on to amlodipine; zilebesiran versus placebo 
as add-on to indapamide), these sample sizes will provide at least 80% power to detect the 
following difference between zilebesiran versus placebo: 
• 5 mmHg as add-on to olmesartan  
• 6 mmHg as add-on to amlodipine 
• 8 mmHg as add-on to indapamide 
The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS): All randomized patients who received any amount of study 
drug. All by-treatment analyses based on the FAS will be grouped according to the 
randomized treatment arm.  
• Safety Analysis Set: All patients who received any amount of study drug. All by-
treatment analyses based on the Safety Analysis Set will be grouped according to the 
treatment actually received. 
• Pharmacokinetic (PK) Analysis Set: All patients who received at least 1 full dose of 
zilebesiran and have at least 1 nonmissing postdose PK assessment. 
• PD Analysis Set: All patients who received at least 1 full dose of study drug. All by-
treatment analyses based on the PD Analysis Set will be grouped according to the 
treatment actually received. 
• All Zilebesiran Treated Set: All patients who received any amount of zilebesiran, 
including patients who took zilebesiran during the 6-month DB period and patients 
who initially took placebo and then switched to zilebesiran after the Month 6 visit. 
For the analyses of the 6-month DB period, the analysis population used to evaluate efficacy will 
be the FAS. Safety data will be analyzed using the Safety Analysis Set. The PK and PD Analysis 
Sets will be used to conduct PK and PD analyses, respectively.  
The All Zilebesiran Treated Set will be used to summarize the efficacy and safety of zilebesiran 
throughout the 6-month DB period and the OLE period. 
To control the overall type I error, the primary and key secondary endpoints will be tested in 
hierarchical order. 
 


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 3, 20 July 2023 
Alnylam Pharmaceuticals 
Confidential 
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Figure 1: 
Study Design 
 
Abbreviations: aHTN=antihypertensive medication; BL=baseline; DB=double-blind; EOT=end of treatment; 
M=month; OLE=open-label extension; PBO=placebo; PO=per os (oral); qd=once daily; q6M=once every 6 months; 
R=randomization; SC=subcutaneous. 
Note: Patients may have been eligible to participate in a separate zilebesiran OLE study upon completion of the 
Month 6 predose assessments. If an individual patient reached Month 6 prior to availability of the separate OLE 
study, they may have received open-label zilebesiran once every 6 months in the OLE period for up to 30 additional 
months during the OLE period until the OLE study was open and then transition. Upon implementation of 
Amendment 3, the OLE period will be closed because a separate OLE study will not be conducted. Patients in the 
6-month DB period will continue their planned visits through the end of the 6-month DB period and then enter the 
Safety Follow-up period. Patients will not receive a dose of study drug at Month 6. Patients who are already in the 
OLE period will not receive any additional doses of study drug. Patients should complete all planned assessments at 
Months 7, 8, and 9. For visits at Month 12 or later, patients should complete EOT assessments in lieu of their 
scheduled visit assessments and enter the Safety Follow-up period. Patients who were previously taking 
antihypertensives at screening should discontinue these medications at Run-in Visit 1. 
 












Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 3, 20 July 2023 
Alnylam Pharmaceuticals 
Confidential 
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HbA1c=hemoglobin A1C; HBPM=home blood pressure monitoring; ICF=informed consent form; LFT=liver function test; M=month; No.=number; OLE=open-
label extension; PD=pharmacodynamics; PK=pharmacokinetics; Q6M=once every 6 months; RAAS=renin-angiotensin-aldosterone system; SAE=serious 
adverse event; W=week. 
 
Notes:  
• 
When scheduled at the same time points and where feasible, the assessments of vital signs and blood sample collections for RAAS biomarkers (renin, 
aldosterone, and Ang I/II) should be performed before physical examinations and 12-lead ECGs. 
• 
Run-in Visit 2 should occur at least 4 weeks after Run-in Visit 1. 
• 
Patients may have been eligible to participate in a separate zilebesiran OLE study upon completion of the Month 6 predose assessments. If an individual 
patient reached Month 6 prior to availability of the separate OLE study, they may have received open-label zilebesiran beginning at the Month 6 visit 
and continue for up to 30 additional months during the OLE period until the separate OLE study was open and then transition. Upon implementation of 
Amendment 3, the OLE period will be closed because a separate OLE study will not be conducted. Patients in the 6-month DB period will continue their 
planned visits through the end of the 6-month DB period and then enter the Safety Follow-up period. Patients will not receive a dose of study drug at 
Month 6. Patients who are already in the OLE period will not receive any additional doses of study drug. Patients should complete all planned 
assessments at Months 7, 8, and 9. For visits at Month 12 or later, patients should complete EOT assessments in lieu of their scheduled visit assessments 
and enter the Safety Follow-up period. 
• 
Patients will be asked to perform Safety Follow-up visits once every 6 months after the last dose of study drug until serum AGT levels return to ≥50% 
of their individual mean baseline level (if known) or 12 months after the last dose of study drug, whichever comes earlier. During this Follow-up period, 
HBPM monitoring may continue at the discretion of the Investigator. The ADA sample should only be collected at the first Follow-up visit during the 
Follow-up period. 
• 
Patients who discontinue study drug prior to the Month 6 visit will also be asked to complete the remainder of scheduled study visits and assessments 
(except for study drug administration) through Month 6. If a patient discontinues study drug after the Month 6 visit, EOT/ET assessments should be 
performed.  
Footnotes: 
a All assessments, except for postdose PK sample collection (Table 2), are to be performed prior to administration of protocol-specified background 
antihypertensive medications (including Run-In Visit 1) and study drug (as applicable).  
b When applicable, pregnancy test results must be known prior to dosing with study drug at dosing visits.  
c Laboratory assessments at Day 1 do not need to be repeated, per Investigator discretion, if they were collected within 7 days before Day 1 at Run-in Visit 2.  
d Office blood pressure must be measured before the patient takes oral antihypertensive medications or study drug (as applicable).  
e ABPM recordings associated with study drug dosing visits should be obtained within 7 days before the visit and results reviewed before dosing.  
f HBPM should be measured at least 3 times during the week prior to the second randomization to establish baseline. After Day 1, HBPM should be measured at 
least once per week in the morning upon waking and may be increased at the Investigator’s discretion if more frequent measurement is warranted. HBPM is not 
required on days when ABPM is being assessed. In the Safety Follow-up period, the frequency of HBPM assessments can be reduced after the first Safety 
Follow-up visit per Investigator judgement. 
g Neurological evaluation will also be performed as part of the full physical examination. 
h ABPM should only be performed as part of ET assessments if the patient discontinues the study prior to Month 12 and has not had an ABPM within the last 3 
months. ABPM should not be performed at Month 36. 


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 3, 20 July 2023 
Alnylam Pharmaceuticals 
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Table 2: 
PK Time Points 
Study Day 
Sampling Time 
(hh:mm) 
Plasma PK Sample 
Day 1  
Predose (any time before dosing) 
X 
04:00 (±30 min) 
X 
Day 169±7 
Predose (any time before dosing) 
X 
04:00 (±30 min) 
X 
Abbreviations: hh:mm=hour:minute; min=minutes; PK=pharmacokinetics. 
Notes:  
• 
The hour (±range) indicates sample collection timing relative to dosing. Precise PK sample times (hour and 
minute) are recorded. Refer to Section 6.4 for additional information on PK assessments. 
 


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 3, 20 July 2023 
Alnylam Pharmaceuticals 
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TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................17 
LIST OF TABLES .........................................................................................................................21 
LIST OF FIGURES .......................................................................................................................21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................22 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Study Rationale ...........................................................................................................24 
1.2. 
Background .................................................................................................................24 
1.3. 
Benefit-Risk Assessment ............................................................................................26 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................27 
3. 
INVESTIGATIONAL PLAN .....................................................................................29 
3.1. 
Summary of Study Design ..........................................................................................29 
3.2. 
Scientific Rationale for Study Design ........................................................................30 
3.3. 
Justification for Dose ..................................................................................................32 
3.4. 
Method of Assigning Patients to Treatment Groups ..................................................33 
3.5. 
Blinding ......................................................................................................................33 
3.5.1. 
Emergency Unblinding ...............................................................................................34 
3.6. 
Data Monitoring Committee .......................................................................................34 
3.7. 
Clinical Event Adjudication Committees ...................................................................34 
3.8. 
Definition of End of Study for an Individual Patient .................................................34 
4. 
SELECTION AND REMOVAL OF PATIENTS ......................................................34 
4.1. 
Inclusion Criteria ........................................................................................................34 
4.2. 
Exclusion Criteria .......................................................................................................35 
4.3. 
Removal from Study Drug or Assessment .................................................................37 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................38 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................39 
4.3.2.1. 
Patient Stops Participation in the Study ......................................................................39 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data or Objection 
to Process Patient’s Personal Data ..............................................................................39 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................40 


Clinical Study Protocol ALN-AGT01-003  
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4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................40 
4.3.3. 
Lost to Follow-Up.......................................................................................................40 
4.3.4. 
Replacement of Study Patients ...................................................................................40 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................41 
5.1. 
Treatments Administered ............................................................................................41 
5.2. 
Study Drug ..................................................................................................................41 
5.2.1. 
Description ..................................................................................................................41 
5.2.2. 
Dose and Administration ............................................................................................41 
5.2.3. 
Dose Modifications .....................................................................................................42 
5.2.4. 
LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing...........42 
5.2.5. 
Neurological Criteria for Withholding, Monitoring, and Stopping Study 
Drug Dosing ................................................................................................................43 
5.3. 
Protocol-specified Background Antihypertensive Medications .................................43 
5.4. 
Preparation, Handling, and Storage ............................................................................44 
5.5. 
Packaging and Labeling ..............................................................................................44 
5.6. 
Accountability .............................................................................................................45 
5.7. 
Clinical Product Complaints .......................................................................................45 
5.7.1. 
Definition ....................................................................................................................45 
5.7.2. 
Reporting ....................................................................................................................45 
5.8. 
Monitoring for Potential Clinical Events ....................................................................45 
5.8.1. 
Monitoring and Approach for Potential Hypotension ................................................45 
5.8.2. 
Monitoring and Approach for Clinically Significant Blood Pressure 
Elevation .....................................................................................................................46 
5.8.3. 
Monitoring and Approach for Potential Renal Dysfunction .......................................48 
5.8.4. 
Monitoring and Approach for Potential Hyperkalemia ..............................................49 
5.9. 
Concomitant Medications and Procedures .................................................................50 
5.9.1. 
Prohibited Concomitant Medication ...........................................................................51 
5.10. 
Treatment Compliance ................................................................................................51 
5.11. 
Other Requirements ....................................................................................................51 
5.11.1. 
Contraception ..............................................................................................................51 
5.11.2. 
Alcohol Restrictions ...................................................................................................52 
5.11.3. 
Tobacco and Nicotine Restrictions .............................................................................53 
5.11.4. 
Dietary Recommendations ..........................................................................................53 


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 3, 20 July 2023 
Alnylam Pharmaceuticals 
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5.11.5. 
Exercise .......................................................................................................................53 
6. 
STUDY ASSESSMENTS ..........................................................................................53 
6.1. 
Screening Assessments ...............................................................................................53 
6.1.1. 
Retesting .....................................................................................................................54 
6.1.2. 
Rescreening .................................................................................................................54 
6.2. 
Efficacy Assessments .................................................................................................54 
6.2.1. 
ABPM .........................................................................................................................55 
6.2.2. 
Office Blood Pressure .................................................................................................55 
6.2.3. 
HBPM .........................................................................................................................55 
6.3. 
Pharmacodynamic Assessments .................................................................................55 
6.4. 
Pharmacokinetic Assessments ....................................................................................56 
6.5. 
Safety Assessments .....................................................................................................56 
6.5.1. 
Vital Signs ..................................................................................................................56 
6.5.2. 
Weight, Height, and Morphometrics ..........................................................................56 
6.5.3. 
Physical Examination .................................................................................................57 
6.5.4. 
Electrocardiogram .......................................................................................................57 
6.5.5. 
Clinical Laboratory Assessments ...............................................................................58 
6.5.5.1. 
Fasting Lipid Panel and Glycemic Assessments ........................................................60 
6.5.5.2. 
Immunogenicity ..........................................................................................................60 
6.5.5.3. 
Pregnancy Testing ......................................................................................................60 
6.5.5.4. 
Additional Liver Function Assessments .....................................................................60 
6.5.6. 
Adverse Events ...........................................................................................................61 
6.5.6.1. 
Definitions ..................................................................................................................61 
6.5.6.2. 
Eliciting and Recording Adverse Events ....................................................................63 
6.5.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................64 
6.5.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........64 
6.5.6.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................65 
6.5.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................65 
6.5.6.7. 
Pregnancy Reporting ..................................................................................................65 
6.5.6.8. 
Reporting of Overdose and Other Special Situations .................................................65 
6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................66 
7. 
STATISTICS ..............................................................................................................66 


Clinical Study Protocol ALN-AGT01-003  
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7.1. 
Determination of Sample Size ....................................................................................67 
7.2. 
Statistical Methodology ..............................................................................................67 
7.2.1. 
Populations to be Analyzed ........................................................................................67 
7.2.2. 
Examination of Subgroups .........................................................................................68 
7.2.3. 
Handling of Missing Data ...........................................................................................68 
7.2.4. 
Baseline Evaluations ...................................................................................................68 
7.2.5. 
Efficacy Analyses .......................................................................................................68 
7.2.6. 
Pharmacodynamic Analysis........................................................................................69 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................69 
7.2.8. 
Safety Analyses ..........................................................................................................69 
7.2.9. 
Immunogenicity Analyses ..........................................................................................70 
7.2.10. 
Interim Analysis ..........................................................................................................70 
7.2.11. 
Optional Additional Research .....................................................................................70 
8. 
STUDY ADMINISTRATION ...................................................................................70 
8.1. 
Ethical and Regulatory Considerations ......................................................................70 
8.1.1. 
Informed Consent .......................................................................................................70 
8.1.2. 
Ethical Review ............................................................................................................71 
8.1.3. 
Serious Breach of Protocol .........................................................................................71 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................71 
8.1.5. 
End of Study ...............................................................................................................72 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................72 
8.2. 
Data Quality Control and Quality Assurance .............................................................72 
8.2.1. 
Data Handling .............................................................................................................72 
8.2.2. 
Study Monitoring ........................................................................................................73 
8.2.3. 
Audits and Inspections ................................................................................................73 
8.3. 
Publication Policy .......................................................................................................73 
9. 
LIST OF REFERENCES ............................................................................................74 
10. 
APPENDICES ............................................................................................................77 
10.1. 
Formula for Estimated Glomerular Filtration Rate Calculation .................................77 
10.2. 
Measurement of Blood Pressure .................................................................................77 
10.3. 
Procedures for Optional Home Healthcare Visits ......................................................80 
10.4. 
Amendment History ....................................................................................................80 
10.4.1. 
Amendment 3 Summary of Changes ..........................................................................80 


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10.4.2. 
Amendment 2 Summary of Changes ..........................................................................81 
10.4.2.1. 
Rationale for Protocol Amendment ............................................................................81 
10.4.2.2. 
Protocol Amendment 2 Detailed Summary of Changes .............................................84 
10.4.3. 
Amendment 1 Summary of Changes ..........................................................................94 
10.4.3.1. 
Rationale for Protocol Amendment ............................................................................94 
10.4.3.2. 
Protocol Amendment 1 Detailed Summary of Changes .............................................96 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................10 
Table 2: 
PK Time Points ...........................................................................................................16 
Table 3: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................43 
Table 4: 
Recommended Interventions for Potentially Clinically Significant Blood 
Pressure Elevation ......................................................................................................47 
Table 5: 
Recommended Interventions for Hyperkalemia .........................................................49 
Table 6: 
Clinical Laboratory Assessments ...............................................................................59 
Table 7: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............61 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ABPM 
Ambulatory blood pressure monitoring 
ACE 
Angiotensin converting enzyme 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AGT 
Angiotensinogen 
ALT 
Alanine aminotransferase 
AngI/II 
Angiotensin I/II 
ARB 
Angiotensin II-receptor blocker 
AST 
Aspartate aminotransferase 
CCB 
Calcium channel blocker 
CPC 
Clinical product complaint 
DB 
Double-blind 
DBP 
Diastolic blood pressure 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOT 
End of treatment 
ET 
Early termination 
FAS 
Full analysis set 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HBPM 
Home blood pressure monitoring 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein 
HOMA 
Homeostatic model assessment 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 


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Abbreviation  
Definition 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR 
Injection site reactions 
LFT 
Liver function test 
MAO 
Monoamine oxidase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model with repeated measurements 
mRNA 
Messenger ribonucleic acid 
NSAID 
Nonsteroidal anti-inflammatory drug 
OLE 
Open-label extension 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PT 
Preferred term 
RAAS 
Renin-angiotensin-aldosterone system 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
siRNA 
Small interfering RNA 
SGLT2 
Sodium-glucose co-transporter 2 
THC 
Delta-9-tetrahydrocannibinol 
ULN 
Upper limit of normal 
 


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1. 
INTRODUCTION 
Alnylam Pharmaceuticals, Inc. (the Sponsor) is developing zilebesiran (ALN-AGT01), a 
subcutaneously (SC) administered investigational agent comprised of a synthetic small 
interfering RNA (siRNA) covalently linked to a triantennary N-acetylgalactosamine (GalNAc) 
ligand, which is designed to suppress liver production of angiotensinogen (AGT) and thereby 
reduce blood pressure in individuals with hypertension. 
1.1. 
Study Rationale 
Study ALN-AGT01-003 (KARDIA-2) is a randomized, double-blind, placebo-controlled, 
multicenter study designed to evaluate the efficacy, safety, and pharmacodynamics (PD) of 
zilebesiran administered SC as an add-on therapy in patients with hypertension despite treatment 
with a standard of care antihypertensive medication. Patients will be randomized to run-in on 1 
of 3 protocol-specified antihypertensive medications open-label for at least 4 weeks (olmesartan, 
amlodipine, or indapamide). At the end of the Run-in period, patients with uncontrolled blood 
pressure will be randomized 1:1 to receive zilebesiran or placebo as add-on therapy to the 
protocol-specified background antihypertensive medication for 6 months during the double-blind 
(DB) period. After completion of the 6-month DB period, patients may have been eligible to 
participate in a separate zilebesiran open-label extension (OLE) study. Patients will discontinue 
their protocol-specified background antihypertensive medication at Month 6. If an individual 
patient reached Month 6 prior to availability of the separate OLE study, they may have received 
open-label zilebesiran (600 mg once every 6 months) for up to 30 additional months during the 
OLE period of this study (ALN-AGT01-003) until the separate OLE study was open and then 
transition. Upon implementation of Amendment 3, the OLE period of this study will be closed 
because a separate OLE study will not be conducted. Patients in the 6-month DB period will 
continue their planned visits through the end of the 6-month DB period and then enter the Safety 
Follow-up period. Patients will not receive a dose of study drug at Month 6. Patients who are 
already in the OLE period will not receive any additional doses of study drug. Patients should 
complete all planned assessments at Months 7, 8, and 9. For visits at Month 12 or later, patients 
should complete end of treatment (EOT) assessments in lieu of their scheduled visit assessments 
and enter the Safety Follow-up period. 
The primary objective of the study is to evaluate the efficacy of zilebesiran as an add-on therapy 
for the treatment of hypertension by evaluating the change in 24-hour mean systolic blood 
pressure (SBP), assessed by ambulatory blood pressure monitoring (ABPM), from baseline to 
Month 3, relative to placebo. Secondary and exploratory objectives of the study include 
evaluating the add-on efficacy of zilebesiran on other measures of blood pressure response 
(including longer treatment durations, eg, up to 36 months) and evaluating the PD effect of 
zilebesiran, including reduction in circulating AGT concentration. 
The full rationale for the study and design is presented in Section 3.2. 
1.2. 
Background 
Hypertension affects 30% to 45% of adults and is the strongest modifiable risk factor for 
cardiovascular disease, primarily strokes and myocardial infarction.[Olsen 2016; Williams 2018] 
The worldwide disease burden is profound, with a global prevalence of over 1 billion,[Kearney 


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2005; NCD Risk Factor Collaboration 2017] and approximately 9 million deaths attributed to 
hypertension annually.[Angell 2015] 
Currently available pharmacologic therapies achieve target blood pressure in only a minority of 
patients, due in large part to physician inertia and patient nonadherence to daily oral 
medication.[Whelton 2018; Williams 2018] Low adherence to oral antihypertensives is 
associated with poor cardiovascular outcomes and is prevalent at all stages of disease.[Corrao 
2011; Peacock 2017; Schulz 2016; van der Laan 2017] Thus, despite the availability of multiple 
efficacious agents, current rates of control are low, and the global burden of death and disability-
adjusted life-years attributed to elevated blood pressure remains high.[Forouzanfar 2017; 
Muntner 2020] Development of new approaches to treat hypertension and to overcome the 
limitations of current therapies is a key unmet need.[Dzau 2019; McClellan 2019; Services 2020] 
The Sponsor is developing zilebesiran, a novel synthetic RNA interference (RNAi) therapeutic, 
for SC administration for the treatment of hypertension. RNAi is a naturally occurring cellular 
mechanism for regulation of gene expression, mediated through the binding of siRNA to its 
complementary messenger RNA (mRNA) sequence, leading to mRNA cleavage and subsequent 
suppression of the synthesis and levels of the target protein. Zilebesiran contains an siRNA 
targeting AGT mRNA, conjugated to a GalNAc-containing ligand to facilitate delivery to the 
liver. Based on the mechanism of RNAi, zilebesiran is specifically designed to reduce the hepatic 
synthesis of AGT protein, the first substrate in the renin-angiotensin-aldosterone system (RAAS) 
and the sole precursor of vasoactive angiotensin peptides.[Khanna 2017; Romero 2015] Because 
hepatocytes are the predominant source of circulating AGT, zilebesiran has been developed to 
reduce blood pressure by decreasing circulating AGT levels and the downstream effects of 
angiotensin II (AngII). 
Zilebesiran is being studied in the ongoing Phase 1 Study ALN-AGT01-001 (hereafter referred 
to as Study 001) in patients with hypertension as single ascending doses of 10 to 800 mg (Part 
A), as a single dose of 800 mg under low-salt or high-salt conditions (Part B), as 2 doses of 
800 mg administered every 3 months in obese patients (Part D), and as a single dose of 800 mg 
co-administered for 2 weeks with 300 mg irbesartan (Part E). Preliminary data are available from 
Parts A, B, and E. Dose-dependent and durable reductions in circulating AGT were observed 
after single SC doses of zilebesiran, accompanied by clinically significant reductions in SBP and 
diastolic blood pressure (DBP). Sustained reductions in serum AGT were observed for up to 6 
months following a single dose of zilebesiran.  
Most adverse events (AEs) have been mild or moderate in severity, and there have been no 
severe or serious adverse events (SAEs) related to study drug. There have been no clinically 
significant elevations in serum creatinine or serum potassium. No patient has required 
intervention for low blood pressure. No clinically significant alanine aminotransferase (ALT) 
elevations have been observed in patients who received zilebesiran doses as high as 800 mg. 
Injection site reactions (ISRs) were reported in a minority of patients and were all mild and 
transient events that resolved without intervention. 
Because most patients with hypertension eventually progress to require treatment with more than 
1 antihypertensive class,[Williams 2018] it is anticipated that zilebesiran may be used together 
with other standard of care antihypertensive medication. This Phase 2 study will further quantify 
the antihypertensive effects of zilebesiran as add-on therapy in patients with hypertension not 
adequately controlled by a standard of care antihypertensive medication. The consistent and 


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durable PD effect of zilebesiran is expected to achieve the unique benefit of continuous 24-hour 
blood pressure lowering with infrequent SC dosing.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of zilebesiran is 
provided in the Investigator’s Brochure. 
1.3. 
Benefit-Risk Assessment 
Clinical data available from Study 001 indicate that zilebesiran may offer the benefit of sustained 
blood pressure reduction to patients with hypertension with infrequent administration (ie, once 
every 3 months or once every 6 months). The mean SBP reduction observed after single 
zilebesiran doses of 100 mg or higher exceeds 10 mmHg, which is comparable to the effect of 
conventional antihypertensives.[Abraham 2015; Materson 1993] The blood pressure of patients 
will be closely monitored, and after Month 3, escape antihypertensive medications will be added 
as needed to control blood pressure. 
Given the mechanism of action and mode of administration of zilebesiran, potential theoretical 
risks include liver transaminase elevations and ISRs. Like any antihypertensive therapy, there is 
also a theoretical risk of hypotension with zilebesiran. Based upon the disease population, there 
is also a risk of blood pressure elevation. Because eligible patients have mild to moderate 
primary hypertension, the likelihood of disease progression during the course of the study is low. 
This study has exclusion criteria intended to minimize these risks, as well as frequent monitoring 
for laboratory and blood pressure abnormalities. Furthermore, the duration of the placebo period 
is limited, and escape antihypertensive medications are permitted to manage uncontrolled blood 
pressure following 3 months of add-on treatment with zilebesiran. Detailed guidance is provided 
to Investigators for potential liver transaminase elevations (Section 5.2.4), hypotension 
(Section 5.8.1), hypertension (Section 5.8.2), renal dysfunction (Section 5.8.3), and 
hyperkalemia (Section 5.8.4). An independent Data Monitoring Committee (DMC) will monitor 
and ensure the safety of study participants (see Section 3.6).  
Based on available data from Study 001, zilebesiran has an acceptable safety profile in patients 
with hypertension as a monotherapy or with the addition of conventional antihypertensives in 
patients who were inadequately controlled on zilebesiran alone. This experience supports that the 
theoretical risks of treatment are low and can be managed through the proposed monitoring and 
safety mitigations. In addition to study drug, each patient will receive a protocol-specified 
background antihypertensive medication (olmesartan, amlodipine, or indapamide). These agents 
are approved standard medications that will be dosed in accordance with local labeling. 
While zilebesiran is designed to inhibit the RAAS, its site of action (AGT) in the RAAS is 
unique, and its tissue specificity for the liver is hypothesized to improve its renal safety profile 
relative to conventional RAAS blockade,[Mullick 2017; Uijl 2019] both in the context of 
monotherapy and when used together with a conventional RAAS blocker such as olmesartan. In 
the latter setting, zilebesiran is hypothesized to add antihypertensive benefit when added to a 
conventional RAAS blocker without the increased incidence of RAAS inhibitor-associated renal 
adverse effects that have been observed in prior trials of conventional dual RAAS 
blockade.[Makani 2013] Patients with estimated glomerular filtration rate (eGFR) 
<45 mL/min/1.73m2 or urine albumin:creatinine ≥300 mg/g will be exclusively assigned to the 
olmesartan cohort to ensure that patients with proteinuric chronic kidney disease or diabetes 






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3. 
INVESTIGATIONAL PLAN 
3.1. 
Summary of Study Design 
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy, safety, and PD of zilebesiran administered SC as an add-on therapy in patients with 
hypertension despite treatment with a standard of care antihypertensive medication. A schematic 
of the study design is provided in Figure 1.  
Run-in Period 
Patients who complete the Screening period and meet all inclusion/exclusion criteria for 
enrollment will be randomized as described in Section 3.4 to receive open-label therapy with 
olmesartan (40 mg orally once daily [or 20 mg orally once daily for patients with creatinine 
clearance ≤60 mL/min at screening enrolled at sites outside of the US and Australia, consistent 
with local labeling for olmesartan]), amlodipine (5 mg orally once daily), or indapamide (2.5 mg 
orally once daily) as their protocol-specified background antihypertensive medication during a 
Run-in period of at least 4 weeks. Prior antihypertensive medications (if taking) will be 
discontinued upon the start of this Run-in period (Run-in Visit 1). 
Patients who do not tolerate run-in treatment or who do not meet eligibility for randomization at 
Day 1 will be withdrawn from the study and returned to their prior medication regimen in 
coordination with their usual health providers.  
DB Period 
Patients who meet all inclusion/exclusion criteria will be randomized 1:1 to receive 600 mg 
zilebesiran SC or placebo SC on Day 1 of a 6-month DB period as add-on therapy to their 
protocol-specified background antihypertensive medication (olmesartan, amlodipine, or 
indapamide). Randomization on Day 1 will be stratified by race (black or all other races), 
baseline blood pressure (24-hour mean SBP < or ≥145 mmHg), and screening eGFR (<60 or 
≥60 mL/min/1.73m2). 
Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive 
medications”) may be added to the patient’s protocol-specified background antihypertensive 
medication per Investigator judgement for elevated blood pressure as described in Table 4.  
OLE Period 
After the 6-month DB period, protocol-specified background antihypertensive medications will 
be discontinued, and patients may have been eligible to participate in a separate zilebesiran OLE 
study. If an individual patient reached Month 6 prior to availability of the separate OLE study, 
they may have received open-label zilebesiran at 600 mg SC once every 6 months for up to 
30 additional months during the OLE period until the separate OLE study was open and then 
transition. Upon implementation of Amendment 3, the OLE period will be closed because a 
separate OLE study will not be conducted. Patients in the 6-month DB period will continue their 
planned visits through the end of the 6-month DB period. Patients will not receive a dose of 
study drug at Month 6. Upon completion of predose assessments at the Month 6 visit, patients 
will enter the Safety Follow-up period. Patients who are already in the OLE period will not 
receive any additional doses of study drug. Patients should complete all planned assessments at 


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Months 7, 8, and 9. For visits at Month 12 or later, patients should complete EOT assessments in 
lieu of their scheduled visit assessments and enter the Safety Follow-up period. 
During the OLE period of this study, Investigators will use escape antihypertensive medications 
as described in Table 4 to control blood pressure, guided by continued blood pressure 
monitoring. 
Patients will be considered as completing study drug if they received a dose of study drug at 
Day 1 and completed the Month 6 visit. 
Safety Follow-up Period 
Patients will be asked to complete Safety Follow-up visits once every 6 months after their last 
dose of study drug until serum AGT levels return to ≥50% of their individual mean baseline level 
(if known) or 12 months after the last dose of study drug, whichever comes earlier. During the 
Safety Follow-up period, patients should return to their pre-study medical care (usual care). 
Patients who discontinue study drug prior to the Month 6 visit will also be asked to complete the 
remainder of scheduled study visits and assessments (except for study drug administration) 
through Month 6. If a patient discontinues study drug after the Month 6 visit, EOT/early 
termination (ET) assessments should be performed. 
An independent DMC will oversee the safety and overall conduct of this study, and an 
independent Clinical Event Adjudication Committee will review suspected renal events to 
adjudicate whether they meet criteria for acute kidney injury. 
The planned enrollment for this study is approximately 1800 patients to be randomized into the 
Run-in period and approximately 630 patients (300 patients in the olmesartan arm, 210 patients 
in the amlodipine arm, and 120 patients in the indapamide arm) to be randomized in the DB 
period.  
The duration of treatment with zilebesiran is up to 36 months. The estimated total time on study 
for each patient is up to approximately 45 months, including up to 75 days in the Screening and 
Run-in periods, up to 36 months of treatment, and up to 12 months after the last dose of study 
drug in the Safety Follow-up period. 
3.2. 
Scientific Rationale for Study Design 
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy and safety of zilebesiran administered SC as an add-on therapy in patients with 
hypertension despite treatment with a standard of care antihypertensive medication.  
The primary objective of the study is to evaluate the efficacy of zilebesiran as an add-on therapy 
for the treatment of hypertension by evaluating the change in 24-hour mean SBP, assessed by 
ABPM, from baseline to Month 3, relative to placebo. 
Patients with hypertension often require treatment with multiple antihypertensive drugs to reach 
target blood pressure,[Williams 2018] and it is anticipated that zilebesiran may be administered 
to individuals on a background of other antihypertensive medications. Therefore, this study 
evaluates the effects of zilebesiran relative to placebo in patients whose blood pressure is not 
adequately controlled despite treatment with 1 of the 3 major drug classes recommended for 
initial treatment of hypertension by all clinical guidelines: RAAS inhibitors (ie, angiotensin 


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converting enzyme [ACE] inhibitors, angiotensin II-receptor blockers, or a direct renin 
inhibitor), diuretics, and calcium channel blockers (CCBs).[Whelton 2018; Williams 2018] 
Studying coadministration with olmesartan will assess if the synergistic antihypertensive effects 
recently observed in rodents treated with both an ARB and an AGT-targeting GalNAc-siRNA 
will translate into clinically significant blood pressure reduction in hypertensive patients given 
zilebesiran as an add-on to conventional RAAS inhibition.[Uijl 2019] In addition, it will examine 
the safety and tolerability of liver-specific AGT targeting during treatment with a conventional 
RAAS blocker (olmesartan). The newer-generation ARB olmesartan was selected because of its 
high potency relative to early-generation RAAS inhibitors,[Ojima 2011; White 2011] enabling a 
robust test for added efficacy when combined with zilebesiran. The maximum dose of 
olmesartan permitted per local labeling will be used to further increase the rigor of this efficacy 
evaluation. The thiazide-like diuretic indapamide was selected in accordance with recent 
guidelines that highlight the greater potency and durability of thiazide-like diuretics over other 
diuretics.[Burnier 2019] The long-acting dihydropyridine CCB amlodipine was selected given its 
extensive use in clinical practice and randomized controlled trials.[Dahlof 2005; Jamerson 2008; 
Julius 2004]  
During the study, blood pressure will be monitored with both automated office blood pressure 
measurements and outpatient 24-hour ABPM (EMA/CHMP/29947/2013/Rev. 4; Guideline on 
Clinical Investigation of Medicinal Products in the Treatment of Hypertension, 2016). In 
addition to having greater precision, ABPM can assess short-term blood pressure variability and 
circadian patterns (including potential restoration of the normal nocturnal blood pressure dipping 
pattern that is lost in 24% to 35% of hypertensive patients). More frequent (at least once per 
week) measurements will be collected through a third method, oscillometric home blood 
pressure monitoring (HBPM), to assess long-term blood pressure variability and provide close 
safety monitoring for potential hypotension (or hypertension) while not in the clinic.  
As recommended by current guidance (International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use [ICH] Principles for Clinical Evaluation of 
New Antihypertensive Drugs, 2000 and EMA/CHMP/29947/2013/Rev. 4; Guideline on Clinical 
Investigation of Medicinal Products in the Treatment of Hypertension, 2016), the 6-month DB 
period is designed as a randomized, placebo-controlled, parallel-group study. To adhere to best 
ethical standards for the treatment of patients with hypertension, the use of oral antihypertensive 
medications per Investigator judgement to maintain blood pressure within target is permitted 
starting at Month 3 and will continue throughout the remainder of the study (see Table 4). The 
term “escape antihypertensive medication” is used to refer to any oral antihypertensive 
medication initiated to control blood pressure after Day 1. Separate from these treat-to-target 
modifications, any confirmed event of severe hypertension (office SBP ≥180 mmHg and/or 
office DBP ≥120 mmHg) will be appropriately treated with escape antihypertensive medication 
regardless of its timing relative to study drug administration. 
If a patient requires treatment with an oral escape antihypertensive medication before Month 6, a 
CCB and/or thiazide/thiazide-like diuretic (whichever agent is not already the protocol-specified 
background antihypertensive medication) should be added because there is extensive experience 
combining these classes with antihypertensive drugs that impact the RAAS.  
After the 6-month DB period, protocol-specified background antihypertensive medication 
(olmesartan, amlodipine, or indapamide) will be discontinued, and patients may have been 


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eligible to participate in a separate zilebesiran OLE study. If an individual patient reached 
Month 6 prior to availability of the separate OLE study, they may have received open-label 
zilebesiran at 600 mg SC once every 6 months for up to 30 additional months during the OLE 
period until the separate OLE study was open and then transition. Because many patients would 
have received zilebesiran for the first time at Month 6, office blood pressure and serum 
chemistries were monitored monthly from Month 6 to Month 9. Upon implementation of 
Amendment 3, the OLE period will be closed because a separate OLE study will not be 
conducted. Patients in the 6-month DB period will continue their planned visits through the end 
of the 6-month DB period and then enter the Safety Follow-up period. Patients will not receive a 
dose of study drug at Month 6. Patients who are already in the OLE period will not receive any 
additional doses of study drug. Patients should complete all planned assessments at Months 7, 8, 
and 9. For visits at Month 12 or later, patients should complete EOT assessments in lieu of their 
scheduled visit assessments and enter the Safety Follow-up period. 
During the OLE period, Investigators may use escape antihypertensive medications of permitted 
classes as described in Table 4 to control blood pressure, guided by continued blood pressure 
monitoring and following current care guidelines.[Whelton 2018; Williams 2018] Olmesartan, 
amlodipine, and indapamide will be discontinued as protocol-specified background 
antihypertensive medication during the OLE period; however, patients may continue to receive 
amlodipine or indapamide as escape antihypertensive medication at the Investigator’s discretion. 
The use of conventional RAAS inhibitors (ARBs, ACE inhibitors, or direct renin inhibitors) as 
escape antihypertensive agents for high blood pressure should be avoided throughout the study. 
While the tissue specificity of zilebesiran for the liver is hypothesized to improve tolerability 
relative to current oral antihypertensives,[Mullick 2017; Uijl 2019] the protocol’s monitoring 
plan is designed to meet the standards set by prior studies of conventional RAAS 
inhibitors[McMurray 2016; Parving 2012].  
3.3. 
Justification for Dose 
The dose of zilebesiran in this study (600 mg once every 6 months) was selected on the basis of 
data from the Phase 1 Study 001, in which single zilebesiran doses up to 800 mg were found to 
have an acceptable safety profile, and dose-dependent, clinically significant placebo-corrected 
reductions in mean SBP >10 mmHg by 24-hour ABPM were observed at doses as low as 
100 mg. An acceptable safety profile was also observed for a single zilebesiran dose of 800 mg 
under low-salt/high-salt conditions or co-administered for 2 weeks with 300 mg irbesartan once 
daily. The selected dose of 600 mg is predicted to result in a median serum AGT reduction of 
94.9% at trough (Month 6), translating to a median SBP reduction of 11.6 mmHg as 
monotherapy. 
The protocol-specified background antihypertensive medications are standard agents 
recommended in international and regional hypertension guidelines, and the selected regimens 
are standard doses used for their approved indication of hypertension.[Whelton 2018; Williams 
2018] Indapamide will be dosed at 2.5 mg orally once daily, and amlodipine will be dosed at 
5 mg orally once daily. The dose regimens for indapamide and amlodipine used in this study 
were selected on the basis of their common use in clinical care (when used both individually and 
combined with other classes of antihypertensives) and their expected efficacy, safety, and 
tolerability. Olmesartan will be dosed at the maximum dose allowed per local labeling: 40 mg 


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orally once daily (or 20 mg orally once daily for patients with creatinine clearance ≤60 mL/min 
at screening enrolled at sites outside of the US or Australia; Olmetec Product Information, 
September 2020).[von Bergmann 2001] 
3.4. 
Method of Assigning Patients to Treatment Groups 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number. After the patient signs the informed consent form (ICF) and before 
proceeding with screening procedures, the Investigator or designee should contact the Interactive 
Response Technology (IRT) to obtain a patient identification number. 
The Investigator or designee will contact the IRT to randomize the patient at Run-in Visit 1 and 
again at Day 1 after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria at each visit. 
At Run-in Visit 1, patients with screening eGFR <45 mL/min/1.73m2 or urine albumin:creatinine 
≥300mg/g will be assigned to receive olmesartan. To avoid over-enrollment, patients with eGFR 
<45 mL/min/1.73m2 or urine albumin:creatinine ≥300 mg/g will be excluded from the study after 
100 such patients are randomized to study drug on Day 1.  
All other patients will be randomized 10:7:4 to run-in open-label on 1 of 3 protocol-specified 
background antihypertensive medications (olmesartan, amlodipine, or indapamide), with targeted 
sample sizes across cohorts as described in Section 7.1. If 1 cohort completes enrollment first, 
this cohort will be deactivated for future randomization. The remaining 2 cohorts will be 
randomized using the original ratio. After the second cohort completes enrollment, all 
subsequent patients will be assigned to the last cohort.  
At Day 1, patients will be randomized 1:1 to receive zilebesiran or placebo as an add-on to their 
protocol-specified background antihypertensive medication using the IRT. Randomization at 
Day 1 will be stratified by race (black or all other races), baseline blood pressure (24-hour mean 
SBP < or ≥145 mmHg), and screening eGFR (<60 or ≥60 mL/min/1.73m2). 
3.5. 
Blinding 
The Sponsor, all site personnel and patients will be blinded to study drug treatment through 
Month 3 of the 6-month DB period. After the interim analysis at Month 3 is complete, Sponsor 
staff members who will not have direct roles or responsibilities in interacting with study sites 
may be unblinded to the analysis results according to the prespecified blinding plan. Site 
personnel, patients, and Sponsor staff members who have direct roles or responsibilities in 
interacting with study sites will remain blinded to both Month 3 interim analysis results and 
treatment assignment until after the analysis of Month 6 data is complete. All Sponsor and site 
personnel and patients will be blinded to any clinical laboratory result that could potentially 
unblind them (eg, AGT levels) until treatment assignment unblinding. 
Zilebesiran and placebo will be packaged identically. Because zilebesiran may be slightly 
visually distinguishable from placebo, the vials will be masked in such a way as to hide the 
identity of the study drug contained within. For administration, syringes will be masked by a site 
pharmacist or delegate prior to withdrawing the study drug from vial. See the Pharmacy Manual 
for additional details. The study drug will be administered under the supervision of the 
Investigator (see Section 5.2.2). 


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3.5.1. 
Emergency Unblinding 
If the treating physician determines that the clinical management of the patient requires 
knowledge of the study drug assignment, the Investigator may break the blind, as necessary, in 
IRT. If time permits, clinical study center personnel should contact the Medical Monitor before 
unblinding to discuss the need to unblind the patient but must do so within 1 working day after 
the unblinding event. Unblinding information should be limited to the fewest number of people 
on a need-to-know basis. A record of when the blind was broken, who was unblinded, who broke 
the blind, and why it was broken, will be maintained in the electronic trial master file (eTMF). 
Refer to the IRT instructions for details on unblinding. 
3.6. 
Data Monitoring Committee 
An independent DMC will oversee the safety and overall conduct of this study. The DMC will 
operate under the rules of a charter that will be reviewed and approved at the organizational 
meeting of the DMC. Details are provided in the DMC Charter. 
3.7. 
Clinical Event Adjudication Committees 
An independent Clinical Event Adjudication Committee of 2 or more nephrologists will review 
the suspected renal events blinded to treatment assignment to adjudicate whether they meet 
diagnostic criteria for acute kidney injury and, if so, their potential staging and contributing 
factors. Details are provided in the Renal Event Adjudication Committee charter. 
3.8. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the end of the study if the patient has completed the 
Safety Follow-up visits as described in Section 3.1. 
A definition of the end of the overall study is provided in Section 8.1.5. 
4. 
SELECTION AND REMOVAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age and Sex 
1. Age 18 to 75 years, inclusive, at time of initial informed consent 
2. Male or female 
Patient and Disease Characteristics 
3. Has hypertension as follows: 
a. Untreated hypertension (not taking antihypertensive medication), or  
b. Treated hypertension on stable therapy with up to 2 antihypertensive medications. 
Stable therapy is defined as having no change in antihypertensive medication or dose 
within 30 days prior to screening.  


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4. Seated office SBP at Run-in Visit 1 as follows: 
a. ≥155 mmHg and ≤180 mmHg for patients with untreated hypertension  
b. ≥145 mmHg and ≤180 mmHg for patients on antihypertensive medications  
5. 24-hour mean SBP ≥130 mmHg and ≤160 mmHg by ABPM at Run-in Visit 2 after at 
least 4 weeks of run-in. 
6. ≥80% adherence to the protocol-specified background antihypertensive medication 
during the Run-in period as assessed by pill count performed at Run-in Visit 2. 
Informed Consent 
7. Patient is able to understand and is willing and able to comply with the study 
requirements and to provide written informed consent. 
4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Secondary hypertension (including, but not limited to, due to known history of moderate-
to-severe obstructive sleep apnea not treated with continuous positive airway pressure 
therapy, renovascular hypertension, primary aldosteronism, pheochromocytoma, Cushing 
syndrome, or aortic coarctation) 
2. Orthostatic hypotension, defined as a fall of ≥20 mmHg SBP or ≥10 mmHg DBP within 
approximately 1 to 3 minutes of standing up from a seated position by office blood 
pressure that is symptomatic (such as dizziness, weakness, lightheadedness, or syncope) 
at screening or during the Run-in period 
Laboratory Assessments 
3. Has any of the following laboratory parameter assessments at screening or Run-in 
Visit 2:  
a. ALT or aspartate aminotransferase (AST) >2× upper limit of normal (ULN) 
b. Total bilirubin >1.5×ULN. Patients with elevated total bilirubin that is secondary to 
documented Gilbert’s syndrome are eligible if the total bilirubin is <2×ULN 
c. International normalized ratio (INR) >2.0 (patients on oral anticoagulant [eg, 
warfarin] with an INR <3.5 will be allowed) 
d. Potassium <lower limit of normal range or >5 mEq/L  
e. Sodium <lower limit of normal range 
f. eGFR <30 mL/min/1.73m2 (calculation will be based on the Modification of Diet in 
Renal Disease formula; refer to Section 10.1) 
Prior/Concomitant Therapy 
4. Received an investigational agent within the last 30 days or 5 half-lives of the 
investigational agent, whichever is longer, prior to Run-in Visit 1 or are in follow-up of 
another clinical study prior to study enrollment. Any agent that has received health 
agency authorization (including for emergency use) by local or regional regulatory 


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authorities is not considered investigational. Patients who are in follow-up for a 
coronavirus disease 2019 vaccine (authorized or investigational) study are allowed. 
5. Currently taking, taken within 30 days prior to first randomization, or anticipated to 
receive during the study treatment period, any medication or herbal supplement known to 
significantly affect blood pressure (with the exception of medications for the treatment of 
essential hypertension). Patients who require medications such as monoamine oxidase 
(MAO) inhibitors that are associated with hypertensive crisis should be 
excluded.[Whelton 2018]  
6. Currently taking beta blockers and unable to discontinue prior to Run-in Visit 1 
7. Changes, such as initiation or discontinuation, of sodium-glucose co-transporter 2 
(SGLT2) inhibitor therapy within 30 days prior to screening. Patients on a stable dose of 
SGLT2 therapy for at least 30 days prior to screening with no anticipated changes during 
the study treatment period are permitted. 
8. Prescription nonsteroidal anti-inflammatory drugs (NSAIDs) are not permitted. Patients 
receiving low-dose aspirin (defined as ≤100 mg per day) for at least 30 days prior to 
screening are permitted. Paracetamol/acetaminophen for analgesia will be allowed.  
9. Anticipates using organic nitrate preparations (eg, nitroglycerin, isosorbide mononitrate, 
isosorbide dinitrate, pentaerythritol) during the study treatment period 
10. Currently taking, taken within 6 months prior to first randomization, or anticipated to 
receive an RNAi therapeutic (approved or investigational) during the study 
Medical Conditions 
11. Current or prior history of intolerance to an ARB, ACE inhibitor (other than cough), 
direct renin inhibitor, CCB (including but not limited to significant peripheral edema), or 
thiazide/thiazide-like diuretic 
12. History of multiple drug allergies or history of allergic reaction to any component of or 
excipient in the study drug 
13. Type 1 diabetes mellitus, poorly controlled Type 2 diabetes mellitus (hemoglobin A1c 
[HbA1c] >9.0%), or laboratory evidence of diabetes during screening (HbA1c ≥7.0%) 
without known diagnosis of diabetes 
14. Has known active human immunodeficiency virus infection; or known current or chronic 
hepatitis C virus (HCV) or hepatitis B virus infection. 
15. History of clinically significant cardiovascular event (eg, stroke, transient ischemic 
attack, myocardial infarction, unstable angina, coronary artery bypass grafting or other 
cardiothoracic surgeries, percutaneous coronary intervention, hospitalization due to heart 
failure) within 6 months prior to first randomization 
16. Known history of angioedema 
17. Clinically significant valvular heart disease 
18. New York Heart Association II to IV heart failure 


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19. Uncontrolled serious cardiac arrhythmia, defined as recurrent and highly symptomatic 
ventricular tachycardia/supraventricular tachycardia, or atrial fibrillation with rapid 
ventricular response in the 3 months prior to first randomization 
20. Has undergone liver transplantation or is anticipated to be on an active liver 
transplantation waiting list during the study treatment period 
21. History of renal transplantation  
22. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation; or, in the opinion of the 
Investigator, taking part in the study would jeopardize the safety of the patient 
23. Clinically significant illness, in the opinion of the Investigator, within 7 days prior to 
either randomization 
24. History of intolerance to SC injection(s) that could potentially hinder study drug 
administration or evaluation of local tolerability 
25. Has planned major surgery or general anesthesia during the study 
Contraception, Pregnancy, and Breastfeeding 
26. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.11.1  
27. Female patient is pregnant, planning a pregnancy, or breast-feeding 
Alcohol or Nicotine Use and Substance Abuse 
28. Unwilling or unable to limit alcohol consumption throughout the course of the study. 
Alcohol intake of >2 units/day is excluded during the study (unit: 1 glass of wine 
[approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of 
beer [approximately 284 mL]). 
29. History of alcohol or substance abuse (licit or illicit drugs) within the last 12 months 
before screening, in the opinion of the Investigator 
30. Unwilling or unable to abstain from use of nicotine or tobacco-containing products 
(including but not limited to snuff, chewing tobacco, cigars, cigarettes, pipes, nicotine 
patches, or e-cigarettes) within 30 minutes prior to office blood pressure measurements  
Other Restrictions 
31. Third shift, night shift, or 24-hour shift workers 
32. Arm circumference exceeds the maximum cuff size of any of the blood pressure 
instruments provided by the Sponsor 
33. Placed in an institution on the basis of an official or court order 
4.3. 
Removal from Study Drug or Assessment 
Patients are free to discontinue study drug and/or stop protocol procedural assessments, or 
participation in the study as a whole at any time and for any reason, without penalty to their 
continuing medical care. The Investigator or the Sponsor may discontinue study drug or stop a 


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patient’s participation in the study at any time if this is considered to be in the patient’s best 
interest. Any discontinuation of treatment or the stopping of the patient’s participation in the 
study must be fully documented in the electronic case report form (eCRF) and should be 
followed up by the Investigator. 
Discontinuation of study drug or declining procedural assessments is described in Section 4.3.1, 
while the stopping of a patient’s participation in the study is detailed in Section 4.3.2. 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments 
Reasons for discontinuation of study drug include any of the following: 
• Significant protocol deviation; which includes required treatment with prohibited 
medication (as defined in Section 5.9.1) per Investigator discretion 
• AE 
• Non-adherence to treatment regimen 
• Pregnancy 
• Lost to follow-up 
• Other reason (non-AE) 
• Or, study is terminated by the Sponsor 
If possible, the Investigator will confer with the Sponsor or Medical Monitor before 
discontinuing dosing in the patient. Patients who are pregnant will be discontinued from study 
drug dosing immediately (see Section 6.5.6.7 for reporting and follow-up of pregnancy). A 
positive urine pregnancy test should be confirmed by a serum pregnancy test prior to 
discontinuing the study drug. 
Patients who discontinue study drug and/or decline procedural assessments should not be 
automatically removed from study. In general, patients who discontinue study drug dosing for 
any reason will be encouraged to remain on the study to complete the remaining assessments so 
that their experience is captured in the final analyses.  
If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedule of Assessments (Table 1), including different options for follow-up and collection 
of data (eg, in person, by phone, by mail, through family or friends, or from options not 
involving patient contact, such as communication with other treating physicians or from review 
of medical records), including endpoints and AEs, and must document this decision in the 
patient’s medical records. 
If a patient has an AE, including SAEs, and/or laboratory abnormalities that in the judgment of 
the investigator, taking into account the patient’s overall status, requires interruption or 
discontinuation from treatment with study drug, the event should be followed as described in 
Section 6.5.6. When a patient discontinues study drug dosing, the primary reason must be 
recorded in the eCRF. Patients who discontinue study drug and remain on study may receive 
treatment consistent with local standard practice for their disease per Investigator judgement, as 
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Patients who discontinue from study drug during the 6-month DB period (defined as the time the 
first dose of study drug is administered on Study Day 1 through completion of the Month 6 
assessments) will be encouraged to remain on the study and complete assessments (excluding 
pharmacokinetic [PK] assessments) through Month 6. They will also be asked to complete Safety 
Follow-up visits once every 6 months after the last dose of study drug per the safety follow-up 
schedule (see Table 1) until PD recovery or 12 months after the last dose of study drug 
(whichever is earlier); see Section 3.1. 
Patients who discontinue study drug during the OLE period will be asked to return for their next 
scheduled visit to complete EOT/ET assessments and complete Safety Follow-up visits once 
every 6 months after the last dose of study drug per the safety follow-up schedule (see Table 1) 
until PD recovery or 12 months after the last dose of study drug (whichever is earlier); see 
Section 3.1. 
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient Stops Participation in the Study 
A patient may stop participation in the study at any time. A patient considering stopping 
participation in the study before Month 6 should be informed that the patient can discontinue 
study drug and/or decline procedural assessments and remain in the study to complete their study 
assessments, through the Month 6 visit and complete Safety Follow-up visits as described in 
Section 4.3.1, or alternatively may complete any minimal assessments for which the patient 
consents. If a patient still chooses to discontinue study drug and stop participation in all follow-
up prior to the completion of the 6-month DB period, every effort should be made to conduct the 
Month 6 visit assessments at an earlier time (see Table 1). 
A patient considering stopping participation in the study during the OLE period should be 
informed that the patient can discontinue study drug and/or decline procedural assessments and 
remain in the study to complete the assessments scheduled for the EOT/ET visit and complete 
Safety Follow-up visits as described in Section 4.3.1, or alternatively may complete any minimal 
assessments for which the patient consents. 
If the patient does not wish to or is unable to continue further study participation, the Investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study. Data 
collected from the patient can continue to be used. 
Note, in countries where the collection and processing of the patient’s personal data is based on 
consent, if a patient withdraws consent to collect and process the patient’s personal data (see 
Section 4.3.2.2), as applicable, personal data up to the withdrawal of consent will be included in 
the analysis of the study. In addition, where permitted, publicly available data (such as 
appropriate national or regional vital status registry or other relevant databases) can be included 
after withdrawal of consent, where available and allowable by local law. 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data or Objection to 
Process Patient’s Personal Data 
Where allowed by local law, the patient may decide to withdraw consent to collect, store, and 
use biological samples and, as applicable, other personal data, informing the Investigator at any 
time in writing or in any other form that may be locally required. Also, where allowed by local 


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law, the patient may object to the collection, storage, and use of the patient’s personal data, 
informing the Investigator at any time in writing or in any other form that may be locally 
required. In both cases, the Sponsor will continue to keep and use the patient’s study information 
(including any data resulting from the analysis of the patient’s biological samples until the time 
of withdrawal/objection) according to applicable law. The process for the storage and, as 
applicable, further use of remaining samples will be followed per local requirements. 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest. However, study integrity and interpretation are 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 
Termination of the clinical study and site closure are described in Section 8.1.6. 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation 
The primary reason that a patient’s study participation is stopped must be recorded in the 
appropriate section of the eCRF and all efforts will be made to complete and report the 
observations as thoroughly as possible. If a patient’s study participation is stopped due to an AE, 
including SAEs, the event should be followed as described in Section 6.5.6. 
4.3.3. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for 
scheduled visits and is unable to be contacted by the clinical study center. The following actions 
must be taken if a patient fails to return to the clinic for a required study visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain if the patient wishes to continue in the study, and/or should 
continue in the study. 
• Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, 
if necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the patient’s 
medical record. 
• Should the patient continue to be unreachable, the patient will be considered to have 
stopped participation in the study. 
• For patients who are lost to follow-up, the Investigator can search publicly available 
records (where permitted and allowed by local law) to ascertain survival status. This 
ensures that the outcome of the study is as comprehensive as possible. 
4.3.4. 
Replacement of Study Patients 
No additional patients may be enrolled to mitigate the impact of patients who discontinue the 
study drug or stop participation in the study after the second randomization at Day 1.  


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5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug and protocol-specified background antihypertensive medication supplied by the 
Sponsor for this study must not be used for any purpose other than the present study and must 
not be administered to any person not enrolled in the study. Study drug and protocol-specified 
background antihypertensive medication that have been dispensed and returned unused must not 
be re-dispensed. 
5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of zilebesiran SC 
and placebo SC is provided in the Pharmacy Manual. 
5.2.1. 
Description 
Zilebesiran will be supplied as a sterile solution for SC injection. See the Pharmacy Manual for 
further details of solution concentration and fill volume. 
The control drug for this study will be a placebo (phosphate-buffered saline for SC 
administration). Placebo will be provided by the Sponsor; it will be packaged identically to 
zilebesiran. 
5.2.2. 
Dose and Administration 
During the 6-month DB period, patients will be administered a single dose of 600 mg zilebesiran 
or placebo, at the same volume, as SC injection on Day 1. Before Amendment 3, patients who 
entered the OLE period received 600 mg zilebesiran SC at Month 6 after all predose assessments 
were conducted and once every 6 months during the OLE period. Upon implementation of 
Amendment 3, patients in the 6-month DB period will continue their planned visits through the 
end of the 6-month DB period but will not be eligible to enter the OLE period and receive a dose 
of study drug at Month 6. Patients in the OLE period will not receive any additional doses of 
study drug. 
Study drug injections will be administered by qualified clinical study center staff under the 
supervision of the Investigator or designee. The injection site may be marked and mapped for 
later observation. Injections may be administered in the abdomen, thigh, or the side or back of 
the upper arms. If a local reaction around the injection site occurs, photographs may be obtained. 
Detailed instructions for study drug administration are found in the Pharmacy Manual. 
To maintain the blind, the syringes are to be masked by the site pharmacist or designee prior to 
study drug withdrawal from the vial. A full description of the blinding procedure is included in 
the Pharmacy Manual. 
If a patient does not receive a dose of study drug within the specified dosing window, the 
Investigator should contact the Medical Monitor. After such consultation, the dose may be 
administered up to 85 days before the next scheduled dose. Thereafter, the dose will be 
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If a patient misses a dose of study drug, the Investigator should discuss with the Medical Monitor 
whether the patient will be able to continue the study (see also Section 4.3). 
Additional details can be found in the Pharmacy Manual.  
The definition of study drug overdose, follow-up procedures, and reporting requirements are 
provided Section 6.5.6.8. 
5.2.3. 
Dose Modifications 
Dose modifications of study drug are not permitted. 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator, and the Medical Monitor should be contacted.  
5.2.4. 
LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing  
1. Dosing decisions may be made based on the most recently available liver function test 
(LFT) results from a central laboratory (Table 6). 
2. For any ALT or AST elevation >3×ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 3. 
3. For any ALT or AST elevation >3×ULN: 
a. If local laboratory results are obtained, confirm with a central laboratory as soon as 
possible, ideally within 2 to 3 days, but no later than 7 days. 
b. If an alternative cause is found, provide appropriate care. 
c. If an alternative cause is not found, perform assessments per Table 6 and Table 7. 
4. For any ALT or AST elevation >3×ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2×ULN or INR ≥1.5, permanently 
discontinue dosing. 
5. For confirmed ALT or AST elevations >3×ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2×ULN or INR ≥1.5, see Table 3. 


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Table 3: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative Cause 
Identified 
Transaminase Level 
Action 
>3× to 5×ULN 
• 
May continue dosing 
• 
Evaluate the initial elevation in LFT per the following assessments: 
­ Table 7 (all assessments to be performed once) 
­ Hematology, serum chemistry, LFT, and coagulation per Table 6 
• 
Monitor at least every 2 weeks (LFT and coagulation per Table 6) 
• 
If elevation persists for ≥2 months, must discuss with the Medical 
Monitor before continuing dosing 
>5× to 8×ULN 
• 
Hold study drug dosing until recovery to ≤1.5×ULN or baseline; may 
resume dosing after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments 
­ Table 7 (all assessments to be performed once) 
­ Hematology, serum chemistry, LFT, and coagulation per Table 6 
• 
Monitor at least weekly: LFT and coagulation per Table 6 until ALT 
and/or AST is declining on 2 consecutive draws, then may decrease 
monitoring to biweekly 
• 
If ALT or AST rises to >5×ULN following resumption of dosing, 
permanently discontinue dosing 
>8×ULN 
Permanently discontinue study drug dosing after confirmation of the 
transaminase value at the central laboratory. 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; LFT=liver function test(s); 
ULN=upper limit of normal. 
Notes: In addition to these criteria, other assessments or evaluations may be performed per Investigator discretion, 
as appropriate. 
5.2.5. 
Neurological Criteria for Withholding, Monitoring, and Stopping Study Drug 
Dosing 
Clinically significant events that may be consistent with potential decreased proprioception 
(including but not limited to unusual clumsiness, gait abnormalities, and unexplained 
balance/coordination issues that are either absent at or worsening from the baseline) should be 
reported as an AE. If the treatment-emergent AE is persistent and considered related to study 
drug, specialty consultation with a neurologist should be considered. However, if such a 
treatment-emergent AE is serious or severe (regardless of the Investigator’s assessment of 
relatedness), the patient must be referred for neurologist consultation, and study drug dosing 
must be held until that consultation is complete. Resumption of dosing must be approved by the 
Medical Monitor. 
5.3. 
Protocol-specified Background Antihypertensive Medications 
All patients will be randomized to receive 1 of the 3 following standard of care oral 
antihypertensive medications during a Run-in period of at least 4 weeks and will continue this 


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protocol-specified background antihypertensive medication through Month 6. Protocol-specified 
background antihypertensive medications will be supplied by the Sponsor. 
• Olmesartan: 40 mg orally once daily (or 20 mg orally once daily for patients with 
creatinine clearance ≤60 mL/min at screening enrolled at sites outside of the US or 
Australia, consistent with local labeling). At the Investigator’s discretion, patients 
who are randomized to receive 40 mg olmesartan once daily may initiate treatment at 
20 mg once daily and then uptitrate to the full dose of 40 mg once daily after 1 to 2 
weeks (in this case, the patient must take the full olmesartan dose of 40 mg once daily 
for at least 4 weeks prior to reassessment at Run-in Visit 2). 
• Amlodipine: 5 mg orally once daily 
• Indapamide: 2.5 mg orally once daily 
Protocol-specified antihypertensive medications may be downtitrated or temporarily 
discontinued per Investigator judgement for low blood pressure (see Section 5.8.1). At the 
Investigator’s discretion, oral antihypertensive agents, including protocol-specified background 
antihypertensive medication, may be prophylactically held during intercurrent illness or volume 
depletion. Additional information on the protocol-specified background antihypertensive 
medications, including side effects, drug-drug interactions, and other important prescribing 
information can be found in the Pharmacy Manual. 
5.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center will be responsible for preparing zilebesiran or placebo doses 
and dispensing protocol-specified background antihypertensive medication, according to 
procedures detailed in the Pharmacy Manual. No special procedures for the safe handling of 
study drug or protocol-specified background antihypertensive medication are required. 
Study drug will be stored at approximately 2 to 30°C until dose preparation. Protocol-specified 
background antihypertensive medication will be stored according to the storage instructions on 
the label. Deviations from the recommended storage conditions should be reported to the 
Sponsor and use of the affected study drug or protocol-specified background antihypertensive 
medication halted until authorization for its continued use has been provided by the Sponsor or 
designee, as described in the Pharmacy Manual. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and protocol-specified background antihypertensive 
medication and additional storage will be provided in the Pharmacy Manual. 
5.5. 
Packaging and Labeling 
All packaging, labeling, and production of study drug and protocol-specified background 
antihypertensive medication will be in compliance with current Good Manufacturing Practice 
specifications, as well as applicable local regulations. Study drug and protocol-specified 
background antihypertensive medication labels and external packaging will include all 
appropriate information as per local labeling requirements. Additional details will be available in 
the Pharmacy Manual. 


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5.6. 
Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
study drug and protocol-specified background antihypertensive medication supplied for this 
study, including dates of receipt. In addition, accurate records will be kept of when and how 
much study drug and protocol-specified background antihypertensive medication is dispensed 
and administered to each patient in the study. Any reasons for departure from the protocol 
dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all study drugs and 
protocol-specified background antihypertensive medication. Used, partially used, and unused 
study drug and protocol-specified background antihypertensive medication will be returned to 
the Sponsor (or designee) or destroyed at the clinical study center according to applicable 
regulations. 
Further instructions about accountability will be detailed in the Pharmacy Manual. 
5.7. 
Clinical Product Complaints 
5.7.1. 
Definition 
A clinical product complaint (CPC) is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of the study drug and its packaging after it is released for distribution to the site at 
which study drug will be administered. 
A CPC may be detected prior to use of study drug, during use, or after use. A CPC is typically 
nonmedical in nature; however, it is possible that study drug complaints could be associated with 
an AE. Examples of a CPC include, but are not limited to: illegible clinical label, missing clinical 
label, damaged vial, empty vial, and contamination of study drug. 
5.7.2. 
Reporting 
For product complaints, the Sponsor or its designee should be notified within 24 hours using the 
process outlined in the Pharmacy Manual. CPCs that may be associated with an AE must be 
evaluated and reported as indicated in Section 6.5.6. Detailed instructions on reporting CPCs will 
be provided in the Pharmacy Manual. 
5.8. 
Monitoring for Potential Clinical Events 
5.8.1. 
Monitoring and Approach for Potential Hypotension 
Hypotension is an obligate risk of antihypertensive medications. In addition to office blood 
pressure monitoring, outpatient blood pressure will be monitored weekly with HBPM to ensure 
the early detection of potential hypotension. Whenever possible, management decisions will be 
based on blood pressure measurements confirmed by office blood pressure. 
The following management recommendations for hypotension are provided: 
• Patients who experience low blood pressure that is associated with symptoms should 
promptly seek medical evaluation at the clinical study site or another hospital setting. 


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Clinical study site evaluation for low blood pressure should include the assessment of 
orthostatic blood pressure (supine to standing).  
• The Investigator should consider downtitration or interruption of oral 
antihypertensives (if taking) if confirmed office SBP <90 mmHg or if clinical 
symptoms, such as lightheadedness or dizziness, develop coupled with a significantly 
lower SBP compared to prior visits (ie, SBP <100 mmHg). Oral antihypertensives 
should be downtitrated/interrupted in reverse order to how they were added (ie, 
interrupt escape antihypertensive medications before protocol-specified background 
antihypertensive medications). 
• Clinically significant events discovered during the course of a patient’s general 
medical care should be promptly communicated to the site and evaluated by the 
Investigator, especially if hypotension is noted. Patients will carry Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)-approved patient cards to 
facilitate this physician-to-physician communication.  
• If hypotension is confirmed, serum electrolytes and creatinine should be measured 
and any oral antihypertensive(s) should be downtitrated or interrupted per 
Investigator judgement as outlined above.  
• The frequency of blood pressure and laboratory monitoring (serum electrolytes and 
creatinine) should be increased during intercurrent illnesses that predispose patients to 
dehydration (eg, vomiting or diarrhea that persists for more than 24 hours) or when 
symptoms consistent with decreased effective circulating volume (eg, presyncopal 
symptoms, unexplained falls, decreased urine output) manifest, even if a patient’s 
recent blood pressure measurements have been normal. 
• Hypotension that warrants direct evaluation at the site should be communicated to the 
Medical Monitor within 24 hours. In addition, other clinical events consistent with 
potential hypotension (eg, unexplained presyncope, syncope, or falls) should be 
communicated to the Medical Monitor within 24 hours of the site being notified. 
• Management of persistent hypotension may include increased salt intake or, if 
unresponsive, standard treatments for orthostatic intolerance syndromes such as 
fludrocortisone or midodrine. 
• Low blood pressure that requires medical treatment (including intravenous fluid 
support) or other clinical events consistent with potential hypotension (see above) 
should be recorded as AEs. 
5.8.2. 
Monitoring and Approach for Clinically Significant Blood Pressure Elevation 
In addition to office blood pressure monitoring, outpatient blood pressure will be monitored 
frequently with HBPM to ensure the early detection of potential significant elevations. Whenever 
possible, management decisions will be based on blood pressure measurements confirmed by 
office blood pressure. The recommended interventions for potentially clinically significant blood 
pressure elevation are presented in Table 4.  


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Table 4: 
Recommended Interventions for Potentially Clinically Significant Blood 
Pressure Elevation 
Study Period 
Intervention 
Throughout Study 
• 
Whenever possible, management decisions should be based on blood 
pressure measurements confirmed by office blood pressure. 
• 
Any confirmed event of severe hypertension (office SBP ≥180 mmHg 
and/or office DBP ≥120 mmHg) should be appropriately treated regardless 
of its timing relative to study drug administration.  
• 
Until double-blind data are generated that demonstrate acceptable safety 
and added antihypertensive efficacy of zilebesiran when combined with 
olmesartan, the use of conventional RAAS inhibitors (ARBs, ACE 
inhibitors, or direct renin inhibitors) as escape antihypertensive agents for 
high blood pressure will be avoided throughout the study.  
• 
If added, escape antihypertensives must be used per their labeled 
instructions and in accordance with current clinical guidelines.[Whelton 
2018; Williams 2018] 
Day 1 to Month 3 
Intervene if clinically significant blood pressure elevation: 
• 
Because of the gradual onset of effects of zilebesiran, interventions for 
asymptomatic hypertension should be avoided in the first 6 weeks after the 
patient’s first administration of study drug.  
• 
After Week 6, patients who develop office SBP >160 mmHg and increased 
>10 mmHg from their baseline office SBP that persists for ≥24 hours on 2 
consecutive measurements or that is accompanied by hypertensive 
symptoms should be evaluated by the clinical study site. Severely 
symptomatic patients should be evaluated at the clinical study site or 
another hospital setting within 24 hours. 
• 
If persistent hypertension is confirmed (without the identification of a 
specific treatable cause) and the Investigator deems it to be a clinically 
significant change, treatment may be initiated at the medical discretion of 
the Investigator using a CCB and/or a thiazide/thiazide-like diuretic 
(whichever agent is not already the protocol-specified background 
antihypertensive medication) as an escape antihypertensive medication.  
Months 3 to 6 
Treat to target blood pressure using a CCB and/or thiazide/thiazide-like diuretic 
(whichever agent is not already a protocol-specified background 
antihypertensive medication): 
• 
At Month 3, a CCB and/or a thiazide/thiazide-like diuretic may be added as 
an escape antihypertensive medication if the daytime mean SBP is 
≥135 mmHg by ABPM. If the Investigator feels there is a compelling 
clinical reason to wait, the rationale for exception should be documented in 
the eCRF. 
• 
After Month 3, other escape antihypertensive medications may also be 
added per Investigator judgement for persistent elevations in SBP above 
recommended target per treatment guidelines (eg, office SBP <140 mmHg, 
HBPM SBP <135 mmHg, or daytime mean SBP by ABPM <135 
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Study Period 
Intervention 
Month 6 to End of 
Study (OLE period) 
Treat to target blood pressure using Investigator’s choice of oral 
antihypertensive(s). 
• 
At Month 6, protocol-specified background antihypertensive medications 
(olmesartan, amlodipine, or indapamide) will be discontinued.  
• 
Patients who continued into the OLE period initiated open-label treatment 
with 600 mg zilebesiran once every 6 months. As many patients would have 
received zilebesiran for the first time at Month 6, office blood pressure and 
serum chemistries will be carefully monitored monthly from Month 6 to 
Month 9, and Investigators will be prepared to downtitrate or interrupt 
escape antihypertensive medications if low blood pressure develops (see 
Section 5.8.1). 
• 
If the Month 6 ABPM is in target (daytime mean SBP <135 mmHg), escape 
antihypertensive medications (if taken) may be downtitrated or interrupted 
per Investigator judgement to determine if the patient’s blood pressure 
remains within target on zilebesiran treatment alone.  
• 
During the OLE period, oral antihypertensive medications may be added 
per Investigator judgement for persistent elevations in blood pressure above 
recommended target per treatment guidelines (eg, office SBP <140 mmHg, 
HBPM SBP <135 mmHg, or daytime mean SBP by ABPM <135 
mmHg).[Whelton 2018; Williams 2018] 
Abbreviations: ABPM=ambulatory blood pressure monitoring; ACE=angiotensin converting enzyme; 
ARB=angiotensin II-receptor blocker; CCB=calcium channel blocker; DBP=diastolic blood pressure; 
eCRF=electronic case report form; HBPM=home blood pressure monitoring; OLE=open-label extension; 
RAAS=renin-angiotensin-aldosterone system; SBP=systolic blood pressure. 
5.8.3. 
Monitoring and Approach for Potential Renal Dysfunction 
The Schedule of Assessments (Table 1) includes frequent laboratory monitoring of eGFR 
through the anticipated onset of initial zilebesiran PD. Based upon the renal dysfunction 
associated with conventional RAAS inhibitors,[McMurray 2016; Parving 2012] the following 
guidelines apply throughout the study: 
• If an individual patient experiences a decrease in eGFR by ≥30% from baseline or to 
≤30 mL/min/1.73m2, the Investigator should obtain confirmatory repeat tests, contact 
the Sponsor, and look for potentially reversible causes of renal dysfunction such as: 
− NSAIDs, antibiotics, or other treatments known to impair renal function 
− Recent exposure to intravenous contrast agents 
− Hypovolemia 
− Hypotension 
− Urinary infection 
− Urinary tract obstruction 
• If an individual patient experiences a decrease in eGFR by ≥40% from baseline or to 
≤25 mL/min/1.73m2, the Investigator should obtain confirmatory repeats tests, look 


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for potentially reversible causes of renal dysfunction, and contact the Sponsor to 
discuss the potential interruption of study drug and/or oral antihypertensives. Serum 
creatinine should be monitored at least weekly until improving. 
5.8.4. 
Monitoring and Approach for Potential Hyperkalemia 
The Schedule of Assessments (Table 1) includes frequent laboratory monitoring of serum 
electrolytes (at least monthly through the anticipated onset of zilebesiran PD). The guidelines in 
Table 5 apply for potassium elevations detected by laboratory monitoring.[McMurray 2016; 
Parving 2012] 
Table 5: 
Recommended Interventions for Hyperkalemia 
Serum K+ >5.2 and <5.5 mmol/L 
Serum K+ ≥5.5 and <6.0 mmol/L 
Serum K+ ≥6.0 mmol/L 
• 
Confirm potassium 
concentration in a non-
hemolyzed sample. 
• 
Reinforce low-potassium diet 
and restriction of food/drinks 
with high potassium content  
• 
Review medical regimen 
(including dietary supplements 
and over-the-counter 
medications) for agents known 
to cause hyperkalemia.a 
Consider reduction in dose or 
discontinuation of these agents 
only if clinically acceptable. 
• 
Repeat K+ measurement within 
3 to 5 days. 
• 
If K+ remains >5.2 and <5.5 
mmol/L, regularly monitor K+ 
levels to ensure stability (at 
least weekly if in the first 6 
weeks of treatment or at least 
once monthly afterwards) 
• 
Confirm potassium 
concentration in a non-
hemolyzed sample 
• 
Consider interruption of open-
label olmesartan (in patients 
randomized to receive it as their 
protocol-specified background 
antihypertensive medication) 
according to Investigator 
medical judgement 
• 
Consider interruption or delay 
of study drug administration, 
according to Investigator 
medical judgment  
• 
Apply all measures outlined for 
serum K+ >5.2 and <5.5 
mmol/L 
• 
Repeat K+ measurement after 2 
to 3 days 
• 
If K+ <5.5 mmol/L, consider 
resumption of study drug (if 
interrupted) with repeat 
potassium within 5 days 
• 
If K+ persistently elevated ≥5.5 
mmol/L, consider treatment 
with patiromer (or with sodium 
zirconium cyclosilicate), if 
available 
• 
Immediately interrupt 
study drug 
• 
Confirm potassium 
concentration in a 
non-hemolyzed 
sample 
• 
Urgently evaluate 
patient and treat 
hyperkalemia as 
clinically indicated. 
After urgent 
treatment, consider 
treatment with 
patiromer (or with 
sodium zirconium 
cyclosilicate), if 
available 
• 
Apply all measures 
outlined for serum K+ 
≥5.5 and <6.0 
mmol/L 
• 
No resumption of 
study drug without 
individualized case 
discussion with and 
permission from 
Alnylam Medical 
Monitor 
Abbreviations: NSAID=nonsteroidal anti-inflammatory drug. 
a This list is not meant to be exhaustive: potassium-sparing diuretics (eg, amiloride and triamterene), potassium 
supplements (eg potassium chloride), salt substitutes, NSAIDs, cyclo-oxygenase-2 inhibitors, trimethoprim and 
trimethoprim-containing combination products, herbal supplements (eg, Noni juice, alfalfa [Medicago sativa], 
dandelion [Taraxacum officinale], horsetail [Equisetum arvense], nettle [Urtica dioica], milkweed, lily of the 
valley, Siberian ginseng, hawthorn berries). 


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The availability of patiromer and sodium zirconium cyclosilicate (ZS-9) will be assessed at 
participating study sites. These potassium-binding drugs are indicated for the treatment of 
hyperkalemia and have been shown to safely reduce serum potassium levels and to maintain 
long-term normokalemia in chronic kidney disease patients receiving background conventional 
RAAS inhibitor therapy.[Georgianos 2018; Weir 2015] 
5.9. 
Concomitant Medications and Procedures 
Use of concomitant medications and procedures will be recorded on the patient’s eCRF as 
specified in the Schedule of Assessments (see Table 1). Concomitant medications include all 
prescription medications, herbal preparations, over the counter medications, vitamins, and 
minerals. Any changes in medications during the study will also be recorded on the eCRF. 
Standard vitamins and topical medications are permitted. However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated. For other permitted 
concomitant medications administered SC, do not administer in same injection site area as the 
study drug for at least 4 days after each dose of study drug. 
Patients receiving low-dose aspirin (defined as ≤100 mg per day) for at least 30 days prior to 
screening and during the study treatment period are allowed. Occasional use of other systemic 
over-the-counter NSAIDs is allowed. However, given their association with increased blood 
pressure, they should be avoided when possible and for at least 2 days prior to ABPM and office 
blood pressure assessments, and alternative analgesics (acetaminophen, topical NSAIDs) should 
be considered.[Whelton 2018] When used, the dosing of systemic NSAIDs should be at the 
lower end of the labeled range and for the shortest duration possible.  
Patients receiving SGLT2 inhibitors (eg, empagliflozin, canagliflozin, and dapagliflozin) should 
be on a stable dose for at least 30 days prior to screening and during the study treatment period. 
These medications should not be initiated or discontinued, if possible, during the study treatment 
period. 
Patients receiving stable doses of tamsulosin, alfuzosin, or silodosin for at least 30 days prior to 
screening are allowed. 
Patients will be allowed to receive vaccines (eg, for SARS-CoV-2) that have received health 
agency authorization (including for emergency use) by local or regional regulatory authorities. 
Use of cannabis or delta-9-tetrahydrocannibinol (THC)-containing substances (including by 
smoking, vaping, dabbing, or ingesting/edibles) should be avoided when possible and for at least 
2 days prior to ABPM and office blood pressure assessments. 
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator, except as described in Section 5.9.1 and after consulting the Pharmacy Manual, 
which contains information on drug-drug interactions and other important prescribing 
information for the protocol-specified background antihypertensive medications. However, it is 
the responsibility of the Investigator to ensure that details regarding the medication are recorded 
on the eCRF. Concomitant medication will be coded using an internationally recognized and 
accepted coding dictionary. 


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5.9.1. 
Prohibited Concomitant Medication 
The following medications, treatments, and supplements are prohibited throughout the study 
treatment period (until the EOT visit): 
• Conventional RAAS inhibitors (ARBs, ACE inhibitors, or direct renin inhibitors), 
except for olmesartan as protocol-specified background antihypertensive medication 
during the 6-month DB period  
• Prescription NSAIDs  
• Organic nitrate preparations (eg, nitroglycerin, isosorbide mononitrate, isosorbide 
dinitrate, pentaerythritol) 
• An RNAi therapeutic (other than zilebesiran) 
• Medications, herbal supplements (including Ma Huang and St. John’s wort), or other 
substances (such as licorice) that are associated with increases in LFT abnormalities 
or with blood pressure abnormalities are prohibited. This includes certain stimulants 
(eg, amphetamine, methylphenidate dexmethylphenidate, dextroamphetamine), MAO 
inhibitors, atypical antipsychotics (eg, clozapine, olanzapine), diet pills (eg, 
phenylpropanolamine, sibutramine), and nasal decongestants (eg, phenylephrine 
hydrochloride, pseudoephedrine, naphazoline hydrochloride), unless individually 
approved by both the Investigator and the Medical Monitor. 
• Medications, herbal medicines, over-the-counter medications, or supplements known 
to cause hyperkalemia are prohibited unless individually approved by both the 
Investigator and the Medical Monitor. This includes potassium-sparing diuretics, 
potassium supplements, cyclo-oxygenase-2 inhibitors, trimethoprim and 
trimethoprim-containing combination products, mineralocorticoid receptor 
antagonists, Noni juice, alfalfa, dandelion, horsetail, nettle, milkweed, lily of the 
valley, Siberian ginseng, and hawthorn berries. 
All concomitant medications must be reviewed and approved by the Investigator, with particular 
attention to avoiding drugs that may affect blood pressure. 
5.10. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff. 
Compliance with protocol-specified background antihypertensive medication will be assessed 
through pill count by study staff. 
5.11. 
Other Requirements 
5.11.1. 
Contraception 
Females of child-bearing potential must be willing to use a highly effective method of 
contraception from 14 days before the first dose of protocol-specified background 
antihypertensive medication, throughout study participation, and through safety follow-up (if 
applicable; see Section 3.1). 


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Birth control methods which are considered highly effective include: 
• Placement of an intrauterine device. 
• Placement of an intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
• Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female patients on the 
study, the vasectomized male partner should be the sole partner for that patient). 
• Established use of oral (except low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception associated with the inhibition of 
ovulation. 
• True sexual abstinence, when in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. Abstinent 
patients must agree to use one of the above-mentioned contraceptive methods if they 
start heterosexual relationships during the study and through safety follow-up (if 
applicable; see Section 3.1) 
Investigators should advise females of childbearing potential of the most appropriate birth 
control method available within their country taking into account local medical practice. 
Females of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study), and who are not postmenopausal or permanently 
sterilized (eg, bilateral oophorectomy, hysterectomy, or bilateral salpingectomy). A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by follicle stimulating hormone level within the postmenopausal 
range.  
For male patients, no contraception is required. However, use by males of contraception 
(condom) may be required in some countries, eg, France, in order to comply with local 
requirements as described in the corresponding patient ICFs.  
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.5.5.3). Pregnancy testing will be 
performed before every dose for postmenarcheal females throughout the course of the study (see 
Section 6.5.5.3). 
5.11.2. 
Alcohol Restrictions 
Patients should limit alcohol consumption throughout the course of the study. Alcohol is limited 
to no more than 2 units per day (unit: 1 glass of wine [approximately 125 mL] =1 measure of 
spirits [approximately 1 fluid ounce] =½ pint of beer [approximately 284 mL]) for the duration 
of the study. Compliance with alcohol restrictions should be assessed on a regular basis by the 
Investigator throughout the course of the study. 


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5.11.3. 
Tobacco and Nicotine Restrictions 
Use of nicotine or tobacco-containing products (including, but not limited to, snuff, chewing 
tobacco, cigars, cigarettes, pipes, nicotine patches, or e-cigarettes) must be avoided within 30 
minutes prior to office blood pressure measurements. 
5.11.4. 
Dietary Recommendations 
All patients will receive educational materials on diet with recommendations to limit sodium 
consumption to approximately 2.0 g per day from screening through the end of the Treatment 
period. This direction should be provided at the start of the Screening period, and treatment-
naïve patients should follow these recommendations for at least 1 week prior to screening 
assessments of blood pressure. This is the sodium intake recommended in the 2018 European 
Society of Cardiology/European Society of Hypertension Guidelines for both hypertensive 
patients and for the general population.[Williams 2018]  
On days on which samples for fasting lipid panel and glycemic assessments are collected, 
patients are required to fast for ≥10 hours before sample collection (Section 6.5.5.1). 
5.11.5. 
Exercise 
Patients should abstain from strenuous exercise for 48 hours before each blood collection for 
clinical laboratory tests and from any exercise for 30 minutes prior to office blood pressure 
measurements. 
6. 
STUDY ASSESSMENTS 
The schedule of study assessments is provided in Table 1. Study visits should be scheduled for 
the morning. All assessments, except for postdose PK sample collection, are to be performed 
prior to dosing with protocol-specified background antihypertensive medication or study drug. 
Additional information on the collection of study assessments will be detailed in the study 
manuals. 
Where applicable country and local regulations and infrastructure for home healthcare allow, 
home healthcare may take place at a location other than the clinical trial site to perform study 
assessments, which may include collection of blood and urine samples, measurement of vital 
signs (including blood pressure assessments), performing pill counts of protocol-specified 
background antihypertensive medications, and collection of weight (at the discretion and 
oversight of the Investigator). See further details in Section 10.3. 
6.1. 
Screening Assessments 
An ICF that has been approved by the appropriate IRB/IEC must be signed (in paper or 
electronic format per local regulations and institutional standards) by the patient before the 
screening procedures are initiated. All patients will be given a copy of the signed and dated ICF. 
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria. Rescreening of patients once is permitted with agreement of the Medical 
Monitor (see Section 6.1.2). 


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Patient demographic data and medical history/disease history will be obtained. Any changes to 
medical history occurring between the screening assessment and Run-in Visit 1 will be updated 
prior to administration of protocol-specified background antihypertensive medication. 
6.1.1. 
Retesting  
If in the Investigator’s judgement, the screening or Run-in laboratory abnormalities are likely to 
be transient, then laboratory tests may be repeated. The Investigator’s rationale must be 
documented. Laboratory values can be retested once during screening and once during the Run-
in period provided that the patient can be evaluated for eligibility and randomized within the 
allowed Screening and Run-in periods. Retesting of office blood pressure at Run-in Visit 1 is 
permitted once if in the Investigator’s judgement, the result is not accurate due to a transient 
condition. Retesting of ABPM at Run-in Visit 2 is permitted once if the first ABPM is invalid. A 
valid ABPM recording must be obtained within 7 days prior to randomization for all patients. If 
a valid ABPM recording that meets the inclusion criterion exceeds the 7-day window prior to 
randomization, a single additional ABPM assessment is permitted, with no option for retesting in 
case of an invalid reading. Eligibility is assessed by the most recent ABPM result obtained. If a 
valid ABPM recording that meets the inclusion criterion is not obtained within the 7 days prior to 
randomization, the patient is a run-in failure. 
6.1.2. 
Rescreening 
A patient who does not meet all study eligibility criteria due to a transient condition observed at 
screening (eg, prohibited medications that were subsequently discontinued) will be allowed to 
return once for rescreening following agreement with the Medical Monitor. A patient will be re-
consented if rescreening occurs outside of the Screening period. In this case, all screening 
procedures must be repeated. Patients who do not meet eligibility criteria after Run-in Visit 1 
will not be rescreened. 
6.2. 
Efficacy Assessments 
All blood pressure measurements (ABPM, office, and HBPM) must be taken at the times 
specified in the Schedule of Assessments (Table 1) using the standardized equipment provided 
by the Sponsor, according to the methods described in Section 10.2. Office blood pressure 
assessments and ABPM initiation must be performed before administration of any oral 
antihypertensive medications and study drug (as applicable). 
Patients taking oral antihypertensives prior to screening should discontinue these medications at 
Run-in Visit 1. The baseline ABPM and office blood pressure measured at Run-in Visit 2 must 
be taken within 7 days before Day 1. An HBPM unit will be provided before Run-in Visit 2 to 
establish the HBPM baseline, and HBPM should be collected at least 3 times during the last 
week prior to Day 1. 
ABPM placement may be performed at home by appropriately trained individuals, as detailed in 
the ABPM Investigator Manual. If a patient is unable to report to the site for an office blood 
pressure assessment, a substitute “remote visit blood pressure measurement” may be obtained 
remotely using the methods described in Section 10.2. 
Recommendations for approach and monitoring of low blood pressure/hypotension and 
hypertensive escape are provided in Section 5.8.1 and Section 5.8.2, respectively. 


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6.2.1. 
ABPM 
The ABPM should be started prior to the morning dose of oral antihypertensive medication. 
Consecutive (daily) use of over-the-counter NSAIDs (other than aspirin ≤100 mg per day) and 
use of cannabis or THC-containing substances should be avoided for at least 2 days prior to 
ABPM measurements.  
Validity will be assessed for all ABPMs. If the ABPM recording is invalid at any point during 
the study, the patient will be provided 1 opportunity to repeat the recording. During the Run-in 
period, if a valid ABPM recording that meets the inclusion criterion exceeds the 7-day window 
prior to randomization, a single additional ABPM assessment is permitted, with no option for 
retesting in case of an invalid reading. Eligibility is assessed by the most recent ABPM result 
obtained. If a valid ABPM recording that meets the inclusion criterion is not obtained within the 
7 days prior to randomization, the patient is a run-in failure. 
See further details in Section 10.2 and the ABPM Investigator Manual. 
6.2.2. 
Office Blood Pressure 
Office blood pressure must be measured in triplicate using the automated blood pressure device 
provided by the Sponsor at trough (prior to taking oral antihypertensives) and should be at 
approximately the same time of day for each assessment; therefore, visits should be scheduled at 
approximately the same time of day, whenever possible. Office blood pressure must include 
orthostatic measurements (seated and standing).  
Exercise, caffeine, alcohol consumption, and use of nicotine or tobacco-containing products 
(including but not limited to snuff, chewing tobacco, cigars, cigarettes, pipes, nicotine patches, or 
e-cigarettes) must be avoided within 30 minutes prior to blood pressure measurements. The use 
of inhaled short-acting beta agonists should be avoided within 6 hours prior to measuring blood 
pressure and/or heart rate. The use of phosphodiesterase type 5 inhibitors (eg, sildenafil, 
tadalafil, vardenafil, avanafil) should be avoided within 48 hours prior to measuring blood 
pressure. Consecutive (daily) use of over-the-counter NSAIDs (other than aspirin ≤100 mg per 
day) and use of cannabis or THC-containing substances should be avoided for at least 2 days 
prior to blood pressure measurements. 
The patient should be seated comfortably with the back supported and the feet flat on the floor as 
detailed in Section 10.2 and the HBPM and OBPM Investigator Manual.  
6.2.3. 
HBPM 
The HBPM should be measured in the morning upon waking, prior to breakfast/caffeine or 
taking morning oral antihypertensive medications. HBPM is not required on days when ABPM is 
being assessed. The patient should be seated comfortably with the back supported and the feet 
flat on the floor as detailed in Section 10.2 and the HBPM and OBPM Investigator Manual. 
6.3. 
Pharmacodynamic Assessments 
Blood samples for determination of AGT will be collected according to the Schedule of 
Assessments (Table 1). In addition, blood samples for determination of RAAS biomarkers 
(plasma renin concentration, AngI, AngII, and aldosterone) will be collected only for patients 
randomized to receive olmesartan as protocol-specified background antihypertensive medication. 


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Blood samples for PD assessments must be collected before study drug administration (on days 
when study drug is to be dosed) or at a time point corresponding to the time of study drug dosing 
(on other days). Blood AGT levels will be analyzed at a regulated bioanalytical laboratory by 
enzyme-linked immunosorbent assay for measurement of PD effect. Biomarkers may be 
analyzed using qualified assays. Details regarding the collection, processing, shipping, and 
storage of the samples will be provided in the Laboratory Manual.  
Results will not be used to adjust dosing of zilebesiran or guide clinical management and will not 
be shared with sites until after study unblinding. 
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for the assessment of plasma concentrations of zilebesiran and 
its primary metabolite AS(N-1)3′ zilebesiran at the time points indicated in the Schedule of 
Assessments (Table 1). A detailed schedule of time points for the collection of blood samples for 
PK analysis is in Table 2. 
Plasma concentrations of zilebesiran and AS(N-1)3′ zilebesiran will be determined using a 
validated assay. Details regarding sample volumes to be collected, and the processing, shipping, 
and analysis of the samples will be provided in the Laboratory Manual. 
6.5. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of AEs, 
including SAEs, recording of concomitant medication and measurements of vital signs, weight, 
electrocardiogram (ECG) findings, and laboratory tests. Clinically significant abnormalities 
observed during the physical examination will be recorded. 
6.5.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1) and include 
office blood pressure, heart rate, body temperature, and respiratory rate. Vital signs are to be 
collected prior to administration of oral antihypertensive medications and study drug (as 
applicable). When vital signs and blood sample collection occur at the same time, vital signs 
should be performed before blood samples are drawn, where possible. Vital signs should be 
measured in the seated position, after the patient has rested comfortably for approximately 5 
minutes. Body temperature in degrees Celsius will be obtained via oral, tympanic, forehead, or 
axillary methods. Heart rate will be counted for a full minute and recorded in beats per minute, 
and respiration rate will be counted for a full minute and recorded in breaths per minute. Blood 
pressure is described in Section 6.2.  
Additional vital sign assessments, as medically indicated, may be added at the discretion of the 
Investigator, or as per DMC advice. 
6.5.2. 
Weight, Height, and Morphometrics 
Height and body weight measurements will be collected as specified in the Schedule of 
Assessments (Table 1) and will be recorded in the eCRF. Height will be measured at Day 1 only. 
Height will be measured in centimeters. Body weight should be measured in kilograms to the 
first decimal point in patients wearing light clothing and without shoes.  


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Waist circumference and waist-to-hip-ratio will also be collected as specified in the Schedule of 
Assessments (Table 1) and will be recorded on the eCRF. For waist circumference and waist-to-
hip ratio, patients should wear minimal clothing to ensure that the measuring tape is correctly 
positioned. Patients should stand erect with the abdomen relaxed, arms at the sides, feet together 
and with their weight equally divided over both legs. To perform the waist measurement, the 
lowest rib margin is first located and marked with a pen. The iliac crest is then palpated in the 
midaxillary line, and also marked. It is recommended to apply an elastic tape horizontally 
midway between the lowest rib margin and the iliac crest, and tie firmly so that it stays in 
position around the abdomen about the level of the umbilicus. The elastic tape thus defines the 
level of the waist circumference, which can then be measured by positioning the measuring tape 
over the elastic tape. Hip circumference measurement should be taken around the widest portion 
of the buttocks. Patients are asked to breathe normally, and to breathe out gently at the time of 
the measurement to prevent them from contracting their muscles or from holding their breath. A 
stretch-resistant tape that provides a constant 100 g of tension is recommended. Measurements 
should be obtained with the tape positioned parallel to the floor and performed using the same 
procedure throughout the study. 
The reading is taken to the nearest centimeter and entered in the source document. Each 
measurement should be repeated twice; if the measurements are within 1 cm of each other, the 
average should be calculated. If the difference between the 2 measurements exceeds 1 cm, the 2 
measurements should be repeated.  
6.5.3. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedule 
of Assessments (Table 1); if a physical examination is scheduled for a study drug dosing visit, it 
should be conducted prior to dosing. Full physical examinations will include the examination of 
the following: general appearance; head, eyes, ears, nose and throat; respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, and dermatological systems; thyroid; lymph nodes; and 
neurological evaluation (see the Recommended Neurological Assessments for All Physical 
Examinations document for further details on the assessments to be performed as part of the 
neurological evaluation). 
Symptom-directed physical examinations will be guided by evaluation of changes in symptoms, 
or the onset of new symptoms, since the last visit. Neurological evaluation should be performed 
during all symptom-directed physical examinations regardless of whether neurological 
symptoms have been experienced by the patient.  
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF. 
6.5.4. 
Electrocardiogram 
The 12-lead ECGs reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, 
QT interval, and Fridericia-corrected QT interval will be obtained using a local machine, as 
specified in the Schedule of Assessments (Table 1). Patients should be supine for at least 10 
minutes before each ECG is obtained. The Investigator or qualified designee will review all 
single 12-lead ECGs to assess whether the results have changed since the Baseline visit and to 


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determine the clinical significance of the results. These assessments will be recorded in the 
eCRF.  
When ECG and blood sample collection for RAAS biomarkers (renin, aldosterone, and Ang I/II) 
occur at the same visit and where feasible, blood sample collection should occur first. ECGs 
should be performed at least 30 minutes after phlebotomy or other stressful assessments. 
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since the baseline visit and to determine the clinical significance of the results. These 
assessments will be recorded in the eCRF. Additional ECGs may be collected at the discretion of 
the Investigator, or as per DMC advice.  
6.5.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory. Specific 
instructions for transaminase elevations are provided in Section 5.2.4. For any other unexplained 
clinically relevant abnormal laboratory test occurring after study drug administration, the test 
should be repeated and followed up at the discretion of the Investigator, or as per DMC advice, 
until it has returned to the normal range or stabilized, and/or a diagnosis is made to adequately 
explain the abnormality. Additional safety laboratories and assessments as indicated by the 
clinical situation may be requested. Clinical laboratory assessments are listed in Table 6 and will 
be assessed as specified in the Schedule of Assessments (Table 1).  
While local laboratory results may be used for urgent clinical decisions, on the day of the 
assessments, all laboratory assessments specified in Table 6 that are performed at the clinic 
should also be sent in parallel to the central laboratory. In the case of discrepant local and central 
laboratory results on samples drawn on the same day, central laboratory results will be relied 
upon for clinical decisions. 
Clinical laboratory assessments may be collected at the clinical study center or at home by a 
trained healthcare professional. In patients randomized to receive olmesartan as the protocol-
specified background antihypertensive medication, blood samples for RAAS biomarkers should 
be collected in the morning and in the seated/upright position (after blood pressure 
measurements and before any assessments collected in the supine position). Blood samples for 
laboratory evaluation should be collected after the completion of blood pressure assessments. 
Spot urine collections for albumin and creatinine should be obtained in the morning.  
For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the Medical 
Monitor; results may be collected and should be included in the clinical database. 


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Table 6: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Uric acid 
Albumin 
Total protein 
Calcium 
Glucose 
Bicarbonate 
Creatinine and eGFR 
Chloride 
Creatinine clearance (screening only) 
 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT 
 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Protein 
Leukocyte esterase 
Glucose 
Microscopy (if clinically indicated) 
Coagulation  
Prothrombin time 
International normalized ratio 
Partial thromboplastin time  
 
Fasting Lipid Panel and Glycemic Assessments (see Section 6.5.5.1) 
Lipid panel, including 
HDL-C, non-HDL-C, LDL-C, apolipoprotein A1, 
triglycerides, total cholesterol  
Insulin 
Fasting plasma glucose 
HbA1c 
Immunogenicity (see Section 6.5.5.2) 
ADA 
 
Pregnancy Testing/FSH Screening (see Section 6.5.5.3) 
β-human chorionic gonadotropin (females of 
child-bearing potential only) 
Follicle-stimulating hormone (postmenopausal 
women only) 
Abbreviations: ADA=anti-drug antibodies; ALP=alkaline phosphatase; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; 
FSH=follicle-stimulating hormone; GGT=gamma glutamyl transferase; HbA1c=hemoglobin A1c; HDL-C=high-
density lipoprotein; LDL-C=low-density lipoprotein; RBCs=red blood cells. 


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6.5.5.1. 
Fasting Lipid Panel and Glycemic Assessments 
Blood samples for fasting plasma glucose, insulin, lipid panel (including total cholesterol, high-
density lipoprotein [HDL-C], non-HDL-C, low-density lipoprotein, apolipoprotein A1, and 
triglycerides), and HbA1c will be collected at the time points listed in the Schedule of 
Assessments (Table 1). Patients are required to fast for ≥10 hours before sample collection for 
fasting glucose, insulin, lipid panel, and HbA1c. Samples should be collected at approximately 
the same time of day (±2 hours). 
6.5.5.2. 
Immunogenicity 
Blood samples will be collected to evaluate anti-drug antibodies (ADA). Blood samples for ADA 
testing must be collected before study drug administration (on days when study drug is to be 
dosed) or at a time point corresponding to the time of study drug dosing (on other days) as 
specified in the Schedule of Assessments (Table 1). A blood sample to evaluate ADA will be 
collected at the ET visit, if applicable. Blood samples for ADA will be analyzed at a regulated 
bioanalytical laboratory. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 
6.5.5.3. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential. A serum pregnancy 
test will be performed at screening, and urine pregnancy tests will be performed thereafter per 
the Schedule of Assessments and any time pregnancy is suspected. More frequent pregnancy 
testing may be performed where required per local requirements. The results of the pregnancy 
test must be known before study drug administration. Patients who are pregnant at screening are 
not eligible for study participation. Any woman with a positive urine pregnancy test, 
subsequently confirmed by a positive serum pregnancy test, during the study will be 
discontinued from study drug but will continue to be followed for safety. Patients who become 
pregnant while on study will be followed at least until the pregnancy outcome is known (see 
Section 6.5.6.7 for follow-up instructions). 
A blood sample will be drawn at screening to measure the levels of follicle stimulating hormone 
in order to confirm postmenopausal status in all women suspected to be postmenopausal (see 
Section 5.11.1 for definition of postmenopausal state). 
6.5.5.4. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 5.2.4. Following the occurrence of elevated liver 
transaminases or other LFT abnormalities per central laboratory, all assessments in Table 7 will 
be performed 1 time, as well as hematology, serum chemistry, LFT, and coagulation assessments 
from Table 6, and other assessments or evaluations per Investigator discretion, as appropriate.  
Monitoring, including criteria for dose modification or withholding the study drug, is described 
in Section 5.2.4.  


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Table 7: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
HBsAg, HBc antibody IgM  
Parvovirus B19 DNA - quantitative 
HAV antibody IgM 
HHV-6 DNA viral load - quantitative 
HCV antibody 
Anti-nuclear antibodies 
HCV RNA PCR – quantitative 
Anti-smooth muscle antibodies 
HEV antibody IgM 
Anti-LKM1 antibody 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
Anti-mitochondrial antibodies 
Herpes Zoster Virus IgM, IgG 
Anti-SLA 
Epstein-Barr Virus antibodies, IgM and IgG 
Ferritin 
Cytomegalovirus antibodies, IgM, IgG 
Ceruloplasmin 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant medications, 
including over the counter medications and herbal remedies 
Alcohol consumption and drugs of 
abuse  
Other potentially hepatotoxic agents including any work-
related exposures 
Recent travels to areas where 
hepatitis A or E is endemic 
Abbreviations: CT=computed tomography; DNA=deoxyribonucleic acid; HAV=hepatitis A virus; HBc=hepatitis B 
core; HBsAg=hepatitis B virus surface antigen; HCV=hepatitis C virus; HEV=hepatitis E virus; HHV-6=human 
herpesvirus 6; IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; LKM1=liver/kidney 
microsome-1 antibody MRI=magnetic resonance imagery; PCR=polymerase chain reaction; RNA=ribonucleic acid; 
SLA=soluble liver antigen 
Note: 
• 
All laboratory assessments will be measured in a central laboratory. The full panel of assessments should only 
be performed once; individual assessments may be repeated, as needed. 
6.5.6. 
Adverse Events 
6.5.6.1. 
Definitions 
Adverse Event 
According to the ICH E2A guideline Definitions and Standards for Expedited Reporting, and 
21 Code of Federal Regulations 312.32, IND Safety Reporting, an AE is any untoward medical 
occurrence in a patient or clinical investigational subject administered a medicinal product and 
which does not necessarily have a causal relationship with this treatment. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 


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• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred. It does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias, convulsions, or the development of drug 
dependency or abuse). 
Adverse Events of Clinical Interest 
The following are considered to be AEs of clinical interest: 
• ALT or AST >3×ULN 
• Severe or serious ISRs; ISRs that are associated with a recall phenomenon (reaction 
at the site of a prior injection with subsequent injections), or those that lead to 
temporary dose interruption or permanent discontinuation of zilebesiran. 
An ISR is defined as a local reaction at or near the site of injection. “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as 
may occur with swelling or hematoma). A systemic reaction which includes the 
injection site, eg, generalized urticaria, other distinct entities or conditions like 
lymphadenopathy that may be near the injection site is not considered an ISR. 
For information on recording and reporting of AEs of clinical interest, see Section 6.5.6.2 and 
Section 6.5.6.3, respectively. 
Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living (ie, bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden); OR life-threatening consequences; urgent intervention indicated; 
OR death related to an adverse event. 


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Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity. Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence. When changes in the severity of an 
AE occur more frequently than once a day, the maximum severity for the experience that day 
should be noted. If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
Adverse event severity and seriousness are assessed independently. ‘Severity’ characterizes the 
intensity of an AE. ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for 
defining regulatory reporting obligations (see definition for SAE). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?” A “yes” response indicates that the event is considered as related to 
the study drug. 
The relationship of each AE to the protocol-specified background antihypertensive medication 
should also be assessed by the Investigator. 
6.5.6.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient should be asked about medically relevant changes in the patient’s health since the 
last visit. The patient should also be asked if the patient has been hospitalized, had any accidents, 
used any new medications, or changed concomitant medication routines (both prescription and 
over-the-counter). In addition to patient observations, AEs will be documented from any 
clinically relevant laboratory findings, physical examination findings, ECG changes, or other 
findings that are relevant to patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study treatment during the Run-in period 
regardless of their relationship to the study treatment through the end of study. Study treatment is 
defined as protocol-specified background antihypertensive medication or study drug (zilebesiran 
or placebo). Non-serious AEs will be followed until the end of study. Events occurring after 
signing of the ICF and before the Run-in period will be captured as medical history (see 
Section 6.1), while AEs that occur after study treatment, and baseline events that worsen after 
study treatment, must be recorded as AEs. 
The Investigator is responsible for recording SAEs that are observed or reported by the patient 
after the time when the informed consent is signed regardless of their relationship to study 
treatment through the end of study. SAEs will be followed until satisfactory resolution, until 
baseline level is reached, or until the SAE is considered by the Investigator to be chronic or the 
patient is stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be related. Each AE must be described in 


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detail: onset time and date, description of event, severity, relationship to study treatment, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) in the eCRF and, as applicable, the SAE form. 
For AEs that are considered AEs of clinical interest (Section 6.5.6.1), the supplemental AEs of 
Clinical Interest eCRF should be completed. Additional clinical and laboratory information may 
be collected. Refer to eCRF completion guidelines for details on reporting events in the 
supplemental AEs of Clinical Interest eCRF. 
For all ISRs, the Investigator, or delegate, should submit an Injection Site Reaction Signs or 
Symptoms eCRF, recording additional information regarding each injection site reaction that is 
entered on the AE eCRF (eg, symptom[s], injection site location, follow-up actions taken). 
6.5.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AEs of clinical interest (Section 6.5.6.1), the Sponsor or its designee 
should be notified within 24 hours using the appropriate eCRF. 
6.5.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee 
An assessment of the seriousness of each AE will be made by the Investigator. Any AE and 
laboratory abnormality that meets the SAE criteria in Section 6.5.6.1 must be reported to the 
Sponsor or designee immediately and no later than 24 hours from the time that clinical study 
center staff first learns of the event. All SAEs must be reported regardless of the relationship to 
study treatment. 
The initial report should include at least the following information: 
• Patient’s study number 
• Description and date of onset of the event 
• Criterion for serious 
• Preliminary assignment of relationship to study treatment, and 
• Investigator/site information 
To report the SAE, complete the eCRF and, as applicable, the SAE form. Immediately and no 
later than 24 hours after receipt of follow-up information, the Investigator must update the eCRF 
and, as applicable, the SAE form.  
Appropriate remedial measures should be taken by the Investigator using the Investigator’s best 
medical judgment to treat the SAE. These measures and the patient’s response to these measures 
should be recorded. All SAEs, regardless of relationship to study treatment, will be followed by 
the Investigator until satisfactory resolution or the Investigator deems the SAE to be chronic or 
stable. Clinical, laboratory, and diagnostic measures should be employed by the Investigator as 
needed to adequately determine the etiology of the event. 
If the Investigator becomes aware of an SAE with a suspected causal relationship to the study 
drug that occurs after a patient withdraws from the study, the Investigator shall report the SAE to 
the Sponsor or designee within 24 hours of first awareness of the event. 


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If the Investigator becomes aware of an SAE with a suspected causal relationship to the study 
drug that occurs after the end of the study in a patient, the Investigator shall report the SAE to the 
Sponsor within 24 hours of first awareness of the event using the paper SAE form. 
6.5.6.5. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative will report certain study events in an expedited manner to the 
Food and Drug Administration, the European Medicines Agency’s EudraVigilance electronic 
system according to Clinical Trials Regulation (EU) No 536/2014 (CTR), and to all country 
Regulatory Authorities where the study is being conducted, according to local applicable 
regulations. 
6.5.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
Suspected unexpected serious adverse reactions will be reported to the IRB/IEC per their 
institutional policy by the Investigator or Sponsor (or Sponsor designee) according to country 
requirements. Copies of each report and documentation of IRB/IEC notification and 
acknowledgement of receipt will be kept in the Investigator’s study file. 
6.5.6.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through safety follow-up (see Section 3.1), 
the Investigator must report the pregnancy to the Sponsor or designee within 24 hours of being 
notified of the pregnancy. Details of the pregnancy will be recorded on the pregnancy reporting 
form. The patient should receive any necessary counseling regarding the risks of continuing the 
pregnancy, the possible effects on the fetus, and be counseled to not breastfeed for 90 days after 
the last dose of study drug. 
The pregnancy should be followed by the Investigator until completion. At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy. If the outcome of the 
pregnancy results in a postpartum complication, spontaneous abortion, stillbirth, neonatal death, 
or congenital anomaly, then the Investigator should follow the procedures for reporting an SAE 
as outlined in Section 6.5.6.4. 
6.5.6.8. 
Reporting of Overdose and Other Special Situations  
An overdose is defined as any dose of study drug administered to the participant or taken by the 
participant that is >2× the assigned dose during a single administration and/or ≥2 doses within ½ 
the intended dosing interval. 
The Sponsor does not recommend specific treatment for an overdose.  
In an event of an overdose or other special situations (eg, medication error, abuse, misuse, or 
CPC associated with an AE), the Investigator should: 
• Contact the Medical Monitor and Sponsor within 24 hours using the contact 
information in the Pharmacy Manual 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities 
• Document the amount of study drug given  


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Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or 
a concomitant medication will be considered AEs/SAEs.  
Full details of reporting instructions for overdose and other special situations will be outlined in 
the Pharmacy Manual. 
6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
Alnylam’s RNAi therapeutics platform permits the highly specific targeting of investigational 
therapies based on genetic sequence. It is possible that variations in the target genetic sequence 
will result in variations in drug effect. More generally, genetic variations may account for the 
well-described heterogeneous manifestations of disease in patients with hypertension, as well as 
their responses to treatment. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and patient consent, 
samples will be collected as part of this study to permit exploratory investigations and the 
application of novel approaches to bioanalyses that may further elucidate the outcomes of this 
study, or potentially advance understanding of the safety, mechanism of action, and/or efficacy 
of zilebesiran. 
Biological specimens will be collected at the intervals indicated in the Schedule of Assessments 
(Table 1). These specimens will be analyzed at a central laboratory. Potential exploratory 
investigations may include DNA, RNA, or biochemical metabolite assessments as they relate to 
disease progression, efficacy, or safety. 
The biospecimen repository will also include residual material from routine samples (safety 
laboratory samples, PK samples, etc) that are obtained during the study. 
These specimens will be securely stored in a central biorepository for up to 10 years following 
the completion of this clinical study (ie, last patient last visit), or as per local regulations. After 
10 years have elapsed, samples will be destroyed. 
Details regarding the collection, processing, storage, and shipping of the samples will be 
provided in the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
When biobanking is permitted by local regulation, study participants will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 
7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before study unblinding for the analysis of the 
primary endpoints and secondary endpoints measured at Month 3. The plan will detail the 
implementation of the statistical analyses in accordance with the principal features stated in the 
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7.1. 
Determination of Sample Size 
Approximately 630 patients will be randomized to receive either zilebesiran or placebo with 
sample sizes in each of the patient cohorts with protocol-specified background antihypertensive 
medication as follows:  
• Olmesartan cohort: 300 patients  
• Amlodipine cohort: 210 patients 
• Indapamide cohort: 120 patients 
Assuming a standard deviation of 16 mmHg in change from baseline in 24-hour mean SBP 
assessed by ABPM and 15% dropout rate from baseline to Month 3, with 2-sided significance 
level of 0.05 for each of the comparisons (zilebesiran versus placebo as add-on to olmesartan; 
zilebesiran versus placebo as add-on to amlodipine; zilebesiran versus placebo as add-on to 
indapamide), these sample sizes will provide at least 80% power to detect the following 
difference between zilebesiran versus placebo: 
• 5 mmHg as add-on to olmesartan  
• 6 mmHg as add-on to amlodipine 
• 8 mmHg as add-on to indapamide  
The power is assessed by simulation based on the Mixed Model with Repeated Measurements 
(MMRM), with change from baseline in 24-hour mean SBP assessed by ABPM at Month 3 as 
response variable and treatment, time, treatment-by-time as fixed factors and corresponding 
baseline value as a covariate. 
7.2. 
Statistical Methodology 
All analyses will be performed within each of the 3 protocol-specified background 
antihypertensive medication cohorts. The statistical and analytical plans presented below are 
brief summaries of planned analyses. More complete plans will be detailed in the SAP. Changes 
to the methods described in the final SAP will be described and justified as needed in the clinical 
study report. For information on study endpoints, see Section 2. 
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS): All randomized patients who received any amount of study 
drug. All by-treatment analyses based on the FAS will be grouped according to the 
randomized treatment arm.  
• Safety Analysis Set: All patients who received any amount of study drug. All by-
treatment analyses based on the Safety Analysis Set will be grouped according to the 
treatment actually received. 
• PK Analysis Set: All patients who received at least 1 full dose of zilebesiran and 
have at least 1 nonmissing postdose PK assessment. 


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• PD Analysis Set: All patients who received at least 1 full dose of study drug. All by-
treatment analyses based on the PD Analysis Set will be grouped according to the 
treatment actually received. 
• All Zilebesiran Treated Set: All patients who received any amount of zilebesiran, 
including patients who took zilebesiran during the 6-month DB period and patients 
who initially took placebo and then switched to zilebesiran after the Month 6 visit. 
For the analyses of the 6-month DB period, the analysis population used to evaluate efficacy will 
be the FAS. Safety data will be analyzed using the Safety Analysis Set. The PK and PD Analysis 
Sets will be used to conduct PK and PD analyses, respectively.  
The All Zilebesiran Treated Set will be used to summarize the efficacy and safety of zilebesiran 
throughout the 6-month DB period and the OLE period. 
7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints. Detailed methodology will be 
provided in the SAP. 
7.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other disease-specific baseline characteristics will be summarized. 
In general, baseline will be defined as the average of all assessments, including unscheduled 
assessments, between Run-in Visit 2 and prior to the first dose of study drug. Details of the 
definition will be specified in the SAP. 
7.2.5. 
Efficacy Analyses 
The primary endpoint is the change from baseline at Month 3 in 24-hour mean SBP, assessed by 
ABPM. The primary hypothesis of the add-on effect of zilebesiran compared to placebo in 
patients receiving each of 3 protocol-specified background antihypertensive medications 
(olmesartan, amlodipine or indapamide) will be tested separately at a 2-sided significance level 
of 0.05 using MMRM. The MMRM model will include treatment, time, treatment-by-time, and 
race (black or all other races) as fixed factors and baseline 24-hour mean SBP assessed by 
ABPM and screening eGFR as covariates.  
The key secondary endpoints are: 
• Change from baseline at Month 3 in office SBP 
• Time-adjusted change from baseline through Month 6 in 24-hour mean SBP, assessed 
by ABPM 
• Time-adjusted change from baseline through Month 6 in office SBP  
• Proportion of patients with 24-hour mean SBP assessed by ABPM <130 mmHg 
and/or reduction ≥20 mmHg without escape antihypertensive medication at Month 6  


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To control the overall type I error, the primary and key secondary endpoints will be tested in 
hierarchical order. 
Details of the analysis method for primary, secondary, and exploratory endpoints will be 
described in the SAP. 
7.2.6. 
Pharmacodynamic Analysis 
Pharmacodynamic analyses will include the evaluation of changes in levels of serum AGT and 
other exploratory biomarkers of the RAAS pathway. Descriptive statistics for observed levels 
and the relative change from baseline for all measured biomarkers will be presented for each of 
the postdose time points. 
Statistical comparison of the biomarker levels (absolute and/or change from baseline) across 
treatment groups may be explored. Details of the analysis will be specified in the SAP.  
Population PK/PD analysis may be conducted to evaluate the dose-response relationships for PD 
reduction after zilebesiran treatment. Additionally, the relationship between lowering of serum 
AGT and blood pressure may be explored within a modeling framework. If conducted, these 
analyses will be described in a pharmacometrics analysis plan and results will be presented in a 
separate report. 
7.2.7. 
Pharmacokinetic Analysis 
Plasma concentrations of zilebesiran and its metabolite AS(N-1)3′ zilebesiran will be 
summarized using descriptive statistics. 
Population PK analysis may be conducted on the PK data from this study. If conducted, the 
analysis methods will be described in a pharmacometrics analysis plan and results will be 
presented in a separate report. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs). Safety parameters also include vital signs, ECGs, clinical laboratory assessments and 
physical exams. Extent of exposure will be summarized.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. Results will be tabulated by Anatomical Therapeutic Chemical Classification System 
and Preferred Term (PT). 
Adverse events will be classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class and Preferred Term [by dose level and overall]. AEs, SAEs, 
related AEs, AEs leading to discontinuation of study drug, and AEs leading to death will be 
summarized by System Organ Class and PT for each treatment arm. By patient listings will be 
provided for deaths, SAEs, and AEs leading to discontinuation of study drug. Adverse events 
collected during the Run-in period will be summarized. 
Descriptive statistics will be provided for clinical laboratory parameters, ECG, and vital signs 
summarizing the observed values and changes from baseline over time. Laboratory shift tables 
from baseline grade (or category) to worst post-baseline grade (or category) will be presented for 


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laboratory parameters that are graded or categorized. Abnormal physical exam findings will be 
presented in listings. 
Other safety summaries will be presented as appropriate. Further details will be specified in the 
SAP. 
7.2.9. 
Immunogenicity Analyses 
The frequency and percentage of patients with confirmed positive ADA assay at any time during 
study as well as at each scheduled visit will be summarized. The titer results for patients with 
confirmed positive ADA results will be summarized. 
7.2.10. 
Interim Analysis 
The analysis of the primary endpoint and secondary endpoints measured at Month 3 will be 
conducted after all patients complete the Month 3 visit or withdraw from the study prior to the 
Month 3 visit. No formal interim analysis is planned before the analysis at Month 3. 
7.2.11. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the ICF (see Section 4.3.2). 
8. 
STUDY ADMINISTRATION 
8.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the current guidelines of Good Clinical Practice (GCP). Compliance with GCP 
provides public assurance that the rights, safety, and well-being of study patients are protected 
consistent with the principles that have their origin in the Declaration of Helsinki. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. Patients must also 
be notified that they are free to discontinue from the study at any time. The patient should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The Investigator will inform the patient if new information becomes available that may be 
relevant to the patient’s willingness to continue participation in the study. Communication of this 
information should be documented. 
The patient’s signed and dated informed consent (in paper or electronic format per local 
regulations and institutional standards) must be obtained before conducting any study tests or 
procedures that are not part of routine care. 
The Investigator must maintain the original, signed ICF. All patients will be given a copy of the 
signed and dated ICF. 


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8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate. The Investigator must submit written approval before he or she 
can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements. In addition, the IRB or IEC must approve all patient 
materials for the study. The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
Initial IRB or IEC approval of the protocol, and all materials approved by the IRB or IEC for this 
study including the patient consent form and recruitment materials must be maintained by the 
Investigator and made available for inspection. 
The Investigator will submit reports of SAEs as outlined in Section 6.5.6. In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study. The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies, IRBs, or IECs in regard to inspections, other 
studies that impact this protocol or the qualifications of study personnel should be promptly 
reported to the Sponsor or its designee. 
The Investigator is also responsible for providing the IRB or IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the study drug. The Sponsor 
or designee will provide this information to the Investigator. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study. Amendments to the protocol must be submitted in writing to the Investigator’s IRB or IEC 
and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol, and patients must be re-consented to the most current version of the ICF. 
8.1.3. 
Serious Breach of Protocol 
Investigators must notify the Medical Monitor within 24 hours of becoming aware of a potential 
serious breach of the protocol. A serious breach is a breach that is likely to affect to a significant 
degree the safety and rights of a study participant or the reliability and robustness of the data 
generated in the clinical study. 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention 
All documentation (including personal data) relating to the study should be retained for 2 years 
after the last approval in an ICH territory or as required by local laws and regulations, whichever 
is longer. 
If it becomes necessary for the Sponsor, the Sponsor’s designee, applicable IRB/IEC, or 
applicable regulatory authorities to review or audit any documentation relating to the study, the 
Investigator must permit direct access to all source documents/data. Records will not be 
destroyed without informing the Sponsor in writing and giving the Sponsor the opportunity to 
store the records for a longer period of time at the Sponsor’s expense. 


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The Investigator must ensure that the patients’ confidentiality will be maintained. On the eCRFs 
or other documents submitted to the Sponsor or designees, patients should not be identified by 
their names, but by the assigned patient number or code. If patient names are included on copies 
of documents to be submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number added to the document, before sending to the Sponsor. Documents not 
for submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
The Investigator must treat all of the information related to the study and the compiled data as 
confidential, whose use is for the purpose of conducting the study. The Sponsor must approve 
any transfer of information not directly involved in the study. 
To comply with local and/or regional regulations, this clinical study may be registered, and study 
results may be posted on public registries, such as ClinicalTrials.gov. 
8.1.5. 
End of Study 
The end of study is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor, or designee, reserves the right to terminate the study or a clinical study site at any 
time. Conditions that may warrant this action may include, but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to patients participating 
in the study 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• The decision on the part of the Sponsor to suspend or discontinue treatment with the 
study drug 
Should the study be terminated, and/or the site closed for whatever reason, all documentation and 
study drug pertaining to the study must be returned to the Sponsor or its representative, and the 
Investigators, IRB/IEC and Regulatory Authorities will be promptly informed of the termination 
and the reason for the decision. The Investigator should promptly inform the patients and assure 
appropriate therapy and follow-up. 
8.2. 
Data Quality Control and Quality Assurance 
8.2.1. 
Data Handling 
Study data must be recorded on CRFs (paper and/or electronic) provided by the Sponsor or 
designee on behalf of the Sponsor. Case report forms must be completed only by persons 
designated by the Investigator. If eCRFs are used, study data must be entered by trained site 
personnel with access to a valid and secure eCRF system. All data entered into the eCRF must 
also be available in the source documents. Corrections on paper CRFs must be made so as to not 
obliterate the original data and must be initialed and dated by the person who made the 
correction. 


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8.2.2. 
Study Monitoring 
The Monitor, as a representative of the Sponsor, has an obligation to closely follow the study 
conduct at the site. The Monitor will visit the Investigator and clinical study center periodically 
and will maintain frequent telephone and written contact. The Monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the Investigator and staff. 
The Monitor will review source documents, systems and CRFs to ensure overall quality and 
completeness of the data and to confirm study procedures are complied with the requirements in 
the study protocol accurately. The Sponsor, or its designee, will be allowed to conduct site visits 
to the investigation facilities for the purpose of monitoring any aspect of the study. The 
Investigator agrees to allow the Monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and study source documents, site standard operating 
procedures and training records, and other records relative to study conduct. 
Where local regulations allow, the Monitor may request remote access to source documents and 
systems. Should this take place, it will be done in a manner that protects the confidentiality of the 
data. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core study processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements. A regulatory 
authority, an IEC or an IRB may visit the site to perform audits or inspections, including source 
data verification. The Investigator should contact the Sponsor and designee immediately if 
contacted by a regulatory agency, an IEC or an IRB about an inspection. 
8.3. 
Publication Policy 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting. A copy of any proposed publication 
(eg, manuscript, abstracts, oral/slide presentations, book chapters) based on this study, must be 
provided and confirmed received at the Sponsor at least 30 days before its submission. The 
Clinical Trial Agreement will detail the procedures for publications. 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors). 


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9. 
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Dzau VJ, Balatbat CA. Future of Hypertension. Hypertension. 2019 Sep;74(3):450-7. 
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Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990-2015. JAMA. 
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van der Laan DM, Elders PJM, Boons C, Beckeringh JJ, Nijpels G, Hugtenburg JG. Factors 
associated with antihypertensive medication non-adherence: a systematic review. J Hum 
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2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the 
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10. 
APPENDICES 
10.1. 
Formula for Estimated Glomerular Filtration Rate Calculation 
Estimated glomerular filtration rate (eGFR; in mL/min/1.73m2) will be calculated from serum 
creatinine (SCr) based on the Modification of Diet in Renal Disease formula. 
Modification of Diet in Renal Disease Formula [Levey 2009] 
• Conventional units 
− eGFR (mL/min/1.73m2) = 175 × (SCr [mg/dL])-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
• SI units 
− eGFR (mL/min/1.73m2) = 175 × (SCr [μmol/L]/88.4)-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
10.2. 
Measurement of Blood Pressure 
All blood pressure measurements (office, ABPM, and HBPM) must be taken using the 
standardized equipment provided by the Sponsor, according to the methods described in the 
relevant user manuals.  
The appropriately sized cuff for each modality must be used for all assessments. The arm’s 
circumference at midpoint (halfway between the acromion and olecranon) should be determined 
at screening with a metric tape measure and used to select the appropriately sized blood pressure 
cuff/bladder for each instrument as described in the ABPM Investigator Manual and the HBPM 
and OBPM Investigator Manual. Unless significant weight loss or gain occurs between visits, the 
patient should use the same cuff/bladder size throughout the study. 
At the first Screening visit only, office blood pressure will be measured in both arms to select the 
appropriate arm to use for office blood pressure and HBPM measurements. Unless a concomitant 
condition favors the use of a specific arm, the arm with the higher office SBP should be used for 
all subsequent office blood pressure and HBPM readings. The ABPM should be measured using 
the patient’s nondominant arm. If the patient is ambidextrous, the same arm used for office blood 
pressure and HBPM readings should be used. 
ABPM 
The appropriately sized cuff should be placed on the correct arm following the instructions in the 
ABPM Investigator Manual. Consecutive (daily) use of over-the-counter NSAIDs (other than 
aspirin ≤100 mg per day) and use of cannabis or THC-containing substances should be avoided 
for at least 2 days prior to ABPM measurements. ABPM should be started prior to the morning 
dose of antihypertensive medication. All ABPM collections must be in the outpatient/ambulatory 
state. ABPM recordings that are associated with dosing visits must be obtained in advance of the 
visit (within 7 days before the corresponding dosing visit) and the results reviewed prior to 
dosing. 
During the 24-hour monitoring period, patients must avoid strenuous exercise but should 
otherwise maintain their usual level of physical activity. The ABPM is programmed to take 


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readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the 
night (10 pm to 5:59 am). While awake, the patient should hold their arm still by their side while 
the device is inflating for a reading. Patients must record the timing of going to sleep, waking up, 
and any oral medications taken during the ABPM, and these responses must be entered into the 
eCRF. 
After the monitoring period is complete, upload the ABPM data to receive a report with validity 
assessment. An ABPM will be considered valid if (1) the number of successful daytime readings 
is ≥33, (2) the number of successful nighttime readings is ≥11, and (3) no more than 3 hours are 
not represented (ie, 3 sections of 60 minutes where 0 valid readings were obtained). If the ABPM 
recording is invalid (either during the Run-in Period or after the second randomization), the 
patient will be provided 1 opportunity to repeat the study within 7 days from the end time of the 
invalid ABPM. During the Run-in period, if a valid ABPM recording that meets the inclusion 
criterion exceeds the 7-day window prior to randomization, a single additional ABPM 
assessment is permitted, with no option for retesting in case of an invalid reading. Eligibility is 
assessed by the most recent ABPM result obtained. If a valid ABPM recording that meets the 
inclusion criterion is not obtained within the 7 days prior to randomization, the patient is a run-in 
failure. 
Office Blood Pressure 
Office blood pressure must be measured using the automated blood pressure device provided by 
the Sponsor and the arm selected during screening. 
Office blood pressure should be measured early in the visit prior to the morning dose of 
antihypertensive medications, before phlebotomy or other potentially stressful assessments. To 
minimize confounding by circadian changes, study visits should be scheduled for a consistent 
timeframe of the day. The use of inhaled short-acting beta agonists should be avoided within 6 
hours prior to measuring blood pressure and/or heart rate. The use of phosphodiesterase type 5 
inhibitors (eg, sildenafil, tadalafil, vardenafil, avanafil) should be avoided within 48 hours prior 
to measuring blood pressure. Consecutive (daily) use of over-the-counter NSAIDs (other than 
aspirin ≤100 mg per day) use of cannabis or THC-containing substances should be avoided for at 
least 2 days prior to office blood pressure measurements. 
Before measuring blood pressure, confirm that there has been no exercise or use of caffeine or 
nicotine- or tobacco-containing products (including but not limited to snuff, chewing tobacco, 
cigars, cigarettes, pipes, nicotine patches, or e-cigarettes) within the last 30 minutes. If necessary, 
delay blood pressure assessment to meet these requirements. Because a full bladder can impact 
blood pressure measurements, ask the patient to use the bathroom before the assessment. 
All office blood pressure assessments will include both seated and standing measurements.  
Seated Office Blood Pressure Measurement: For seated measurements, the patient should be in a 
comfortable resting position in a chair with their back supported and their feet flat on the floor. 
• Place the appropriately sized cuff on the correct arm with no clothing between the 
patient’s arm and the cuff and with the midpoint of the bladder length positioned over 
the brachial artery (located by palpation). The arm should be supported on an armrest 
or table with mid-cuff at heart level and the palm facing the ceiling. 


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• Follow the HBPM and OBPM Investigator Manual to initiate the automated blood 
pressure device’s seated measurement protocol. This program includes a 5-minute 
period of rest, followed by 4 sequential blood pressure measurements at 1-minute 
intervals. The seated blood pressure for the visit will be defined by the average of the 
last 3 individual measurements. 
• During the device’s seated measurement protocol, the patient should remain at rest 
without distraction (avoid mobile phones). The following script may be used: “The 
blood pressure device works best when you are at rest and without any distraction, so 
the staff will avoid interacting with you during this assessment. This assessment will 
include a 5-minute period of rest, followed by about 5 minutes of the device inflating 
to measure your blood pressure”. 
Standing Office Blood Pressure Measurement: A standing measurement should be obtained 
immediately after collection of the seated measurements. 
• Being careful to maintain the cuff’s position, ask the patient to stand with the cuffed 
arm bent slightly and the hand of the cuffed arm supported at heart level.  
• Measure standing blood pressure 1 to 3 minutes after standing using the automated 
blood pressure device’s single measurement protocol.  
• After the standing measurement, ask the patient if they experienced dizziness or light-
headedness when standing and record their response. 
If a patient is unable to report to the site for an office blood pressure assessment, a substitute 
“remote visit blood pressure measurement” may be obtained remotely by a visiting nurse or other 
appropriately trained personnel. If a home visit is not possible, a “remote visit blood pressure 
measurement” should instead be obtained using the patient’s HBPM instrument under direct 
supervision (phone call or teleconferencing) by appropriately trained study staff, following the 
instructions detailed in the HBPM and OBPM Investigator Manual. Results and the remote 
method used will be recorded. 
HBPM 
Patients should measure HBPM in the morning, prior to breakfast/caffeine or taking morning 
oral medications. HBPM is not required on days when ABPM is being assessed. The HBPM 
measurement should be obtained in a room without distractions, seated comfortably with the 
back supported and feet flat on the floor. The patient will initiate the automated blood pressure 
program on their HBPM device. This program includes a 5-minute period of rest, followed by 4 
sequential blood pressure measurements at 1-minute intervals. The seated blood pressure for the 
visit will be defined by the average of the last 3 individual measurements.  
To establish baseline, each patient should measure HBPM 3 times during the week prior to the 
second randomization.  
After Day 1, HBPM should be measured at least once per week and may be increased at the 
Investigator’s discretion if more frequent measurement is warranted. Patients may select the day 
of the week that is most convenient for their personal schedule.  


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10.3. 
Procedures for Optional Home Healthcare Visits 
Home healthcare may be allowed where applicable country and local regulations and 
infrastructure for home healthcare allow and will follow procedures that are in compliance with 
relevant local regulations and guidelines (eg, General Data Protection Regulation [EU no 
2016/679], ICH E6[R2], and the Declaration of Helsinki). The use of home healthcare is optional 
and will not be utilized for visits at which study drug is administered or for visits that are 
required to be performed at the site (see Table 1).  
The option for home healthcare aims to improve patient diversity, participation, engagement, and 
retention in the study by reducing patient burden and minimizing study-related travel to the site, 
allowing flexibility in the study visit schedule. 
For clinical study sites where home healthcare is utilized, the Investigator will retain 
responsibility for oversight, patient safety, and conduct of the trial, and will be responsible for 
reviewing the qualifications of and approving each home healthcare professional, delegating 
responsibilities to the home healthcare professional in the site delegation log, providing 
instructions for home healthcare visits, communicating with the home healthcare professional at 
home visits as needed, and reviewing the source data files collected during the home healthcare 
visit. The home healthcare professional will be trained on the protocol and other relevant study 
documents and procedures and will be responsible for conducting vital sign assessments 
(including blood pressure assessments), collecting blood and urine samples, collecting weight, 
performing pill counts of protocol-specified background antihypertensive medications, and 
documenting and notifying the site study team of any suspected or potential AE symptoms or 
changes to concomitant medications. The home healthcare professional will be responsible for 
providing source documentation of the visit to the study site. 
10.4. 
Amendment History 
10.4.1. 
Amendment 3 Summary of Changes  
The primary purpose of this amendment is to close the OLE period of the study, and to provide 
instructions for patients to complete the study. Patients who completed the 6-month DB period 
may have been eligible to enter a separate OLE study to continue to receive zilebesiran. If the 
separate OLE study was not yet available at the time patients completed the 6-month DB period, 
they could have entered the optional OLE period of the study to continue receiving zilebesiran 
uninterrupted and then transition to the separate OLE study when it opened. The Sponsor has 
made the decision not to conduct a separate OLE study; therefore, the OLE period is no longer 
needed. Upon implementation of this amendment, patients in the 6-month DB period will enter 
safety follow-up following completion of the 6-month DB period. Patients will not receive a 
dose of study drug at Month 6. Patients who are already in the OLE period will not receive any 
additional doses of study drug. Patients should complete all planned assessments at Months 7, 8, 
and 9. For visits at Month 12 or later, patients should complete EOT assessments in lieu of their 
scheduled visit assessments and enter the Safety Follow-up period. 


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Section(s)  
Description of Change 
Brief Rationale 
Synopsis, 
Figure 1, 
Table 1, 
Table 4, 
Sections 
1.1, 3.1, 
3.2, 3.8, 
and 5.2.2 
Closed the OLE period and provided 
instructions for patients to complete the 
study. 
A separate OLE study will not be 
conducted; therefore, the OLE period 
of the study is not required after the 
end of the 6-month DB period. 
Instructions are provided for how 
patients should complete the study. 
Sections 
3.5 and 7 
Removed the reference to database 
lock for the Month 3 analysis. 
To clarify that a database lock will not 
be performed for the interim analysis 
at Month 3 and that Month 3 interim 
analysis results will not be shared with 
blinded team members. 
Sections 6 
and 10.3 
Added details on the home healthcare 
process. 
To incorporate revisions requested by 
a Regulatory Agency or Ethics 
Committee. 
Section 
6.5.6.4 
Clarified that SAEs should be reported 
to the Sponsor immediately. 
To incorporate revisions requested by 
a Regulatory Agency or Ethics 
Committee. 
Section 
6.5.6.4 
Added wording on collecting SAEs 
with a suspected causal relationship to 
study drug that occur after a patient 
withdraws from the study or after the 
end of the study. 
To align with Article 41 of Regulation 
(EU) No 536/2014 of the European 
Parliament and of the Council. 
Throughout 
the 
document 
Minor updates (typographical, 
editorial, administrative) were made. 
To ensure clarity, accuracy, and 
consistency. 
10.4.2. 
Amendment 2 Summary of Changes  
10.4.2.1. Rationale for Protocol Amendment 
The primary purposes for this protocol amendment are to extend the duration of the study to 
allow patients to continue to receive zilebesiran until a separate open-label extension study is 
initiated and to increase the number of patients randomized into the Run-in period to 1800. 
Several additional changes are being implemented as outlined below.  
• Allowed for patients with a valid ambulatory blood pressure monitoring (ABPM) at 
Run-in Visit 2 that meets inclusion criteria to repeat ABPM once if the assessment 


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was obtained outside the 7-day window prior to randomization into the Double-blind 
period. 
• Clarified that the inclusion criterion for ABPM is inclusive of 130 mmHg 
• Revised the timing of repeat ABPM measurements from 4 days to 7 days 
• Clarified that retesting of office blood pressure at Run-in Visit 1 is permitted once if 
the Investigator believes that the result is not accurate due to a transient condition  
• Revised the serum potassium cutoff in the recommended interventions for 
hyperkalemia to align with the normal range of potassium 
• Increased the number of clinical study centers  
• Clarified timing of age determination for eligibility 
• Clarified the timing of blood sample collections for renin-angiotensin-aldosterone 
system (RAAS) biomarkers in relation to electrocardiograms (ECGs) 
• Added exclusion criterion for patients placed in an institution on the basis of an 
official or court order to align with local requirements in some countries 
• Removed references to legal guardian throughout the protocol because inclusion 
criterion 7 requires that the patient provide written informed consent 
• Revised the duration of rest required before vital sign collection to align with 
automated processes on the machines used to collect this information 
• Removed the reference that ECG recordings will be archived because these are not 
being archived 
• Clarified that creatinine clearance is required during screening only to determine the 
dose of olmesartan for patients enrolled at sites outside of the US and Australia who 
are randomized to receive olmesartan as protocol-specified background 
antihypertensive medication  
• Clarified that home blood pressure monitoring (HBPM) is not required on days when 
ABPM is being performed 
• Clarified that medications, supplements, or other substances that may be associated 
with increases in LFT abnormalities or with blood pressure abnormalities may be 
used as needed after approval by the Investigator and Medical Monitor 
• Specified the titles of study manuals 
• Added forehead scan as a method of temperature collection to reflect site standard 
practice 
• Clarified that patients should return to their usual care during the Safety Follow-up 
period 
A detailed summary of changes is provided in Section 10.4.2.2.  The following changes are not 
detailed: administrative changes, changes associated with administrative letters (between 


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protocol amendments 1 and 2), and corrections to typographical errors, punctuation, grammar, 
abbreviations, and formatting. 
 


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10.4.2.2. Protocol Amendment 2 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 2 are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose: Extended the duration of the study. 
The primary change occurs in Section 3.1, Study Design 
Revised text:  
OLE Period 
After the 6-month DB period, protocol-specified background antihypertensive medications will be discontinued, and patients may be 
eligible to participate in a separate zilebesiran OLE study. If an individual patient reaches Month 6 prior to availability of the separate 
OLE study, they may receive open-label zilebesiran at 600 mg SC once every 6 months for up to 12 30 additional months until the 
separate OLE study is open and then transition. Once the separate OLE study is open for enrollment, eligible patients may rollover 
into that OLE study at Month 6, 12, or 18, 24, 30, or 36 (first visit after the separate OLE study is open). 
The duration of treatment with zilebesiran is up to 18 36 months. The estimated total time on study for patients who rollover to the 
separate OLE study is up to approximately 2039 months, including up to 2 months75 days of the Screening and Run-in periods, and 
up to 18 36 months of treatment. For all patients who discontinue study drug or do not roll over to the separate OLE study, the Safety 
Follow-up period is up to 12 months after the last dose of study drug. 
Section(s) also reflecting this change: 
• Synopsis 
• Figure 1, Study Design 
• Table 1, Schedule of Assessments 
• Section 1.1 
• Section 2 
• Section 3.2 
Purpose: Increased the number of patients randomized into the Run-in period. 
The primary change occurs in Section 3.1, Study Design 


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Revised text: The planned enrollment for this study is approximately 800 1800 patients to be randomized into the Run-in period and 
approximately 630 patients (300 patients in the olmesartan arm, 210 patients in the amlodipine arm, and 120 patients in the 
indapamide arm) to be randomized in the DB period. 
Section(s) also reflecting this change: 
• Synopsis 
Purpose: Allowed for patients with a valid ABPM at Run-in Visit 2 that meets inclusion criteria to repeat ABPM once if the 
assessment was obtained outside the 7-day window prior to randomization into the Double-blind period. 
The primary change occurs in Section 6.1.1, Retesting 
Revised text: If in the Investigator’s judgement, the screening or Run-in laboratory abnormalities are likely to be transient, then 
laboratory tests may be repeated. The Investigator’s rationale must be documented. Laboratory values can be retested once during 
screening and once during the Run-in period provided that the patient can be evaluated for eligibility and randomized within the 
allowed Screening and Run-in periods. Retesting of office blood pressure at Run-in Visit 1 is permitted once if in the 
Investigator’s judgement, the result is not accurate due to a transient condition. Retesting of ABPM at Run-in Visit 2 is 
permitted once if the first ABPM is invalid. A valid ABPM recording must be obtained within 7 days prior to randomization 
for all patients. If a valid ABPM recording that meets the inclusion criterion exceeds the 7-day window prior to 
randomization, a single additional ABPM assessment is permitted, with no option for retesting in case of an invalid reading. 
Eligibility is assessed by the most recent ABPM result obtained. If a valid ABPM recording that meets the inclusion criterion 
is not obtained within the 7 days prior to randomization, the patient is a run-in failureonce, with eligibility assessed by the 
second ABPM result. 
Section(s) also reflecting this change: 
• Section 6.2.1 
• Section 10.2 
Purpose: Clarified that the inclusion criterion for ABPM is inclusive of 130 mmHg. 
The primary change occurs in Section 4.1, Inclusion Criteria (criterion 5) 
Revised text: 5. 24-hour mean SBP ≥>130 mmHg and ≤160 mmHg by ABPM at Run-in Visit 2 after at least 4 weeks of run-in. 
Section(s) also reflecting this change: 
• Synopsis 


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Purpose: Revised the timing of repeat ABPM measurements from 4 days to 7 days. 
The primary change occurs in Section 10.2, Measurement of Blood Pressure 
Revised text: After the monitoring period is complete, upload the ABPM data to receive a report with validity assessment. An ABPM 
will be considered valid if (1) the number of successful daytime readings is ≥33, (2) the number of successful nighttime readings is 
≥11, and (3) no more than 3 hours are not represented (ie, 3 sections of 60 minutes where 0 valid readings were obtained). If the 
ABPM recording is invalid (either during the Run-in Period or after the second randomization), the patient will be provided 1 
opportunity to repeat the study within 4 7 days from the end time of the invalid ABPM. During the Run-in period, if a valid 
ABPM recording that meets the inclusion criterion exceeds the 7-day window prior to randomization, a single additional 
ABPM assessment is permitted, with no option for retesting in case of an invalid reading. Eligibility is assessed by the most 
recent ABPM result obtained. If a valid ABPM recording that meets the inclusion criterion is not obtained within the 7 days 
prior to randomization, the patient is a run-in failure.If the second ABPM recording is also invalid during screening, the patient is 
a run in failure. 
Purpose: Clarified that retesting of office blood pressure at Run-in Visit 1 is permitted once if the Investigator believes that the result 
is not accurate due to a transient condition. 
The primary change occurs in Section 6.1.1, Retesting 
Revised text: If in the Investigator’s judgement, the screening or Run-in laboratory abnormalities are likely to be transient, then 
laboratory tests may be repeated. The Investigator’s rationale must be documented. Laboratory values can be retested once during 
screening and once during the Run-in period provided that the patient can be evaluated for eligibility and randomized within the 
allowed Screening and Run-in periods. Retesting of office blood pressure at Run-in Visit 1 is permitted once if in the 
Investigator’s judgement, the result is not accurate due to a transient condition. Retesting of ABPM at Run-in Visit 2 is 
permitted once if the first ABPM is invalid. A valid ABPM recording must be obtained within 7 days prior to randomization 
for all patients. If a valid ABPM recording that meets the inclusion criterion exceeds the 7-day window prior to 
randomization, a single additional ABPM assessment is permitted, with no option for retesting in case of an invalid reading. 
Eligibility is assessed by the most recent ABPM result obtained. If a valid ABPM recording that meets the inclusion criterion 
is not obtained within the 7 days prior to randomization, the patient is a run-in failureonce, with eligibility assessed by the 
second ABPM result. 
Purpose: Revised the serum potassium cutoff in the recommended interventions for hyperkalemia. 
The primary change occurs in Table 5, Recommended Interventions for Hyperkalemia 
Revised text:  


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Table 5: 
Recommended Interventions for Hyperkalemia 
Serum K+ ≥>5.2 and <5.5 mmol/L 
Serum K+ ≥5.5 and <6.0 mmol/L 
Serum K+ ≥6.0 mmol/L 
• 
Confirm potassium concentration in a non-
hemolyzed sample. 
• 
Reinforce low-potassium diet and restriction of 
food/drinks with high potassium content  
• 
Review medical regimen (including dietary 
supplements and over-the-counter 
medications) for agents known to cause 
hyperkalemia.a Consider reduction in dose or 
discontinuation of these agents only if 
clinically acceptable. 
• 
Repeat K+ measurement within 3 to 5 days. 
• 
If K+ remains ≥>5.2 and <5.5 mmol/L, 
regularly monitor K+ levels to ensure stability 
(at least weekly if in the first 6 weeks of 
treatment or at least once monthly afterwards) 
• 
Confirm potassium concentration in a non-
hemolyzed sample 
• 
Consider interruption of open-label olmesartan 
(in patients randomized to receive it as their 
protocol-specified background 
antihypertensive medication) according to 
Investigator medical judgement 
• 
Consider interruption or delay of study drug 
administration, according to Investigator 
medical judgment  
• 
Apply all measures outlined for serum K+ 
≥>5.2 and <5.5 mmol/L 
• 
Repeat K+ measurement after 2 to 3 days 
• 
If K+ <5.5 mmol/L, consider resumption of 
study drug (if interrupted) with repeat 
potassium within 5 days 
• 
If K+ persistently elevated ≥5.5 mmol/L, 
consider treatment with patiromer (or with 
sodium zirconium cyclosilicate), if available 
• 
Immediately interrupt study drug 
• 
Confirm potassium 
concentration in a non-
hemolyzed sample 
• 
Urgently evaluate patient and 
treat hyperkalemia as clinically 
indicated. After urgent 
treatment, consider treatment 
with patiromer (or with sodium 
zirconium cyclosilicate), if 
available 
• 
Apply all measures outlined for 
serum K+ ≥5.5 and <6.0 mmol/L 
• 
No resumption of study drug 
without individualized case 
discussion with and permission 
from Alnylam Medical Monitor 
Abbreviations: NSAID=nonsteroidal anti-inflammatory drug. 
a This list is not meant to be exhaustive: potassium-sparing diuretics (eg, amiloride and triamterene), potassium supplements (eg potassium chloride), salt 
substitutes, NSAIDs, cyclo-oxygenase-2 inhibitors, trimethoprim and trimethoprim-containing combination products, herbal supplements (eg, Noni juice, 
alfalfa [Medicago sativa], dandelion [Taraxacum officinale], horsetail [Equisetum arvense], nettle [Urtica dioica], milkweed, lily of the valley, Siberian 
ginseng, hawthorn berries). 
Purpose: Increased the number of clinical study sites. 
The primary change occurs in the Synopsis 
Revised text: The study will be conducted at approximately 120 175 clinical study centers worldwide. 


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Purpose: Clarified timing of age determination for eligibility. 
The primary change occurs in Section 4.1, Inclusion Criteria (criterion 1) 
Revised text: 1. Age 18 to 75 years, inclusive, at time of initial informed consent 
Section(s) also reflecting this change: 
• Synopsis 
Purpose: Clarified the timing of blood sample collections for RAAS biomarkers in relation to ECGs. 
The primary change occurs in Section 6.5.4, Electrocardiogram 
Revised text: When ECG and blood sample collection for RAAS biomarkers (renin, aldosterone, and Ang I/II) occur at the same 
visit and where feasible, blood sample collection should occur first. ECGs should be performed at least 30 minutes after phlebotomy 
or other stressful assessments. 
Section(s) also reflecting this change: 
• Table 1, Schedule of Assessments 
Purpose: Added exclusion criterion for patients placed in an institution on the basis of an official or court order. 
The primary change occurs in Section 4.2, Exclusion Criteria (criterion 33) 
Added text: 33. Placed in an institution on the basis of an official or court order 
Purpose: Removed references to legal guardian throughout the protocol. 
The primary change occurs in Section 4.3.2.1, Patient Stops Participation in the Study 
Revised text:  
4.3.2.1 Patient or Legal Guardian Stops Participation in the Study 
A patient or their legal guardian may stop participation in the study at any time. A patient or legal guardian considering stopping 
participation in the study before Month 6 should be informed that the patient can discontinue study drug and/or decline procedural 
assessments and remain in the study to complete their study assessments, through the Month 6 visit and complete Safety Follow-up 
visits as described in Section 4.3.1, or alternatively may complete any minimal assessments for which the patient or legal guardian 
consents. If a patient or legal guardian still chooses to discontinue study drug and stop participation in all follow-up prior to the 


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completion of the 6-month DB period, every effort should be made to conduct the Month 6 visit assessments at an earlier time (see 
Table 1). 
Sections also reflecting this change:   
• Section 4.3 
• Section 4.3.3 
• Section 6.1 
• Section 6.5.6.2 
• Section 8.1.1 
• Section 8.1.2 
Purpose: Revised the duration of rest required before vital sign collection. 
The primary change occurs in Section 6.5.1, Vital Signs 
Revised text: Vital signs will be measured as specified in the Schedule of Assessments (Table 1) and include office blood pressure, 
heart rate, body temperature, and respiratory rate. Vital signs are to be collected prior to administration of oral antihypertensive 
medications and study drug (as applicable). When vital signs and blood sample collection occur at the same time, vital signs should be 
performed before blood samples are drawn, where possible. Vital signs should be measured in the seated position, after the patient has 
rested comfortably for approximately 10 5 minutes. Body temperature in degrees Celsius will be obtained via oral, tympanic, 
forehead, or axillary methods. Heart rate will be counted for a full minute and recorded in beats per minute, and respiration rate will 
be counted for a full minute and recorded in breaths per minute. Blood pressure is described in Section 6.2. 
Purpose: Removed the reference that ECG recordings will be archived. 
The primary change occurs in Section 6.5.4, Electrocardiogram 
Revised text: The Investigator or qualified designee will review all ECGs to assess whether the results have changed since the baseline 
visit and to determine the clinical significance of the results. These assessments will be recorded in the eCRF. Additional ECGs may 
be collected at the discretion of the Investigator, or as per DMC advice. Recordings will be archived according to the Study Manual. 
Purpose: Clarified that creatinine clearance is required during screening only. 
The primary change occurs in Table 6, Clinical Laboratory Assessments  


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Revised text:  
Table 6: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Uric acid 
Albumin 
Total protein 
Calcium 
Glucose 
Bicarbonate 
Creatinine and eGFR 
Chloride 
Creatinine clearance (screening only) 
 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT 
 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Protein 
Leukocyte esterase 
Glucose 
Microscopy (if clinically indicated) 
Coagulation  
Prothrombin time 
International normalized ratio 
Partial thromboplastin time  
 
Fasting Lipid Panel and Glycemic Assessments (see Section 6.5.5.1) 


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Lipid panel, including 
HDL-C, non-HDL-C, LDL-C, apolipoprotein A1, triglycerides, total 
cholesterol  
Insulin 
Fasting plasma glucose 
HbA1c 
Immunogenicity (see Section 6.5.5.2) 
ADA 
 
Pregnancy Testing/FSH Screening (see Section 6.5.5.3) 
β-human chorionic gonadotropin (females of 
child-bearing potential only) 
Follicle-stimulating hormone (postmenopausal women only) 
Abbreviations: ADA=anti-drug antibodies; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; eGFR=estimated glomerular filtration rate; FSH=follicle-stimulating hormone; GGT=gamma glutamyl transferase; HbA1c=hemoglobin A1c; HDL-
C=high-density lipoprotein; LDL-C=low-density lipoprotein; RBCs=red blood cells. 
Section(s) also reflecting this change: 
• Table 1, Schedule of Assessments 
Purpose: Clarified that HBPM is not required on days when ABPM is being performed. 
The primary change occurs in Section 6.2.3, HBPM  
Revised text: The HBPM should be measured in the morning upon waking, prior to breakfast/caffeine or taking morning oral 
antihypertensive medications. HBPM is not required at timeson days when ABPM is being assessed. The patient should be seated 
comfortably with the back supported and the feet flat on the floor as detailed in Section 10.2 and the HBPM and OBPM Investigator 
Study Manual. 
Section(s) also reflecting this change: 
• Table 1, Schedule of Assessments 
Purpose: Clarified that medications, supplements, or other substances that may be associated with increases in LFT abnormalities or 
with blood pressure abnormalities may be used as needed after approval by the Investigator and Medical Monitor. 
The primary change occurs in Section 5.9.1, Prohibited Concomitant Medication  
Revised text: Medications, herbal supplements (including Ma Huang and St. John’s wort), or other substances (such as licorice) that 
are associated with increases in LFT abnormalities or with blood pressure abnormalities are prohibited. This includes certain 
stimulants (eg, amphetamine, methylphenidate dexmethylphenidate, dextroamphetamine), MAO inhibitors, atypical antipsychotics 


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(eg, clozapine, olanzapine), diet pills (eg, phenylpropanolamine, sibutramine), and nasal decongestants (eg, phenylephrine 
hydrochloride, pseudoephedrine, naphazoline hydrochloride), unless individually approved by both the Investigator and the 
Medical Monitor. 
Purpose: Specified the titles of study manuals. 
The primary change occurs in Section 10.2, Measurement of Blood Pressure 
Revised text: The appropriately sized cuff for each modality must be used for all assessments. The arm’s circumference at midpoint 
(halfway between the acromion and olecranon) should be determined at screening with a metric tape measure and used to select the 
appropriately sized blood pressure cuff/bladder for each instrument as described in the Study Manual ABPM Investigator Manual 
and the HBPM and OBPM Investigator Manual. Unless significant weight loss or gain occurs between visits, the patient should 
use the same cuff/bladder size throughout the study. 
Section(s) also reflecting this change: 
• Sections 6.2, 6.2.1, 6.2.2, and 6.2.3 
• Section 6.5.3 
Purpose: Added forehead scan as a method of temperature collection. 
The primary change occurs in Section 6.5.1, Vital Signs 
Revised text: Vital signs will be measured as specified in the Schedule of Assessments (Table 1) and include office blood pressure, 
heart rate, body temperature, and respiratory rate. Vital signs are to be collected prior to administration of oral antihypertensive 
medications and study drug (as applicable). When vital signs and blood sample collection occur at the same time, vital signs should be 
performed before blood samples are drawn, where possible. Vital signs should be measured in the seated position, after the patient has 
rested comfortably for approximately 10 5 minutes. Body temperature in degrees Celsius will be obtained via oral, tympanic, 
forehead, or axillary methods. Heart rate will be counted for a full minute and recorded in beats per minute, and respiration rate will 
be counted for a full minute and recorded in breaths per minute. Blood pressure is described in Section 6.2. 
Purpose: Clarified that patients should return to their usual care during the Safety Follow-up period. 
The primary change occurs in Section 3.1, Summary of Study Design 
Revised text: 
Safety Follow-up Period 


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Patients who discontinue study drug or do not enroll in the separate zilebesiran OLE study will be asked to complete Safety Follow-up 
visits once every 6 months after their last dose of study drug until serum AGT levels return to ≥50% of their individual mean baseline 
level (if known) or 12 months after the last dose of study drug, whichever comes earlier. During the Safety Follow-up period, 
patients should return to their pre-study medical care (usual care). 
Purpose: Administrative changes, changes associated with administrative letters (since the original protocol was finalized), and 
corrections to typographical errors, punctuation, grammar, abbreviations, and formatting.  
These changes are not listed individually. 


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10.4.3. 
Amendment 1 Summary of Changes  
10.4.3.1. Rationale for Protocol Amendment 
The primary purpose for this protocol amendment is to reduce patient burden by removing or 
modifying procedures that are not considered necessary for analysis of primary or secondary 
efficacy endpoints or for safety; and by providing clarifications and updates to 
inclusion/exclusion criteria and concomitant medications to better take into account common 
characteristics of patients with mild-to-moderate hypertension. 
Changes to Procedures: 
• Clarified that 3 measurements are sufficient to establish baseline for home blood 
pressure monitoring (HBPM).  Removed the requirement to consider patients who do 
not establish baseline HBPM as run-in failures because evaluation of change in 
HBPM is an exploratory endpoint. Revised the frequency of HBPMs after 
randomization to at least once per week and clarified that they may be increased at 
the Investigator’s discretion if more frequent measurement is warranted. 
• Removed 24-hour ambulatory blood pressure monitoring (ABPM) at Month 18 and 
during the safety follow-up period because office blood pressures and HBPM will be 
sufficient to monitor safety 
• Removed 24-hour urine samples for assessment of sodium status  
• Clarified the extended hepatic panel required in patients who experience elevated 
transaminases 
• Clarified that patients did not have to avoid over-the-counter nonsteroidal anti-
inflammatory drugs (NSAIDs) before laboratory assessments 
Changes to Eligibility Criteria and Concomitant Medications: 
• Removed limitations on the allowable classes and doses of prior antihypertensive 
medication because these were not meant to be limiting, and patients will be 
discontinuing their prior antihypertensives and starting the protocol specified 
background antihypertensive 
• Clarified that patients who are currently taking beta blockers may be enrolled if beta 
blockers can be discontinued prior to the Run-in period 
• Clarified that over-the-counter NSAIDs are permitted because low-dose aspirin is 
commonly used in this population as a cardioprotectant and should not have an 
additional effect on blood pressure. Doses of aspirin ≤100 mg daily are not expected 
to have a significant effect on blood pressure. In addition, the period in which patients 
should avoid NSAIDs before office blood pressure and ABPM assessments was 
revised to 2 days because the effects of these medications are expected to be washed 
out within 2 days. 
• Clarified that patients are allowed to be on sodium-glucose co-transporter 2 (SGLT2) 
inhibitors as long as patients are on a stable dose prior to and during the study 
treatment period. This change was made because SGLT2 inhibitors may be 


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commonly used in this population, and stable doses of SGLT2 inhibitors are not 
expected to have an additional appreciable effect on blood pressure. 
• Revised and simplified the exclusion criterion for diabetes mellitus as this is not 
expected to have a significant effect on blood pressure  
• Clarified that patients with mild-to-moderate obstructive sleep apnea are eligible if 
they are on continuous positive airway pressure therapy because these patients would 
not be expected to have spikes in nighttime blood pressure 
• Clarified that patients who are in follow-up for a coronavirus-19 vaccine study for 
approved or investigational agents are allowed to be enrolled because follow-up 
procedures for these studies are not expected to impact patient safety in this study 
• Removed exclusions on cannabis use and clarified that use of cannabis or delta-9-
tetrahydrocannibinol-containing substances should be avoided when possible and for 
at least 2 days before ABPM and office blood pressure measurements 
• Removed the exclusion criterion for being unable or unwilling to perform HBPM as 
specified as it is redundant with the inclusion criteria specifying that the patient is 
willing and able to comply with the study requirements, which includes procedures 
• Clarified that physicians should refer to recommended target per treatment guidelines 
when considering the addition of oral antihypertensive medication for persistent 
elevations in blood pressure 
• Clarified the duration of medication restrictions during the study 
Several additional changes are being implemented as outlined below.  
• Defined key secondary and other secondary endpoints to account for the 
implementation of a hierarchical testing procedure in this study. Modified exploratory 
endpoints to better reflect the objectives of the study 
• Modified analysis sets to better reflect the analysis methods of the study  
• Increased number of clinical study centers worldwide to approximately 120 
• Clarified dosing of study drug during the study to be consistent with other parts of the 
protocol 
• Corrected the definition of permanent sterilization 
• Clarified that analysis of urinalysis measures protein, which includes albumin 
A detailed summary of changes is provided in Section 10.4.3.2.  The following changes are not 
detailed: administrative changes, changes associated with administrative letters (since the 
original protocol was finalized), and corrections to typographical errors, punctuation, grammar, 
abbreviations, and formatting. 


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10.4.3.2. Protocol Amendment 1 Detailed Summary of Changes 
The primary section(s) of the protocol affected by the changes in Protocol Amendment 1 are indicated.  The corresponding text has 
been revised throughout the protocol.  Deleted text is indicated by strikeout; added text is indicated by bold font. 
Purpose: Clarified the criteria for establishing baseline for HBPM, removed the requirement to consider patients who do not establish 
baseline HBPM as run-in failures, and revised the frequency of HBPM measurements after randomization. 
The primary change occurs in Section 10.2, Measurement of Blood Pressure 
Revised text: To establish baseline, each patient mustshould measure HBPM daily at least 1 3 times during the week prior to the 
second randomization. If adequate baseline HBPM data are not collected during the Run-in Period, the patient is a run-in failure. 
After Day 1, HBPM should be measured at least 3 timesonce per week and may be increased at the Investigator’s discretion if 
more frequent measurement is warranted. Patients may select the 3 days of the week that areis most convenient for their personal 
schedule. 
Section(s) also reflecting this change: 
• Table 1, Schedule of Assessments 
• Section 3.2 
• Section 5.8.1 
• Sections 6.2 and 6.2.3 
• Section 10.2 
Purpose: Removed 24-hour ABPMs at Month 18 and during the safety follow-up period. 
The primary change occurs in Table 1, Schedule of Assessments 
Change: The “X” was removed from the ABPM row under the Safety Follow-up column, and the following footnote was added to the 
“X” in the ABPM row under the M18/EOT/ET column. 
h  ABPM should only be performed as part of ET assessments if the patient discontinues the study prior to Month 12 and has 
 
not had an ABPM within the last 3 months. ABPM should not be performed at Month 18. 
Purpose: Removed 24-hour urine samples. 
The primary change occurs in Section 6.5.5, Clinical Laboratory Assessments 


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Revised text: Spot urine collections for albumin and creatinine should be obtained in the morning. A 24 hour urine collection for 
sodium and creatinine will be performed at time points listed in the Schedule of Assessments (Table 1). These 24 hour collections 
should be obtained within 2 days before the ABPM associated with the same visit. 
Section(s) also reflecting this change: 
• Table 1, Schedule of Assessments 
• Section 6.6 
Purpose: Clarified the extended hepatic panel required in patients who experience elevated transaminases. 
The primary change occurs in Table 7, Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Revised text:  
Table 7: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
HBsAg, HBsAb, HBc antibody IgM  
Parvovirus B19 DNA - quantitative 
HAV antibody IgM 
HHV-6 DNA viral load - quantitative 
HCV antibody 
Anti-nuclear antibodies 
HCV RNA PCR – quantitative 
Anti-smooth muscle antibodies 
HEV antibody IgM 
Anti-LKM1 antibody 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
Anti-mitochondrial antibodies 
Herpes Zoster Virus IgM, IgG 
Anti-SLA 
Epstein-Barr Virus antibodies, IgM and IgG 
Ferritin 
Cytomegalovirus antibodies, IgM, IgG 
Ceruloplasmin 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant medications, including over the 
counter medications and herbal remedies 
Alcohol consumption and drugs of abuse  


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Other potentially hepatotoxic agents including any work-related exposures 
Recent travels to areas where hepatitis A or E is 
endemic 
 
Purpose: Clarified that patients did not have to avoid NSAIDs before laboratory assessments. 
The primary change occurs in Section 6.5.5, Clinical Laboratory Assessments 
Revised text: Clinical laboratory assessments may be collected at the clinical study center or at home by a trained healthcare 
professional. Consecutive (daily) use of over the counter NSAIDs should be avoided for at least 7 days prior to laboratory 
assessments. In patients randomized to receive olmesartan as the protocol-specified background antihypertensive medication, blood 
samples for RAAS biomarkers should be collected in the morning and in the seated/upright position (after blood pressure 
measurements and before any assessments collected in the supine position). Blood samples for laboratory evaluation should be 
collected after the completion of blood pressure assessments. 
Purpose: Removed limitations on the allowable classes and doses of prior antihypertensive medication. 
The primary change occurs in Section 4.1, Inclusion Criteria (criterion 3b) 
Revised text: Treated hypertension on stable therapy with up to 2 antihypertensive medications that include the following classes: an 
ACE inhibitor, ARB, renin inhibitor, CCB, thiazide diuretic, and/or thiazide like diuretic. Stable therapy is defined as having no 
change in antihypertensive medication or dose within 30 days prior to screening, and the doses have to be at least half of the 
maximally approved daily doses per local labeling..  
Section(s) also reflecting this change: 
• Synopsis 
Purpose: Clarified that patients who are currently taking beta blockers may be enrolled if beta blockers can be discontinued prior to 
the Run-in period. 
The primary change occurs in Section 4.2, Exclusion Criteria (criterion 6) 
Revised text: Currently taking beta blockers and unable to discontinue prior to Run-in Visit 1 
Purpose: Clarified that over-the-counter NSAIDs are permitted and revised the washout period to 2 days. 
The primary change occurs in Section 5.9, Concomitant Medications and Procedures 


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Revised text: Occasional use ofPatients receiving low-dose aspirin (defined as ≤100 mg per day) for at least 30 days prior to 
screening and during the study treatment period are allowed. Occasional use of other systemic over-the-counter NSAIDs is 
allowed. However, given their association with increased blood pressure, they should be avoided when possible and for at least 72 
days prior to ABPM and office blood pressure assessments, and alternative analgesics (acetaminophen, topical NSAIDs) should be 
considered.[Whelton 2018] When used, the dosing of systemic NSAIDs should be at the lower end of the labeled range and for the 
shortest duration possible. 
Section(s) also reflecting this change: 
• Section 4.2 
• Sections 6.2.1 and 6.2.2 
• Section 10.2 
Purpose: Clarified that patients are allowed to be on SGLT2 inhibitors as long as patients are on a stable dose prior to and during the 
study treatment period. 
The primary change occurs in Section 5.9, Concomitant Medications and Procedures 
Revised text: Patients receiving SGLT2 inhibitors (eg, empagliflozin, canagliflozin, and dapagliflozin) should be on a stable 
dose for at least 30 days prior to screening and during the study treatment period. These medications should not be initiated or 
discontinued, if possible, during the study treatment period. 
Section(s) also reflecting this change: 
• Section 4.2 
Purpose: Revised exclusion criterion for diabetes mellitus. 
The primary change occurs in Section 4.2, Exclusion Criteria (criterion 13) 
Revised text: Type 1 diabetes mellitus, poorly controlled Type 2 diabetes mellitus (hemoglobin A1c [HbA1c] >89.0%), newly 
diagnosed Type 2 diabetes mellitus (within 6 months prior to first randomization), or laboratory evidence of diabetes during screening 
(fasting plasma glucose ≥126 mg/dL [7.0 mmol/L], random plasma glucose ≥200 mg/dL [11.1 mmol/L], or HbA1c ≥6.57.0%) without 
known diagnosis of diabetes 
Purpose: Clarified that patients with mild-to-moderate obstructive sleep apnea are eligible if they are on continuous positive airway 
pressure therapy. 


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The primary change occurs in Section 4.2, Exclusion Criteria (criterion 1) 
Revised text: Secondary hypertension (including, but not limited to, due to known history of moderate-to-severe obstructive sleep 
apnea not treated with or without receiving nasal continuous positive airway pressure therapy, renovascular hypertension, primary 
aldosteronism, pheochromocytoma, Cushing syndrome, or aortic coarctation, or other cause of secondary hypertension) 
Purpose: Clarified that patients who are in follow-up for a coronavirus-19 vaccine study for approved or investigational agents are 
allowed to be enrolled. 
The primary change occurs in Section 4.2, Exclusion Criteria (criterion 4) 
Revised text: Received an investigational agent within the last 30 days or 5 half-lives of the investigational agent, whichever is longer, 
prior to Run-in Visit 1 or are in follow-up of another clinical study prior to study enrollment. Any agent that has received health 
agency authorization (including for emergency use) by local or regional regulatory authorities is not considered investigational. 
Patients who are in follow-up for a coronavirus disease 2019 vaccine (authorized or investigational) study are allowed. 
Purpose: Removed exclusions on cannabis use and clarified that use of cannabis or delta-9-tetrahydrocannibinol-containing 
substances should be avoided when possible and for at least 2 days before ABPM and office blood pressure measurements. 
The primary change occurs in Section 5.9, Concomitant Medications and Procedures 
Revised text: Use of cannabis or delta-9-tetrahydrocannibinol (THC)-containing substances (including by smoking, vaping, 
dabbing, or ingesting/edibles) should be avoided when possible and for at least 2 days prior to ABPM and office blood 
pressure assessments. 
Section(s) also reflecting this change: 
• Section 4.2 
• Section 5.11 
• Sections 6.2.1 and 6.2.2 
• Section 10.2 
Purpose: Removed the exclusion criterion for being unable or unwilling to perform HBPM. 
The primary change occurs in Section 4.2, Exclusion Criteria (previous criterion 33) 
Revised text: Unable or unwilling to perform HBPM as specified 


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Purpose: Clarified that physicians should refer to recommended target treatment guidelines when considering the addition of oral 
antihypertensive medication for persistent elevations in blood pressure. 
The primary change occurs in Table 4, Recommended Interventions for Potentially Clinically Significant Blood Pressure Elevation 
Revised text:  
Table 4: 
Recommended Interventions for Potentially Clinically Significant Blood Pressure Elevation 
Study Period 
Intervention 
Throughout Study 
• 
Whenever possible, management decisions should be based on blood pressure measurements confirmed by office blood pressure. 
• 
Any confirmed event of severe hypertension (office SBP ≥180 mmHg and/or office DBP ≥120 mmHg) should be appropriately 
treated regardless of its timing relative to study drug administration.  
• 
Until double-blind data are generated that demonstrate acceptable safety and added antihypertensive efficacy of zilebesiran when 
combined with olmesartan, the use of conventional RAAS inhibitors (ARBs, ACE inhibitors, or direct renin inhibitors) as escape 
antihypertensive agents for high blood pressure will be avoided throughout the study.  
• 
If added, escape antihypertensives must be used per their labeled instructions and in accordance with current clinical 
guidelines.[Whelton 2018; Williams 2018] 
Day 1 to Month 3 
Intervene if clinically significant blood pressure elevation: 
• 
Because of the gradual onset of effects of zilebesiran, interventions for asymptomatic hypertension should be avoided in the first 
6 weeks after the patient’s first administration of study drug.  
• 
After Week 6, patients who develop office SBP >160 mmHg and increased >10 mmHg from their baseline office SBP that 
persists for ≥24 hours on 2 consecutive measurements or that is accompanied by hypertensive symptoms should be evaluated by 
the clinical study site. Severely symptomatic patients should be evaluated at the clinical study site or another hospital setting 
within 24 hours. 
• 
If persistent hypertension is confirmed (without the identification of a specific treatable cause) and the Investigator deems it to be 
a clinically significant change, treatment may be initiated at the medical discretion of the Investigator using a CCB and/or a 
thiazide/thiazide-like diuretic (whichever agent is not already the protocol-specified background antihypertensive medication) as 
an escape antihypertensive medication.  
Months 3 to 6 
Treat to target blood pressure using a CCB and/or thiazide/thiazide-like diuretic (whichever agent is not already a protocol-specified 
background antihypertensive medication): 
• 
At Month 3, a CCB and/or a thiazide/thiazide-like diuretic mayshould be added as an escape antihypertensive medication if the 
daytime mean SBP is ≥135 mmHg by ABPM. If the Investigator feels there is a compelling clinical reason to wait, the rationale 
for exception should be documented in the eCRF. 


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Study Period 
Intervention 
• 
After Month 3, other escape antihypertensive medications may also be added per Investigator judgement for persistent elevations 
in SBP above recommended target per treatment guidelines (eg, target defined as office SBP <140 mmHg, HBPM SBP 
<135 mmHg, or daytime mean SBP by ABPM <135 mmHg).[Williams 2018] 
Month 6 to End of 
Study (OLE period) 
Treat to target blood pressure using Investigator’s choice of oral antihypertensive(s). 
• 
At Month 6, protocol-specified background antihypertensive medications (olmesartan, amlodipine, or indapamide) will be 
discontinued.  
• 
Patients who continue into the OLE period will initiate open-label treatment with 600 mg zilebesiran once every 6 months. As 
many patients will receive zilebesiran for the first time at Month 6, office blood pressure and serum chemistries will be carefully 
monitored monthly from Month 6 to Month 9, and Investigators will be prepared to downtitrate or interrupt escape 
antihypertensive medications if low blood pressure develops (see Section 5.8.1). 
• 
If the Month 6 ABPM is in target (daytime mean SBP <135 mmHg), escape antihypertensive medications (if taken) may be 
downtitrated or interrupted per Investigator judgement to determine if the patient’s blood pressure remains within target on 
zilebesiran treatment alone.  
• 
During the OLE period, oral antihypertensive medications may be added per Investigator judgement for persistent elevations in 
blood pressure above recommended target per treatment guidelines (eg, target defined as office SBP <140 mmHg, HBPM SBP 
<135 mmHg, or daytime mean SBP by ABPM <135 mmHg).[Whelton 2018; Williams 2018] 
Section(s) also reflecting this change: 
• Section 3.2 
Purpose: Clarified the duration of medication restrictions during the study. 
The primary change occurs in Section 5.9.1, Prohibited Concomitant Medication 
Revised text: The following medications, treatments, and supplements are prohibited throughout the study treatment period (until the 
EOT visit) 
Section(s) also reflecting this change: 
• Section 4.2 
Purpose: Defined key secondary and other secondary endpoints and modified exploratory endpoints. 
The primary change occurs in Section 2, Objectives and Endpoints 




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Objectives 
Endpoints 
• 
Office blood pressure and ABPM response rate (by blood 
pressure normalization) 
• 
Proportion of patients requiring treatment with escape 
antihypertensive medications 
• 
Change in pulse pressure from baseline to Month 3 and 
Month 6, assessed by ABPM and office blood pressure 
• 
Change in SBP and DBP from baseline assessed by 
HBPM 
• 
To characterize the plasma PK of zilebesiran 
• 
Plasma concentrations of zilebesiran and its metabolite 
AS(N-1)3′ zilebesiran 
• 
To assess the effect of zilebesiran on 
exploratory biomarkers of the RAAS (only 
for patients randomized to olmesartan as 
their protocol-specified background 
antihypertensive medication) 
• 
Change from baseline in plasma renin concentration, 
aldosterone, AngI, and AngII 
• 
To evaluate the immunogenicity of 
zilebesiran 
• 
Incidence and titers of ADA  
• 
To assess the effect of zilebesiran on body 
weight, BMI, and morphometric 
measurements 
• 
Change from baseline in body weight, BMI, waist 
circumference, and waist-to-hip ratio 
• 
To assess the effect of zilebesiran on 
metabolic syndrome parameters 
• 
Change from baseline in HbA1c, fasting plasma glucose, 
insulin, HOMA index, and serum lipid profile 
• 
To characterize the PD effects of zilebesiran 
(after Month 6) 
• 
Change in serum AGT  
• 
To assess the long-term treatment effect of 
zilebesiran (through Month 18) 
• 
Change from baseline in SBP and DBP assessed by 
ABPM, office blood pressure, and HBPM  
Section(s) also reflecting this change: 
• Synopsis 


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• Section 7.2.5 
Purpose: Modified analysis sets. 
The primary change occurs in Section 7.2.1, Populations to be Analyzed  
Revised text:  
• Full Analysis Set (FAS): All randomized patients who received any amount of study drug. All by-treatment analyses based 
on the FAS will be grouped according to the randomized treatment arm.  
• Safety Analysis Set: All patients who received any amount of study drug., All by-treatment analyses based on the Safety 
Analysis Set will be grouped according to the treatment actually received. 
• PK Analysis Set: All patients who received at least 1 full dose of study drugzilebesiran and have at least 1 nonmissing 
postdose blood sample for PK parameters and have evaluable PK dataassessment. 
• PD Analysis Set: All patients who received at least 1 full dose of study drug. All by-treatment analyses based on the PD 
Analysis Set and who have an evaluable baseline and at least 1 evaluable post-baseline PD measurement will be included 
in the PD analysesgrouped according to the treatment actually received. 
• All Zilebesiran Treated Set: All patients who received any amount of zilebesiran, including patients who took 
zilebesiran during the 6-month DB period and patients who initially took placebo and then switched to zilebesiran 
after the Month 6 visit. 
For the analyses of the 6-month DB period, Tthe primary analysis population used to evaluate efficacy will be the FAS. Safety 
data will be analyzed using the Safety Analysis Set. The PK and PD Analysis Sets will be used to conduct PK and PD analyses, 
respectively.  
The All Zilebesiran Treated Set will be used to summarize the efficacy and safety of zilebesiran throughout the 6-month DB 
period and the OLE period. 
Section(s) also reflecting this change: 
• Synopsis 
Purpose: Increased number of clinical study centers worldwide to approximately 120. 
The primary change occurs in the Synopsis 
Revised text: The study will be conducted at approximately 80120 clinical study centers worldwide. 


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Purpose: Clarified dosing of study drug during the study. 
The primary change occurs in Section 5.2.2, Dose and Administration 
Revised text: During the 6-month DB period, patients will be administered a single dose of 600 mg zilebesiran or placebo, at the same 
volume, as SC injections once every 6 months. Duringinjection on Day 1. Patients who enter the OLE period, all patients will 
receive 600 mg zilebesiran SC at Month 6 after all predose assessments are conducted and once every 6 months during the OLE 
period. 
Purpose: Corrected the definition of permanent sterilization 
The primary change occurs in Section 5.11.1, Contraception 
Revised text: Females of child-bearing potential include female patients who have experienced menarche (or begin menarche over the 
course of the study), and who are not postmenopausal or permanently sterilized (eg, bilateral tubal occlusionoophorectomy, 
hysterectomy, or bilateral salpingectomy). A postmenopausal state is defined as the absence of menses for 12 months without an 
alternative medical cause, confirmed by follicle stimulating hormone level within the postmenopausal range. 
Purpose: Clarified that analysis of urinalysis measures protein, which includes albumin. 
The primary change occurs in Table 6, Clinical Laboratory Assessments 
Revised text:  
Table 6: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Uric acid 
Albumin 
Total protein 
Calcium 
Glucose 
Bicarbonate 
Creatinine and eGFR 
Chloride 


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Creatinine clearance 
 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT 
 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
AlbuminProtein 
Leukocyte esterase 
Glucose 
Microscopy (if clinically indicated) 
Protein 
 
Coagulation  
Prothrombin time 
International normalized ratio 
Partial thromboplastin time  
 
Fasting Lipid Panel and Glycemic Assessments (see Section 6.5.5.1) 
Lipid panel, including 
HDL-C, non-HDL-C, LDL-C, apolipoprotein A1, triglycerides, total 
cholesterol  
Insulin 
Fasting plasma glucose 
HbA1c 
Immunogenicity (see Section 6.5.5.2) 
ADA 
 


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Pregnancy Testing/FSH Screening (see Section 6.5.5.3) 
β-human chorionic gonadotropin (females of 
child-bearing potential only) 
Follicle-stimulating hormone (postmenopausal women only) 
 
Purpose: Administrative changes, changes associated with administrative letters (since the original protocol was finalized), and 
corrections to typographical errors, punctuation, grammar, abbreviations, and formatting.  
These changes are not listed individually. 
 
 


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 2, 22 September 2022 
Alnylam Pharmaceuticals 
Confidential 
1 
 
CLINICAL STUDY PROTOCOL 
ALN-AGT01-003 
DATED 22 SEPTEMBER 2022 
 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled, Multicenter 
Study to Evaluate the Efficacy and Safety of Zilebesiran Used as 
Add-on Therapy in Patients With Hypertension Not Adequately 
Controlled by a Standard of Care Antihypertensive Medication  
Short Title: 
Zilebesiran as Add-on Therapy in Patients With Hypertension Not 
Adequately Controlled by a Standard of Care Antihypertensive 
Medication (KARDIA-2)  
Study Drug: 
Zilebesiran (ALN-AGT01)  
EudraCT Number: 
2021-003776-13 
IND Number: 
143503 
Protocol Date: 
Original protocol, 25 August 2021 
Amendment 1, 22 March 2022 
Amendment 2, 22 September 2022 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Telephone: +1-617-551-8200 
Sponsor Contact:  
 
  
The concepts and information contained in this document or generated during the study are considered 
proprietary and may not be disclosed in whole or in part without expressed written authorization of 
Alnylam Pharmaceuticals, Inc. 
 
PPD
PPD


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 2, 22 September 2022 
Alnylam Pharmaceuticals 
Confidential 
2 
SPONSOR PROTOCOL APPROVAL 
 
I have read this protocol and I approve the design of this study. 
 
 
 
 
___________________________________________  
 
 
Alnylam Pharmaceuticals, Inc. 
 
 
___________________________________________  
Date 
PPD
PPD


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 2, 22 September 2022 
Alnylam Pharmaceuticals 
Confidential 
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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-AGT01-003 protocol and agree to conduct the study in accordance with the 
protocol and all applicable regulations. I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol.  
 
___________________________________________  
Printed Name of Investigator 
 
___________________________________________  
Signature of Investigator 
 
___________________________________________  
Date 






Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 2, 22 September 2022 
Alnylam Pharmaceuticals 
Confidential 
6 
Study Design 
This is a Phase 2 randomized, double-blind (DB), placebo-controlled, multicenter study to 
evaluate the efficacy, safety, and pharmacodynamics (PD) of zilebesiran administered 
subcutaneously (SC) as an add-on therapy in patients with hypertension despite treatment with a 
standard of care antihypertensive medication. A schematic of the study design is provided in 
Figure 1. 
Patients who complete the Screening period and meet all inclusion/exclusion criteria for 
enrollment will be randomized to receive open-label therapy with olmesartan (40 mg orally once 
daily [or 20 mg orally once daily for patients with creatinine clearance ≤60 mL/min at screening 
enrolled at sites outside of the United States (US) or Australia, consistent with local labeling for 
olmesartan]), amlodipine (5 mg orally once daily), or indapamide (2.5 mg orally once daily) as 
their protocol-specified background antihypertensive medication during a Run-in period of at 
least 4 weeks. 
Patients who meet all inclusion/exclusion criteria after the Run-in period will be randomized 1:1 
to receive 600 mg zilebesiran SC or placebo SC on Day 1 of a 6-month DB treatment period as 
add-on therapy to their protocol-specified background antihypertensive medication.  
Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive 
medications”) may be added to the patient’s protocol-specified background antihypertensive 
medication per Investigator judgement for elevated blood pressure. 
After the 6-month DB period, protocol-specified background antihypertensive medications will 
be discontinued, and patients may be eligible to participate in a separate zilebesiran open-label 
extension (OLE) study. If an individual patient reaches Month 6 prior to availability of the 
separate OLE study, they may receive open-label zilebesiran at 600 mg SC once every 6 months 
for up to 30 additional months until the separate OLE study is open and then transition.  
Number of Planned Patients 
The planned enrollment for this study is approximately 1800 patients to be randomized into the 
Run-in period and approximately 630 patients (300 patients in the olmesartan arm, 210 patients 
in the amlodipine arm, and 120 patients in the indapamide arm) to be randomized in the DB 
period. 
Diagnosis and Main Eligibility Criteria 
This study will include adults (18 to 75 years, inclusive, at time of initial informed consent) with 
untreated hypertension or on stable therapy with up to 2 antihypertensive medications. Patients 
should have a 24-hour mean systolic blood pressure (SBP) ≥130 mmHg and ≤160 mmHg by 
ambulatory blood pressure monitoring (ABPM) after at least 4 weeks of run-in on protocol-
specified background antihypertensive medication. Patients with secondary hypertension or 
orthostatic hypotension will be excluded. 
Study Drug, Dose, and Mode of Administration 
Zilebesiran is an SC administered N-acetylgalactosamine (GalNAc)-conjugated small interfering 
RNA (siRNA) targeting liver-expressed messenger RNA (mRNA) for angiotensinogen (AGT). 


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 2, 22 September 2022 
Alnylam Pharmaceuticals 
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Patients randomized to receive zilebesiran will be administered 600 mg SC once during the 6-
month DB treatment period; all patients will receive 600 mg SC once every 6 months during the 
OLE period. 
Reference Treatment, Dose, and Mode of Administration 
Placebo (phosphate-buffered saline for SC administration) will be administered at the same 
dosing interval and volume as the study drug during the 6-month DB period. 
Protocol-specified Background Antihypertensive Medication, Dose, and Mode of 
Administration 
Patients will be randomized to 1 of the following protocol-specified background antihypertensive 
medications to be administered orally once daily during the Run-in and 6-month DB periods: 
• Olmesartan: 40 mg (or 20 mg for patients with creatinine clearance ≤60 mL/min at 
screening enrolled at sites outside of the US or Australia, consistent with local 
labeling). At the Investigator’s discretion, patients who are randomized to receive 40 
mg olmesartan once daily may initiate treatment at 20 mg once daily and then 
uptitrate to the full dose of 40 mg once daily after 1 to 2 weeks. 
• Amlodipine: 5 mg  
• Indapamide: 2.5 mg  
Duration of Treatment and Study Participation 
The duration of treatment with zilebesiran is up to 36 months. The estimated total time on study 
for patients who rollover to the separate OLE study is up to approximately 39 months, including 
up to 75 days of the Screening and Run-in periods, and up to 36 months of treatment. For all 
patients who discontinue study drug or do not roll over to the separate OLE study, the Safety 
Follow-up period is up to 12 months. 
Statistical Methods 
The planned enrollment for this study is approximately 1800 patients to be randomized into the 
Run-in period and approximately 630 patients (300 patients in the olmesartan arm, 210 patients 
in the amlodipine arm, and 120 patients in the indapamide arm) to be randomized in the DB 
period. Randomization on Day 1 will be stratified by race (black or all other races), baseline 
blood pressure (24-hour mean SBP < or ≥145 mmHg), and screening estimated glomerular 
filtration rate (<60 or ≥60 mL/min/1.73m2). 
For the primary endpoint, assuming a standard deviation of 16 mmHg in change from baseline in 
24-hour mean SBP assessed by ABPM and 15% dropout rate from baseline to Month 3, with 2-
sided significance level of 0.05 for each of the comparisons (zilebesiran versus placebo as add-
on to olmesartan; zilebesiran versus placebo as add-on to amlodipine; zilebesiran versus placebo 
as add-on to indapamide), these sample sizes will provide at least 80% power to detect the 
following difference between zilebesiran versus placebo: 
• 5 mmHg as add-on to olmesartan  
• 6 mmHg as add-on to amlodipine 
• 8 mmHg as add-on to indapamide 


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 2, 22 September 2022 
Alnylam Pharmaceuticals 
Confidential 
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The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS): All randomized patients who received any amount of study 
drug. All by-treatment analyses based on the FAS will be grouped according to the 
randomized treatment arm.  
• Safety Analysis Set: All patients who received any amount of study drug. All by-
treatment analyses based on the Safety Analysis Set will be grouped according to the 
treatment actually received. 
• Pharmacokinetic (PK) Analysis Set: All patients who received at least 1 full dose of 
zilebesiran and have at least 1 nonmissing postdose PK assessment. 
• PD Analysis Set: All patients who received at least 1 full dose of study drug. All by-
treatment analyses based on the PD Analysis Set will be grouped according to the 
treatment actually received. 
• All Zilebesiran Treated Set: All patients who received any amount of zilebesiran, 
including patients who took zilebesiran during the 6-month DB period and patients 
who initially took placebo and then switched to zilebesiran after the Month 6 visit. 
For the analyses of the 6-month DB period, the analysis population used to evaluate efficacy will 
be the FAS. Safety data will be analyzed using the Safety Analysis Set. The PK and PD Analysis 
Sets will be used to conduct PK and PD analyses, respectively.  
The All Zilebesiran Treated Set will be used to summarize the efficacy and safety of zilebesiran 
throughout the 6-month DB period and the OLE period. 
To control the overall type I error, the primary and key secondary endpoints will be tested in 
hierarchical order. 
 


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 2, 22 September 2022 
Alnylam Pharmaceuticals 
Confidential 
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Figure 1: 
Study Design 
 
Abbreviations: aHTN=antihypertensive medication; BL=baseline; DB=double-blind; M=month; OLE=open-label 
extension; PBO=placebo; PO=per os (oral); qd=once daily; q6M=once every 6 months; R=randomization; 
SC=subcutaneous. 
Note: Patients may be eligible to participate in a separate zilebesiran OLE study upon completion of the Month 6 
predose assessments. If an individual patient reaches Month 6 prior to availability of the separate OLE study, they 
may receive open-label zilebesiran once every 6 months in the OLE period for up to 30 additional months until the 
OLE study is open and then transition. Once the separate OLE study is open for enrollment, eligible patients may 
rollover into the separate OLE study at Month 6, 12, 18, 24, 30, or 36 (first visit after the separate OLE study is 
open). 
Patients who were previously taking antihypertensives at screening should discontinue these medications at Run-in 
Visit 1. 
 












Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 2, 22 September 2022 
Alnylam Pharmaceuticals 
Confidential 
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Notes:  
• 
When scheduled at the same time points and where feasible, the assessments of vital signs and blood sample collections for RAAS biomarkers (renin, 
aldosterone, and Ang I/II) should be performed before physical examinations and 12-lead ECGs. 
• 
Run-in Visit 2 should occur at least 4 weeks after Run-in Visit 1. 
• 
Patients may be eligible to participate in a separate zilebesiran OLE study upon completion of the Month 6 predose assessments. If an individual patient 
reaches Month 6 prior to availability of the separate OLE study, they may receive open-label zilebesiran beginning at the Month 6 visit and continue for 
up to 30 additional months until the separate OLE study is open and then transition at Month 12, 18, 24, 30, or 36 (first visit after the separate OLE 
study is open). Patients who rollover at Month 6 should complete all assessments scheduled for the Month 6 visit except for study drug administration. 
Patients who rollover at Month 12 should complete the EOT visit instead of the assessments scheduled at Month 12. 
• 
Patients who discontinue study drug at any time during the study or do not enroll in the separate OLE study will be asked to perform Safety Follow-up 
visits once every 6 months after the last dose of study drug until serum AGT levels return to ≥50% of their individual mean baseline level (if known) or 
12 months after the last dose of study drug, whichever comes earlier. During this Follow-up period, HBPM monitoring may continue at the discretion of 
the Investigator. The ADA sample should only be collected at the first Follow-up visit during the Follow-up period. 
• 
Patients who discontinue study drug prior to the Month 6 visit will also be asked to complete the remainder of scheduled study visits and assessments 
(except for study drug administration) through Month 6. If a patient discontinues study drug after the Month 6 visit, EOT/ET assessments should be 
performed.  
Footnotes: 
a All assessments, except for postdose PK sample collection (Table 2), are to be performed prior to administration of protocol-specified background 
antihypertensive medications (including Run-In Visit 1) and study drug (as applicable).  
b When applicable, pregnancy test results must be known prior to dosing with study drug at dosing visits.  
c Laboratory assessments at Day 1 do not need to be repeated, per Investigator discretion, if they were collected within 7 days before Day 1 at Run-in Visit 2.  
d Office blood pressure must be measured before the patient takes oral antihypertensive medications or study drug (as applicable).  
e ABPM recordings associated with study drug dosing visits should be obtained within 7 days before the visit and results reviewed before dosing.  
f HBPM should be measured at least 3 times during the week prior to the second randomization to establish baseline. After Day 1, HBPM should be measured at 
least once per week in the morning upon waking and may be increased at the Investigator’s discretion if more frequent measurement is warranted. HBPM is not 
required on days when ABPM is being assessed. In the Safety Follow-up period, the frequency of HBPM assessments can be reduced after the first Safety 
Follow-up visit per Investigator judgement. 
g Neurological evaluation will also be performed as part of the full physical examination. 
h ABPM should only be performed as part of ET assessments if the patient discontinues the study prior to Month 12 and has not had an ABPM within the last 3 
 months. ABPM should not be performed at Month 36. 


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 2, 22 September 2022 
Alnylam Pharmaceuticals 
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Table 2: 
PK Time Points 
Study Day 
Sampling Time 
(hh:mm) 
Plasma PK Sample 
Day 1  
Predose (any time before dosing) 
X 
04:00 (±30 min) 
X 
Day 169±7 
Predose (any time before dosing) 
X 
04:00 (±30 min) 
X 
Abbreviations: hh:mm=hour:minute; min=minutes; PK=pharmacokinetics. 
Notes:  
• 
The hour (±range) indicates sample collection timing relative to dosing. Precise PK sample times (hour 
and minute) are recorded. Refer to Section 6.4 for additional information on PK assessments. 
 


Clinical Study Protocol ALN-AGT01-003  
ALN-AGT01 (zilebesiran) 
Amendment 2, 22 September 2022 
Alnylam Pharmaceuticals 
Confidential 
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TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................17 
LIST OF TABLES .........................................................................................................................20 
LIST OF FIGURES .......................................................................................................................21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................22 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Study Rationale ...........................................................................................................24 
1.2. 
Background .................................................................................................................24 
1.3. 
Benefit-Risk Assessment ............................................................................................26 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................27 
3. 
INVESTIGATIONAL PLAN .....................................................................................28 
3.1. 
Summary of Study Design ..........................................................................................28 
3.2. 
Scientific Rationale for Study Design ........................................................................30 
3.3. 
Justification for Dose ..................................................................................................32 
3.4. 
Method of Assigning Patients to Treatment Groups ..................................................32 
3.5. 
Blinding ......................................................................................................................33 
3.5.1. 
Emergency Unblinding ...............................................................................................33 
3.6. 
Data Monitoring Committee .......................................................................................33 
3.7. 
Clinical Event Adjudication Committees ...................................................................33 
3.8. 
Definition of End of Study for an Individual Patient .................................................34 
4. 
SELECTION AND REMOVAL OF PATIENTS ......................................................34 
4.1. 
Inclusion Criteria ........................................................................................................34 
4.2. 
Exclusion Criteria .......................................................................................................35 
4.3. 
Removal from Study Drug or Assessment .................................................................37 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................37 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................39 
4.3.2.1. 
Patient Stops Participation in the Study ......................................................................39 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data or Objection 
to Process Patient’s Personal Data ..............................................................................39 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................39 


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4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................40 
4.3.3. 
Lost to Follow-Up.......................................................................................................40 
4.3.4. 
Replacement of Study Patients ...................................................................................40 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................40 
5.1. 
Treatments Administered ............................................................................................40 
5.2. 
Study Drug ..................................................................................................................41 
5.2.1. 
Description ..................................................................................................................41 
5.2.2. 
Dose and Administration ............................................................................................41 
5.2.3. 
Dose Modifications .....................................................................................................41 
5.2.4. 
LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing...........42 
5.2.5. 
Neurological Criteria for Withholding, Monitoring, and Stopping Study 
Drug Dosing ................................................................................................................43 
5.3. 
Protocol-specified Background Antihypertensive Medications .................................43 
5.4. 
Preparation, Handling, and Storage ............................................................................44 
5.5. 
Packaging and Labeling ..............................................................................................44 
5.6. 
Accountability .............................................................................................................45 
5.7. 
Clinical Product Complaints .......................................................................................45 
5.7.1. 
Definition ....................................................................................................................45 
5.7.2. 
Reporting ....................................................................................................................45 
5.8. 
Monitoring for Potential Clinical Events ....................................................................45 
5.8.1. 
Monitoring and Approach for Potential Hypotension ................................................45 
5.8.2. 
Monitoring and Approach for Clinically Significant Blood Pressure 
Elevation .....................................................................................................................46 
5.8.3. 
Monitoring and Approach for Potential Renal Dysfunction .......................................48 
5.8.4. 
Monitoring and Approach for Potential Hyperkalemia ..............................................49 
5.9. 
Concomitant Medications and Procedures .................................................................50 
5.9.1. 
Prohibited Concomitant Medication ...........................................................................51 
5.10. 
Treatment Compliance ................................................................................................51 
5.11. 
Other Requirements ....................................................................................................51 
5.11.1. 
Contraception ..............................................................................................................51 
5.11.2. 
Alcohol Restrictions ...................................................................................................52 
5.11.3. 
Tobacco and Nicotine Restrictions .............................................................................53 
5.11.4. 
Dietary Recommendations ..........................................................................................53 


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5.11.5. 
Exercise .......................................................................................................................53 
6. 
STUDY ASSESSMENTS ..........................................................................................53 
6.1. 
Screening Assessments ...............................................................................................53 
6.1.1. 
Retesting .....................................................................................................................54 
6.1.2. 
Rescreening .................................................................................................................54 
6.2. 
Efficacy Assessments .................................................................................................54 
6.2.1. 
ABPM .........................................................................................................................55 
6.2.2. 
Office Blood Pressure .................................................................................................55 
6.2.3. 
HBPM .........................................................................................................................55 
6.3. 
Pharmacodynamic Assessments .................................................................................55 
6.4. 
Pharmacokinetic Assessments ....................................................................................56 
6.5. 
Safety Assessments .....................................................................................................56 
6.5.1. 
Vital Signs ..................................................................................................................56 
6.5.2. 
Weight, Height, and Morphometrics ..........................................................................56 
6.5.3. 
Physical Examination .................................................................................................57 
6.5.4. 
Electrocardiogram .......................................................................................................57 
6.5.5. 
Clinical Laboratory Assessments ...............................................................................58 
6.5.5.1. 
Fasting Lipid Panel and Glycemic Assessments ........................................................60 
6.5.5.2. 
Immunogenicity ..........................................................................................................60 
6.5.5.3. 
Pregnancy Testing ......................................................................................................60 
6.5.5.4. 
Additional Liver Function Assessments .....................................................................60 
6.5.6. 
Adverse Events ...........................................................................................................61 
6.5.6.1. 
Definitions ..................................................................................................................61 
6.5.6.2. 
Eliciting and Recording Adverse Events ....................................................................63 
6.5.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................64 
6.5.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........64 
6.5.6.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................64 
6.5.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................65 
6.5.6.7. 
Pregnancy Reporting ..................................................................................................65 
6.5.6.8. 
Reporting of Overdose and Other Special Situations .................................................65 
6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................66 
7. 
STATISTICS ..............................................................................................................66 


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7.1. 
Determination of Sample Size ....................................................................................66 
7.2. 
Statistical Methodology ..............................................................................................67 
7.2.1. 
Populations to be Analyzed ........................................................................................67 
7.2.2. 
Examination of Subgroups .........................................................................................68 
7.2.3. 
Handling of Missing Data ...........................................................................................68 
7.2.4. 
Baseline Evaluations ...................................................................................................68 
7.2.5. 
Efficacy Analyses .......................................................................................................68 
7.2.6. 
Pharmacodynamic Analysis........................................................................................69 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................69 
7.2.8. 
Safety Analyses ..........................................................................................................69 
7.2.9. 
Immunogenicity Analyses ..........................................................................................70 
7.2.10. 
Interim Analysis ..........................................................................................................70 
7.2.11. 
Optional Additional Research .....................................................................................70 
8. 
STUDY ADMINISTRATION ...................................................................................70 
8.1. 
Ethical and Regulatory Considerations ......................................................................70 
8.1.1. 
Informed Consent .......................................................................................................70 
8.1.2. 
Ethical Review ............................................................................................................70 
8.1.3. 
Serious Breach of Protocol .........................................................................................71 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................71 
8.1.5. 
End of Study ...............................................................................................................72 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................72 
8.2. 
Data Quality Control and Quality Assurance .............................................................72 
8.2.1. 
Data Handling .............................................................................................................72 
8.2.2. 
Study Monitoring ........................................................................................................72 
8.2.3. 
Audits and Inspections ................................................................................................73 
8.3. 
Publication Policy .......................................................................................................73 
9. 
LIST OF REFERENCES ............................................................................................74 
10. 
APPENDICES ............................................................................................................77 
10.1. 
Formula for Estimated Glomerular Filtration Rate Calculation .................................77 
10.2. 
Measurement of Blood Pressure .................................................................................77 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................10 


Clinical Study Protocol ALN-AGT01-003  
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Table 2: 
PK Time Points ...........................................................................................................16 
Table 3: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................43 
Table 4: 
Recommended Interventions for Potentially Clinically Significant Blood 
Pressure Elevation ......................................................................................................47 
Table 5: 
Recommended Interventions for Hyperkalemia .........................................................49 
Table 6: 
Clinical Laboratory Assessments ...............................................................................59 
Table 7: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............61 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 
 


Clinical Study Protocol ALN-AGT01-003  
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ABPM 
Ambulatory blood pressure monitoring 
ACE 
Angiotensin converting enzyme 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AGT 
Angiotensinogen 
ALT 
Alanine aminotransferase 
AngI/II 
Angiotensin I/II 
ARB 
Angiotensin II-receptor blocker 
AST 
Aspartate aminotransferase 
CCB 
Calcium channel blocker 
CPC 
Clinical product complaint 
DB 
Double-blind 
DBP 
Diastolic blood pressure 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOT 
End of treatment 
ET 
Early termination 
FAS 
Full analysis set 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HBPM 
Home blood pressure monitoring 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein 
HOMA 
Homeostatic model assessment 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 


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Abbreviation  
Definition 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR 
Injection site reactions 
LFT 
Liver function test 
MAO 
Monoamine oxidase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model with repeated measurements 
mRNA 
Messenger ribonucleic acid 
NSAID 
Nonsteroidal anti-inflammatory drug 
OLE 
Open-label extension 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PT 
Preferred term 
RAAS 
Renin-angiotensin-aldosterone system 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
siRNA 
Small interfering RNA 
SGLT2 
Sodium-glucose co-transporter 2 
THC 
Delta-9-tetrahydrocannibinol 
ULN 
Upper limit of normal 
 


Clinical Study Protocol ALN-AGT01-003  
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1. 
INTRODUCTION 
Alnylam Pharmaceuticals, Inc. (the Sponsor) is developing zilebesiran (ALN-AGT01), a 
subcutaneously (SC) administered investigational agent comprised of a synthetic small 
interfering RNA (siRNA) covalently linked to a triantennary N-acetylgalactosamine (GalNAc) 
ligand, which is designed to suppress liver production of angiotensinogen (AGT) and thereby 
reduce blood pressure in individuals with hypertension. 
1.1. 
Study Rationale 
Study ALN-AGT01-003 (KARDIA-2) is a randomized, double-blind, placebo-controlled, 
multicenter study designed to evaluate the efficacy, safety, and pharmacodynamics (PD) of 
zilebesiran administered SC as an add-on therapy in patients with hypertension despite treatment 
with a standard of care antihypertensive medication. Patients will be randomized to run-in on 1 
of 3 protocol-specified antihypertensive medications open-label for at least 4 weeks (olmesartan, 
amlodipine, or indapamide). At the end of the Run-in period, patients with uncontrolled blood 
pressure will be randomized 1:1 to receive zilebesiran or placebo as add-on therapy to the 
protocol-specified background antihypertensive medication for 6 months during the double-blind 
(DB) period. After completion of the 6-month DB period, patients may be eligible to participate 
in a separate zilebesiran open-label extension (OLE) study. If an individual patient reaches 
Month 6 prior to availability of the OLE study, they may discontinue their protocol-specified 
background antihypertensive medication and receive open-label zilebesiran (600 mg once every 
6 months) for up to 30 additional months until the OLE study is open and then transition. 
The primary objective of the study is to evaluate the efficacy of zilebesiran as an add-on therapy 
for the treatment of hypertension by evaluating the change in 24-hour mean systolic blood 
pressure (SBP), assessed by ambulatory blood pressure monitoring (ABPM), from baseline to 
Month 3, relative to placebo. Secondary and exploratory objectives of the study include 
evaluating the add-on efficacy of zilebesiran on other measures of blood pressure response 
(including longer treatment durations, eg, up to 36 months) and evaluating the PD effect of 
zilebesiran, including reduction in circulating AGT concentration. 
The full rationale for the study and design is presented in Section 3.2. 
1.2. 
Background 
Hypertension affects 30% to 45% of adults and is the strongest modifiable risk factor for 
cardiovascular disease, primarily strokes and myocardial infarction.[Olsen 2016; Williams 2018] 
The worldwide disease burden is profound, with a global prevalence of over 1 billion,[Kearney 
2005; NCD Risk Factor Collaboration 2017] and approximately 9 million deaths attributed to 
hypertension annually.[Angell 2015] 
Currently available pharmacologic therapies achieve target blood pressure in only a minority of 
patients, due in large part to physician inertia and patient nonadherence to daily oral 
medication.[Whelton 2018; Williams 2018] Low adherence to oral antihypertensives is 
associated with poor cardiovascular outcomes and is prevalent at all stages of disease.[Corrao 
2011; Peacock and Krousel-Wood 2017; Schulz 2016; van der Laan 2017] Thus, despite the 
availability of multiple efficacious agents, current rates of control are low, and the global burden 
of death and disability-adjusted life-years attributed to elevated blood pressure remains 


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high.[Forouzanfar 2017; Muntner 2020] Development of new approaches to treat hypertension 
and to overcome the limitations of current therapies is a key unmet need.[Dzau and Balatbat 
2019; McClellan 2019; Services 2020] 
The Sponsor is developing zilebesiran, a novel synthetic RNA interference (RNAi) therapeutic, 
for SC administration for the treatment of hypertension. RNAi is a naturally occurring cellular 
mechanism for regulation of gene expression, mediated through the binding of siRNA to its 
complementary messenger RNA (mRNA) sequence, leading to mRNA cleavage and subsequent 
suppression of the synthesis and levels of the target protein. Zilebesiran contains an siRNA 
targeting AGT mRNA, conjugated to a GalNAc-containing ligand to facilitate delivery to the 
liver. Based on the mechanism of RNAi, zilebesiran is specifically designed to reduce the hepatic 
synthesis of AGT protein, the first substrate in the renin-angiotensin-aldosterone system (RAAS) 
and the sole precursor of vasoactive angiotensin peptides.[Khanna 2017; Romero 2015] Because 
hepatocytes are the predominant source of circulating AGT, zilebesiran has been developed to 
reduce blood pressure by decreasing circulating AGT levels and the downstream effects of 
angiotensin II (AngII). 
Zilebesiran is being studied in the ongoing Phase 1 Study ALN-AGT01-001 (hereafter referred 
to as Study 001) in patients with hypertension as single ascending doses of 10 to 800 mg (Part 
A), as a single dose of 800 mg under low-salt or high-salt conditions (Part B), as 2 doses of 
800 mg administered every 3 months in obese patients (Part D), and as a single dose of 800 mg 
co-administered for 2 weeks with 300 mg irbesartan (Part E). Preliminary data are available from 
Parts A, B, and E. Dose-dependent and durable reductions in circulating AGT were observed 
after single SC doses of zilebesiran, accompanied by clinically significant reductions in SBP and 
diastolic blood pressure (DBP). Sustained reductions in serum AGT were observed for up to 6 
months following a single dose of zilebesiran.  
Most adverse events (AEs) have been mild or moderate in severity, and there have been no 
severe or serious adverse events (SAEs) related to study drug. There have been no clinically 
significant elevations in serum creatinine or serum potassium. No patient has required 
intervention for low blood pressure. No clinically significant alanine aminotransferase (ALT) 
elevations have been observed in patients who received zilebesiran doses as high as 800 mg. 
Injection site reactions (ISRs) were reported in a minority of patients and were all mild and 
transient events that resolved without intervention. 
Because most patients with hypertension eventually progress to require treatment with more than 
1 antihypertensive class,[Williams 2018] it is anticipated that zilebesiran may be used together 
with other standard of care antihypertensive medication. This Phase 2 study will further quantify 
the antihypertensive effects of zilebesiran as add-on therapy in patients with hypertension not 
adequately controlled by a standard of care antihypertensive medication. The consistent and 
durable PD effect of zilebesiran is expected to achieve the unique benefit of continuous 24-hour 
blood pressure lowering with infrequent SC dosing.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of zilebesiran is 
provided in the Investigator’s Brochure. 


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1.3. 
Benefit-Risk Assessment 
Clinical data available from Study 001 indicate that zilebesiran may offer the benefit of sustained 
blood pressure reduction to patients with hypertension with infrequent administration (ie, once 
every 3 months or once every 6 months). The mean SBP reduction observed after single 
zilebesiran doses of 100 mg or higher exceeds 10 mmHg, which is comparable to the effect of 
conventional antihypertensives.[Abraham 2015; Materson 1993] The blood pressure of patients 
will be closely monitored, and after Month 3, escape antihypertensive medications will be added 
as needed to control blood pressure. 
Given the mechanism of action and mode of administration of zilebesiran, potential theoretical 
risks include liver transaminase elevations and ISRs. Like any antihypertensive therapy, there is 
also a theoretical risk of hypotension with zilebesiran. Based upon the disease population, there 
is also a risk of blood pressure elevation. Because eligible patients have mild to moderate 
primary hypertension, the likelihood of disease progression during the course of the study is low. 
This study has exclusion criteria intended to minimize these risks, as well as frequent monitoring 
for laboratory and blood pressure abnormalities. Furthermore, the duration of the placebo period 
is limited, and escape antihypertensive medications are permitted to manage uncontrolled blood 
pressure following 3 months of add-on treatment with zilebesiran. Detailed guidance is provided 
to Investigators for potential liver transaminase elevations (Section 5.2.4), hypotension 
(Section 5.8.1), hypertension (Section 5.8.2), renal dysfunction (Section 5.8.3), and 
hyperkalemia (Section 5.8.4). An independent Data Monitoring Committee (DMC) will monitor 
and ensure the safety of study participants (see Section 3.6).  
Based on available data from Study 001, zilebesiran has an acceptable safety profile in patients 
with hypertension as a monotherapy or with the addition of conventional antihypertensives in 
patients who were inadequately controlled on zilebesiran alone. This experience supports that the 
theoretical risks of treatment are low and can be managed through the proposed monitoring and 
safety mitigations. In addition to study drug, each patient will receive a protocol-specified 
background antihypertensive medication (olmesartan, amlodipine, or indapamide). These agents 
are approved standard medications that will be dosed in accordance with local labeling. 
While zilebesiran is designed to inhibit the RAAS, its site of action (AGT) in the RAAS is 
unique, and its tissue specificity for the liver is hypothesized to improve its renal safety profile 
relative to conventional RAAS blockade,[Mullick 2017; Uijl 2019] both in the context of 
monotherapy and when used together with a conventional RAAS blocker such as olmesartan. In 
the latter setting, zilebesiran is hypothesized to add antihypertensive benefit when added to a 
conventional RAAS blocker without the increased incidence of RAAS inhibitor-associated renal 
adverse effects that have been observed in prior trials of conventional dual RAAS 
blockade.[Makani 2013] Patients with estimated glomerular filtration rate (eGFR) 
<45 mL/min/1.73m2 or urine albumin:creatinine ≥300mg/g will be exclusively assigned to the 
olmesartan cohort to ensure that patients with proteinuric chronic kidney disease or diabetes 
continue the RAAS inhibition standardly recommended for their renal indication throughout the 
study. 
This study’s monitoring plan is designed to meet the standards set by prior studies of 
conventional RAAS inhibitors.[McMurray 2016; Parving 2012] The risk of renal safety events is 
further mitigated in this study by its eligibility criteria, which exclude patients who are at highest 






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Run-in Period 
Patients who complete the Screening period and meet all inclusion/exclusion criteria for 
enrollment will be randomized as described in Section 3.4 to receive open-label therapy with 
olmesartan (40 mg orally once daily [or 20 mg orally once daily for patients with creatinine 
clearance ≤60 mL/min at screening enrolled at sites outside of the US and Australia, consistent 
with local labeling for olmesartan]), amlodipine (5 mg orally once daily), or indapamide (2.5 mg 
orally once daily) as their protocol-specified background antihypertensive medication during a 
Run-in period of at least 4 weeks. Prior antihypertensive medications (if taking) will be 
discontinued upon the start of this Run-in period (Run-in Visit 1). 
Patients who do not tolerate run-in treatment or who do not meet eligibility for randomization at 
Day 1 will be withdrawn from the study and returned to their prior medication regimen in 
coordination with their usual health providers.  
DB Period 
Patients who meet all inclusion/exclusion criteria will be randomized 1:1 to receive 600 mg 
zilebesiran SC or placebo SC on Day 1 of a 6-month DB period as add-on therapy to their 
protocol-specified background antihypertensive medication (olmesartan, amlodipine, or 
indapamide). Randomization on Day 1 will be stratified by race (black or all other races), 
baseline blood pressure (24-hour mean SBP < or ≥145 mmHg), and screening eGFR (<60 or 
≥60 mL/min/1.73m2). 
Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive 
medications”) may be added to the patient’s protocol-specified background antihypertensive 
medication per Investigator judgement for elevated blood pressure as described in Table 4.  
OLE Period 
After the 6-month DB period, protocol-specified background antihypertensive medications will 
be discontinued, and patients may be eligible to participate in a separate zilebesiran OLE study. 
If an individual patient reaches Month 6 prior to availability of the separate OLE study, they may 
receive open-label zilebesiran at 600 mg SC once every 6 months for up to 30 additional months 
until the separate OLE study is open and then transition. Once the separate OLE study is open for 
enrollment, eligible patients may rollover into that OLE study at Month 6, 12, 18, 24, 30, or 36 
(first visit after the separate OLE study is open). 
During the OLE period of this study, Investigators will use escape antihypertensive medications 
as described in Table 4 to control blood pressure, guided by continued blood pressure 
monitoring. 
Safety Follow-up Period 
Patients who discontinue study drug or do not enroll in the separate zilebesiran OLE study will 
be asked to complete Safety Follow-up visits once every 6 months after their last dose of study 
drug until serum AGT levels return to ≥50% of their individual mean baseline level (if known) or 
12 months after the last dose of study drug, whichever comes earlier. During the Safety Follow-
up period, patients should return to their pre-study medical care (usual care). 
Patients who discontinue study drug prior to the Month 6 visit will also be asked to complete the 
remainder of scheduled study visits and assessments (except for study drug administration) 


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through Month 6. If a patient discontinues study drug after the Month 6 visit, end of treatment 
(EOT)/early termination (ET) assessments should be performed. 
An independent DMC will oversee the safety and overall conduct of this study, and an 
independent Clinical Event Adjudication Committee will review suspected renal events to 
adjudicate whether they meet criteria for acute kidney injury. 
The planned enrollment for this study is approximately 1800 patients to be randomized into the 
Run-in period and approximately 630 patients (300 patients in the olmesartan arm, 210 patients 
in the amlodipine arm, and 120 patients in the indapamide arm) to be randomized in the DB 
period.  
The duration of treatment with zilebesiran is up to 36 months. The estimated total time on study 
for patients who rollover to the separate OLE study is up to approximately 39 months, including 
up to 75 days of the Screening and Run-in periods, and up to 36 months of treatment. For all 
patients who discontinue study drug or do not roll over to the separate OLE study, the Safety 
Follow-up period is up to 12 months after the last dose of study drug. 
3.2. 
Scientific Rationale for Study Design 
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy and safety of zilebesiran administered SC as an add-on therapy in patients with 
hypertension despite treatment with a standard of care antihypertensive medication.  
The primary objective of the study is to evaluate the efficacy of zilebesiran as an add-on therapy 
for the treatment of hypertension by evaluating the change in 24-hour mean SBP, assessed by 
ABPM, from baseline to Month 3, relative to placebo. 
Patients with hypertension often require treatment with multiple antihypertensive drugs to reach 
target blood pressure,[Williams 2018] and it is anticipated that zilebesiran may be administered 
to individuals on a background of other antihypertensive medications. Therefore, this study 
evaluates the effects of zilebesiran relative to placebo in patients whose blood pressure is not 
adequately controlled despite treatment with 1 of the 3 major drug classes recommended for 
initial treatment of hypertension by all clinical guidelines: RAAS inhibitors (ie, angiotensin 
converting enzyme [ACE] inhibitors, angiotensin II-receptor blockers, or a direct renin 
inhibitor), diuretics, and calcium channel blockers (CCBs).[Whelton 2018; Williams 2018] 
Studying coadministration with olmesartan will assess if the synergistic antihypertensive effects 
recently observed in rodents treated with both an ARB and an AGT-targeting GalNAc-siRNA 
will translate into clinically significant blood pressure reduction in hypertensive patients given 
zilebesiran as an add-on to conventional RAAS inhibition.[Uijl 2019] In addition, it will examine 
the safety and tolerability of liver-specific AGT targeting during treatment with a conventional 
RAAS blocker (olmesartan). The newer-generation ARB olmesartan was selected because of its 
high potency relative to early-generation RAAS inhibitors,[Ojima 2011; White 2011] enabling a 
robust test for added efficacy when combined with zilebesiran. The maximum dose of 
olmesartan permitted per local labeling will be used to further increase the rigor of this efficacy 
evaluation. The thiazide-like diuretic indapamide was selected in accordance with recent 
guidelines that highlight the greater potency and durability of thiazide-like diuretics over other 
diuretics.[Burnier 2019] The long-acting dihydropyridine CCB amlodipine was selected given its 


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extensive use in clinical practice and randomized controlled trials.[Dahlof 2005; Jamerson 2008; 
Julius 2004]  
During the study, blood pressure will be monitored with both automated office blood pressure 
measurements and outpatient 24-hour ABPM (EMA/CHMP/29947/2013/Rev. 4; Guideline on 
Clinical Investigation of Medicinal Products in the Treatment of Hypertension, 2016). In 
addition to having greater precision, ABPM can assess short-term blood pressure variability and 
circadian patterns (including potential restoration of the normal nocturnal blood pressure dipping 
pattern that is lost in 24% to 35% of hypertensive patients). More frequent (at least once per 
week) measurements will be collected through a third method, oscillometric home blood 
pressure monitoring (HBPM), to assess long-term blood pressure variability and provide close 
safety monitoring for potential hypotension (or hypertension) while not in the clinic.  
As recommended by current guidance (International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use [ICH] Principles for Clinical Evaluation of 
New Antihypertensive Drugs, 2000 and EMA/CHMP/29947/2013/Rev. 4; Guideline on Clinical 
Investigation of Medicinal Products in the Treatment of Hypertension, 2016), the 6-month DB 
period is designed as a randomized, placebo-controlled, parallel-group study. To adhere to best 
ethical standards for the treatment of patients with hypertension, the use of oral antihypertensive 
medications per Investigator judgement to maintain blood pressure within target is permitted 
starting at Month 3 and will continue throughout the remainder of the study (see Table 4). The 
term “escape antihypertensive medication” is used to refer to any oral antihypertensive 
medication initiated to control blood pressure after Day 1. Separate from these treat-to-target 
modifications, any confirmed event of severe hypertension (office SBP ≥180 mmHg and/or 
office DBP ≥120 mmHg) will be appropriately treated with escape antihypertensive medication 
regardless of its timing relative to study drug administration. 
If a patient requires treatment with an oral escape antihypertensive medication before Month 6, a 
CCB and/or thiazide/thiazide-like diuretic (whichever agent is not already the protocol-specified 
background antihypertensive medication) should be added because there is extensive experience 
combining these classes with antihypertensive drugs that impact the RAAS.  
After the 6-month DB period, protocol-specified background antihypertensive medication 
(olmesartan, amlodipine, or indapamide) will be discontinued, and patients may be eligible to 
participate in a separate zilebesiran OLE study. If an individual patient reaches Month 6 prior to 
availability of the separate OLE study, they may receive open-label zilebesiran at 600 mg SC 
once every 6 months for up to 30 additional months until the separate OLE study is open and 
then transition. Because many patients will receive zilebesiran for the first time at Month 6, 
office blood pressure and serum chemistries will be monitored monthly from Month 6 to Month 
9.  
During the OLE period, Investigators may use escape antihypertensive medications of permitted 
classes as described in Table 4 to control blood pressure, guided by continued blood pressure 
monitoring and following current care guidelines.[Whelton 2018; Williams 2018] Olmesartan, 
amlodipine, and indapamide will be discontinued as protocol-specified background 
antihypertensive medication during the OLE period; however, patients may continue to receive 
amlodipine or indapamide as escape antihypertensive medication at the Investigator’s discretion. 
The use of conventional RAAS inhibitors (ARBs, ACE inhibitors, or direct renin inhibitors) as 
escape antihypertensive agents for high blood pressure should be avoided throughout the study. 


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While the tissue specificity of zilebesiran for the liver is hypothesized to improve tolerability 
relative to current oral antihypertensives,[Mullick 2017; Uijl 2019] the protocol’s monitoring 
plan is designed to meet the standards set by prior studies of conventional RAAS 
inhibitors[McMurray 2016; Parving 2012].  
3.3. 
Justification for Dose 
The dose of zilebesiran in this study (600 mg once every 6 months) was selected on the basis of 
data from the Phase 1 Study 001, in which single zilebesiran doses up to 800 mg were found to 
have an acceptable safety profile, and dose-dependent, clinically significant placebo-corrected 
reductions in mean SBP >10 mmHg by 24-hour ABPM were observed at doses as low as 
100 mg. An acceptable safety profile was also observed for a single zilebesiran dose of 800 mg 
under low-salt/high-salt conditions or co-administered for 2 weeks with 300 mg irbesartan once 
daily. The selected dose of 600 mg is predicted to result in a median serum AGT reduction of 
94.9% at trough (Month 6), translating to a median SBP reduction of 11.6 mmHg as 
monotherapy. 
The protocol-specified background antihypertensive medications are standard agents 
recommended in international and regional hypertension guidelines, and the selected regimens 
are standard doses used for their approved indication of hypertension.[Whelton 2018; Williams 
2018] Indapamide will be dosed at 2.5 mg orally once daily, and amlodipine will be dosed at 
5 mg orally once daily. The dose regimens for indapamide and amlodipine used in this study 
were selected on the basis of their common use in clinical care (when used both individually and 
combined with other classes of antihypertensives) and their expected efficacy, safety, and 
tolerability. Olmesartan will be dosed at the maximum dose allowed per local labeling: 40 mg 
orally once daily (or 20 mg orally once daily for patients with creatinine clearance ≤60 mL/min 
at screening enrolled at sites outside of the US or Australia; Olmetec Product Information, 
September 2020).[von Bergmann 2001] 
3.4. 
Method of Assigning Patients to Treatment Groups 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number. After the patient signs the informed consent form (ICF) and before 
proceeding with screening procedures, the Investigator or designee should contact the Interactive 
Response Technology (IRT) to obtain a patient identification number. 
The Investigator or designee will contact the IRT to randomize the patient at Run-in Visit 1 and 
again at Day 1 after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria at each visit. 
At Run-in Visit 1, patients with screening eGFR <45 mL/min/1.73m2 or urine albumin:creatinine 
≥300mg/g will be assigned to receive olmesartan. To avoid over-enrollment, patients with eGFR 
<45 mL/min/1.73m2 or urine albumin:creatinine ≥300 mg/g will be excluded from the study after 
100 such patients are randomized to study drug on Day 1.  
All other patients will be randomized 10:7:4 to run-in open-label on 1 of 3 protocol-specified 
background antihypertensive medications (olmesartan, amlodipine, or indapamide), with targeted 
sample sizes across cohorts as described in Section 7.1. If 1 cohort completes enrollment first, 
this cohort will be deactivated for future randomization. The remaining 2 cohorts will be 


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randomized using the original ratio. After the second cohort completes enrollment, all 
subsequent patients will be assigned to the last cohort.  
At Day 1, patients will be randomized 1:1 to receive zilebesiran or placebo as an add-on to their 
protocol-specified background antihypertensive medication using the IRT. Randomization at 
Day 1 will be stratified by race (black or all other races), baseline blood pressure (24-hour mean 
SBP < or ≥145 mmHg), and screening eGFR (<60 or ≥60 mL/min/1.73m2). 
3.5. 
Blinding 
The Sponsor, all site personnel and patients will be blinded to study drug treatment through 
Month 3 of the 6-month DB period. After the database lock to support the analysis of the primary 
endpoint and secondary endpoints measured at Month 3 is complete, Sponsor staff members who 
will not have direct roles or responsibilities in interacting with study sites will be unblinded to 
the analysis results according to the prespecified blinding plan. Site personnel, patients, and 
Sponsor staff members who have direct roles or responsibilities in interacting with study sites 
will remain blinded to treatment assignment until after the analysis of Month 6 data is complete. 
All Sponsor and site personnel and patients will be blinded to any clinical laboratory result that 
could potentially unblind them (eg, AGT levels) until unblinding. 
Zilebesiran and placebo will be packaged identically. Because zilebesiran may be slightly 
visually distinguishable from placebo, the vials will be masked in such a way as to hide the 
identity of the study drug contained within. For administration, syringes will be masked by a site 
pharmacist or delegate prior to withdrawing the study drug from vial. See the Pharmacy Manual 
for additional details. The study drug will be administered under the supervision of the 
Investigator (see Section 5.2.2). 
3.5.1. 
Emergency Unblinding 
If the treating physician determines that the clinical management of the patient requires 
knowledge of the study drug assignment, the Investigator may break the blind, as necessary, in 
IRT. If time permits, clinical study center personnel should contact the Medical Monitor before 
unblinding to discuss the need to unblind the patient but must do so within 1 working day after 
the unblinding event. Unblinding information should be limited to the fewest number of people 
on a need-to-know basis. A record of when the blind was broken, who was unblinded, who broke 
the blind, and why it was broken, will be maintained in the electronic trial master file (eTMF). 
Refer to the IRT instructions for details on unblinding. 
3.6. 
Data Monitoring Committee 
An independent DMC will oversee the safety and overall conduct of this study. The DMC will 
operate under the rules of a charter that will be reviewed and approved at the organizational 
meeting of the DMC. Details are provided in the DMC Charter. 
3.7. 
Clinical Event Adjudication Committees 
An independent Clinical Event Adjudication Committee of 2 or more nephrologists will review 
the suspected renal events blinded to treatment assignment to adjudicate whether they meet 


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diagnostic criteria for acute kidney injury and, if so, their potential staging and contributing 
factors. Details are provided in the Renal Event Adjudication Committee charter. 
3.8. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the end of the study if the patient: 
• has completed at least the Month 6 visit and enrolled in the separate OLE study, or 
• has completed the Safety Follow-up visits as described in Section 3.1 for patients who 
discontinue study drug or do not enroll in the separate OLE study. 
A definition of the end of the overall study is provided in Section 8.1.5. 
4. 
SELECTION AND REMOVAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age and Sex 
1. Age 18 to 75 years, inclusive, at time of initial informed consent 
2. Male or female 
Patient and Disease Characteristics 
3. Has hypertension as follows: 
a. Untreated hypertension (not taking antihypertensive medication), or  
b. Treated hypertension on stable therapy with up to 2 antihypertensive medications. 
Stable therapy is defined as having no change in antihypertensive medication or dose 
within 30 days prior to screening.  
4. Seated office SBP at Run-in Visit 1 as follows: 
a. ≥155 mmHg and ≤180 mmHg for patients with untreated hypertension  
b. ≥145 mmHg and ≤180 mmHg for patients on antihypertensive medications  
5. 24-hour mean SBP ≥130 mmHg and ≤160 mmHg by ABPM at Run-in Visit 2 after at 
least 4 weeks of run-in. 
6. ≥80% adherence to the protocol-specified background antihypertensive medication 
during the Run-in period as assessed by pill count performed at Run-in Visit 2. 
Informed Consent 
7. Patient is able to understand and is willing and able to comply with the study 
requirements and to provide written informed consent. 


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4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Secondary hypertension (including, but not limited to, due to known history of moderate-
to-severe obstructive sleep apnea not treated with continuous positive airway pressure 
therapy, renovascular hypertension, primary aldosteronism, pheochromocytoma, Cushing 
syndrome, or aortic coarctation) 
2. Orthostatic hypotension, defined as a fall of ≥20 mmHg SBP or ≥10 mmHg DBP within 
approximately 1 to 3 minutes of standing up from a seated position by office blood 
pressure that is symptomatic (such as dizziness, weakness, lightheadedness, or syncope) 
at screening or during the Run-in period 
Laboratory Assessments 
3. Has any of the following laboratory parameter assessments at screening or Run-in 
Visit 2:  
a. ALT or aspartate aminotransferase (AST) >2× upper limit of normal (ULN) 
b. Total bilirubin >1.5×ULN. Patients with elevated total bilirubin that is secondary to 
documented Gilbert’s syndrome are eligible if the total bilirubin is <2×ULN 
c. International normalized ratio (INR) >2.0 (patients on oral anticoagulant [eg, 
warfarin] with an INR <3.5 will be allowed) 
d. Potassium <lower limit of normal range or >5 mEq/L  
e. Sodium <lower limit of normal range 
f. eGFR <30 mL/min/1.73m2 (calculation will be based on the Modification of Diet in 
Renal Disease formula; refer to Section 10.1) 
Prior/Concomitant Therapy 
4. Received an investigational agent within the last 30 days or 5 half-lives of the 
investigational agent, whichever is longer, prior to Run-in Visit 1 or are in follow-up of 
another clinical study prior to study enrollment. Any agent that has received health 
agency authorization (including for emergency use) by local or regional regulatory 
authorities is not considered investigational. Patients who are in follow-up for a 
coronavirus disease 2019 vaccine (authorized or investigational) study are allowed. 
5. Currently taking, taken within 30 days prior to first randomization, or anticipated to 
receive during the study treatment period, any medication or herbal supplement known to 
significantly affect blood pressure (with the exception of medications for the treatment of 
essential hypertension). Patients who require medications such as monoamine oxidase 
(MAO) inhibitors that are associated with hypertensive crisis should be 
excluded.[Whelton 2018]  
6. Currently taking beta blockers and unable to discontinue prior to Run-in Visit 1 
7. Changes, such as initiation or discontinuation, of sodium-glucose co-transporter 2 
(SGLT2) inhibitor therapy within 30 days prior to screening. Patients on a stable dose of 
SGLT2 therapy for at least 30 days prior to screening with no anticipated changes during 
the study treatment period are permitted. 


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8. Prescription nonsteroidal anti-inflammatory drugs (NSAIDs) are not permitted. Patients 
receiving low-dose aspirin (defined as ≤100 mg per day) for at least 30 days prior to 
screening are permitted. Paracetamol/acetaminophen for analgesia will be allowed.  
9. Anticipates using organic nitrate preparations (eg, nitroglycerin, isosorbide mononitrate, 
isosorbide dinitrate, pentaerythritol) during the study treatment period 
10. Currently taking, taken within 6 months prior to first randomization, or anticipated to 
receive an RNAi therapeutic (approved or investigational) during the study 
Medical Conditions 
11. Current or prior history of intolerance to an ARB, ACE inhibitor (other than cough), 
direct renin inhibitor, CCB (including but not limited to significant peripheral edema), or 
thiazide/thiazide-like diuretic 
12. History of multiple drug allergies or history of allergic reaction to any component of or 
excipient in the study drug 
13. Type 1 diabetes mellitus, poorly controlled Type 2 diabetes mellitus (hemoglobin A1c 
[HbA1c] >9.0%), or laboratory evidence of diabetes during screening (HbA1c ≥7.0%) 
without known diagnosis of diabetes 
14. Has known active human immunodeficiency virus infection; or known current or chronic 
hepatitis C virus (HCV) or hepatitis B virus infection. 
15. History of clinically significant cardiovascular event (eg, stroke, transient ischemic 
attack, myocardial infarction, unstable angina, coronary artery bypass grafting or other 
cardiothoracic surgeries, percutaneous coronary intervention, hospitalization due to heart 
failure) within 6 months prior to first randomization 
16. Known history of angioedema 
17. Clinically significant valvular heart disease 
18. New York Heart Association II to IV heart failure 
19. Uncontrolled serious cardiac arrhythmia, defined as recurrent and highly symptomatic 
ventricular tachycardia/supraventricular tachycardia, or atrial fibrillation with rapid 
ventricular response in the 3 months prior to first randomization 
20. Has undergone liver transplantation or is anticipated to be on an active liver 
transplantation waiting list during the study treatment period 
21. History of renal transplantation  
22. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation; or, in the opinion of the 
Investigator, taking part in the study would jeopardize the safety of the patient 
23. Clinically significant illness, in the opinion of the Investigator, within 7 days prior to 
either randomization 
24. History of intolerance to SC injection(s) that could potentially hinder study drug 
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25. Has planned major surgery or general anesthesia during the study 
Contraception, Pregnancy, and Breastfeeding 
26. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.11.1  
27. Female patient is pregnant, planning a pregnancy, or breast-feeding 
Alcohol or Nicotine Use and Substance Abuse 
28. Unwilling or unable to limit alcohol consumption throughout the course of the study. 
Alcohol intake of >2 units/day is excluded during the study (unit: 1 glass of wine 
[approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of 
beer [approximately 284 mL]). 
29. History of alcohol or substance abuse (licit or illicit drugs) within the last 12 months 
before screening, in the opinion of the Investigator 
30. Unwilling or unable to abstain from use of nicotine or tobacco-containing products 
(including but not limited to snuff, chewing tobacco, cigars, cigarettes, pipes, nicotine 
patches, or e-cigarettes) within 30 minutes prior to office blood pressure measurements  
Other Restrictions 
31. Third shift, night shift, or 24-hour shift workers 
32. Arm circumference exceeds the maximum cuff size of any of the blood pressure 
instruments provided by the Sponsor 
33. Placed in an institution on the basis of an official or court order 
4.3. 
Removal from Study Drug or Assessment 
Patients are free to discontinue study drug and/or stop protocol procedural assessments, or 
participation in the study as a whole at any time and for any reason, without penalty to their 
continuing medical care. The Investigator or the Sponsor may discontinue study drug or stop a 
patient’s participation in the study at any time if this is considered to be in the patient’s best 
interest. Any discontinuation of treatment or the stopping of the patient’s participation in the 
study must be fully documented in the electronic case report form (eCRF) and should be 
followed up by the Investigator. 
Discontinuation of study drug or declining procedural assessments is described in Section 4.3.1, 
while the stopping of a patient’s participation in the study is detailed in Section 4.3.2. 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments 
Reasons for discontinuation of study drug include any of the following: 
• Significant protocol deviation; which includes required treatment with prohibited 
medication (as defined in Section 5.9.1) per Investigator discretion 
• AE 
• Non-adherence to treatment regimen 


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• Pregnancy 
• Lost to follow-up 
• Other reason (non-AE) 
• Or, study is terminated by the Sponsor 
If possible, the Investigator will confer with the Sponsor or Medical Monitor before 
discontinuing dosing in the patient. Patients who are pregnant will be discontinued from study 
drug dosing immediately (see Section 6.5.6.7 for reporting and follow-up of pregnancy). A 
positive urine pregnancy test should be confirmed by a serum pregnancy test prior to 
discontinuing the study drug. 
Patients who discontinue study drug and/or decline procedural assessments should not be 
automatically removed from study. In general, patients who discontinue study drug dosing for 
any reason will be encouraged to remain on the study to complete the remaining assessments so 
that their experience is captured in the final analyses.  
If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedule of Assessments (Table 1), including different options for follow-up and collection 
of data (eg, in person, by phone, by mail, through family or friends, or from options not 
involving patient contact, such as communication with other treating physicians or from review 
of medical records), including endpoints and AEs, and must document this decision in the 
patient’s medical records. 
If a patient has an AE, including SAEs, and/or laboratory abnormalities that in the judgment of 
the investigator, taking into account the patient’s overall status, requires interruption or 
discontinuation from treatment with study drug, the event should be followed as described in 
Section 6.5.6. When a patient discontinues study drug dosing, the primary reason must be 
recorded in the eCRF. Patients who discontinue study drug and remain on study may receive 
treatment consistent with local standard practice for their disease per Investigator judgement, as 
applicable. 
Patients who discontinue from study drug during the 6-month DB period (defined as the time the 
first dose of study drug is administered on Study Day 1 through completion of the Month 6 
assessments) will be encouraged to remain on the study and complete assessments (excluding 
pharmacokinetic [PK] assessments) through Month 6. They will also be asked to complete Safety 
Follow-up visits once every 6 months after the last dose of study drug per the safety follow-up 
schedule (see Table 1) until PD recovery or 12 months after the last dose of study drug 
(whichever is earlier); see Section 3.1. 
Patients who discontinue study drug during the OLE period will be asked to return for their next 
scheduled visit to complete EOT/ET assessments and complete Safety Follow-up visits once 
every 6 months after the last dose of study drug per the safety follow-up schedule (see Table 1) 
until PD recovery or 12 months after the last dose of study drug (whichever is earlier); see 
Section 3.1. 


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4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient Stops Participation in the Study 
A patient may stop participation in the study at any time. A patient considering stopping 
participation in the study before Month 6 should be informed that the patient can discontinue 
study drug and/or decline procedural assessments and remain in the study to complete their study 
assessments, through the Month 6 visit and complete Safety Follow-up visits as described in 
Section 4.3.1, or alternatively may complete any minimal assessments for which the patient 
consents. If a patient still chooses to discontinue study drug and stop participation in all follow-
up prior to the completion of the 6-month DB period, every effort should be made to conduct the 
Month 6 visit assessments at an earlier time (see Table 1). 
A patient considering stopping participation in the study during the OLE period should be 
informed that the patient can discontinue study drug and/or decline procedural assessments and 
remain in the study to complete the assessments scheduled for the EOT/ET visit and complete 
Safety Follow-up visits as described in Section 4.3.1, or alternatively may complete any minimal 
assessments for which the patient consents. 
If the patient does not wish to or is unable to continue further study participation, the Investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study. Data 
collected from the patient can continue to be used. 
Note, in countries where the collection and processing of the patient’s personal data is based on 
consent, if a patient withdraws consent to collect and process the patient’s personal data (see 
Section 4.3.2.2), as applicable, personal data up to the withdrawal of consent will be included in 
the analysis of the study. In addition, where permitted, publicly available data (such as 
appropriate national or regional vital status registry or other relevant databases) can be included 
after withdrawal of consent, where available and allowable by local law. 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data or Objection to 
Process Patient’s Personal Data 
Where allowed by local law, the patient may decide to withdraw consent to collect, store, and 
use biological samples and, as applicable, other personal data, informing the Investigator at any 
time in writing or in any other form that may be locally required. Also, where allowed by local 
law, the patient may object to the collection, storage, and use of the patient’s personal data, 
informing the Investigator at any time in writing or in any other form that may be locally 
required. In both cases, the Sponsor will continue to keep and use the patient’s study information 
(including any data resulting from the analysis of the patient’s biological samples until the time 
of withdrawal/objection) according to applicable law. The process for the storage and, as 
applicable, further use of remaining samples will be followed per local requirements. 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest. However, study integrity and interpretation are 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 


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Termination of the clinical study and site closure are described in Section 8.1.6. 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation 
The primary reason that a patient’s study participation is stopped must be recorded in the 
appropriate section of the eCRF and all efforts will be made to complete and report the 
observations as thoroughly as possible. If a patient’s study participation is stopped due to an AE, 
including SAEs, the event should be followed as described in Section 6.5.6. 
4.3.3. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for 
scheduled visits and is unable to be contacted by the clinical study center. The following actions 
must be taken if a patient fails to return to the clinic for a required study visit: 
• The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule and ascertain if the patient wishes to continue in the study, and/or should 
continue in the study. 
• Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient (where possible, 3 telephone calls and, 
if necessary, a certified letter to the patient’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the patient’s 
medical record. 
• Should the patient continue to be unreachable, the patient will be considered to have 
stopped participation in the study. 
• For patients who are lost to follow-up, the Investigator can search publicly available 
records (where permitted and allowed by local law) to ascertain survival status. This 
ensures that the outcome of the study is as comprehensive as possible. 
4.3.4. 
Replacement of Study Patients 
No additional patients may be enrolled to mitigate the impact of patients who discontinue the 
study drug or stop participation in the study after the second randomization at Day 1.  
5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug and protocol-specified background antihypertensive medication supplied by the 
Sponsor for this study must not be used for any purpose other than the present study and must 
not be administered to any person not enrolled in the study. Study drug and protocol-specified 
background antihypertensive medication that have been dispensed and returned unused must not 
be re-dispensed. 


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5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of zilebesiran SC 
and placebo SC is provided in the Pharmacy Manual. 
5.2.1. 
Description 
Zilebesiran will be supplied as a sterile solution for SC injection. See the Pharmacy Manual for 
further details of solution concentration and fill volume. 
The control drug for this study will be a placebo (phosphate-buffered saline for SC 
administration). Placebo will be provided by the Sponsor; it will be packaged identically to 
zilebesiran. 
5.2.2. 
Dose and Administration 
During the 6-month DB period, patients will be administered a single dose of 600 mg zilebesiran 
or placebo, at the same volume, as SC injection on Day 1. Patients who enter the OLE period 
will receive 600 mg zilebesiran SC at Month 6 after all predose assessments are conducted and 
once every 6 months during the OLE period. 
Study drug injections will be administered by qualified clinical study center staff under the 
supervision of the Investigator or designee. The injection site may be marked and mapped for 
later observation. Injections may be administered in the abdomen, thigh, or the side or back of 
the upper arms. If a local reaction around the injection site occurs, photographs may be obtained. 
Detailed instructions for study drug administration are found in the Pharmacy Manual. 
To maintain the blind, the syringes are to be masked by the site pharmacist or designee prior to 
study drug withdrawal from the vial. A full description of the blinding procedure is included in 
the Pharmacy Manual. 
If a patient does not receive a dose of study drug within the specified dosing window, the 
Investigator should contact the Medical Monitor. After such consultation, the dose may be 
administered up to 85 days before the next scheduled dose. Thereafter, the dose will be 
considered missed and not administered. 
If a patient misses a dose of study drug, the Investigator should discuss with the Medical Monitor 
whether the patient will be able to continue the study (see also Section 4.3). 
Additional details can be found in the Pharmacy Manual.  
The definition of study drug overdose, follow-up procedures, and reporting requirements are 
provided Section 6.5.6.8. 
5.2.3. 
Dose Modifications 
Dose modifications of study drug are not permitted. 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator, and the Medical Monitor should be contacted.  


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5.2.4. 
LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing  
1. Dosing decisions may be made based on the most recently available liver function test 
(LFT) results from a central laboratory (Table 6). 
2. For any ALT or AST elevation >3×ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 3. 
3. For any ALT or AST elevation >3×ULN: 
a. If local laboratory results are obtained, confirm with a central laboratory as soon as 
possible, ideally within 2 to 3 days, but no later than 7 days. 
b. If an alternative cause is found, provide appropriate care. 
c. If an alternative cause is not found, perform assessments per Table 6 and Table 7. 
4. For any ALT or AST elevation >3×ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2×ULN or INR ≥1.5, permanently 
discontinue dosing. 
5. For confirmed ALT or AST elevations >3×ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2×ULN or INR ≥1.5, see Table 3. 


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Table 3: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative Cause 
Identified 
Transaminase Level 
Action 
>3× to 5×ULN 
• 
May continue dosing 
• 
Evaluate the initial elevation in LFT per the following assessments: 
­ Table 7 (all assessments to be performed once) 
­ Hematology, serum chemistry, LFT, and coagulation per Table 6 
• 
Monitor at least every 2 weeks (LFT and coagulation per Table 6) 
• 
If elevation persists for ≥2 months, must discuss with the Medical 
Monitor before continuing dosing 
>5× to 8×ULN 
• 
Hold study drug dosing until recovery to ≤1.5×ULN or baseline; may 
resume dosing after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments 
­ Table 7 (all assessments to be performed once) 
­ Hematology, serum chemistry, LFT, and coagulation per Table 6 
• 
Monitor at least weekly: LFT and coagulation per Table 6 until ALT 
and/or AST is declining on 2 consecutive draws, then may decrease 
monitoring to biweekly 
• 
If ALT or AST rises to >5×ULN following resumption of dosing, 
permanently discontinue dosing 
>8×ULN 
Permanently discontinue study drug dosing after confirmation of the 
transaminase value at the central laboratory. 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; LFT=liver function test(s); 
ULN=upper limit of normal. 
Notes: In addition to these criteria, other assessments or evaluations may be performed per Investigator 
discretion, as appropriate. 
5.2.5. 
Neurological Criteria for Withholding, Monitoring, and Stopping Study Drug 
Dosing 
Clinically significant events that may be consistent with potential decreased proprioception 
(including but not limited to unusual clumsiness, gait abnormalities, and unexplained 
balance/coordination issues that are either absent at or worsening from the baseline) should be 
reported as an AE. If the treatment-emergent AE is persistent and considered related to study 
drug, specialty consultation with a neurologist should be considered. However, if such a 
treatment-emergent AE is serious or severe (regardless of the Investigator’s assessment of 
relatedness), the patient must be referred for neurologist consultation, and study drug dosing 
must be held until that consultation is complete. Resumption of dosing must be approved by the 
Medical Monitor. 
5.3. 
Protocol-specified Background Antihypertensive Medications 
All patients will be randomized to receive 1 of the 3 following standard of care oral 
antihypertensive medications during a Run-in period of at least 4 weeks and will continue this 


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protocol-specified background antihypertensive medication through Month 6. Protocol-specified 
background antihypertensive medications will be supplied by the Sponsor. 
• Olmesartan: 40 mg orally once daily (or 20 mg orally once daily for patients with 
creatinine clearance ≤60 mL/min at screening enrolled at sites outside of the US or 
Australia, consistent with local labeling). At the Investigator’s discretion, patients 
who are randomized to receive 40 mg olmesartan once daily may initiate treatment at 
20 mg once daily and then uptitrate to the full dose of 40 mg once daily after 1 to 2 
weeks (in this case, the patient must take the full olmesartan dose of 40 mg once daily 
for at least 4 weeks prior to reassessment at Run-in Visit 2). 
• Amlodipine: 5 mg orally once daily 
• Indapamide: 2.5 mg orally once daily 
Protocol-specified antihypertensive medications may be downtitrated or temporarily 
discontinued per Investigator judgement for low blood pressure (see Section 5.8.1). At the 
Investigator’s discretion, oral antihypertensive agents, including protocol-specified background 
antihypertensive medication, may be prophylactically held during intercurrent illness or volume 
depletion. Additional information on the protocol-specified background antihypertensive 
medications, including side effects, drug-drug interactions, and other important prescribing 
information can be found in the Pharmacy Manual. 
5.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center will be responsible for preparing zilebesiran or placebo doses 
and dispensing protocol-specified background antihypertensive medication, according to 
procedures detailed in the Pharmacy Manual. No special procedures for the safe handling of 
study drug or protocol-specified background antihypertensive medication are required. 
Study drug will be stored at approximately 2 to 30°C until dose preparation. Protocol-specified 
background antihypertensive medication will be stored according to the storage instructions on 
the label. Deviations from the recommended storage conditions should be reported to the 
Sponsor and use of the affected study drug or protocol-specified background antihypertensive 
medication halted until authorization for its continued use has been provided by the Sponsor or 
designee, as described in the Pharmacy Manual. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and protocol-specified background antihypertensive 
medication and additional storage will be provided in the Pharmacy Manual. 
5.5. 
Packaging and Labeling 
All packaging, labeling, and production of study drug and protocol-specified background 
antihypertensive medication will be in compliance with current Good Manufacturing Practice 
specifications, as well as applicable local regulations. Study drug and protocol-specified 
background antihypertensive medication labels and external packaging will include all 
appropriate information as per local labeling requirements. Additional details will be available in 
the Pharmacy Manual. 


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5.6. 
Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
study drug and protocol-specified background antihypertensive medication supplied for this 
study, including dates of receipt. In addition, accurate records will be kept of when and how 
much study drug and protocol-specified background antihypertensive medication is dispensed 
and administered to each patient in the study. Any reasons for departure from the protocol 
dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all study drugs and 
protocol-specified background antihypertensive medication. Used, partially used, and unused 
study drug and protocol-specified background antihypertensive medication will be returned to 
the Sponsor (or designee) or destroyed at the clinical study center according to applicable 
regulations. 
Further instructions about accountability will be detailed in the Pharmacy Manual. 
5.7. 
Clinical Product Complaints 
5.7.1. 
Definition 
A clinical product complaint (CPC) is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of the study drug and its packaging after it is released for distribution to the site at 
which study drug will be administered. 
A CPC may be detected prior to use of study drug, during use, or after use. A CPC is typically 
nonmedical in nature; however, it is possible that study drug complaints could be associated with 
an AE. Examples of a CPC include, but are not limited to: illegible clinical label, missing clinical 
label, damaged vial, empty vial, and contamination of study drug. 
5.7.2. 
Reporting 
For product complaints, the Sponsor or its designee should be notified within 24 hours using the 
process outlined in the Pharmacy Manual. CPCs that may be associated with an AE must be 
evaluated and reported as indicated in Section 6.5.6. Detailed instructions on reporting CPCs will 
be provided in the Pharmacy Manual. 
5.8. 
Monitoring for Potential Clinical Events 
5.8.1. 
Monitoring and Approach for Potential Hypotension 
Hypotension is an obligate risk of antihypertensive medications. In addition to office blood 
pressure monitoring, outpatient blood pressure will be monitored weekly with HBPM to ensure 
the early detection of potential hypotension. Whenever possible, management decisions will be 
based on blood pressure measurements confirmed by office blood pressure. 
The following management recommendations for hypotension are provided: 
• Patients who experience low blood pressure that is associated with symptoms should 
promptly seek medical evaluation at the clinical study site or another hospital setting. 


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Clinical study site evaluation for low blood pressure should include the assessment of 
orthostatic blood pressure (supine to standing).  
• The Investigator should consider downtitration or interruption of oral 
antihypertensives (if taking) if confirmed office SBP <90 mmHg or if clinical 
symptoms, such as lightheadedness or dizziness, develop coupled with a significantly 
lower SBP compared to prior visits (ie, SBP <100 mmHg). Oral antihypertensives 
should be downtitrated/interrupted in reverse order to how they were added (ie, 
interrupt escape antihypertensive medications before protocol-specified background 
antihypertensive medications). 
• Clinically significant events discovered during the course of a patient’s general 
medical care should be promptly communicated to the site and evaluated by the 
Investigator, especially if hypotension is noted. Patients will carry Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)-approved patient cards to 
facilitate this physician-to-physician communication.  
• If hypotension is confirmed, serum electrolytes and creatinine should be measured 
and any oral antihypertensive(s) should be downtitrated or interrupted per 
Investigator judgement as outlined above.  
• The frequency of blood pressure and laboratory monitoring (serum electrolytes and 
creatinine) should be increased during intercurrent illnesses that predispose patients to 
dehydration (eg, vomiting or diarrhea that persists for more than 24 hours) or when 
symptoms consistent with decreased effective circulating volume (eg, presyncopal 
symptoms, unexplained falls, decreased urine output) manifest, even if a patient’s 
recent blood pressure measurements have been normal. 
• Hypotension that warrants direct evaluation at the site should be communicated to the 
Medical Monitor within 24 hours. In addition, other clinical events consistent with 
potential hypotension (eg, unexplained presyncope, syncope, or falls) should be 
communicated to the Medical Monitor within 24 hours of the site being notified. 
• Management of persistent hypotension may include increased salt intake or, if 
unresponsive, standard treatments for orthostatic intolerance syndromes such as 
fludrocortisone or midodrine. 
• Low blood pressure that requires medical treatment (including intravenous fluid 
support) or other clinical events consistent with potential hypotension (see above) 
should be recorded as AEs. 
5.8.2. 
Monitoring and Approach for Clinically Significant Blood Pressure Elevation 
In addition to office blood pressure monitoring, outpatient blood pressure will be monitored 
frequently with HBPM to ensure the early detection of potential significant elevations. Whenever 
possible, management decisions will be based on blood pressure measurements confirmed by 
office blood pressure. The recommended interventions for potentially clinically significant blood 
pressure elevation are presented in Table 4.  


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Table 4: 
Recommended Interventions for Potentially Clinically Significant Blood 
Pressure Elevation 
Study Period 
Intervention 
Throughout Study 
• 
Whenever possible, management decisions should be based on blood 
pressure measurements confirmed by office blood pressure. 
• 
Any confirmed event of severe hypertension (office SBP ≥180 mmHg 
and/or office DBP ≥120 mmHg) should be appropriately treated regardless 
of its timing relative to study drug administration.  
• 
Until double-blind data are generated that demonstrate acceptable safety 
and added antihypertensive efficacy of zilebesiran when combined with 
olmesartan, the use of conventional RAAS inhibitors (ARBs, ACE 
inhibitors, or direct renin inhibitors) as escape antihypertensive agents for 
high blood pressure will be avoided throughout the study.  
• 
If added, escape antihypertensives must be used per their labeled 
instructions and in accordance with current clinical guidelines.[Whelton 
2018; Williams 2018] 
Day 1 to Month 3 
Intervene if clinically significant blood pressure elevation: 
• 
Because of the gradual onset of effects of zilebesiran, interventions for 
asymptomatic hypertension should be avoided in the first 6 weeks after the 
patient’s first administration of study drug.  
• 
After Week 6, patients who develop office SBP >160 mmHg and increased 
>10 mmHg from their baseline office SBP that persists for ≥24 hours on 2 
consecutive measurements or that is accompanied by hypertensive 
symptoms should be evaluated by the clinical study site. Severely 
symptomatic patients should be evaluated at the clinical study site or 
another hospital setting within 24 hours. 
• 
If persistent hypertension is confirmed (without the identification of a 
specific treatable cause) and the Investigator deems it to be a clinically 
significant change, treatment may be initiated at the medical discretion of 
the Investigator using a CCB and/or a thiazide/thiazide-like diuretic 
(whichever agent is not already the protocol-specified background 
antihypertensive medication) as an escape antihypertensive medication.  
Months 3 to 6 
Treat to target blood pressure using a CCB and/or thiazide/thiazide-like diuretic 
(whichever agent is not already a protocol-specified background 
antihypertensive medication): 
• 
At Month 3, a CCB and/or a thiazide/thiazide-like diuretic may be added as 
an escape antihypertensive medication if the daytime mean SBP is 
≥135 mmHg by ABPM. If the Investigator feels there is a compelling 
clinical reason to wait, the rationale for exception should be documented in 
the eCRF. 
• 
After Month 3, other escape antihypertensive medications may also be 
added per Investigator judgement for persistent elevations in SBP above 
recommended target per treatment guidelines (eg, office SBP <140 mmHg, 
HBPM SBP <135 mmHg, or daytime mean SBP by ABPM <135 
mmHg).[Williams 2018] 


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Study Period 
Intervention 
Month 6 to End of 
Study (OLE period) 
Treat to target blood pressure using Investigator’s choice of oral 
antihypertensive(s). 
• 
At Month 6, protocol-specified background antihypertensive medications 
(olmesartan, amlodipine, or indapamide) will be discontinued.  
• 
Patients who continue into the OLE period will initiate open-label treatment 
with 600 mg zilebesiran once every 6 months. As many patients will receive 
zilebesiran for the first time at Month 6, office blood pressure and serum 
chemistries will be carefully monitored monthly from Month 6 to Month 9, 
and Investigators will be prepared to downtitrate or interrupt escape 
antihypertensive medications if low blood pressure develops (see 
Section 5.8.1). 
• 
If the Month 6 ABPM is in target (daytime mean SBP <135 mmHg), escape 
antihypertensive medications (if taken) may be downtitrated or interrupted 
per Investigator judgement to determine if the patient’s blood pressure 
remains within target on zilebesiran treatment alone.  
• 
During the OLE period, oral antihypertensive medications may be added 
per Investigator judgement for persistent elevations in blood pressure above 
recommended target per treatment guidelines (eg, office SBP <140 mmHg, 
HBPM SBP <135 mmHg, or daytime mean SBP by ABPM <135 
mmHg).[Whelton 2018; Williams 2018] 
Abbreviations: ABPM=ambulatory blood pressure monitoring; ACE=angiotensin converting enzyme; 
ARB=angiotensin II-receptor blocker; CCB=calcium channel blocker; DBP=diastolic blood pressure; 
eCRF=electronic case report form; HBPM=home blood pressure monitoring; OLE=open-label extension; 
RAAS=renin-angiotensin-aldosterone system; SBP=systolic blood pressure. 
5.8.3. 
Monitoring and Approach for Potential Renal Dysfunction 
The Schedule of Assessments (Table 1) includes frequent laboratory monitoring of eGFR 
through the anticipated onset of initial zilebesiran PD. Based upon the renal dysfunction 
associated with conventional RAAS inhibitors,[McMurray 2016; Parving 2012] the following 
guidelines apply throughout the study: 
• If an individual patient experiences a decrease in eGFR by ≥30% from baseline or to 
≤30 mL/min/1.73m2, the Investigator should obtain confirmatory repeat tests, contact 
the Sponsor, and look for potentially reversible causes of renal dysfunction such as: 
− NSAIDs, antibiotics, or other treatments known to impair renal function 
− Recent exposure to intravenous contrast agents 
− Hypovolemia 
− Hypotension 
− Urinary infection 
− Urinary tract obstruction 
• If an individual patient experiences a decrease in eGFR by ≥40% from baseline or to 
≤25 mL/min/1.73m2, the Investigator should obtain confirmatory repeats tests, look 


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for potentially reversible causes of renal dysfunction, and contact the Sponsor to 
discuss the potential interruption of study drug and/or oral antihypertensives. Serum 
creatinine should be monitored at least weekly until improving. 
5.8.4. 
Monitoring and Approach for Potential Hyperkalemia 
The Schedule of Assessments (Table 1) includes frequent laboratory monitoring of serum 
electrolytes (at least monthly through the anticipated onset of zilebesiran PD). The guidelines in 
Table 5 apply for potassium elevations detected by laboratory monitoring.[McMurray 2016; 
Parving 2012] 
Table 5: 
Recommended Interventions for Hyperkalemia 
Serum K+ >5.2 and <5.5 mmol/L 
Serum K+ ≥5.5 and <6.0 mmol/L 
Serum K+ ≥6.0 mmol/L 
• 
Confirm potassium 
concentration in a non-
hemolyzed sample. 
• 
Reinforce low-potassium diet 
and restriction of food/drinks 
with high potassium content  
• 
Review medical regimen 
(including dietary supplements 
and over-the-counter 
medications) for agents known 
to cause hyperkalemia.a 
Consider reduction in dose or 
discontinuation of these agents 
only if clinically acceptable. 
• 
Repeat K+ measurement within 
3 to 5 days. 
• 
If K+ remains >5.2 and <5.5 
mmol/L, regularly monitor K+ 
levels to ensure stability (at 
least weekly if in the first 6 
weeks of treatment or at least 
once monthly afterwards) 
• 
Confirm potassium 
concentration in a non-
hemolyzed sample 
• 
Consider interruption of open-
label olmesartan (in patients 
randomized to receive it as their 
protocol-specified background 
antihypertensive medication) 
according to Investigator 
medical judgement 
• 
Consider interruption or delay 
of study drug administration, 
according to Investigator 
medical judgment  
• 
Apply all measures outlined for 
serum K+ >5.2 and <5.5 
mmol/L 
• 
Repeat K+ measurement after 2 
to 3 days 
• 
If K+ <5.5 mmol/L, consider 
resumption of study drug (if 
interrupted) with repeat 
potassium within 5 days 
• 
If K+ persistently elevated ≥5.5 
mmol/L, consider treatment 
with patiromer (or with sodium 
zirconium cyclosilicate), if 
available 
• 
Immediately interrupt 
study drug 
• 
Confirm potassium 
concentration in a 
non-hemolyzed 
sample 
• 
Urgently evaluate 
patient and treat 
hyperkalemia as 
clinically indicated. 
After urgent 
treatment, consider 
treatment with 
patiromer (or with 
sodium zirconium 
cyclosilicate), if 
available 
• 
Apply all measures 
outlined for serum K+ 
≥5.5 and <6.0 
mmol/L 
• 
No resumption of 
study drug without 
individualized case 
discussion with and 
permission from 
Alnylam Medical 
Monitor 
Abbreviations: NSAID=nonsteroidal anti-inflammatory drug. 
a This list is not meant to be exhaustive: potassium-sparing diuretics (eg, amiloride and triamterene), potassium 
supplements (eg potassium chloride), salt substitutes, NSAIDs, cyclo-oxygenase-2 inhibitors, trimethoprim and 
trimethoprim-containing combination products, herbal supplements (eg, Noni juice, alfalfa [Medicago sativa], 
dandelion [Taraxacum officinale], horsetail [Equisetum arvense], nettle [Urtica dioica], milkweed, lily of the 
valley, Siberian ginseng, hawthorn berries). 


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The availability of patiromer and sodium zirconium cyclosilicate (ZS-9) will be assessed at 
participating study sites. These potassium-binding drugs are indicated for the treatment of 
hyperkalemia and have been shown to safely reduce serum potassium levels and to maintain 
long-term normokalemia in chronic kidney disease patients receiving background conventional 
RAAS inhibitor therapy.[Georgianos and Agarwal 2018; Weir 2015] 
5.9. 
Concomitant Medications and Procedures 
Use of concomitant medications and procedures will be recorded on the patient’s eCRF as 
specified in the Schedule of Assessments (see Table 1). Concomitant medications include all 
prescription medications, herbal preparations, over the counter medications, vitamins, and 
minerals. Any changes in medications during the study will also be recorded on the eCRF. 
Standard vitamins and topical medications are permitted. However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated. For other permitted 
concomitant medications administered SC, do not administer in same injection site area as the 
study drug for at least 4 days after each dose of study drug. 
Patients receiving low-dose aspirin (defined as ≤100 mg per day) for at least 30 days prior to 
screening and during the study treatment period are allowed. Occasional use of other systemic 
over-the-counter NSAIDs is allowed. However, given their association with increased blood 
pressure, they should be avoided when possible and for at least 2 days prior to ABPM and office 
blood pressure assessments, and alternative analgesics (acetaminophen, topical NSAIDs) should 
be considered.[Whelton 2018] When used, the dosing of systemic NSAIDs should be at the 
lower end of the labeled range and for the shortest duration possible.  
Patients receiving SGLT2 inhibitors (eg, empagliflozin, canagliflozin, and dapagliflozin) should 
be on a stable dose for at least 30 days prior to screening and during the study treatment period. 
These medications should not be initiated or discontinued, if possible, during the study treatment 
period. 
Patients receiving stable doses of tamsulosin, alfuzosin, or silodosin for at least 30 days prior to 
screening are allowed. 
Patients will be allowed to receive vaccines (eg, for SARS-CoV-2) that have received health 
agency authorization (including for emergency use) by local or regional regulatory authorities. 
Use of cannabis or delta-9-tetrahydrocannibinol (THC)-containing substances (including by 
smoking, vaping, dabbing, or ingesting/edibles) should be avoided when possible and for at least 
2 days prior to ABPM and office blood pressure assessments. 
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator, except as described in Section 5.9.1 and after consulting the Pharmacy Manual, 
which contains information on drug-drug interactions and other important prescribing 
information for the protocol-specified background antihypertensive medications. However, it is 
the responsibility of the Investigator to ensure that details regarding the medication are recorded 
on the eCRF. Concomitant medication will be coded using an internationally recognized and 
accepted coding dictionary. 


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5.9.1. 
Prohibited Concomitant Medication 
The following medications, treatments, and supplements are prohibited throughout the study 
treatment period (until the EOT visit): 
• Conventional RAAS inhibitors (ARBs, ACE inhibitors, or direct renin inhibitors), 
except for olmesartan as protocol-specified background antihypertensive medication 
during the 6-month DB period  
• Prescription NSAIDs  
• Organic nitrate preparations (eg, nitroglycerin, isosorbide mononitrate, isosorbide 
dinitrate, pentaerythritol) 
• An RNAi therapeutic (other than zilebesiran) 
• Medications, herbal supplements (including Ma Huang and St. John’s wort), or other 
substances (such as licorice) that are associated with increases in LFT abnormalities 
or with blood pressure abnormalities are prohibited. This includes certain stimulants 
(eg, amphetamine, methylphenidate dexmethylphenidate, dextroamphetamine), MAO 
inhibitors, atypical antipsychotics (eg, clozapine, olanzapine), diet pills (eg, 
phenylpropanolamine, sibutramine), and nasal decongestants (eg, phenylephrine 
hydrochloride, pseudoephedrine, naphazoline hydrochloride), unless individually 
approved by both the Investigator and the Medical Monitor. 
• Medications, herbal medicines, over-the-counter medications, or supplements known 
to cause hyperkalemia are prohibited unless individually approved by both the 
Investigator and the Medical Monitor. This includes potassium-sparing diuretics, 
potassium supplements, cyclo-oxygenase-2 inhibitors, trimethoprim and 
trimethoprim-containing combination products, mineralocorticoid receptor 
antagonists, Noni juice, alfalfa, dandelion, horsetail, nettle, milkweed, lily of the 
valley, Siberian ginseng, and hawthorn berries. 
All concomitant medications must be reviewed and approved by the Investigator, with particular 
attention to avoiding drugs that may affect blood pressure. 
5.10. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff. 
Compliance with protocol-specified background antihypertensive medication will be assessed 
through pill count by study staff. 
5.11. 
Other Requirements 
5.11.1. 
Contraception 
Females of child-bearing potential must be willing to use a highly effective method of 
contraception from 14 days before the first dose of protocol-specified background 
antihypertensive medication, throughout study participation, and through safety follow-up (if 
applicable; see Section 3.1). 
Birth control methods which are considered highly effective include: 


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• Placement of an intrauterine device. 
• Placement of an intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
• Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female patients on the 
study, the vasectomized male partner should be the sole partner for that patient). 
• Established use of oral (except low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception associated with the inhibition of 
ovulation. 
• True sexual abstinence, when in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. Abstinent 
patients must agree to use one of the above-mentioned contraceptive methods if they 
start heterosexual relationships during the study and through safety follow-up (if 
applicable; see Section 3.1) 
Investigators should advise females of childbearing potential of the most appropriate birth 
control method available within their country taking into account local medical practice. 
Females of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study), and who are not postmenopausal or permanently 
sterilized (eg, bilateral oophorectomy, hysterectomy, or bilateral salpingectomy). A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by follicle stimulating hormone level within the postmenopausal 
range.  
For male patients, no contraception is required. However, use by males of contraception 
(condom) may be required in some countries, eg, France, in order to comply with local 
requirements as described in the corresponding patient ICFs.  
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.5.5.3). Pregnancy testing will be 
performed before every dose for postmenarcheal females throughout the course of the study (see 
Section 6.5.5.3). 
5.11.2. 
Alcohol Restrictions 
Patients should limit alcohol consumption throughout the course of the study. Alcohol is limited 
to no more than 2 units per day (unit: 1 glass of wine [approximately 125 mL] =1 measure of 
spirits [approximately 1 fluid ounce] =½ pint of beer [approximately 284 mL]) for the duration 
of the study. Compliance with alcohol restrictions should be assessed on a regular basis by the 
Investigator throughout the course of the study. 


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5.11.3. 
Tobacco and Nicotine Restrictions 
Use of nicotine or tobacco-containing products (including, but not limited to, snuff, chewing 
tobacco, cigars, cigarettes, pipes, nicotine patches, or e-cigarettes) must be avoided within 30 
minutes prior to office blood pressure measurements. 
5.11.4. 
Dietary Recommendations 
All patients will receive educational materials on diet with recommendations to limit sodium 
consumption to approximately 2.0 g per day from screening through the end of the Treatment 
period. This direction should be provided at the start of the Screening period, and treatment-
naïve patients should follow these recommendations for at least 1 week prior to screening 
assessments of blood pressure. This is the sodium intake recommended in the 2018 European 
Society of Cardiology/European Society of Hypertension Guidelines for both hypertensive 
patients and for the general population.[Williams 2018]  
On days on which samples for fasting lipid panel and glycemic assessments are collected, 
patients are required to fast for ≥10 hours before sample collection (Section 6.5.5.1). 
5.11.5. 
Exercise 
Patients should abstain from strenuous exercise for 48 hours before each blood collection for 
clinical laboratory tests and from any exercise for 30 minutes prior to office blood pressure 
measurements. 
6. 
STUDY ASSESSMENTS 
The schedule of study assessments is provided in Table 1. Study visits should be scheduled for 
the morning. All assessments, except for postdose PK sample collection, are to be performed 
prior to dosing with protocol-specified background antihypertensive medication or study drug. 
Additional information on the collection of study assessments will be detailed in the study 
manuals. 
Where applicable country and local regulations and infrastructure for home healthcare allow, 
home healthcare may take place at a location other than the clinical trial site to perform study 
assessments, which may include collection of blood and urine samples and measurement of vital 
signs (at the discretion and oversight of the Investigator). 
6.1. 
Screening Assessments 
An ICF that has been approved by the appropriate IRB/IEC must be signed (in paper or 
electronic format per local regulations and institutional standards) by the patient before the 
screening procedures are initiated. All patients will be given a copy of the signed and dated ICF. 
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria. Rescreening of patients once is permitted with agreement of the Medical 
Monitor (see Section 6.1.2). 


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Patient demographic data and medical history/disease history will be obtained. Any changes to 
medical history occurring between the screening assessment and Run-in Visit 1 will be updated 
prior to administration of protocol-specified background antihypertensive medication. 
6.1.1. 
Retesting  
If in the Investigator’s judgement, the screening or Run-in laboratory abnormalities are likely to 
be transient, then laboratory tests may be repeated. The Investigator’s rationale must be 
documented. Laboratory values can be retested once during screening and once during the Run-
in period provided that the patient can be evaluated for eligibility and randomized within the 
allowed Screening and Run-in periods. Retesting of office blood pressure at Run-in Visit 1 is 
permitted once if in the Investigator’s judgement, the result is not accurate due to a transient 
condition. Retesting of ABPM at Run-in Visit 2 is permitted once if the first ABPM is invalid. A 
valid ABPM recording must be obtained within 7 days prior to randomization for all patients. If 
a valid ABPM recording that meets the inclusion criterion exceeds the 7-day window prior to 
randomization, a single additional ABPM assessment is permitted, with no option for retesting in 
case of an invalid reading. Eligibility is assessed by the most recent ABPM result obtained. If a 
valid ABPM recording that meets the inclusion criterion is not obtained within the 7 days prior to 
randomization, the patient is a run-in failure. 
6.1.2. 
Rescreening 
A patient who does not meet all study eligibility criteria due to a transient condition observed at 
screening (eg, prohibited medications that were subsequently discontinued) will be allowed to 
return once for rescreening following agreement with the Medical Monitor. A patient will be re-
consented if rescreening occurs outside of the Screening period. In this case, all screening 
procedures must be repeated. Patients who do not meet eligibility criteria after Run-in Visit 1 
will not be rescreened. 
6.2. 
Efficacy Assessments 
All blood pressure measurements (ABPM, office, and HBPM) must be taken at the times 
specified in the Schedule of Assessments (Table 1) using the standardized equipment provided 
by the Sponsor, according to the methods described in Section 10.2. Office blood pressure 
assessments and ABPM initiation must be performed before administration of any oral 
antihypertensive medications and study drug (as applicable). 
Patients taking oral antihypertensives prior to screening should discontinue these medications at 
Run-in Visit 1. The baseline ABPM and office blood pressure measured at Run-in Visit 2 must 
be taken within 7 days before Day 1. An HBPM unit will be provided before Run-in Visit 2 to 
establish the HBPM baseline, and HBPM should be collected at least 3 times during the last 
week prior to Day 1. 
ABPM placement may be performed at home by appropriately trained individuals, as detailed in 
the ABPM Investigator Manual. If a patient is unable to report to the site for an office blood 
pressure assessment, a substitute “remote visit blood pressure measurement” may be obtained 
remotely using the methods described in Section 10.2. 
Recommendations for approach and monitoring of low blood pressure/hypotension and 
hypertensive escape are provided in Section 5.8.1 and Section 5.8.2, respectively. 


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6.2.1. 
ABPM 
The ABPM should be started prior to the morning dose of oral antihypertensive medication. 
Consecutive (daily) use of over-the-counter NSAIDs (other than aspirin ≤100 mg per day) and 
use of cannabis or THC-containing substances should be avoided for at least 2 days prior to 
ABPM measurements.  
Validity will be assessed for all ABPMs. If the ABPM recording is invalid at any point during 
the study, the patient will be provided 1 opportunity to repeat the recording. During the Run-in 
period, if a valid ABPM recording that meets the inclusion criterion exceeds the 7-day window 
prior to randomization, a single additional ABPM assessment is permitted, with no option for 
retesting in case of an invalid reading. Eligibility is assessed by the most recent ABPM result 
obtained. If a valid ABPM recording that meets the inclusion criterion is not obtained within the 
7 days prior to randomization, the patient is a run-in failure. 
See further details in Section 10.2 and the ABPM Investigator Manual. 
6.2.2. 
Office Blood Pressure 
Office blood pressure must be measured in triplicate using the automated blood pressure device 
provided by the Sponsor at trough (prior to taking oral antihypertensives) and should be at 
approximately the same time of day for each assessment; therefore, visits should be scheduled at 
approximately the same time of day, whenever possible. Office blood pressure must include 
orthostatic measurements (seated and standing).  
Exercise, caffeine, alcohol consumption, and use of nicotine or tobacco-containing products 
(including but not limited to snuff, chewing tobacco, cigars, cigarettes, pipes, nicotine patches, or 
e-cigarettes) must be avoided within 30 minutes prior to blood pressure measurements. The use 
of inhaled short-acting beta agonists should be avoided within 6 hours prior to measuring blood 
pressure and/or heart rate. The use of phosphodiesterase type 5 inhibitors (eg, sildenafil, 
tadalafil, vardenafil, avanafil) should be avoided within 48 hours prior to measuring blood 
pressure. Consecutive (daily) use of over-the-counter NSAIDs (other than aspirin ≤100 mg per 
day) and use of cannabis or THC-containing substances should be avoided for at least 2 days 
prior to blood pressure measurements. 
The patient should be seated comfortably with the back supported and the feet flat on the floor as 
detailed in Section 10.2 and the HBPM and OBPM Investigator Manual.  
6.2.3. 
HBPM 
The HBPM should be measured in the morning upon waking, prior to breakfast/caffeine or 
taking morning oral antihypertensive medications. HBPM is not required on days when ABPM is 
being assessed. The patient should be seated comfortably with the back supported and the feet 
flat on the floor as detailed in Section 10.2 and the HBPM and OBPM Investigator Manual. 
6.3. 
Pharmacodynamic Assessments 
Blood samples for determination of AGT will be collected according to the Schedule of 
Assessments (Table 1). In addition, blood samples for determination of RAAS biomarkers 
(plasma renin concentration, AngI, AngII, and aldosterone) will be collected only for patients 
randomized to receive olmesartan as protocol-specified background antihypertensive medication. 


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Blood samples for PD assessments must be collected before study drug administration (on days 
when study drug is to be dosed) or at a time point corresponding to the time of study drug dosing 
(on other days). Blood AGT levels will be analyzed at a regulated bioanalytical laboratory by 
enzyme-linked immunosorbent assay for measurement of PD effect. Biomarkers may be 
analyzed using qualified assays. Details regarding the collection, processing, shipping, and 
storage of the samples will be provided in the Laboratory Manual.  
Results will not be used to adjust dosing of zilebesiran or guide clinical management and will not 
be shared with sites until after study unblinding. 
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for the assessment of plasma concentrations of zilebesiran and 
its primary metabolite AS(N-1)3′ zilebesiran at the time points indicated in the Schedule of 
Assessments (Table 1). A detailed schedule of time points for the collection of blood samples for 
PK analysis is in Table 2. 
Plasma concentrations of zilebesiran and AS(N-1)3′ zilebesiran will be determined using a 
validated assay. Details regarding sample volumes to be collected, and the processing, shipping, 
and analysis of the samples will be provided in the Laboratory Manual. 
6.5. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of AEs, 
including SAEs, recording of concomitant medication and measurements of vital signs, weight, 
electrocardiogram (ECG) findings, and laboratory tests. Clinically significant abnormalities 
observed during the physical examination will be recorded. 
6.5.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1) and include 
office blood pressure, heart rate, body temperature, and respiratory rate. Vital signs are to be 
collected prior to administration of oral antihypertensive medications and study drug (as 
applicable). When vital signs and blood sample collection occur at the same time, vital signs 
should be performed before blood samples are drawn, where possible. Vital signs should be 
measured in the seated position, after the patient has rested comfortably for approximately 5 
minutes. Body temperature in degrees Celsius will be obtained via oral, tympanic, forehead, or 
axillary methods. Heart rate will be counted for a full minute and recorded in beats per minute, 
and respiration rate will be counted for a full minute and recorded in breaths per minute. Blood 
pressure is described in Section 6.2.  
Additional vital sign assessments, as medically indicated, may be added at the discretion of the 
Investigator, or as per DMC advice. 
6.5.2. 
Weight, Height, and Morphometrics 
Height and body weight measurements will be collected as specified in the Schedule of 
Assessments (Table 1) and will be recorded in the eCRF. Height will be measured at Day 1 only. 
Height will be measured in centimeters. Body weight should be measured in kilograms to the 
first decimal point in patients wearing light clothing and without shoes.  


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Waist circumference and waist-to-hip-ratio will also be collected as specified in the Schedule of 
Assessments (Table 1) and will be recorded on the eCRF. For waist circumference and waist-to-
hip ratio, patients should wear minimal clothing to ensure that the measuring tape is correctly 
positioned. Patients should stand erect with the abdomen relaxed, arms at the sides, feet together 
and with their weight equally divided over both legs. To perform the waist measurement, the 
lowest rib margin is first located and marked with a pen. The iliac crest is then palpated in the 
midaxillary line, and also marked. It is recommended to apply an elastic tape horizontally 
midway between the lowest rib margin and the iliac crest, and tie firmly so that it stays in 
position around the abdomen about the level of the umbilicus. The elastic tape thus defines the 
level of the waist circumference, which can then be measured by positioning the measuring tape 
over the elastic tape. Hip circumference measurement should be taken around the widest portion 
of the buttocks. Patients are asked to breathe normally, and to breathe out gently at the time of 
the measurement to prevent them from contracting their muscles or from holding their breath. A 
stretch-resistant tape that provides a constant 100 g of tension is recommended. Measurements 
should be obtained with the tape positioned parallel to the floor and performed using the same 
procedure throughout the study. 
The reading is taken to the nearest centimeter and entered in the source document. Each 
measurement should be repeated twice; if the measurements are within 1 cm of each other, the 
average should be calculated. If the difference between the 2 measurements exceeds 1 cm, the 2 
measurements should be repeated.  
6.5.3. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedule 
of Assessments (Table 1); if a physical examination is scheduled for a study drug dosing visit, it 
should be conducted prior to dosing. Full physical examinations will include the examination of 
the following: general appearance; head, eyes, ears, nose and throat; respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, and dermatological systems; thyroid; lymph nodes; and 
neurological evaluation (see the Recommended Neurological Assessments for All Physical 
Examinations document for further details on the assessments to be performed as part of the 
neurological evaluation). 
Symptom-directed physical examinations will be guided by evaluation of changes in symptoms, 
or the onset of new symptoms, since the last visit. Neurological evaluation should be performed 
during all symptom-directed physical examinations regardless of whether neurological 
symptoms have been experienced by the patient.  
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF. 
6.5.4. 
Electrocardiogram 
The 12-lead ECGs reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, 
QT interval, and Fridericia-corrected QT interval will be obtained using a local machine, as 
specified in the Schedule of Assessments (Table 1). Patients should be supine for at least 10 
minutes before each ECG is obtained. The Investigator or qualified designee will review all 
single 12-lead ECGs to assess whether the results have changed since the Baseline visit and to 


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determine the clinical significance of the results. These assessments will be recorded in the 
eCRF.  
When ECG and blood sample collection for RAAS biomarkers (renin, aldosterone, and Ang I/II) 
occur at the same visit and where feasible, blood sample collection should occur first. ECGs 
should be performed at least 30 minutes after phlebotomy or other stressful assessments. 
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since the baseline visit and to determine the clinical significance of the results. These 
assessments will be recorded in the eCRF. Additional ECGs may be collected at the discretion of 
the Investigator, or as per DMC advice.  
6.5.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory. Specific 
instructions for transaminase elevations are provided in Section 5.2.4. For any other unexplained 
clinically relevant abnormal laboratory test occurring after study drug administration, the test 
should be repeated and followed up at the discretion of the Investigator, or as per DMC advice, 
until it has returned to the normal range or stabilized, and/or a diagnosis is made to adequately 
explain the abnormality. Additional safety laboratories and assessments as indicated by the 
clinical situation may be requested. Clinical laboratory assessments are listed in Table 6 and will 
be assessed as specified in the Schedule of Assessments (Table 1).  
While local laboratory results may be used for urgent clinical decisions, on the day of the 
assessments, all laboratory assessments specified in Table 6 that are performed at the clinic 
should also be sent in parallel to the central laboratory. In the case of discrepant local and central 
laboratory results on samples drawn on the same day, central laboratory results will be relied 
upon for clinical decisions. 
Clinical laboratory assessments may be collected at the clinical study center or at home by a 
trained healthcare professional. In patients randomized to receive olmesartan as the protocol-
specified background antihypertensive medication, blood samples for RAAS biomarkers should 
be collected in the morning and in the seated/upright position (after blood pressure 
measurements and before any assessments collected in the supine position). Blood samples for 
laboratory evaluation should be collected after the completion of blood pressure assessments. 
Spot urine collections for albumin and creatinine should be obtained in the morning.  
For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the Medical 
Monitor; results may be collected and should be included in the clinical database. 


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Table 6: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Uric acid 
Albumin 
Total protein 
Calcium 
Glucose 
Bicarbonate 
Creatinine and eGFR 
Chloride 
Creatinine clearance (screening only) 
 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT 
 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Protein 
Leukocyte esterase 
Glucose 
Microscopy (if clinically indicated) 
Coagulation  
Prothrombin time 
International normalized ratio 
Partial thromboplastin time  
 
Fasting Lipid Panel and Glycemic Assessments (see Section 6.5.5.1) 
Lipid panel, including 
HDL-C, non-HDL-C, LDL-C, apolipoprotein A1, 
triglycerides, total cholesterol  
Insulin 
Fasting plasma glucose 
HbA1c 
Immunogenicity (see Section 6.5.5.2) 
ADA 
 
Pregnancy Testing/FSH Screening (see Section 6.5.5.3) 
β-human chorionic gonadotropin (females of 
child-bearing potential only) 
Follicle-stimulating hormone (postmenopausal 
women only) 
Abbreviations: ADA=anti-drug antibodies; ALP=alkaline phosphatase; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; 
FSH=follicle-stimulating hormone; GGT=gamma glutamyl transferase; HbA1c=hemoglobin A1c; HDL-C=high-
density lipoprotein; LDL-C=low-density lipoprotein; RBCs=red blood cells. 


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6.5.5.1. 
Fasting Lipid Panel and Glycemic Assessments 
Blood samples for fasting plasma glucose, insulin, lipid panel (including total cholesterol, high-
density lipoprotein [HDL-C], non-HDL-C, low-density lipoprotein, apolipoprotein A1, and 
triglycerides), and HbA1c will be collected at the time points listed in the Schedule of 
Assessments (Table 1). Patients are required to fast for ≥10 hours before sample collection for 
fasting glucose, insulin, lipid panel, and HbA1c. Samples should be collected at approximately 
the same time of day (±2 hours). 
6.5.5.2. 
Immunogenicity 
Blood samples will be collected to evaluate anti-drug antibodies (ADA). Blood samples for ADA 
testing must be collected before study drug administration (on days when study drug is to be 
dosed) or at a time point corresponding to the time of study drug dosing (on other days) as 
specified in the Schedule of Assessments (Table 1). A blood sample to evaluate ADA will be 
collected at the ET visit, if applicable. Blood samples for ADA will be analyzed at a regulated 
bioanalytical laboratory. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 
6.5.5.3. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential. A serum pregnancy 
test will be performed at screening, and urine pregnancy tests will be performed thereafter per 
the Schedule of Assessments and any time pregnancy is suspected. More frequent pregnancy 
testing may be performed where required per local requirements. The results of the pregnancy 
test must be known before study drug administration. Patients who are pregnant at screening are 
not eligible for study participation. Any woman with a positive urine pregnancy test, 
subsequently confirmed by a positive serum pregnancy test, during the study will be 
discontinued from study drug but will continue to be followed for safety. Patients who become 
pregnant while on study will be followed at least until the pregnancy outcome is known (see 
Section 6.5.6.7 for follow-up instructions). 
A blood sample will be drawn at screening to measure the levels of follicle stimulating hormone 
in order to confirm postmenopausal status in all women suspected to be postmenopausal (see 
Section 5.11.1 for definition of postmenopausal state). 
6.5.5.4. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 5.2.4. Following the occurrence of elevated liver 
transaminases or other LFT abnormalities per central laboratory, all assessments in Table 7 will 
be performed 1 time, as well as hematology, serum chemistry, LFT, and coagulation assessments 
from Table 6, and other assessments or evaluations per Investigator discretion, as appropriate.  
Monitoring, including criteria for dose modification or withholding the study drug, is described 
in Section 5.2.4.  


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Table 7: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
HBsAg, HBc antibody IgM  
Parvovirus B19 DNA - quantitative 
HAV antibody IgM 
HHV-6 DNA viral load - quantitative 
HCV antibody 
Anti-nuclear antibodies 
HCV RNA PCR – quantitative 
Anti-smooth muscle antibodies 
HEV antibody IgM 
Anti-LKM1 antibody 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
Anti-mitochondrial antibodies 
Herpes Zoster Virus IgM, IgG 
Anti-SLA 
Epstein-Barr Virus antibodies, IgM and IgG 
Ferritin 
Cytomegalovirus antibodies, IgM, IgG 
Ceruloplasmin 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant medications, 
including over the counter medications and herbal remedies 
Alcohol consumption and drugs of 
abuse  
Other potentially hepatotoxic agents including any work-
related exposures 
Recent travels to areas where 
hepatitis A or E is endemic 
Abbreviations: CT=computed tomography; DNA=deoxyribonucleic acid; HAV=hepatitis A virus; HBc=hepatitis B 
core; HBsAg=hepatitis B virus surface antigen; HCV=hepatitis C virus; HEV=hepatitis E virus; HHV-6=human 
herpesvirus 6; IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; LKM1=liver/kidney 
microsome-1 antibody MRI=magnetic resonance imagery; PCR=polymerase chain reaction; RNA=ribonucleic acid; 
SLA=soluble liver antigen 
Note: 
• 
All laboratory assessments will be measured in a central laboratory. The full panel of assessments should only 
be performed once; individual assessments may be repeated, as needed. 
6.5.6. 
Adverse Events 
6.5.6.1. 
Definitions 
Adverse Event 
According to the ICH E2A guideline Definitions and Standards for Expedited Reporting, and 
21 Code of Federal Regulations 312.32, IND Safety Reporting, an AE is any untoward medical 
occurrence in a patient or clinical investigational subject administered a medicinal product and 
which does not necessarily have a causal relationship with this treatment. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 


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• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred. It does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias, convulsions, or the development of drug 
dependency or abuse). 
Adverse Events of Clinical Interest 
The following are considered to be AEs of clinical interest: 
• ALT or AST >3×ULN 
• Severe or serious ISRs; ISRs that are associated with a recall phenomenon (reaction 
at the site of a prior injection with subsequent injections), or those that lead to 
temporary dose interruption or permanent discontinuation of zilebesiran. 
An ISR is defined as a local reaction at or near the site of injection. “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as 
may occur with swelling or hematoma). A systemic reaction which includes the 
injection site, eg, generalized urticaria, other distinct entities or conditions like 
lymphadenopathy that may be near the injection site is not considered an ISR. 
For information on recording and reporting of AEs of clinical interest, see Section 6.5.6.2 and 
Section 6.5.6.3, respectively. 
Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living (ie, bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden); OR life-threatening consequences; urgent intervention indicated; 
OR death related to an adverse event. 


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Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity. Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence. When changes in the severity of an 
AE occur more frequently than once a day, the maximum severity for the experience that day 
should be noted. If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
Adverse event severity and seriousness are assessed independently. ‘Severity’ characterizes the 
intensity of an AE. ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for 
defining regulatory reporting obligations (see definition for SAE). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?” A “yes” response indicates that the event is considered as related to 
the study drug. 
The relationship of each AE to the protocol-specified background antihypertensive medication 
should also be assessed by the Investigator. 
6.5.6.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient should be asked about medically relevant changes in the patient’s health since the 
last visit. The patient should also be asked if the patient has been hospitalized, had any accidents, 
used any new medications, or changed concomitant medication routines (both prescription and 
over-the-counter). In addition to patient observations, AEs will be documented from any 
clinically relevant laboratory findings, physical examination findings, ECG changes, or other 
findings that are relevant to patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study treatment during the Run-in period 
regardless of their relationship to the study treatment through the end of study. Study treatment is 
defined as protocol-specified background antihypertensive medication or study drug (zilebesiran 
or placebo). Non-serious AEs will be followed until the end of study. Events occurring after 
signing of the ICF and before the Run-in period will be captured as medical history (see 
Section 6.1), while AEs that occur after study treatment, and baseline events that worsen after 
study treatment, must be recorded as AEs. 
The Investigator is responsible for recording SAEs that are observed or reported by the patient 
after the time when the informed consent is signed regardless of their relationship to study 
treatment through the end of study. SAEs will be followed until satisfactory resolution, until 
baseline level is reached, or until the SAE is considered by the Investigator to be chronic or the 
patient is stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be related. Each AE must be described in 


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detail: onset time and date, description of event, severity, relationship to study treatment, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) in the eCRF and, as applicable, the SAE form. 
For AEs that are considered AEs of clinical interest (Section 6.5.6.1), the supplemental AEs of 
Clinical Interest eCRF should be completed. Additional clinical and laboratory information may 
be collected. Refer to eCRF completion guidelines for details on reporting events in the 
supplemental AEs of Clinical Interest eCRF. 
For all ISRs, the Investigator, or delegate, should submit an Injection Site Reaction Signs or 
Symptoms eCRF, recording additional information regarding each injection site reaction that is 
entered on the AE eCRF (eg, symptom[s], injection site location, follow-up actions taken). 
6.5.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AEs of clinical interest (Section 6.5.6.1), the Sponsor or its designee 
should be notified within 24 hours using the appropriate eCRF. 
6.5.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee 
An assessment of the seriousness of each AE will be made by the Investigator. Any AE and 
laboratory abnormality that meets the SAE criteria in Section 6.5.6.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event. All SAEs must be reported regardless of the relationship to study treatment. 
The initial report should include at least the following information: 
• Patient’s study number 
• Description and date of onset of the event 
• Criterion for serious 
• Preliminary assignment of relationship to study treatment, and 
• Investigator/site information 
To report the SAE, complete the eCRF and, as applicable, the SAE form. Within 24 hours of 
receipt of follow-up information, the Investigator must update the eCRF and, as applicable, the 
SAE form.  
Appropriate remedial measures should be taken by the Investigator using the Investigator’s best 
medical judgment to treat the SAE. These measures and the patient’s response to these measures 
should be recorded. All SAEs, regardless of relationship to study treatment, will be followed by 
the Investigator until satisfactory resolution or the Investigator deems the SAE to be chronic or 
stable. Clinical, laboratory, and diagnostic measures should be employed by the Investigator as 
needed to adequately determine the etiology of the event. 
6.5.6.5. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative will report certain study events in an expedited manner to the 
Food and Drug Administration, the European Medicines Agency’s EudraVigilance electronic 


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system according to Directive 2001/20/EC, and to all country Regulatory Authorities where the 
study is being conducted, according to local applicable regulations. 
6.5.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
Suspected unexpected serious adverse reactions will be reported to the IRB/IEC per their 
institutional policy by the Investigator or Sponsor (or Sponsor designee) according to country 
requirements. Copies of each report and documentation of IRB/IEC notification and 
acknowledgement of receipt will be kept in the Investigator’s study file. 
6.5.6.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through safety follow-up (see Section 3.1), 
the Investigator must report the pregnancy to the Sponsor or designee within 24 hours of being 
notified of the pregnancy. Details of the pregnancy will be recorded on the pregnancy reporting 
form. The patient should receive any necessary counseling regarding the risks of continuing the 
pregnancy, the possible effects on the fetus, and be counseled to not breastfeed for 90 days after 
the last dose of study drug. 
The pregnancy should be followed by the Investigator until completion. At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy. If the outcome of the 
pregnancy results in a postpartum complication, spontaneous abortion, stillbirth, neonatal death, 
or congenital anomaly, then the Investigator should follow the procedures for reporting an SAE 
as outlined in Section 6.5.6.4. 
6.5.6.8. 
Reporting of Overdose and Other Special Situations  
An overdose is defined as any dose of study drug administered to the participant or taken by the 
participant that is >2× the assigned dose during a single administration and/or ≥2 doses within ½ 
the intended dosing interval. 
The Sponsor does not recommend specific treatment for an overdose.  
In an event of an overdose or other special situations (eg, medication error, abuse, misuse, or 
CPC associated with an AE), the Investigator should: 
• Contact the Medical Monitor and Sponsor within 24 hours using the contact 
information in the Pharmacy Manual 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities 
• Document the amount of study drug given  
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or 
a concomitant medication will be considered AEs/SAEs.  
Full details of reporting instructions for overdose and other special situations will be outlined in 
the Pharmacy Manual. 


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6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
Alnylam’s RNAi therapeutics platform permits the highly specific targeting of investigational 
therapies based on genetic sequence. It is possible that variations in the target genetic sequence 
will result in variations in drug effect. More generally, genetic variations may account for the 
well-described heterogeneous manifestations of disease in patients with hypertension, as well as 
their responses to treatment. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and patient consent, 
samples will be collected as part of this study to permit exploratory investigations and the 
application of novel approaches to bioanalyses that may further elucidate the outcomes of this 
study, or potentially advance understanding of the safety, mechanism of action, and/or efficacy 
of zilebesiran. 
Biological specimens will be collected at the intervals indicated in the Schedule of Assessments 
(Table 1). These specimens will be analyzed at a central laboratory. Potential exploratory 
investigations may include DNA, RNA, or biochemical metabolite assessments as they relate to 
disease progression, efficacy, or safety. 
The biospecimen repository will also include residual material from routine samples (safety 
laboratory samples, PK samples, etc) that are obtained during the study. 
These specimens will be securely stored in a central biorepository for up to 10 years following 
the completion of this clinical study (ie, last patient last visit), or as per local regulations. After 
10 years have elapsed, samples will be destroyed. 
Details regarding the collection, processing, storage, and shipping of the samples will be 
provided in the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
When biobanking is permitted by local regulation, study participants will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 
7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock and study unblinding for 
the analysis of the primary endpoints and secondary endpoints measured at Month 3. The plan 
will detail the implementation of the statistical analyses in accordance with the principal features 
stated in the protocol. 
7.1. 
Determination of Sample Size 
Approximately 630 patients will be randomized to receive either zilebesiran or placebo with 
sample sizes in each of the patient cohorts with protocol-specified background antihypertensive 
medication as follows:  
• Olmesartan cohort: 300 patients  
• Amlodipine cohort: 210 patients 


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• Indapamide cohort: 120 patients 
Assuming a standard deviation of 16 mmHg in change from baseline in 24-hour mean SBP 
assessed by ABPM and 15% dropout rate from baseline to Month 3, with 2-sided significance 
level of 0.05 for each of the comparisons (zilebesiran versus placebo as add-on to olmesartan; 
zilebesiran versus placebo as add-on to amlodipine; zilebesiran versus placebo as add-on to 
indapamide), these sample sizes will provide at least 80% power to detect the following 
difference between zilebesiran versus placebo: 
• 5 mmHg as add-on to olmesartan  
• 6 mmHg as add-on to amlodipine 
• 8 mmHg as add-on to indapamide  
The power is assessed by simulation based on the Mixed Model with Repeated Measurements 
(MMRM), with change from baseline in 24-hour mean SBP assessed by ABPM at Month 3 as 
response variable and treatment, time, treatment-by-time as fixed factors and corresponding 
baseline value as a covariate. 
7.2. 
Statistical Methodology 
All analyses will be performed within each of the 3 protocol-specified background 
antihypertensive medication cohorts. The statistical and analytical plans presented below are 
brief summaries of planned analyses. More complete plans will be detailed in the SAP. Changes 
to the methods described in the final SAP will be described and justified as needed in the clinical 
study report. For information on study endpoints, see Section 2. 
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS): All randomized patients who received any amount of study 
drug. All by-treatment analyses based on the FAS will be grouped according to the 
randomized treatment arm.  
• Safety Analysis Set: All patients who received any amount of study drug. All by-
treatment analyses based on the Safety Analysis Set will be grouped according to the 
treatment actually received. 
• PK Analysis Set: All patients who received at least 1 full dose of zilebesiran and 
have at least 1 nonmissing postdose PK assessment. 
• PD Analysis Set: All patients who received at least 1 full dose of study drug. All by-
treatment analyses based on the PD Analysis Set will be grouped according to the 
treatment actually received. 
• All Zilebesiran Treated Set: All patients who received any amount of zilebesiran, 
including patients who took zilebesiran during the 6-month DB period and patients 
who initially took placebo and then switched to zilebesiran after the Month 6 visit. 


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For the analyses of the 6-month DB period, the analysis population used to evaluate efficacy will 
be the FAS. Safety data will be analyzed using the Safety Analysis Set. The PK and PD Analysis 
Sets will be used to conduct PK and PD analyses, respectively.  
The All Zilebesiran Treated Set will be used to summarize the efficacy and safety of zilebesiran 
throughout the 6-month DB period and the OLE period. 
7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints. Detailed methodology will be 
provided in the SAP. 
7.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other disease-specific baseline characteristics will be summarized. 
In general, baseline will be defined as the average of all assessments, including unscheduled 
assessments, between Run-in Visit 2 and prior to the first dose of study drug. Details of the 
definition will be specified in the SAP. 
7.2.5. 
Efficacy Analyses 
The primary endpoint is the change from baseline at Month 3 in 24-hour mean SBP, assessed by 
ABPM. The primary hypothesis of the add-on effect of zilebesiran compared to placebo in 
patients receiving each of 3 protocol-specified background antihypertensive medications 
(olmesartan, amlodipine or indapamide) will be tested separately at a 2-sided significance level 
of 0.05 using MMRM. The MMRM model will include treatment, time, treatment-by-time, and 
race (black or all other races) as fixed factors and baseline 24-hour mean SBP assessed by 
ABPM and screening eGFR as covariates.  
The key secondary endpoints are: 
• Change from baseline at Month 3 in office SBP 
• Time-adjusted change from baseline through Month 6 in 24-hour mean SBP, assessed 
by ABPM 
• Time-adjusted change from baseline through Month 6 in office SBP  
• Proportion of patients with 24-hour mean SBP assessed by ABPM <130 mmHg 
and/or reduction ≥20 mmHg without escape antihypertensive medication at Month 6  
To control the overall type I error, the primary and key secondary endpoints will be tested in 
hierarchical order. 
Details of the analysis method for primary, secondary, and exploratory endpoints will be 
described in the SAP. 


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7.2.6. 
Pharmacodynamic Analysis 
Pharmacodynamic analyses will include the evaluation of changes in levels of serum AGT and 
other exploratory biomarkers of the RAAS pathway. Descriptive statistics for observed levels 
and the relative change from baseline for all measured biomarkers will be presented for each of 
the postdose time points. 
Statistical comparison of the biomarker levels (absolute and/or change from baseline) across 
treatment groups may be explored. Details of the analysis will be specified in the SAP.  
Population PK/PD analysis may be conducted to evaluate the dose-response relationships for PD 
reduction after zilebesiran treatment. Additionally, the relationship between lowering of serum 
AGT and blood pressure may be explored within a modeling framework. If conducted, these 
analyses will be described in a pharmacometrics analysis plan and results will be presented in a 
separate report. 
7.2.7. 
Pharmacokinetic Analysis 
Plasma concentrations of zilebesiran and its metabolite AS(N-1)3′ zilebesiran will be 
summarized using descriptive statistics. 
Population PK analysis may be conducted on the PK data from this study. If conducted, the 
analysis methods will be described in a pharmacometrics analysis plan and results will be 
presented in a separate report. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs). Safety parameters also include vital signs, ECGs, clinical laboratory assessments and 
physical exams. Extent of exposure will be summarized.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. Results will be tabulated by Anatomical Therapeutic Chemical Classification System 
and Preferred Term (PT). 
Adverse events will be classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class and Preferred Term [by dose level and overall]. AEs, SAEs, 
related AEs, AEs leading to discontinuation of study drug, and AEs leading to death will be 
summarized by System Organ Class and PT for each treatment arm. By patient listings will be 
provided for deaths, SAEs, and AEs leading to discontinuation of study drug. Adverse events 
collected during the Run-in period will be summarized. 
Descriptive statistics will be provided for clinical laboratory parameters, ECG, and vital signs 
summarizing the observed values and changes from baseline over time. Laboratory shift tables 
from baseline grade (or category) to worst post-baseline grade (or category) will be presented for 
laboratory parameters that are graded or categorized. Abnormal physical exam findings will be 
presented in listings. 
Other safety summaries will be presented as appropriate. Further details will be specified in the 
SAP. 


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7.2.9. 
Immunogenicity Analyses 
The frequency and percentage of patients with confirmed positive ADA assay at any time during 
study as well as at each scheduled visit will be summarized. The titer results for patients with 
confirmed positive ADA results will be summarized. 
7.2.10. 
Interim Analysis 
The analysis of the primary endpoint and secondary endpoints measured at Month 3 will be 
conducted after all patients complete the Month 3 visit or withdraw from the study prior to the 
Month 3 visit. No formal interim analysis is planned before the analysis at Month 3. 
7.2.11. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the ICF (see Section 4.3.2). 
8. 
STUDY ADMINISTRATION 
8.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the current guidelines of Good Clinical Practice (GCP). Compliance with GCP 
provides public assurance that the rights, safety, and well-being of study patients are protected 
consistent with the principles that have their origin in the Declaration of Helsinki. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. Patients must also 
be notified that they are free to discontinue from the study at any time. The patient should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The Investigator will inform the patient if new information becomes available that may be 
relevant to the patient’s willingness to continue participation in the study. Communication of this 
information should be documented. 
The patient’s signed and dated informed consent (in paper or electronic format per local 
regulations and institutional standards) must be obtained before conducting any study tests or 
procedures that are not part of routine care. 
The Investigator must maintain the original, signed ICF. All patients will be given a copy of the 
signed and dated ICF. 
8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate. The Investigator must submit written approval before he or she 
can enroll any patient into the study. 


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The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements. In addition, the IRB or IEC must approve all patient 
materials for the study. The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
Initial IRB or IEC approval of the protocol, and all materials approved by the IRB or IEC for this 
study including the patient consent form and recruitment materials must be maintained by the 
Investigator and made available for inspection. 
The Investigator will submit reports of SAEs as outlined in Section 6.5.6. In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study. The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies, IRBs, or IECs in regard to inspections, other 
studies that impact this protocol or the qualifications of study personnel should be promptly 
reported to the Sponsor or its designee. 
The Investigator is also responsible for providing the IRB or IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the study drug. The Sponsor 
or designee will provide this information to the Investigator. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study. Amendments to the protocol must be submitted in writing to the Investigator’s IRB or IEC 
and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol, and patients must be re-consented to the most current version of the ICF. 
8.1.3. 
Serious Breach of Protocol 
Investigators must notify the Medical Monitor within 24 hours of becoming aware of a potential 
serious breach of the protocol. A serious breach is a breach that is likely to affect to a significant 
degree the safety and rights of a study participant or the reliability and robustness of the data 
generated in the clinical study. 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention 
All documentation (including personal data) relating to the study should be retained for 2 years 
after the last approval in an ICH territory or as required by local laws and regulations, whichever 
is longer. 
If it becomes necessary for the Sponsor, the Sponsor’s designee, applicable IRB/IEC, or 
applicable regulatory authorities to review or audit any documentation relating to the study, the 
Investigator must permit direct access to all source documents/data. Records will not be 
destroyed without informing the Sponsor in writing and giving the Sponsor the opportunity to 
store the records for a longer period of time at the Sponsor’s expense. 
The Investigator must ensure that the patients’ confidentiality will be maintained. On the eCRFs 
or other documents submitted to the Sponsor or designees, patients should not be identified by 
their names, but by the assigned patient number or code. If patient names are included on copies 
of documents to be submitted to the Sponsor or designees, the names will be obliterated, and the 


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assigned patient number added to the document, before sending to the Sponsor. Documents not 
for submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
The Investigator must treat all of the information related to the study and the compiled data as 
confidential, whose use is for the purpose of conducting the study. The Sponsor must approve 
any transfer of information not directly involved in the study. 
To comply with local and/or regional regulations, this clinical study may be registered, and study 
results may be posted on public registries, such as ClinicalTrials.gov. 
8.1.5. 
End of Study 
The end of study is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor, or designee, reserves the right to terminate the study or a clinical study site at any 
time. Conditions that may warrant this action may include, but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to patients participating 
in the study 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• The decision on the part of the Sponsor to suspend or discontinue treatment with the 
study drug 
Should the study be terminated, and/or the site closed for whatever reason, all documentation and 
study drug pertaining to the study must be returned to the Sponsor or its representative, and the 
Investigators, IRB/IEC and Regulatory Authorities will be promptly informed of the termination 
and the reason for the decision. The Investigator should promptly inform the patients and assure 
appropriate therapy and follow-up. 
8.2. 
Data Quality Control and Quality Assurance 
8.2.1. 
Data Handling 
Study data must be recorded on CRFs (paper and/or electronic) provided by the Sponsor or 
designee on behalf of the Sponsor. Case report forms must be completed only by persons 
designated by the Investigator. If eCRFs are used, study data must be entered by trained site 
personnel with access to a valid and secure eCRF system. All data entered into the eCRF must 
also be available in the source documents. Corrections on paper CRFs must be made so as to not 
obliterate the original data and must be initialed and dated by the person who made the 
correction. 
8.2.2. 
Study Monitoring 
The Monitor, as a representative of the Sponsor, has an obligation to closely follow the study 
conduct at the site. The Monitor will visit the Investigator and clinical study center periodically 


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and will maintain frequent telephone and written contact. The Monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the Investigator and staff. 
The Monitor will review source documents, systems and CRFs to ensure overall quality and 
completeness of the data and to confirm study procedures are complied with the requirements in 
the study protocol accurately. The Sponsor, or its designee, will be allowed to conduct site visits 
to the investigation facilities for the purpose of monitoring any aspect of the study. The 
Investigator agrees to allow the Monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and study source documents, site standard operating 
procedures and training records, and other records relative to study conduct. 
Where local regulations allow, the Monitor may request remote access to source documents and 
systems. Should this take place, it will be done in a manner that protects the confidentiality of the 
data. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core study processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements. A regulatory 
authority, an IEC or an IRB may visit the site to perform audits or inspections, including source 
data verification. The Investigator should contact the Sponsor and designee immediately if 
contacted by a regulatory agency, an IEC or an IRB about an inspection. 
8.3. 
Publication Policy 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting. A copy of any proposed publication 
(eg, manuscript, abstracts, oral/slide presentations, book chapters) based on this study, must be 
provided and confirmed received at the Sponsor at least 30 days before its submission. The 
Clinical Trial Agreement will detail the procedures for publications. 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors). 


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9. 
LIST OF REFERENCES 
Abraham HM, White CM,White WB. The comparative efficacy and safety of the angiotensin 
receptor blockers in the management of hypertension and other cardiovascular diseases. Drug 
Saf. 2015 Jan;38(1):33-54. 
Angell SY, De Cock KM,Frieden TR. A public health approach to global management of 
hypertension. Lancet. 2015 Feb 28;385(9970):825-7. 
Burnier M, Bakris G,Williams B. Redefining diuretics use in hypertension: why select a thiazide-
like diuretic? J Hypertens. 2019 Aug;37(8):1574-86. 
Corrao G, Parodi A, Nicotra F, Zambon A, Merlino L, Cesana G, et al. Better compliance to 
antihypertensive medications reduces cardiovascular risk. J Hypertens. 2011 Mar;29(3):610-8. 
Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. Prevention of 
cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as 
required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian 
Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre 
randomised controlled trial. Lancet. 2005 Sep 10-16;366(9489):895-906. 
Dzau VJ,Balatbat CA. Future of Hypertension. Hypertension. 2019 Sep;74(3):450-7. 
Forouzanfar MH, Liu P, Roth GA, Ng M, Biryukov S, Marczak L, et al. Global Burden of 
Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990-2015. JAMA. 
2017 Jan 10;317(2):165-82. 
Georgianos PI,Agarwal R. Revisiting RAAS blockade in CKD with newer potassium-binding 
drugs. Kidney Int. 2018 Feb;93(2):325-34. 
Jamerson K, Weber MA, Bakris GL, Dahlof B, Pitt B, Shi V, et al. Benazepril plus amlodipine 
or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008 Dec 
4;359(23):2417-28. 
Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al. Outcomes in 
hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or 
amlodipine: the VALUE randomised trial. Lancet. 2004 Jun 19;363(9426):2022-31. 
Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK,He J. Global burden of 
hypertension: analysis of worldwide data. Lancet. 2005 Jan 15-21;365(9455):217-23. 
Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al. Angiotensin II for the 
Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-30. 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12. 
Makani H, Bangalore S, Desouza KA, Shah A,Messerli FH. Efficacy and safety of dual blockade 
of the renin-angiotensin system: meta-analysis of randomised trials. BMJ. 2013 Jan 28;346:f360. 
Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, et al. Single-drug 
therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The 
Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J 
Med. 1993 Apr 1;328(13):914-21. 


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McClellan M, Brown N, Califf RM,Warner JJ. Call to Action: Urgent Challenges in 
Cardiovascular Disease: A Presidential Advisory From the American Heart Association. 
Circulation. 2019 Feb 26;139(9):e44-e54. 
McMurray JJ, Krum H, Abraham WT, Dickstein K, Kober LV, Desai AS, et al. Aliskiren, 
Enalapril, or Aliskiren and Enalapril in Heart Failure. N Engl J Med. 2016 Apr 21;374(16):1521-
32. 
Mullick AE, Yeh ST, Graham MJ, Engelhardt JA, Prakash TP,Crooke RM. Blood Pressure 
Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of 
Hypertension and Kidney Injury. Hypertension. 2017 Sep;70(3):566-76. 
Muntner P, Hardy ST, Fine LJ, Jaeger BC, Wozniak G, Levitan EB, et al. Trends in Blood 
Pressure Control Among US Adults With Hypertension, 1999-2000 to 2017-2018. JAMA. 2020 
Sep 22;324(12):1190-200. 
NCD Risk Factor Collaboration. Worldwide trends in blood pressure from 1975 to 2015: a 
pooled analysis of 1479 population-based measurement studies with 19.1 million participants. 
Lancet. 2017 Jan 7;389(10064):37-55. 
Ojima M, Igata H, Tanaka M, Sakamoto H, Kuroita T, Kohara Y, et al. In vitro antagonistic 
properties of a new angiotensin type 1 receptor blocker, azilsartan, in receptor binding and 
function studies. J Pharmacol Exp Ther. 2011 Mar;336(3):801-8. 
Olsen MH, Angell SY, Asma S, Boutouyrie P, Burger D, Chirinos JA, et al. A call to action and 
a lifecourse strategy to address the global burden of raised blood pressure on current and future 
generations: the Lancet Commission on hypertension. Lancet. 2016 Nov 26;388(10060):2665-
712. 
Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. 
Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012 Dec 
6;367(23):2204-13. 
Peacock E,Krousel-Wood M. Adherence to Antihypertensive Therapy. Med Clin North Am. 
2017 Jan;101(1):229-45. 
Romero CA, Orias M,Weir MR. Novel RAAS agonists and antagonists: clinical applications and 
controversies. Nat Rev Endocrinol. 2015 Apr;11(4):242-52. 
Schulz M, Krueger K, Schuessel K, Friedland K, Laufs U, Mueller WE, et al. Medication 
adherence and persistence according to different antihypertensive drug classes: A retrospective 
cohort study of 255,500 patients. Int J Cardiol. 2016 Oct 1;220:668-76. 
Services UDoHaH. The Surgeon General's Call to Action to Control Hypertension. 2020 October 
2020:1-50. 
Uijl E, Mirabito Colafella KM, Sun Y, Ren L, van Veghel R, Garrelds IM, et al. Strong and 
Sustained Antihypertensive Effect of Small Interfering RNA Targeting Liver Angiotensinogen. 
Hypertension. 2019 Jun;73(6):1249-57. 
van der Laan DM, Elders PJM, Boons C, Beckeringh JJ, Nijpels G,Hugtenburg JG. Factors 
associated with antihypertensive medication non-adherence: a systematic review. J Hum 
Hypertens. 2017 Nov;31(11):687-94. 


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von Bergmann K, Laeis P, Puchler K, Sudhop T, Schwocho LR,Gonzalez L. Olmesartan 
medoxomil: influence of age, renal and hepatic function on the pharmacokinetics of olmesartan 
medoxomil. J Hypertens Suppl. 2001 Jun;19(1):S33-40. 
Weir MR, Bakris GL, Bushinsky DA, Mayo MR, Garza D, Stasiv Y, et al. Patiromer in patients 
with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015 Jan 
15;372(3):211-21. 
Whelton PK, Carey RM, Aronow WS, Casey DE, Jr., Collins KJ, Dennison Himmelfarb C, et al. 
2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the 
Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report 
of the American College of Cardiology/American Heart Association Task Force on Clinical 
Practice Guidelines. Hypertension. 2018 Jun;71(6):e13-e115. 
White WB, Weber MA, Sica D, Bakris GL, Perez A, Cao C, et al. Effects of the angiotensin 
receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic 
blood pressure in patients with stages 1 and 2 hypertension. Hypertension. 2011 Mar;57(3):413-
20. 
Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH 
Guidelines for the management of arterial hypertension: The Task Force for the management of 
arterial hypertension of the European Society of Cardiology and the European Society of 
Hypertension: The Task Force for the management of arterial hypertension of the European 
Society of Cardiology and the European Society of Hypertension. J Hypertens. 2018 
Oct;36(10):1953-2041. 
 


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10. 
APPENDICES 
10.1. 
Formula for Estimated Glomerular Filtration Rate Calculation 
Estimated glomerular filtration rate (eGFR; in mL/min/1.73m2) will be calculated from serum 
creatinine (SCr) based on the Modification of Diet in Renal Disease formula. 
Modification of Diet in Renal Disease Formula [Levey 2009] 
• Conventional units 
− eGFR (mL/min/1.73m2) = 175 × (SCr [mg/dL])-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
• SI units 
− eGFR (mL/min/1.73m2) = 175 × (SCr [μmol/L]/88.4)-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
10.2. 
Measurement of Blood Pressure 
All blood pressure measurements (office, ABPM, and HBPM) must be taken using the 
standardized equipment provided by the Sponsor, according to the methods described in the 
relevant user manuals.  
The appropriately sized cuff for each modality must be used for all assessments. The arm’s 
circumference at midpoint (halfway between the acromion and olecranon) should be determined 
at screening with a metric tape measure and used to select the appropriately sized blood pressure 
cuff/bladder for each instrument as described in the ABPM Investigator Manual and the HBPM 
and OBPM Investigator Manual. Unless significant weight loss or gain occurs between visits, the 
patient should use the same cuff/bladder size throughout the study. 
At the first Screening visit only, office blood pressure will be measured in both arms to select the 
appropriate arm to use for office blood pressure and HBPM measurements. Unless a concomitant 
condition favors the use of a specific arm, the arm with the higher office SBP should be used for 
all subsequent office blood pressure and HBPM readings. The ABPM should be measured using 
the patient’s nondominant arm. If the patient is ambidextrous, the same arm used for office blood 
pressure and HBPM readings should be used. 
ABPM 
The appropriately sized cuff should be placed on the correct arm following the instructions in the 
ABPM Investigator Manual. Consecutive (daily) use of over-the-counter NSAIDs (other than 
aspirin ≤100 mg per day) and use of cannabis or THC-containing substances should be avoided 
for at least 2 days prior to ABPM measurements. ABPM should be started prior to the morning 
dose of antihypertensive medication. All ABPM collections must be in the outpatient/ambulatory 
state. ABPM recordings that are associated with dosing visits must be obtained in advance of the 
visit (within 7 days before the corresponding dosing visit) and the results reviewed prior to 
dosing. 
During the 24-hour monitoring period, patients must avoid strenuous exercise but should 
otherwise maintain their usual level of physical activity. The ABPM is programmed to take 


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readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the 
night (10 pm to 5:59 am). While awake, the patient should hold their arm still by their side while 
the device is inflating for a reading. Patients must record the timing of going to sleep, waking up, 
and any oral medications taken during the ABPM, and these responses must be entered into the 
eCRF. 
After the monitoring period is complete, upload the ABPM data to receive a report with validity 
assessment. An ABPM will be considered valid if (1) the number of successful daytime readings 
is ≥33, (2) the number of successful nighttime readings is ≥11, and (3) no more than 3 hours are 
not represented (ie, 3 sections of 60 minutes where 0 valid readings were obtained). If the ABPM 
recording is invalid (either during the Run-in Period or after the second randomization), the 
patient will be provided 1 opportunity to repeat the study within 7 days from the end time of the 
invalid ABPM. During the Run-in period, if a valid ABPM recording that meets the inclusion 
criterion exceeds the 7-day window prior to randomization, a single additional ABPM 
assessment is permitted, with no option for retesting in case of an invalid reading. Eligibility is 
assessed by the most recent ABPM result obtained. If a valid ABPM recording that meets the 
inclusion criterion is not obtained within the 7 days prior to randomization, the patient is a run-in 
failure. 
Office Blood Pressure 
Office blood pressure must be measured using the automated blood pressure device provided by 
the Sponsor and the arm selected during screening. 
Office blood pressure should be measured early in the visit prior to the morning dose of 
antihypertensive medications, before phlebotomy or other potentially stressful assessments. To 
minimize confounding by circadian changes, study visits should be scheduled for a consistent 
timeframe of the day. The use of inhaled short-acting beta agonists should be avoided within 6 
hours prior to measuring blood pressure and/or heart rate. The use of phosphodiesterase type 5 
inhibitors (eg, sildenafil, tadalafil, vardenafil, avanafil) should be avoided within 48 hours prior 
to measuring blood pressure. Consecutive (daily) use of over-the-counter NSAIDs (other than 
aspirin ≤100 mg per day) use of cannabis or THC-containing substances should be avoided for at 
least 2 days prior to office blood pressure measurements. 
Before measuring blood pressure, confirm that there has been no exercise or use of caffeine or 
nicotine- or tobacco-containing products (including but not limited to snuff, chewing tobacco, 
cigars, cigarettes, pipes, nicotine patches, or e-cigarettes) within the last 30 minutes. If necessary, 
delay blood pressure assessment to meet these requirements. Because a full bladder can impact 
blood pressure measurements, ask the patient to use the bathroom before the assessment. 
All office blood pressure assessments will include both seated and standing measurements.  
Seated Office Blood Pressure Measurement: For seated measurements, the patient should be in a 
comfortable resting position in a chair with their back supported and their feet flat on the floor. 
• Place the appropriately sized cuff on the correct arm with no clothing between the 
patient’s arm and the cuff and with the midpoint of the bladder length positioned over 
the brachial artery (located by palpation). The arm should be supported on an armrest 
or table with mid-cuff at heart level and the palm facing the ceiling. 


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• Follow the HBPM and OBPM Investigator Manual to initiate the automated blood 
pressure device’s seated measurement protocol. This program includes a 5-minute 
period of rest, followed by 4 sequential blood pressure measurements at 1-minute 
intervals. The seated blood pressure for the visit will be defined by the average of the 
last 3 individual measurements. 
• During the device’s seated measurement protocol, the patient should remain at rest 
without distraction (avoid mobile phones). The following script may be used: “The 
blood pressure device works best when you are at rest and without any distraction, so 
the staff will avoid interacting with you during this assessment. This assessment will 
include a 5-minute period of rest, followed by about 5 minutes of the device inflating 
to measure your blood pressure”. 
Standing Office Blood Pressure Measurement: A standing measurement should be obtained 
immediately after collection of the seated measurements. 
• Being careful to maintain the cuff’s position, ask the patient to stand with the cuffed 
arm bent slightly and the hand of the cuffed arm supported at heart level.  
• Measure standing blood pressure 1 to 3 minutes after standing using the automated 
blood pressure device’s single measurement protocol.  
• After the standing measurement, ask the patient if they experienced dizziness or light-
headedness when standing and record their response. 
If a patient is unable to report to the site for an office blood pressure assessment, a substitute 
“remote visit blood pressure measurement” may be obtained remotely by a visiting nurse or other 
appropriately trained personnel. If a home visit is not possible, a “remote visit blood pressure 
measurement” should instead be obtained using the patient’s HBPM instrument under direct 
supervision (phone call or teleconferencing) by appropriately trained study staff, following the 
instructions detailed in the HBPM and OBPM Investigator Manual. Results and the remote 
method used will be recorded. 
HBPM 
Patients should measure HBPM in the morning, prior to breakfast/caffeine or taking morning 
oral medications. HBPM is not required on days when ABPM is being assessed. The HBPM 
measurement should be obtained in a room without distractions, seated comfortably with the 
back supported and feet flat on the floor. The patient will initiate the automated blood pressure 
program on their HBPM device. This program includes a 5-minute period of rest, followed by 4 
sequential blood pressure measurements at 1-minute intervals. The seated blood pressure for the 
visit will be defined by the average of the last 3 individual measurements.  
To establish baseline, each patient should measure HBPM 3 times during the week prior to the 
second randomization.  
After Day 1, HBPM should be measured at least once per week and may be increased at the 
Investigator’s discretion if more frequent measurement is warranted. Patients may select the day 
of the week that is most convenient for their personal schedule.  


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CLINICAL STUDY PROTOCOL 
ALN-AGT01-003 
DATED 22 MARCH 2022 
 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled, Multicenter 
Study to Evaluate the Efficacy and Safety of Zilebesiran Used as 
Add-on Therapy in Patients With Hypertension Not Adequately 
Controlled by a Standard of Care Antihypertensive Medication  
Short Title: 
Zilebesiran as Add-on Therapy in Patients With Hypertension Not 
Adequately Controlled by a Standard of Care Antihypertensive 
Medication (KARDIA-2)  
Study Drug: 
Zilebesiran (ALN-AGT01)  
EudraCT Number: 
2021-003776-13 
IND Number: 
143503 
Protocol Date: 
Original protocol, 25 August 2021 
Amendment 1, 22 March 2022 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Telephone: +1-617-551-8200 
Sponsor Contact:  
 
  
The concepts and information contained in this document or generated during the study are considered 
proprietary and may not be disclosed in whole or in part without expressed written authorization of 
Alnylam Pharmaceuticals, Inc. 
 
PPD
PPD


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SPONSOR PROTOCOL APPROVAL 
 
I have read this protocol and I approve the design of this study. 
 
 
 
___________________________________________  
 
 
Alnylam Pharmaceuticals, Inc. 
 
 
___________________________________________  
Date 
PPD
PPD


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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-AGT01-003 protocol and agree to conduct the study in accordance with the 
protocol and all applicable regulations. I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol.  
 
___________________________________________  
Printed Name of Investigator 
 
___________________________________________  
Signature of Investigator 
 
___________________________________________  
Date 






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Study Design 
This is a Phase 2 randomized, double-blind (DB), placebo-controlled, multicenter study to 
evaluate the efficacy, safety, and pharmacodynamics (PD) of zilebesiran administered 
subcutaneously (SC) as an add-on therapy in patients with hypertension despite treatment with a 
standard of care antihypertensive medication. A schematic of the study design is provided in 
Figure 1. 
Patients who complete the Screening period and meet all inclusion/exclusion criteria for 
enrollment will be randomized to receive open-label therapy with olmesartan (40 mg orally once 
daily [or 20 mg orally once daily for patients with creatinine clearance ≤60 mL/min enrolled at 
sites outside of the United States (US), consistent with local labeling for olmesartan]), 
amlodipine (5 mg orally once daily), or indapamide (2.5 mg orally once daily) as their protocol-
specified background antihypertensive medication during a Run-in period of at least 4 weeks. 
Patients who meet all inclusion/exclusion criteria after the Run-in period will be randomized 1:1 
to receive 600 mg zilebesiran SC or placebo SC on Day 1 of a 6-month DB treatment period as 
add-on therapy to their protocol-specified background antihypertensive medication.  
Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive 
medications”) may be added to the patient’s protocol-specified background antihypertensive 
medication per Investigator judgement for elevated blood pressure. 
After the 6-month DB period, protocol-specified background antihypertensive medications will 
be discontinued, and patients may be eligible to participate in a separate zilebesiran open-label 
extension (OLE) study. If an individual patient reaches Month 6 prior to availability of the 
separate OLE study, they may receive open-label zilebesiran at 600 mg SC once every 6 months 
for up to 12 additional months until the separate OLE study is open and then transition.  
Number of Planned Patients 
The planned enrollment for this study is approximately 800 patients to be randomized into the 
Run-in period and approximately 630 patients (300 patients in the olmesartan arm, 210 patients 
in the amlodipine arm, and 120 patients in the indapamide arm) to be randomized in the DB 
period. 
Diagnosis and Main Eligibility Criteria 
This study will include adults (18 to 75 years, inclusive) with untreated hypertension or on stable 
therapy with up to 2 antihypertensive medications. Patients should have a 24-hour mean systolic 
blood pressure (SBP) >130 mmHg and ≤160 mmHg by ambulatory blood pressure monitoring 
(ABPM) after at least 4 weeks of run-in on protocol-specified background antihypertensive 
medication. Patients with secondary hypertension or orthostatic hypotension will be excluded. 
Study Drug, Dose, and Mode of Administration 
Zilebesiran is an SC administered N-acetylgalactosamine (GalNAc)-conjugated small interfering 
RNA (siRNA) targeting liver-expressed messenger RNA (mRNA) for angiotensinogen (AGT). 
Patients randomized to receive zilebesiran will be administered 600 mg SC once during the 6-
month DB treatment period; all patients will receive 600 mg SC once every 6 months during the 
OLE period. 


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Reference Treatment, Dose, and Mode of Administration 
Placebo (phosphate-buffered saline for SC administration) will be administered at the same 
dosing interval and volume as the study drug during the 6-month DB period. 
Protocol-specified Background Antihypertensive Medication, Dose, and Mode of 
Administration 
Patients will be randomized to 1 of the following protocol-specified background antihypertensive 
medications to be administered orally once daily during the Run-in and 6-month DB periods: 
• Olmesartan: 40 mg (or 20 mg for patients with creatinine clearance ≤60 mL/min 
enrolled at sites outside of the US, consistent with local labeling). At the 
Investigator’s discretion, patients who are randomized to receive 40 mg olmesartan 
once daily may initiate treatment at 20 mg once daily and then uptitrate to the full 
dose of 40 mg once daily after 1 to 2 weeks. 
• Amlodipine: 5 mg  
• Indapamide: 2.5 mg  
Duration of Treatment and Study Participation 
The duration of treatment with zilebesiran is up to 18 months. The estimated total time on study 
for patients who rollover to the separate OLE study is up to approximately 20 months, including 
up to 2 months of the Screening and Run-in periods, and up to 18 months of treatment. For all 
patients who discontinue study drug or do not roll over to the separate OLE study, the Safety 
Follow-up period is up to 12 months. 
Statistical Methods 
The planned enrollment for this study is approximately 800 patients to be randomized into the 
Run-in period and approximately 630 patients (300 patients in the olmesartan arm, 210 patients 
in the amlodipine arm, and 120 patients in the indapamide arm) to be randomized in the DB 
period. Randomization on Day 1 will be stratified by race (black or all other races), baseline 
blood pressure (24-hour mean SBP < or ≥145 mmHg), and screening estimated glomerular 
filtration rate (<60 or ≥60 mL/min/1.73m2). 
For the primary endpoint, assuming a standard deviation of 16 mmHg in change from baseline in 
24-hour mean SBP assessed by ABPM and 15% dropout rate from baseline to Month 3, with 2-
sided significance level of 0.05 for each of the comparisons (zilebesiran versus placebo as add-
on to olmesartan; zilebesiran versus placebo as add-on to amlodipine; zilebesiran versus placebo 
as add-on to indapamide), these sample sizes will provide at least 80% power to detect the 
following difference between zilebesiran versus placebo: 
• 5 mmHg as add-on to olmesartan  
• 6 mmHg as add-on to amlodipine 
• 8 mmHg as add-on to indapamide 
The populations (analysis sets) are defined as follows: 


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• Full Analysis Set (FAS): All randomized patients who received any amount of study 
drug. All by-treatment analyses based on the FAS will be grouped according to the 
randomized treatment arm.  
• Safety Analysis Set: All patients who received any amount of study drug. All by-
treatment analyses based on the Safety Analysis Set will be grouped according to the 
treatment actually received. 
• Pharmacokinetic (PK) Analysis Set: All patients who received at least 1 full dose of 
zilebesiran and have at least 1 nonmissing postdose PK assessment. 
• PD Analysis Set: All patients who received at least 1 full dose of study drug. All by-
treatment analyses based on the PD Analysis Set will be grouped according to the 
treatment actually received. 
• All Zilebesiran Treated Set: All patients who received any amount of zilebesiran, 
including patients who took zilebesiran during the 6-month DB period and patients 
who initially took placebo and then switched to zilebesiran after the Month 6 visit. 
For the analyses of the 6-month DB period, the analysis population used to evaluate efficacy will 
be the FAS. Safety data will be analyzed using the Safety Analysis Set. The PK and PD Analysis 
Sets will be used to conduct PK and PD analyses, respectively.  
The All Zilebesiran Treated Set will be used to summarize the efficacy and safety of zilebesiran 
throughout the 6-month DB period and the OLE period. 
To control the overall type I error, the primary and key secondary endpoints will be tested in 
hierarchical order. 
 
 


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Figure 1: 
Study Design 
 
Abbreviations: aHTN=antihypertensive medication; BL=baseline; DB=double-blind; M=month; OLE=open-label 
extension; PBO=placebo; PO=per os (oral); qd=once daily; q6M=once every 6 months; R=randomization; 
SC=subcutaneous. 
Note: Patients may be eligible to participate in a separate zilebesiran OLE study upon completion of the Month 6 
predose assessments. If an individual patient reaches Month 6 prior to availability of the separate OLE study, they 
may receive open-label zilebesiran once every 6 months in the OLE period for up to 12 additional months until the 
OLE study is open and then transition. Once the separate OLE study is open for enrollment, eligible patients may 
rollover into the separate OLE study at Month 6, 12, or 18 (first visit after the separate OLE study is open). 
Patients who were previously taking antihypertensives at screening should discontinue these medications at Run-in 
Visit 1. 
 










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A1C; HBPM=home blood pressure monitoring; ICF=informed consent form; LFT=liver function test; M=month; No.=number; OLE=open-label extension; 
PD=pharmacodynamics; PK=pharmacokinetics; Q6M=once every 6 months; RAAS=renin-angiotensin-aldosterone system; SAE=serious adverse event; 
W=week. 
Notes:  
• 
When scheduled at the same time points and where feasible, the assessments of vital signs and blood sample collections should be performed before 
physical examinations and 12-lead ECGs. 
• 
Run-in Visit 2 should occur at least 4 weeks after Run-in Visit 1. 
• 
Patients may be eligible to participate in a separate zilebesiran OLE study upon completion of the Month 6 predose assessments. If an individual patient 
reaches Month 6 prior to availability of the separate OLE study, they may receive open-label zilebesiran beginning at the Month 6 visit and continue for 
up to 12 additional months until the separate OLE study is open and then transition at Month 12 or 18 (first visit after the separate OLE study is open). 
Patients who rollover at Month 6 should complete all assessments scheduled for the Month 6 visit except for study drug administration. Patients who 
rollover at Month 12 should complete the EOT visit instead of the assessments scheduled at Month 12. 
• 
Patients who discontinue study drug at any time during the study or do not enroll in the separate OLE study will be asked to perform Safety Follow-up 
visits once every 6 months after the last dose of study drug until serum AGT levels return to ≥50% of their individual mean baseline level (if known) or 
12 months, whichever comes earlier. During this Follow-up period, HBPM monitoring may continue at the discretion of the Investigator. The ADA 
sample should only be collected at the first Follow-up visit during the Follow-up period. 
• 
Patients who discontinue study drug prior to the Month 6 visit will also be asked to complete the remainder of scheduled study visits and assessments 
(except for study drug administration) through Month 6. If a patient discontinues study drug after the Month 6 visit, EOT/ET assessments should be 
performed.  
 
Footnotes: 
a All assessments, except for postdose PK sample collection (Table 2), are to be performed prior to administration of protocol-specified background 
antihypertensive medications (including Run-In Visit 1) and study drug (as applicable).  
b When applicable, pregnancy test results must be known prior to dosing with study drug at dosing visits.  
c Laboratory assessments at Day 1 do not need to be repeated, per Investigator discretion, if they were collected within 7 days before Day 1 at Run-in Visit 2.  
d Office blood pressure must be measured before the patient takes oral antihypertensive medications or study drug (as applicable).  
e ABPM recordings associated with study drug dosing visits should be obtained within 7 days before the visit and results reviewed before dosing.  
f HBPM should be measured at least 3 times during the week prior to the second randomization to establish baseline. After Day 1, HBPM should be measured at 
least once per week in the morning upon waking and may be increased at the Investigator’s discretion if more frequent measurement is warranted. HBPM is not 
required at times when ABPM is being assessed. In the Safety Follow-up period, the frequency of HBPM assessments can be reduced after the first Safety 
Follow-up visit per Investigator judgement. 
g Neurological evaluation will also be performed as part of the full physical examination. 
h ABPM should only be performed as part of ET assessments if the patient discontinues the study prior to Month 12 and has not had an ABPM within the last 3 
months. ABPM should not be performed at Month 18. 


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Table 2: 
PK Time Points 
Study Day 
Sampling Time 
(hh:mm) 
Plasma PK Sample 
Day 1  
Predose (any time before dosing) 
X 
04:00 (±30 min) 
X 
Day 169±7 
Predose (any time before dosing) 
X 
04:00 (±30 min) 
X 
Abbreviations: hh:mm=hour:minute; min=minutes; PK=pharmacokinetics. 
Notes:  
• 
The hour (±range) indicates sample collection timing relative to dosing. Precise PK sample times (hour and 
minute) are recorded. Refer to Section 6.4 for additional information on PK assessments. 
 


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TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................16 
LIST OF TABLES .........................................................................................................................20 
LIST OF FIGURES .......................................................................................................................20 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................21 
1. 
INTRODUCTION ......................................................................................................23 
1.1. 
Study Rationale ...........................................................................................................23 
1.2. 
Background .................................................................................................................23 
1.3. 
Benefit-Risk Assessment ............................................................................................25 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................26 
3. 
INVESTIGATIONAL PLAN .....................................................................................27 
3.1. 
Summary of Study Design ..........................................................................................27 
3.2. 
Scientific Rationale for Study Design ........................................................................29 
3.3. 
Justification for Dose ..................................................................................................31 
3.4. 
Method of Assigning Patients to Treatment Groups ..................................................31 
3.5. 
Blinding ......................................................................................................................32 
3.5.1. 
Emergency Unblinding ...............................................................................................32 
3.6. 
Data Monitoring Committee .......................................................................................32 
3.7. 
Clinical Event Adjudication Committees ...................................................................32 
3.8. 
Definition of End of Study for an Individual Patient .................................................33 
4. 
SELECTION AND REMOVAL OF PATIENTS ......................................................33 
4.1. 
Inclusion Criteria ........................................................................................................33 
4.2. 
Exclusion Criteria .......................................................................................................34 
4.3. 
Removal from Study Drug or Assessment .................................................................36 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................36 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................37 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................37 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data or Objection 
to Process Patient’s Personal Data ..............................................................................38 


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4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................38 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................39 
4.3.3. 
Lost to Follow-Up.......................................................................................................39 
4.3.4. 
Replacement of Study Patients ...................................................................................39 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................39 
5.1. 
Treatments Administered ............................................................................................39 
5.2. 
Study Drug ..................................................................................................................40 
5.2.1. 
Description ..................................................................................................................40 
5.2.2. 
Dose and Administration ............................................................................................40 
5.2.3. 
Dose Modifications .....................................................................................................40 
5.2.4. 
LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing...........41 
5.2.5. 
Neurological Criteria for Withholding, Monitoring, and Stopping Study 
Drug Dosing ................................................................................................................42 
5.3. 
Protocol-specified Background Antihypertensive Medications .................................42 
5.4. 
Preparation, Handling, and Storage ............................................................................43 
5.5. 
Packaging and Labeling ..............................................................................................43 
5.6. 
Accountability .............................................................................................................44 
5.7. 
Clinical Product Complaints .......................................................................................44 
5.7.1. 
Definition ....................................................................................................................44 
5.7.2. 
Reporting ....................................................................................................................44 
5.8. 
Monitoring for Potential Clinical Events ....................................................................44 
5.8.1. 
Monitoring and Approach for Potential Hypotension ................................................44 
5.8.2. 
Monitoring and Approach for Clinically Significant Blood Pressure 
Elevation .....................................................................................................................45 
5.8.3. 
Monitoring and Approach for Potential Renal Dysfunction .......................................47 
5.8.4. 
Monitoring and Approach for Potential Hyperkalemia ..............................................48 
5.9. 
Concomitant Medications and Procedures .................................................................49 
5.9.1. 
Prohibited Concomitant Medication ...........................................................................49 
5.10. 
Treatment Compliance ................................................................................................50 
5.11. 
Other Requirements ....................................................................................................50 
5.11.1. 
Contraception ..............................................................................................................50 
5.11.2. 
Alcohol Restrictions ...................................................................................................51 
5.11.3. 
Tobacco and Nicotine Restrictions .............................................................................51 


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5.11.4. 
Dietary Recommendations ..........................................................................................52 
5.11.5. 
Exercise .......................................................................................................................52 
6. 
STUDY ASSESSMENTS ..........................................................................................52 
6.1. 
Screening Assessments ...............................................................................................52 
6.1.1. 
Retesting .....................................................................................................................53 
6.1.2. 
Rescreening .................................................................................................................53 
6.2. 
Efficacy Assessments .................................................................................................53 
6.2.1. 
ABPM .........................................................................................................................53 
6.2.2. 
Office Blood Pressure .................................................................................................54 
6.2.3. 
HBPM .........................................................................................................................54 
6.3. 
Pharmacodynamic Assessments .................................................................................54 
6.4. 
Pharmacokinetic Assessments ....................................................................................54 
6.5. 
Safety Assessments .....................................................................................................55 
6.5.1. 
Vital Signs ..................................................................................................................55 
6.5.2. 
Weight, Height, and Morphometrics ..........................................................................55 
6.5.3. 
Physical Examination .................................................................................................56 
6.5.4. 
Electrocardiogram .......................................................................................................56 
6.5.5. 
Clinical Laboratory Assessments ...............................................................................56 
6.5.5.1. 
Fasting Lipid Panel and Glycemic Assessments ........................................................59 
6.5.5.2. 
Immunogenicity ..........................................................................................................59 
6.5.5.3. 
Pregnancy Testing ......................................................................................................59 
6.5.5.4. 
Additional Liver Function Assessments .....................................................................59 
6.5.6. 
Adverse Events ...........................................................................................................60 
6.5.6.1. 
Definitions ..................................................................................................................60 
6.5.6.2. 
Eliciting and Recording Adverse Events ....................................................................62 
6.5.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................63 
6.5.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........63 
6.5.6.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................63 
6.5.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................64 
6.5.6.7. 
Pregnancy Reporting ..................................................................................................64 
6.5.6.8. 
Reporting of Overdose and Other Special Situations .................................................64 
6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................65 


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7. 
STATISTICS ..............................................................................................................65 
7.1. 
Determination of Sample Size ....................................................................................65 
7.2. 
Statistical Methodology ..............................................................................................66 
7.2.1. 
Populations to be Analyzed ........................................................................................66 
7.2.2. 
Examination of Subgroups .........................................................................................67 
7.2.3. 
Handling of Missing Data ...........................................................................................67 
7.2.4. 
Baseline Evaluations ...................................................................................................67 
7.2.5. 
Efficacy Analyses .......................................................................................................67 
7.2.6. 
Pharmacodynamic Analysis........................................................................................68 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................68 
7.2.8. 
Safety Analyses ..........................................................................................................68 
7.2.9. 
Immunogenicity Analyses ..........................................................................................69 
7.2.10. 
Interim Analysis ..........................................................................................................69 
7.2.11. 
Optional Additional Research .....................................................................................69 
8. 
STUDY ADMINISTRATION ...................................................................................69 
8.1. 
Ethical and Regulatory Considerations ......................................................................69 
8.1.1. 
Informed Consent .......................................................................................................69 
8.1.2. 
Ethical Review ............................................................................................................69 
8.1.3. 
Serious Breach of Protocol .........................................................................................70 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................70 
8.1.5. 
End of Study ...............................................................................................................71 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................71 
8.2. 
Data Quality Control and Quality Assurance .............................................................71 
8.2.1. 
Data Handling .............................................................................................................71 
8.2.2. 
Study Monitoring ........................................................................................................72 
8.2.3. 
Audits and Inspections ................................................................................................72 
8.3. 
Publication Policy .......................................................................................................72 
9. 
LIST OF REFERENCES ............................................................................................73 
10. 
APPENDICES ............................................................................................................76 
10.1. 
Formula for Estimated Glomerular Filtration Rate Calculation .................................76 
10.2. 
Measurement of Blood Pressure .................................................................................76 
 


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LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................10 
Table 2: 
PK Time Points ...........................................................................................................15 
Table 3: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................42 
Table 4: 
Recommended Interventions for Potentially Clinically Significant Blood 
Pressure Elevation ......................................................................................................46 
Table 5: 
Recommended Interventions for Hyperkalemia .........................................................48 
Table 6: 
Clinical Laboratory Assessments ...............................................................................58 
Table 7: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............60 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ABPM 
Ambulatory blood pressure monitoring 
ACE 
Angiotensin converting enzyme 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AGT 
Angiotensinogen 
ALT 
Alanine aminotransferase 
AngI/II 
Angiotensin I/II 
ARB 
Angiotensin II-receptor blocker 
AST 
Aspartate aminotransferase 
CCB 
Calcium channel blocker 
CPC 
Clinical product complaint 
DB 
Double-blind 
DBP 
Diastolic blood pressure 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOT 
End of treatment 
ET 
Early termination 
FAS 
Full analysis set 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HBPM 
Home blood pressure monitoring 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein 
HOMA 
Homeostatic model assessment 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 


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IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR 
Injection site reactions 
LFT 
Liver function test 
MAO 
Monoamine oxidase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model with repeated measurements 
mRNA 
Messenger ribonucleic acid 
NSAID 
Nonsteroidal anti-inflammatory drug 
OLE 
Open-label extension 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PT 
Preferred term 
RAAS 
Renin-angiotensin-aldosterone system 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
siRNA 
Small interfering RNA 
SGLT2 
Sodium-glucose co-transporter 2 
THC 
Delta-9-tetrahydrocannibinol 
ULN 
Upper limit of normal 
 


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1. 
INTRODUCTION 
Alnylam Pharmaceuticals, Inc. (the Sponsor) is developing zilebesiran (ALN-AGT01), a 
subcutaneously (SC) administered investigational agent comprised of a synthetic small 
interfering RNA (siRNA) covalently linked to a triantennary N-acetylgalactosamine (GalNAc) 
ligand, which is designed to suppress liver production of angiotensinogen (AGT) and thereby 
reduce blood pressure in individuals with hypertension. 
1.1. 
Study Rationale 
Study ALN-AGT01-003 (KARDIA-2) is a randomized, double-blind, placebo-controlled, 
multicenter study designed to evaluate the efficacy, safety, and pharmacodynamics (PD) of 
zilebesiran administered SC as an add-on therapy in patients with hypertension despite treatment 
with a standard of care antihypertensive medication. Patients will be randomized to run-in on 1 
of 3 protocol-specified antihypertensive medications open-label for at least 4 weeks (olmesartan, 
amlodipine, or indapamide). At the end of the Run-in period, patients with uncontrolled blood 
pressure will be randomized 1:1 to receive zilebesiran or placebo as add-on therapy to the 
protocol-specified background antihypertensive medication for 6 months during the double-blind 
(DB) period. After completion of the 6-month DB period, patients may be eligible to participate 
in a separate zilebesiran open-label extension (OLE) study. If an individual patient reaches 
Month 6 prior to availability of the OLE study, they may discontinue their protocol-specified 
background antihypertensive medication and receive open-label zilebesiran (600 mg once every 
6 months) for up to 12 additional months until the OLE study is open and then transition. 
The primary objective of the study is to evaluate the efficacy of zilebesiran as an add-on therapy 
for the treatment of hypertension by evaluating the change in 24-hour mean systolic blood 
pressure (SBP), assessed by ambulatory blood pressure monitoring (ABPM), from baseline to 
Month 3, relative to placebo. Secondary and exploratory objectives of the study include 
evaluating the add-on efficacy of zilebesiran on other measures of blood pressure response 
(including longer treatment durations, eg, 6 months) and evaluating the PD effect of zilebesiran, 
including reduction in circulating AGT concentration. 
The full rationale for the study and design is presented in Section 3.2. 
1.2. 
Background 
Hypertension affects 30% to 45% of adults and is the strongest modifiable risk factor for 
cardiovascular disease, primarily strokes and myocardial infarction.[Olsen 2016; Williams 2018] 
The worldwide disease burden is profound, with a global prevalence of over 1 billion,[Kearney 
2005; NCD Risk Factor Collaboration 2017] and approximately 9 million deaths attributed to 
hypertension annually.[Angell 2015] 
Currently available pharmacologic therapies achieve target blood pressure in only a minority of 
patients, due in large part to physician inertia and patient nonadherence to daily oral 
medication.[Whelton 2018; Williams 2018] Low adherence to oral antihypertensives is 
associated with poor cardiovascular outcomes and is prevalent at all stages of disease.[Corrao 
2011; Peacock and Krousel-Wood 2017; Schulz 2016; van der Laan 2017] Thus, despite the 
availability of multiple efficacious agents, current rates of control are low, and the global burden 


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of death and disability-adjusted life-years attributed to elevated blood pressure remains 
high.[Forouzanfar 2017; Muntner 2020] Development of new approaches to treat hypertension 
and to overcome the limitations of current therapies is a key unmet need.[Dzau and Balatbat 
2019; McClellan 2019; Services 2020] 
The Sponsor is developing zilebesiran, a novel synthetic RNA interference (RNAi) therapeutic, 
for SC administration for the treatment of hypertension. RNAi is a naturally occurring cellular 
mechanism for regulation of gene expression, mediated through the binding of siRNA to its 
complementary messenger RNA (mRNA) sequence, leading to mRNA cleavage and subsequent 
suppression of the synthesis and levels of the target protein. Zilebesiran contains an siRNA 
targeting AGT mRNA, conjugated to a GalNAc-containing ligand to facilitate delivery to the 
liver. Based on the mechanism of RNAi, zilebesiran is specifically designed to reduce the hepatic 
synthesis of AGT protein, the first substrate in the renin-angiotensin-aldosterone system (RAAS) 
and the sole precursor of vasoactive angiotensin peptides.[Khanna 2017; Romero 2015] Because 
hepatocytes are the predominant source of circulating AGT, zilebesiran has been developed to 
reduce blood pressure by decreasing circulating AGT levels and the downstream effects of 
angiotensin II (AngII). 
Zilebesiran is being studied in the ongoing Phase 1 Study ALN-AGT01-001 (hereafter referred 
to as Study 001) in patients with hypertension as single ascending doses of 10 to 800 mg (Part 
A), as a single dose of 800 mg under low-salt or high-salt conditions (Part B), as 2 doses of 
800 mg administered every 3 months in obese patients (Part D), and as a single dose of 800 mg 
co-administered for 2 weeks with 300 mg irbesartan (Part E). Preliminary data are available from 
Parts A, B, and E. Dose-dependent and durable reductions in circulating AGT were observed 
after single SC doses of zilebesiran, accompanied by clinically significant reductions in SBP and 
diastolic blood pressure (DBP). Sustained reductions in serum AGT were observed for up to 6 
months following a single dose of zilebesiran.  
Most adverse events (AEs) have been mild or moderate in severity, and there have been no 
severe or serious adverse events (SAEs) related to study drug. There have been no clinically 
significant elevations in serum creatinine or serum potassium. No patient has required 
intervention for low blood pressure. No clinically significant alanine aminotransferase (ALT) 
elevations have been observed in patients who received zilebesiran doses as high as 800 mg. 
Injection site reactions (ISRs) were reported in a minority of patients and were all mild and 
transient events that resolved without intervention. 
Because most patients with hypertension eventually progress to require treatment with more than 
1 antihypertensive class,[Williams 2018] it is anticipated that zilebesiran may be used together 
with other standard of care antihypertensive medication. This Phase 2 study will further quantify 
the antihypertensive effects of zilebesiran as add-on therapy in patients with hypertension not 
adequately controlled by a standard of care antihypertensive medication. The consistent and 
durable PD effect of zilebesiran is expected to achieve the unique benefit of continuous 24-hour 
blood pressure lowering with infrequent SC dosing.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of zilebesiran is 
provided in the Investigator’s Brochure. 


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1.3. 
Benefit-Risk Assessment 
Clinical data available from Study 001 indicate that zilebesiran may offer the benefit of sustained 
blood pressure reduction to patients with hypertension with infrequent administration (ie, once 
every 3 months or once every 6 months). The mean SBP reduction observed after single 
zilebesiran doses of 100 mg or higher exceeds 10 mmHg, which is comparable to the effect of 
conventional antihypertensives.[Abraham 2015; Materson 1993] The blood pressure of patients 
will be closely monitored, and after Month 3, escape antihypertensive medications will be added 
as needed to control blood pressure. 
Given the mechanism of action and mode of administration of zilebesiran, potential theoretical 
risks include liver transaminase elevations and ISRs. Like any antihypertensive therapy, there is 
also a theoretical risk of hypotension with zilebesiran. Based upon the disease population, there 
is also a risk of blood pressure elevation. Because eligible patients have mild to moderate 
primary hypertension, the likelihood of disease progression during the course of the study is low. 
This study has exclusion criteria intended to minimize these risks, as well as frequent monitoring 
for laboratory and blood pressure abnormalities. Furthermore, the duration of the placebo period 
is limited, and escape antihypertensive medications are permitted to manage uncontrolled blood 
pressure following 3 months of add-on treatment with zilebesiran. Detailed guidance is provided 
to Investigators for potential liver transaminase elevations (Section 5.2.4), hypotension 
(Section 5.8.1), hypertension (Section 5.8.2), renal dysfunction (Section 5.8.3), and 
hyperkalemia (Section 5.8.4). An independent Data Monitoring Committee (DMC) will monitor 
and ensure the safety of study participants (see Section 3.6).  
Based on available data from Study 001, zilebesiran has an acceptable safety profile in patients 
with hypertension as a monotherapy or with the addition of conventional antihypertensives in 
patients who were inadequately controlled on zilebesiran alone. This experience supports that the 
theoretical risks of treatment are low and can be managed through the proposed monitoring and 
safety mitigations. In addition to study drug, each patient will receive a protocol-specified 
background antihypertensive medication (olmesartan, amlodipine, or indapamide). These agents 
are approved standard medications that will be dosed in accordance with local labeling. 
While zilebesiran is designed to inhibit the RAAS, its site of action (AGT) in the RAAS is 
unique, and its tissue specificity for the liver is hypothesized to improve its renal safety profile 
relative to conventional RAAS blockade,[Mullick 2017; Uijl 2019] both in the context of 
monotherapy and when used together with a conventional RAAS blocker such as olmesartan. In 
the latter setting, zilebesiran is hypothesized to add antihypertensive benefit when added to a 
conventional RAAS blocker without the increased incidence of RAAS inhibitor-associated renal 
adverse effects that have been observed in prior trials of conventional dual RAAS 
blockade.[Makani 2013] Patients with estimated glomerular filtration rate (eGFR) 
<45 mL/min/1.73m2 or urine albumin:creatinine ≥300mg/g will be exclusively assigned to the 
olmesartan cohort to ensure that patients with proteinuric chronic kidney disease or diabetes 
continue the RAAS inhibition standardly recommended for their renal indication throughout the 
study. 
This study’s monitoring plan is designed to meet the standards set by prior studies of 
conventional RAAS inhibitors,[McMurray 2016; Parving 2012]. The risk of renal safety events 
is further mitigated in this study by its eligibility criteria, which exclude patients who are at 






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Run-in Period 
Patients who complete the Screening period and meet all inclusion/exclusion criteria for 
enrollment will be randomized as described in Section 3.4 to receive open-label therapy with 
olmesartan (40 mg orally once daily [or 20 mg orally once daily for patients with creatinine 
clearance ≤60 mL/min enrolled at sites outside of the US, consistent with local labeling for 
olmesartan]), amlodipine (5 mg orally once daily), or indapamide (2.5 mg orally once daily) as 
their protocol-specified background antihypertensive medication during a Run-in period of at 
least 4 weeks. Prior antihypertensive medications (if taking) will be discontinued upon the start 
of this Run-in period (Run-in Visit 1). 
Patients who do not tolerate run-in treatment or who do not meet eligibility for randomization at 
Day 1 will be withdrawn from the study and returned to their prior medication regimen in 
coordination with their usual health providers.  
DB Period 
Patients who meet all inclusion/exclusion criteria will be randomized 1:1 to receive 600 mg 
zilebesiran SC or placebo SC on Day 1 of a 6-month DB period as add-on therapy to their 
protocol-specified background antihypertensive medication (olmesartan, amlodipine, or 
indapamide). Randomization on Day 1 will be stratified by race (black or all other races), 
baseline blood pressure (24-hour mean SBP < or ≥145 mmHg), and screening eGFR (<60 or 
≥60 mL/min/1.73m2). 
Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive 
medications”) may be added to the patient’s protocol-specified background antihypertensive 
medication per Investigator judgement for elevated blood pressure as described in Table 4.  
OLE Period 
After the 6-month DB period, protocol-specified background antihypertensive medications will 
be discontinued, and patients may be eligible to participate in a separate zilebesiran OLE study. 
If an individual patient reaches Month 6 prior to availability of the separate OLE study, they may 
receive open-label zilebesiran at 600 mg SC once every 6 months for up to 12 additional months 
until the separate OLE study is open and then transition. Once the separate OLE study is open for 
enrollment, eligible patients may rollover into that OLE study at Month 6, 12, or 18 (first visit 
after the separate OLE study is open). 
During the OLE period of this study, Investigators will use escape antihypertensive medications 
as described in Table 4 to control blood pressure, guided by continued blood pressure 
monitoring. 
Safety Follow-up Period 
Patients who discontinue study drug or do not enroll in the separate zilebesiran OLE study will 
be asked to complete Safety Follow-up visits once every 6 months after their last dose of study 
drug until serum AGT levels return to ≥50% of their individual mean baseline level (if known) or 
12 months, whichever comes earlier. 
Patients who discontinue study drug prior to the Month 6 visit will also be asked to complete the 
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through Month 6. If a patient discontinues study drug after the Month 6 visit, end of treatment 
(EOT)/early termination (ET) assessments should be performed. 
An independent DMC will oversee the safety and overall conduct of this study, and an 
independent Clinical Event Adjudication Committee will review suspected renal events to 
adjudicate whether they meet criteria for acute kidney injury. 
The planned enrollment for this study is approximately 800 patients to be randomized into the 
Run-in period and approximately 630 patients (300 patients in the olmesartan arm, 210 patients 
in the amlodipine arm, and 120 patients in the indapamide arm) to be randomized in the DB 
period.  
The duration of treatment with zilebesiran is up to 18 months. The estimated total time on study 
for patients who rollover to the separate OLE study is up to approximately 20 months, including 
up to 2 months of the Screening and Run-in periods, and up to 18 months of treatment. For all 
patients who discontinue study drug or do not roll over to the separate OLE study, the Safety 
Follow-up period is up to 12 months. 
3.2. 
Scientific Rationale for Study Design 
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy and safety of zilebesiran administered SC as an add-on therapy in patients with 
hypertension despite treatment with a standard of care antihypertensive medication.  
The primary objective of the study is to evaluate the efficacy of zilebesiran as an add-on therapy 
for the treatment of hypertension by evaluating the change in 24-hour mean SBP, assessed by 
ABPM, from baseline to Month 3, relative to placebo. 
Patients with hypertension often require treatment with multiple antihypertensive drugs to reach 
target blood pressure,[Williams 2018] and it is anticipated that zilebesiran may be administered 
to individuals on a background of other antihypertensive medications. Therefore, this study 
evaluates the effects of zilebesiran relative to placebo in patients whose blood pressure is not 
adequately controlled despite treatment with 1 of the 3 major drug classes recommended for 
initial treatment of hypertension by all clinical guidelines: RAAS inhibitors (ie, angiotensin 
converting enzyme [ACE] inhibitors, angiotensin II-receptor blockers, or a direct renin 
inhibitor), diuretics, and calcium channel blockers (CCBs).[Whelton 2018; Williams 2018] 
Studying coadministration with olmesartan will assess if the synergistic antihypertensive effects 
recently observed in rodents treated with both an ARB and an AGT-targeting GalNAc-siRNA 
will translate into clinically significant blood pressure reduction in hypertensive patients given 
zilebesiran as an add-on to conventional RAAS inhibition.[Uijl 2019] In addition, it will examine 
the safety and tolerability of liver-specific AGT targeting during treatment with a conventional 
RAAS blocker (olmesartan). The newer-generation ARB olmesartan was selected because of its 
high potency relative to early-generation RAAS inhibitors,[Ojima 2011; White 2011] enabling a 
robust test for added efficacy when combined with zilebesiran. The maximum dose of 
olmesartan permitted per local labeling will be used to further increase the rigor of this efficacy 
evaluation. The thiazide-like diuretic indapamide was selected in accordance with recent 
guidelines that highlight the greater potency and durability of thiazide-like diuretics over other 
diuretics.[Burnier 2019] The long-acting dihydropyridine CCB amlodipine was selected given its 


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extensive use in clinical practice and randomized controlled trials.[Dahlof 2005; Jamerson 2008; 
Julius 2004]  
During the study, blood pressure will be monitored with both automated office blood pressure 
measurements and outpatient 24-hour ABPM (EMA/CHMP/29947/2013/Rev. 4; Guideline on 
Clinical Investigation of Medicinal Products in the Treatment of Hypertension, 2016). In 
addition to having greater precision, ABPM can assess short-term blood pressure variability and 
circadian patterns (including potential restoration of the normal nocturnal blood pressure dipping 
pattern that is lost in 24% to 35% of hypertensive patients). More frequent (at least once per 
week) measurements will be collected through a third method, oscillometric home blood 
pressure monitoring (HBPM), to assess long-term blood pressure variability and provide close 
safety monitoring for potential hypotension (or hypertension) while not in the clinic.  
As recommended by current guidance (International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use [ICH] Principles for Clinical Evaluation of 
New Antihypertensive Drugs, 2000 and EMA/CHMP/29947/2013/Rev. 4; Guideline on Clinical 
Investigation of Medicinal Products in the Treatment of Hypertension, 2016), the 6-month DB 
period is designed as a randomized, placebo-controlled, parallel-group study. To adhere to best 
ethical standards for the treatment of patients with hypertension, the use of oral antihypertensive 
medications per Investigator judgement to maintain blood pressure within target is permitted 
starting at Month 3 and will continue throughout the remainder of the study (see Table 4). The 
term “escape antihypertensive medication” is used to refer to any oral antihypertensive 
medication initiated to control blood pressure after Day 1. Separate from these treat-to-target 
modifications, any confirmed event of severe hypertension (office SBP ≥180 mmHg and/or 
office DBP ≥120 mmHg) will be appropriately treated with escape antihypertensive medication 
regardless of its timing relative to study drug administration. 
If a patient requires treatment with an oral escape antihypertensive medication before Month 6, a 
CCB and/or thiazide/thiazide-like diuretic (whichever agent is not already the protocol-specified 
background antihypertensive medication) should be added because there is extensive experience 
combining these classes with antihypertensive drugs that impact the RAAS.  
After the 6-month DB period, protocol-specified background antihypertensive medication 
(olmesartan, amlodipine, or indapamide) will be discontinued, and patients may be eligible to 
participate in a separate zilebesiran OLE study. If an individual patient reaches Month 6 prior to 
availability of the separate OLE study, they may receive open-label zilebesiran at 600 mg SC 
once every 6 months for up to 12 additional months until the separate OLE study is open and 
then transition. Because many patients will receive zilebesiran for the first time at Month 6, 
office blood pressure and serum chemistries will be monitored monthly from Month 6 to Month 
9.  
During the OLE period, Investigators may use escape antihypertensive medications of permitted 
classes as described in Table 4 to control blood pressure, guided by continued blood pressure 
monitoring and following current care guidelines.[Whelton 2018; Williams 2018] Olmesartan, 
amlodipine, and indapamide will be discontinued as protocol-specified background 
antihypertensive medication during the OLE period; however, patients may continue to receive 
amlodipine or indapamide as escape antihypertensive medication at the Investigator’s discretion. 
The use of conventional RAAS inhibitors (ARBs, ACE inhibitors, or direct renin inhibitors) as 
escape antihypertensive agents for high blood pressure should be avoided throughout the study. 


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While the tissue specificity of zilebesiran for the liver is hypothesized to improve tolerability 
relative to current oral antihypertensives,[Mullick 2017; Uijl 2019] the protocol’s monitoring 
plan is designed to meet the standards set by prior studies of conventional RAAS 
inhibitors[McMurray 2016; Parving 2012].  
3.3. 
Justification for Dose 
The dose of zilebesiran in this study (600 mg once every 6 months) was selected on the basis of 
data from the Phase 1 Study 001, in which single zilebesiran doses up to 800 mg were found to 
have an acceptable safety profile, and dose-dependent, clinically significant placebo-corrected 
reductions in mean SBP >10 mmHg by 24-hour ABPM were observed at doses as low as 
100 mg. An acceptable safety profile was also observed for a single zilebesiran dose of 800 mg 
under low-salt/high-salt conditions or co-administered for 2 weeks with 300 mg irbesartan once 
daily. The selected dose of 600 mg is predicted to result in a median serum AGT reduction of 
94.9% at trough (Month 6), translating to a median SBP reduction of 11.6 mmHg as 
monotherapy. 
The protocol-specified background antihypertensive medications are standard agents 
recommended in international and regional hypertension guidelines, and the selected regimens 
are standard doses used for their approved indication of hypertension.[Whelton 2018; Williams 
2018] Indapamide will be dosed at 2.5 mg orally once daily, and amlodipine will be dosed at 
5 mg orally once daily. The dose regimens for indapamide and amlodipine used in this study 
were selected on the basis of their common use in clinical care (when used both individually and 
combined with other classes of antihypertensives) and their expected efficacy, safety, and 
tolerability. Olmesartan will be dosed at the maximum dose allowed per local labeling: 40 mg 
orally once daily (or 20 mg orally once daily for patients with creatinine clearance ≤60 mL/min 
enrolled at sites outside of the US; Olmetec Product Information, September 2020).[von 
Bergmann 2001] 
3.4. 
Method of Assigning Patients to Treatment Groups 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number. After the patient signs the informed consent form (ICF) and before 
proceeding with screening procedures, the Investigator or designee should contact the Interactive 
Response Technology (IRT) to obtain a patient identification number. 
The Investigator or designee will contact the IRT to randomize the patient at Run-in Visit 1 and 
again at Day 1 after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria at each visit. 
At Run-in Visit 1, patients with screening eGFR <45 mL/min/1.73m2 or urine albumin:creatinine 
≥300mg/g will be assigned to receive olmesartan. To avoid over-enrollment, patients with eGFR 
<45 mL/min/1.73m2 or urine albumin:creatinine ≥300mg/g will be excluded from the study after 
100 such patients are randomized to study drug on Day 1.  
All other patients will be randomized 10:7:4 to run-in open-label on 1 of 3 protocol-specified 
background antihypertensive medications (olmesartan, amlodipine, or indapamide), with targeted 
sample sizes across cohorts as described in Section 7.1. If 1 cohort completes enrollment first, 
this cohort will be deactivated for future randomization. The remaining 2 cohorts will be 


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randomized using the original ratio. After the second cohort completes enrollment, all 
subsequent patients will be assigned to the last cohort.  
At Day 1, patients will be randomized 1:1 to receive zilebesiran or placebo as an add-on to their 
protocol-specified background antihypertensive medication using the IRT. Randomization at 
Day 1 will be stratified by race (black or all other races), baseline blood pressure (24-hour mean 
SBP < or ≥145 mmHg), and screening eGFR (<60 or ≥60 mL/min/1.73m2). 
3.5. 
Blinding 
The Sponsor, all site personnel and patients will be blinded to study drug treatment through 
Month 3 of the 6-month DB period. After the database lock to support the analysis of the primary 
endpoint and secondary endpoints measured at Month 3 is complete, Sponsor staff members who 
will not have direct roles or responsibilities in interacting with study sites will be unblinded to 
the analysis results according to the prespecified blinding plan. Site personnel, patients, and 
Sponsor staff members who have direct roles or responsibilities in interacting with study sites 
will remain blinded to treatment assignment until after the analysis of Month 6 data is complete. 
All Sponsor and site personnel and patients will be blinded to any clinical laboratory result that 
could potentially unblind them (eg, AGT levels) until unblinding. 
Zilebesiran and placebo will be packaged identically. Because zilebesiran may be slightly 
visually distinguishable from placebo, the vials will be masked in such a way as to hide the 
identity of the study drug contained within. For administration, syringes will be masked by a site 
pharmacist or delegate prior to withdrawing the study drug from vial. See the Pharmacy Manual 
for additional details. The study drug will be administered under the supervision of the 
Investigator (see Section 5.2.2). 
3.5.1. 
Emergency Unblinding 
If the treating physician determines that the clinical management of the patient requires 
knowledge of the study drug assignment, the Investigator may break the blind, as necessary, in 
IRT. If time permits, clinical study center personnel should contact the Medical Monitor before 
unblinding to discuss the need to unblind the patient but must do so within 1 working day after 
the unblinding event. Unblinding information should be limited to the fewest number of people 
on a need-to-know basis. A record of when the blind was broken, who was unblinded, who broke 
the blind, and why it was broken, will be maintained in the electronic trial master file (eTMF). 
Refer to the IRT instructions for details on unblinding. 
3.6. 
Data Monitoring Committee 
An independent DMC will oversee the safety and overall conduct of this study. The DMC will 
operate under the rules of a charter that will be reviewed and approved at the organizational 
meeting of the DMC. Details are provided in the DMC Charter. 
3.7. 
Clinical Event Adjudication Committees 
An independent Clinical Event Adjudication Committee of 2 or more nephrologists will review 
the suspected renal events blinded to treatment assignment to adjudicate whether they meet 


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diagnostic criteria for acute kidney injury and, if so, their potential staging and contributing 
factors. Details are provided in the Renal Event Adjudication Committee charter. 
3.8. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the end of the study if the patient: 
• has completed at least the Month 6 visit and enrolled in the separate OLE study, or 
• has completed the Safety Follow-up visits as described in Section 3.1 for patients who 
discontinue study drug or do not enroll in the separate OLE study. 
A definition of the end of the overall study is provided in Section 8.1.5. 
4. 
SELECTION AND REMOVAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age and Sex 
1. Age 18 to 75 years, inclusive 
2. Male or female 
Patient and Disease Characteristics 
3. Has hypertension as follows: 
a. Untreated hypertension (not taking antihypertensive medication), or  
b. Treated hypertension on stable therapy with up to 2 antihypertensive medications. 
Stable therapy is defined as having no change in antihypertensive medication or dose 
within 30 days prior to screening.  
4. Office SBP at Run-in Visit 1 as follows: 
a. ≥155 mmHg and ≤180 mmHg for patients with untreated hypertension  
b. ≥145 mmHg and ≤180 mmHg for patients on antihypertensive medications  
5. 24-hour mean SBP >130 mmHg and ≤160 mmHg by ABPM at Run-in Visit 2 after at 
least 4 weeks of run-in. 
6. ≥80% adherence to the protocol-specified background antihypertensive medication 
during the Run-in period as assessed by pill count performed at Run-in Visit 2. 
Informed Consent 
7. Patient is able to understand and is willing and able to comply with the study 
requirements and to provide written informed consent. 


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4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Secondary hypertension (including, but not limited to, due to known history of moderate-
to-severe obstructive sleep apnea not treated with continuous positive airway pressure 
therapy, renovascular hypertension, primary aldosteronism, pheochromocytoma, Cushing 
syndrome, or aortic coarctation) 
2. Orthostatic hypotension, defined as a fall of ≥20 mmHg SBP or ≥10 mmHg DBP within 
approximately 1 to 3 minutes of standing up from a seated position by office blood 
pressure that is symptomatic (such as dizziness, weakness, lightheadedness, or syncope) 
at screening or during the Run-in period 
Laboratory Assessments 
3. Has any of the following laboratory parameter assessments at screening or Run-in 
Visit 2:  
a. ALT or aspartate aminotransferase (AST) >2× upper limit of normal (ULN) 
b. Total bilirubin >1.5×ULN. Patients with elevated total bilirubin that is secondary to 
documented Gilbert’s syndrome are eligible if the total bilirubin is <2×ULN 
c. International normalized ratio (INR) >2.0 (patients on oral anticoagulant [eg, 
warfarin] with an INR <3.5 will be allowed) 
d. Potassium <lower limit of normal range or >5 mEq/L  
e. Sodium <lower limit of normal range 
f. eGFR <30 mL/min/1.73m2 (calculation will be based on the Modification of Diet in 
Renal Disease formula; refer to Section 10.1) 
Prior/Concomitant Therapy 
4. Received an investigational agent within the last 30 days or 5 half-lives of the 
investigational agent, whichever is longer, prior to Run-in Visit 1 or are in follow-up of 
another clinical study prior to study enrollment. Any agent that has received health 
agency authorization (including for emergency use) by local or regional regulatory 
authorities is not considered investigational. Patients who are in follow-up for a 
coronavirus disease 2019 vaccine (authorized or investigational) study are allowed. 
5. Currently taking, taken within 30 days prior to first randomization, or anticipated to 
receive during the study treatment period, any medication or herbal supplement known to 
significantly affect blood pressure (with the exception of medications for the treatment of 
essential hypertension). Patients who require medications such as monoamine oxidase 
(MAO) inhibitors that are associated with hypertensive crisis should be 
excluded.[Whelton 2018]  
6. Currently taking beta blockers and unable to discontinue prior to Run-in Visit 1 
7. Changes, such as initiation or discontinuation, of sodium-glucose co-transporter 2 
(SGLT2) inhibitor therapy within 30 days prior to screening. Patients on a stable dose of 
SGLT2 therapy for at least 30 days prior to screening with no anticipated changes during 
the study treatment period are permitted. 


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8. Prescription nonsteroidal anti-inflammatory drugs (NSAIDs) are not permitted. Patients 
receiving low-dose aspirin (defined as ≤100 mg per day) for at least 30 days prior to 
screening are permitted. Paracetamol/acetaminophen for analgesia will be allowed.  
9. Anticipates using organic nitrate preparations (eg, nitroglycerin, isosorbide mononitrate, 
isosorbide dinitrate, pentaerythritol) during the study treatment period 
10. Currently taking, taken within 6 months prior to first randomization, or anticipated to 
receive an RNAi therapeutic (approved or investigational) during the study 
Medical Conditions 
11. Current or prior history of intolerance to an ARB, ACE inhibitor (other than cough), 
direct renin inhibitor, CCB (including but not limited to significant peripheral edema), or 
thiazide/thiazide-like diuretic 
12. History of multiple drug allergies or history of allergic reaction to any component of or 
excipient in the study drug 
13. Type 1 diabetes mellitus, poorly controlled Type 2 diabetes mellitus (hemoglobin A1c 
[HbA1c] >9.0%), or laboratory evidence of diabetes during screening (HbA1c ≥7.0%) 
without known diagnosis of diabetes 
14. Has known active human immunodeficiency virus infection; or known current or chronic 
hepatitis C virus (HCV) or hepatitis B virus infection. 
15. History of clinically significant cardiovascular event (eg, stroke, transient ischemic 
attack, myocardial infarction, unstable angina, coronary artery bypass grafting or other 
cardiothoracic surgeries, percutaneous coronary intervention, hospitalization due to heart 
failure) within 6 months prior to first randomization 
16. Known history of angioedema 
17. Clinically significant valvular heart disease 
18. New York Heart Association II to IV heart failure 
19. Uncontrolled serious cardiac arrhythmia, defined as recurrent and highly symptomatic 
ventricular tachycardia/supraventricular tachycardia, or atrial fibrillation with rapid 
ventricular response in the 3 months prior to first randomization 
20. Has undergone liver transplantation or is anticipated to be on an active liver 
transplantation waiting list during the study treatment period 
21. History of renal transplantation  
22. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation; or, in the opinion of the 
Investigator, taking part in the study would jeopardize the safety of the patient 
23. Clinically significant illness, in the opinion of the Investigator, within 7 days prior to 
either randomization 
24. History of intolerance to SC injection(s) that could potentially hinder study drug 
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25. Has planned major surgery or general anesthesia during the study 
Contraception, Pregnancy, and Breastfeeding 
26. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.11.1  
27. Female patient is pregnant, planning a pregnancy, or breast-feeding 
Alcohol or Nicotine Use and Substance Abuse 
28. Unwilling or unable to limit alcohol consumption throughout the course of the study. 
Alcohol intake of >2 units/day is excluded during the study (unit: 1 glass of wine 
[approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of 
beer [approximately 284 mL]). 
29. History of alcohol or substance abuse (licit or illicit drugs) within the last 12 months 
before screening, in the opinion of the Investigator 
30. Unwilling or unable to abstain from use of nicotine or tobacco-containing products 
(including but not limited to snuff, chewing tobacco, cigars, cigarettes, pipes, nicotine 
patches, or e-cigarettes) within 30 minutes prior to office blood pressure measurements  
Other Restrictions 
31. Third shift, night shift, or 24-hour shift workers 
32. Arm circumference exceeds the maximum cuff size of any of the blood pressure 
instruments provided by the Sponsor 
4.3. 
Removal from Study Drug or Assessment 
Patients or their legal guardians are free to discontinue study drug and/or stop protocol 
procedural assessments, or participation in the study as a whole at any time and for any reason, 
without penalty to their continuing medical care. The Investigator or the Sponsor may 
discontinue study drug or stop a patient’s participation in the study at any time if this is 
considered to be in the patient’s best interest. Any discontinuation of treatment or the stopping of 
the patient’s participation in the study must be fully documented in the electronic case report 
form (eCRF) and should be followed up by the Investigator. 
Discontinuation of study drug or declining procedural assessments is described in Section 4.3.1, 
while the stopping of a patient’s participation in the study is detailed in Section 4.3.2. 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments 
Reasons for discontinuation of study drug include any of the following: 
• Significant protocol deviation; which includes required treatment with prohibited 
medication (as defined in Section 5.9.1) per Investigator discretion 
• AE 
• Non-adherence to treatment regimen 
• Pregnancy 


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• Lost to follow-up 
• Other reason (non-AE) 
• Or, study is terminated by the Sponsor 
If possible, the Investigator will confer with the Sponsor or Medical Monitor before 
discontinuing dosing in the patient. Patients who are pregnant will be discontinued from study 
drug dosing immediately (see Section 6.5.6.7 for reporting and follow-up of pregnancy). A 
positive urine pregnancy test should be confirmed by a serum pregnancy test prior to 
discontinuing the study drug. 
Patients who discontinue study drug and/or decline procedural assessments should not be 
automatically removed from study. In general, patients who discontinue study drug dosing for 
any reason will be encouraged to remain on the study to complete the remaining assessments so 
that their experience is captured in the final analyses.  
If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedule of Assessments (Table 1), including different options for follow-up and collection 
of data (eg, in person, by phone, by mail, through family or friends, or from options not 
involving patient contact, such as communication with other treating physicians or from review 
of medical records), including endpoints and AEs, and must document this decision in the 
patient’s medical records. 
If a patient has an AE, including SAEs, and/or laboratory abnormalities that in the judgment of 
the investigator, taking into account the patient’s overall status, requires interruption or 
discontinuation from treatment with study drug, the event should be followed as described in 
Section 6.5.6. When a patient discontinues study drug dosing, the primary reason must be 
recorded in the eCRF. Patients who discontinue study drug and remain on study may receive 
treatment consistent with local standard practice for their disease per Investigator judgement, as 
applicable. 
Patients who discontinue from study drug during the 6-month DB period (defined as the time the 
first dose of study drug is administered on Study Day 1 through completion of the Month 6 
assessments) will be encouraged to remain on the study and complete assessments (excluding 
pharmacokinetic [PK] assessments) through Month 6. They will also be asked to complete Safety 
Follow-up visits once every 6 months after the last dose of study drug per the safety follow-up 
schedule (see Table 1) until PD recovery or 12 months (whichever is earlier); see Section 3.1. 
Patients who discontinue study drug during the OLE period will be asked to return for their next 
scheduled visit to complete EOT/ET assessments and complete Safety Follow-up visits once 
every 6 months after the last dose of study drug per the safety follow-up schedule (see Table 1) 
until PD recovery or 12 months (whichever is earlier); see Section 3.1. 
4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study 
A patient or their legal guardian may stop participation in the study at any time. A patient or 
legal guardian considering stopping participation in the study before Month 6 should be 


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informed that the patient can discontinue study drug and/or decline procedural assessments and 
remain in the study to complete their study assessments, through the Month 6 visit and complete 
Safety Follow-up visits as described in Section 4.3.1, or alternatively may complete any minimal 
assessments for which the patient or legal guardian consents. If a patient or legal guardian still 
chooses to discontinue study drug and stop participation in all follow-up prior to the completion 
of the 6-month DB period, every effort should be made to conduct the Month 6 visit assessments 
at an earlier time (see Table 1). 
A patient considering stopping participation in the study during the OLE period should be 
informed that the patient can discontinue study drug and/or decline procedural assessments and 
remain in the study to complete the assessments scheduled for the EOT/ET visit and complete 
Safety Follow-up visits as described in Section 4.3.1, or alternatively may complete any minimal 
assessments for which the patient consents. 
If the patient does not wish to or is unable to continue further study participation, the Investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study. Data 
collected from the patient can continue to be used. 
Note, in countries where the collection and processing of the patient’s personal data is based on 
consent, if a patient withdraws consent to collect and process the patient’s personal data (see 
Section 4.3.2.2), as applicable, personal data up to the withdrawal of consent will be included in 
the analysis of the study. In addition, where permitted, publicly available data (such as 
appropriate national or regional vital status registry or other relevant databases) can be included 
after withdrawal of consent, where available and allowable by local law. 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data or Objection to 
Process Patient’s Personal Data 
Where allowed by local law, the patient may decide to withdraw consent to collect, store, and 
use biological samples and, as applicable, other personal data, informing the Investigator at any 
time in writing or in any other form that may be locally required. Also, where allowed by local 
law, the patient may object to the collection, storage, and use of the patient’s personal data, 
informing the Investigator at any time in writing or in any other form that may be locally 
required. In both cases, the Sponsor will continue to keep and use the patient’s study information 
(including any data resulting from the analysis of the patient’s biological samples until the time 
of withdrawal/objection) according to applicable law. The process for the storage and, as 
applicable, further use of remaining samples will be followed per local requirements. 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest. However, study integrity and interpretation are 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 
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4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation 
The primary reason that a patient’s study participation is stopped must be recorded in the 
appropriate section of the eCRF and all efforts will be made to complete and report the 
observations as thoroughly as possible. If a patient’s study participation is stopped due to an AE, 
including SAEs, the event should be followed as described in Section 6.5.6. 
4.3.3. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for 
scheduled visits and is unable to be contacted by the clinical study center. The following actions 
must be taken if a patient fails to return to the clinic for a required study visit: 
• The site must attempt to contact the patient or legal guardian and reschedule the 
missed visit as soon as possible and counsel the patient or legal guardian on the 
importance of maintaining the assigned visit schedule and ascertain if the patient or 
legal guardian wishes [for the patient] to continue in the study, and/or should continue 
in the study. 
• Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient or legal guardian (where possible, 3 
telephone calls and, if necessary, a certified letter to the patient’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the patient’s medical record. 
• Should the patient or legal guardian continue to be unreachable, the patient will be 
considered to have stopped participation in the study. 
• For patients who are lost to follow-up, the Investigator can search publicly available 
records (where permitted and allowed by local law) to ascertain survival status. This 
ensures that the outcome of the study is as comprehensive as possible. 
4.3.4. 
Replacement of Study Patients 
No additional patients may be enrolled to mitigate the impact of patients who discontinue the 
study drug or stop participation in the study after the second randomization at Day 1.  
5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug and protocol-specified background antihypertensive medication supplied by the 
Sponsor for this study must not be used for any purpose other than the present study and must 
not be administered to any person not enrolled in the study. Study drug and protocol-specified 
background antihypertensive medication that have been dispensed and returned unused must not 
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5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of zilebesiran SC 
and placebo SC is provided in the Pharmacy Manual. 
5.2.1. 
Description 
Zilebesiran will be supplied as a sterile solution for SC injection. See the Pharmacy Manual for 
further details of solution concentration and fill volume. 
The control drug for this study will be a placebo (phosphate-buffered saline for SC 
administration). Placebo will be provided by the Sponsor; it will be packaged identically to 
zilebesiran. 
5.2.2. 
Dose and Administration 
During the 6-month DB period, patients will be administered a single dose of 600 mg zilebesiran 
or placebo, at the same volume, as SC injection on Day 1. Patients who enter the OLE period 
will receive 600 mg zilebesiran SC at Month 6 after all predose assessments are conducted and 
once every 6 months during the OLE period. 
Study drug injections will be administered by qualified clinical study center staff under the 
supervision of the Investigator or designee. The injection site may be marked and mapped for 
later observation. Injections may be administered in the abdomen, thigh, or the side or back of 
the upper arms. If a local reaction around the injection site occurs, photographs may be obtained. 
Detailed instructions for study drug administration are found in the Pharmacy Manual. 
To maintain the blind, the syringes are to be masked by the site pharmacist or designee prior to 
study drug withdrawal from the vial. A full description of the blinding procedure is included in 
the Pharmacy Manual. 
If a patient does not receive a dose of study drug within the specified dosing window, the 
Investigator should contact the Medical Monitor. After such consultation, the dose may be 
administered up to 85 days before the next scheduled dose. Thereafter, the dose will be 
considered missed and not administered. 
If a patient misses a dose of study drug, the Investigator should discuss with the Medical Monitor 
whether the patient will be able to continue the study (see also Section 4.3). 
Additional details can be found in the Pharmacy Manual.  
The definition of study drug overdose, follow-up procedures, and reporting requirements are 
provided Section 6.5.6.8. 
5.2.3. 
Dose Modifications 
Dose modifications of study drug are not permitted. 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator, and the Medical Monitor should be contacted.  


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5.2.4. 
LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing  
1. Dosing decisions may be made based on the most recently available liver function test 
(LFT) results from a central laboratory (Table 6). 
2. For any ALT or AST elevation >3×ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 3. 
3. For any ALT or AST elevation >3×ULN: 
a. If local laboratory results are obtained, confirm with a central laboratory as soon as 
possible, ideally within 2 to 3 days, but no later than 7 days. 
b. If an alternative cause is found, provide appropriate care. 
c. If an alternative cause is not found, perform assessments per Table 6 and Table 7. 
4. For any ALT or AST elevation >3×ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2×ULN or INR ≥1.5, permanently 
discontinue dosing. 
5. For confirmed ALT or AST elevations >3×ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2×ULN or INR ≥1.5, see Table 3. 


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Table 3: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative Cause 
Identified 
Transaminase Level 
Action 
>3× to 5×ULN 
• 
May continue dosing 
• 
Evaluate the initial elevation in LFT per the following assessments: 
­ Table 7 (all assessments to be performed once) 
­ Hematology, serum chemistry, LFT, and coagulation per Table 6 
• 
Monitor at least every 2 weeks (LFT and coagulation per Table 6) 
• 
If elevation persists for ≥2 months, must discuss with the Medical 
Monitor before continuing dosing 
>5× to 8×ULN 
• 
Hold study drug dosing until recovery to ≤1.5×ULN or baseline; may 
resume dosing after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments 
­ Table 7 (all assessments to be performed once) 
­ Hematology, serum chemistry, LFT, and coagulation per Table 6 
• 
Monitor at least weekly: LFT and coagulation per Table 6 until ALT 
and/or AST is declining on 2 consecutive draws, then may decrease 
monitoring to biweekly 
• 
If ALT or AST rises to >5×ULN following resumption of dosing, 
permanently discontinue dosing 
>8×ULN 
Permanently discontinue study drug dosing after confirmation of the 
transaminase value at the central laboratory. 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; LFT=liver function test(s); 
ULN=upper limit of normal. 
Notes: In addition to these criteria, other assessments or evaluations may be performed per Investigator 
discretion, as appropriate. 
5.2.5. 
Neurological Criteria for Withholding, Monitoring, and Stopping Study Drug 
Dosing 
Clinically significant events that may be consistent with potential decreased proprioception 
(including but not limited to unusual clumsiness, gait abnormalities, and unexplained 
balance/coordination issues that are either absent at or worsening from the baseline) should be 
reported as an AE. If the treatment-emergent AE is persistent and considered related to study 
drug, specialty consultation with a neurologist should be considered. However, if such a 
treatment-emergent AE is serious or severe (regardless of the Investigator’s assessment of 
relatedness), the patient must be referred for neurologist consultation, and study drug dosing 
must be held until that consultation is complete. Resumption of dosing must be approved by the 
Medical Monitor. 
5.3. 
Protocol-specified Background Antihypertensive Medications 
All patients will be randomized to receive 1 of the 3 following standard of care oral 
antihypertensive medications during a Run-in period of at least 4 weeks and will continue this 


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protocol-specified background antihypertensive medication through Month 6. Protocol-specified 
background antihypertensive medications will be supplied by the Sponsor. 
• Olmesartan: 40 mg orally once daily (or 20 mg orally once daily for patients with 
creatinine clearance ≤60 mL/min enrolled at sites outside of the US, consistent with 
local labeling). At the Investigator’s discretion, patients who are randomized to 
receive 40 mg olmesartan once daily may initiate treatment at 20 mg once daily and 
then uptitrate to the full dose of 40 mg once daily after 1 to 2 weeks (in this case, the 
patient must take the full olmesartan dose of 40 mg once daily for at least 4 weeks 
prior to reassessment at Run-in Visit 2). 
• Amlodipine: 5 mg orally once daily 
• Indapamide: 2.5 mg orally once daily 
Protocol-specified antihypertensive medications may be downtitrated or temporarily 
discontinued per Investigator judgement for low blood pressure (see Section 5.8.1). At the 
Investigator’s discretion, oral antihypertensive agents, including protocol-specified background 
antihypertensive medication, may be prophylactically held during intercurrent illness or volume 
depletion. Additional information on the protocol-specified background antihypertensive 
medications, including side effects, drug-drug interactions, and other important prescribing 
information can be found in the Pharmacy Manual. 
5.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center will be responsible for preparing zilebesiran or placebo doses 
and dispensing protocol-specified background antihypertensive medication, according to 
procedures detailed in the Pharmacy Manual. No special procedures for the safe handling of 
study drug or protocol-specified background antihypertensive medication are required. 
Study drug will be stored at approximately 2 to 30°C until dose preparation. Protocol-specified 
background antihypertensive medication will be stored according to the storage instructions on 
the label. Deviations from the recommended storage conditions should be reported to the 
Sponsor and use of the affected study drug or protocol-specified background antihypertensive 
medication halted until authorization for its continued use has been provided by the Sponsor or 
designee, as described in the Pharmacy Manual. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and protocol-specified background antihypertensive 
medication and additional storage will be provided in the Pharmacy Manual. 
5.5. 
Packaging and Labeling 
All packaging, labeling, and production of study drug and protocol-specified background 
antihypertensive medication will be in compliance with current Good Manufacturing Practice 
specifications, as well as applicable local regulations. Study drug and protocol-specified 
background antihypertensive medication labels and external packaging will include all 
appropriate information as per local labeling requirements. Additional details will be available in 
the Pharmacy Manual. 


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5.6. 
Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
study drug and protocol-specified background antihypertensive medication supplied for this 
study, including dates of receipt. In addition, accurate records will be kept of when and how 
much study drug and protocol-specified background antihypertensive medication is dispensed 
and administered to each patient in the study. Any reasons for departure from the protocol 
dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all study drugs and 
protocol-specified background antihypertensive medication. Used, partially used, and unused 
study drug and protocol-specified background antihypertensive medication will be returned to 
the Sponsor (or designee) or destroyed at the clinical study center according to applicable 
regulations. 
Further instructions about accountability will be detailed in the Pharmacy Manual. 
5.7. 
Clinical Product Complaints 
5.7.1. 
Definition 
A clinical product complaint (CPC) is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of the study drug and its packaging after it is released for distribution to the site at 
which study drug will be administered. 
A CPC may be detected prior to use of study drug, during use, or after use. A CPC is typically 
nonmedical in nature; however, it is possible that study drug complaints could be associated with 
an AE. Examples of a CPC include, but are not limited to: illegible clinical label, missing clinical 
label, damaged vial, empty vial, and contamination of study drug. 
5.7.2. 
Reporting 
For product complaints, the Sponsor or its designee should be notified within 24 hours using the 
process outlined in the Pharmacy Manual. CPCs that may be associated with an AE must be 
evaluated and reported as indicated in Section 6.5.6. Detailed instructions on reporting CPCs will 
be provided in the Pharmacy Manual. 
5.8. 
Monitoring for Potential Clinical Events 
5.8.1. 
Monitoring and Approach for Potential Hypotension 
Hypotension is an obligate risk of antihypertensive medications. In addition to office blood 
pressure monitoring, outpatient blood pressure will be monitored weekly with HBPM to ensure 
the early detection of potential hypotension. Whenever possible, management decisions will be 
based on blood pressure measurements confirmed by office blood pressure. 
The following management recommendations for hypotension are provided: 
• Patients who experience low blood pressure that is associated with symptoms should 
promptly seek medical evaluation at the clinical study site or another hospital setting. 


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Clinical study site evaluation for low blood pressure should include the assessment of 
orthostatic blood pressure (supine to standing).  
• The Investigator should consider downtitration or interruption of oral 
antihypertensives (if taking) if confirmed office SBP <90 mmHg or if clinical 
symptoms, such as lightheadedness or dizziness, develop coupled with a significantly 
lower SBP compared to prior visits (ie, SBP <100 mmHg). Oral antihypertensives 
should be downtitrated/interrupted in reverse order to how they were added (ie, 
interrupt escape antihypertensive medications before protocol-specified background 
antihypertensive medications). 
• Clinically significant events discovered during the course of a patient’s general 
medical care should be promptly communicated to the site and evaluated by the 
Investigator, especially if hypotension is noted. Patients will carry Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)-approved patient cards to 
facilitate this physician-to-physician communication.  
• If hypotension is confirmed, serum electrolytes and creatinine should be measured 
and any oral antihypertensive(s) should be downtitrated or interrupted per 
Investigator judgement as outlined above.  
• The frequency of blood pressure and laboratory monitoring (serum electrolytes and 
creatinine) should be increased during intercurrent illnesses that predispose patients to 
dehydration (eg, vomiting or diarrhea that persists for more than 24 hours) or when 
symptoms consistent with decreased effective circulating volume (eg, presyncopal 
symptoms, unexplained falls, decreased urine output) manifest, even if a patient’s 
recent blood pressure measurements have been normal. 
• Hypotension that warrants direct evaluation at the site should be communicated to the 
Medical Monitor within 24 hours. In addition, other clinical events consistent with 
potential hypotension (eg, unexplained presyncope, syncope, or falls) should be 
communicated to the Medical Monitor within 24 hours of the site being notified. 
• Management of persistent hypotension may include increased salt intake or, if 
unresponsive, standard treatments for orthostatic intolerance syndromes such as 
fludrocortisone or midodrine. 
• Low blood pressure that requires medical treatment (including intravenous fluid 
support) or other clinical events consistent with potential hypotension (see above) 
should be recorded as AEs. 
5.8.2. 
Monitoring and Approach for Clinically Significant Blood Pressure Elevation 
In addition to office blood pressure monitoring, outpatient blood pressure will be monitored 
frequently with HBPM to ensure the early detection of potential significant elevations. Whenever 
possible, management decisions will be based on blood pressure measurements confirmed by 
office blood pressure. The recommended interventions for potentially clinically significant blood 
pressure elevation are presented in Table 4.  


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Table 4: 
Recommended Interventions for Potentially Clinically Significant Blood 
Pressure Elevation 
Study Period 
Intervention 
Throughout Study 
• 
Whenever possible, management decisions should be based on blood 
pressure measurements confirmed by office blood pressure. 
• 
Any confirmed event of severe hypertension (office SBP ≥180 mmHg 
and/or office DBP ≥120 mmHg) should be appropriately treated regardless 
of its timing relative to study drug administration.  
• 
Until double-blind data are generated that demonstrate acceptable safety 
and added antihypertensive efficacy of zilebesiran when combined with 
olmesartan, the use of conventional RAAS inhibitors (ARBs, ACE 
inhibitors, or direct renin inhibitors) as escape antihypertensive agents for 
high blood pressure will be avoided throughout the study.  
• 
If added, escape antihypertensives must be used per their labeled 
instructions and in accordance with current clinical guidelines.[Whelton 
2018; Williams 2018] 
Day 1 to Month 3 
Intervene if clinically significant blood pressure elevation: 
• 
Because of the gradual onset of effects of zilebesiran, interventions for 
asymptomatic hypertension should be avoided in the first 6 weeks after the 
patient’s first administration of study drug.  
• 
After Week 6, patients who develop office SBP >160 mmHg and increased 
>10 mmHg from their baseline office SBP that persists for ≥24 hours on 2 
consecutive measurements or that is accompanied by hypertensive 
symptoms should be evaluated by the clinical study site. Severely 
symptomatic patients should be evaluated at the clinical study site or 
another hospital setting within 24 hours. 
• 
If persistent hypertension is confirmed (without the identification of a 
specific treatable cause) and the Investigator deems it to be a clinically 
significant change, treatment may be initiated at the medical discretion of 
the Investigator using a CCB and/or a thiazide/thiazide-like diuretic 
(whichever agent is not already the protocol-specified background 
antihypertensive medication) as an escape antihypertensive medication.  
Months 3 to 6 
Treat to target blood pressure using a CCB and/or thiazide/thiazide-like diuretic 
(whichever agent is not already a protocol-specified background 
antihypertensive medication): 
• 
At Month 3, a CCB and/or a thiazide/thiazide-like diuretic may be added as 
an escape antihypertensive medication if the daytime mean SBP is 
≥135 mmHg by ABPM. If the Investigator feels there is a compelling 
clinical reason to wait, the rationale for exception should be documented in 
the eCRF. 
• 
After Month 3, other escape antihypertensive medications may also be 
added per Investigator judgement for persistent elevations in SBP above 
recommended target per treatment guidelines (eg, office SBP <140 mmHg, 
HBPM SBP <135 mmHg, or daytime mean SBP by ABPM <135 
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Study Period 
Intervention 
Month 6 to End of 
Study (OLE period) 
Treat to target blood pressure using Investigator’s choice of oral 
antihypertensive(s). 
• 
At Month 6, protocol-specified background antihypertensive medications 
(olmesartan, amlodipine, or indapamide) will be discontinued.  
• 
Patients who continue into the OLE period will initiate open-label treatment 
with 600 mg zilebesiran once every 6 months. As many patients will receive 
zilebesiran for the first time at Month 6, office blood pressure and serum 
chemistries will be carefully monitored monthly from Month 6 to Month 9, 
and Investigators will be prepared to downtitrate or interrupt escape 
antihypertensive medications if low blood pressure develops (see 
Section 5.8.1). 
• 
If the Month 6 ABPM is in target (daytime mean SBP <135 mmHg), escape 
antihypertensive medications (if taken) may be downtitrated or interrupted 
per Investigator judgement to determine if the patient’s blood pressure 
remains within target on zilebesiran treatment alone.  
• 
During the OLE period, oral antihypertensive medications may be added 
per Investigator judgement for persistent elevations in blood pressure above 
recommended target per treatment guidelines (eg, office SBP <140 mmHg, 
HBPM SBP <135 mmHg, or daytime mean SBP by ABPM <135 
mmHg).[Whelton 2018; Williams 2018] 
Abbreviations: ABPM=ambulatory blood pressure monitoring; ACE=angiotensin converting enzyme; 
ARB=angiotensin II-receptor blocker; CCB=calcium channel blocker; DBP=diastolic blood pressure; 
eCRF=electronic case report form; HBPM=home blood pressure monitoring; OLE=open-label extension; 
RAAS=renin-angiotensin-aldosterone system; SBP=systolic blood pressure. 
5.8.3. 
Monitoring and Approach for Potential Renal Dysfunction 
The Schedule of Assessments (Table 1) includes frequent laboratory monitoring of eGFR 
through the anticipated onset of initial zilebesiran PD. Based upon the renal dysfunction 
associated with conventional RAAS inhibitors,[McMurray 2016; Parving 2012] the following 
guidelines apply throughout the study: 
• If an individual patient experiences a decrease in eGFR by ≥30% from baseline or to 
≤30 mL/min/1.73m2, the Investigator should obtain confirmatory repeat tests, contact 
the Sponsor, and look for potentially reversible causes of renal dysfunction such as: 
− NSAIDs, antibiotics, or other treatments known to impair renal function 
− Recent exposure to intravenous contrast agents 
− Hypovolemia 
− Hypotension 
− Urinary infection 
− Urinary tract obstruction 
• If an individual patient experiences a decrease in eGFR by ≥40% from baseline or to 
≤25 mL/min/1.73m2, the Investigator should obtain confirmatory repeats tests, look 


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for potentially reversible causes of renal dysfunction, and contact the Sponsor to 
discuss the potential interruption of study drug and/or oral antihypertensives. Serum 
creatinine should be monitored at least weekly until improving. 
5.8.4. 
Monitoring and Approach for Potential Hyperkalemia 
The Schedule of Assessments (Table 1) includes frequent laboratory monitoring of serum 
electrolytes (at least monthly through the anticipated onset of zilebesiran PD). The guidelines in 
Table 5 apply for potassium elevations detected by laboratory monitoring.[McMurray 2016; 
Parving 2012] 
Table 5: 
Recommended Interventions for Hyperkalemia 
Serum K+ ≥5.2 and <5.5 mmol/L 
Serum K+ ≥5.5 and <6.0 mmol/L 
Serum K+ ≥6.0 mmol/L 
• 
Confirm potassium 
concentration in a non-
hemolyzed sample. 
• 
Reinforce low-potassium diet 
and restriction of food/drinks 
with high potassium content  
• 
Review medical regimen 
(including dietary supplements 
and over-the-counter 
medications) for agents known 
to cause hyperkalemia.a 
Consider reduction in dose or 
discontinuation of these agents 
only if clinically acceptable. 
• 
Repeat K+ measurement within 
3 to 5 days. 
• 
If K+ remains ≥5.2 and <5.5 
mmol/L, regularly monitor K+ 
levels to ensure stability (at 
least weekly if in the first 6 
weeks of treatment or at least 
once monthly afterwards) 
• 
Confirm potassium 
concentration in a non-
hemolyzed sample 
• 
Consider interruption of open-
label olmesartan (in patients 
randomized to receive it as their 
protocol-specified background 
antihypertensive medication) 
according to Investigator 
medical judgement 
• 
Consider interruption or delay 
of study drug administration, 
according to Investigator 
medical judgment  
• 
Apply all measures outlined for 
serum K+ ≥5.2 and <5.5 
mmol/L 
• 
Repeat K+ measurement after 2 
to 3 days 
• 
If K+ <5.5 mmol/L, consider 
resumption of study drug (if 
interrupted) with repeat 
potassium within 5 days 
• 
If K+ persistently elevated ≥5.5 
mmol/L, consider treatment 
with patiromer (or with sodium 
zirconium cyclosilicate), if 
available 
• 
Immediately interrupt 
study drug 
• 
Confirm potassium 
concentration in a 
non-hemolyzed 
sample 
• 
Urgently evaluate 
patient and treat 
hyperkalemia as 
clinically indicated. 
After urgent 
treatment, consider 
treatment with 
patiromer (or with 
sodium zirconium 
cyclosilicate), if 
available 
• 
Apply all measures 
outlined for serum K+ 
≥5.5 and <6.0 
mmol/L 
• 
No resumption of 
study drug without 
individualized case 
discussion with and 
permission from 
Alnylam Medical 
Monitor 
Abbreviations: NSAID=nonsteroidal anti-inflammatory drug. 
a This list is not meant to be exhaustive: potassium-sparing diuretics (eg, amiloride and triamterene), potassium 
supplements (eg potassium chloride), salt substitutes, NSAIDs, cyclo-oxygenase-2 inhibitors, trimethoprim and 
trimethoprim-containing combination products, herbal supplements (eg, Noni juice, alfalfa [Medicago sativa], 
dandelion [Taraxacum officinale], horsetail [Equisetum arvense], nettle [Urtica dioica], milkweed, lily of the 
valley, Siberian ginseng, hawthorn berries). 
 


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The availability of patiromer and sodium zirconium cyclosilicate (ZS-9) will be assessed at 
participating study sites. These potassium-binding drugs are indicated for the treatment of 
hyperkalemia and have been shown to safely reduce serum potassium levels and to maintain 
long-term normokalemia in chronic kidney disease patients receiving background conventional 
RAAS inhibitor therapy.[Georgianos and Agarwal 2018; Weir 2015] 
5.9. 
Concomitant Medications and Procedures 
Use of concomitant medications and procedures will be recorded on the patient’s eCRF as 
specified in the Schedule of Assessments (see Table 1). Concomitant medications include all 
prescription medications, herbal preparations, over the counter medications, vitamins, and 
minerals. Any changes in medications during the study will also be recorded on the eCRF. 
Standard vitamins and topical medications are permitted. However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated. For other permitted 
concomitant medications administered SC, do not administer in same injection site area as the 
study drug for at least 4 days after each dose of study drug. 
Patients receiving low-dose aspirin (defined as ≤100 mg per day) for at least 30 days prior to 
screening and during the study treatment period are allowed. Occasional use of other systemic 
over-the-counter NSAIDs is allowed. However, given their association with increased blood 
pressure, they should be avoided when possible and for at least 2 days prior to ABPM and office 
blood pressure assessments, and alternative analgesics (acetaminophen, topical NSAIDs) should 
be considered.[Whelton 2018] When used, the dosing of systemic NSAIDs should be at the 
lower end of the labeled range and for the shortest duration possible.  
Patients receiving SGLT2 inhibitors (eg, empagliflozin, canagliflozin, and dapagliflozin) should 
be on a stable dose for at least 30 days prior to screening and during the study treatment period. 
These medications should not be initiated or discontinued, if possible, during the study treatment 
period. 
Patients will be allowed to receive vaccines (eg, for SARS-CoV-2) that have received health 
agency authorization (including for emergency use) by local or regional regulatory authorities. 
Use of cannabis or delta-9-tetrahydrocannibinol (THC)-containing substances (including by 
smoking, vaping, dabbing, or ingesting/edibles) should be avoided when possible and for at least 
2 days prior to ABPM and office blood pressure assessments. 
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator, except as described in Section 5.9.1 and after consulting the Pharmacy Manual, 
which contains information on drug-drug interactions and other important prescribing 
information for the protocol-specified background antihypertensive medications. However, it is 
the responsibility of the Investigator to ensure that details regarding the medication are recorded 
on the eCRF. Concomitant medication will be coded using an internationally recognized and 
accepted coding dictionary. 
5.9.1. 
Prohibited Concomitant Medication 
The following medications, treatments, and supplements are prohibited throughout the study 
treatment period (until the EOT visit): 


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• Conventional RAAS inhibitors (ARBs, ACE inhibitors, or direct renin inhibitors), 
except for olmesartan as protocol-specified background antihypertensive medication 
during the 6-month DB period  
• Prescription NSAIDs  
• Organic nitrate preparations (eg, nitroglycerin, isosorbide mononitrate, isosorbide 
dinitrate, pentaerythritol) 
• An RNAi therapeutic (other than zilebesiran) 
• Medications, herbal supplements (including Ma Huang and St. John’s wort), or other 
substances (such as licorice) that are associated with increases in LFT abnormalities 
or with blood pressure abnormalities are prohibited. This includes certain stimulants 
(eg, amphetamine, methylphenidate dexmethylphenidate, dextroamphetamine), MAO 
inhibitors, atypical antipsychotics (eg, clozapine, olanzapine), diet pills (eg, 
phenylpropanolamine, sibutramine), and nasal decongestants (eg, phenylephrine 
hydrochloride, pseudoephedrine, naphazoline hydrochloride). 
• Medications, herbal medicines, over-the-counter medications, or supplements known 
to cause hyperkalemia are prohibited unless individually approved by both the 
Investigator and the Medical Monitor. This includes potassium-sparing diuretics, 
potassium supplements, cyclo-oxygenase-2 inhibitors, trimethoprim and 
trimethoprim-containing combination products, mineralocorticoid receptor 
antagonists, Noni juice, alfalfa, dandelion, horsetail, nettle, milkweed, lily of the 
valley, Siberian ginseng, and hawthorn berries. 
All concomitant medications must be reviewed and approved by the Investigator, with particular 
attention to avoiding drugs that may affect blood pressure. 
5.10. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff. 
Compliance with protocol-specified background antihypertensive medication will be assessed 
through pill count by study staff. 
5.11. 
Other Requirements 
5.11.1. 
Contraception 
Females of child-bearing potential must be willing to use a highly effective method of 
contraception from 14 days before the first dose of protocol-specified background 
antihypertensive medication, throughout study participation, and through safety follow-up (if 
applicable; see Section 3.1). 
Birth control methods which are considered highly effective include: 
• Placement of an intrauterine device. 
• Placement of an intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 


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• Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female patients on the 
study, the vasectomized male partner should be the sole partner for that patient). 
• Established use of oral (except low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception associated with the inhibition of 
ovulation. 
• True sexual abstinence, when in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception. Abstinent 
patients must agree to use one of the above-mentioned contraceptive methods if they 
start heterosexual relationships during the study and through safety follow-up (if 
applicable; see Section 3.1) 
Investigators should advise females of childbearing potential of the most appropriate birth 
control method available within their country taking into account local medical practice. 
Females of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study), and who are not postmenopausal or permanently 
sterilized (eg, bilateral oophorectomy, hysterectomy, or bilateral salpingectomy). A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by follicle stimulating hormone level within the postmenopausal 
range.  
For male patients, no contraception is required. However, use by males of contraception 
(condom) may be required in some countries, eg, France, in order to comply with local 
requirements as described in the corresponding patient ICFs.  
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.5.5.3). Pregnancy testing will be 
performed before every dose for postmenarcheal females throughout the course of the study (see 
Section 6.5.5.3). 
5.11.2. 
Alcohol Restrictions 
Patients should limit alcohol consumption throughout the course of the study. Alcohol is limited 
to no more than 2 units per day (unit: 1 glass of wine [approximately 125 mL] =1 measure of 
spirits [approximately 1 fluid ounce] =½ pint of beer [approximately 284 mL]) for the duration 
of the study. Compliance with alcohol restrictions should be assessed on a regular basis by the 
Investigator throughout the course of the study. 
5.11.3. 
Tobacco and Nicotine Restrictions 
Use of nicotine or tobacco-containing products (including, but not limited to, snuff, chewing 
tobacco, cigars, cigarettes, pipes, nicotine patches, or e-cigarettes) must be avoided within 30 
minutes prior to office blood pressure measurements. 


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5.11.4. 
Dietary Recommendations 
All patients will receive educational materials on diet with recommendations to limit sodium 
consumption to approximately 2.0 g per day from screening through the end of the Treatment 
period. This direction should be provided at the start of the Screening period, and treatment-
naïve patients should follow these recommendations for at least 1 week prior to screening 
assessments of blood pressure. This is the sodium intake recommended in the 2018 European 
Society of Cardiology/European Society of Hypertension Guidelines for both hypertensive 
patients and for the general population.[Williams 2018]  
On days on which samples for fasting lipid panel and glycemic assessments are collected, 
patients are required to fast for ≥10 hours before sample collection (Section 6.5.5.1). 
5.11.5. 
Exercise 
Patients should abstain from strenuous exercise for 48 hours before each blood collection for 
clinical laboratory tests and from any exercise for 30 minutes prior to office blood pressure 
measurements. 
6. 
STUDY ASSESSMENTS 
The schedule of study assessments is provided in Table 1. Study visits should be scheduled for 
the morning. All assessments, except for postdose PK sample collection, are to be performed 
prior to dosing with protocol-specified background antihypertensive medication or study drug. 
Additional information on the collection of study assessments will be detailed in the Study 
Manuals. 
Where applicable country and local regulations and infrastructure for home healthcare allow, 
home healthcare may take place at a location other than the clinical trial site to perform study 
assessments, which may include collection of blood and urine samples and measurement of vital 
signs (at the discretion and oversight of the Investigator). 
6.1. 
Screening Assessments 
An ICF that has been approved by the appropriate IRB/IEC must be signed (in paper or 
electronic format per local regulations and institutional standards) by the patient or legal 
guardian before the screening procedures are initiated. All patients or their legal guardians will 
be given a copy of the signed and dated ICF. 
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria. Rescreening of patients once is permitted with agreement of the Medical 
Monitor (see Section 6.1.2). 
Patient demographic data and medical history/disease history will be obtained. Any changes to 
medical history occurring between the screening assessment and Run-in Visit 1 will be updated 
prior to administration of protocol-specified background antihypertensive medication. 


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6.1.1. 
Retesting  
If in the Investigator’s judgement, the screening or Run-in laboratory abnormalities are likely to 
be transient, then laboratory tests may be repeated. The Investigator’s rationale must be 
documented. Laboratory values can be retested once during screening and once during the Run-
in period provided that the patient can be evaluated for eligibility and randomized within the 
allowed Screening and Run-in periods. Retesting of ABPM at Run-in Visit 2 is permitted once, 
with eligibility assessed by the second ABPM result. 
6.1.2. 
Rescreening 
A patient who does not meet all study eligibility criteria due to a transient condition observed at 
screening (eg, prohibited medications that were subsequently discontinued) will be allowed to 
return once for rescreening following agreement with the Medical Monitor. A patient will be re-
consented if rescreening occurs outside of the Screening period. In this case, all screening 
procedures must be repeated. Patients who do not meet eligibility criteria after Run-in Visit 1 
will not be rescreened. 
6.2. 
Efficacy Assessments 
All blood pressure measurements (ABPM, office, and HBPM) must be taken at the times 
specified in the Schedule of Assessments (Table 1) using the standardized equipment provided 
by the Sponsor, according to the methods described in Section 10.2. Office blood pressure 
assessments and ABPM initiation must be performed before administration of any oral 
antihypertensive medications and study drug (as applicable). 
Patients taking oral antihypertensives prior to screening should discontinue these medications at 
Run-in Visit 1. The baseline ABPM and office blood pressure measured at Run-in Visit 2 must 
be taken within 7 days before Day 1. An HBPM unit will be provided before Run-in Visit 2 to 
establish the HBPM baseline, and HBPM should be collected at least 3 times during the last 
week prior to Day 1. 
ABPM placement may be performed at home by appropriately trained individuals, as detailed in 
the Study Manual. If a patient is unable to report to the site for an office blood pressure 
assessment, a substitute “remote visit blood pressure measurement” may be obtained remotely 
using the methods described in Section 10.2. 
Recommendations for approach and monitoring of low blood pressure/hypotension and 
hypertensive escape are provided in Section 5.8.1 and Section 5.8.2, respectively. 
6.2.1. 
ABPM 
The ABPM should be started prior to the morning dose of oral antihypertensive medication. 
Consecutive (daily) use of over-the-counter NSAIDs (other than aspirin ≤100 mg per day) and 
use of cannabis or THC-containing substances should be avoided for at least 2 days prior to 
ABPM measurements.  
Validity will be assessed for all ABPMs. If the ABPM recording is invalid at any point during 
the study, the patient will be provided 1 opportunity to repeat the recording. During the Run-in 
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See further details in Section 10.2 and the Study Manual. 
6.2.2. 
Office Blood Pressure 
Office blood pressure must be measured in triplicate using the automated blood pressure device 
provided by the Sponsor at trough (prior to taking oral antihypertensives) and should be at 
approximately the same time of day for each assessment; therefore, visits should be scheduled at 
approximately the same time of day, whenever possible. Office blood pressure must include 
orthostatic measurements (seated and standing).  
Exercise, caffeine, alcohol consumption, and use of nicotine or tobacco-containing products 
(including but not limited to snuff, chewing tobacco, cigars, cigarettes, pipes, nicotine patches, or 
e-cigarettes) must be avoided within 30 minutes prior to blood pressure measurements. The use 
of inhaled short-acting beta agonists should be avoided within 6 hours prior to measuring blood 
pressure and/or heart rate. The use of phosphodiesterase type 5 inhibitors (eg, sildenafil, 
tadalafil, vardenafil, avanafil) should be avoided within 48 hours prior to measuring blood 
pressure. Consecutive (daily) use of over-the-counter NSAIDs (other than aspirin ≤100 mg per 
day) and use of cannabis or THC-containing substances should be avoided for at least 2 days 
prior to blood pressure measurements. 
The patient should be seated comfortably with the back supported and the feet flat on the floor as 
detailed in Section 10.2 and the Study Manual.  
6.2.3. 
HBPM 
The HBPM should be measured in the morning upon waking, prior to breakfast/caffeine or 
taking morning oral antihypertensive medications. HBPM is not required at times when ABPM 
is being assessed. The patient should be seated comfortably with the back supported and the feet 
flat on the floor as detailed in Section 10.2 and the Study Manual. 
6.3. 
Pharmacodynamic Assessments 
Blood samples for determination of AGT will be collected according to the Schedule of 
Assessments (Table 1). In addition, blood samples for determination of RAAS biomarkers 
(plasma renin concentration, AngI, AngII, and aldosterone) will be collected only for patients 
randomized to receive olmesartan as protocol-specified background antihypertensive medication. 
Blood samples for PD assessments must be collected before study drug administration (on days 
when study drug is to be dosed) or at a time point corresponding to the time of study drug dosing 
(on other days). Blood AGT levels will be analyzed at a regulated bioanalytical laboratory by 
enzyme-linked immunosorbent assay for measurement of PD effect. Biomarkers may be 
analyzed using qualified assays. Details regarding the collection, processing, shipping, and 
storage of the samples will be provided in the Laboratory Manual.  
Results will not be used to adjust dosing of zilebesiran or guide clinical management and will not 
be shared with sites until after study unblinding. 
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for the assessment of plasma concentrations of zilebesiran and 
its primary metabolite AS(N-1)3′ zilebesiran at the time points indicated in the Schedule of 


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Assessments (Table 1). A detailed schedule of time points for the collection of blood samples for 
PK analysis is in Table 2. 
Plasma concentrations of zilebesiran and AS(N-1)3′ zilebesiran will be determined using a 
validated assay. Details regarding sample volumes to be collected, and the processing, shipping, 
and analysis of the samples will be provided in the Laboratory Manual. 
6.5. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of AEs, 
including SAEs, recording of concomitant medication and measurements of vital signs, weight, 
electrocardiogram (ECG) findings, and laboratory tests. Clinically significant abnormalities 
observed during the physical examination will be recorded. 
6.5.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1) and include 
blood pressure, heart rate, body temperature, and respiratory rate. Vital signs are to be collected 
prior to administration of oral antihypertensive medications and study drug (as applicable). 
When vital signs and blood sample collection occur at the same time, vital signs should be 
performed before blood samples are drawn, where possible. Vital signs should be measured in 
the seated position, after the patient has rested comfortably for approximately 10 minutes. Body 
temperature in degrees Celsius will be obtained via oral, tympanic, or axillary methods. Heart 
rate will be counted for a full minute and recorded in beats per minute, and respiration rate will 
be counted for a full minute and recorded in breaths per minute. Blood pressure is described in 
Section 6.2.  
Additional vital sign assessments, as medically indicated, may be added at the discretion of the 
Investigator, or as per DMC advice. 
6.5.2. 
Weight, Height, and Morphometrics 
Height and body weight measurements will be collected as specified in the Schedule of 
Assessments (Table 1) and will be recorded in the eCRF. Height will be measured at Day 1 only. 
Height will be measured in centimeters. Body weight should be measured in kilograms to the 
first decimal point in patients wearing light clothing and without shoes.  
Waist circumference and waist-to-hip-ratio will also be collected as specified in the Schedule of 
Assessments (Table 1) and will be recorded on the eCRF. For waist circumference and waist-to-
hip ratio, patients should wear minimal clothing to ensure that the measuring tape is correctly 
positioned. Patients should stand erect with the abdomen relaxed, arms at the sides, feet together 
and with their weight equally divided over both legs. To perform the waist measurement, the 
lowest rib margin is first located and marked with a pen. The iliac crest is then palpated in the 
midaxillary line, and also marked. It is recommended to apply an elastic tape horizontally 
midway between the lowest rib margin and the iliac crest, and tie firmly so that it stays in 
position around the abdomen about the level of the umbilicus. The elastic tape thus defines the 
level of the waist circumference, which can then be measured by positioning the measuring tape 
over the elastic tape. Hip circumference measurement should be taken around the widest portion 
of the buttocks. Patients are asked to breathe normally, and to breathe out gently at the time of 
the measurement to prevent them from contracting their muscles or from holding their breath. A 


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stretch-resistant tape that provides a constant 100 g of tension is recommended. Measurements 
should be obtained with the tape positioned parallel to the floor and performed using the same 
procedure throughout the study. 
The reading is taken to the nearest centimeter and entered in the source document. Each 
measurement should be repeated twice; if the measurements are within 1 cm of each other, the 
average should be calculated. If the difference between the 2 measurements exceeds 1 cm, the 2 
measurements should be repeated.  
6.5.3. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedule 
of Assessments (Table 1); if a physical examination is scheduled for a study drug dosing visit, it 
should be conducted prior to dosing. Full physical examinations will include the examination of 
the following: general appearance; head, eyes, ears, nose and throat; respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, and dermatological systems; thyroid; lymph nodes; and 
neurological evaluation (see the Study Manual for further details on the assessments to be 
performed as part of the neurological evaluation). 
Symptom-directed physical examinations will be guided by evaluation of changes in symptoms, 
or the onset of new symptoms, since the last visit. Neurological evaluation should be performed 
according to the Study Manual during all symptom-directed physical examinations regardless of 
whether neurological symptoms have been experienced by the patient.  
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF. 
6.5.4. 
Electrocardiogram 
The 12-lead ECGs reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, 
QT interval, and Fridericia-corrected QT interval will be obtained using a local machine, as 
specified in the Schedule of Assessments (Table 1). Patients should be supine for at least 10 
minutes before each ECG is obtained. The Investigator or qualified designee will review all 
single 12-lead ECGs to assess whether the results have changed since the Baseline visit and to 
determine the clinical significance of the results. These assessments will be recorded in the 
eCRF.  
When ECG and blood sample collection occur at the same visit, blood sample collection should 
occur first. ECGs should be performed at least 30 minutes after phlebotomy or other stressful 
assessments. 
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since the baseline visit and to determine the clinical significance of the results. These 
assessments will be recorded in the eCRF. Additional ECGs may be collected at the discretion of 
the Investigator, or as per DMC advice. Recordings will be archived according to the Study 
Manual. 
6.5.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory. Specific 
instructions for transaminase elevations are provided in Section 5.2.4. For any other unexplained 


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clinically relevant abnormal laboratory test occurring after study drug administration, the test 
should be repeated and followed up at the discretion of the Investigator, or as per DMC advice, 
until it has returned to the normal range or stabilized, and/or a diagnosis is made to adequately 
explain the abnormality. Additional safety laboratories and assessments as indicated by the 
clinical situation may be requested. Clinical laboratory assessments are listed in Table 6 and will 
be assessed as specified in the Schedule of Assessments (Table 1).  
While local laboratory results may be used for urgent clinical decisions, on the day of the 
assessments, all laboratory assessments specified in Table 6 that are performed at the clinic 
should also be sent in parallel to the central laboratory. In the case of discrepant local and central 
laboratory results on samples drawn on the same day, central laboratory results will be relied 
upon for clinical decisions. 
Clinical laboratory assessments may be collected at the clinical study center or at home by a 
trained healthcare professional. In patients randomized to receive olmesartan as the protocol-
specified background antihypertensive medication, blood samples for RAAS biomarkers should 
be collected in the morning and in the seated/upright position (after blood pressure 
measurements and before any assessments collected in the supine position). Blood samples for 
laboratory evaluation should be collected after the completion of blood pressure assessments. 
Spot urine collections for albumin and creatinine should be obtained in the morning.  
For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the Medical 
Monitor; results may be collected and should be included in the clinical database. 


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Table 6: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Uric acid 
Albumin 
Total protein 
Calcium 
Glucose 
Bicarbonate 
Creatinine and eGFR 
Chloride 
Creatinine clearance 
 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT 
 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 
Ketones 
Urobilinogen 
Protein 
Leukocyte esterase 
Glucose 
Microscopy (if clinically indicated) 
Coagulation  
Prothrombin time 
International normalized ratio 
Partial thromboplastin time  
 
Fasting Lipid Panel and Glycemic Assessments (see Section 6.5.5.1) 
Lipid panel, including 
HDL-C, non-HDL-C, LDL-C, apolipoprotein A1, 
triglycerides, total cholesterol  
Insulin 
Fasting plasma glucose 
HbA1c 
Immunogenicity (see Section 6.5.5.2) 
ADA 
 
Pregnancy Testing/FSH Screening (see Section 6.5.5.3) 
β-human chorionic gonadotropin (females of 
child-bearing potential only) 
Follicle-stimulating hormone (postmenopausal 
women only) 
Abbreviations: ADA=anti-drug antibodies; ALP=alkaline phosphatase; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; 
FSH=follicle-stimulating hormone; GGT=gamma glutamyl transferase; HbA1c=hemoglobin A1c; HDL-C=high-
density lipoprotein; LDL-C=low-density lipoprotein; RBCs=red blood cells. 


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6.5.5.1. 
Fasting Lipid Panel and Glycemic Assessments 
Blood samples for fasting plasma glucose, insulin, lipid panel (including total cholesterol, high-
density lipoprotein [HDL-C], non-HDL-C, low-density lipoprotein, apolipoprotein A1, and 
triglycerides), and HbA1c will be collected at the time points listed in the Schedule of 
Assessments (Table 1). Patients are required to fast for ≥10 hours before sample collection for 
fasting glucose, insulin, lipid panel, and HbA1c. Samples should be collected at approximately 
the same time of day (±2 hours). 
6.5.5.2. 
Immunogenicity 
Blood samples will be collected to evaluate anti-drug antibodies (ADA). Blood samples for ADA 
testing must be collected before study drug administration (on days when study drug is to be 
dosed) or at a time point corresponding to the time of study drug dosing (on other days) as 
specified in the Schedule of Assessments (Table 1). A blood sample to evaluate ADA will be 
collected at the ET visit, if applicable. Blood samples for ADA will be analyzed at a regulated 
bioanalytical laboratory. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 
6.5.5.3. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential. A serum pregnancy 
test will be performed at screening, and urine pregnancy tests will be performed thereafter per 
the Schedule of Assessments and any time pregnancy is suspected. More frequent pregnancy 
testing may be performed where required per local requirements. The results of the pregnancy 
test must be known before study drug administration. Patients who are pregnant at screening are 
not eligible for study participation. Any woman with a positive urine pregnancy test, 
subsequently confirmed by a positive serum pregnancy test, during the study will be 
discontinued from study drug but will continue to be followed for safety. Patients who become 
pregnant while on study will be followed at least until the pregnancy outcome is known (see 
Section 6.5.6.7 for follow-up instructions). 
A blood sample will be drawn at screening to measure the levels of follicle stimulating hormone 
in order to confirm postmenopausal status in all women suspected to be postmenopausal (see 
Section 5.11.1 for definition of postmenopausal state). 
6.5.5.4. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 5.2.4. Following the occurrence of elevated liver 
transaminases or other LFT abnormalities per central laboratory, all assessments in Table 7 will 
be performed 1 time, as well as hematology, serum chemistry, LFT, and coagulation assessments 
from Table 6, and other assessments or evaluations per Investigator discretion, as appropriate.  
Monitoring, including criteria for dose modification or withholding the study drug, is described 
in Section 5.2.4.  


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Table 7: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
HBsAg, HBc antibody IgM  
Parvovirus B19 DNA - quantitative 
HAV antibody IgM 
HHV-6 DNA viral load - quantitative 
HCV antibody 
Anti-nuclear antibodies 
HCV RNA PCR – quantitative 
Anti-smooth muscle antibodies 
HEV antibody IgM 
Anti-LKM1 antibody 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
Anti-mitochondrial antibodies 
Herpes Zoster Virus IgM, IgG 
Anti-SLA 
Epstein-Barr Virus antibodies, IgM and IgG 
Ferritin 
Cytomegalovirus antibodies, IgM, IgG 
Ceruloplasmin 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant medications, 
including over the counter medications and herbal remedies 
Alcohol consumption and drugs of 
abuse  
Other potentially hepatotoxic agents including any work-
related exposures 
Recent travels to areas where hepatitis 
A or E is endemic 
Abbreviations: CT=computed tomography; DNA=deoxyribonucleic acid; HAV=hepatitis A virus; HBc=hepatitis B 
core; HBsAg=hepatitis B virus surface antigen; HCV=hepatitis C virus; HEV=hepatitis E virus; HHV-6=human 
herpesvirus 6; IgG=immunoglobulin G antibody; IgM=immunoglobulin M antibody; LKM1=liver/kidney 
microsome-1 antibody MRI=magnetic resonance imagery; PCR=polymerase chain reaction; RNA=ribonucleic acid; 
SLA=soluble liver antigen 
Note: 
• 
All laboratory assessments will be measured in a central laboratory. The full panel of assessments should only 
be performed once; individual assessments may be repeated, as needed. 
6.5.6. 
Adverse Events 
6.5.6.1. 
Definitions 
Adverse Event 
According to the ICH E2A guideline Definitions and Standards for Expedited Reporting, and 
21 Code of Federal Regulations 312.32, IND Safety Reporting, an AE is any untoward medical 
occurrence in a patient or clinical investigational subject administered a medicinal product and 
which does not necessarily have a causal relationship with this treatment. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 


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• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred. It does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias, convulsions, or the development of drug 
dependency or abuse). 
Adverse Events of Clinical Interest 
The following are considered to be AEs of clinical interest: 
• ALT or AST >3×ULN 
• Severe or serious ISRs; ISRs that are associated with a recall phenomenon (reaction 
at the site of a prior injection with subsequent injections), or those that lead to 
temporary dose interruption or permanent discontinuation of zilebesiran. 
An ISR is defined as a local reaction at or near the site of injection. “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as 
may occur with swelling or hematoma). A systemic reaction which includes the 
injection site, eg, generalized urticaria, other distinct entities or conditions like 
lymphadenopathy that may be near the injection site is not considered an ISR. 
For information on recording and reporting of AEs of clinical interest, see Section 6.5.6.2 and 
Section 6.5.6.3, respectively. 
Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living (ie, bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden); OR life-threatening consequences; urgent intervention indicated; 
OR death related to an adverse event. 


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Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity. Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence. When changes in the severity of an 
AE occur more frequently than once a day, the maximum severity for the experience that day 
should be noted. If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
Adverse event severity and seriousness are assessed independently. ‘Severity’ characterizes the 
intensity of an AE. ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for 
defining regulatory reporting obligations (see definition for SAE). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?” A “yes” response indicates that the event is considered as related to 
the study drug. 
The relationship of each AE to the protocol-specified background antihypertensive medication 
should also be assessed by the Investigator. 
6.5.6.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient and legal guardian, if applicable, should be asked about medically relevant changes 
in the patient’s health since the last visit. The patient and legal guardian, if applicable, should 
also be asked if the patient has been hospitalized, had any accidents, used any new medications, 
or changed concomitant medication routines (both prescription and over-the-counter). In addition 
to patient observations, AEs will be documented from any clinically relevant laboratory findings, 
physical examination findings, ECG changes, or other findings that are relevant to patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study treatment during the Run-in period 
regardless of their relationship to the study treatment through the end of study. Study treatment is 
defined as protocol-specified background antihypertensive medication or study drug (zilebesiran 
or placebo). Non-serious AEs will be followed until the end of study. Events occurring after 
signing of the ICF and before the Run-in period will be captured as medical history (see 
Section 6.1), while AEs that occur after study treatment, and baseline events that worsen after 
study treatment, must be recorded as AEs. 
The Investigator is responsible for recording SAEs that are observed or reported by the patient 
after the time when the informed consent is signed regardless of their relationship to study 
treatment through the end of study. SAEs will be followed until satisfactory resolution, until 
baseline level is reached, or until the SAE is considered by the Investigator to be chronic or the 
patient is stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be related. Each AE must be described in 


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detail: onset time and date, description of event, severity, relationship to study treatment, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) in the eCRF and, as applicable, the SAE form. 
For AEs that are considered AEs of clinical interest (Section 6.5.6.1), the supplemental AEs of 
Clinical Interest eCRF should be completed. Additional clinical and laboratory information may 
be collected. Refer to eCRF completion guidelines for details on reporting events in the 
supplemental AEs of Clinical Interest eCRF. 
For all ISRs, the Investigator, or delegate, should submit an Injection Site Reaction Signs or 
Symptoms eCRF, recording additional information regarding each injection site reaction that is 
entered on the AE eCRF (eg, symptom[s], injection site location, follow-up actions taken). 
6.5.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AEs of clinical interest (Section 6.5.6.1), the Sponsor or its designee 
should be notified within 24 hours using the appropriate eCRF. 
6.5.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee 
An assessment of the seriousness of each AE will be made by the Investigator. Any AE and 
laboratory abnormality that meets the SAE criteria in Section 6.5.6.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event. All SAEs must be reported regardless of the relationship to study treatment. 
The initial report should include at least the following information: 
• Patient’s study number 
• Description and date of onset of the event 
• Criterion for serious 
• Preliminary assignment of relationship to study treatment, and 
• Investigator/site information 
To report the SAE, complete the eCRF and, as applicable, the SAE form. Within 24 hours of 
receipt of follow-up information, the Investigator must update the eCRF and, as applicable, the 
SAE form. SAEs must be reported using the contact information provided in the Study Manual. 
Appropriate remedial measures should be taken by the Investigator using the Investigator’s best 
medical judgment to treat the SAE. These measures and the patient’s response to these measures 
should be recorded. All SAEs, regardless of relationship to study treatment, will be followed by 
the Investigator until satisfactory resolution or the Investigator deems the SAE to be chronic or 
stable. Clinical, laboratory, and diagnostic measures should be employed by the Investigator as 
needed to adequately determine the etiology of the event. 
6.5.6.5. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative will report certain study events in an expedited manner to the 
Food and Drug Administration, the European Medicines Agency’s EudraVigilance electronic 


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system according to Directive 2001/20/EC, and to all country Regulatory Authorities where the 
study is being conducted, according to local applicable regulations. 
6.5.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
Suspected unexpected serious adverse reactions will be reported to the IRB/IEC per their 
institutional policy by the Investigator or Sponsor (or Sponsor designee) according to country 
requirements. Copies of each report and documentation of IRB/IEC notification and 
acknowledgement of receipt will be kept in the Investigator’s study file. 
6.5.6.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through safety follow-up (see Section 3.1), 
the Investigator must report the pregnancy to the Sponsor or designee within 24 hours of being 
notified of the pregnancy. Details of the pregnancy will be recorded on the pregnancy reporting 
form. The patient should receive any necessary counseling regarding the risks of continuing the 
pregnancy, the possible effects on the fetus, and be counseled to not breastfeed for 90 days after 
the last dose of study drug. 
The pregnancy should be followed by the Investigator until completion. At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy. If the outcome of the 
pregnancy results in a postpartum complication, spontaneous abortion, stillbirth, neonatal death, 
or congenital anomaly, then the Investigator should follow the procedures for reporting an SAE 
as outlined in Section 6.5.6.4. 
6.5.6.8. 
Reporting of Overdose and Other Special Situations  
An overdose is defined as any dose of study drug administered to the participant or taken by the 
participant that is >2× the assigned dose during a single administration and/or ≥2 doses within ½ 
the intended dosing interval. 
The Sponsor does not recommend specific treatment for an overdose.  
In an event of an overdose or other special situations (eg, medication error, abuse, misuse, or 
CPC associated with an AE), the Investigator should: 
• Contact the Medical Monitor and Sponsor within 24 hours using the contact 
information in the Pharmacy Manual 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities 
• Document the amount of study drug given  
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or 
a concomitant medication will be considered AEs/SAEs.  
Full details of reporting instructions for overdose and other special situations will be outlined in 
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6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
Alnylam’s RNAi therapeutics platform permits the highly specific targeting of investigational 
therapies based on genetic sequence. It is possible that variations in the target genetic sequence 
will result in variations in drug effect. More generally, genetic variations may account for the 
well-described heterogeneous manifestations of disease in patients with hypertension, as well as 
their responses to treatment. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and patient consent, 
samples will be collected as part of this study to permit exploratory investigations and the 
application of novel approaches to bioanalyses that may further elucidate the outcomes of this 
study, or potentially advance understanding of the safety, mechanism of action, and/or efficacy 
of zilebesiran. 
Biological specimens will be collected at the intervals indicated in the Schedule of Assessments 
(Table 1). These specimens will be analyzed at a central laboratory. Potential exploratory 
investigations may include DNA, RNA, or biochemical metabolite assessments as they relate to 
disease progression, efficacy, or safety. 
The biospecimen repository will also include residual material from routine samples (safety 
laboratory samples, PK samples, etc) that are obtained during the study. 
These specimens will be securely stored in a central biorepository for up to 10 years following 
the completion of this clinical study (ie, last patient last visit), or as per local regulations. After 
10 years have elapsed, samples will be destroyed. 
Details regarding the collection, processing, storage, and shipping of the samples will be 
provided in the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
When biobanking is permitted by local regulation, study participants will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 
7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock and study unblinding for 
the analysis of the primary endpoints and secondary endpoints measured at Month 3. The plan 
will detail the implementation of the statistical analyses in accordance with the principal features 
stated in the protocol. 
7.1. 
Determination of Sample Size 
Approximately 630 patients will be randomized to receive either zilebesiran or placebo with 
sample sizes in each of the patient cohorts with protocol-specified background antihypertensive 
medication as follows:  
• Olmesartan cohort: 300 patients  
• Amlodipine cohort: 210 patients 


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• Indapamide cohort: 120 patients 
Assuming a standard deviation of 16 mmHg in change from baseline in 24-hour mean SBP 
assessed by ABPM and 15% dropout rate from baseline to Month 3, with 2-sided significance 
level of 0.05 for each of the comparisons (zilebesiran versus placebo as add-on to olmesartan; 
zilebesiran versus placebo as add-on to amlodipine; zilebesiran versus placebo as add-on to 
indapamide), these sample sizes will provide at least 80% power to detect the following 
difference between zilebesiran versus placebo: 
• 5 mmHg as add-on to olmesartan  
• 6 mmHg as add-on to amlodipine 
• 8 mmHg as add-on to indapamide  
The power is assessed by simulation based on the Mixed Model with Repeated Measurements 
(MMRM), with change from baseline in 24-hour mean SBP assessed by ABPM at Month 3 as 
response variable and treatment, time, treatment-by-time as fixed factors and corresponding 
baseline value as a covariate. 
7.2. 
Statistical Methodology 
All analyses will be performed within each of the 3 protocol-specified background 
antihypertensive medication cohorts. The statistical and analytical plans presented below are 
brief summaries of planned analyses. More complete plans will be detailed in the SAP. Changes 
to the methods described in the final SAP will be described and justified as needed in the clinical 
study report. For information on study endpoints, see Section 2. 
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS): All randomized patients who received any amount of study 
drug. All by-treatment analyses based on the FAS will be grouped according to the 
randomized treatment arm.  
• Safety Analysis Set: All patients who received any amount of study drug. All by-
treatment analyses based on the Safety Analysis Set will be grouped according to the 
treatment actually received. 
• PK Analysis Set: All patients who received at least 1 full dose of zilebesiran and 
have at least 1 nonmissing postdose PK assessment. 
• PD Analysis Set: All patients who received at least 1 full dose of study drug. All by-
treatment analyses based on the PD Analysis Set will be grouped according to the 
treatment actually received. 
• All Zilebesiran Treated Set: All patients who received any amount of zilebesiran, 
including patients who took zilebesiran during the 6-month DB period and patients 
who initially took placebo and then switched to zilebesiran after the Month 6 visit. 


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For the analyses of the 6-month DB period, the analysis population used to evaluate efficacy will 
be the FAS. Safety data will be analyzed using the Safety Analysis Set. The PK and PD Analysis 
Sets will be used to conduct PK and PD analyses, respectively.  
The All Zilebesiran Treated Set will be used to summarize the efficacy and safety of zilebesiran 
throughout the 6-month DB period and the OLE period. 
7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints. Detailed methodology will be 
provided in the SAP. 
7.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other disease-specific baseline characteristics will be summarized. 
In general, baseline will be defined as the average of all assessments, including unscheduled 
assessments, between Run-in Visit 2 and prior to the first dose of study drug. Details of the 
definition will be specified in the SAP. 
7.2.5. 
Efficacy Analyses 
The primary endpoint is the change from baseline at Month 3 in 24-hour mean SBP, assessed by 
ABPM. The primary hypothesis of the add-on effect of zilebesiran compared to placebo in 
patients receiving each of 3 protocol-specified background antihypertensive medications 
(olmesartan, amlodipine or indapamide) will be tested separately at a 2-sided significance level 
of 0.05 using MMRM. The MMRM model will include treatment, time, treatment-by-time, and 
race (black or all other races) as fixed factors and baseline 24-hour mean SBP assessed by 
ABPM and screening eGFR as covariates.  
The key secondary endpoints are: 
• Change from baseline at Month 3 in office SBP 
• Time-adjusted change from baseline through Month 6 in 24-hour mean SBP, assessed 
by ABPM 
• Time-adjusted change from baseline through Month 6 in office SBP  
• Proportion of patients with 24-hour mean SBP assessed by ABPM <130 mmHg 
and/or reduction ≥20 mmHg without escape antihypertensive medication at Month 6  
To control the overall type I error, the primary and key secondary endpoints will be tested in 
hierarchical order. 
Details of the analysis method for primary, secondary, and exploratory endpoints will be 
described in the SAP. 


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7.2.6. 
Pharmacodynamic Analysis 
Pharmacodynamic analyses will include the evaluation of changes in levels of serum AGT and 
other exploratory biomarkers of the RAAS pathway. Descriptive statistics for observed levels 
and the relative change from baseline for all measured biomarkers will be presented for each of 
the postdose time points. 
Statistical comparison of the biomarker levels (absolute and/or change from baseline) across 
treatment groups may be explored. Details of the analysis will be specified in the SAP.  
Population PK/PD analysis may be conducted to evaluate the dose-response relationships for PD 
reduction after zilebesiran treatment. Additionally, the relationship between lowering of serum 
AGT and blood pressure may be explored within a modeling framework. If conducted, these 
analyses will be described in a pharmacometrics analysis plan and results will be presented in a 
separate report. 
7.2.7. 
Pharmacokinetic Analysis 
Plasma concentrations of zilebesiran and its metabolite AS(N-1)3′ zilebesiran will be 
summarized using descriptive statistics. 
Population PK analysis may be conducted on the PK data from this study. If conducted, the 
analysis methods will be described in a pharmacometrics analysis plan and results will be 
presented in a separate report. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs). Safety parameters also include vital signs, ECGs, clinical laboratory assessments and 
physical exams. Extent of exposure will be summarized.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. Results will be tabulated by Anatomical Therapeutic Chemical Classification System 
and Preferred Term (PT). 
Adverse events will be classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class and Preferred Term [by dose level and overall]. AEs, SAEs, 
related AEs, AEs leading to discontinuation of study drug, and AEs leading to death will be 
summarized by System Organ Class and PT for each treatment arm. By patient listings will be 
provided for deaths, SAEs, and AEs leading to discontinuation of study drug. Adverse events 
collected during the Run-in period will be summarized. 
Descriptive statistics will be provided for clinical laboratory parameters, ECG, and vital signs 
summarizing the observed values and changes from baseline over time. Laboratory shift tables 
from baseline grade (or category) to worst post-baseline grade (or category) will be presented for 
laboratory parameters that are graded or categorized. Abnormal physical exam findings will be 
presented in listings. 
Other safety summaries will be presented as appropriate. Further details will be specified in the 
SAP. 


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7.2.9. 
Immunogenicity Analyses 
The frequency and percentage of patients with confirmed positive ADA assay at any time during 
study as well as at each scheduled visit will be summarized. The titer results for patients with 
confirmed positive ADA results will be summarized. 
7.2.10. 
Interim Analysis 
The analysis of the primary endpoint and secondary endpoints measured at Month 3 will be 
conducted after all patients complete the Month 3 visit or withdraw from the study prior to the 
Month 3 visit. No formal interim analysis is planned before the analysis at Month 3. 
7.2.11. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the ICF (see Section 4.3.2). 
8. 
STUDY ADMINISTRATION 
8.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the current guidelines of Good Clinical Practice (GCP). Compliance with GCP 
provides public assurance that the rights, safety, and well-being of study patients are protected 
consistent with the principles that have their origin in the Declaration of Helsinki. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. Patients must also 
be notified that they are free to discontinue from the study at any time. The patient should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The Investigator will inform the patient/legal guardian if new information becomes available that 
may be relevant to the patient’s/legal guardian’s willingness to continue participation in the 
study. Communication of this information should be documented. 
The patient’s signed and dated informed consent (in paper or electronic format per local 
regulations and institutional standards) must be obtained before conducting any study tests or 
procedures that are not part of routine care. 
The Investigator must maintain the original, signed ICF. All patients will be given a copy of the 
signed and dated ICF. 
8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate. The Investigator must submit written approval before he or she 
can enroll any patient into the study. 


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The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements. In addition, the IRB or IEC must approve all patient 
materials for the study. The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
Initial IRB or IEC approval of the protocol, and all materials approved by the IRB or IEC for this 
study including the patient consent form and recruitment materials must be maintained by the 
Investigator and made available for inspection. 
The Investigator will submit reports of SAEs as outlined in Section 6.5.6. In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study. The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies, IRBs, or IECs in regard to inspections, other 
studies that impact this protocol or the qualifications of study personnel should be promptly 
reported to the Sponsor or its designee. 
The Investigator is also responsible for providing the IRB or IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the study drug. The Sponsor 
or designee will provide this information to the Investigator. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study. Amendments to the protocol must be submitted in writing to the Investigator’s IRB or IEC 
and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol, and patients or their legal guardians must be re-consented to the most current version of 
the ICF. 
8.1.3. 
Serious Breach of Protocol 
Investigators must notify the Medical Monitor within 24 hours of becoming aware of a potential 
serious breach of the protocol. A serious breach is a breach that is likely to affect to a significant 
degree the safety and rights of a study participant or the reliability and robustness of the data 
generated in the clinical study. 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention 
All documentation (including personal data) relating to the study should be retained for 2 years 
after the last approval in an ICH territory or as required by local laws and regulations, whichever 
is longer. 
If it becomes necessary for the Sponsor, the Sponsor’s designee, applicable IRB/IEC, or 
applicable regulatory authorities to review or audit any documentation relating to the study, the 
Investigator must permit direct access to all source documents/data. Records will not be 
destroyed without informing the Sponsor in writing and giving the Sponsor the opportunity to 
store the records for a longer period of time at the Sponsor’s expense. 
The Investigator must ensure that the patients’ confidentiality will be maintained. On the eCRFs 
or other documents submitted to the Sponsor or designees, patients should not be identified by 
their names, but by the assigned patient number or code. If patient names are included on copies 


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of documents to be submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number added to the document, before sending to the Sponsor. Documents not 
for submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
The Investigator must treat all of the information related to the study and the compiled data as 
confidential, whose use is for the purpose of conducting the study. The Sponsor must approve 
any transfer of information not directly involved in the study. 
To comply with local and/or regional regulations, this clinical study may be registered, and study 
results may be posted on public registries, such as ClinicalTrials.gov. 
8.1.5. 
End of Study 
The end of study is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor, or designee, reserves the right to terminate the study or a clinical study site at any 
time. Conditions that may warrant this action may include, but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to patients participating 
in the study 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• The decision on the part of the Sponsor to suspend or discontinue treatment with the 
study drug 
Should the study be terminated, and/or the site closed for whatever reason, all documentation and 
study drug pertaining to the study must be returned to the Sponsor or its representative, and the 
Investigators, IRB/IEC and Regulatory Authorities will be promptly informed of the termination 
and the reason for the decision. The Investigator should promptly inform the patients and assure 
appropriate therapy and follow-up. 
8.2. 
Data Quality Control and Quality Assurance 
8.2.1. 
Data Handling 
Study data must be recorded on CRFs (paper and/or electronic) provided by the Sponsor or 
designee on behalf of the Sponsor. Case report forms must be completed only by persons 
designated by the Investigator. If eCRFs are used, study data must be entered by trained site 
personnel with access to a valid and secure eCRF system. All data entered into the eCRF must 
also be available in the source documents. Corrections on paper CRFs must be made so as to not 
obliterate the original data and must be initialed and dated by the person who made the 
correction. 


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8.2.2. 
Study Monitoring 
The Monitor, as a representative of the Sponsor, has an obligation to closely follow the study 
conduct at the site. The Monitor will visit the Investigator and clinical study center periodically 
and will maintain frequent telephone and written contact. The Monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the Investigator and staff. 
The Monitor will review source documents, systems and CRFs to ensure overall quality and 
completeness of the data and to confirm study procedures are complied with the requirements in 
the study protocol accurately. The Sponsor, or its designee, will be allowed to conduct site visits 
to the investigation facilities for the purpose of monitoring any aspect of the study. The 
Investigator agrees to allow the Monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and study source documents, site standard operating 
procedures and training records, and other records relative to study conduct. 
Where local regulations allow, the Monitor may request remote access to source documents and 
systems. Should this take place, it will be done in a manner that protects the confidentiality of the 
data. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core study processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements. A regulatory 
authority, an IEC or an IRB may visit the site to perform audits or inspections, including source 
data verification. The Investigator should contact the Sponsor and designee immediately if 
contacted by a regulatory agency, an IEC or an IRB about an inspection. 
8.3. 
Publication Policy 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting. A copy of any proposed publication 
(eg, manuscript, abstracts, oral/slide presentations, book chapters) based on this study, must be 
provided and confirmed received at the Sponsor at least 30 days before its submission. The 
Clinical Trial Agreement will detail the procedures for publications. 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors). 


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9. 
LIST OF REFERENCES 
Abraham HM, White CM,White WB. The comparative efficacy and safety of the angiotensin 
receptor blockers in the management of hypertension and other cardiovascular diseases. Drug 
Saf. 2015 Jan;38(1):33-54. 
Angell SY, De Cock KM,Frieden TR. A public health approach to global management of 
hypertension. Lancet. 2015 Feb 28;385(9970):825-7. 
Burnier M, Bakris G,Williams B. Redefining diuretics use in hypertension: why select a thiazide-
like diuretic? J Hypertens. 2019 Aug;37(8):1574-86. 
Corrao G, Parodi A, Nicotra F, Zambon A, Merlino L, Cesana G, et al. Better compliance to 
antihypertensive medications reduces cardiovascular risk. J Hypertens. 2011 Mar;29(3):610-8. 
Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. Prevention of 
cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as 
required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian 
Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre 
randomised controlled trial. Lancet. 2005 Sep 10-16;366(9489):895-906. 
Dzau VJ,Balatbat CA. Future of Hypertension. Hypertension. 2019 Sep;74(3):450-7. 
Forouzanfar MH, Liu P, Roth GA, Ng M, Biryukov S, Marczak L, et al. Global Burden of 
Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990-2015. JAMA. 
2017 Jan 10;317(2):165-82. 
Georgianos PI,Agarwal R. Revisiting RAAS blockade in CKD with newer potassium-binding 
drugs. Kidney Int. 2018 Feb;93(2):325-34. 
Jamerson K, Weber MA, Bakris GL, Dahlof B, Pitt B, Shi V, et al. Benazepril plus amlodipine 
or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008 Dec 
4;359(23):2417-28. 
Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al. Outcomes in 
hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or 
amlodipine: the VALUE randomised trial. Lancet. 2004 Jun 19;363(9426):2022-31. 
Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK,He J. Global burden of 
hypertension: analysis of worldwide data. Lancet. 2005 Jan 15-21;365(9455):217-23. 
Khanna A, English SW, Wang XS, Ham K, Tumlin J, Szerlip H, et al. Angiotensin II for the 
Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-30. 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12. 
Makani H, Bangalore S, Desouza KA, Shah A,Messerli FH. Efficacy and safety of dual blockade 
of the renin-angiotensin system: meta-analysis of randomised trials. BMJ. 2013 Jan 28;346:f360. 
Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, et al. Single-drug 
therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The 


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Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J 
Med. 1993 Apr 1;328(13):914-21. 
McClellan M, Brown N, Califf RM,Warner JJ. Call to Action: Urgent Challenges in 
Cardiovascular Disease: A Presidential Advisory From the American Heart Association. 
Circulation. 2019 Feb 26;139(9):e44-e54. 
McMurray JJ, Krum H, Abraham WT, Dickstein K, Kober LV, Desai AS, et al. Aliskiren, 
Enalapril, or Aliskiren and Enalapril in Heart Failure. N Engl J Med. 2016 Apr 21;374(16):1521-
32. 
Mullick AE, Yeh ST, Graham MJ, Engelhardt JA, Prakash TP,Crooke RM. Blood Pressure 
Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of 
Hypertension and Kidney Injury. Hypertension. 2017 Sep;70(3):566-76. 
Muntner P, Hardy ST, Fine LJ, Jaeger BC, Wozniak G, Levitan EB, et al. Trends in Blood 
Pressure Control Among US Adults With Hypertension, 1999-2000 to 2017-2018. JAMA. 2020 
Sep 22;324(12):1190-200. 
NCD Risk Factor Collaboration. Worldwide trends in blood pressure from 1975 to 2015: a 
pooled analysis of 1479 population-based measurement studies with 19.1 million participants. 
Lancet. 2017 Jan 7;389(10064):37-55. 
Ojima M, Igata H, Tanaka M, Sakamoto H, Kuroita T, Kohara Y, et al. In vitro antagonistic 
properties of a new angiotensin type 1 receptor blocker, azilsartan, in receptor binding and 
function studies. J Pharmacol Exp Ther. 2011 Mar;336(3):801-8. 
Olsen MH, Angell SY, Asma S, Boutouyrie P, Burger D, Chirinos JA, et al. A call to action and 
a lifecourse strategy to address the global burden of raised blood pressure on current and future 
generations: the Lancet Commission on hypertension. Lancet. 2016 Nov 26;388(10060):2665-
712. 
Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, et al. 
Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012 Dec 
6;367(23):2204-13. 
Peacock E,Krousel-Wood M. Adherence to Antihypertensive Therapy. Med Clin North Am. 
2017 Jan;101(1):229-45. 
Romero CA, Orias M,Weir MR. Novel RAAS agonists and antagonists: clinical applications and 
controversies. Nat Rev Endocrinol. 2015 Apr;11(4):242-52. 
Schulz M, Krueger K, Schuessel K, Friedland K, Laufs U, Mueller WE, et al. Medication 
adherence and persistence according to different antihypertensive drug classes: A retrospective 
cohort study of 255,500 patients. Int J Cardiol. 2016 Oct 1;220:668-76. 
Services UDoHaH. The Surgeon General's Call to Action to Control Hypertension. 2020 October 
2020:1-50. 
Uijl E, Mirabito Colafella KM, Sun Y, Ren L, van Veghel R, Garrelds IM, et al. Strong and 
Sustained Antihypertensive Effect of Small Interfering RNA Targeting Liver Angiotensinogen. 
Hypertension. 2019 Jun;73(6):1249-57. 


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van der Laan DM, Elders PJM, Boons C, Beckeringh JJ, Nijpels G,Hugtenburg JG. Factors 
associated with antihypertensive medication non-adherence: a systematic review. J Hum 
Hypertens. 2017 Nov;31(11):687-94. 
von Bergmann K, Laeis P, Puchler K, Sudhop T, Schwocho LR,Gonzalez L. Olmesartan 
medoxomil: influence of age, renal and hepatic function on the pharmacokinetics of olmesartan 
medoxomil. J Hypertens Suppl. 2001 Jun;19(1):S33-40. 
Weir MR, Bakris GL, Bushinsky DA, Mayo MR, Garza D, Stasiv Y, et al. Patiromer in patients 
with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015 Jan 
15;372(3):211-21. 
Whelton PK, Carey RM, Aronow WS, Casey DE, Jr., Collins KJ, Dennison Himmelfarb C, et al. 
2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the 
Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report 
of the American College of Cardiology/American Heart Association Task Force on Clinical 
Practice Guidelines. Hypertension. 2018 Jun;71(6):e13-e115. 
White WB, Weber MA, Sica D, Bakris GL, Perez A, Cao C, et al. Effects of the angiotensin 
receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic 
blood pressure in patients with stages 1 and 2 hypertension. Hypertension. 2011 Mar;57(3):413-
20. 
Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH 
Guidelines for the management of arterial hypertension: The Task Force for the management of 
arterial hypertension of the European Society of Cardiology and the European Society of 
Hypertension: The Task Force for the management of arterial hypertension of the European 
Society of Cardiology and the European Society of Hypertension. J Hypertens. 2018 
Oct;36(10):1953-2041. 
 


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10. 
APPENDICES 
10.1. 
Formula for Estimated Glomerular Filtration Rate Calculation 
Estimated glomerular filtration rate (eGFR; in mL/min/1.73m2) will be calculated from serum 
creatinine (SCr) based on the Modification of Diet in Renal Disease formula. 
Modification of Diet in Renal Disease Formula [Levey 2009] 
• Conventional units 
− eGFR (mL/min/1.73m2) = 175 × (SCr [mg/dL])-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
• SI units 
− eGFR (mL/min/1.73m2) = 175 × (SCr [μmol/L]/88.4)-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
10.2. 
Measurement of Blood Pressure 
All blood pressure measurements (office, ABPM, and HBPM) must be taken using the 
standardized equipment provided by the Sponsor, according to the methods described in the 
relevant user manuals.  
The appropriately sized cuff for each modality must be used for all assessments. The arm’s 
circumference at midpoint (halfway between the acromion and olecranon) should be determined 
at screening with a metric tape measure and used to select the appropriately sized blood pressure 
cuff/bladder for each instrument as described in the Study Manual. Unless significant weight loss 
or gain occurs between visits, the patient should use the same cuff/bladder size throughout the 
study. 
At the first Screening visit only, office blood pressure will be measured in both arms to select the 
appropriate arm to use for office blood pressure and HBPM measurements. Unless a concomitant 
condition favors the use of a specific arm, the arm with the higher office SBP should be used for 
all subsequent office blood pressure and HBPM readings. The ABPM should be measured using 
the patient’s nondominant arm. If the patient is ambidextrous, the same arm used for office blood 
pressure and HBPM readings should be used. 
ABPM 
The appropriately sized cuff should be placed on the correct arm following the instructions in the 
Study Manual. Consecutive (daily) use of over-the-counter NSAIDs (other than aspirin ≤100 mg 
per day) and use of cannabis or THC-containing substances should be avoided for at least 2 days 
prior to ABPM measurements. ABPM should be started prior to the morning dose of 
antihypertensive medication. All ABPM collections must be in the outpatient/ambulatory state. 
ABPM recordings that are associated with dosing visits must be obtained in advance of the visit 
(within 7 days before the corresponding dosing visit) and the results reviewed prior to dosing. 
During the 24-hour monitoring period, patients must avoid strenuous exercise but should 
otherwise maintain their usual level of physical activity. The ABPM is programmed to take 


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readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the 
night (10 pm to 5:59 am). While awake, the patient should hold their arm still by their side while 
the device is inflating for a reading. Patients must record the timing of going to sleep, waking up, 
and any oral medications taken during the ABPM, and these responses must be entered into the 
eCRF. 
After the monitoring period is complete, upload the ABPM data to receive a report with validity 
assessment. An ABPM will be considered valid if (1) the number of successful daytime readings 
is ≥33, (2) the number of successful nighttime readings is ≥11, and (3) no more than 3 hours are 
not represented (ie, 3 sections of 60 minutes where 0 valid readings were obtained). If the ABPM 
recording is invalid (either during the Run-in Period or after the second randomization), the 
patient will be provided 1 opportunity to repeat the study within 4 days. If the second ABPM 
recording is also invalid during screening, the patient is a run-in failure. 
Office Blood Pressure 
Office blood pressure must be measured using the automated blood pressure device provided by 
the Sponsor and the arm selected during screening. 
Office blood pressure should be measured early in the visit prior to the morning dose of 
antihypertensive medications, before phlebotomy or other potentially stressful assessments. To 
minimize confounding by circadian changes, study visits should be scheduled for a consistent 
timeframe of the day. The use of inhaled short-acting beta agonists should be avoided within 6 
hours prior to measuring blood pressure and/or heart rate. The use of phosphodiesterase type 5 
inhibitors (eg, sildenafil, tadalafil, vardenafil, avanafil) should be avoided within 48 hours prior 
to measuring blood pressure. Consecutive (daily) use of over-the-counter NSAIDs (other than 
aspirin ≤100 mg per day) use of cannabis or THC-containing substances should be avoided for at 
least 2 days prior to office blood pressure measurements. 
Before measuring blood pressure, confirm that there has been no exercise or use of caffeine or 
nicotine- or tobacco-containing products (including but not limited to snuff, chewing tobacco, 
cigars, cigarettes, pipes, nicotine patches, or e-cigarettes) within the last 30 minutes. If necessary, 
delay blood pressure assessment to meet these requirements. Because a full bladder can impact 
blood pressure measurements, ask the patient to use the bathroom before the assessment. 
All office blood pressure assessments will include both seated and standing measurements.  
Seated Office Blood Pressure Measurement: For seated measurements, the patient should be in a 
comfortable resting position in a chair with their back supported and their feet flat on the floor. 
• Place the appropriately sized cuff on the correct arm with no clothing between the 
patient’s arm and the cuff and with the midpoint of the bladder length positioned over 
the brachial artery (located by palpation). The arm should be supported on an armrest 
or table with mid-cuff at heart level and the palm facing the ceiling. 
• Follow the Study Manual to initiate the automated blood pressure device’s seated 
measurement protocol. This program includes a 5-minute period of rest, followed by 
4 sequential blood pressure measurements at 1-minute intervals. The seated blood 
pressure for the visit will be defined by the average of the last 3 individual 
measurements. 


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• During the device’s seated measurement protocol, the patient should remain at rest 
without distraction (avoid mobile phones). The following script may be used: “The 
blood pressure device works best when you are at rest and without any distraction, so 
the staff will avoid interacting with you during this assessment. This assessment will 
include a 5-minute period of rest, followed by about 5 minutes of the device inflating 
to measure your blood pressure”. 
Standing Office Blood Pressure Measurement: A standing measurement should be obtained 
immediately after collection of the seated measurements. 
• Being careful to maintain the cuff’s position, ask the patient to stand with the cuffed 
arm bent slightly and the hand of the cuffed arm supported at heart level.  
• Measure standing blood pressure 1 minute after standing using the automated blood 
pressure device’s single measurement protocol.  
• After the standing measurement, ask the patient if they experienced dizziness or light-
headedness when standing and record their response. 
If a patient is unable to report to the site for an office blood pressure assessment, a substitute 
“remote visit blood pressure measurement” may be obtained remotely by a visiting nurse or other 
appropriately trained personnel. If a home visit is not possible, a “remote visit blood pressure 
measurement” should instead be obtained using the patient’s HBPM instrument under direct 
supervision (phone call or teleconferencing) by appropriately trained study staff, following the 
instructions detailed in the Study Manual. Results and the remote method used will be recorded. 
HBPM 
Patients should measure HBPM in the morning, prior to breakfast/caffeine or taking morning 
oral medications. HBPM is not required at times when ABPM is being assessed. The HBPM 
measurement should be obtained in a room without distractions, seated comfortably with the 
back supported and feet flat on the floor. The patient will initiate the automated blood pressure 
program on their HBPM device. This program includes a 5-minute period of rest, followed by 4 
sequential blood pressure measurements at 1-minute intervals. The seated blood pressure for the 
visit will be defined by the average of the last 3 individual measurements.  
To establish baseline, each patient should measure HBPM 3 times during the week prior to the 
second randomization.  
After Day 1, HBPM should be measured at least once per week and may be increased at the 
Investigator’s discretion if more frequent measurement is warranted. Patients may select the day 
of the week that is most convenient for their personal schedule.  


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CLINICAL STUDY PROTOCOL 
ALN-AGT01-003 
DATED 25 AUGUST 2021 
 
Protocol Title: 
A Randomized, Double-blind, Placebo-controlled, Multicenter 
Study to Evaluate the Efficacy and Safety of Zilebesiran Used as 
Add-on Therapy in Patients With Hypertension Not Adequately 
Controlled by a Standard of Care Antihypertensive Medication  
Short Title: 
Zilebesiran as Add-on Therapy in Patients With Hypertension Not 
Adequately Controlled by a Standard of Care Antihypertensive 
Medication (KARDIA-2)  
Study Drug: 
Zilebesiran (ALN-AGT01)  
EudraCT Number: 
2021-003776-13 
IND Number: 
143503 
Protocol Date: 
Original protocol, 25 August 2021 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
Telephone: +1-617-551-8200 
Sponsor Contact:  
 
  
The concepts and information contained in this document or generated during the study are considered 
proprietary and may not be disclosed in whole or in part without expressed written authorization of 
Alnylam Pharmaceuticals, Inc. 
 
PPD
PPD


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SPONSOR PROTOCOL APPROVAL 
 
I have read this protocol and I approve the design of this study. 
 
 
 
___________________________________________  
 
 
Alnylam Pharmaceuticals, Inc. 
 
___________________________________________  
Date 
PPD
PPD


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INVESTIGATOR’S AGREEMENT 
 
I have read the ALN-AGT01-003 protocol and agree to conduct the study in accordance with the 
protocol and all applicable regulations. I agree to maintain the confidentiality of all information 
received or developed in connection with this protocol.  
 
___________________________________________  
Printed Name of Investigator 
 
___________________________________________  
Signature of Investigator 
 
___________________________________________  
Date 






Clinical Study Protocol ALN-AGT01-003  
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Study Design 
This is a Phase 2 randomized, double-blind (DB), placebo-controlled, multicenter study to 
evaluate the efficacy, safety, and pharmacodynamics (PD) of zilebesiran administered 
subcutaneously (SC) as an add-on therapy in patients with hypertension despite treatment with a 
standard of care antihypertensive medication. A schematic of the study design is provided in 
Figure 1. 
Patients who complete the Screening period and meet all inclusion/exclusion criteria for 
enrollment will be randomized to receive open-label therapy with olmesartan (40 mg orally once 
daily [or 20 mg orally once daily for patients with creatinine clearance ≤60 mL/min enrolled at 
sites outside of the United States (US), consistent with local labeling for olmesartan]), 
amlodipine (5 mg orally once daily), or indapamide (2.5 mg orally once daily) as their protocol-
specified background antihypertensive medication during a Run-in period of at least 4 weeks. 
Patients who meet all inclusion/exclusion criteria after the Run-in period will be randomized 1:1 
to receive 600 mg zilebesiran SC or placebo SC on Day 1 of a 6-month DB treatment period as 
add-on therapy to their protocol-specified background antihypertensive medication.  
Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive 
medications”) may be added to the patient’s protocol-specified background antihypertensive 
medication per Investigator judgement for elevated blood pressure. 
After the 6-month DB period, protocol-specified background antihypertensive medications will 
be discontinued, and patients may be eligible to participate in a separate zilebesiran open-label 
extension (OLE) study. If an individual patient reaches Month 6 prior to availability of the 
separate OLE study, they may receive open-label zilebesiran at 600 mg SC once every 6 months 
for up to 12 additional months until the separate OLE study is open and then transition.  
Number of Planned Patients 
The planned enrollment for this study is approximately 800 patients to be randomized into the 
Run-in period and approximately 630 patients (300 patients in the olmesartan arm, 210 patients 
in the amlodipine arm, and 120 patients in the indapamide arm) to be randomized in the DB 
period. 
Diagnosis and Main Eligibility Criteria 
This study will include adults (18 to 75 years, inclusive) with untreated hypertension or on stable 
therapy with up to 2 antihypertensive medications of the following classes: an angiotensin 
converting enzyme inhibitor, angiotensin II-receptor blocker, renin inhibitor, calcium channel 
blocker, thiazide diuretic, and/or thiazide-like diuretic. Patients should have a 24-hour mean 
systolic blood pressure (SBP) >130 mmHg and ≤160 mmHg by ambulatory blood pressure 
monitoring (ABPM) after at least 4 weeks of run-in on protocol-specified background 
antihypertensive medication. Patients with secondary hypertension or orthostatic hypotension 
will be excluded. 
Study Drug, Dose, and Mode of Administration 
Zilebesiran is an SC administered N-acetylgalactosamine (GalNAc)-conjugated small interfering 
RNA (siRNA) targeting liver-expressed messenger RNA (mRNA) for angiotensinogen (AGT). 


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Patients randomized to receive zilebesiran will be administered 600 mg SC once during the 6-
month DB treatment period; all patients will receive 600 mg SC once every 6 months during the 
OLE period. 
Reference Treatment, Dose, and Mode of Administration 
Placebo (phosphate-buffered saline for SC administration) will be administered at the same 
dosing interval and volume as the study drug during the 6-month DB period. 
Protocol-specified Background Antihypertensive Medication, Dose, and Mode of 
Administration 
Patients will be randomized to 1 of the following protocol-specified background antihypertensive 
medications to be administered orally once daily during the Run-in and 6-month DB periods: 
• Olmesartan: 40 mg (or 20 mg for patients with creatinine clearance ≤60 mL/min 
enrolled at sites outside of the US, consistent with local labeling). At the 
Investigator’s discretion, patients who are randomized to receive 40 mg olmesartan 
once daily may initiate treatment at 20 mg once daily and then uptitrate to the full 
dose of 40 mg once daily after 1 to 2 weeks. 
• Amlodipine: 5 mg  
• Indapamide: 2.5 mg  
Duration of Treatment and Study Participation 
The duration of treatment with zilebesiran is up to 18 months. The estimated total time on study 
for patients who rollover to the separate OLE study is up to approximately 20 months, including 
up to 2 months of the Screening and Run-in periods, and up to 18 months of treatment. For all 
patients who discontinue study drug or do not roll over to the separate OLE study, the Safety 
Follow-up period is up to 12 months. 
Statistical Methods 
The planned enrollment for this study is approximately 800 patients to be randomized into the 
Run-in period and approximately 630 patients (300 patients in the olmesartan arm, 210 patients 
in the amlodipine arm, and 120 patients in the indapamide arm) to be randomized in the DB 
period. Randomization on Day 1 will be stratified by race (black or all other races), baseline 
blood pressure (24-hour mean SBP < or ≥145 mmHg), and screening estimated glomerular 
filtration rate (<60 or ≥60 mL/min/1.73m2). 
For the primary endpoint, assuming a standard deviation of 16 mmHg in change from baseline in 
24-hour mean SBP assessed by ABPM and 15% dropout rate from baseline to Month 3, with 2-
sided significance level of 0.05 for each of the comparisons (zilebesiran versus placebo as add-
on to olmesartan; zilebesiran versus placebo as add-on to amlodipine; zilebesiran versus placebo 
as add-on to indapamide), these sample sizes will provide at least 80% power to detect the 
following difference between zilebesiran versus placebo: 
• 5 mmHg as add-on to olmesartan  
• 6 mmHg as add-on to amlodipine 
• 8 mmHg as add-on to indapamide 


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The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS): All randomized patients who received any amount of study 
drug. All by-treatment analyses based on the FAS will be according to the 
randomized treatment arm.  
• Safety Analysis Set: All patients who received any amount of study drug, grouped 
according to the treatment actually received. 
• Pharmacokinetic (PK) Analysis Set: All patients who received at least 1 full dose of 
study drug and have at least 1 postdose blood sample for PK parameters and have 
evaluable PK data. 
• PD Analysis Set: All patients who received at least 1 full dose of study drug and who 
have an evaluable baseline and at least 1 evaluable post-baseline PD measurement 
will be included in the PD analyses. 
The primary population used to evaluate efficacy will be the FAS. The primary endpoint is the 
change in 24-hour mean SBP from baseline to Month 3, assessed by ABPM. The primary 
hypothesis of the add-on effect of zilebesiran compared to placebo in patients receiving each of 3 
protocol-specified background antihypertensive medications (olmesartan, amlodipine or 
indapamide) will be tested separately. To control the overall type I error, the following secondary 
endpoints will be tested in hierarchical order, only if the primary endpoint is statistically 
significant: 
• Change in office SBP from baseline to Month 3 
• Change in 24-hour mean SBP from baseline to Month 6, assessed by ABPM 
• Change in office SBP from baseline to Month 6 
Safety data will be summarized descriptively. 


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Figure 1: 
Study Design 
 
Abbreviations: aHTN=antihypertensive medication; BL=baseline; DB=double-blind; M=month; OLE=open-label 
extension; PBO=placebo; PO=per os (oral); qd=once daily; q6M=once every 6 months; R=randomization; 
SC=subcutaneous. 
Note: Patients may be eligible to participate in a separate zilebesiran OLE study upon completion of the Month 6 
predose assessments. If an individual patient reaches Month 6 prior to availability of the separate OLE study, they 
may receive open-label zilebesiran once every 6 months in the OLE period for up to 12 additional months until the 
OLE study is open and then transition. Once the separate OLE study is open for enrollment, eligible patients may 
rollover into the separate OLE study at Month 6, 12, or 18 (first visit after the separate OLE study is open). 
Patients who were previously taking antihypertensives at screening should undergo a washout of these medications 
for at least 4 weeks during the Run-in period. 
 












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12 months, whichever comes earlier. During this Follow-up period, HBPM monitoring may continue at the discretion of the Investigator. The ADA 
sample should only be collected at the first Follow-up visit during the Follow-up period. 
• 
Patients who discontinue study drug prior to the Month 6 visit will also be asked to complete the remainder of scheduled study visits and assessments 
(except for study drug administration) through Month 6. If a patient discontinues study drug after the Month 6 visit, EOT/ET assessments should be 
performed.  
 
Footnotes: 
a All assessments, except for postdose PK sample collection (Table 2), are to be performed prior to administration of protocol-specified background 
antihypertensive medications (including Run-In Visit 1) and study drug (as applicable).  
b When applicable, pregnancy test results must be known prior to dosing with study drug at dosing visits.  
c Laboratory assessments at Day 1 do not need to be repeated, per Investigator discretion, if they were collected within 7 days before Day 1 at Run-in Visit 2.  
d Office blood pressure must be measured before the patient takes oral antihypertensive medications or study drug (as applicable).  
e ABPM recordings associated with study drug dosing visits should be obtained within 7 days before the visit and results reviewed before dosing. In the Safety 
Follow-up period, ABPM assessments may be reduced and are optional per Investigator judgement.  
f HBPM should be measured in the morning upon waking. HBPM must be collected daily for at least 1 week during the Run-in period starting at 3 weeks of run-
in (1 week prior to Run-in Visit 2). HBPM is not required at times when ABPM is being assessed. In the Safety Follow-up period, the frequency of HBPM 
assessments can be reduced after the first Safety Follow-up visit per Investigator judgement. 
g Neurological evaluation will also be performed as part of the full physical examination. 


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Table 2: 
PK Time Points 
Study Day 
Sampling Time 
(hh:mm) 
Plasma PK Sample 
Day 1  
Predose (any time before dosing) 
X 
04:00 (±30 min) 
X 
Day 169±7 
Predose (any time before dosing) 
X 
04:00 (±30 min) 
X 
Abbreviations: hh:mm=hour:minute; min=minutes; PK=pharmacokinetics. 
Notes:  
• 
The hour (±range) indicates sample collection timing relative to dosing. Precise PK sample times (hour 
and minute) are recorded. Refer to Section 6.4 for additional information on PK assessments. 
 


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TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................2 
INVESTIGATOR’S AGREEMENT ...............................................................................................3 
PROTOCOL SYNOPSIS ................................................................................................................4 
TABLE OF CONTENTS ...............................................................................................................17 
LIST OF TABLES .........................................................................................................................21 
LIST OF FIGURES .......................................................................................................................21 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................22 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Study Rationale ...........................................................................................................24 
1.2. 
Background .................................................................................................................24 
1.3. 
Benefit-Risk Assessment ............................................................................................26 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................27 
3. 
INVESTIGATIONAL PLAN .....................................................................................28 
3.1. 
Summary of Study Design ..........................................................................................28 
3.2. 
Scientific Rationale for Study Design ........................................................................30 
3.3. 
Justification for Dose ..................................................................................................32 
3.4. 
Method of Assigning Patients to Treatment Groups ..................................................32 
3.5. 
Blinding ......................................................................................................................33 
3.5.1. 
Emergency Unblinding ...............................................................................................33 
3.6. 
Data Monitoring Committee .......................................................................................33 
3.7. 
Clinical Event Adjudication Committees ...................................................................33 
3.8. 
Definition of End of Study for an Individual Patient .................................................34 
4. 
SELECTION AND REMOVAL OF PATIENTS ......................................................34 
4.1. 
Inclusion Criteria ........................................................................................................34 
4.2. 
Exclusion Criteria .......................................................................................................35 
4.3. 
Removal from Study Drug or Assessment .................................................................37 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments ......................37 
4.3.2. 
Stopping a Patient’s Study Participation ....................................................................39 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study .......................................39 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data or Objection 
to Process Patient’s Personal Data ..............................................................................39 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study ........................39 


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4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation ................................40 
4.3.3. 
Lost to Follow-Up.......................................................................................................40 
4.3.4. 
Replacement of Study Patients ...................................................................................40 
5. 
TREATMENTS AND OTHER REQUIREMENTS ..................................................40 
5.1. 
Treatments Administered ............................................................................................40 
5.2. 
Study Drug ..................................................................................................................41 
5.2.1. 
Description ..................................................................................................................41 
5.2.2. 
Dose and Administration ............................................................................................41 
5.2.3. 
Dose Modifications .....................................................................................................41 
5.2.4. 
LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing...........42 
5.2.5. 
Neurological Criteria for Withholding, Monitoring, and Stopping Study 
Drug Dosing ................................................................................................................43 
5.3. 
Protocol-specified Background Antihypertensive Medications .................................43 
5.4. 
Preparation, Handling, and Storage ............................................................................44 
5.5. 
Packaging and Labeling ..............................................................................................44 
5.6. 
Accountability .............................................................................................................45 
5.7. 
Clinical Product Complaints .......................................................................................45 
5.7.1. 
Definition ....................................................................................................................45 
5.7.2. 
Reporting ....................................................................................................................45 
5.8. 
Monitoring for Potential Clinical Events ....................................................................45 
5.8.1. 
Monitoring and Approach for Potential Hypotension ................................................45 
5.8.2. 
Monitoring and Approach for Clinically Significant Blood Pressure 
Elevation .....................................................................................................................46 
5.8.3. 
Monitoring and Approach for Potential Renal Dysfunction .......................................48 
5.8.4. 
Monitoring and Approach for Potential Hyperkalemia ..............................................49 
5.9. 
Concomitant Medications and Procedures .................................................................50 
5.9.1. 
Prohibited Concomitant Medication ...........................................................................50 
5.10. 
Treatment Compliance ................................................................................................51 
5.11. 
Other Requirements ....................................................................................................51 
5.11.1. 
Contraception ..............................................................................................................51 
5.11.2. 
Alcohol Restrictions ...................................................................................................52 
5.11.3. 
Tobacco and Nicotine Restrictions .............................................................................52 
5.11.4. 
Cannabis Restriction ...................................................................................................52 


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5.11.5. 
Dietary Recommendations ..........................................................................................52 
5.11.6. 
Exercise .......................................................................................................................53 
6. 
STUDY ASSESSMENTS ..........................................................................................53 
6.1. 
Screening Assessments ...............................................................................................53 
6.1.1. 
Retesting .....................................................................................................................53 
6.1.2. 
Rescreening .................................................................................................................54 
6.2. 
Efficacy Assessments .................................................................................................54 
6.2.1. 
ABPM .........................................................................................................................54 
6.2.2. 
Office Blood Pressure .................................................................................................54 
6.2.3. 
HBPM .........................................................................................................................55 
6.3. 
Pharmacodynamic Assessments .................................................................................55 
6.4. 
Pharmacokinetic Assessments ....................................................................................55 
6.5. 
Safety Assessments .....................................................................................................55 
6.5.1. 
Vital Signs ..................................................................................................................56 
6.5.2. 
Weight, Height, and Morphometrics ..........................................................................56 
6.5.3. 
Physical Examination .................................................................................................57 
6.5.4. 
Electrocardiogram .......................................................................................................57 
6.5.5. 
Clinical Laboratory Assessments ...............................................................................57 
6.5.5.1. 
Fasting Lipid Panel and Glycemic Assessments ........................................................59 
6.5.5.2. 
Immunogenicity ..........................................................................................................59 
6.5.5.3. 
Pregnancy Testing ......................................................................................................60 
6.5.5.4. 
Additional Liver Function Assessments .....................................................................60 
6.5.6. 
Adverse Events ...........................................................................................................61 
6.5.6.1. 
Definitions ..................................................................................................................61 
6.5.6.2. 
Eliciting and Recording Adverse Events ....................................................................63 
6.5.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee .........................64 
6.5.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee ...........64 
6.5.6.5. 
Sponsor Safety Reporting to Regulatory Authorities .................................................64 
6.5.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee ........................................................................65 
6.5.6.7. 
Pregnancy Reporting ..................................................................................................65 
6.5.6.8. 
Reporting of Overdose and Other Special Situations .................................................65 
6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository ...................................66 


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7. 
STATISTICS ..............................................................................................................66 
7.1. 
Determination of Sample Size ....................................................................................66 
7.2. 
Statistical Methodology ..............................................................................................67 
7.2.1. 
Populations to be Analyzed ........................................................................................67 
7.2.2. 
Examination of Subgroups .........................................................................................68 
7.2.3. 
Handling of Missing Data ...........................................................................................68 
7.2.4. 
Baseline Evaluations ...................................................................................................68 
7.2.5. 
Efficacy Analyses .......................................................................................................68 
7.2.5.1. 
Primary Endpoint ........................................................................................................68 
7.2.5.2. 
Secondary Endpoints ..................................................................................................68 
7.2.6. 
Pharmacodynamic Analysis........................................................................................69 
7.2.7. 
Pharmacokinetic Analysis ..........................................................................................69 
7.2.8. 
Safety Analyses ..........................................................................................................69 
7.2.9. 
Immunogenicity Analyses ..........................................................................................70 
7.2.10. 
Interim Analysis ..........................................................................................................70 
7.2.11. 
Optional Additional Research .....................................................................................70 
8. 
STUDY ADMINISTRATION ...................................................................................70 
8.1. 
Ethical and Regulatory Considerations ......................................................................70 
8.1.1. 
Informed Consent .......................................................................................................70 
8.1.2. 
Ethical Review ............................................................................................................71 
8.1.3. 
Serious Breach of Protocol .........................................................................................71 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention .................................71 
8.1.5. 
End of Study ...............................................................................................................72 
8.1.6. 
Termination of the Clinical Study or Site Closure .....................................................72 
8.2. 
Data Quality Control and Quality Assurance .............................................................72 
8.2.1. 
Data Handling .............................................................................................................72 
8.2.2. 
Study Monitoring ........................................................................................................73 
8.2.3. 
Audits and Inspections ................................................................................................73 
8.3. 
Publication Policy .......................................................................................................73 
9. 
LIST OF REFERENCES ............................................................................................74 
10. 
APPENDICES ............................................................................................................77 
10.1. 
Formula for Estimated Glomerular Filtration Rate Calculation .................................77 
10.2. 
Measurement of Blood Pressure .................................................................................77 


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LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................10 
Table 2: 
PK Time Points ...........................................................................................................16 
Table 3: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative 
Cause Identified ..........................................................................................................43 
Table 4: 
Recommended Interventions for Potentially Clinically Significant Blood 
Pressure Elevation ......................................................................................................47 
Table 5: 
Recommended Interventions for Hyperkalemia .........................................................49 
Table 6: 
Clinical Laboratory Assessments ...............................................................................58 
Table 7: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases .............61 
 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Definition 
ABPM 
Ambulatory blood pressure monitoring 
ACE 
Angiotensin converting enzyme 
ADA 
Anti-drug antibody 
AE 
Adverse event 
AGT 
Angiotensinogen 
ALT 
Alanine aminotransferase 
AngI/II 
Angiotensin I/II 
ARB 
Angiotensin II-receptor blocker 
AST 
Aspartate aminotransferase 
CCB 
Calcium channel blocker 
CPC 
Clinical product complaint 
DB 
Double-blind 
DBP 
Diastolic blood pressure 
DMC 
Data Monitoring Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOT 
End of treatment 
ET 
Early termination 
FAS 
Full analysis set 
GalNAc 
N-acetylgalactosamine 
GCP 
Good Clinical Practice 
HbA1c 
Hemoglobin A1c 
HBPM 
Home blood pressure monitoring 
HCV 
Hepatitis C virus 
HDL-C 
High-density lipoprotein 
HOMA 
Homeostatic model assessment 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 


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IND 
Investigational New Drug 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR 
Injection site reactions 
LFT 
Liver function test 
MAO 
Monoamine oxidase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model with repeated measurements 
mRNA 
Messenger ribonucleic acid 
NSAID 
Nonsteroidal anti-inflammatory drug 
OLE 
Open-label extension 
PD 
Pharmacodynamics 
PK 
Pharmacokinetic 
PT 
Preferred term 
RAAS 
Renin-angiotensin-aldosterone system 
RNAi 
RNA interference 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
siRNA 
Small interfering RNA 
SGLT2 
Sodium-glucose co-transporter 2 
ULN 
Upper limit of normal 
 


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1. 
INTRODUCTION 
Alnylam Pharmaceuticals, Inc. (the Sponsor) is developing zilebesiran (ALN-AGT01), a 
subcutaneously (SC) administered investigational agent comprised of a synthetic small 
interfering RNA (siRNA) covalently linked to a triantennary N-acetylgalactosamine (GalNAc) 
ligand, which is designed to suppress liver production of angiotensinogen (AGT) and thereby 
reduce blood pressure in individuals with hypertension. 
1.1. 
Study Rationale 
Study ALN-AGT01-003 (KARDIA-2) is a randomized, double-blind, placebo-controlled, 
multicenter study designed to evaluate the efficacy, safety, and pharmacodynamics (PD) of 
zilebesiran administered SC as an add-on therapy in patients with hypertension despite treatment 
with a standard of care antihypertensive medication. Patients will be randomized to run-in on 1 
of 3 protocol-specified antihypertensive medications open-label for at least 4 weeks (olmesartan, 
amlodipine, or indapamide). At the end of the Run-in period, patients with uncontrolled blood 
pressure will be randomized 1:1 to receive zilebesiran or placebo as add-on therapy to the 
protocol-specified background antihypertensive medication for 6 months during the double-blind 
(DB) period. After completion of the 6-month DB period, patients may be eligible to participate 
in a separate zilebesiran open-label extension (OLE) study. If an individual patient reaches 
Month 6 prior to availability of the OLE study, they may discontinue their protocol-specified 
background antihypertensive medication and receive open-label zilebesiran (600 mg once every 
6 months) for up to 12 additional months until the OLE study is open and then transition. 
The primary objective of the study is to evaluate the efficacy of zilebesiran as an add-on therapy 
for the treatment of hypertension by evaluating the change in 24-hour mean systolic blood 
pressure (SBP), assessed by ambulatory blood pressure monitoring (ABPM), from baseline to 
Month 3, relative to placebo. Secondary and exploratory objectives of the study include 
evaluating the add-on efficacy of zilebesiran on other measures of blood pressure response 
(including longer treatment durations, eg, 6 months) and evaluating the PD effect of zilebesiran, 
including reduction in circulating AGT concentration. 
The full rationale for the study and design is presented in Section 3.2. 
1.2. 
Background 
Hypertension affects 30% to 45% of adults and is the strongest modifiable risk factor for 
cardiovascular disease, primarily strokes and myocardial infarction.[Olsen 2016; Williams 2018] 
The worldwide disease burden is profound, with a global prevalence of over 1 billion,[Kearney 
2005; NCD Risk Factor Collaboration 2017] and approximately 9 million deaths attributed to 
hypertension annually.[Angell 2015] 
Currently available pharmacologic therapies achieve target blood pressure in only a minority of 
patients, due in large part to physician inertia and patient nonadherence to daily oral 
medication.[Whelton 2018; Williams 2018] Low adherence to oral antihypertensives is 
associated with poor cardiovascular outcomes and is prevalent at all stages of disease.[Corrao 
2011; Peacock and Krousel-Wood 2017; Schulz 2016; van der Laan 2017] Thus, despite the 
availability of multiple efficacious agents, current rates of control are low, and the global burden 
of death and disability-adjusted life-years attributed to elevated blood pressure remains 


Clinical Study Protocol ALN-AGT01-003  
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high.[Forouzanfar 2017; Muntner 2020] Development of new approaches to treat hypertension 
and to overcome the limitations of current therapies is a key unmet need.[Dzau and Balatbat 
2019; McClellan 2019; Services 2020] 
The Sponsor is developing zilebesiran, a novel synthetic RNA interference (RNAi) therapeutic, 
for SC administration for the treatment of hypertension. RNAi is a naturally occurring cellular 
mechanism for regulation of gene expression, mediated through the binding of siRNA to its 
complementary messenger RNA (mRNA) sequence, leading to mRNA cleavage and subsequent 
suppression of the synthesis and levels of the target protein. Zilebesiran contains an siRNA 
targeting AGT mRNA, conjugated to a GalNAc-containing ligand to facilitate delivery to the 
liver. Based on the mechanism of RNAi, zilebesiran is specifically designed to reduce the hepatic 
synthesis of AGT protein, the first substrate in the renin-angiotensin-aldosterone system (RAAS) 
and the sole precursor of vasoactive angiotensin peptides.[Khanna 2017; Romero 2015] Because 
hepatocytes are the predominant source of circulating AGT, zilebesiran has been developed to 
reduce blood pressure by decreasing circulating AGT levels and the downstream effects of 
angiotensin II (AngII). 
Zilebesiran is being studied in the ongoing Phase 1 Study ALN-AGT01-001 (hereafter referred 
to as Study 001) in patients with hypertension as single ascending doses of 10 to 800 mg (Part 
A), as a single dose of 800 mg under low-salt or high-salt conditions (Part B), as 2 doses of 
800 mg administered every 3 months in obese patients (Part D), and as a single dose of 800 mg 
co-administered for 2 weeks with 300 mg irbesartan (Part E). Preliminary data are available from 
Parts A, B, and E. Dose-dependent and durable reductions in circulating AGT were observed 
after single SC doses of zilebesiran, accompanied by clinically significant reductions in SBP and 
diastolic blood pressure (DBP). Sustained reductions in serum AGT were observed for up to 6 
months following a single dose of zilebesiran.  
Most adverse events (AEs) have been mild or moderate in severity, and there have been no 
severe or serious adverse events (SAEs) related to study drug. There have been no clinically 
significant elevations in serum creatinine or serum potassium. No patient has required 
intervention for low blood pressure. No clinically significant alanine aminotransferase (ALT) 
elevations have been observed in patients who received zilebesiran doses as high as 800 mg. 
Injection site reactions (ISRs) were reported in a minority of patients and were all mild and 
transient events that resolved without intervention. 
Because most patients with hypertension eventually progress to require treatment with more than 
1 antihypertensive class,[Williams 2018] it is anticipated that zilebesiran may be used together 
with other standard of care antihypertensive medication. This Phase 2 study will further quantify 
the antihypertensive effects of zilebesiran as add-on therapy in patients with hypertension not 
adequately controlled by a standard of care antihypertensive medication. The consistent and 
durable PD effect of zilebesiran is expected to achieve the unique benefit of continuous 24-hour 
blood pressure lowering with infrequent SC dosing.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of zilebesiran is 
provided in the Investigator’s Brochure. 


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1.3. 
Benefit-Risk Assessment 
Clinical data available from Study 001 indicate that zilebesiran may offer the benefit of sustained 
blood pressure reduction to patients with hypertension with infrequent administration (ie, once 
every 3 months or once every 6 months). The mean SBP reduction observed after single 
zilebesiran doses of 100 mg or higher exceeds 10 mmHg, which is comparable to the effect of 
conventional antihypertensives.[Abraham 2015; Materson 1993] The blood pressure of patients 
will be closely monitored, and after Month 3, escape antihypertensive medications will be added 
as needed to control blood pressure. 
Given the mechanism of action and mode of administration of zilebesiran, potential theoretical 
risks include liver transaminase elevations and ISRs. Like any antihypertensive therapy, there is 
also a theoretical risk of hypotension with zilebesiran. Based upon the disease population, there 
is also a risk of blood pressure elevation. Because eligible patients have mild to moderate 
primary hypertension, the likelihood of disease progression during the course of the study is low. 
This study has exclusion criteria intended to minimize these risks, as well as frequent monitoring 
for laboratory and blood pressure abnormalities. Furthermore, the duration of the placebo period 
is limited, and escape antihypertensive medications are permitted to manage uncontrolled blood 
pressure following 3 months of add-on treatment with zilebesiran. Detailed guidance is provided 
to Investigators for potential liver transaminase elevations (Section 5.2.4), hypotension 
(Section 5.8.1), hypertension (Section 5.8.2), renal dysfunction (Section 5.8.3), and 
hyperkalemia (Section 5.8.4). An independent Data Monitoring Committee (DMC) will monitor 
and ensure the safety of study participants (see Section 3.6).  
Based on available data from Study 001, zilebesiran has an acceptable safety profile in patients 
with hypertension as a monotherapy or with the addition of conventional antihypertensives in 
patients who were inadequately controlled on zilebesiran alone. This experience supports that the 
theoretical risks of treatment are low and can be managed through the proposed monitoring and 
safety mitigations. In addition to study drug, each patient will receive a protocol-specified 
background antihypertensive medication (olmesartan, amlodipine, or indapamide). These agents 
are approved standard medications that will be dosed in accordance with local labeling. 
While zilebesiran is designed to inhibit the RAAS, its site of action (AGT) in the RAAS is 
unique, and its tissue specificity for the liver is hypothesized to improve its renal safety profile 
relative to conventional RAAS blockade,[Mullick 2017; Uijl 2019] both in the context of 
monotherapy and when used together with a conventional RAAS blocker such as olmesartan. In 
the latter setting, zilebesiran is hypothesized to add antihypertensive benefit when added to a 
conventional RAAS blocker without the increased incidence of RAAS inhibitor-associated renal 
adverse effects that have been observed in prior trials of conventional dual RAAS 
blockade.[Makani 2013] Patients with estimated glomerular filtration rate (eGFR) 
<45 mL/min/1.73m2 or urine albumin:creatinine ≥300mg/g will be exclusively assigned to the 
olmesartan cohort to ensure that patients with proteinuric chronic kidney disease or diabetes 
continue the RAAS inhibition standardly recommended for their renal indication throughout the 
study. 
This study’s monitoring plan is designed to meet the standards set by prior studies of 
conventional RAAS inhibitors,[McMurray 2016; Parving 2012]. The risk of renal safety events 
is further mitigated in this study by its eligibility criteria, which exclude patients who are at 






Clinical Study Protocol ALN-AGT01-003  
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Run-in Period 
Patients who complete the Screening period and meet all inclusion/exclusion criteria for 
enrollment will be randomized as described in Section 3.4 to receive open-label therapy with 
olmesartan (40 mg orally once daily [or 20 mg orally once daily for patients with creatinine 
clearance ≤60 mL/min enrolled at sites outside of the US, consistent with local labeling for 
olmesartan]), amlodipine (5 mg orally once daily), or indapamide (2.5 mg orally once daily) as 
their protocol-specified background antihypertensive medication during a Run-in period of at 
least 4 weeks. Prior antihypertensive medications (if taking) will be discontinued upon the start 
of this Run-in period (Run-in Visit 1) for at least 4 weeks before Run-in Visit 2 to washout their 
effects. 
Patients who do not tolerate run-in treatment or who do not meet eligibility for randomization at 
Day 1 will be withdrawn from the study and returned to their prior medication regimen in 
coordination with their usual health providers.  
DB Period 
Patients who meet all inclusion/exclusion criteria will be randomized 1:1 to receive 600 mg 
zilebesiran SC or placebo SC on Day 1 of a 6-month DB period as add-on therapy to their 
protocol-specified background antihypertensive medication (olmesartan, amlodipine, or 
indapamide). Randomization on Day 1 will be stratified by race (black or all other races), 
baseline blood pressure (24-hour mean SBP < or ≥145 mmHg), and screening eGFR (<60 or 
≥60 mL/min/1.73m2). 
Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive 
medications”) may be added to the patient’s protocol-specified background antihypertensive 
medication per Investigator judgement for elevated blood pressure as described in Table 4.  
OLE Period 
After the 6-month DB period, protocol-specified background antihypertensive medications will 
be discontinued, and patients may be eligible to participate in a separate zilebesiran OLE study. 
If an individual patient reaches Month 6 prior to availability of the separate OLE study, they may 
receive open-label zilebesiran at 600 mg SC once every 6 months for up to 12 additional months 
until the separate OLE study is open and then transition. Once the separate OLE study is open for 
enrollment, eligible patients may rollover into that OLE study at Month 6, 12, or 18 (first visit 
after the separate OLE study is open). 
During the OLE period of this study, Investigators will use escape antihypertensive medications 
as described in Table 4 to control blood pressure, guided by continued blood pressure 
monitoring. 
Safety Follow-up Period 
Patients who discontinue study drug or do not enroll in the separate zilebesiran OLE study will 
be asked to complete Safety Follow-up visits once every 6 months after their last dose of study 
drug until serum AGT levels return to ≥50% of their individual mean baseline level (if known) or 
12 months, whichever comes earlier. 
Patients who discontinue study drug prior to the Month 6 visit will also be asked to complete the 
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through Month 6. If a patient discontinues study drug after the Month 6 visit, end of treatment 
(EOT)/early termination (ET) assessments should be performed. 
An independent DMC will oversee the safety and overall conduct of this study, and an 
independent Clinical Event Adjudication Committee will review suspected renal events to 
adjudicate whether they meet criteria for acute kidney injury. 
The planned enrollment for this study is approximately 800 patients to be randomized into the 
Run-in period and approximately 630 patients (300 patients in the olmesartan arm, 210 patients 
in the amlodipine arm, and 120 patients in the indapamide arm) to be randomized in the DB 
period.  
The duration of treatment with zilebesiran is up to 18 months. The estimated total time on study 
for patients who rollover to the separate OLE study is up to approximately 20 months, including 
up to 2 months of the Screening and Run-in periods, and up to 18 months of treatment. For all 
patients who discontinue study drug or do not roll over to the separate OLE study, the Safety 
Follow-up period is up to 12 months. 
3.2. 
Scientific Rationale for Study Design 
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy and safety of zilebesiran administered SC as an add-on therapy in patients with 
hypertension despite treatment with a standard of care antihypertensive medication.  
The primary objective of the study is to evaluate the efficacy of zilebesiran as an add-on therapy 
for the treatment of hypertension by evaluating the change in 24-hour mean SBP, assessed by 
ABPM, from baseline to Month 3, relative to placebo. 
Patients with hypertension often require treatment with multiple antihypertensive drugs to reach 
target blood pressure,[Williams 2018] and it is anticipated that zilebesiran may be administered 
to individuals on a background of other antihypertensive medications. Therefore, this study 
evaluates the effects of zilebesiran relative to placebo in patients whose blood pressure is not 
adequately controlled despite treatment with 1 of the 3 major drug classes recommended for 
initial treatment of hypertension by all clinical guidelines: RAAS inhibitors (ie, angiotensin 
converting enzyme [ACE] inhibitors, angiotensin II-receptor blockers [Avni], or a direct renin 
inhibitor), diuretics, and calcium channel blockers (CCBs).[Whelton 2018; Williams 2018] 
Studying coadministration with olmesartan will assess if the synergistic antihypertensive effects 
recently observed in rodents treated with both an ARB and an AGT-targeting GalNAc-siRNA 
will translate into clinically significant blood pressure reduction in hypertensive patients given 
zilebesiran as an add-on to conventional RAAS inhibition.[Uijl 2019] In addition, it will examine 
the safety and tolerability of liver-specific AGT targeting during treatment with a conventional 
RAAS blocker (olmesartan). The newer-generation ARB olmesartan was selected because of its 
high potency relative to early-generation RAAS inhibitors,[Ojima 2011; White 2011] enabling a 
robust test for added efficacy when combined with zilebesiran. The maximum dose of 
olmesartan permitted per local labeling will be used to further increase the rigor of this efficacy 
evaluation. The thiazide-like diuretic indapamide was selected in accordance with recent 
guidelines that highlight the greater potency and durability of thiazide-like diuretics over other 
diuretics.[Burnier 2019] The long-acting dihydropyridine CCB amlodipine was selected given its 


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extensive use in clinical practice and randomized controlled trials.[Dahlof 2005; Jamerson 2008; 
Julius 2004]  
During the study, blood pressure will be monitored with both automated office blood pressure 
measurements and outpatient 24-hour ABPM (EMA/CHMP/29947/2013/Rev. 4; Guideline on 
Clinical Investigation of Medicinal Products in the Treatment of Hypertension, 2016). In 
addition to having greater precision, ABPM can assess short-term blood pressure variability and 
circadian patterns (including potential restoration of the normal nocturnal blood pressure dipping 
pattern that is lost in 24% to 35% of hypertensive patients). More frequent (at least 3 times per 
week) measurements will be collected through a third method, oscillometric home blood 
pressure monitoring (HBPM), to assess long-term blood pressure variability and provide close 
safety monitoring for potential hypotension (or hypertension) while not in the clinic.  
As recommended by current guidance (International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use [ICH] Principles for Clinical Evaluation of 
New Antihypertensive Drugs, 2000 and EMA/CHMP/29947/2013/Rev. 4; Guideline on Clinical 
Investigation of Medicinal Products in the Treatment of Hypertension, 2016), the 6-month DB 
period is designed as a randomized, placebo-controlled, parallel-group study. To adhere to best 
ethical standards for the treatment of patients with hypertension, the use of oral antihypertensive 
medications per Investigator judgement to maintain blood pressure within target is permitted 
starting at Month 3 and will continue throughout the remainder of the study (see Table 4). The 
term “escape antihypertensive medication” is used to refer to any oral antihypertensive 
medication initiated to control blood pressure after Day 1. Separate from these treat-to-target 
modifications, any confirmed event of severe hypertension (office SBP ≥180 mmHg and/or 
office DBP ≥120 mmHg) will be appropriately treated with escape antihypertensive medication 
regardless of its timing relative to study drug administration. 
If a patient requires treatment with an oral escape antihypertensive medication before Month 6, a 
CCB and/or thiazide/thiazide-like diuretic (whichever agent is not already the protocol-specified 
background antihypertensive medication) should be added because there is extensive experience 
combining these classes with antihypertensive drugs that impact the RAAS.  
After the 6-month DB period, protocol-specified background antihypertensive medication 
(olmesartan, amlodipine, or indapamide) will be discontinued, and patients may be eligible to 
participate in a separate zilebesiran OLE study. If an individual patient reaches Month 6 prior to 
availability of the separate OLE study, they may receive open-label zilebesiran at 600 mg SC 
once every 6 months for up to 12 additional months until the separate OLE study is open and 
then transition. Because many patients will receive zilebesiran for the first time at Month 6, 
office blood pressure and serum chemistries will be monitored monthly from Month 6 to Month 
9.  
During the OLE period, Investigators will use escape antihypertensive medications of permitted 
classes as described in Table 4 to control blood pressure, guided by continued blood pressure 
monitoring and following current care guidelines.[Whelton 2018; Williams 2018] Olmesartan, 
amlodipine, and indapamide will be discontinued as protocol-specified background 
antihypertensive medication during the OLE period; however, patients may continue to receive 
amlodipine or indapamide as escape antihypertensive medication at the Investigator’s discretion. 
The use of conventional RAAS inhibitors (ARBs, ACE inhibitors, or direct renin inhibitors) as 
escape antihypertensive agents for high blood pressure should be avoided throughout the study. 


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While the tissue specificity of zilebesiran for the liver is hypothesized to improve tolerability 
relative to current oral antihypertensives,[Mullick 2017; Uijl 2019] the protocol’s monitoring 
plan is designed to meet the standards set by prior studies of conventional RAAS 
inhibitors[McMurray 2016; Parving 2012].  
3.3. 
Justification for Dose 
The dose of zilebesiran in this study (600 mg once every 6 months) was selected on the basis of 
data from the Phase 1 Study 001, in which single zilebesiran doses up to 800 mg were found to 
have an acceptable safety profile, and dose-dependent, clinically significant placebo-corrected 
reductions in mean SBP >10 mmHg by 24-hour ABPM were observed at doses as low as 
100 mg. An acceptable safety profile was also observed for a single zilebesiran dose of 800 mg 
under low-salt/high-salt conditions or co-administered for 2 weeks with 300 mg irbesartan once 
daily. The selected dose of 600 mg is predicted to result in a median serum AGT reduction of 
94.9% at trough (Month 6), translating to a median SBP reduction of 11.6 mmHg as 
monotherapy. 
The protocol-specified background antihypertensive medications are standard agents 
recommended in international and regional hypertension guidelines, and the selected regimens 
are standard doses used for their approved indication of hypertension.[Whelton 2018; Williams 
2018] Indapamide will be dosed at 2.5 mg orally once daily, and amlodipine will be dosed at 
5 mg orally once daily. The dose regimens for indapamide and amlodipine used in this study 
were selected on the basis of their common use in clinical care (when used both individually and 
combined with other classes of antihypertensives) and their expected efficacy, safety, and 
tolerability. Olmesartan will be dosed at the maximum dose allowed per local labeling: 40 mg 
orally once daily (or 20 mg orally once daily for patients with creatinine clearance ≤60 mL/min 
enrolled at sites outside of the US; Olmetec Product Information, September 2020).[von 
Bergmann 2001] 
3.4. 
Method of Assigning Patients to Treatment Groups 
Each patient will be uniquely identified in the study by a combination of the site number and 
patient identification number. After the patient signs the informed consent form (ICF) and before 
proceeding with screening procedures, the Investigator or designee should contact the Interactive 
Response Technology (IRT) to obtain a patient identification number. 
The Investigator or designee will contact the IRT to randomize the patient at Run-in Visit 1 and 
again at Day 1 after confirming that the patient fulfills all the inclusion criteria and none of the 
exclusion criteria at each visit. 
At Run-in Visit 1, patients with screening eGFR <45 mL/min/1.73m2 or urine albumin:creatinine 
≥300mg/g will be assigned to receive olmesartan. To avoid over-enrollment, patients with eGFR 
<45 mL/min/1.73m2 or urine albumin:creatinine ≥300mg/g will be excluded from the study after 
100 such patients are randomized to study drug on Day 1.  
All other patients will be randomized 10:7:4 to run-in open-label on 1 of 3 protocol-specified 
background antihypertensive medications (olmesartan, amlodipine, or indapamide), with targeted 
sample sizes across cohorts as described in Section 7.1. If 1 cohort completes enrollment first, 
this cohort will be deactivated for future randomization. The remaining 2 cohorts will be 


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randomized using the original ratio. After the second cohort completes enrollment, all 
subsequent patients will be assigned to the last cohort.  
At Day 1, patients will be randomized 1:1 to receive zilebesiran or placebo as an add-on to their 
protocol-specified background antihypertensive medication using the IRT. Randomization at 
Day 1 will be stratified by race (black or all other races), baseline blood pressure (24-hour mean 
SBP < or ≥145 mmHg), and screening eGFR (<60 or ≥60 mL/min/1.73m2). 
3.5. 
Blinding 
The Sponsor, all site personnel and patients will be blinded to study drug treatment through 
Month 3 of the 6-month DB period. After the database lock to support the analysis of the primary 
endpoint and secondary endpoints measured at Month 3 is complete, Sponsor staff members who 
will not have direct roles or responsibilities in interacting with study sites will be unblinded to 
the analysis results according to the prespecified blinding plan. Site personnel, patients, and 
Sponsor staff members who have direct roles or responsibilities in interacting with study sites 
will remain blinded to treatment assignment until after the analysis of Month 6 data is complete. 
All Sponsor and site personnel and patients will be blinded to any clinical laboratory result that 
could potentially unblind them (eg, AGT levels) until unblinding. 
Zilebesiran and placebo will be packaged identically. Because zilebesiran may be slightly 
visually distinguishable from placebo, the vials will be masked in such a way as to hide the 
identity of the study drug contained within. For administration, syringes will be masked by a site 
pharmacist or delegate prior to withdrawing the study drug from vial. See the Pharmacy Manual 
for additional details. The study drug will be administered under the supervision of the 
Investigator (see Section 5.2.2). 
3.5.1. 
Emergency Unblinding 
If the treating physician determines that the clinical management of the patient requires 
knowledge of the study drug assignment, the Investigator may break the blind, as necessary, in 
IRT. If time permits, clinical study center personnel should contact the Medical Monitor before 
unblinding to discuss the need to unblind the patient but must do so within 1 working day after 
the unblinding event. Unblinding information should be limited to the fewest number of people 
on a need-to-know basis. A record of when the blind was broken, who was unblinded, who broke 
the blind, and why it was broken, will be maintained in the electronic trial master file (eTMF). 
Refer to the IRT instructions for details on unblinding. 
3.6. 
Data Monitoring Committee 
An independent DMC will oversee the safety and overall conduct of this study. The DMC will 
operate under the rules of a charter that will be reviewed and approved at the organizational 
meeting of the DMC. Details are provided in the DMC Charter. 
3.7. 
Clinical Event Adjudication Committees 
An independent Clinical Event Adjudication Committee of 2 or more nephrologists will review 
the suspected renal events blinded to treatment assignment to adjudicate whether they meet 


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diagnostic criteria for acute kidney injury and, if so, their potential staging and contributing 
factors. Details are provided in the Renal Event Adjudication Committee charter. 
3.8. 
Definition of End of Study for an Individual Patient 
A patient is considered to have reached the end of the study if the patient: 
• has completed at least the Month 6 visit and enrolled in the separate OLE study, or 
• has completed the Safety Follow-up visits as described in Section 3.1 for patients who 
discontinue study drug or do not enroll in the separate OLE study. 
A definition of the end of the overall study is provided in Section 8.1.5. 
4. 
SELECTION AND REMOVAL OF PATIENTS 
4.1. 
Inclusion Criteria 
Patients are eligible to be included in the study if all the following criteria apply: 
Age and Sex 
1. Age 18 to 75 years, inclusive 
2. Male or female 
Patient and Disease Characteristics 
3. Has hypertension as follows: 
a. Untreated hypertension (not taking antihypertensive medication), or  
b. Treated hypertension on stable therapy with up to 2 antihypertensive medications that 
include the following classes: an ACE inhibitor, ARB, renin inhibitor, CCB, thiazide 
diuretic, and/or thiazide-like diuretic. Stable therapy is defined as having no change in 
antihypertensive medication or dose within 30 days prior to screening, and the doses 
have to be at least half of the maximally approved daily doses per local labeling.  
4. Office SBP at Run-in Visit 1 as follows: 
a. ≥155 mmHg and ≤180 mmHg for patients with untreated hypertension  
b. ≥145 mmHg and ≤180 mmHg for patients on antihypertensive medications  
5. 24-hour mean SBP >130 mmHg and ≤160 mmHg by ABPM at Run-in Visit 2 after at 
least 4 weeks of run-in. 
6. ≥80% adherence to the protocol-specified background antihypertensive medication 
during the Run-in period as assessed by pill count performed at Run-in Visit 2. 
Informed Consent 
7. Patient is able to understand and is willing and able to comply with the study 
requirements and to provide written informed consent. 


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4.2. 
Exclusion Criteria 
Patients are excluded from the study if any of the following criteria apply: 
Disease-specific Conditions 
1. Secondary hypertension (including, but not limited to, due to moderate-to-severe 
obstructive sleep apnea with or without receiving nasal continuous positive airway 
pressure therapy, renovascular hypertension, primary aldosteronism, pheochromocytoma, 
Cushing syndrome, aortic coarctation, or other cause of secondary hypertension) 
2. Orthostatic hypotension, defined as a fall of ≥20 mmHg SBP or ≥10 mmHg DBP within 
approximately 1 to 3 minutes of standing up from a seated position by office blood 
pressure that is symptomatic (such as dizziness, weakness, lightheadedness, or syncope) 
at screening or during the Run-in period 
Laboratory Assessments 
3. Has any of the following laboratory parameter assessments at screening or Run-in 
Visit 2:  
a. ALT or aspartate aminotransferase (AST) >2× upper limit of normal (ULN) 
b. Total bilirubin >1.5×ULN. Patients with elevated total bilirubin that is secondary to 
documented Gilbert’s syndrome are eligible if the total bilirubin is <2×ULN 
c. International normalized ratio (INR) >2.0 (patients on oral anticoagulant [eg, 
warfarin] with an INR <3.5 will be allowed) 
d. Potassium <lower limit of normal range or >5 mEq/L  
e. Sodium <lower limit of normal range 
f. eGFR <30 mL/min/1.73m2 (calculation will be based on the Modification of Diet in 
Renal Disease formula; refer to Section 10.1) 
Prior/Concomitant Therapy 
4. Received an investigational agent within the last 30 days or 5 half-lives of the 
investigational agent, whichever is longer, prior to Run-in Visit 1 or are in follow-up of 
another clinical study prior to study enrollment. Any agent that has received health 
agency authorization (including for emergency use) by local or regional regulatory 
authorities is not considered investigational. 
5. Currently taking, taken within 30 days prior to first randomization, or anticipated to 
receive during the course of the study, any medication or herbal supplement known to 
significantly affect blood pressure (with the exception of medications for the treatment of 
essential hypertension). Patients who require medications such as monoamine oxidase 
(MAO) inhibitors that are associated with hypertensive crisis should be 
excluded.[Whelton 2018]  
6. Currently taking, taken within 30 days prior to first randomization, or anticipated to 
receive during the course of the study, sodium-glucose co-transporter 2 (SGLT2) 
inhibitors 
7. Prescription nonsteroidal anti-inflammatory drugs (NSAIDs) are not permitted. In 
addition, consecutive (daily) use of over-the-counter NSAIDs should be avoided for at 


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least 7 days prior to ABPM, office blood pressure, or laboratory assessments. 
Paracetamol/acetaminophen for analgesia will be allowed.  
8. Anticipates using organic nitrate preparations (eg, nitroglycerin, isosorbide mononitrate, 
isosorbide dinitrate, pentaerythritol) during the course of the study 
9. Currently taking, taken within 6 months prior to first randomization, or anticipated to 
receive an RNAi therapeutic (approved or investigational)  
Medical Conditions 
10. Current or prior history of intolerance to an ARB, ACE inhibitor (other than cough), 
direct renin inhibitor, CCB (including but not limited to significant peripheral edema), or 
thiazide/thiazide-like diuretic 
11. History of multiple drug allergies or history of allergic reaction to any component of or 
excipient in the study drug 
12. Type 1 diabetes mellitus, poorly controlled Type 2 diabetes mellitus (hemoglobin A1c 
[HbA1c] >8.0%), newly diagnosed Type 2 diabetes mellitus (within 6 months prior to 
first randomization), or laboratory evidence of diabetes during screening (fasting plasma 
glucose ≥126 mg/dL [7.0 mmol/L], random plasma glucose ≥200 mg/dL [11.1 mmol/L], 
or HbA1c ≥6.5%) without known diagnosis of diabetes 
13. Has known active human immunodeficiency virus infection; or known current or chronic 
hepatitis C virus (HCV) or hepatitis B virus infection. 
14. History of clinically significant cardiovascular event (eg, stroke, transient ischemic 
attack, myocardial infarction, unstable angina, coronary artery bypass grafting or other 
cardiothoracic surgeries, percutaneous coronary intervention, hospitalization due to heart 
failure) within 6 months prior to first randomization 
15. Known history of angioedema 
16. Clinically significant valvular heart disease 
17. New York Heart Association II to IV heart failure 
18. Uncontrolled serious cardiac arrhythmia, defined as recurrent and highly symptomatic 
ventricular tachycardia/supraventricular tachycardia, or atrial fibrillation with rapid 
ventricular response in the 3 months prior to first randomization 
19. Has undergone liver transplantation or is anticipated to be on an active liver 
transplantation waiting list during the study treatment period 
20. History of renal transplantation  
21. Has other medical conditions or comorbidities which, in the opinion of the Investigator, 
would interfere with study compliance or data interpretation; or, in the opinion of the 
Investigator, taking part in the study would jeopardize the safety of the patient 
22. Clinically significant illness, in the opinion of the Investigator, within 7 days prior to 
either randomization 
23. History of intolerance to SC injection(s) that could potentially hinder study drug 
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24. Has planned major surgery or general anesthesia during the study 
Contraception, Pregnancy, and Breastfeeding 
25. Is not willing to comply with the contraceptive requirements during the study period, as 
described in Section 5.11.1  
26. Female patient is pregnant, planning a pregnancy, or breast-feeding 
Alcohol, Nicotine, or Cannabis Use and Substance Abuse 
27. Unwilling or unable to limit alcohol consumption throughout the course of the study. 
Alcohol intake of >2 units/day is excluded during the study (unit: 1 glass of wine 
[approximately 125 mL] = 1 measure of spirits [approximately 1 fluid ounce] = ½ pint of 
beer [approximately 284 mL]). 
28. History of alcohol or substance abuse (licit or illicit drugs) within the last 12 months 
before screening, in the opinion of the Investigator 
29. Unwilling or unable to abstain from use of nicotine or tobacco-containing products 
(including but not limited to snuff, chewing tobacco, cigars, cigarettes, pipes, nicotine 
patches, or e-cigarettes) within 30 minutes prior to office blood pressure measurements  
30. Unwilling or unable to abstain from use of cannabis or delta-9-tetrahydrocannibinol-
containing substances (included by smoking, vaping, dabbing, or ingesting/edibles) 
Other Restrictions 
31. Third shift, night shift, or 24-hour shift workers 
32. Arm circumference exceeds the maximum cuff size of any of the blood pressure 
instruments provided by the Sponsor 
33. Unable or unwilling to perform HBPM as specified 
4.3. 
Removal from Study Drug or Assessment 
Patients or their legal guardians are free to discontinue study drug and/or stop protocol 
procedural assessments, or participation in the study as a whole at any time and for any reason, 
without penalty to their continuing medical care. The Investigator or the Sponsor may 
discontinue study drug or stop a patient’s participation in the study at any time if this is 
considered to be in the patient’s best interest. Any discontinuation of treatment or the stopping of 
the patient’s participation in the study must be fully documented in the electronic case report 
form (eCRF) and should be followed up by the Investigator. 
Discontinuation of study drug or declining procedural assessments is described in Section 4.3.1, 
while the stopping of a patient’s participation in the study is detailed in Section 4.3.2. 
4.3.1. 
Discontinuation of Study Drug or Declining Procedural Assessments 
Reasons for discontinuation of study drug include any of the following: 
• Significant protocol deviation; which includes required treatment with prohibited 
medication (as defined in Section 5.9.1) per Investigator discretion 
• AE 


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• Non-adherence to treatment regimen 
• Pregnancy 
• Lost to follow-up 
• Other reason (non-AE) 
• Or, study is terminated by the Sponsor 
If possible, the Investigator will confer with the Sponsor or Medical Monitor before 
discontinuing dosing in the patient. Patients who are pregnant will be discontinued from study 
drug dosing immediately (see Section 6.5.6.7 for reporting and follow-up of pregnancy). A 
positive urine pregnancy test should be confirmed by a serum pregnancy test prior to 
discontinuing the study drug. 
Patients who discontinue study drug and/or decline procedural assessments should not be 
automatically removed from study. In general, patients who discontinue study drug dosing for 
any reason will be encouraged to remain on the study to complete the remaining assessments so 
that their experience is captured in the final analyses.  
If this occurs, the Investigator is to discuss with the patient the appropriate processes for 
discontinuation from study drug and must discuss with the patient the options for continuation of 
the Schedule of Assessments (Table 1), including different options for follow-up and collection 
of data (eg, in person, by phone, by mail, through family or friends, or from options not 
involving patient contact, such as communication with other treating physicians or from review 
of medical records), including endpoints and AEs, and must document this decision in the 
patient’s medical records. 
If a patient has an AE, including SAEs, and/or laboratory abnormalities that in the judgment of 
the investigator, taking into account the patient’s overall status, requires interruption or 
discontinuation from treatment with study drug, the event should be followed as described in 
Section 6.5.6. When a patient discontinues study drug dosing, the primary reason must be 
recorded in the eCRF. Patients who discontinue study drug and remain on study may receive 
treatment consistent with local standard practice for their disease per Investigator judgement, as 
applicable. 
Patients who discontinue from study drug during the 6-month DB period (defined as the time the 
first dose of study drug is administered on Study Day 1 through completion of the Month 6 
assessments) will be encouraged to remain on the study and complete assessments (excluding 
pharmacokinetic [PK] assessments) through Month 6. They will also be asked to complete Safety 
Follow-up visits once every 6 months after the last dose of study drug per the safety follow-up 
schedule (see Table 1) until PD recovery or 12 months (whichever is earlier); see Section 3.1. 
Patients who discontinue study drug during the OLE period will be asked to return for their next 
scheduled visit to complete EOT/ET assessments and complete Safety Follow-up visits once 
every 6 months after the last dose of study drug per the safety follow-up schedule (see Table 1) 
until PD recovery or 12 months (whichever is earlier); see Section 3.1. 


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4.3.2. 
Stopping a Patient’s Study Participation 
4.3.2.1. 
Patient or Legal Guardian Stops Participation in the Study 
A patient or their legal guardian may stop participation in the study at any time. A patient or 
legal guardian considering stopping participation in the study before Month 6 should be 
informed that the patient can discontinue study drug and/or decline procedural assessments and 
remain in the study to complete their study assessments, through the Month 6 visit and complete 
Safety Follow-up visits as described in Section 4.3.1, or alternatively may complete any minimal 
assessments for which the patient or legal guardian consents. If a patient or legal guardian still 
chooses to discontinue study drug and stop participation in all follow-up prior to the completion 
of the 6-month DB period, every effort should be made to conduct the Month 6 visit assessments 
at an earlier time (see Table 1). 
A patient considering stopping participation in the study during the OLE period should be 
informed that the patient can discontinue study drug and/or decline procedural assessments and 
remain in the study to complete the assessments scheduled for the EOT/ET visit and complete 
Safety Follow-up visits as described in Section 4.3.1, or alternatively may complete any minimal 
assessments for which the patient consents. 
If the patient does not wish to or is unable to continue further study participation, the Investigator 
is to discuss with the patient appropriate procedures for stopping participation in the study. Data 
collected from the patient can continue to be used. 
Note, in countries where the collection and processing of the patient’s personal data is based on 
consent, if a patient withdraws consent to collect and process the patient’s personal data (see 
Section 4.3.2.2), as applicable, personal data up to the withdrawal of consent will be included in 
the analysis of the study. In addition, where permitted, publicly available data (such as 
appropriate national or regional vital status registry or other relevant databases) can be included 
after withdrawal of consent, where available and allowable by local law. 
4.3.2.2. 
Withdrawal of Consent to Process the Patient’s Personal Data or Objection to 
Process Patient’s Personal Data 
Where allowed by local law, the patient may decide to withdraw consent to collect, store, and 
use biological samples and, as applicable, other personal data, informing the Investigator at any 
time in writing or in any other form that may be locally required. Also, where allowed by local 
law, the patient may object to the collection, storage, and use of the patient’s personal data, 
informing the Investigator at any time in writing or in any other form that may be locally 
required. In both cases, the Sponsor will continue to keep and use the patient’s study information 
(including any data resulting from the analysis of the patient’s biological samples until the time 
of withdrawal/objection) according to applicable law. The process for the storage and, as 
applicable, further use of remaining samples will be followed per local requirements. 
4.3.2.3. 
Investigator or Sponsor Stops Participation of a Patient in the Study 
The Investigator or Sponsor may stop the participation of a patient in the study at any time if this 
is considered to be in the patient’s best interest. However, study integrity and interpretation are 
best maintained if all enrolled patients continue study assessments and follow-up even if study 
drug is discontinued. 


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Termination of the clinical study and site closure are described in Section 8.1.6. 
4.3.2.4. 
Recording Reason for Stopping a Patient’s Study Participation 
The primary reason that a patient’s study participation is stopped must be recorded in the 
appropriate section of the eCRF and all efforts will be made to complete and report the 
observations as thoroughly as possible. If a patient’s study participation is stopped due to an AE, 
including SAEs, the event should be followed as described in Section 6.5.6. 
4.3.3. 
Lost to Follow-Up 
A patient will be considered lost to follow-up if the patient repeatedly fails to return for 
scheduled visits and is unable to be contacted by the clinical study center. The following actions 
must be taken if a patient fails to return to the clinic for a required study visit: 
• The site must attempt to contact the patient or legal guardian and reschedule the 
missed visit as soon as possible and counsel the patient or legal guardian on the 
importance of maintaining the assigned visit schedule and ascertain if the patient or 
legal guardian wishes [for the patient] to continue in the study, and/or should continue 
in the study. 
• Before a patient is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the patient or legal guardian (where possible, 3 
telephone calls and, if necessary, a certified letter to the patient’s last known mailing 
address or local equivalent methods). These contact attempts should be documented 
in the patient’s medical record. 
• Should the patient or legal guardian continue to be unreachable, the patient will be 
considered to have stopped participation in the study. 
• For patients who are lost to follow-up, the Investigator can search publicly available 
records (where permitted and allowed by local law) to ascertain survival status. This 
ensures that the outcome of the study is as comprehensive as possible. 
4.3.4. 
Replacement of Study Patients 
No additional patients may be enrolled to mitigate the impact of patients who discontinue the 
study drug or stop participation in the study after the second randomization at Day 1.  
5. 
TREATMENTS AND OTHER REQUIREMENTS 
5.1. 
Treatments Administered 
Study drug and protocol-specified background antihypertensive medication supplied by the 
Sponsor for this study must not be used for any purpose other than the present study and must 
not be administered to any person not enrolled in the study. Study drug and protocol-specified 
background antihypertensive medication that have been dispensed and returned unused must not 
be re-dispensed. 


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5.2. 
Study Drug 
Detailed information describing the preparation, administration, and storage of zilebesiran SC 
and placebo SC is provided in the Pharmacy Manual. 
5.2.1. 
Description 
Zilebesiran will be supplied as a sterile solution for SC injection. See the Pharmacy Manual for 
further details of solution concentration and fill volume. 
The control drug for this study will be a placebo (phosphate-buffered saline for SC 
administration). Placebo will be provided by the Sponsor; it will be packaged identically to 
zilebesiran. 
5.2.2. 
Dose and Administration 
During the 6-month DB period, patients will be administered 600 mg zilebesiran or placebo, at 
the same volume, as SC injections once every 6 months. During the OLE period, all patients will 
receive 600 mg zilebesiran SC once every 6 months. 
Study drug injections will be administered by qualified clinical study center staff under the 
supervision of the Investigator or designee. The injection site may be marked and mapped for 
later observation. Injections may be administered in the abdomen, thigh, or the side or back of 
the upper arms. If a local reaction around the injection site occurs, photographs may be obtained. 
Detailed instructions for study drug administration are found in the Pharmacy Manual. 
To maintain the blind, the syringes are to be masked by the site pharmacist or designee prior to 
study drug withdrawal from the vial. A full description of the blinding procedure is included in 
the Pharmacy Manual. 
If a patient does not receive a dose of study drug within the specified dosing window, the 
Investigator should contact the Medical Monitor. After such consultation, the dose may be 
administered up to 85 days before the next scheduled dose. Thereafter, the dose will be 
considered missed and not administered. 
If a patient misses a dose of study drug, the Investigator should discuss with the Medical Monitor 
whether the patient will be able to continue the study (see also Section 4.3). 
Additional details can be found in the Pharmacy Manual.  
The definition of study drug overdose, follow-up procedures, and reporting requirements are 
provided Section 6.5.6.8. 
5.2.3. 
Dose Modifications 
Dose modifications of study drug are not permitted. 
If a study drug-related AE occurs in a patient that the Investigator judges as presenting a 
potential risk to the patient for further dosing, the study drug dose may be held at the discretion 
of the Investigator, and the Medical Monitor should be contacted.  


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5.2.4. 
LFT Criteria for Withholding, Monitoring and Stopping Study Drug Dosing  
1. Dosing decisions may be made based on the most recently available liver function test 
(LFT) results from a central laboratory (Table 6). 
2. For any ALT or AST elevation >3×ULN, central laboratory results should be used to 
guide subsequent monitoring as detailed in Table 3. 
3. For any ALT or AST elevation >3×ULN: 
a. If local laboratory results are obtained, confirm with a central laboratory as soon as 
possible, ideally within 2 to 3 days, but no later than 7 days. 
b. If an alternative cause is found, provide appropriate care. 
c. If an alternative cause is not found, perform assessments per Table 6 and Table 7. 
4. For any ALT or AST elevation >3×ULN without alternative cause that is accompanied 
by clinical symptoms consistent with liver injury (eg, nausea, right upper quadrant 
abdominal pain, jaundice) or elevated bilirubin to ≥2×ULN or INR ≥1.5, permanently 
discontinue dosing. 
5. For confirmed ALT or AST elevations >3×ULN without alternative cause and not 
accompanied by symptoms or elevated bilirubin ≥2×ULN or INR ≥1.5, see Table 3. 


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Table 3: 
Monitoring and Dosing Rules for Asymptomatic Patients with Confirmed 
Isolated Elevations of ALT and/or AST >3× ULN, with No Alternative Cause 
Identified 
Transaminase Level 
Action 
>3× to 5×ULN 
• 
May continue dosing 
• 
Evaluate the initial elevation in LFT per the following assessments: 
­ Table 7 (all assessments to be performed once) 
­ Hematology, serum chemistry, LFT, and coagulation per Table 6 
• 
Monitor at least every 2 weeks (LFT and coagulation per Table 6) 
• 
If elevation persists for ≥2 months, must discuss with the Medical 
Monitor before continuing dosing 
>5× to 8×ULN 
• 
Hold study drug dosing until recovery to ≤1.5×ULN or baseline; may 
resume dosing after discussion with the Medical Monitor 
• 
Evaluate the initial elevation in LFT per the following assessments 
­ Table 7 (all assessments to be performed once) 
­ Hematology, serum chemistry, LFT, and coagulation per Table 6 
• 
Monitor at least weekly: LFT and coagulation per Table 6 until ALT 
and/or AST is declining on 2 consecutive draws, then may decrease 
monitoring to biweekly 
• 
If ALT or AST rises to >5×ULN following resumption of dosing, 
permanently discontinue dosing 
>8×ULN 
Permanently discontinue study drug dosing after confirmation of the 
transaminase value at the central laboratory. 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; LFT=liver function test(s); 
ULN=upper limit of normal. 
Notes: In addition to these criteria, other assessments or evaluations may be performed per Investigator 
discretion, as appropriate. 
5.2.5. 
Neurological Criteria for Withholding, Monitoring, and Stopping Study Drug 
Dosing 
Clinically significant events that may be consistent with potential decreased proprioception 
(including but not limited to unusual clumsiness, gait abnormalities, and unexplained 
balance/coordination issues that are either absent at or worsening from the baseline) should be 
reported as an AE. If the treatment-emergent AE is persistent and considered related to study 
drug, specialty consultation with a neurologist should be considered. However, if such a 
treatment-emergent AE is serious or severe (regardless of the Investigator’s assessment of 
relatedness), the patient must be referred for neurologist consultation, and study drug dosing 
must be held until that consultation is complete. Resumption of dosing must be approved by the 
Medical Monitor. 
5.3. 
Protocol-specified Background Antihypertensive Medications 
All patients will be randomized to receive 1 of the 3 following standard of care oral 
antihypertensive medications during a Run-in period of at least 4 weeks and will continue this 


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protocol-specified background antihypertensive medication through Month 6. Protocol-specified 
background antihypertensive medications will be supplied by the Sponsor. 
• Olmesartan: 40 mg orally once daily (or 20 mg orally once daily for patients with 
creatinine clearance ≤60 mL/min enrolled at sites outside of the US, consistent with 
local labeling). At the Investigator’s discretion, patients who are randomized to 
receive 40 mg olmesartan once daily may initiate treatment at 20 mg once daily and 
then uptitrate to the full dose of 40 mg once daily after 1 to 2 weeks (in this case, the 
patient must take the full olmesartan dose of 40 mg once daily for at least 4 weeks 
prior to reassessment at Run-in Visit 2). 
• Amlodipine: 5 mg orally once daily 
• Indapamide: 2.5 mg orally once daily 
Protocol-specified antihypertensive medications may be downtitrated or temporarily 
discontinued per Investigator judgement for low blood pressure (see Section 5.8.1). At the 
Investigator’s discretion, oral antihypertensive agents, including protocol-specified background 
antihypertensive medication, may be prophylactically held during intercurrent illness or volume 
depletion. 
5.4. 
Preparation, Handling, and Storage 
Staff at each clinical study center will be responsible for preparing zilebesiran or placebo doses 
and dispensing protocol-specified background antihypertensive medication, according to 
procedures detailed in the Pharmacy Manual. No special procedures for the safe handling of 
study drug or protocol-specified background antihypertensive medication are required. 
Study drug will be stored upright at approximately 2 to 30°C until dose preparation. Protocol-
specified background antihypertensive medication will be stored according to the storage 
instructions on the label. Deviations from the recommended storage conditions should be 
reported to the Sponsor and use of the affected study drug or protocol-specified background 
antihypertensive medication halted until authorization for its continued use has been provided by 
the Sponsor or designee, as described in the Pharmacy Manual. 
A Sponsor representative or designee will be permitted, upon request, to audit the supplies, 
storage, dispensing procedures, and records. 
Instructions specific to unused study drug and protocol-specified background antihypertensive 
medication and additional storage will be provided in the Pharmacy Manual. 
5.5. 
Packaging and Labeling 
All packaging, labeling, and production of study drug and protocol-specified background 
antihypertensive medication will be in compliance with current Good Manufacturing Practice 
specifications, as well as applicable local regulations. Study drug and protocol-specified 
background antihypertensive medication labels and external packaging will include all 
appropriate information as per local labeling requirements. Additional details will be available in 
the Pharmacy Manual. 


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5.6. 
Accountability 
The Investigator or designee will maintain accurate records of receipt and the condition of the 
study drug and protocol-specified background antihypertensive medication supplied for this 
study, including dates of receipt. In addition, accurate records will be kept of when and how 
much study drug and protocol-specified background antihypertensive medication is dispensed 
and administered to each patient in the study. Any reasons for departure from the protocol 
dispensing regimen must also be recorded. 
At the completion of the study, there will be a final reconciliation of all study drugs and 
protocol-specified background antihypertensive medication. Used, partially used, and unused 
study drug and protocol-specified background antihypertensive medication will be returned to 
the Sponsor (or designee) or destroyed at the clinical study center according to applicable 
regulations. 
Further instructions about accountability will be detailed in the Pharmacy Manual. 
5.7. 
Clinical Product Complaints 
5.7.1. 
Definition 
A clinical product complaint (CPC) is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or 
performance of the study drug and its packaging after it is released for distribution to the site at 
which study drug will be administered. 
A CPC may be detected prior to use of study drug, during use, or after use. A CPC is typically 
nonmedical in nature; however, it is possible that investigational product complaints could be 
associated with an AE. Examples of a CPC include, but are not limited to: illegible clinical label, 
missing clinical label, damaged vial, empty vial, and contamination of study drug. 
5.7.2. 
Reporting 
For product complaints, the Sponsor or its designee should be notified within 24 hours using the 
process outlined in the Pharmacy Manual. CPCs that may be associated with an AE must be 
evaluated and reported as indicated in Section 6.5.6. Detailed instructions on reporting CPCs will 
be provided in the Pharmacy Manual. 
5.8. 
Monitoring for Potential Clinical Events 
5.8.1. 
Monitoring and Approach for Potential Hypotension 
Hypotension is an obligate risk of antihypertensive medications. In addition to office blood 
pressure monitoring, outpatient blood pressure will be monitored at least 3 times per week with 
HBPM to ensure the early detection of potential hypotension. Whenever possible, management 
decisions will be based on blood pressure measurements confirmed by office blood pressure. 
The following management recommendations for hypotension are provided: 
• Patients who experience low blood pressure that is associated with symptoms should 
promptly seek medical evaluation at the clinical study site or another hospital setting. 


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Clinical study site evaluation for low blood pressure should include the assessment of 
orthostatic blood pressure (supine to standing).  
• The Investigator should consider downtitration or interruption of oral 
antihypertensives (if taking) if confirmed office SBP <90 mmHg or if clinical 
symptoms, such as lightheadedness or dizziness, develop coupled with a significantly 
lower SBP compared to prior visits (ie, SBP <100 mmHg). Oral antihypertensives 
should be downtitrated/interrupted in reverse order to how they were added (ie, 
interrupt escape antihypertensive medications before protocol-specified background 
antihypertensive medications). 
• Clinically significant events discovered during the course of a patient’s general 
medical care should be promptly communicated to the site and evaluated by the 
Investigator, especially if hypotension is noted. Patients will carry Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC)-approved patient cards to 
facilitate this physician-to-physician communication.  
• If hypotension is confirmed, serum electrolytes and creatinine should be measured 
and any oral antihypertensive(s) should be downtitrated or interrupted per 
Investigator judgement as outlined above.  
• The frequency of blood pressure and laboratory monitoring (serum electrolytes and 
creatinine) should be increased during intercurrent illnesses that predispose patients to 
dehydration (eg, vomiting or diarrhea that persists for more than 24 hours) or when 
symptoms consistent with decreased effective circulating volume (eg, presyncopal 
symptoms, unexplained falls, decreased urine output) manifest, even if a patient’s 
recent blood pressure measurements have been normal. 
• Hypotension that warrants direct evaluation at the site should be communicated to the 
Medical Monitor within 24 hours. In addition, other clinical events consistent with 
potential hypotension (eg, unexplained presyncope, syncope, or falls) should be 
communicated to the Medical Monitor within 24 hours of the site being notified. 
• Management of persistent hypotension may include increased salt intake or, if 
unresponsive, standard treatments for orthostatic intolerance syndromes such as 
fludrocortisone or midodrine. 
• Low blood pressure that requires medical treatment (including intravenous fluid 
support) or other clinical events consistent with potential hypotension (see above) 
should be recorded as AEs. 
5.8.2. 
Monitoring and Approach for Clinically Significant Blood Pressure Elevation 
In addition to office blood pressure monitoring, outpatient blood pressure will be monitored 
frequently with HBPM to ensure the early detection of potential significant elevations. Whenever 
possible, management decisions will be based on blood pressure measurements confirmed by 
office blood pressure. The recommended interventions for potentially clinically significant blood 
pressure elevation are presented in Table 4.  


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Table 4: 
Recommended Interventions for Potentially Clinically Significant Blood 
Pressure Elevation 
Study Period 
Intervention 
Throughout Study 
• 
Whenever possible, management decisions should be based on blood 
pressure measurements confirmed by office blood pressure. 
• 
Any confirmed event of severe hypertension (office SBP ≥180 mmHg 
and/or office DBP ≥120 mmHg) should be appropriately treated regardless 
of its timing relative to study drug administration.  
• 
Until double-blind data are generated that demonstrate acceptable safety 
and added antihypertensive efficacy of zilebesiran when combined with 
olmesartan, the use of conventional RAAS inhibitors (ARBs, ACE 
inhibitors, or direct renin inhibitors) as escape antihypertensive agents for 
high blood pressure will be avoided throughout the study.  
• 
If added, escape antihypertensives must be used per their labeled 
instructions and in accordance with current clinical guidelines.[Whelton 
2018; Williams 2018] 
Day 1 to Month 3 
Intervene if clinically significant blood pressure elevation: 
• 
Because of the gradual onset of effects of zilebesiran, interventions for 
asymptomatic hypertension should be avoided in the first 6 weeks after the 
patient’s first administration of study drug.  
• 
After Week 6, patients who develop office SBP >160 mmHg and increased 
>10 mmHg from their baseline office SBP that persists for ≥24 hours on 2 
consecutive measurements or that is accompanied by hypertensive 
symptoms should be evaluated by the clinical study site. Severely 
symptomatic patients should be evaluated at the clinical study site or 
another hospital setting within 24 hours. 
• 
If persistent hypertension is confirmed (without the identification of a 
specific treatable cause) and the Investigator deems it to be a clinically 
significant change, treatment may be initiated at the medical discretion of 
the Investigator using a CCB and/or a thiazide/thiazide-like diuretic 
(whichever agent is not already the protocol-specified background 
antihypertensive medication) as an escape antihypertensive medication.  
Months 3 to 6 
Treat to target blood pressure using a CCB and/or thiazide/thiazide-like diuretic 
(whichever agent is not already a protocol-specified background 
antihypertensive medication): 
• 
At Month 3, a CCB and/or a thiazide/thiazide-like diuretic should be added 
as an escape antihypertensive medication if the daytime mean SBP is 
≥135 mmHg by ABPM. If the Investigator feels there is a compelling 
clinical reason to wait, the rationale for exception should be documented in 
the eCRF. 
• 
After Month 3, other escape antihypertensive medications may also be 
added per Investigator judgement for persistent elevations in SBP above 
target (target defined as office SBP <140 mmHg, HBPM SBP <135 mmHg, 
or daytime mean SBP by ABPM <135 mmHg).[Williams 2018] 


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Study Period 
Intervention 
Month 6 to End of 
Study (OLE period) 
Treat to target blood pressure using Investigator’s choice of oral 
antihypertensive(s). 
• 
At Month 6, protocol-specified background antihypertensive medications 
(olmesartan, amlodipine, or indapamide) will be discontinued.  
• 
Patients who continue into the OLE period will initiate open-label treatment 
with 600 mg zilebesiran once every 6 months. As many patients will receive 
zilebesiran for the first time at Month 6, office blood pressure and serum 
chemistries will be carefully monitored monthly from Month 6 to Month 9, 
and Investigators will be prepared to downtitrate or interrupt escape 
antihypertensive medications if low blood pressure develops (see 
Section 5.8.1). 
• 
If the Month 6 ABPM is in target (daytime mean SBP <135 mmHg), escape 
antihypertensive medications (if taken) may be downtitrated or interrupted 
per Investigator judgement to determine if the patient’s blood pressure 
remains within target on zilebesiran treatment alone.  
• 
During the OLE period, oral antihypertensive medications may be added 
per Investigator judgement for persistent elevations in blood pressure above 
target (target defined as office SBP <140 mmHg, HBPM SBP <135 mmHg, 
or daytime mean SBP by ABPM <135 mmHg).[Whelton 2018; Williams 
2018] 
Abbreviations: ABPM=ambulatory blood pressure monitoring; ACE=angiotensin converting enzyme; 
ARB=angiotensin II-receptor blocker; CCB=calcium channel blocker; DBP=diastolic blood pressure; 
eCRF=electronic case report form; HBPM=home blood pressure monitoring; OLE=open-label extension; 
RAAS=renin-angiotensin-aldosterone system; SBP=systolic blood pressure. 
5.8.3. 
Monitoring and Approach for Potential Renal Dysfunction 
The Schedule of Assessments (Table 1) includes frequent laboratory monitoring of eGFR 
through the anticipated onset of initial zilebesiran PD. Based upon the renal dysfunction 
associated with conventional RAAS inhibitors,[McMurray 2016; Parving 2012] the following 
guidelines apply throughout the study: 
• If an individual patient experiences a decrease in eGFR by ≥30% from baseline or to 
≤30 mL/min/1.73m2, the Investigator should obtain confirmatory repeat tests, contact 
the Sponsor, and look for potentially reversible causes of renal dysfunction such as: 
− NSAIDs, antibiotics, or other treatments known to impair renal function 
− Recent exposure to intravenous contrast agents 
− Hypovolemia 
− Hypotension 
− Urinary infection 
− Urinary tract obstruction 
• If an individual patient experiences a decrease in eGFR by ≥40% from baseline or to 
≤25 mL/min/1.73m2, the Investigator should obtain confirmatory repeats tests, look 


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for potentially reversible causes of renal dysfunction, and contact the Sponsor to 
discuss the potential interruption of study drug and/or oral antihypertensives. Serum 
creatinine should be monitored at least weekly until improving. 
5.8.4. 
Monitoring and Approach for Potential Hyperkalemia 
The Schedule of Assessments (Table 1) includes frequent laboratory monitoring of serum 
electrolytes (at least monthly through the anticipated onset of zilebesiran PD). The guidelines in 
Table 5 apply for potassium elevations detected by laboratory monitoring.[McMurray 2016; 
Parving 2012] 
Table 5: 
Recommended Interventions for Hyperkalemia 
Serum K+ ≥5.2 and <5.5 mmol/L 
Serum K+ ≥5.5 and <6.0 mmol/L 
Serum K+ ≥6.0 mmol/L 
• 
Confirm potassium 
concentration in a non-
hemolyzed sample. 
• 
Reinforce low-potassium diet 
and restriction of food/drinks 
with high potassium content  
• 
Review medical regimen 
(including dietary supplements 
and over-the-counter 
medications) for agents known 
to cause hyperkalemia.a 
Consider reduction in dose or 
discontinuation of these agents 
only if clinically acceptable. 
• 
Repeat K+ measurement within 
3 to 5 days. 
• 
If K+ remains ≥5.2 and <5.5 
mmol/L, regularly monitor K+ 
levels to ensure stability (at 
least weekly if in the first 6 
weeks of treatment or at least 
once monthly afterwards) 
• 
Confirm potassium 
concentration in a non-
hemolyzed sample 
• 
Consider interruption of open-
label olmesartan (in patients 
randomized to receive it as their 
protocol-specified background 
antihypertensive medication) 
according to Investigator 
medical judgement 
• 
Consider interruption or delay 
of study drug administration, 
according to Investigator 
medical judgment  
• 
Apply all measures outlined for 
serum K+ ≥5.2 and <5.5 
mmol/L 
• 
Repeat K+ measurement after 2 
to 3 days 
• 
If K+ <5.5 mmol/L, consider 
resumption of study drug (if 
interrupted) with repeat 
potassium within 5 days 
• 
If K+ persistently elevated ≥5.5 
mmol/L, consider treatment 
with patiromer (or with sodium 
zirconium cyclosilicate), if 
available 
• 
Immediately interrupt 
study drug 
• 
Confirm potassium 
concentration in a 
non-hemolyzed 
sample 
• 
Urgently evaluate 
patient and treat 
hyperkalemia as 
clinically indicated. 
After urgent 
treatment, consider 
treatment with 
patiromer (or with 
sodium zirconium 
cyclosilicate), if 
available 
• 
Apply all measures 
outlined for serum K+ 
≥5.5 and <6.0 
mmol/L 
• 
No resumption of 
study drug without 
individualized case 
discussion with and 
permission from 
Alnylam Medical 
Monitor 
Abbreviations: NSAID=nonsteroidal anti-inflammatory drug. 
a This list is not meant to be exhaustive: potassium-sparing diuretics (eg, amiloride and triamterene), potassium 
supplements (eg potassium chloride), salt substitutes, NSAIDs, cyclo-oxygenase-2 inhibitors, trimethoprim and 
trimethoprim-containing combination products, herbal supplements (eg, Noni juice, alfalfa [Medicago sativa], 
dandelion [Taraxacum officinale], horsetail [Equisetum arvense], nettle [Urtica dioica], milkweed, lily of the 
valley, Siberian ginseng, hawthorn berries). 


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The availability of patiromer and sodium zirconium cyclosilicate (ZS-9) will be assessed at 
participating study sites. These potassium-binding drugs are indicated for the treatment of 
hyperkalemia and have been shown to safely reduce serum potassium levels and to maintain 
long-term normokalemia in chronic kidney disease patients receiving background conventional 
RAAS inhibitor therapy.[Georgianos and Agarwal 2018; Weir 2015] 
5.9. 
Concomitant Medications and Procedures 
Use of concomitant medications and procedures will be recorded on the patient’s eCRF as 
specified in the Schedule of Assessments (see Table 1). Concomitant medications include all 
prescription medications, herbal preparations, over the counter medications, vitamins, and 
minerals. Any changes in medications during the study will also be recorded on the eCRF. 
Standard vitamins and topical medications are permitted. However, topical steroids must not be 
applied anywhere near the injection site(s) unless medically indicated. For other permitted 
concomitant medications administered SC, do not administer in same injection site area as the 
study drug for at least 4 days after each dose of study drug. 
Occasional use of systemic over-the-counter NSAIDs is allowed. However, given their 
association with increased blood pressure, they should be avoided when possible and for at least 
7 days prior to ABPM and office blood pressure assessments, and alternative analgesics 
(acetaminophen, topical NSAIDs) should be considered.[Whelton 2018] When used, the dosing 
of systemic NSAIDs should be at the lower end of the labeled range and for the shortest duration 
possible.  
Patients will be allowed to receive vaccines (eg, for SARS-CoV-2) that have received health 
agency authorization (including for emergency use) by local or regional regulatory authorities. 
Any concomitant medication that is required for the patient’s welfare may be administered by the 
Investigator, except as described in Section 5.9.1. However, it is the responsibility of the 
Investigator to ensure that details regarding the medication are recorded on the eCRF. 
Concomitant medication will be coded using an internationally recognized and accepted coding 
dictionary. 
5.9.1. 
Prohibited Concomitant Medication 
The following medications, treatments, and supplements are prohibited throughout the study 
(until the EOT visit): 
• Conventional RAAS inhibitors (ARBs, ACE inhibitors, or direct renin inhibitors), 
except for olmesartan as protocol-specified background antihypertensive medication 
during the 6-month DB period  
• SGLT2 inhibitors (eg, empagliflozin, canagliflozin, and dapagliflozin) 
• Prescription NSAIDs  
• Organic nitrate preparations (eg, nitroglycerin, isosorbide mononitrate, isosorbide 
dinitrate, pentaerythritol) 
• An RNAi therapeutic (other than zilebesiran) 


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• Medications, herbal supplements (including Ma Huang and St. John’s wort), or other 
substances (such as licorice) that are associated with increases in LFT abnormalities 
or with blood pressure abnormalities are prohibited. This includes certain stimulants 
(eg, amphetamine, methylphenidate dexmethylphenidate, dextroamphetamine), MAO 
inhibitors, atypical antipsychotics (eg, clozapine, olanzapine), diet pills (eg, 
phenylpropanolamine, sibutramine), and nasal decongestants (eg, phenylephrine 
hydrochloride, pseudoephedrine, naphazoline hydrochloride). 
• Medications, herbal medicines, over-the-counter medications, or supplements known 
to cause hyperkalemia are prohibited unless individually approved by both the 
Investigator and the Medical Monitor. This includes potassium-sparing diuretics, 
potassium supplements, cyclo-oxygenase-2 inhibitors, trimethoprim and 
trimethoprim-containing combination products, mineralocorticoid receptor 
antagonists, Noni juice, alfalfa, dandelion, horsetail, nettle, milkweed, lily of the 
valley, Siberian ginseng, and hawthorn berries. 
All concomitant medications must be reviewed and approved by the Investigator, with particular 
attention to avoiding drugs that may affect blood pressure. 
5.10. 
Treatment Compliance 
Compliance with study drug administration will be verified through observation by study staff. 
Compliance with protocol-specified background antihypertensive medication will be assessed 
through pill count by study staff. 
5.11. 
Other Requirements 
5.11.1. 
Contraception 
Females of child-bearing potential must be willing to use a highly effective method of 
contraception from 14 days before the first dose of protocol-specified background 
antihypertensive medication, throughout study participation, and through safety follow-up (if 
applicable; see Section 3.1). 
Birth control methods which are considered highly effective include: 
• Placement of an intrauterine device. 
• Placement of an intrauterine hormone-releasing system. 
• Bilateral tubal occlusion. 
• Surgical sterilization of male partner (with the appropriate post-vasectomy 
documentation of the absence of sperm in the ejaculate; for female patients on the 
study, the vasectomized male partner should be the sole partner for that patient). 
• Established use of oral (except low-dose gestagens), implantable, injectable, or 
transdermal hormonal methods of contraception associated with the inhibition of 
ovulation. 
• True sexual abstinence, when in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation 


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methods) and withdrawal are not acceptable methods of contraception. Abstinent 
patients must agree to use one of the above-mentioned contraceptive methods if they 
start heterosexual relationships during the study and through safety follow-up (if 
applicable; see Section 3.1) 
Investigators should advise females of childbearing potential of the most appropriate birth 
control method available within their country taking into account local medical practice. 
Females of child-bearing potential include female patients who have experienced menarche (or 
begin menarche over the course of the study), and who are not postmenopausal or permanently 
sterilized (eg, bilateral tubal occlusion, hysterectomy, or bilateral salpingectomy). A 
postmenopausal state is defined as the absence of menses for 12 months without an alternative 
medical cause, confirmed by follicle stimulating hormone level within the postmenopausal 
range.  
For male patients, no contraception is required. However, use by males of contraception 
(condom) may be required in some countries, eg, France, in order to comply with local 
requirements as described in the corresponding patient ICFs.  
Compliance with contraception requirements will be assessed on a regular basis by the 
Investigator throughout the course of the study (see Section 6.5.5.3). Pregnancy testing will be 
performed before every dose for postmenarcheal females throughout the course of the study (see 
Section 6.5.5.3). 
5.11.2. 
Alcohol Restrictions 
Patients should limit alcohol consumption throughout the course of the study. Alcohol is limited 
to no more than 2 units per day (unit: 1 glass of wine [approximately 125 mL] =1 measure of 
spirits [approximately 1 fluid ounce] =½ pint of beer [approximately 284 mL]) for the duration 
of the study. Compliance with alcohol restrictions should be assessed on a regular basis by the 
Investigator throughout the course of the study. 
5.11.3. 
Tobacco and Nicotine Restrictions 
Use of nicotine or tobacco-containing products (including, but not limited to, snuff, chewing 
tobacco, cigars, cigarettes, pipes, nicotine patches, or e-cigarettes) must be avoided within 30 
minutes prior to office blood pressure measurements. 
5.11.4. 
Cannabis Restriction 
Use of cannabis or delta-9-tetrahydrocannibinol-containing substances (included by smoking, 
vaping, dabbing, or ingesting/edibles) should be avoided throughout the course of the study 
given their effects on blood pressure. 
5.11.5. 
Dietary Recommendations 
All patients will receive educational materials on diet with recommendations to limit sodium 
consumption to approximately 2.0 g per day from screening through the end of the Treatment 
period. This direction should be provided at the start of the Screening period, and treatment-
naïve patients should follow these recommendations for at least 1 week prior to screening 
assessments of blood pressure. This is the sodium intake recommended in the 2018 European 


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Society of Cardiology/European Society of Hypertension Guidelines for both hypertensive 
patients and for the general population.[Williams 2018]  
On days on which samples for fasting lipid panel and glycemic assessments are collected, 
patients are required to fast for ≥10 hours before sample collection (Section 6.5.5.1). 
5.11.6. 
Exercise 
Patients should abstain from strenuous exercise for 48 hours before each blood collection for 
clinical laboratory tests. 
6. 
STUDY ASSESSMENTS 
The schedule of study assessments is provided in Table 1. Study visits should be scheduled for 
the morning. All assessments, except for postdose PK sample collection, are to be performed 
prior to dosing with protocol-specified background antihypertensive medication or study drug. 
Additional information on the collection of study assessments will be detailed in the Study 
Manual. 
Where applicable country and local regulations and infrastructure for home healthcare allow, 
home healthcare may take place at a location other than the clinical trial site to perform study 
assessments, which may include collection of blood and urine samples and measurement of vital 
signs (at the discretion and oversight of the Investigator). 
6.1. 
Screening Assessments 
An ICF that has been approved by the appropriate IRB/IEC must be signed (in paper or 
electronic format per local regulations and institutional standards) by the patient or legal 
guardian before the screening procedures are initiated. All patients or their legal guardians will 
be given a copy of the signed and dated ICF. 
Patients will be screened to ensure that they meet all the inclusion criteria and none of the 
exclusion criteria. Rescreening of patients once is permitted with agreement of the Medical 
Monitor (see Section 6.1.2). 
Patient demographic data and medical history/disease history will be obtained. Any changes to 
medical history occurring between the screening assessment and Run-in Visit 1 will be updated 
prior to administration of protocol-specified background antihypertensive medication. 
6.1.1. 
Retesting  
If in the Investigator’s judgement, the screening or Run-in laboratory abnormalities are likely to 
be transient, then laboratory tests may be repeated. The Investigator’s rationale must be 
documented. Laboratory values can be retested once during screening and once during the Run-
in period provided that the patient can be evaluated for eligibility and randomized within the 
allowed Screening and Run-in periods. Retesting of ABPM at Run-in Visit 2 is permitted once as 
described in Section 6.2.1, with eligibility assessed by the second ABPM result. 


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6.1.2. 
Rescreening 
A patient who does not meet all study eligibility criteria due to a transient condition observed at 
screening (eg, prohibited medications that were subsequently discontinued) will be allowed to 
return once for rescreening following agreement with the Medical Monitor. A patient will be re-
consented if rescreening occurs outside of the Screening period. In this case, all screening 
procedures must be repeated. Patients who do not meet eligibility criteria after Run-in Visit 1 
will not be rescreened. 
6.2. 
Efficacy Assessments 
All blood pressure measurements (ABPM, office, and HBPM) must be taken at the times 
specified in the Schedule of Assessments (Table 1) using the standardized equipment provided 
by the Sponsor, according to the methods described in Section 10.2. Office blood pressure 
assessments and ABPM initiation must be performed before administration of any oral 
antihypertensive medications and study drug (as applicable). 
Patients taking oral antihypertensives prior to screening should discontinue these medications at 
Run-in Visit 1. The baseline ABPM and office blood pressure measured at Run-in Visit 2 must 
be taken within 7 days before Day 1. An HBPM unit will be provided before Run-in Visit 2 to 
establish the HBPM baseline. HBPM must be collected daily for at least 1 week during the Run-
in period to establish baseline, starting at 1 week prior to Run-in Visit 2 and continuing to Day 1. 
After Day 1, the frequency of HBPM should be at least 3 recordings per week. 
ABPM placement may be performed at home by appropriately trained individuals, as detailed in 
the Study Manual. If a patient is unable to report to the site for an office blood pressure 
assessment, a substitute “remote visit blood pressure measurement” may be obtained remotely 
using the methods described in Section 10.2. 
Recommendations for approach and monitoring of low blood pressure/hypotension and 
hypertensive escape are provided in Section 5.8.1 and Section 5.8.2, respectively. 
6.2.1. 
ABPM 
The ABPM must be started prior to the morning dose of oral antihypertensive medication. 
Consecutive (daily) use of over-the-counter NSAIDs should be avoided for at least 7 days prior 
to ABPM measurements. 
Adequacy will be assessed for all ABPMs. If the ABPM recording is inadequate, the patient will 
be provided 1 opportunity to repeat the study. During the Run-in period, if the second ABPM 
recording is also inadequate, the patient is a run-in failure.  
See further details in Section 10.2 and the Study Manual. 
6.2.2. 
Office Blood Pressure 
Office blood pressure must be measured in triplicate using the automated blood pressure device 
provided by the Sponsor at trough (prior to taking oral antihypertensives) and should be at 
approximately the same time of day for each assessment; therefore, visits should be scheduled at 
approximately the same time of day, whenever possible. Office blood pressure must include 
orthostatic measurements (seated and standing).  


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Exercise, caffeine, alcohol consumption, and use of nicotine or tobacco-containing products 
(including but not limited to snuff, chewing tobacco, cigars, cigarettes, pipes, nicotine patches, or 
e-cigarettes) must be avoided within 30 minutes prior to blood pressure measurements. The use 
of inhaled short-acting beta agonists should be avoided within 6 hours prior to measuring blood 
pressure and/or heart rate. The use of phosphodiesterase type 5 inhibitors (eg, sildenafil, 
tadalafil, vardenafil, avanafil) should be avoided within 48 hours prior to measuring blood 
pressure. Consecutive (daily) use of over-the-counter NSAIDs should be avoided for at least 7 
days prior to blood pressure measurements. 
The patient should be seated comfortably with the back supported and the feet flat on the floor as 
detailed in Section 10.2 and the Study Manual.  
6.2.3. 
HBPM 
The HBPM should be measured in the morning upon waking, prior to breakfast/caffeine or 
taking morning oral antihypertensive medications. HBPM is not required at times when ABPM 
is being assessed. The patient should be seated comfortably with the back supported and the feet 
flat on the floor as detailed in Section 10.2 and the Study Manual. 
6.3. 
Pharmacodynamic Assessments 
Blood samples for determination of AGT will be collected according to the Schedule of 
Assessments (Table 1). In addition, blood samples for determination of RAAS biomarkers 
(plasma renin concentration, AngI, AngII, and aldosterone) will be collected only for patients 
randomized to receive olmesartan as protocol-specified background antihypertensive medication. 
Blood samples for PD assessments must be collected before study drug administration (on days 
when study drug is to be dosed) or at a time point corresponding to the time of study drug dosing 
(on other days). Blood AGT levels will be analyzed at a regulated bioanalytical laboratory by 
enzyme-linked immunosorbent assay for measurement of PD effect. Biomarkers may be 
analyzed using qualified assays. Details regarding the collection, processing, shipping, and 
storage of the samples will be provided in the Laboratory Manual.  
Results will not be used to adjust dosing of zilebesiran or guide clinical management and will not 
be shared with sites until after study unblinding. 
6.4. 
Pharmacokinetic Assessments 
Blood samples will be collected for the assessment of plasma concentrations of zilebesiran and 
its primary metabolite AS(N-1)3′ zilebesiran at the time points indicated in the Schedule of 
Assessments (Table 1). A detailed schedule of time points for the collection of blood samples for 
PK analysis is in Table 2. 
Plasma concentrations of zilebesiran and AS(N-1)3′ zilebesiran will be determined using a 
validated assay. Details regarding sample volumes to be collected, and the processing, shipping, 
and analysis of the samples will be provided in the Laboratory Manual. 
6.5. 
Safety Assessments 
The assessment of safety during the study will consist of the surveillance and recording of AEs, 
including SAEs, recording of concomitant medication and measurements of vital signs, weight, 


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electrocardiogram (ECG) findings, and laboratory tests. Clinically significant abnormalities 
observed during the physical examination will be recorded. 
6.5.1. 
Vital Signs 
Vital signs will be measured as specified in the Schedule of Assessments (Table 1) and include 
blood pressure, heart rate, body temperature, and respiratory rate. Vital signs are to be collected 
prior to administration of oral antihypertensive medications and study drug (as applicable). 
When vital signs and blood sample collection occur at the same time, vital signs should be 
performed before blood samples are drawn, where possible. Vital signs should be measured in 
the seated position, after the patient has rested comfortably for approximately 10 minutes. Body 
temperature in degrees Celsius will be obtained via oral, tympanic, or axillary methods. Heart 
rate will be counted for a full minute and recorded in beats per minute, and respiration rate will 
be counted for a full minute and recorded in breaths per minute. Blood pressure is described in 
Section 6.2.  
Additional vital sign assessments, as medically indicated, may be added at the discretion of the 
Investigator, or as per DMC advice. 
6.5.2. 
Weight, Height, and Morphometrics 
Height and body weight measurements will be collected as specified in the Schedule of 
Assessments (Table 1) and will be recorded in the eCRF. Height will be measured at Day 1 only. 
Height will be measured in centimeters. Body weight should be measured in kilograms to the 
first decimal point in patients wearing light clothing and without shoes.  
Waist circumference and waist-to-hip-ratio will also be collected as specified in the Schedule of 
Assessments (Table 1) and will be recorded on the eCRF. For waist circumference and waist-to-
hip ratio, patients should wear minimal clothing to ensure that the measuring tape is correctly 
positioned. Patients should stand erect with the abdomen relaxed, arms at the sides, feet together 
and with their weight equally divided over both legs. To perform the waist measurement, the 
lowest rib margin is first located and marked with a pen. The iliac crest is then palpated in the 
midaxillary line, and also marked. It is recommended to apply an elastic tape horizontally 
midway between the lowest rib margin and the iliac crest, and tie firmly so that it stays in 
position around the abdomen about the level of the umbilicus. The elastic tape thus defines the 
level of the waist circumference, which can then be measured by positioning the measuring tape 
over the elastic tape. Hip circumference measurement should be taken around the widest portion 
of the buttocks. Patients are asked to breathe normally, and to breathe out gently at the time of 
the measurement to prevent them from contracting their muscles or from holding their breath. A 
stretch-resistant tape that provides a constant 100 g of tension is recommended. Measurements 
should be obtained with the tape positioned parallel to the floor and performed using the same 
procedure throughout the study. 
The reading is taken to the nearest centimeter and entered in the source document. Each 
measurement should be repeated twice; if the measurements are within 1 cm of each other, the 
average should be calculated. If the difference between the 2 measurements exceeds 1 cm, the 2 
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6.5.3. 
Physical Examination 
Full and symptom-directed physical examinations will be conducted according to the Schedule 
of Assessments (Table 1); if a physical examination is scheduled for a study drug dosing visit, it 
should be conducted prior to dosing. Full physical examinations will include the examination of 
the following: general appearance; head, eyes, ears, nose and throat; respiratory, cardiovascular, 
gastrointestinal, musculoskeletal, and dermatological systems; thyroid; lymph nodes; and 
neurological evaluation (see the Study Manual for further details on the assessments to be 
performed as part of the neurological evaluation). 
Symptom-directed physical examinations will be guided by evaluation of changes in symptoms, 
or the onset of new symptoms, since the last visit. Neurological evaluation should be performed 
according to the Study Manual during all symptom-directed physical examinations regardless of 
whether neurological symptoms have been experienced by the patient.  
Clinically significant abnormalities observed during the physical examination are recorded on 
the medical history or AE eCRF. 
6.5.4. 
Electrocardiogram 
The 12-lead ECGs reporting rhythm, ventricular rate, RR interval, PR interval, QRS duration, 
QT interval, and Fridericia-corrected QT interval will be obtained using a local machine, as 
specified in the Schedule of Assessments (Table 1). Patients should be supine for at least 10 
minutes before each ECG is obtained. The Investigator or qualified designee will review all 
single 12-lead ECGs to assess whether the results have changed since the Baseline visit and to 
determine the clinical significance of the results. These assessments will be recorded in the 
eCRF.  
When ECG and blood sample collection occur at the same visit, blood sample collection should 
occur first. ECGs should be performed at least 30 minutes after phlebotomy or other stressful 
assessments. 
The Investigator or qualified designee will review all ECGs to assess whether the results have 
changed since the baseline visit and to determine the clinical significance of the results. These 
assessments will be recorded in the eCRF. Additional ECGs may be collected at the discretion of 
the Investigator, or as per DMC advice. Recordings will be archived according to the Study 
Manual. 
6.5.5. 
Clinical Laboratory Assessments 
The following clinical laboratory tests will be evaluated by a central laboratory. Specific 
instructions for transaminase elevations are provided in Section 5.2.4. For any other unexplained 
clinically relevant abnormal laboratory test occurring after study drug administration, the test 
should be repeated and followed up at the discretion of the Investigator, or as per DMC advice, 
until it has returned to the normal range or stabilized, and/or a diagnosis is made to adequately 
explain the abnormality. Additional safety laboratories and assessments as indicated by the 
clinical situation may be requested. Clinical laboratory assessments are listed in Table 6 and will 
be assessed as specified in the Schedule of Assessments (Table 1).  
While local laboratory results may be used for urgent clinical decisions, on the day of the 
assessments, all laboratory assessments specified in Table 6 that are performed at the clinic 


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should also be sent in parallel to the central laboratory. In the case of discrepant local and central 
laboratory results on samples drawn on the same day, central laboratory results will be relied 
upon for clinical decisions. 
Clinical laboratory assessments may be collected at the clinical study center or at home by a 
trained healthcare professional. Consecutive (daily) use of over-the-counter NSAIDs should be 
avoided for at least 7 days prior to laboratory assessments. In patients randomized to receive 
olmesartan as the protocol-specified background antihypertensive medication, blood samples for 
RAAS biomarkers should be collected in the morning and in the seated/upright position (after 
blood pressure measurements and before any assessments collected in the supine position). 
Blood samples for laboratory evaluation should be collected after the completion of blood 
pressure assessments. 
Spot urine collections for albumin and creatinine should be obtained in the morning. A 24-hour 
urine collection for sodium and creatinine will be performed at time points listed in the Schedule 
of Assessments (Table 1). These 24-hour collections should be obtained within 2 days before the 
ABPM associated with the same visit. 
For any safety event or laboratory abnormality, additional laboratory assessments, imaging, and 
consultation may be performed for clinical evaluation and/or in consultation with the Medical 
Monitor; results may be collected and should be included in the clinical database. 
Table 6: 
Clinical Laboratory Assessments 
Hematology 
Complete blood count with differential 
 
Serum Chemistry 
Sodium 
Potassium 
BUN 
Phosphate 
Uric acid 
Albumin 
Total protein 
Calcium 
Glucose 
Bicarbonate 
Creatinine and eGFR 
Chloride 
Creatinine clearance 
 
Liver Function Tests 
 
AST 
ALP 
ALT 
Bilirubin (total and direct) 
GGT 
 
Urinalysis 
Visual inspection for appearance and color 
Bilirubin 
pH (dipstick) 
Nitrite 
Specific gravity 
RBCs 


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Ketones 
Urobilinogen 
Albumin 
Leukocyte esterase 
Glucose 
Microscopy (if clinically indicated) 
Protein 
 
Coagulation  
Prothrombin time 
International normalized ratio 
Partial thromboplastin time  
 
Fasting Lipid Panel and Glycemic Assessments (see Section 6.5.5.1) 
Lipid panel, including 
HDL-C, non-HDL-C, LDL-C, apolipoprotein A1, 
triglycerides, total cholesterol  
Insulin 
Fasting plasma glucose 
HbA1c 
Immunogenicity (see Section 6.5.5.2) 
ADA 
 
Pregnancy Testing/FSH Screening (see Section 6.5.5.3) 
β-human chorionic gonadotropin (females of 
child-bearing potential only) 
Follicle-stimulating hormone (postmenopausal 
women only) 
Abbreviations: ADA=anti-drug antibodies; ALP=alkaline phosphatase; ALT=alanine aminotransferase; 
AST=aspartate aminotransferase; BUN=blood urea nitrogen; eGFR=estimated glomerular filtration rate; 
FSH=follicle-stimulating hormone; GGT=gamma glutamyl transferase; HbA1c=hemoglobin A1c; HDL-C=high-
density lipoprotein; LDL-C=low-density lipoprotein; RBCs=red blood cells. 
6.5.5.1. 
Fasting Lipid Panel and Glycemic Assessments 
Blood samples for fasting plasma glucose, insulin, lipid panel (including total cholesterol, high-
density lipoprotein [HDL-C], non-HDL-C, low-density lipoprotein, apolipoprotein A1, and 
triglycerides), and HbA1c will be collected at the time points listed in the Schedule of 
Assessments (Table 1). Patients are required to fast for ≥10 hours before sample collection for 
fasting glucose, insulin, lipid panel, and HbA1c. Samples should be collected at approximately 
the same time of day (±2 hours). 
6.5.5.2. 
Immunogenicity 
Blood samples will be collected to evaluate anti-drug antibodies (ADA). Blood samples for ADA 
testing must be collected before study drug administration (on days when study drug is to be 
dosed) or at a time point corresponding to the time of study drug dosing (on other days) as 
specified in the Schedule of Assessments (Table 1). A blood sample to evaluate ADA will be 
collected at the ET visit, if applicable. Blood samples for ADA will be analyzed at a regulated 
bioanalytical laboratory. 
Details regarding the processing, shipping, and analysis of the samples will be provided in the 
Laboratory Manual. 


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6.5.5.3. 
Pregnancy Testing 
A pregnancy test will be performed for females of child-bearing potential. A serum pregnancy 
test will be performed at screening, and urine pregnancy tests will be performed thereafter per 
the Schedule of Assessments and any time pregnancy is suspected. More frequent pregnancy 
testing may be performed where required per local requirements. The results of the pregnancy 
test must be known before study drug administration. Patients who are pregnant at screening are 
not eligible for study participation. Any woman with a positive urine pregnancy test, 
subsequently confirmed by a positive serum pregnancy test, during the study will be 
discontinued from study drug but will continue to be followed for safety. Patients who become 
pregnant while on study will be followed at least until the pregnancy outcome is known (see 
Section 6.5.6.7 for follow-up instructions). 
A blood sample will be drawn at screening to measure the levels of follicle stimulating hormone 
in order to confirm postmenopausal status in all women suspected to be postmenopausal (see 
Section 5.11.1 for definition of postmenopausal state). 
6.5.5.4. 
Additional Liver Function Assessments 
Additional laboratory assessments will be performed in patients who experience any LFT 
abnormalities as outlined in Section 5.2.4. Following the occurrence of elevated liver 
transaminases or other LFT abnormalities per central laboratory, all assessments in Table 7 will 
be performed 1 time, as well as hematology, serum chemistry, LFT, and coagulation assessments 
from Table 6, and other assessments or evaluations per Investigator discretion, as appropriate.  
Monitoring, including criteria for dose modification or withholding the study drug, is described 
in Section 5.2.4.  


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Table 7: 
Hepatic Assessments in Patients Who Experience Elevated Transaminases 
Extended Hepatic Panel 
HBsAg, HBsAb, HBc antibody IgM  
Parvovirus B19 DNA - quantitative 
HAV antibody IgM 
HHV-6 DNA viral load - quantitative 
HCV antibody 
Anti-nuclear antibodies 
HCV RNA PCR – quantitative 
Anti-smooth muscle antibodies 
HEV antibody IgM 
Anti-LKM1 antibody 
Herpes Simplex Virus 1 and 2 antibody IgM, IgG 
Anti-mitochondrial antibodies 
Herpes Zoster Virus IgM, IgG 
Anti-SLA 
Epstein-Barr Virus antibodies, IgM and IgG 
Ferritin 
Cytomegalovirus antibodies, IgM, IgG 
Ceruloplasmin 
Imaging 
Abdominal ultrasound with Doppler flow (or CT or MRI) including right upper quadrant 
Focused Medical and Travel History 
Use of any potentially hepatotoxic concomitant medications, 
including over the counter medications and herbal remedies 
Alcohol consumption and drugs of 
abuse  
Other potentially hepatotoxic agents including any work-
related exposures 
Recent travels to areas where 
hepatitis A or E is endemic 
Abbreviations: CT=computed tomography; DNA=deoxyribonucleic acid; HAV=hepatitis A virus; HBc=hepatitis B 
core; HBsAb=hepatitis B surface antibody; HBsAg=hepatitis B virus surface antigen; HCV=hepatitis C virus; 
HEV=hepatitis E virus; HHV-6=human herpesvirus 6; IgG=immunoglobulin G antibody; IgM=immunoglobulin M 
antibody; LKM1=liver/kidney microsome-1 antibody MRI=magnetic resonance imagery; PCR=polymerase chain 
reaction; RNA=ribonucleic acid; SLA=soluble liver antigen 
Note: 
• 
All assessments will be measured in central laboratory. The full panel of assessments should only be 
performed once; individual assessments may be repeated, as needed. 
6.5.6. 
Adverse Events 
6.5.6.1. 
Definitions 
Adverse Event 
According to the ICH E2A guideline Definitions and Standards for Expedited Reporting, and 
21 Code of Federal Regulations 312.32, IND Safety Reporting, an AE is any untoward medical 
occurrence in a patient or clinical investigational subject administered a medicinal product and 
which does not necessarily have a causal relationship with this treatment. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 


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• Is life-threatening (an event which places the patient at immediate risk of death from 
the event as it occurred. It does not include an event that had it occurred in a more 
severe form might have caused death) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is an important medical event that may not be immediately life-threatening or result 
in death or hospitalization but may jeopardize the patient and may require 
intervention to prevent one of the other outcomes listed in the definition above (eg, 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias, convulsions, or the development of drug 
dependency or abuse). 
Adverse Events of Clinical Interest 
The following are considered to be AEs of clinical interest: 
• ALT or AST >3×ULN 
• Severe or serious ISRs; ISRs that are associated with a recall phenomenon (reaction 
at the site of a prior injection with subsequent injections), or those that lead to 
temporary dose interruption or permanent discontinuation of zilebesiran. 
An ISR is defined as a local reaction at or near the site of injection. “At or near” the 
injection site includes reactions at the injection site, adjacent to the injection site, or a 
reaction which may shift slightly away from the injection site due to gravity (eg, as 
may occur with swelling or hematoma). A systemic reaction which includes the 
injection site, eg, generalized urticaria, other distinct entities or conditions like 
lymphadenopathy that may be near the injection site is not considered an ISR. 
For information on recording and reporting of AEs of clinical interest, see Section 6.5.6.2 and 
Section 6.5.6.3, respectively. 
Adverse Event Severity 
Adverse events are to be graded according to the categories detailed below: 
Mild: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Moderate: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age 
appropriate instrumental activities of daily living (eg, preparing meals, 
shopping for groceries or clothes, using the telephone, managing money). 
Severe: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living (ie, bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden); OR life-threatening consequences; urgent intervention indicated; 
OR death related to an adverse event. 


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Changes in severity should be documented in the medical record to allow assessment of the 
duration of the event at each level of severity. Adverse events characterized as intermittent 
require documentation of the start and stop of each incidence. When changes in the severity of an 
AE occur more frequently than once a day, the maximum severity for the experience that day 
should be noted. If the severity category changes over a number of days, then those changes 
should be recorded separately (with distinct onset dates). 
Adverse event severity and seriousness are assessed independently. ‘Severity’ characterizes the 
intensity of an AE. ‘Serious’ is a regulatory definition and serves as a guide to the Sponsor for 
defining regulatory reporting obligations (see definition for SAE). 
Relationship of the Adverse Event to Study Treatment 
The relationship of each AE to study drug should be evaluated by the Investigator by a “yes” or 
“no” response to the question: “Is there a reasonable possibility that the event may have been 
caused by the study drug?” A “yes” response indicates that the event is considered as related to 
the study drug. 
The relationship of each AE to the protocol-specified background antihypertensive medication 
should also be assessed by the Investigator. 
6.5.6.2. 
Eliciting and Recording Adverse Events 
Eliciting Adverse Events 
The patient and legal guardian, if applicable, should be asked about medically relevant changes 
in the patient’s health since the last visit. The patient and legal guardian, if applicable, should 
also be asked if the patient has been hospitalized, had any accidents, used any new medications, 
or changed concomitant medication routines (both prescription and over-the-counter). In addition 
to patient observations, AEs will be documented from any clinically relevant laboratory findings, 
physical examination findings, ECG changes, or other findings that are relevant to patient safety. 
Recording Adverse Events 
The Investigator is responsible for recording non-serious AEs that are observed or reported by 
the patient after administration of the first dose of study treatment during the Run-in period 
regardless of their relationship to the study treatment through the end of study. Study treatment is 
defined as protocol-specified background antihypertensive medication or study drug (zilebesiran 
or placebo). Non-serious AEs will be followed until the end of study. Events occurring after 
signing of the ICF and before the Run-in period will be captured as medical history (see 
Section 6.1), while AEs that occur after study treatment, and baseline events that worsen after 
study treatment, must be recorded as AEs. 
The Investigator is responsible for recording SAEs that are observed or reported by the patient 
after the time when the informed consent is signed regardless of their relationship to study 
treatment through the end of study. SAEs will be followed until satisfactory resolution, until 
baseline level is reached, or until the SAE is considered by the Investigator to be chronic or the 
patient is stable, as appropriate. 
All AEs must be recorded in the source records for the clinical study center and in the eCRF for 
the patient, whether or not they are considered to be related. Each AE must be described in 


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detail: onset time and date, description of event, severity, relationship to study treatment, action 
taken, and outcome (including time and date of resolution, if applicable). 
For SAEs, record the event(s) in the eCRF and, as applicable, the SAE form. 
For AEs that are considered AEs of clinical interest (Section 6.5.6.1), the supplemental AEs of 
Clinical Interest eCRF should be completed. Additional clinical and laboratory information may 
be collected. Refer to eCRF completion guidelines for details on reporting events in the 
supplemental AEs of Clinical Interest eCRF. 
For all ISRs, the Investigator, or delegate, should submit an Injection Site Reaction Signs or 
Symptoms eCRF, recording additional information regarding each injection site reaction that is 
entered on the AE eCRF (eg, symptom[s], injection site location, follow-up actions taken). 
6.5.6.3. 
Reporting Adverse Events of Clinical Interest to Sponsor/Designee 
For AEs that are considered AEs of clinical interest (Section 6.5.6.1), the Sponsor or its designee 
should be notified within 24 hours using the appropriate eCRF. 
6.5.6.4. 
Serious Adverse Events Require Immediate Reporting to Sponsor/Designee 
An assessment of the seriousness of each AE will be made by the Investigator. Any AE and 
laboratory abnormality that meets the SAE criteria in Section 6.5.6.1 must be reported to the 
Sponsor or designee within 24 hours from the time that clinical study center staff first learns of 
the event. All SAEs must be reported regardless of the relationship to study treatment. 
The initial report should include at least the following information: 
• Patient’s study number 
• Description and date of onset of the event 
• Criterion for serious 
• Preliminary assignment of relationship to study treatment, and 
• Investigator/site information 
To report the SAE, complete the eCRF and, as applicable, the SAE form. Within 24 hours of 
receipt of follow-up information, the Investigator must update the eCRF and, as applicable, the 
SAE form. SAEs must be reported using the contact information provided in the Study Manual. 
Appropriate remedial measures should be taken by the Investigator using the Investigator’s best 
medical judgment to treat the SAE. These measures and the patient’s response to these measures 
should be recorded. All SAEs, regardless of relationship to study treatment, will be followed by 
the Investigator until satisfactory resolution or the Investigator deems the SAE to be chronic or 
stable. Clinical, laboratory, and diagnostic measures should be employed by the Investigator as 
needed to adequately determine the etiology of the event. 
6.5.6.5. 
Sponsor Safety Reporting to Regulatory Authorities 
The Sponsor or its representative will report certain study events in an expedited manner to the 
Food and Drug Administration, the European Medicines Agency’s EudraVigilance electronic 


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system according to Directive 2001/20/EC, and to all country Regulatory Authorities where the 
study is being conducted, according to local applicable regulations. 
6.5.6.6. 
Serious Adverse Event Notification to the Institutional Review 
Board/Independent Ethics Committee 
Suspected unexpected serious adverse reactions will be reported to the IRB/IEC per their 
institutional policy by the Investigator or Sponsor (or Sponsor designee) according to country 
requirements. Copies of each report and documentation of IRB/IEC notification and 
acknowledgement of receipt will be kept in the Investigator’s study file. 
6.5.6.7. 
Pregnancy Reporting 
If a female patient becomes pregnant during the study through safety follow-up (see Section 3.1), 
the Investigator must report the pregnancy to the Sponsor or designee within 24 hours of being 
notified of the pregnancy. Details of the pregnancy will be recorded on the pregnancy reporting 
form. The patient should receive any necessary counseling regarding the risks of continuing the 
pregnancy, the possible effects on the fetus, and be counseled to not breastfeed for 90 days after 
the last dose of study drug. 
The pregnancy should be followed by the Investigator until completion. At the completion of the 
pregnancy, the Investigator will document the outcome of the pregnancy. If the outcome of the 
pregnancy results in a postpartum complication, spontaneous abortion, stillbirth, neonatal death, 
or congenital anomaly, then the Investigator should follow the procedures for reporting an SAE 
as outlined in Section 6.5.6.4. 
6.5.6.8. 
Reporting of Overdose and Other Special Situations  
An overdose is defined as any dose of study drug administered to the participant or taken by the 
participant that is >2× the assigned dose during a single administration and/or ≥2 doses within ½ 
the intended dosing interval. 
The Sponsor does not recommend specific treatment for an overdose.  
In an event of an overdose or other special situations (eg, medication error, abuse, misuse, or 
CPC associated with an AE), the Investigator should: 
• Contact the Medical Monitor and Sponsor within 24 hours using the contact 
information in the Pharmacy Manual 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities 
• Document the amount of study drug given  
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or 
a concomitant medication will be considered AEs/SAEs.  
Full details of reporting instructions for overdose and other special situations will be outlined in 
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6.6. 
Biomarkers, DNA Genotyping, and Biospecimen Repository 
Alnylam’s RNAi therapeutics platform permits the highly specific targeting of investigational 
therapies based on genetic sequence. It is possible that variations in the target genetic sequence 
will result in variations in drug effect. More generally, genetic variations may account for the 
well-described heterogeneous manifestations of disease in patients with hypertension, as well as 
their responses to treatment. 
Where allowed per local regulations, ethics committee (IRB/IEC) approval, and patient consent, 
samples will be collected as part of this study to permit exploratory investigations and the 
application of novel approaches to bioanalyses that may further elucidate the outcomes of this 
study, or potentially advance understanding of the safety, mechanism of action, and/or efficacy 
of zilebesiran. 
Biological specimens will be collected at the intervals indicated in the Schedule of Assessments 
(Table 1). In addition to the dedicated collections for optional exploratory biomarkers (urine, 
plasma, serum), aliquots from each 24-hour urine collection will be archived for optional 
potential exploratory investigations. These specimens will be analyzed at a central laboratory. 
Potential exploratory investigations may include DNA, RNA, or biochemical metabolite 
assessments as they relate to disease progression, efficacy, or safety. 
The biospecimen repository will also include residual material from routine samples (safety 
laboratory samples, PK samples, etc) that are obtained during the study. 
These specimens will be securely stored in a central biorepository for up to 10 years following 
the completion of this clinical study (ie, last patient last visit), or as per local regulations. After 
10 years have elapsed, samples will be destroyed. 
Details regarding the collection, processing, storage, and shipping of the samples will be 
provided in the Laboratory Manual. 
Exploratory analysis of these biospecimens will be performed by Alnylam Pharmaceuticals or its 
designees. 
When biobanking is permitted by local regulation, study participants will be advised during the 
informed consent process of these biobanking details and the potential for exploratory 
investigation of their samples. 
7. 
STATISTICS 
A Statistical Analysis Plan (SAP) will be finalized before database lock and study unblinding for 
the analysis of the primary endpoints and secondary endpoints measured at Month 3. The plan 
will detail the implementation of the statistical analyses in accordance with the principal features 
stated in the protocol. 
7.1. 
Determination of Sample Size 
Approximately 630 patients will be randomized to receive either zilebesiran or placebo with 
sample sizes in each of the patient cohorts with protocol-specified background antihypertensive 
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• Olmesartan cohort: 300 patients  
• Amlodipine cohort: 210 patients 
• Indapamide cohort: 120 patients 
Assuming a standard deviation of 16 mmHg in change from baseline in 24-hour mean SBP 
assessed by ABPM and 15% dropout rate from baseline to Month 3, with 2-sided significance 
level of 0.05 for each of the comparisons (zilebesiran versus placebo as add-on to olmesartan; 
zilebesiran versus placebo as add-on to amlodipine; zilebesiran versus placebo as add-on to 
indapamide), these sample sizes will provide at least 80% power to detect the following 
difference between zilebesiran versus placebo: 
• 5 mmHg as add-on to olmesartan  
• 6 mmHg as add-on to amlodipine 
• 8 mmHg as add-on to indapamide  
The power is assessed by mixed model with repeated measurements (MMRM), with change 
from baseline in 24-hour mean SBP assessed by ABPM at Month 3 as response variable and 
treatment, time, treatment-by-time as fixed factors and corresponding baseline value as a 
covariate. 
7.2. 
Statistical Methodology 
All analyses will be performed within each of the 3 protocol-specified background 
antihypertensive medication cohorts. The statistical and analytical plans presented below are 
brief summaries of planned analyses. More complete plans will be detailed in the SAP. Changes 
to the methods described in the final SAP will be described and justified as needed in the clinical 
study report. For information on study endpoints, see Section 2. 
7.2.1. 
Populations to be Analyzed 
The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS): All randomized patients who received any amount of study 
drug. All by-treatment analyses based on the FAS will be according to the 
randomized treatment arm.  
• Safety Analysis Set: All patients who received any amount of study drug, grouped 
according to the treatment actually received. 
• PK Analysis Set: All patients who received at least 1 full dose of study drug and 
have at least 1 postdose blood sample for PK parameters and have evaluable PK data. 
• PD Analysis Set: All patients who received at least 1 full dose of study drug and who 
have an evaluable baseline and at least 1 evaluable post-baseline PD measurement 
will be included in the PD analyses. 
The primary population used to evaluate efficacy will be the FAS. Safety will be analyzed using 
the Safety Analysis Set. The PK and PD Analysis Sets will be used to conduct PK and PD 
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7.2.2. 
Examination of Subgroups 
Subgroup analyses may be conducted for selected endpoints. Detailed methodology will be 
provided in the SAP. 
7.2.3. 
Handling of Missing Data 
Handling of missing data will be described in the SAP. 
7.2.4. 
Baseline Evaluations 
Demographics and other disease-specific baseline characteristics will be summarized. 
In general, baseline will be defined as the average of all assessments, including unscheduled 
assessments, between Run-in Visit 2 and prior to the first dose of study drug. Details of the 
definition will be specified in the SAP. 
7.2.5. 
Efficacy Analyses 
7.2.5.1. 
Primary Endpoint 
The primary endpoint is the change in 24-hour mean SBP from baseline to Month 3, assessed by 
ABPM. The primary hypothesis of the add-on effect of zilebesiran compared to placebo in 
patients receiving each of 3 protocol-specified background antihypertensive medications 
(olmesartan, amlodipine or indapamide) will be tested separately at a 2-sided significance level 
of 0.05 using MMRM. The MMRM model will include change from baseline in 24-hour mean 
SBP assessed by ABPM at Month 3 as the response variable; treatment, time, treatment-by-time, 
and race (black or all other races) as fixed factors; and corresponding baseline value and 
screening eGFR as covariates.  
7.2.5.2. 
Secondary Endpoints 
To control the overall type I error, the following secondary endpoints will be tested in 
hierarchical order, only if the primary endpoint is statistically significant: 
• Change in office SBP from baseline to Month 3 
• Change in 24-hour mean SBP from baseline to Month 6, assessed by ABPM 
• Change in office SBP from baseline to Month 6 
The remaining secondary endpoints below will not be tested in the hierarchical order: 
• Change in 24-hour mean DBP from baseline to Months 3 and 6, assessed by ABPM 
• Change in office DBP from baseline to Months 3 and 6 
• Change in daytime and nighttime mean SBP and DBP from baseline to Month 3 and 
Month 6, assessed by ABPM 
• Change in serum AGT 
Blood pressure-related secondary endpoints will be analyzed by the MMRM model similar to the 
primary endpoint. In addition, for change in office SBP and DBP, time-adjusted average from 


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Month 1 to Month 3 and from Month 1 to Month 6 will be analyzed. Change in serum AGT will 
be summarized descriptively. 
Details of the analysis method for primary, secondary, and exploratory endpoints will be 
described in the SAP. 
7.2.6. 
Pharmacodynamic Analysis 
Pharmacodynamic analyses will include the evaluation of changes in levels of serum AGT and 
other exploratory biomarkers of the RAAS pathway. Descriptive statistics for observed levels 
and the relative change from baseline for all measured biomarkers will be presented for each of 
the postdose time points. 
Statistical comparison of the biomarker levels (absolute and/or change from baseline) across 
treatment groups may be explored. Details of the analysis will be specified in the SAP.  
Population PK/PD analysis may be conducted to evaluate the dose-response relationships for PD 
reduction after zilebesiran treatment. Additionally, the relationship between lowering of serum 
AGT and blood pressure may be explored within a modeling framework. If conducted, these 
analyses will be described in a pharmacometrics analysis plan and results will be presented in a 
separate report. 
7.2.7. 
Pharmacokinetic Analysis 
Plasma concentrations of zilebesiran and its metabolite AS(N-1)3′ zilebesiran will be 
summarized using descriptive statistics. 
Population PK analysis may be conducted on the PK data from this study. If conducted, the 
analysis methods will be described in a pharmacometrics analysis plan and results will be 
presented in a separate report. 
7.2.8. 
Safety Analyses 
The primary parameter is the frequency of treatment-emergent AEs (hereafter referred to simply 
as AEs). Safety parameters also include vital signs, ECGs, clinical laboratory assessments and 
physical exams. Extent of exposure will be summarized.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary. Results will be tabulated by Anatomical Therapeutic Chemical Classification System 
and Preferred Term (PT). 
Adverse events will be classified according to the Medical Dictionary for Regulatory Activities 
(MedDRA) System Organ Class and Preferred Term [by dose level and overall]. AEs, SAEs, 
related AEs, AEs leading to discontinuation of study drug, and AEs leading to death will be 
summarized by System Organ Class and PT for each treatment arm. By patient listings will be 
provided for deaths, SAEs, and AEs leading to discontinuation of study drug. Adverse events 
collected during the Run-in period will be summarized. 
Descriptive statistics will be provided for clinical laboratory parameters, ECG, and vital signs 
summarizing the observed values and changes from baseline over time. Laboratory shift tables 
from baseline grade (or category) to worst post-baseline grade (or category) will be presented for 


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laboratory parameters that are graded or categorized. Abnormal physical exam findings will be 
presented in listings. 
Other safety summaries will be presented as appropriate. Further details will be specified in the 
SAP. 
7.2.9. 
Immunogenicity Analyses 
The frequency and percentage of patients with confirmed positive ADA assay at any time during 
study as well as at each scheduled visit will be summarized. The titer results for patients with 
confirmed positive ADA results will be summarized. 
7.2.10. 
Interim Analysis 
The analysis of the primary endpoint and secondary endpoints measured at Month 3 will be 
conducted after all patients complete the Month 3 visit or withdraw from the study prior to the 
Month 3 visit. No formal interim analysis is planned before the analysis at Month 3. 
7.2.11. 
Optional Additional Research 
Optional additional research may be conducted in the future on the biological samples and/or 
data collected during the study in accordance with the strict terms of the ICF (see Section 4.3.2). 
8. 
STUDY ADMINISTRATION 
8.1. 
Ethical and Regulatory Considerations 
This study will be conducted in accordance with the protocol, all applicable regulatory 
requirements, and the current guidelines of Good Clinical Practice (GCP). Compliance with GCP 
provides public assurance that the rights, safety, and well-being of study patients are protected 
consistent with the principles that have their origin in the Declaration of Helsinki. 
8.1.1. 
Informed Consent 
The Investigator will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. Patients must also 
be notified that they are free to discontinue from the study at any time. The patient should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The Investigator will inform the patient/legal guardian if new information becomes available that 
may be relevant to the patient’s/legal guardian’s willingness to continue participation in the 
study. Communication of this information should be documented. 
The patient’s signed and dated informed consent (in paper or electronic format per local 
regulations and institutional standards) must be obtained before conducting any study tests or 
procedures that are not part of routine care. 
The Investigator must maintain the original, signed ICF. All patients will be given a copy of the 
signed and dated ICF. 


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8.1.2. 
Ethical Review 
The study protocol, including the ICF, must be approved or given a favorable opinion in writing 
by an IRB or IEC, as appropriate. The Investigator must submit written approval before he or she 
can enroll any patient into the study. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements. In addition, the IRB or IEC must approve all patient 
materials for the study. The protocol must be reapproved by the IRB or IEC upon receipt of 
amendments and annually, as local regulations require. 
Initial IRB or IEC approval of the protocol, and all materials approved by the IRB or IEC for this 
study including the patient consent form and recruitment materials must be maintained by the 
Investigator and made available for inspection. 
The Investigator will submit reports of SAEs as outlined in Section 6.5.6. In addition, the 
Investigator agrees to submit progress reports to the IRB or IEC per their local reporting 
requirements, or at least annually and at the conclusion of the study. The reports will be made 
available to the Sponsor or designee. 
Any communications from regulatory agencies, IRBs, or IECs in regard to inspections, other 
studies that impact this protocol or the qualifications of study personnel should be promptly 
reported to the Sponsor or its designee. 
The Investigator is also responsible for providing the IRB or IEC with reports of any reportable 
serious adverse drug reactions from any other study conducted with the study drug. The Sponsor 
or designee will provide this information to the Investigator. 
Major changes in this research activity, except those to remove an apparent immediate hazard to 
the patient, must be reviewed and approved by the Sponsor and the IRB or IEC that approved the 
study. Amendments to the protocol must be submitted in writing to the Investigator’s IRB or IEC 
and the Regulatory Authority for approval before patients are enrolled under the amended 
protocol, and patients or their legal guardians must be re-consented to the most current version of 
the ICF. 
8.1.3. 
Serious Breach of Protocol 
Investigators must notify the Medical Monitor within 24 hours of becoming aware of a potential 
serious breach of the protocol. A serious breach is a breach that is likely to affect to a significant 
degree the safety and rights of a study participant or the reliability and robustness of the data 
generated in the clinical study. 
8.1.4. 
Study Documentation, Confidentiality, and Records Retention 
All documentation (including personal data) relating to the study should be retained for 2 years 
after the last approval in an ICH territory or as required by local laws and regulations, whichever 
is longer. 
If it becomes necessary for the Sponsor, the Sponsor’s designee, applicable IRB/IEC, or 
applicable regulatory authorities to review or audit any documentation relating to the study, the 
Investigator must permit direct access to all source documents/data. Records will not be 


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destroyed without informing the Sponsor in writing and giving the Sponsor the opportunity to 
store the records for a longer period of time at the Sponsor’s expense. 
The Investigator must ensure that the patients’ confidentiality will be maintained. On the eCRFs 
or other documents submitted to the Sponsor or designees, patients should not be identified by 
their names, but by the assigned patient number or code. If patient names are included on copies 
of documents to be submitted to the Sponsor or designees, the names will be obliterated, and the 
assigned patient number added to the document, before sending to the Sponsor. Documents not 
for submission to the Sponsor (eg, signed ICFs) should be maintained by the Investigator in strict 
confidence. 
The Investigator must treat all of the information related to the study and the compiled data as 
confidential, whose use is for the purpose of conducting the study. The Sponsor must approve 
any transfer of information not directly involved in the study. 
To comply with local and/or regional regulations, this clinical study may be registered, and study 
results may be posted on public registries, such as ClinicalTrials.gov. 
8.1.5. 
End of Study 
The end of study is defined as the last patient last visit. 
8.1.6. 
Termination of the Clinical Study or Site Closure 
The Sponsor, or designee, reserves the right to terminate the study or a clinical study site at any 
time. Conditions that may warrant this action may include, but are not limited to: 
• The discovery of an unexpected, serious, or unacceptable risk to patients participating 
in the study 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• The decision on the part of the Sponsor to suspend or discontinue treatment with the 
study drug 
Should the study be terminated, and/or the site closed for whatever reason, all documentation and 
study drug pertaining to the study must be returned to the Sponsor or its representative, and the 
Investigators, IRB/IEC and Regulatory Authorities will be promptly informed of the termination 
and the reason for the decision. The Investigator should promptly inform the patients and assure 
appropriate therapy and follow-up. 
8.2. 
Data Quality Control and Quality Assurance 
8.2.1. 
Data Handling 
Study data must be recorded on CRFs (paper and/or electronic) provided by the Sponsor or 
designee on behalf of the Sponsor. Case report forms must be completed only by persons 
designated by the Investigator. If eCRFs are used, study data must be entered by trained site 
personnel with access to a valid and secure eCRF system. All data entered into the eCRF must 


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also be available in the source documents. Corrections on paper CRFs must be made so as to not 
obliterate the original data and must be initialed and dated by the person who made the 
correction. 
8.2.2. 
Study Monitoring 
The Monitor, as a representative of the Sponsor, has an obligation to closely follow the study 
conduct at the site. The Monitor will visit the Investigator and clinical study center periodically 
and will maintain frequent telephone and written contact. The Monitor will maintain current 
personal knowledge of the study through observation, review of study records and source 
documentation, and discussion of the conduct of the study with the Investigator and staff. 
The Monitor will review source documents, systems and CRFs to ensure overall quality and 
completeness of the data and to confirm study procedures are complied with the requirements in 
the study protocol accurately. The Sponsor, or its designee, will be allowed to conduct site visits 
to the investigation facilities for the purpose of monitoring any aspect of the study. The 
Investigator agrees to allow the Monitor to inspect the drug storage area, study drug stocks, drug 
accountability records, patient charts and study source documents, site standard operating 
procedures and training records, and other records relative to study conduct. 
Where local regulations allow, the Monitor may request remote access to source documents and 
systems. Should this take place, it will be done in a manner that protects the confidentiality of the 
data. 
8.2.3. 
Audits and Inspections 
Periodically, the Sponsor or its authorized representatives audit clinical investigative sites as an 
independent review of core study processes and documents to determine whether these activities 
were conducted, and data were recorded, analyzed, and accurately reported according to the 
protocol, GCP guidelines of the ICH, and any applicable regulatory requirements. A regulatory 
authority, an IEC or an IRB may visit the site to perform audits or inspections, including source 
data verification. The Investigator should contact the Sponsor and designee immediately if 
contacted by a regulatory agency, an IEC or an IRB about an inspection. 
8.3. 
Publication Policy 
It is intended that after completion of the study, the data are to be submitted for publication in a 
scientific journal and/or for reporting at a scientific meeting. A copy of any proposed publication 
(eg, manuscript, abstracts, oral/slide presentations, book chapters) based on this study, must be 
provided and confirmed received at the Sponsor at least 30 days before its submission. The 
Clinical Trial Agreement will detail the procedures for publications. 
Authorship of any publications resulting from this study will be determined on the basis of the 
Uniform Requirement for Manuscripts Submitted to Biomedical Journals (International 
Committee of Medical Journal Editors). 


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9. 
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Avni I, Garzozi HJ, Barequet IS, Segev F, Varssano D, Sartani G, et al. Treatment of dry eye 
syndrome with orally administered CF101: data from a phase 2 clinical trial. Ophthalmology. 
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Burnier M, Bakris G,Williams B. Redefining diuretics use in hypertension: why select a thiazide-
like diuretic? J Hypertens. 2019 Aug;37(8):1574-86. 
Corrao G, Parodi A, Nicotra F, Zambon A, Merlino L, Cesana G, et al. Better compliance to 
antihypertensive medications reduces cardiovascular risk. J Hypertens. 2011 Mar;29(3):610-8. 
Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. Prevention of 
cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as 
required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian 
Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre 
randomised controlled trial. Lancet. 2005 Sep 10-16;366(9489):895-906. 
Dzau VJ,Balatbat CA. Future of Hypertension. Hypertension. 2019 Sep;74(3):450-7. 
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Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990-2015. JAMA. 
2017 Jan 10;317(2):165-82. 
Georgianos PI,Agarwal R. Revisiting RAAS blockade in CKD with newer potassium-binding 
drugs. Kidney Int. 2018 Feb;93(2):325-34. 
Jamerson K, Weber MA, Bakris GL, Dahlof B, Pitt B, Shi V, et al. Benazepril plus amlodipine 
or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008 Dec 
4;359(23):2417-28. 
Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L, et al. Outcomes in 
hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or 
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hypertension: analysis of worldwide data. Lancet. 2005 Jan 15-21;365(9455):217-23. 
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Treatment of Vasodilatory Shock. N Engl J Med. 2017 Aug 3;377(5):419-30. 
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, 3rd, Feldman HI, et al. A new 
equation to estimate glomerular filtration rate. Ann Intern Med. 2009 May 5;150(9):604-12. 
Makani H, Bangalore S, Desouza KA, Shah A,Messerli FH. Efficacy and safety of dual blockade 
of the renin-angiotensin system: meta-analysis of randomised trials. BMJ. 2013 Jan 28;346:f360. 


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Materson BJ, Reda DJ, Cushman WC, Massie BM, Freis ED, Kochar MS, et al. Single-drug 
therapy for hypertension in men. A comparison of six antihypertensive agents with placebo. The 
Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. N Engl J 
Med. 1993 Apr 1;328(13):914-21. 
McClellan M, Brown N, Califf RM,Warner JJ. Call to Action: Urgent Challenges in 
Cardiovascular Disease: A Presidential Advisory From the American Heart Association. 
Circulation. 2019 Feb 26;139(9):e44-e54. 
McMurray JJ, Krum H, Abraham WT, Dickstein K, Kober LV, Desai AS, et al. Aliskiren, 
Enalapril, or Aliskiren and Enalapril in Heart Failure. N Engl J Med. 2016 Apr 21;374(16):1521-
32. 
Mullick AE, Yeh ST, Graham MJ, Engelhardt JA, Prakash TP,Crooke RM. Blood Pressure 
Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of 
Hypertension and Kidney Injury. Hypertension. 2017 Sep;70(3):566-76. 
Muntner P, Hardy ST, Fine LJ, Jaeger BC, Wozniak G, Levitan EB, et al. Trends in Blood 
Pressure Control Among US Adults With Hypertension, 1999-2000 to 2017-2018. JAMA. 2020 
Sep 22;324(12):1190-200. 
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properties of a new angiotensin type 1 receptor blocker, azilsartan, in receptor binding and 
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a lifecourse strategy to address the global burden of raised blood pressure on current and future 
generations: the Lancet Commission on hypertension. Lancet. 2016 Nov 26;388(10060):2665-
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6;367(23):2204-13. 
Peacock E,Krousel-Wood M. Adherence to Antihypertensive Therapy. Med Clin North Am. 
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controversies. Nat Rev Endocrinol. 2015 Apr;11(4):242-52. 
Schulz M, Krueger K, Schuessel K, Friedland K, Laufs U, Mueller WE, et al. Medication 
adherence and persistence according to different antihypertensive drug classes: A retrospective 
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Services UDoHaH. The Surgeon General's Call to Action to Control Hypertension. 2020 October 
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Uijl E, Mirabito Colafella KM, Sun Y, Ren L, van Veghel R, Garrelds IM, et al. Strong and 
Sustained Antihypertensive Effect of Small Interfering RNA Targeting Liver Angiotensinogen. 
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van der Laan DM, Elders PJM, Boons C, Beckeringh JJ, Nijpels G,Hugtenburg JG. Factors 
associated with antihypertensive medication non-adherence: a systematic review. J Hum 
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medoxomil: influence of age, renal and hepatic function on the pharmacokinetics of olmesartan 
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with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015 Jan 
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2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the 
Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report 
of the American College of Cardiology/American Heart Association Task Force on Clinical 
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White WB, Weber MA, Sica D, Bakris GL, Perez A, Cao C, et al. Effects of the angiotensin 
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Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH 
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Oct;36(10):1953-2041. 
 


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10. 
APPENDICES 
10.1. 
Formula for Estimated Glomerular Filtration Rate Calculation 
Estimated glomerular filtration rate (eGFR; in mL/min/1.73m2) will be calculated from serum 
creatinine (SCr) based on the Modification of Diet in Renal Disease formula. 
Modification of Diet in Renal Disease Formula [Levey 2009] 
• Conventional units 
− eGFR (mL/min/1.73m2) = 175 × (SCr [mg/dL])-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
• SI units 
− eGFR (mL/min/1.73m2) = 175 × (SCr [μmol/L]/88.4)-1.154 × (age)-0.203 × (0.742, if 
female), or × (1.212, if African American) 
10.2. 
Measurement of Blood Pressure 
All blood pressure measurements (office, ABPM, and HBPM) must be taken using the 
standardized equipment provided by the Sponsor, according to the methods described in the 
relevant user manuals.  
The appropriately sized cuff for each modality must be used for all assessments. The arm’s 
circumference at midpoint (halfway between the acromion and olecranon) should be determined 
at screening with a metric tape measure and used to select the appropriately sized blood pressure 
cuff/bladder for each instrument as described in the Study Manual. Unless significant weight loss 
or gain occurs between visits, the patient should use the same cuff/bladder size throughout the 
study. 
At the first Screening visit only, office blood pressure will be measured in both arms to select the 
appropriate arm to use for office blood pressure and HBPM measurements. Unless a concomitant 
condition favors the use of a specific arm, the arm with the higher office SBP should be used for 
all subsequent office blood pressure and HBPM readings. The ABPM should be measured using 
the patient’s nondominant arm. If the patient is ambidextrous, the same arm used for office blood 
pressure and HBPM readings should be used. 
ABPM 
The appropriately sized cuff should be placed on the correct arm following the instructions in the 
Study Manual. Consecutive (daily) use of over-the-counter NSAIDs should be avoided for at 
least 7 days prior to ABPM measurements. ABPM should be started prior to the morning dose of 
antihypertensive medication. All ABPM collections must be in the outpatient/ambulatory state. 
ABPM recordings that are associated with dosing visits must be obtained in advance of the visit 
(within 7 days before the corresponding dosing visit) and the results reviewed prior to dosing. 
During the 24-hour monitoring period, patients must avoid strenuous exercise but should 
otherwise maintain their usual level of physical activity. The ABPM is programmed to take 
readings every 20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the 
night (10 pm to 5:59 am). While awake, the patient should hold their arm still by their side while 


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the device is inflating for a reading. Patients must record the timing of going to sleep, waking up, 
and any oral medications taken during the ABPM, and these responses must be entered into the 
eCRF. 
After the monitoring period is complete, upload the ABPM data to receive a report with 
adequacy assessment. An ABPM will be considered adequate if (1) the number of successful 
daytime readings is ≥33, (2) the number of successful nighttime readings is ≥11, and (3) no more 
than 3 hours are not represented (ie, 3 sections of 60 minutes where 0 valid readings were 
obtained). If the ABPM recording is inadequate (either during the Run-in Period or after the 
second randomization), the patient will be provided 1 opportunity to repeat the study within 2 
days. If the second ABPM recording is also inadequate during screening, the patient is a run-in 
failure. 
Office Blood Pressure 
Office blood pressure must be measured using the automated blood pressure device provided by 
the Sponsor and the arm selected during screening. 
Office blood pressure should be measured early in the visit, before phlebotomy or other 
potentially stressful assessments. To minimize confounding by circadian changes, study visits 
should be scheduled for a consistent timeframe of the day. The use of inhaled short-acting beta 
agonists should be avoided within 6 hours prior to measuring blood pressure and/or heart rate. 
The use of phosphodiesterase type 5 inhibitors (eg, sildenafil, tadalafil, vardenafil, avanafil) 
should be avoided within 48 hours prior to measuring blood pressure. Consecutive (daily) use of 
over-the-counter NSAIDs should be avoided for at least 7 days prior to office blood pressure 
measurements. 
Before measuring blood pressure, confirm that there has been no exercise or use of caffeine or 
nicotine- or tobacco-containing products (including but not limited to snuff, chewing tobacco, 
cigars, cigarettes, pipes, nicotine patches, or e-cigarettes) within the last 30 minutes. If necessary, 
delay blood pressure assessment to meet these requirements. Because a full bladder can impact 
blood pressure measurements, ask the patient to use the bathroom before the assessment. 
All office blood pressure assessments will include both seated and standing measurements.  
Seated Office Blood Pressure Measurement: For seated measurements, the patient should be in a 
comfortable resting position in a chair with their back supported and their feet flat on the floor. 
• Place the appropriately sized cuff on the correct arm with no clothing between the 
patient’s arm and the cuff and with the midpoint of the bladder length positioned over 
the brachial artery (located by palpation). The arm should be supported on an armrest 
or table with mid-cuff at heart level and the palm facing the ceiling. 
• Follow the Study Manual to initiate the automated blood pressure device’s seated 
measurement protocol. This program includes a 5-minute period of rest, followed by 
4 sequential blood pressure measurements at 1-minute intervals. The seated blood 
pressure for the visit will be defined by the average of the last 3 individual 
measurements. 
• During the device’s seated measurement protocol, the patient should remain at rest 
without distraction (avoid mobile phones). The following script may be used: “The 


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blood pressure device works best when you are at rest and without any distraction, so 
the staff will avoid interacting with you during this assessment. This assessment will 
include a 5-minute period of rest, followed by about 5 minutes of the device inflating 
to measure your blood pressure”. 
Standing Office Blood Pressure Measurement: A standing measurement should be obtained 
immediately after collection of the seated measurements. 
• Being careful to maintain the cuff’s position, ask the patient to stand with the cuffed 
arm bent slightly and the hand of the cuffed arm supported at heart level.  
• Measure standing blood pressure 1 minute after standing using the automated blood 
pressure device’s single measurement protocol.  
• After the standing measurement, ask the patient if they experienced dizziness or light-
headedness when standing and record their response. 
If a patient is unable to report to the site for an office blood pressure assessment, a substitute 
“remote visit blood pressure measurement” may be obtained remotely by a visiting nurse or other 
appropriately trained personnel. If a home visit is not possible, a “remote visit blood pressure 
measurement” should instead be obtained using the patient’s HBPM instrument under direct 
supervision (phone call or teleconferencing) by appropriately trained study staff, following the 
instructions detailed in the Study Manual. Results and the remote method used will be recorded. 
HBPM 
Patients should measure HBPM in the morning, prior to breakfast/caffeine or taking morning 
oral medications. HBPM is not required at times when ABPM is being assessed. The HBPM 
measurement should be obtained in a room without distractions, seated comfortably with the 
back supported and feet flat on the floor. The patient will initiate the automated blood pressure 
program on their HBPM device. This program includes a 5-minute period of rest, followed by 4 
sequential blood pressure measurements at 1-minute intervals. The seated blood pressure for the 
visit will be defined by the average of the last 3 individual measurements.  
To establish baseline, each patient must measure HBPM daily at least 1 week prior to the second 
randomization. If adequate baseline HBPM data are not collected during the Run-in Period, the 
patient is a run-in failure. 
After Day 1, HBPM should be measured at least 3 times per week. Patients may select the 3 days 
of the week that are most convenient for their personal schedule.  

SAP_001.pdf: 
Statistical Analysis Plan, ALN-AGT01-003 (KARDIA-2) 
zilebesiran (ALN-AGT01) 
Amendment 2, 15 July 2024 
Alnylam Pharmaceuticals 
Confidential 
1 
STATISTICAL ANALYSIS PLAN 
ALN-AGT01-003 (KARDIA-2) 
Protocol Title: 
A Randomized, Double-blind, Placebo-
controlled, Multicenter Study to Evaluate the 
Efficacy and Safety of Zilebesiran Used as 
Add-on Therapy in Patients With Hypertension 
Not Adequately Controlled by a Standard of 
Care Antihypertensive Medication 
Short Title: 
Zilebesiran as Add-on Therapy in Patients 
With Hypertension Not Adequately Controlled 
by a Standard of Care Antihypertensive 
Medication (KARDIA-2) 
Study Drug: 
Zilebesiran (ALN-AGT01) 
Protocol Date: 
Original protocol, 25 August 2021 
Amendment 1, 22 March 2022 
Amendment 2, 22 September 2022 
Amendment 3, 20 July 2023 
SAP Date: 
Original SAP: 29 March 2022 
Amendment 1, 06 February 2024 
Amendment 2, 15 July 2024 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA 02142 USA 
Telephone: +1-617-551-8200 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without expressed written 
authorization of Alnylam Pharmaceuticals, Inc. 


Statistical Analysis Plan, ALN-AGT01-003 (KARDIA-2) 
zilebesiran (ALN-AGT01) 
Amendment 2, 15 July 2024 
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Confidential 
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APPROVAL SIGNATURE PAGE 
 
 
 
 
 
 
This document has been authored, approved, and signed electronically on the final page by 
the following: 
 
  
 
Alnylam Pharmaceuticals, Inc. 
 
 
This document has been approved and signed electronically on the final page by the 
following: 
 
 
 
 
Alnylam Pharmaceuticals, Inc. 
 
 
 
 
Alnylam Pharmaceuticals, Inc. 
PPD
PPD
PPD
PPD
PPD
PPD


Statistical Analysis Plan, ALN-AGT01-003 (KARDIA-2) 
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TABLE OF CONTENTS 
APPROVAL SIGNATURE PAGE .................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................5 
LIST OF FIGURES .........................................................................................................................5 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY DESIGN .........................................................................................................8 
2.1. 
General Study Design ...................................................................................................8 
2.2. 
Objectives and Endpoints ...........................................................................................10 
2.3. 
Study Procedure ..........................................................................................................12 
2.4. 
Randomization Methodology .....................................................................................12 
2.5. 
Blinding ......................................................................................................................13 
2.6. 
Determination of Sample Size ....................................................................................13 
3. 
ANALYSIS POPULATIONS ....................................................................................14 
3.1. 
Randomization and Treatment Errors .........................................................................14 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................15 
4.1. 
General Considerations ...............................................................................................15 
4.2. 
Blood Pressure Collection and Handling ....................................................................16 
4.2.1. 
24-Hour Ambulatory Blood Pressure Monitoring ......................................................16 
4.2.2. 
Office Blood Pressure .................................................................................................16 
4.2.3. 
Home Blood Pressure Monitoring ..............................................................................16 
4.3. 
Multiple Comparison/Testing Procedure ....................................................................16 
4.4. 
Handling of Missing Data ...........................................................................................17 
4.5. 
Baseline Definitions ....................................................................................................17 
4.6. 
Randomization Stratification Factors .........................................................................18 
4.7. 
Planned Analyses and Data Cutoffs ...........................................................................18 
4.7.1. 
Month 3 Analysis ........................................................................................................18 
4.7.2. 
Month 6 Analysis ........................................................................................................18 
4.7.3. 
Final Analysis .............................................................................................................18 
5. 
STATISTICAL ANALYSES .....................................................................................18 
5.1. 
Patient Disposition ......................................................................................................18 


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5.2. 
Demographics and Baseline Characteristics ...............................................................19 
5.3. 
Medical History ..........................................................................................................19 
5.4. 
Protocol Deviations ....................................................................................................19 
5.5. 
Study Drug Exposure and Compliance .......................................................................20 
5.6. 
Prior and Concomitant Medications ...........................................................................20 
5.7. 
Efficacy Analyses .......................................................................................................21 
5.7.1. 
Primary Endpoint ........................................................................................................21 
5.7.1.1. 
Definition of Estimand ...............................................................................................21 
5.7.1.2. 
Primary Analysis ........................................................................................................22 
5.7.1.3. 
Sensitivity Analyses ....................................................................................................22 
5.7.1.4. 
Other Analyses ............................................................................................................22 
5.7.2. 
Secondary Endpoints ..................................................................................................22 
5.7.2.1. 
Key Secondary Endpoints ...........................................................................................22 
5.7.2.2. 
Other Secondary Endpoints ........................................................................................24 
5.7.3. 
Exploratory Endpoints ................................................................................................24 
5.7.4. 
Evaluation of Subgroups .............................................................................................25 
5.8. 
Pharmacodynamic Analyses .......................................................................................25 
5.9. 
Pharmacokinetic Analyses ..........................................................................................26 
5.10. 
Anti-Drug Antibody ....................................................................................................26 
5.11. 
Safety Analyses ..........................................................................................................26 
5.11.1. 
Adverse Events ...........................................................................................................26 
5.11.2. 
Laboratory Data ..........................................................................................................29 
5.11.3. 
Electrocardiogram .......................................................................................................30 
5.11.4. 
Vital Signs ..................................................................................................................30 
5.11.5. 
Evaluation of Subgroups .............................................................................................30 
5.12. 
Interim Analysis ..........................................................................................................30 
5.13. 
COVID-19 ..................................................................................................................30 
5.13.1. 
General Impact ............................................................................................................31 
5.13.2. 
Impact on Adverse Events ..........................................................................................31 
6. 
CHANGES FROM PLANNED ANALYSES............................................................31 
7. 
APPENDICES ............................................................................................................34 
7.1. 
List of Escape Antihypertensive Medication ATC Code ...........................................34 
7.2. 
Preferred Terms for Hyperkalemia and Potentially Related to Hypotension .............35 


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7.3. 
Protocol Schedule of Assessments .............................................................................36 
7.4. 
Time-Adjusted Change from Baseline .......................................................................42 
7.5. 
Missing or Partial Dates ..............................................................................................42 
7.5.1. 
Prior and Concomitant Medications ...........................................................................42 
7.5.2. 
Adverse Events ...........................................................................................................43 
7.5.3. 
Others ..........................................................................................................................43 
 
LIST OF TABLES 
Table 1  
Multiplicity Procedure ................................................................................................17 
Table 2 
Schedule of Assessments ............................................................................................37 
Table 3 
Time-Adjusted Endpoints ...........................................................................................42 
 
LIST OF FIGURES 
Figure 1 
Study Design ...............................................................................................................10 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation  
Definition 
ABPM 
Ambulatory blood pressure monitoring 
ADA 
Anti-drug antibody(ies) 
AE 
Adverse event 
AGT 
Angiotensinogen 
ALT 
Alanine aminotransferase 
AngI/II 
Angiotensin I/II 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
DB 
Double-blind 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
eDISH 
Evaluation of drug-induced serious hepatotoxicity 
EOT 
End of treatment 
ET 
Early termination 
ECG 
Electrocardiogram 
FAS 
Full analysis set 
HbA1c 
Hemoglobin A1c 
HBPM 
Home blood pressure monitoring 
HLT 
High level term 
IRT 
Interactive Response Technology 
ISR 
Injection site reaction 
LFT 
Liver function test 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measurements 
OLE 
Open-label extension 
PD 
Pharmacodynamic(s) 


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Abbreviation  
Definition 
PK 
Pharmacokinetic(s) 
PT 
Preferred term 
Q6M 
Once every 6 months 
RAAS 
Renin-angiotensin-aldosterone system 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous(ly) 
SD 
Standard deviation 
SOC 
System Organ Class 
ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantification 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) details comprehensive specifications of the efficacy, safety, 
pharmacokinetic (PK) and pharmacodynamic (PD) data summaries and statistical analyses in 
support of the clinical study report (CSR) for Study ALN-AGT01-003 (KARDIA-2).  
SAP amendment 1 was finalized prior to conducting the analysis of the primary and secondary 
endpoints measured up to Month 6. Updates to the SAP were made in Amendment 2 to address 
the handling of data for several patients that were identified, following the primary analysis, to 
have multiple randomization numbers.  Additional details for these patients are included in 
Section 3. No changes were made to the statistical methodology. Changes to planned analyses 
specified in this SAP made after database lock will be documented in the CSR. 
Table, figure, and listing (TFL) mocked shells and specifications are contained in a separate 
document. 
2. 
STUDY DESIGN  
2.1. 
General Study Design  
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy, safety, and PD of zilebesiran administered SC as an add-on therapy in patients with 
hypertension despite treatment with a standard of care antihypertensive medication. A schematic 
of the study design is provided in Figure 1. 
Run-in Period 
Patients who complete the Screening period and meet all inclusion/exclusion criteria for 
enrollment will be randomized to receive open-label therapy with olmesartan (40 mg orally once 
daily [or 20 mg orally once daily for patients with creatinine clearance ≤60 mL/min at screening 
enrolled at sites outside of the US or Australia, consistent with local labeling for olmesartan]), 
amlodipine (5 mg orally once daily), or indapamide (2.5 mg orally once daily) as their protocol-
specified background antihypertensive medication during a Run-in period of at least 4 weeks. 
Prior antihypertensive medications (if taking) will be discontinued upon the start of this Run-in 
period (Run-in Visit 1) for at least 4 weeks before Run-in Visit 2 to washout their effects. 
DB Period 
Patients who meet all inclusion/exclusion criteria will be randomized 1:1 to receive 600 mg 
zilebesiran SC or placebo SC on Day 1 of a 6-month DB period as add-on therapy to their 
protocol-specified background antihypertensive medication (olmesartan, amlodipine, or 
indapamide). Randomization on Day 1 will be stratified by race (black or all other races), 
baseline blood pressure (24-hour mean SBP < or ≥145 mmHg), and screening eGFR (<60 or 
≥60 mL/min/1.73m2). 
Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive 
medications”) may be added to the patient’s protocol-specified background antihypertensive 
medication per Investigator judgement.  


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OLE Period 
After the 6-month DB period, protocol-specified background antihypertensive medications will 
be discontinued, and patients may have been eligible to participate in a separate zilebesiran OLE 
study. If an individual patient reached Month 6 prior to availability of the separate OLE study, 
they may have received open-label zilebesiran at 600 mg SC once every 6 months for up to 30 
additional months during the OLE period until the separate OLE study was open and then 
transition. Upon implementation of Protocol Amendment 3, the OLE period will be closed 
because a separate OLE study will not be conducted. Patients in the 6-month DB period will 
continue their planned visits through the end of the 6-month DB period. Patients will not receive 
a dose of study drug at Month 6. Upon completion of predose assessments at the Month 6 visit, 
patients will enter the Safety Follow-up period. Patients who are already in the OLE period will 
not receive any additional doses of study drug. Patients should complete all planned assessments 
at Months 7, 8, and 9. For visits at Month 12 or later, patients should complete EOT assessments 
in lieu of their scheduled visit assessments and enter the Safety Follow-up period. 
Safety Follow-up Period 
Patients will be asked to complete Safety Follow-up visits once every 6 months after their last 
dose of study drug until serum AGT levels return to ≥50% of their individual mean baseline level 
(if known) or 12 months after the last dose of study drug, whichever comes earlier. During the 
Safety Follow-up period, patients should return to their pre-study medical care (usual care). 
Patients who discontinue study drug prior to the Month 6 visit will also be asked to complete the 
remainder of scheduled study visits and assessments (except for study drug administration) 
through Month 6. If a patient discontinues study drug after the Month 6 visit, EOT/early 
termination (ET) assessments should be performed. 


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Figure 1 
Study Design 
 
 
Abbreviations: aHTN=antihypertensive medication; BL=baseline; DB=double-blind; EOT=end of treatment; 
M=month; OLE=open-label extension; PBO=placebo; PO=per os (oral); qd=once daily; q6M=once every 6 months; 
R=randomization; SC=subcutaneous.  
Note: Patients may have been eligible to participate in a separate zilebesiran OLE study upon completion of the 
Month 6 predose assessments. If an individual patient reached Month 6 prior to availability of the separate OLE 
study, they may have received open-label zilebesiran once every 6 months in the OLE period for up to 30 additional 
months during the OLE period until the OLE study was open and then transition. Upon implementation of 
Amendment 3, the OLE period will be closed because a separate OLE study will not be conducted. Patients in the 6 
month DB period will continue their planned visits through the end of the 6-month DB period and then enter the 
Safety Follow-up period. Patients will not receive a dose of study drug at Month 6. Patients who are already in the 
OLE period will not receive any additional doses of study drug. Patients should complete all planned assessments at 
Months 7, 8, and 9. For visits at Month 12 or later, patients should complete EOT assessments in lieu of their 
scheduled visit assessments and enter the Safety Follow-up period. Patients who were previously taking 
antihypertensives at screening should discontinue these medications at Run-in Visit 1.  
2.2. 
Objectives and Endpoints 
The following objectives will be evaluated separately for each protocol-specified background 
antihypertensive medication (olmesartan, amlodipine, or indapamide). 






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2.5. 
Blinding  
The Sponsor, all site personnel and patients will be blinded to study drug treatment through 
Month 3 of the 6-month DB period. After the interim analysis at Month 3 is complete, Sponsor 
staff members who will not have direct roles or responsibilities in interacting with study sites 
may be unblinded to the analysis results according to the prespecified blinding plan. Site 
personnel, patients, and Sponsor staff members who have direct roles or responsibilities in 
interacting with study sites will remain blinded to both Month 3 interim analysis results and 
treatment assignment until after the analysis of Month 6 data is complete. All Sponsor and site 
personnel and patients will be blinded to any clinical laboratory result that could potentially 
unblind them (e.g., AGT levels) until treatment assignment unblinding. 
Details about the specifics of the blinding aspects throughout the entire study are available in the 
Randomization and Blinding Plan.  
Any unplanned/emergency unblinding occurring during the DB Period will be documented and 
reported in the CSR. 
Refer to the study Randomization and Blinding Plan for more details. 
2.6. 
Determination of Sample Size 
Approximately 630 patients will be randomized to receive either zilebesiran or placebo, with 
sample sizes in each of the patient cohorts with protocol-specified background antihypertensive 
medication as follows:  
• Olmesartan cohort: 300 patients  
• Amlodipine cohort: 210 patients 
• Indapamide cohort: 120 patients 
Assuming a common standard deviation of 16 mmHg in change from baseline in 24-hour mean 
SBP assessed by ABPM and 15% dropout rate from baseline to Month 3, with 2-sided 
significance level of 0.05 for each of the comparisons (zilebesiran versus placebo as add-on to 
olmesartan; zilebesiran versus placebo as add-on to amlodipine; zilebesiran versus placebo as 
add-on to indapamide), these sample sizes will provide at least 80% power to detect the 
following difference between zilebesiran versus placebo: 
• 5 mmHg as add-on to olmesartan  
• 6 mmHg as add-on to amlodipine 
• 8 mmHg as add-on to indapamide  
The power is assessed by mixed model with repeated measurements (MMRM), with change 
from baseline in 24-hour mean SBP assessed by ABPM at Month 3 as response variable and 
treatment, time, treatment-by-time as fixed factors and corresponding baseline value as a 
covariate. 




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For patients who were not treated, not randomized, or received incorrect treatment, the following 
rules will be used:  
• Randomized but not treated: they will be excluded from the modified FAS and 
modified Safety Analysis Set for efficacy and safety evaluations as actual treatment is 
missing.  
• Treated but not randomized: they will be excluded from the efficacy analyses since 
randomized treatment is missing but will be reported under the treatment actually 
received for all safety analyses.  
• Randomized but took incorrect treatment: they will be reported under their 
randomized treatment arm for all efficacy analyses. But for safety analyses, a patient 
will be reported under the active treatment arm if the patient is randomized to placebo 
arm and received any dose of zilebesiran by mistake. 
4. 
GENERAL STATISTICAL CONSIDERATIONS 
4.1. 
General Considerations 
In general, data will be summarized for each planned analysis defined in Section 4.7 separately. 
All analyses will be performed within each of the 3 protocol-specified background 
antihypertensive medication cohorts. 
A pooled analysis across all 3 protocol-specified background antihypertensive medication 
cohorts will also be performed for patient disposition, demographics, baseline characteristics, 
exposure during the zilebesiran treatment period, by-visit tables during the OLE period and 
select adverse event analyses.  
Categorical variables will be summarized using counts and percentages. Continuous variables 
will be summarized using the following descriptive summary statistics: number of patients (n), 
mean, standard deviation (SD), median, first quartile (Q1), third quartile (Q3), minimum, and 
maximum. 
Study drug is zilebesiran 600 mg or placebo. 
The day of the first dose of study drug administered is defined as Day 1. The Study Day of a 
time point of interest is calculated as follows: 
• If on or after Day 1, Study Day = date of interest – date of the first dose of stud y drug 
+ 1 
• If prior to Day 1, Study Day = date of interest – date of the first dose of study drug 
There is no Day 0. For example, the day before the first study drug dose is defined as Day -1. 
For laboratory parameters, assessments collected and recorded as lower than the lower limit of 
quantification/detection (LLOQ) will be replaced by the LLOQ. Any assessment collected and 
recorded as greater than the upper limit of quantification (ULOQ) will be replaced by the ULOQ. 
All descriptive summaries will be presented by treatment arm. 


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Statistical analyses will be conducted using SAS software Version 9.4 or newer or R version 3.6 
or newer. 
4.2. 
Blood Pressure Collection and Handling 
4.2.1. 
24-Hour Ambulatory Blood Pressure Monitoring 
24-hour ambulatory blood pressure monitoring (ABPM) is programmed to take readings every 
20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 
5:59 am). An ABPM will be considered adequate if (1) the number of successful daytime 
readings is ≥33, (2) the number of successful nighttime readings is ≥11, and (3) no more than 3 
hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). If 
the ABPM recording is inadequate, the patient will be provided 1 opportunity to repeat the study 
within 4 days.  
To summarize the 24-hour ABPM, hourly adjusted mean will be calculated. Hourly adjusted 
mean will be calculated by two steps:  
1. Calculate the hourly mean of BP by each hour of the day (e.g., mean of BP measurements 
from 16:00 to 16:59). If there is no reading in a specific hour, this hourly mean will be 
considered as missing.    
2. Calculate the 24-hour mean SBP/DBP, daytime and nighttime means of the SBP/DBP 
based on the hourly means.  
4.2.2. 
Office Blood Pressure 
The office BP in the sitting position will be used for the analysis. Office BP will be collected 
with a set of 4 replicates. The average of the last 3 replicates will be calculated and used for 
analysis. Office BP collected in standing position will be listed only. 
4.2.3. 
Home Blood Pressure Monitoring 
Home blood pressure will be measured both pre and post randomization. To establish baseline, 
each patient should measure HBPM during the week (with at least 3 successful readings) 
immediately prior to randomization. After Day 1, HBPM will be measured at least once per 
week. Four sequential blood pressure measurements at 1-minute intervals will be recorded. The 
seated blood pressure for the visit will be defined by the average of the last 3 individual 
measurements. HBPM will be summarized by weekly average.  
Details of the blood pressure collection are in Study Protocol Section 10. 
4.3. 
Multiple Comparison/Testing Procedure 
All analyses will be performed within each of the 3 protocol-specified background 
antihypertensive medication cohorts. To control the overall Type I error at α=0.05 within each 
cohort, the primary endpoint and the key secondary endpoints will be tested in hierarchical order.  


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Table 1  
Multiplicity Procedure 
Test 
Stepa 
Endpoint 
Success criteria 
1 
Primary: Change from baseline at Month 3 in 24-hour mean SBP, 
assessed by ABPM 
Nominal p-value < 0.05 
2 
Key secondary: Change from baseline at Month 3 in office SBP 
Nominal p-value < 0.05 
3 
Key secondary: Time-adjusted change from baseline through Month 
6 in 24-hour mean SBP, assessed by ABPM  
Nominal p-value < 0.05 
4 
Key secondary: Time-adjusted change from baseline through Month 
6 in office SBP  
Nominal p-value < 0.05 
5 
key secondary: Proportion of patients with 24-hour mean SBP 
assessed by ABPM <130 mmHg and/or reduction from baseline ≥ 
20 mmHg without escape antihypertensive medication at Month 6 
Nominal p-value < 0.05 
a If the success criterion is satisfied in a given step, the hypothesis test is deemed statistically significant and the 
next step will be evaluated; otherwise all hypotheses in the given and subsequent steps are deemed not statistically 
significant 
4.4. 
Handling of Missing Data 
No imputation will be done for missing values for the primary analysis of the primary endpoint. 
A sensitivity analysis of the primary endpoint will be performed (details described in 
Section 5.7.1.3). For all analyses using mixed model repeated measures, no explicit imputation 
of missing values will be done. 
4.5. 
Baseline Definitions 
For the analyses of 6-month DB period, for office BP, baseline is the average of the office BP 
value on Day 1 prior to receiving the first dose of study drug and last non-missing value prior to 
Day 1 during run-in period. For 24-hour ABPM, baseline is the measurement used for eligibility 
for randomization to study drug. For HBPM, baseline will be the average of all assessments 
during the last week prior to receiving the first dose of study drug. For all other endpoints, 
baseline is the last non-missing value (including unscheduled visit) prior to receiving the first 
dose of study drug. 
For the final analyses, patients initially randomized to placebo and switched to zilebesiran at 
Month 6 will be summarized in two ways:  
• From Day 1. Baseline is the same as the one for the primary analysis. 
• From the start of zilebesiran dosing at Month 6. Baseline will be the last assessment 
prior to Month 6 dosing. 
For patients initially randomized to zilebesiran, baseline remains the same as the one for the 
primary analysis.  


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4.6. 
Randomization Stratification Factors 
Stratification factors are recorded in the IRT database. Key data is integrated into the clinical 
database. In statistical analyses that use randomization stratification factors as covariates, the 
stratum assignment will reflect the values as recorded in the clinical database (EDC). In the 
presence of stratification errors, the stratification used in analysis may not match that in the IRT. 
A comparison of the number and percentage of patients in each randomization stratification 
factor in IRT versus the clinical database will be summarized by randomized treatment arm and 
overall. 
4.7. 
Planned Analyses and Data Cutoffs 
4.7.1. 
Month 3 Analysis 
The analysis of the primary endpoint and secondary endpoints measured at Month 3 will be 
performed prior to the primary database lock at the end of the double-blind period. Additional 
details regarding the interim analysis will be documented in the study Data Management Plan 
and Month 3 Interim Statistical Analysis Plan for the Month 3 interim analysis. 
The analysis will include data on, or prior to, this prespecified cutoff date. For assessments with 
starting/ending dates (e.g., adverse events [AEs], medications), the starting date will be 
compared with the pre-specified cutoff date. Data records with starting dates after the specified 
data cutoff date will be excluded. 
4.7.2. 
Month 6 Analysis 
The analysis after the end of double-blind period is the Month 6 analysis. The protocol-specified 
primary, secondary, exploratory and all other pre-specified analysis will be performed after all 
randomized patients have completed the Month 6 Visit or otherwise withdrawn from the study.  
The database will undergo an primary database lock, and the data will be summarized in a CSR. 
4.7.3. 
Final Analysis 
After all patients reach the end of the study or otherwise withdrawn from the study, the database 
will undergo a final database lock, and the data will be summarized in a CSR.  
A patient is considered to have reached the end of the study if the patient has completed the 
safety follow-up visits.  
5. 
STATISTICAL ANALYSES 
5.1. 
Patient Disposition 
The number and percentage of patients in the following categories will be summarized by 
randomized treatment arm and overall based on the modified randomized set: 
• Randomized to study drug 
• Treated with study drug 


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• Completed the 6-month double-blind (DB) treatment period 
• Withdrawal from study and primary reason for withdrawal from study during 6-
month DB period. 
The number and percentage of patients that entered into the OLE and/or safety follow up period 
will be summarized in the following categories: 
• Completed 6 Month DB Period 
• Entered into OLE period 
• Entered into Safety FU period 
• Completed the study 
• Withdrawal from study and primary reason for withdrawal from study 
• Ongoing 
• Discontinued from study drug and primary reason for discontinuation from study 
drug. 
In addition to the primary reason for discontinuation of study drug and withdrawal from study, 
patients will also be categorized if discontinuation/withdrawal was due to COVID-19. 
Screen failures and run-in failures will also be summarized.  
5.2. 
Demographics and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized by treatment arm and 
overall for Modified Full Analysis Set, and also presented in listings. 
Age at consent, height, weight, body mass index (BMI), 24-hour ABPM, OBP, and urine 
albumin-to-creatinine ratio will be summarized using descriptive statistics. Sex, race, ethnicity, 
country, eGFR, and diabetes mellitus status will be summarized by presenting the frequencies 
and percentages of patients in each category.  
5.3. 
Medical History 
Medical history and prior procedures reported will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 26.0 or newer. Unique patients who report medical 
history events will be summarized by MedDRA system organ class (SOC), high level term 
(HLT) and preferred term (PT). Medical history and prior procedures will also be presented in 
listings. Analysis will be based on the modified safety analysis set.  
5.4. 
Protocol Deviations 
Protocol deviations will be classified by medical review prior to each planned analysis database 
lock, and major protocol deviations will be identified. A major protocol deviation is a deviation 
that may significantly impact the completeness, accuracy, and/or reliability of the trial data; that 
may significantly affect a subject's rights, safety, or well-being. (ICH E3 R1 Structure and 
Contents of Clinical Study Reports Guidance for Industry, 2013). 


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The Sponsor or designee will be responsible for producing the protocol deviation file. This file 
will include a description of each protocol deviation and classification as major or minor. The 
protocol deviations will be reviewed and finalized prior to the planned analysis database lock. 
All protocol deviations and major protocol deviations will be summarized and listed using 
modified randomized set. 
5.5. 
Study Drug Exposure and Compliance 
The following variables will be summarized by descriptive statistics and/or frequency tabulation 
based on the modified safety analysis set: 
• Duration of exposure, defined as: date of last exposure – date of first dose of study 
drug +1. Date of last exposure is the earliest date of the following: 
− date of last dose of study drug + the length of dosing interval (169 days)  
− date of end of study 
− date of analysis data cutoff 
• Number of doses received; as continuous and/or categorical variable 
• Number of missed doses; as a categorical variable 
For analysis during the Zilebesiran treatment period, zilebesiran exposure will be summarized 
both within each cohort and across all cohorts in the final analysis based on the modified all 
zilebesiran treated set. 
5.6. 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization (WHO) Drug Dictionary, 
version WHO-DD Global B3, March 2023 or newer. Unique patients who reported medications 
will be summarized by Anatomical Therapeutic Chemical (ATC) level 3 class (or level 2 if not 
available) and PT. Summaries will be provided for prior and concomitant medications separately. 
Summaries by ATC and PT will also be provided for both prior and concomitant anti-
hypertensive medications.  
The proportion of patients with escape antihypertensive medication at each visit, will also be 
provided by treatment group. 
Prior medications are those medications with start date prior to the first dose of study drug. 
Concomitant medications are medications, other than the study drug or protocol-specified 
background antihypertensive medication, administered at or after the first dose of study drug, as 
well as medications that started prior to the first dose of study drug and are ongoing after the first 
dose of study drug.  
Escape antihypertensive medication is defined as any antihypertensive medication other than 
background medication (by ATC codes) that were started after the first dose; or background 
medication with dose increased to be higher than the baseline level. 


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Protocol-specified background antihypertensive medication, not identified as escape 
antihypertensive medication, will be excluded from analysis of prior and concomitant 
medications. 
If the medication start date is on or after the date of first dose of study drug, the medication will 
be summarized as a concomitant medication even if the medication end date is missing.  
If the end date of a medication is missing or incomplete, such that it cannot be determined 
whether it is after the first dose of study drug, it will be counted as a concomitant medication. 
For missing or partial dates for medications, the imputation of start and end dates is described in 
Section 7.4.  
Background Medication Compliance  
Compliance to background medication (%): (number of tablets returned – number of tablets 
dispensed) divided by number of expected tablets taken x 100.  
Number of expected tablets is the number of days that a patient should be taking background 
medication during a specific period (Run-in period and 6 month double blind period).  
All analysis during the 6-month double-blind treatment period will be based on the modified 
safety analysis set. All analysis during the zilebesiran treatment will be based on the modified all 
zilebesiran treated set. 
5.7. 
Efficacy Analyses 
5.7.1. 
Primary Endpoint 
5.7.1.1. 
Definition of Estimand 
The primary objective of the study is to evaluate the add-on effect of zilebesiran on SBP as 
assessed by ABPM at Month 3. Primary estimand is defined as: 
• Treatment condition: add-on therapy: placebo or zilebesiran 600 mg Q6M in addition 
to one of the protocol-specified background antihypertensive medication (olmesartan, 
amlodipine, or indapamide)  
• Target population: patients with hypertension not adequately controlled by a standard 
of care antihypertensive medication 
• Endpoint: Change from baseline at Month 3 in 24-hour mean SBP assessed by ABPM 
• Population-level summary: Least square mean difference between zilebesiran and 
placebo in change from baseline at Month 3 in 24-hour mean SBP assessed by 
ABPM, on top of each background antihypertensive medication 
• Intercurrent events strategy: Hypertensive escape medication taken before Month 3 
visit will be considered as an intercurrent event. For patients who require escape 
antihypertensive medication, given the expected number of such patients at Month 3 
is low, hypothetical strategy will be used, i.e., ABPM assessed while patients are on 
and within 2 weeks after stopping any escape antihypertensive medication will be 


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excluded for analysis. This will provide the estimated treatment effect of zilebesiran 
compared with placebo on top of each background antihypertensive medication. 
5.7.1.2. 
Primary Analysis  
For each background antihypertensive medication cohort, the hypothesis to be tested for the 
primary endpoint is: 
• H0: µ1 =µ0 (there is no add-on effect of zilebesiran) 
• Ha: µ1 ≠ µ0 (there is add-on effect of zilebesiran) 
where µ0 and µ1 are the mean change from baseline at Month 3 in 24-hour mean SBP in placebo 
and zilebesiran arm, respectively. 
MMRM model will be used as primary analysis. The model will include treatment, visit, 
treatment-by-visit, and race (black, all other races) as fixed factors; baseline 24-hour mean SBP 
assessed by ABPM and baseline eGFR as covariates. The LS mean coefficients will be computed 
using the observed proportion of black patients within each cohort, for all analysis of the primary 
endpoint as well as all analyses of secondary endpoints using a similar MMRM model. 
5.7.1.3. 
Sensitivity Analyses  
For the sensitivity analysis, treatment policy strategy will be used for patients who require escape 
antihypertensive medication. All collected blood pressure measurements will be analyzed by the 
same MMRM model as the primary analysis, regardless of the hypertensive escape medication. 
Due to the expected long-acting effect of zilebesiran, the commonly used control-based Pattern 
Mixture Model (PMM) will not be used to assess the missing not at random (MNAR) 
assumption. 
5.7.1.4. 
Other Analyses  
Change from baseline at Month 3 and at Month 6 in SBP assessed by ABPM at each clock hour 
will be plotted for each treatment group. 
5.7.2. 
Secondary Endpoints 
5.7.2.1. 
 Key Secondary Endpoints 
Secondary objectives of the study are to evaluate the add-on effect of zilebesiran on blood 
pressure assessed by ABPM and office blood pressure through Month 6. The estimand is defined 
as: 
• Treatment condition: add-on therapy: placebo or zilebesiran 600 mg Q6M in addition 
to one of the protocol-specified background antihypertensive medication (olmesartan, 
amlodipine, or indapamide)  
• Target population: patients with hypertension not adequately controlled by a standard 
of care antihypertensive medication 
• Endpoint:  
− Change from baseline at Month 3 in office SBP  


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− Time-adjusted change from baseline through Month 6 in 24-hour mean SBP 
assessed by ABPM 
− Time-adjusted change from baseline through Month 6 in office SBP 
− Proportion of patients with 24-hour mean SBP assessed by ABPM <130 mmHg 
and/or reduction from baseline ≥ 20 mmHg without escape antihypertensive 
medication  
• Population-level summary: 
− Least square mean difference between zilebesiran and placebo of the change from 
baseline in SBP on top of each background antihypertensive medication.  
− Odds ratio for BP response rate. 
• Intercurrent events strategy:  
− For Month 3 endpoint: Given the expected number of such patients at Month 3 is 
low, hypothetical strategy will be used. 
− For Month 6 endpoint: Protocol allows escape antihypertensive medication from 
Month 3 through Month 6. Given the expected proportion of such patients may be 
large, the treatment policy strategy will be used. 
Time-adjusted change is defined as the area under the curve (AUC) of BP change from baseline 
divided by the duration of the time period. It leads to the weighted average of change from 
baseline to each scheduled visit. Details of the definition and calculation are in Section 7.4.  
Multiplicity adjustment will be applied across primary and the key secondary endpoints. Details 
of multiplicity control are in Section 4.3. 
MMRM model will be used as the primary analysis. The model will include treatment, visit, 
treatment-by-visit interaction, race (black, all other races) as fixed factors, baseline eGFR and 
corresponding baseline BP as covariates. Least square (LS) mean difference, 95% CI and p-value 
will be generated. 
For the proportion of patients with 24-hour mean SBP assessed by ABPM <130 mmHg and/or 
reduction ≥20 mmHg without escape antihypertensive medication at Month 6, logistic regression 
will be used. The model will include treatment as a factor, baseline 24-hour mean SBP and 
baseline eGFR as covariates. 
Sensitivity analysis for secondary endpoints using MMRM will also be evaluated.  
− For Month 3 endpoint: treatment policy strategy will be used for patients who 
require escape antihypertensive medication. All collected blood pressure 
measurements will be analyzed. 
− For Month 6 endpoint: hypothetical strategy will be used for patients who require 
escape antihypertensive medication. Blood pressure measurements while patients 
are on and within 2 weeks after stopping any escape antihypertensive medication 
will be excluded for analysis. 


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5.7.2.2. 
Other Secondary Endpoints  
Other blood pressure related secondary endpoints are: 
• Change from baseline at Month 3 in 24-hour mean DBP, assessed by ABPM 
• Change from baseline at Month 3 in office DBP  
• Time adjusted change from baseline through Month 3 in 24-hour mean SBP/DBP, 
assessed by ABPM  
• Time adjusted change from baseline in office SBP/DBP through Month 3  
• Change from baseline at Month 6 in 24-hour mean SBP/DBP, assessed by ABPM 
• Change from baseline at Month 6 in office SBP/DBP 
• Time adjusted change from baseline through Month 6 in 24-hour mean DBP, assessed 
by ABPM  
• Time adjusted change from baseline through Month 6 in office DBP  
• Change from baseline in daytime/nighttime SBP and DBP by ABPM by each visit. 
Daytime is defined as 6 am to 9:59 pm and nighttime is defined as 10 pm to 5:59 am.  
In general, the BP related endpoints will be summarized using all collected BP data regardless of 
the use of escape antihypertensive medication. The same MMRM model will be used with 
treatment, visit, treatment-by-visit interaction, race (black, all other races) as fixed factors, 
corresponding baseline as a covariate. Least square (LS) mean difference of each zilebesiran 
dose group compared with placebo dose group, 95% CI and p-value will be generated. 
The secondary endpoint of percent change in serum AGT at each visit will be summarized using 
descriptive statistics. Serum AGT will be analyzed for the 6 month double blinded period, 
zilebesiran treatment period and the entire study. 
 
5.7.3. 
Exploratory Endpoints  
The blood pressure related exploratory endpoints through Month 6 are: 
• BP response rate by each visit, defined as 
− Office SBP < 140 mmHg and/or reduction from baseline ≥ 20 mmHg without 
escape antihypertensive medication 
− 24-hour mean DBP assessed by ABPM < 85 mmHg and/or reduction from 
baseline ≥ 10 mmHg without escape antihypertensive medication 
− Office DBP < 90 mmHg and/or reduction from baseline ≥ 10 mmHg without 
escape antihypertensive medication 
• Proportion of patients with escape antihypertensive medication use by each visit 
• Change from baseline in pulse pressure by each visit, assessed by ABPM and office 
BP 


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• Change from baseline in SBP/DBP by HBPM 
To assess the long-term treatment effect of zilebesiran through Month 36, change from baseline 
in SBP/DBP assessed by ABPM, office BP and HBPM will be summarized.  
Body weight, metabolic related exploratory endpoints are: 
• Change from baseline in body weight/body mass index (BMI)/waist 
circumference/waist-to-hip ratio by each visit 
• Change from baseline in HbA1c/fasting glucose/insulin/serum lipids by each visit. 
Exploratory endpoints will be summarized using descriptive statistics based on all observed data. 
Missing data will not be imputed.  
5.7.4. 
Evaluation of Subgroups 
Subgroup analyses will be conducted to assess the consistency of treatment effect within various 
subgroups defined by the following baseline characteristics: 
• Age (<65; >=65) 
• Sex (male; female) 
• Race (black; all other races) 
• Baseline 24-hour mean SBP assessed by ABPM (<145 mmHg; >=145 mmHg) 
• Baseline eGFR (<60; >=60 mL/min/1.73 m2) 
• Baseline BMI (<30; >=30 kg/m2) 
• Diabetes Mellitus Status (Yes; No)  
• For Olmesartan only: Run-in Visit 1 plasma renin concentration (<= Run-in Visit 1 
median; > median). 
Subgroup analyses will be performed for the primary endpoint and key-secondary endpoints 
using the MMRM within each subgroup. Model will include treatment, visit, treatment-by-visit 
interaction, race ([black, all other races], when race is not the subgroup to be analyzed) as fixed 
factors, baseline eGFR and corresponding baseline BP measurement as covariates. The LS mean 
coefficient of race will be computed using the observed proportion of black patients within each 
cohort. Point estimate of treatment effect and 95% confidence interval are to be generated for 
each subgroup. A forest plot will be generated to illustrate the estimated treatment effect along 
with 95% CI within each subgroup. 
5.8. 
Pharmacodynamic Analyses 
In addition to serum AGT, the PD parameters include plasma renin concentration, aldosterone, 
AngI and AngII. Summary tables will be provided for observed values, changes and percentage 
changes from baseline for each scheduled time point by treatment group. In addition to serum 
AGT percent reduction analyses, the AGT maximum and mean percentage reductions over the 6-
month DB period will be summarized using descriptive statistics. 


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5.9. 
Pharmacokinetic Analyses 
Plasma concentrations of zilebesiran and its metabolite will be summarized descriptively. 
Descriptive statistics for zilebesiran and its metabolite plasma concentrations will include the 
number of patients, mean, SD, coefficient of variation, geometric mean, geometric mean 
coefficient of variation, median, minimum, and maximum.  
Additional analysis may be done as needed.  
5.10. 
Anti-Drug Antibody 
The number and percentage of patients with confirmed positive anti-drug antibody (ADA) assay 
results at baseline and at any time during the 6-month DB period, as well as treatment-emergent 
ADA during the OLE period, will be summarized. All analysis during the 6-month double-blind 
treatment period will be based on the modified safety analysis set. All analysis during the 
zilebesiran treatment will be based on the modified all zilebesiran treated set. 
Treatment-emergent ADA consist of treatment-induced ADA and treatment-boosted ADA, as 
defined below: 
• Treatment-induced ADA: Confirmed positive ADA developed de novo after drug 
administration in patients without preexisting (baseline) confirmed positive ADA 
• Treatment-boosted ADA: Confirmed positive ADA after drug administration with 
ADA titer > 4x baseline ADA titer in patients with preexisting (baseline) confirmed 
positive ADA 
5.11. 
Safety Analyses 
5.11.1. 
Adverse Events 
Adverse events (AEs) will be classified by the MedDRA coding system (Version 26.0 or newer) 
and displayed in tables and data listings using SOC and PT. 
Treatment-emergent AEs (TEAEs) will be summarized for the 6-month DB period and for the 
duration of zilebesiran exposure (defined in Section 5.5) separately.  
For the 6-month DB period, TEAE is defined as any AE occurring or worsening on or after the 
first dose of study drug and through Month 6 Visit (prior to Month 6 dosing). For AE occurring 
in the OLE period, TEAE is defined as any AE occurring or worsening on or after the last dose 
of study drug up to 6 months after last dose. Treatment related AEs that occur after 6-months are 
also counted as TEAE.  
AEs that occurred or worsened during safety follow-up period will be listed and may be 
summarized if needed. 
Because any worsening AE is reported as a new AE with higher severity, programmatical 
comparison of severity is not needed for the classification of TEAE. For missing or partial dates 
for AEs, the imputation of start and end date can be found in Section 7.4. Events with a fully or 
partially missing onset date will be assumed to be treatment emergent unless it can be 
unequivocally determined (from the partial onset date and/or a partial or complete stop date) that 
the event occurred prior to the first dose of study drug. 


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AEs will be summarized by the numbers and percentages of patients reporting a given AE. An 
overall table of TEAEs will include: 
• any AE, 
• any AE related to study drug, 
• any serious AE (SAE), 
• any SAE related to study drug, 
• any severe AE, 
• any severe AE related to study drug, 
• any AE leading to study drug interruption, 
• any study-drug related AE leading to study drug interruption, 
• any AE leading to study drug discontinuation, 
• any study-drug related AE leading to study drug discontinuation, 
• any AE leading to withdrawal from study, 
• any study-drug related AE leading to withdrawal from study, 
• any AE leading to death.  
Tabulations by SOC and PT will be produced for the following:  
• AEs, 
• Study-drug related AEs, 
• AEs by maximum severity, 
• Study-drug related AEs by maximum severity, 
• Severe AEs, 
• SAEs, 
• Study-drug related SAEs, 
• AEs leading to treatment discontinuation. 
Tabulations by PT will be produced for the following: 
• AEs, 
• Study-drug related AEs, 
• SAEs. 
• Study-drug related SAEs, 
For analysis during the Zilebesiran treatment period, summary of TEAE and tabulations by PT 
for AEs and SAE, will also include an overall column, pooling all cohorts and treatments in the 
final analysis. 


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AEs and AEs related to study-drug will also be summarized by maximum severity.  
A patient contributes only once to the count for a given AE (overall, by SOC, by preferred term). 
Patients who report multiple occurrences of the same AE (preferred term) will be classified 
according to the most severe occurrence. An AE with missing severity will be assumed to be 
severe. An AE with missing study drug relatedness will be assumed to be related. 
Listings of all deaths (if any), SAEs, and AEs leading to treatment discontinuation will be 
provided.  
In addition, AE during run-in period will be listed by each background antihypertensive 
medication cohort. 
AEs of Clinical Interest 
AEs of special interest or AEs mapping to certain standardized MedDRA queries (SMQs) will be 
summarized by SOC and PT. Other SMQs or AE groupings may be evaluated.  
Injection Site Reactions [ISRs]: AEs mapping to the High-Level Term (HLT)= “Injection Site 
Reactions” using MedDRA dictionary will be included in the summary. Frequency (percentages) 
of ISRs by HLT and PT will be generated. A separate listing will be generated to display all 
patients who reported ISRs. In addition, a table of the number of patients with at least 1 ISR, 
total number of doses (any dose split into multiple injections will be considered 1 dose), total 
number of doses with ISRs and corresponding % of injections with ISR with the most common 
signs and symptoms reported due to ISRs will be generated. 
Hepatic AEs, including Liver Function Test (LFT) abnormalities: Analysis of hepatic AEs 
will include AEs mapping to the Standardized MedDRA Query (SMQ) Drug-related hepatic 
disorders - comprehensive search (includes all narrow and broad terms).  
Acute renal failure AEs will include AEs mapping to the Standardized MedDRA Query (SMQ) 
Acute renal failure - comprehensive search (includes all narrow and broad terms). The 
adjudicated renal events including severity assessments will be summarized or listed. 
Hyperkalemia AEs will be through Customized MedDRA Query (CMQ) search. PT terms are 
listed in Section 7.2.  
Hypotension AEs include AEs mapping to the FDA Medical Queries (FMQ) hypotension search 
(includes narrow terms), and additional terms potentially related to hypotension. List of 
additional terms is in Section 7.2.  
Frequency (percentages) of these AEs will be summarized by SOC and PT. For analysis during 
the Zilebesiran treatment period, the summaries for AEs of Clinical Interest will also include an 
overall column, pooling all cohorts and treatments in the final analysis. Separate listings will be 
generated of all patients reporting these events. 
All AEs will be presented in patient data listings. AEs mapping to the SMQs as described above 
will also be listed. 
Additional summaries of AEs mapping to a COVID-19 custom query are described in 
Section 5.13.2. 


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5.11.2. 
Laboratory Data 
Clinical laboratory values will be expressed in SI units. Missing laboratory data will not be 
imputed. 
For each continuous clinical laboratory parameter (including hematology, serum chemistry, liver 
function tests and coagulation studies), descriptive statistics will be presented for the actual 
values, change from baseline, and percent change from baseline by visit. These by-visit tables 
will use central laboratory data only. 
Select clinical laboratory parameters may be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 or above. Shift 
summary from baseline CTCAE grade to maximum (worst) post-baseline grade will be presented 
for all graded parameters with directionality specified (e.g., hyper or hypo). To determine the 
worst post-baseline value, all scheduled and unscheduled test results will be used. For 
hematology and serum chemistry, frequency tables of potentially clinically significant (PCS) 
abnormalities will be provided. 
All laboratory data (both central and local) will be provided in data listings.  Out-of-range 
laboratory results will be presented in a separate listing with proper flags. Local laboratory data, 
if available, will also be flagged. 
Liver Function Tests 
A frequency table and a shift table will be produced to summarize the number and percentage of 
patients in each of the below categories at any post-baseline time point.  
• ALT >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20×ULN, 
• AST >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20×ULN, 
• ALT or AST >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20×ULN, 
• ALP > 1.5×ULN, 
• Total Bilirubin >1.5 & ≤2, >2 & ≤3, >3 & ≤5 and >5×ULN, 
• Total Bilirubin > 2×ULN concurrent with ALT or AST > 3×ULN 
In separate evaluation of drug-induced serious hepatotoxicity (eDISH) figures, the peak total 
bilirubin (as multiple of ULN) at any time post-baseline will be plotted against the peak ALT, 
AST, ALT or AST level and at any time post-baseline. 
A listing for all patients with abnormal liver function tests, defined as an ALT >3×ULN, AST 
>3×ULN, or total bilirubin >2×ULN at any time point, will also be provided. 
Renal function  
Estimated glomerular filtration rate (eGFR) will be calculated from serum creatinine (SCr) based 
on the Modification of Diet in Renal Disease (MDRD) Formula: 
• Conventional units – eGFR (mL/min/1.73 m2) = 175 × (SCr[mg/dL])-1.154 × (age)-0.203 
and (× 0.742, if female) and (× 1.212, if African American) 
• SI units – eGFR (mL/min/1.73 m2) = 175 × (SCr[µmol/L]/88.4)-1.154 × (age)-0.203 and 
(× 0.742, if female) and (× 1.212, if African American) 


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The eGFR will be categorized into the following categories: ≥90, 60-89, 30-59, 15-29 and <15. 
A shift table of baseline to worst post-eGFR (i.e. category with the lowest value) will be 
presented according above categories. 
Serum Potassium 
Potassium lab values will be categorized into the following categories: <=4.5, >4.5 to <=5.0, 
>5.0 to <=5.5, >5.5 to <=6.0 & >6.0 (mmol/L). A shift table of baseline to worst post-baseline 
potassium (i.e. category with the highest value) will be presented. Patients with at least one post 
baseline potassium value >5.5 and >6.0 (mmol/L) will also be summarized.  
5.11.3. 
Electrocardiogram 
Electrocardiogram (ECG) findings will include rhythm and overall interpretation. 
Post-baseline overall interpretation (normal vs. abnormal) will be summarized in frequency table 
by treatment and visit. 
All ECG data for each patient will be provided in a data listing. 
5.11.4. 
Vital Signs 
For vital signs except blood pressure, descriptive statistics for actual values and change from 
baseline by visit will be provided for each variable. Vital sign measurements will be presented by 
treatment and patient ID in a data listing, with abnormal vital signs flagged. 
5.11.5. 
Evaluation of Subgroups  
AE summary tables will be separately generated for each of the subgroups as defined for the 
primary efficacy endpoint (except for baseline BP, see Section 5.7.4). 
5.12. 
Interim Analysis 
An analysis of the primary endpoint and secondary endpoints measured at Month 3 will be 
conducted prior to the primary database lock by a small group of designated people who will not 
have direct roles or responsibilities in interacting with study sites. No formal interim analysis is 
planned before the analysis at Month 3 (see Section 4.7.1). 
5.13. 
COVID-19 
Additional data are collected to characterize the impact of the COVID-19 pandemic on general 
study conduct and disposition, and subsequently, additional analyses and summaries will be 
provided in acknowledgement of multiple regulatory guidance (including FDA Guidance on 
Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic: Guidance for 
Industry, Investigators, and Institutional Review Boards, US Food and Drug Administration, 
2020; Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) 
Pandemic, European Medicines Agency, 2020; Points to consider on implications of Coronavirus 
disease (COVID-19) on methodological aspects of ongoing clinical trials, European Medicines 
Agency, 2020; Statistical Considerations for Clinical Trials During the COVID-19 Public Health 
Emergency, US Food and Drug Administration, 2020). 


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5.13.1. 
General Impact 
Patients who discontinue treatment or stop study participation due to COVID-19 will be included 
in patient disposition summaries as described in Section 5.1. 
Impact on study participation due to COVID-19 will be presented in data listings. 
5.13.2. 
Impact on Adverse Events 
An overall summary of AEs mapping to a COVID-19 custom query will be presented. AEs 
mapping to the COVID-19 custom query will be summarized by HLT and PT. Due to the 
evolving nature of COVID-19-related MedDRA terminology, the COVID-19 custom query will 
be based on the latest information available at the specified analysis timepoint. 
AEs mapping to the COVID-19 custom query will also be presented in a data listing. 
6. 
CHANGES FROM PLANNED ANALYSES 
Original SAP  
Section of the SAP Summary of change from protocol 
Rationale 
 
—  
—  
 
Amendment 1  
Section of the SAP Summary of change from original 
SAP 
Rationale 
Section 1   
SAP finalization has been changed to 
prior to treatment unblinding for Month 
6 analysis from Month 3 analysis 
Additional SAP was created for 
Month 3 Interim analysis.  
Section 2.1 
Updated OLE Period definition, Safety 
Follow-up Period definition and study 
design figure 
Updates from protocol amendment. 
Section 2.2 
Updated Exploratory objective “To 
assess the long-term treatment effect of 
zilebesiran” (Changed from Month 18 
to Month 36) 
Updates from protocol amendment. 
Section 2.5, 
Section 4.7.1, 
Section 5.12 
Updated text around the month 3 
analysis  
Additional SAP was created for 
Month 3 Interim analysis. 
Section 3 
 
 
 
 
 
. 
PPD
PPD
PPD
CCI
CCI


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Section of the SAP Summary of change from original 
SAP 
Rationale 
Section 5.1 
Split Patient Disposition into two 
sections  
• 
Six-month double-blind period  
• 
OLE/Safety Follow up period   
Protocol removed the OLE period and 
OLE study. New summarizes required 
for study complexity. 
Section 5.2 
Included urine albumin-to-creatinine 
ratio and diabetes mellitus status 
Requested by study team. 
Section 5.5 
Compliance is calculated as a 
percentage of the number of tablets 
taken over expected number of tablets. 
Requested by study team. 
Section 5.6 
Added analysis for prior and 
concomitant anti-hypertensive 
medications and definitions of escape 
medications 
Requested by study team. 
Section 5.6 
Clarified that background medication 
should not be included in Prior and 
Concomitant Medications analysis  
Requested by study team. 
Section 5.7.1.2, 
Section 5.7.4 
Added texted about model correction 
for observed proportion of black 
patients 
Model was updated to use observed 
proportion of black patients within the 
study. 
Section 5.7.2.1 
Added baseline eGFR as a covariate to 
logistic regression 
Covariate added to match MMRM 
analysis covariates.  
Section 5.7.2.1 
Added sensitivity to key secondary 
endpoints  
Requested by study team. 
Section 5.7.4 
Added additional subgroups of baseline 
BMI and Run-in 1 Plasma renin 
Concentration  
Requested by study team. 
Section 5.11.1 
Added text for TEAE during OLE 
period 
Requested by study team. 
Section 5.11.1 
Added additional AECI of Acute renal 
failure, Hyperkalemia, and Hypotension 
Requested by study team. 
Section 5.11.2 
Added section for Renal Function and 
Serum Potassium  
Requested by study team. 
Section 5.13.1 
Updated to only include listing for 
COVID-19 impact 
Limited data is collected on COVID-
19 impact. 
 


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Amendment 2 
Section of the SAP Summary of change from original 
SAP 
Rationale 
Section 3 
Added text for modified study 
populations 
To remove from the analysis 
populations 4 unique patients who 
enrolled in the study multiple times (3 
patients) or who enrolled in the study 
while enrolled in another clinical 
study (1 patient)  
Section 4.1 
Added text for pooled analysis across 
cohorts for specific analyses for the 
Zilebesiran treatment period, for the 
final analysis 
To provide additional analyses to 
support assessment of safety 
 
Section 5.1 
Added a category of “Completed 6 
Month DB Period” to the disposition 
summary for the patients who entered 
into the OLE/Safety Follow-Up period  
To ensure all necessary categories are 
analyzed for the disposition summary 
of the OLE/Safety Follow-Up period. 
Section 5.5 
Added text for pooling exposure across 
all background cohorts for the 
Zilebesiran treatment period, for the 
final analysis 
To provide additional analyses to 
support assessment of safety 
Section 5.11.1 
Added severe AE and severe related AE 
to the summary of AE section  
To provide additional analyses to 
support assessment of safety 
Section 5.11.1 
Added Study-drug related SAE to the 
Tabulations by SOC and PT 
Clarification to list minor changes to 
analyses 
Section 5.11.1 
Added Study-drug related SAE to the 
Tabulations by PT 
Clarification to list minor changes to 
analyses 
Section 5.11.1 
Added text that select AE outputs 
during the Zilebesiran treatment period 
will have an overall column across all 
cohorts, for the final analysis 
(AE by PT, SAE by PT and all AECI 
SOC by PT tables)  
To provide additional analyses to 
support assessment of safety 
 
 


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7. 
APPENDICES 
7.1. 
List of Escape Antihypertensive Medication ATC Code 
The ATC codes for escape medications are: 
• C02 - Antihypertensives 
• C03 - Diuretics 
• C07 - Beta blocking agents 
• C08 - Calcium channel blockers 
• C09 - Agents acting on the renin-angiotensin system 


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7.2. 
Preferred Terms for Hyperkalemia and Potentially Related to 
Hypotension 
Hyperkalemia: 
Hyperkalemia 
Blood potassium increased 
Blood potassium abnormal 
Potential Hypotension: 
Blood pressure fluctuation 
Labile blood pressure 
Orthostatic intolerance 
Circulatory collapse   
Distributive shock 
Dizziness 
Dizziness exertional 
Dizziness postural 
Hypoperfusion 
Peripheral circulatory failure 
Presyncope 
Procedural shock 
Shock 
Shock symptom 
Syncope 
Cardiovascular insufficiency 
Hypotensive crisis 
Hypotensive transfusion reaction 
Orthostatic hypotension 
Vasolplegia syndrome 
Blood pressure abnormal 
Blood pressure ambulatory abnormal 
Blood pressure ambulatory decreased 
Blood pressure diastolic abnormal 
Blood pressure immeasurable 
Blood pressure orthostatic abnormal 
Blood pressure orthostatic decreased 
Blood pressure systolic decreased 
Blood pressure systolic inspiratory decreased 
Mean arterial pressure decreased 
Loss of consciousness 
 


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7.3. 
Protocol Schedule of Assessments 
Schedule of assessments are listed in Table 2.  










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• 
Patients will be asked to perform Safety Follow-up visits once every 6 months after the last dose of study drug until serum AGT levels return to ≥50% 
of their individual mean baseline level (if known) or 12 months after the last dose of study drug, whichever comes earlier. During this Follow-up period, 
HBPM monitoring may continue at the discretion of the Investigator. The ADA sample should only be collected at the first Follow-up visit during the 
Follow-up period. 
• 
Patients who discontinue study drug prior to the Month 6 visit will also be asked to complete the remainder of scheduled study visits and assessments 
(except for study drug administration) through Month 6. If a patient discontinues study drug after the Month 6 visit, EOT/ET assessments should be 
performed.  
Footnotes: 
a All assessments, except for postdose PK sample collection, are to be performed prior to administration of protocol-specified background 
antihypertensive medications (including Run-In Visit 1) and study drug (as applicable).  
b When applicable, pregnancy test results must be known prior to dosing with study drug at dosing visits.  
c Laboratory assessments at Day 1 do not need to be repeated, per Investigator discretion, if they were collected within 7 days before Day 1 at Run-in Visit 2.  
d Office blood pressure must be measured before the patient takes oral antihypertensive medications or study drug (as applicable).  
e ABPM recordings associated with study drug dosing visits should be obtained within 7 days before the visit and results reviewed before dosing.  
f HBPM should be measured at least 3 times during the week prior to the second randomization to establish baseline. After Day 1, HBPM should be measured at 
least once per week in the morning upon waking and may be increased at the Investigator’s discretion if more frequent measurement is warranted. HBPM is not 
required on days when ABPM is being assessed. In the Safety Follow-up period, the frequency of HBPM assessments can be reduced after the first Safety 
Follow-up visit per Investigator judgement. 
g Neurological evaluation will also be performed as part of the full physical examination. 
h ABPM should only be performed as part of ET assessments if the patient discontinues the study prior to Month 12 and has not had an ABPM within the last 3 
months. ABPM should not be performed at Month 36. 


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7.4. 
Time-Adjusted Change from Baseline 
Time-adjusted change from baseline is the area under the curve (AUC) divided by time interval. 
It leads to a weighted average of all scheduled change from baseline during that time interval.  
E.g., ABPM is assessed at Month 2, 3 and 6. Time-adjusted change from baseline through Month 
6 in 24-hour mean SBP assessed by ABPM is: 
1. AUC is calculated as:  ቂ
1
2 (𝑦𝑦2 + 𝑦𝑦3) ∗1 + 
1
2 (𝑦𝑦3 + 𝑦𝑦6) ∗3 ቃ 
2. Time interval is 4 months, from Month 2 to Month 6. AUC divided by time interval is  
𝐴𝐴𝐴𝐴𝐴𝐴4
⁄
= 0.125 ∗𝑦𝑦2 + 0.5 ∗𝑦𝑦3 + 0.375 ∗𝑦𝑦6 
Where 𝑦𝑦2, 𝑦𝑦3 and 𝑦𝑦6 are the 24-hour mean ABPM at Month 2, 3, and 6.   
Table 3 listed all time-adjusted endpoints and the weights of the assessments. 
Table 3 
Time-Adjusted Endpoints 
Time-adjusted Endpoint 
Weighted average 
Time-adjusted change from baseline 
through Month 3 in 24-hour mean 
SBP/DBP assessed by ABPM 
0.5 ∗𝑦𝑦2 + 0.5 ∗𝑦𝑦3 
Time-adjusted change from baseline 
through Month 3 in office SBP/DBP  
0.25 ∗𝑦𝑦1 + 05 ∗𝑦𝑦2 + 0.25 ∗𝑦𝑦3 
Time-adjusted change from baseline 
through Month 6 in 24-hour mean 
SBP/DBP assessed by ABPM 
0.125 ∗𝑦𝑦2 + 0.5 ∗𝑦𝑦3 + 0.375 ∗𝑦𝑦6 
Time-adjusted change from baseline 
through Month 6 in office SBP/DBP  
0.1 ∗𝑦𝑦1 + 0.2 ∗𝑦𝑦2 + 0.2 ∗𝑦𝑦3 + 0.2 ∗𝑦𝑦4 + 0.2 ∗𝑦𝑦5 + 0.1 ∗𝑦𝑦6 
7.5. 
Missing or Partial Dates 
7.5.1. 
Prior and Concomitant Medications 
For medications with partial start or end dates: the first day/month will be imputed for start date, 
and the last day/month will be imputed for end date. For medications with a completely missing 
start date, the medications will be considered as started one day prior to the first dose of study 
drug. If an imputed start date is after the collected end date, the end date will be used as the 
imputed start date. For medications with a completely missing end date or an imputed end date 
that is after the earliest date of: end of study date, data cutoff date or date of death, the latter (i.e., 
the earliest date of: end of study date, data cutoff date or date of death) will be used as the 
imputed end date. 


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7.5.2. 
Adverse Events 
For records with fully or partially missing AE onset date, conventions for the imputation is as 
below: 
• AE onset dates with missing day and non-missing month will be imputed to occur on 
the first day of the non-missing month, except for AEs occurring in the first month of 
dosing, in which case the date will be the first day of dosing. 
• AE onset dates with missing month will be imputed to occur on the first day of the 
non-missing year (i.e., January 1), except for AEs occurring in the first year of 
dosing, in which case the date will be the first day of dosing.  
• If year of the AE start date is missing, the onset date will be imputed as the first day 
of dosing, except if it can be unequivocally determined (from the partial or complete 
stop date) that the event occurred prior to the first dose of study drug, in which case 
the AE onset date will not be imputed.  
• If an imputed onset date is after the collected AE end date, the end date will be used 
as the imputed onset date.  
7.5.3. 
Others 
For other incomplete dates, unless otherwise specified, the following conventions will be used 
for the calculation of duration (e.g., time in years since diagnosis): 
• Missing day: the first day of the month will be used. 
• Missing month: the January 1 of the non-missing year will be used. 
• Missing year: no duration will be calculated. 


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STATISTICAL ANALYSIS PLAN 
ALN-AGT01-003 (KARDIA-2) 
 
Protocol Title: 
A Randomized, Double-blind, Placebo-
controlled, Multicenter Study to Evaluate the 
Efficacy and Safety of Zilebesiran Used as 
Add-on Therapy in Patients With Hypertension 
Not Adequately Controlled by a Standard of 
Care Antihypertensive Medication 
Short Title: 
Zilebesiran as Add-on Therapy in Patients 
With Hypertension Not Adequately Controlled 
by a Standard of Care Antihypertensive 
Medication (KARDIA-2) 
Study Drug: 
Zilebesiran (ALN-AGT01) 
Protocol Date: 
Original protocol, 25 August 2021 
Amendment 1, 22 March 2022 
Amendment 2, 22 September 2022 
Amendment 3, 20 July 2023 
SAP Date: 
Original SAP: 29 March 2022 
Amendment 1, 06 February 2024 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA 02142 USA 
Telephone: +1-617-551-8200 
 
 
 
 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without expressed written 
authorization of Alnylam Pharmaceuticals, Inc. 
 


Statistical Analysis Plan, ALN-AGT01-003 (KARDIA-2) 
zilebesiran (ALN-AGT01) 
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APPROVAL SIGNATURE PAGE 
 
 
 
 
 
 
This document has been authored, approved, and signed electronically on the final page by 
the following: 
 
  
 
Alnylam Pharmaceuticals, Inc. 
 
 
This document has been approved and signed electronically on the final page by the 
following: 
 
 
 
 
Alnylam Pharmaceuticals, Inc. 
 
 
 
 
Alnylam Pharmaceuticals, Inc. 
PPD
PPD
PPD
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Statistical Analysis Plan, ALN-AGT01-003 (KARDIA-2) 
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TABLE OF CONTENTS 
APPROVAL SIGNATURE PAGE .................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................5 
LIST OF FIGURES .........................................................................................................................5 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY DESIGN .........................................................................................................8 
2.1. 
General Study Design ...................................................................................................8 
2.2. 
Objectives and Endpoints ...........................................................................................10 
2.3. 
Study Procedure ..........................................................................................................12 
2.4. 
Randomization Methodology .....................................................................................12 
2.5. 
Blinding ......................................................................................................................13 
2.6. 
Determination of Sample Size ....................................................................................13 
3. 
ANALYSIS POPULATIONS ....................................................................................14 
3.1. 
Randomization and Treatment Errors .........................................................................14 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................15 
4.1. 
General Considerations ...............................................................................................15 
4.2. 
Blood Pressure Collection and Handling ....................................................................15 
4.2.1. 
24-Hour Ambulatory Blood Pressure Monitoring ......................................................15 
4.2.2. 
Office Blood Pressure .................................................................................................16 
4.2.3. 
Home Blood Pressure Monitoring ..............................................................................16 
4.3. 
Multiple Comparison/Testing Procedure ....................................................................16 
4.4. 
Handling of Missing Data ...........................................................................................17 
4.5. 
Baseline Definitions ....................................................................................................17 
4.6. 
Randomization Stratification Factors .........................................................................17 
4.7. 
Planned Analyses and Data Cutoffs ...........................................................................17 
4.7.1. 
Month 3 Analysis ........................................................................................................17 
4.7.2. 
Month 6 Analysis ........................................................................................................18 
4.7.3. 
Final Analysis .............................................................................................................18 
5. 
STATISTICAL ANALYSES .....................................................................................18 
5.1. 
Patient Disposition ......................................................................................................18 


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5.2. 
Demographics and Baseline Characteristics ...............................................................19 
5.3. 
Medical History ..........................................................................................................19 
5.4. 
Protocol Deviations ....................................................................................................19 
5.5. 
Study Drug Exposure and Compliance .......................................................................19 
5.6. 
Prior and Concomitant Medications ...........................................................................19 
5.7. 
Efficacy Analyses .......................................................................................................20 
5.7.1. 
Primary Endpoint ........................................................................................................20 
5.7.1.1. 
Definition of Estimand ...............................................................................................20 
5.7.1.2. 
Primary Analysis ........................................................................................................21 
5.7.1.3. 
Sensitivity Analyses ....................................................................................................21 
5.7.1.4. 
Other Analyses ............................................................................................................21 
5.7.2. 
Secondary Endpoints ..................................................................................................22 
5.7.2.1. 
Key Secondary Endpoints ...........................................................................................22 
5.7.2.2. 
Other Secondary Endpoints ........................................................................................23 
5.7.3. 
Exploratory Endpoints ................................................................................................23 
5.7.4. 
Evaluation of Subgroups .............................................................................................24 
5.8. 
Pharmacodynamic Analyses .......................................................................................25 
5.9. 
Pharmacokinetic Analyses ..........................................................................................25 
5.10. 
Anti-Drug Antibody ....................................................................................................25 
5.11. 
Safety Analyses ..........................................................................................................25 
5.11.1. 
Adverse Events ...........................................................................................................25 
5.11.2. 
Laboratory Data ..........................................................................................................27 
5.11.3. 
Electrocardiogram .......................................................................................................29 
5.11.4. 
Vital Signs ..................................................................................................................29 
5.11.5. 
Evaluation of Subgroups .............................................................................................29 
5.12. 
Interim Analysis ..........................................................................................................29 
5.13. 
COVID-19 ..................................................................................................................29 
5.13.1. 
General Impact ............................................................................................................29 
5.13.2. 
Impact on Adverse Events ..........................................................................................30 
6. 
CHANGES FROM PLANNED ANALYSES............................................................30 
7. 
APPENDICES ............................................................................................................32 
7.1. 
List of Escape Antihypertensive Medication ATC Code ...........................................32 
7.2. 
Preferred Terms for Hyperkalemia and Potentially Related to Hypotension .............33 


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7.3. 
Protocol Schedule of Assessments .............................................................................34 
7.4. 
Time-Adjusted Change from Baseline .......................................................................40 
7.5. 
Missing or Partial Dates ..............................................................................................40 
7.5.1. 
Prior and Concomitant Medications ...........................................................................40 
7.5.2. 
Adverse Events ...........................................................................................................41 
7.5.3. 
Others ..........................................................................................................................41 
 
LIST OF TABLES 
Table 1  
Multiplicity Procedure ................................................................................................16 
Table 2 
Schedule of Assessments ............................................................................................35 
Table 3 
Time-Adjusted Endpoints ...........................................................................................40 
 
LIST OF FIGURES 
Figure 1 
Study Design ...............................................................................................................10 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation  
Definition 
ABPM 
Ambulatory blood pressure monitoring 
ADA 
Anti-drug antibody(ies) 
AE 
Adverse event 
AGT 
Angiotensinogen 
ALT 
Alanine aminotransferase 
AngI/II 
Angiotensin I/II 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
DB 
Double-blind 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
eDISH 
Evaluation of drug-induced serious hepatotoxicity 
EOT 
End of treatment 
ET 
Early termination 
ECG 
Electrocardiogram 
FAS 
Full analysis set 
HbA1c 
Hemoglobin A1c 
HBPM 
Home blood pressure monitoring 
HLT 
High level term 
IRT 
Interactive Response Technology 
ISR 
Injection site reaction 
LFT 
Liver function test 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measurements 
OLE 
Open-label extension 
PD 
Pharmacodynamic(s) 


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Abbreviation  
Definition 
PK 
Pharmacokinetic(s) 
PT 
Preferred term 
Q6M 
Once every 6 months 
RAAS 
Renin-angiotensin-aldosterone system 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous(ly) 
SD 
Standard deviation 
SOC 
System Organ Class 
ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantification 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) details comprehensive specifications of the efficacy, safety, 
pharmacokinetic (PK) and pharmacodynamic (PD) data summaries and statistical analyses in 
support of the clinical study report (CSR) for Study ALN-AGT01-003 (KARDIA-2). This SAP 
version is finalized prior to conducting the analysis of the primary and secondary endpoints 
measured up to Month 6. Changes to planned analyses specified in this SAP made after database 
lock will be documented in the CSR. 
Table, figure, and listing (TFL) mocked shells and specifications are contained in a separate 
document. 
2. 
STUDY DESIGN  
2.1. 
General Study Design  
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy, safety, and PD of zilebesiran administered SC as an add-on therapy in patients with 
hypertension despite treatment with a standard of care antihypertensive medication. A schematic 
of the study design is provided in Figure 1. 
Run-in Period 
Patients who complete the Screening period and meet all inclusion/exclusion criteria for 
enrollment will be randomized to receive open-label therapy with olmesartan (40 mg orally once 
daily [or 20 mg orally once daily for patients with creatinine clearance ≤60 mL/min at screening 
enrolled at sites outside of the US or Australia, consistent with local labeling for olmesartan]), 
amlodipine (5 mg orally once daily), or indapamide (2.5 mg orally once daily) as their protocol-
specified background antihypertensive medication during a Run-in period of at least 4 weeks. 
Prior antihypertensive medications (if taking) will be discontinued upon the start of this Run-in 
period (Run-in Visit 1) for at least 4 weeks before Run-in Visit 2 to washout their effects. 
DB Period 
Patients who meet all inclusion/exclusion criteria will be randomized 1:1 to receive 600 mg 
zilebesiran SC or placebo SC on Day 1 of a 6-month DB period as add-on therapy to their 
protocol-specified background antihypertensive medication (olmesartan, amlodipine, or 
indapamide). Randomization on Day 1 will be stratified by race (black or all other races), 
baseline blood pressure (24-hour mean SBP < or ≥145 mmHg), and screening eGFR (<60 or 
≥60 mL/min/1.73m2). 
Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive 
medications”) may be added to the patient’s protocol-specified background antihypertensive 
medication per Investigator judgement.  
OLE Period 
After the 6-month DB period, protocol-specified background antihypertensive medications will 
be discontinued, and patients may have been eligible to participate in a separate zilebesiran OLE 
study. If an individual patient reached Month 6 prior to availability of the separate OLE study, 


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they may have received open-label zilebesiran at 600 mg SC once every 6 months for up to 30 
additional months during the OLE period until the separate OLE study was open and then 
transition. Upon implementation of Protocol Amendment 3, the OLE period will be closed 
because a separate OLE study will not be conducted. Patients in the 6-month DB period will 
continue their planned visits through the end of the 6-month DB period. Patients will not receive 
a dose of study drug at Month 6. Upon completion of predose assessments at the Month 6 visit, 
patients will enter the Safety Follow-up period. Patients who are already in the OLE period will 
not receive any additional doses of study drug. Patients should complete all planned assessments 
at Months 7, 8, and 9. For visits at Month 12 or later, patients should complete EOT assessments 
in lieu of their scheduled visit assessments and enter the Safety Follow-up period. 
Safety Follow-up Period 
Patients will be asked to complete Safety Follow-up visits once every 6 months after their last 
dose of study drug until serum AGT levels return to ≥50% of their individual mean baseline level 
(if known) or 12 months after the last dose of study drug, whichever comes earlier. During the 
Safety Follow-up period, patients should return to their pre-study medical care (usual care). 
Patients who discontinue study drug prior to the Month 6 visit will also be asked to complete the 
remainder of scheduled study visits and assessments (except for study drug administration) 
through Month 6. If a patient discontinues study drug after the Month 6 visit, EOT/early 
termination (ET) assessments should be performed. 


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Figure 1 
Study Design 
 
 
Abbreviations: aHTN=antihypertensive medication; BL=baseline; DB=double-blind; EOT=end of treatment; 
M=month; OLE=open-label extension; PBO=placebo; PO=per os (oral); qd=once daily; q6M=once every 6 months; 
R=randomization; SC=subcutaneous.  
Note: Patients may have been eligible to participate in a separate zilebesiran OLE study upon completion of the 
Month 6 predose assessments. If an individual patient reached Month 6 prior to availability of the separate OLE 
study, they may have received open-label zilebesiran once every 6 months in the OLE period for up to 30 additional 
months during the OLE period until the OLE study was open and then transition. Upon implementation of 
Amendment 3, the OLE period will be closed because a separate OLE study will not be conducted. Patients in the 6 
month DB period will continue their planned visits through the end of the 6-month DB period and then enter the 
Safety Follow-up period. Patients will not receive a dose of study drug at Month 6. Patients who are already in the 
OLE period will not receive any additional doses of study drug. Patients should complete all planned assessments at 
Months 7, 8, and 9. For visits at Month 12 or later, patients should complete EOT assessments in lieu of their 
scheduled visit assessments and enter the Safety Follow-up period. Patients who were previously taking 
antihypertensives at screening should discontinue these medications at Run-in Visit 1.  
2.2. 
Objectives and Endpoints 
The following objectives will be evaluated separately for each protocol-specified background 
antihypertensive medication (olmesartan, amlodipine, or indapamide). 






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2.5. 
Blinding  
The Sponsor, all site personnel and patients will be blinded to study drug treatment through 
Month 3 of the 6-month DB period. After the interim analysis at Month 3 is complete, Sponsor 
staff members who will not have direct roles or responsibilities in interacting with study sites 
may be unblinded to the analysis results according to the prespecified blinding plan. Site 
personnel, patients, and Sponsor staff members who have direct roles or responsibilities in 
interacting with study sites will remain blinded to both Month 3 interim analysis results and 
treatment assignment until after the analysis of Month 6 data is complete. All Sponsor and site 
personnel and patients will be blinded to any clinical laboratory result that could potentially 
unblind them (e.g., AGT levels) until treatment assignment unblinding. 
Details about the specifics of the blinding aspects throughout the entire study are available in the 
Randomization and Blinding Plan.  
Any unplanned/emergency unblinding occurring during the DB Period will be documented and 
reported in the CSR. 
Refer to the study Randomization and Blinding Plan for more details. 
2.6. 
Determination of Sample Size 
Approximately 630 patients will be randomized to receive either zilebesiran or placebo, with 
sample sizes in each of the patient cohorts with protocol-specified background antihypertensive 
medication as follows:  
• Olmesartan cohort: 300 patients  
• Amlodipine cohort: 210 patients 
• Indapamide cohort: 120 patients 
Assuming a common standard deviation of 16 mmHg in change from baseline in 24-hour mean 
SBP assessed by ABPM and 15% dropout rate from baseline to Month 3, with 2-sided 
significance level of 0.05 for each of the comparisons (zilebesiran versus placebo as add-on to 
olmesartan; zilebesiran versus placebo as add-on to amlodipine; zilebesiran versus placebo as 
add-on to indapamide), these sample sizes will provide at least 80% power to detect the 
following difference between zilebesiran versus placebo: 
• 5 mmHg as add-on to olmesartan  
• 6 mmHg as add-on to amlodipine 
• 8 mmHg as add-on to indapamide  
The power is assessed by mixed model with repeated measurements (MMRM), with change 
from baseline in 24-hour mean SBP assessed by ABPM at Month 3 as response variable and 
treatment, time, treatment-by-time as fixed factors and corresponding baseline value as a 
covariate. 




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will be reported under the active treatment arm if the patient is randomized to placebo 
arm and received a dose of zilebesiran by mistake. 
4. 
GENERAL STATISTICAL CONSIDERATIONS 
4.1. 
General Considerations 
In general, data will be summarized for each planned analysis defined in Section 4.7 separately. 
All analyses will be performed within each of the 3 protocol-specified background 
antihypertensive medication cohorts. 
Categorical variables will be summarized using counts and percentages. Continuous variables 
will be summarized using the following descriptive summary statistics: number of patients (n), 
mean, standard deviation (SD), median, first quartile (Q1), third quartile (Q3), minimum, and 
maximum. 
Study drug is zilebesiran 600mg or placebo. 
The day of the first dose of study drug administered is defined as Day 1. The Study Day of a 
time point of interest is calculated as follows: 
• If on or after Day 1, Study Day = date of interest – date of the first dose of study drug 
+ 1 
• If prior to Day 1, Study Day = date of interest – date of the first dose of study drug 
There is no Day 0. For example, the day before the first study drug dose is defined as Day -1. 
For laboratory parameters, assessments collected and recorded as lower than the lower limit of 
quantification/detection (LLOQ) will be replaced by the LLOQ. Any assessment collected and 
recorded as greater than the upper limit of quantification (ULOQ) will be replaced by the ULOQ. 
All descriptive summaries will be presented by treatment arm. 
Statistical analyses will be conducted using SAS software Version 9.4 or newer or R version 3.6 
or newer. 
4.2. 
Blood Pressure Collection and Handling 
4.2.1. 
24-Hour Ambulatory Blood Pressure Monitoring 
24-hour ambulatory blood pressure monitoring (ABPM) is programmed to take readings every 
20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 
5:59 am). An ABPM will be considered adequate if (1) the number of successful daytime 
readings is ≥33, (2) the number of successful nighttime readings is ≥11, and (3) no more than 3 
hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). If 
the ABPM recording is inadequate, the patient will be provided 1 opportunity to repeat the study 
within 4 days.  
To summarize the 24-hour ABPM, hourly adjusted mean will be calculated. Hourly adjusted 
mean will be calculated by two steps:  


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1. Calculate the hourly mean of BP by each hour of the day (e.g., mean of BP measurements 
from 16:00 to 16:59). If there is no reading in a specific hour, this hourly mean will be 
considered as missing.    
2. Calculate the 24-hour mean SBP/DBP, daytime and nighttime means of the SBP/DBP 
based on the hourly means.  
4.2.2. 
Office Blood Pressure 
The office BP in the sitting position will be used for the analysis. Office BP will be collected 
with a set of 4 replicates. The average of the last 3 replicates will be calculated and used for 
analysis. Office BP collected in standing position will be listed only. 
4.2.3. 
Home Blood Pressure Monitoring 
Home blood pressure will be measured both pre and post randomization. To establish baseline, 
each patient should measure HBPM during the week (with at least 3 successful readings) 
immediately prior to randomization. After Day 1, HBPM will be measured at least once per 
week. Four sequential blood pressure measurements at 1-minute intervals will be recorded. The 
seated blood pressure for the visit will be defined by the average of the last 3 individual 
measurements. HBPM will be summarized by weekly average.  
Details of the blood pressure collection are in Study Protocol Section 10. 
4.3. 
Multiple Comparison/Testing Procedure 
All analyses will be performed within each of the 3 protocol-specified background 
antihypertensive medication cohorts. To control the overall Type I error at α=0.05 within each 
cohort, the primary endpoint and the key secondary endpoints will be tested in hierarchical order.  
Table 1  
Multiplicity Procedure 
Test 
Stepa 
Endpoint 
Success criteria 
1 
Primary: Change from baseline at Month 3 in 24-hour mean SBP, 
assessed by ABPM 
Nominal p-value < 0.05 
2 
Key secondary: Change from baseline at Month 3 in office SBP 
Nominal p-value < 0.05 
3 
Key secondary: Time-adjusted change from baseline through Month 
6 in 24-hour mean SBP, assessed by ABPM  
Nominal p-value < 0.05 
4 
Key secondary: Time-adjusted change from baseline through Month 
6 in office SBP  
Nominal p-value < 0.05 
5 
key secondary: Proportion of patients with 24-hour mean SBP 
assessed by ABPM <130 mmHg and/or reduction from baseline ≥ 
20 mmHg without escape antihypertensive medication at Month 6 
Nominal p-value < 0.05 
a If the success criterion is satisfied in a given step, the hypothesis test is deemed statistically significant and the 
next step will be evaluated; otherwise all hypotheses in the given and subsequent steps are deemed not statistically 
significant 


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4.4. 
Handling of Missing Data 
No imputation will be done for missing values for the primary analysis of the primary endpoint. 
A sensitivity analysis of the primary endpoint will be performed (details described in Section 
5.7.1.3). For all analyses using mixed model repeated measures, no explicit imputation of 
missing values will be done. 
4.5. 
Baseline Definitions 
For the analyses of 6-month DB period, for office BP, baseline is the average of the office BP 
value on Day 1 prior to receiving the first dose of study drug and last non-missing value prior to 
Day 1 during run-in period. For 24-hour ABPM, baseline is the measurement used for eligibility 
for randomization to study drug. For HBPM, baseline will be the average of all assessments 
during the last week prior to receiving the first dose of study drug. For all other endpoints, 
baseline is the last non-missing value (including unscheduled visit) prior to receiving the first 
dose of study drug. 
For the final analyses, patients initially randomized to placebo and switched to zilebesiran at 
Month 6 will be summarized in two ways:  
• From Day 1. Baseline is the same as the one for the primary analysis. 
• From the start of zilebesiran dosing at Month 6. Baseline will be the last assessment 
prior to Month 6 dosing. 
For patients initially randomized to zilebesiran, baseline remains the same as the one for the 
primary analysis.  
4.6. 
Randomization Stratification Factors 
Stratification factors are recorded in the IRT database. Key data is integrated into the clinical 
database. In statistical analyses that use randomization stratification factors as covariates, the 
stratum assignment will reflect the values as recorded in the clinical database (EDC). In the 
presence of stratification errors, the stratification used in analysis may not match that in the IRT. 
A comparison of the number and percentage of patients in each randomization stratification 
factor in IRT versus the clinical database will be summarized by randomized treatment arm and 
overall. 
4.7. 
Planned Analyses and Data Cutoffs 
4.7.1. 
Month 3 Analysis 
The analysis of the primary endpoint and secondary endpoints measured at Month 3 will be 
performed prior to the primary database lock at the end of the double-blind period. Additional 
details regarding the interim analysis will be documented in the study Data Management Plan 
and Month 3 Interim Statistical Analysis Plan for the Month 3 interim analysis. 
The analysis will include data on, or prior to, this prespecified cutoff date. For assessments with 
starting/ending dates (e.g., adverse events [AEs], medications), the starting date will be 
compared with the pre-specified cutoff date. Data records with starting dates after the specified 
data cutoff date will be excluded. 


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4.7.2. 
Month 6 Analysis 
The analysis after the end of double-blind period is the Month 6 analysis. The protocol-specified 
primary, secondary, exploratory and all other pre-specified analysis will be performed after all 
randomized patients have completed the Month 6 Visit or otherwise withdrawn from the study.  
The database will undergo an primary database lock, and the data will be summarized in a CSR. 
4.7.3. 
Final Analysis 
After all patients reach the end of the study or otherwise withdrawn from the study, the database 
will undergo a final database lock, and the data will be summarized in a CSR.  
A patient is considered to have reached the end of the study if the patient has completed the 
safety follow-up visits.  
5. 
STATISTICAL ANALYSES 
5.1. 
Patient Disposition 
The number and percentage of patients in the following categories will be summarized by 
randomized treatment arm and overall: 
• Randomized to study drug 
• Treated with study drug 
• Completed the 6-month double-blind (DB) treatment period 
• Withdrawal from study and primary reason for withdrawal from study during 6-
month DB period. 
The number and percentage of patients that entered into the OLE and/or safety follow up period 
will be summarized in the following categories: 
• Entered into OLE period 
• Entered into Safety FU period 
• Completed the study 
• Withdrawal from study and primary reason for withdrawal from study 
• Ongoing 
• Discontinued from study drug and primary reason for discontinuation from study 
drug. 
In addition to the primary reason for discontinuation of study drug and withdrawal from study, 
patients will also be categorized if discontinuation/withdrawal was due to COVID-19. 
Screen failures and run-in failures will also be summarized.  


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5.2. 
Demographics and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized by treatment arm and 
overall for Full Analysis Set, and also presented in listings. 
Age at consent, height, weight, body mass index (BMI), 24-hour ABPM, OBP, and urine 
albumin-to-creatinine ratio will be summarized using descriptive statistics. Sex, race, ethnicity, 
country, eGFR, and diabetes mellitus status will be summarized by presenting the frequencies 
and percentages of patients in each category.  
5.3. 
Medical History 
Medical history and prior procedures reported will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 26.0 or newer. Unique patients who report medical 
history events will be summarized by MedDRA system organ class (SOC), high level term 
(HLT) and preferred term (PT). Medical history and prior procedures will also be presented in 
listings. 
5.4. 
Protocol Deviations 
Protocol deviations will be classified by medical review prior to each planned analysis database 
lock, and major protocol deviations will be identified. A major protocol deviation is a deviation 
that may significantly impact the completeness, accuracy, and/or reliability of the trial data; that 
may significantly affect a subject's rights, safety, or well-being. (ICH E3 R1 Structure and 
Contents of Clinical Study Reports Guidance for Industry, 2013). 
The Sponsor or designee will be responsible for producing the protocol deviation file. This file 
will include a description of each protocol deviation and classification as major or minor. The 
protocol deviations will be reviewed and finalized prior to the planned analysis database lock. 
All protocol deviations and major protocol deviations will be summarized and listed. 
5.5. 
Study Drug Exposure and Compliance 
The following variables will be summarized by descriptive statistics and/or frequency tabulation: 
• Duration of exposure, defined as: date of last exposure – date of first dose of study 
drug +1. Date of last exposure is the earliest date of the following: 
− date of last dose of study drug + the length of dosing interval (169 days)  
− date of end of study 
− date of analysis data cutoff 
• Number of doses received; as continuous and/or categorical variable 
• Number of missed doses; as a categorical variable 
5.6. 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization (WHO) Drug Dictionary, 
version WHO-DD Global B3, March 2023 or newer. Unique patients who reported medications 


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will be summarized by Anatomical Therapeutic Chemical (ATC) level 3 class (or level 2 if not 
available) and PT. Summaries will be provided for prior and concomitant medications separately. 
Summaries by ATC and PT will also be provided for both prior and concomitant anti-
hypertensive medications.  
The proportion of patients with escape antihypertensive medication at each visit, will also be 
provided by treatment group. 
Prior medications are those medications with start date prior to the first dose of study drug. 
Concomitant medications are medications, other than the study drug or protocol-specified 
background antihypertensive medication, administered at or after the first dose of study drug, as 
well as medications that started prior to the first dose of study drug and are ongoing after the first 
dose of study drug.  
Escape antihypertensive medication is defined as any antihypertensive medication other than 
background medication (by ATC codes) that were started after the first dose; or background 
medication with dose increased to be higher than the baseline level. 
Protocol-specified background antihypertensive medication, not identified as escape 
antihypertensive medication, will be excluded from analysis of prior and concomitant 
medications. 
If the medication start date is on or after the date of first dose of study drug, the medication will 
be summarized as a concomitant medication even if the medication end date is missing.  
If the end date of a medication is missing or incomplete, such that it cannot be determined 
whether it is after the first dose of study drug, it will be counted as a concomitant medication. 
For missing or partial dates for medications, the imputation of start and end dates is described in 
Section 7.4.  
Background Medication Compliance  
Compliance to background medication (%): (number of tablets returned – number of tablets 
dispensed) divided by number of expected tablets taken x 100.  
Number of expected tablets is the number of days that a patient should be taking background 
medication during a specific period (Run-in period and 6 month double blind period).  
5.7. 
Efficacy Analyses 
5.7.1. 
Primary Endpoint 
5.7.1.1. 
Definition of Estimand 
The primary objective of the study is to evaluate the add-on effect of zilebesiran on SBP as 
assessed by ABPM at Month 3. Primary estimand is defined as: 
• Treatment condition: add-on therapy: placebo or zilebesiran 600 mg Q6M in addition 
to one of the protocol-specified background antihypertensive medication (olmesartan, 
amlodipine, or indapamide)  


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• Target population: patients with hypertension not adequately controlled by a standard 
of care antihypertensive medication 
• Endpoint: Change from baseline at Month 3 in 24-hour mean SBP assessed by ABPM 
• Population-level summary: Least square mean difference between zilebesiran and 
placebo in change from baseline at Month 3 in 24-hour mean SBP assessed by 
ABPM, on top of each background antihypertensive medication 
• Intercurrent events strategy: Hypertensive escape medication taken before Month 3 
visit will be considered as an intercurrent event. For patients who require escape 
antihypertensive medication, given the expected number of such patients at Month 3 
is low, hypothetical strategy will be used, i.e., ABPM assessed while patients are on 
and within 2 weeks after stopping any escape antihypertensive medication will be 
excluded for analysis. This will provide the estimated treatment effect of zilebesiran 
compared with placebo on top of each background antihypertensive medication. 
5.7.1.2. 
Primary Analysis  
For each background antihypertensive medication cohort, the hypothesis to be tested for the 
primary endpoint is: 
• H0: µ1 =µ0 (there is no add-on effect of zilebesiran) 
• Ha: µ1 ≠ µ0 (there is add-on effect of zilebesiran) 
where µ0 and µ1 are the mean change from baseline at Month 3 in 24-hour mean SBP in placebo 
and zilebesiran arm, respectively. 
MMRM model will be used as primary analysis. The model will include treatment, visit, 
treatment-by-visit, and race (black, all other races) as fixed factors; baseline 24-hour mean SBP 
assessed by ABPM and baseline eGFR as covariates. The LS mean coefficients will be computed 
using the observed proportion of black patients within each cohort, for all analysis of the primary 
endpoint as well as all analyses of secondary endpoints using a similar MMRM model. 
5.7.1.3. 
Sensitivity Analyses  
For the sensitivity analysis, treatment policy strategy will be used for patients who require escape 
antihypertensive medication. All collected blood pressure measurements will be analyzed by the 
same MMRM model as the primary analysis, regardless of the hypertensive escape medication. 
Due to the expected long-acting effect of zilebesiran, the commonly used control-based Pattern 
Mixture Model (PMM) will not be used to assess the missing not at random (MNAR) 
assumption. 
5.7.1.4. 
Other Analyses  
Change from baseline at Month 3 and at Month 6 in SBP assessed by ABPM at each clock hour 
will be plotted for each treatment group. 


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5.7.2. 
Secondary Endpoints 
5.7.2.1. 
 Key Secondary Endpoints 
Secondary objectives of the study are to evaluate the add-on effect of zilebesiran on blood 
pressure assessed by ABPM and office blood pressure through Month 6. The estimand is defined 
as: 
• Treatment condition: add-on therapy: placebo or zilebesiran 600 mg Q6M in addition 
to one of the protocol-specified background antihypertensive medication (olmesartan, 
amlodipine, or indapamide)  
• Target population: patients with hypertension not adequately controlled by a standard 
of care antihypertensive medication 
• Endpoint:  
− Change from baseline at Month 3 in office SBP  
− Time-adjusted change from baseline through Month 6 in 24-hour mean SBP 
assessed by ABPM 
− Time-adjusted change from baseline through Month 6 in office SBP 
− Proportion of patients with 24-hour mean SBP assessed by ABPM <130 mmHg 
and/or reduction from baseline ≥ 20 mmHg without escape antihypertensive 
medication  
• Population-level summary: 
− Least square mean difference between zilebesiran and placebo of the change from 
baseline in SBP on top of each background antihypertensive medication.  
− Odds ratio for BP response rate. 
• Intercurrent events strategy:  
− For Month 3 endpoint: Given the expected number of such patients at Month 3 is 
low, hypothetical strategy will be used. 
− For Month 6 endpoint: Protocol allows escape antihypertensive medication from 
Month 3 through Month 6. Given the expected proportion of such patients may be 
large, the treatment policy strategy will be used. 
Time-adjusted change is defined as the area under the curve (AUC) of BP change from baseline 
divided by the duration of the time period. It leads to the weighted average of change from 
baseline to each scheduled visit. Details of the definition and calculation are in Section 7.4.  
Multiplicity adjustment will be applied across primary and the key secondary endpoints. Details 
of multiplicity control are in Section 4.3. 
MMRM model will be used as the primary analysis. The model will include treatment, visit, 
treatment-by-visit interaction, race (black, all other races) as fixed factors, baseline eGFR and 
corresponding baseline BP as covariates. Least square (LS) mean difference, 95% CI and p-value 
will be generated. 


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For the proportion of patients with 24-hour mean SBP assessed by ABPM <130 mmHg and/or 
reduction ≥20 mmHg without escape antihypertensive medication at Month 6, logistic regression 
will be used. The model will include treatment as a factor, baseline 24-hour mean SBP and 
baseline eGFR as covariates. 
Sensitivity analysis for secondary endpoints using MMRM will also be evaluated.  
− For Month 3 endpoint: treatment policy strategy will be used for patients who 
require escape antihypertensive medication. All collected blood pressure 
measurements will be analyzed. 
− For Month 6 endpoint: hypothetical strategy will be used for patients who require 
escape antihypertensive medication. Blood pressure measurements while patients 
are on and within 2 weeks after stopping any escape antihypertensive medication 
will be excluded for analysis. 
5.7.2.2. 
Other Secondary Endpoints  
Other blood pressure related secondary endpoints are: 
• Change from baseline at Month 3 in 24-hour mean DBP, assessed by ABPM 
• Change from baseline at Month 3 in office DBP  
• Time adjusted change from baseline through Month 3 in 24-hour mean SBP/DBP, 
assessed by ABPM  
• Time adjusted change from baseline in office SBP/DBP through Month 3  
• Change from baseline at Month 6 in 24-hour mean SBP/DBP, assessed by ABPM 
• Change from baseline at Month 6 in office SBP/DBP 
• Time adjusted change from baseline through Month 6 in 24-hour mean DBP, assessed 
by ABPM  
• Time adjusted change from baseline through Month 6 in office DBP  
• Change from baseline in daytime/nighttime SBP and DBP by ABPM by each visit. 
Daytime is defined as 6 am to 9:59 pm and nighttime is defined as 10 pm to 5:59 am.  
In general, the BP related endpoints will be summarized using all collected BP data regardless of 
the use of escape antihypertensive medication. The same MMRM model will be used with 
treatment, visit, treatment-by-visit interaction, race (black, all other races) as fixed factors, 
corresponding baseline as a covariate. Least square (LS) mean difference of each zilebesiran 
dose group compared with placebo dose group, 95% CI and p-value will be generated. 
The secondary endpoint of percent change in serum AGT at each visit will be summarized using 
descriptive statistics. 
5.7.3. 
Exploratory Endpoints  
The blood pressure related exploratory endpoints through Month 6 are: 
• BP response rate by each visit, defined as 


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− Office SBP < 140 mmHg and/or reduction from baseline ≥ 20 mmHg without 
escape antihypertensive medication 
− 24-hour mean DBP assessed by ABPM < 85 mmHg and/or reduction from 
baseline ≥ 10 mmHg without escape antihypertensive medication 
− Office DBP < 90 mmHg and/or reduction from baseline ≥ 10 mmHg without 
escape antihypertensive medication 
• Proportion of patients with escape antihypertensive medication use by each visit 
• Change from baseline in pulse pressure by each visit, assessed by ABPM and office 
BP 
• Change from baseline in SBP/DBP by HBPM 
To assess the long-term treatment effect of zilebesiran through Month 36, change from baseline 
in SBP/DBP assessed by ABPM, office BP and HBPM will be summarized.  
Body weight, metabolic related exploratory endpoints are: 
• Change from baseline in body weight/body mass index (BMI)/waist 
circumference/waist-to-hip ratio by each visit 
• Change from baseline in HbA1c/fasting glucose/insulin/serum lipids by each visit. 
Exploratory endpoints will be summarized using descriptive statistics based on all observed data. 
Missing data will not be imputed.  
5.7.4. 
Evaluation of Subgroups 
Subgroup analyses will be conducted to assess the consistency of treatment effect within various 
subgroups defined by the following baseline characteristics: 
• Age (<65; >=65) 
• Sex (male; female) 
• Race (black; all other races) 
• Baseline 24-hour mean SBP assessed by ABPM (<145 mmHg; >=145 mmHg) 
• Baseline eGFR (<60; >=60 mL/min/1.73 m2) 
• Baseline BMI (<30; >=30 kg/m2) 
• Diabetes Mellitus Status (Yes; No)  
• For Olmesartan only: Run-in Visit 1 plasma renin concentration (<= Run-in Visit 1 
median; > median). 
Subgroup analyses will be performed for the primary endpoint and key-secondary endpoints 
using the MMRM within each subgroup. Model will include treatment, visit, treatment-by-visit 
interaction, race ([black, all other races], when race is not the subgroup to be analyzed) as fixed 
factors, baseline eGFR and corresponding baseline BP measurement as covariates. The LS mean 
coefficient of race will be computed using the observed proportion of black patients within each 
cohort. Point estimate of treatment effect and 95% confidence interval are to be generated for 


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each subgroup. A forest plot will be generated to illustrate the estimated treatment effect along 
with 95% CI within each subgroup. 
5.8. 
Pharmacodynamic Analyses 
In addition to serum AGT, the PD parameters include plasma renin concentration, aldosterone, 
AngI and AngII. Summary tables may be provided for observed values, changes and percentage 
changes from baseline for each scheduled time point by treatment group. In addition to serum 
AGT percent reduction analyses, the AGT maximum and mean percentage reductions over the 6-
month DB period will be summarized using descriptive statistics.  
5.9. 
Pharmacokinetic Analyses 
Plasma concentrations of zilebesiran and its metabolite will be summarized descriptively. 
Descriptive statistics for zilebesiran and its metabolite plasma concentrations will include the 
number of patients, mean, SD, coefficient of variation, geometric mean, geometric mean 
coefficient of variation, median, minimum, and maximum.  
Additional analysis may be done as needed.  
5.10. 
Anti-Drug Antibody 
The number and percentage of patients with confirmed positive anti-drug antibody (ADA) assay 
results at baseline and at any time during the 6-month DB period, as well as treatment-emergent 
ADA during the OLE period, will be summarized. Treatment-emergent ADA consist of 
treatment-induced ADA and treatment-boosted ADA, as defined below: 
• Treatment-induced ADA: Confirmed positive ADA developed de novo after drug 
administration in patients without preexisting (baseline) confirmed positive ADA 
• Treatment-boosted ADA: Confirmed positive ADA after drug administration with 
ADA titer > 4x baseline ADA titer in patients with preexisting (baseline) confirmed 
positive ADA 
5.11. 
Safety Analyses 
5.11.1. 
Adverse Events 
Adverse events (AEs) will be classified by the MedDRA coding system (Version 26.0 or newer) 
and displayed in tables and data listings using SOC and PT. 
Treatment-emergent AEs (TEAEs) will be summarized for the 6-month DB period and for the 
duration of zilebesiran exposure (defined in Section 5.5) separately.  
For the 6-month DB period, TEAE is defined as any AE occurring or worsening on or after the 
first dose of study drug and through Month 6 Visit (prior to Month 6 dosing). For AE occurring 
in the OLE period, TEAE is defined as any AE occurring or worsening on or after the last dose 
of study drug up to 6 months after last dose. Treatment related AEs that occur after 6-months are 
also counted as TEAE.  
AEs that occurred or worsened during safety follow-up period will be listed and may be 
summarized if needed. 


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Because any worsening AE is reported as a new AE with higher severity, programmatical 
comparison of severity is not needed for the classification of TEAE. For missing or partial dates 
for AEs, the imputation of start and end date can be found in Section 7.4. Events with a fully or 
partially missing onset date will be assumed to be treatment emergent unless it can be 
unequivocally determined (from the partial onset date and/or a partial or complete stop date) that 
the event occurred prior to the first dose of study drug. 
AEs will be summarized by the numbers and percentages of patients reporting a given AE. An 
overall table of TEAEs will include: 
• any AE, 
• any AE related to study drug, 
• any serious AE (SAE), 
• any SAE related to study drug, 
• any AE leading to study drug interruption, 
• any study-drug related AE leading to study drug interruption, 
• any AE leading to study drug discontinuation, 
• any study-drug related AE leading to study drug discontinuation, 
• any AE leading to withdrawal from study, 
• any study-drug related AE leading to withdrawal from study, 
• any AE leading to death.  
Tabulations by SOC and PT will be produced for the following:  
• AEs, 
• Study-drug related AEs, 
• AEs by maximum severity, 
• Study-drug related AEs by maximum severity, 
• Severe AEs, 
• SAEs, 
• AEs leading to treatment discontinuation. 
Tabulations by PT will be produced for the following: 
• AEs, 
• Study-drug related AEs, 
• SAEs. 
AEs and AEs related to study-drug will also be summarized by maximum severity.  
A patient contributes only once to the count for a given AE (overall, by SOC, by preferred term). 
Patients who report multiple occurrences of the same AE (preferred term) will be classified 


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according to the most severe occurrence. An AE with missing severity will be assumed to be 
severe. An AE with missing study drug relatedness will be assumed to be related. 
Listings of all deaths (if any), SAEs, and AEs leading to treatment discontinuation will be 
provided.  
In addition, AE during run-in period will be listed by each background antihypertensive 
medication cohort. 
AEs of Clinical Interest 
AEs of special interest or AEs mapping to certain standardized MedDRA queries (SMQs) will be 
summarized by SOC and PT. Other SMQs or AE groupings may be evaluated.  
Injection Site Reactions [ISRs]: AEs mapping to the High-Level Term (HLT)= “Injection Site 
Reactions” using MedDRA dictionary will be included in the summary. Frequency (percentages) 
of ISRs by HLT and PT will be generated. A separate listing will be generated to display all 
patients who reported ISRs. In addition, a table of the number of patients with at least 1 ISR, 
total number of doses (any dose split into multiple injections will be considered 1 dose), total 
number of doses with ISRs and corresponding % of injections with ISR with the most common 
signs and symptoms reported due to ISRs will be generated. 
Hepatic AEs, including Liver Function Test (LFT) abnormalities: Analysis of hepatic AEs 
will include AEs mapping to the Standardized MedDRA Query (SMQ) Drug-related hepatic 
disorders - comprehensive search (includes all narrow and broad terms).  
Acute renal failure AEs will include AEs mapping to the Standardized MedDRA Query (SMQ) 
Acute renal failure - comprehensive search (includes all narrow and broad terms). The 
adjudicated renal events including severity assessments will be summarized or listed. 
Hyperkalemia AEs will be through Customized MedDRA Query (CMQ) search. PT terms are 
listed in Section 7.2.  
Hypotension AEs include AEs mapping to the FDA Medical Queries (FMQ) hypotension search 
(includes narrow terms), and additional terms potentially related to hypotension. List of 
additional terms is in Section 7.2.  
Frequency (percentages) of these AEs will be summarized by SOC and PT.  Separate listings 
will be generated of all patients reporting these events. 
All AEs will be presented in patient data listings. AEs mapping to the SMQs as described above 
will also be listed. 
Additional summaries of AEs mapping to a COVID-19 custom query are described in Section 
5.13.2. 
5.11.2. 
Laboratory Data 
Clinical laboratory values will be expressed in SI units. Missing laboratory data will not be 
imputed. 
For each continuous clinical laboratory parameter (including hematology, serum chemistry, liver 
function tests and coagulation studies), descriptive statistics will be presented for the actual 


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values, change from baseline, and percent change from baseline by visit. These by-visit tables 
will use central laboratory data only. 
Select clinical laboratory parameters may be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 or above. Shift 
summary from baseline CTCAE grade to maximum (worst) post-baseline grade will be presented 
for all graded parameters with directionality specified (e.g., hyper or hypo). To determine the 
worst post-baseline value, all scheduled and unscheduled test results will be used. For 
hematology and serum chemistry, frequency tables of potentially clinically significant (PCS) 
abnormalities will be provided. 
All laboratory data (both central and local) will be provided in data listings.  Out-of-range 
laboratory results will be presented in a separate listing with proper flags. Local laboratory data, 
if available, will also be flagged. 
Liver Function Tests 
A frequency table and a shift table will be produced to summarize the number and percentage of 
patients in each of the below categories at any post-baseline time point.  
• ALT >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20×ULN, 
• AST >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20×ULN, 
• ALT or AST >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20×ULN, 
• ALP > 1.5×ULN, 
• Total Bilirubin >1.5 & ≤2, >2 & ≤3, >3 & ≤5 and >5×ULN, 
• Total Bilirubin > 2×ULN concurrent with ALT or AST > 3×ULN 
In separate evaluation of drug-induced serious hepatotoxicity (eDISH) figures, the peak total 
bilirubin (as multiple of ULN) at any time post-baseline will be plotted against the peak ALT, 
AST, ALT or AST level and at any time post-baseline. 
A listing for all patients with abnormal liver function tests, defined as an ALT >3×ULN, AST 
>3×ULN, or total bilirubin >2×ULN at any time point, will also be provided. 
Renal function  
Estimated glomerular filtration rate (eGFR) will be calculated from serum creatinine (SCr) based 
on the Modification of Diet in Renal Disease (MDRD) Formula: 
• Conventional units – eGFR (mL/min/1.73 m2) = 175 × (SCr[mg/dL])-1.154 × (age)-0.203 
and (× 0.742, if female) and (× 1.212, if African American) 
• SI units – eGFR (mL/min/1.73 m2) = 175 × (SCr[µmol/L]/88.4)-1.154 × (age)-0.203 and 
(× 0.742, if female) and (× 1.212, if African American) 
The eGFR will be categorized into the following categories: ≥90, 60-89, 30-59, 15-29 and <15. 
A shift table of baseline to worst post-eGFR (i.e. category with the lowest value) will be 
presented according above categories. 


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Serum Potassium 
Potassium lab values will be categorized into the following categories: <=4.5, >4.5 to <=5.0, 
>5.0 to <=5.5, >5.5 to <=6.0 & >6.0 (mmol/L). A shift table of baseline to worst post-baseline 
potassium (i.e. category with the highest value) will be presented. Patients with at least one post 
baseline potassium value >5.5 and >6.0 (mmol/L) will also be summarized.  
5.11.3. 
Electrocardiogram 
Electrocardiogram (ECG) findings will include rhythm and overall interpretation.  
Post-baseline overall interpretation (normal vs. abnormal) will be summarized in frequency table 
by treatment and visit. 
All ECG data for each patient will be provided in a data listing. 
5.11.4. 
Vital Signs 
For vital signs except blood pressure, descriptive statistics for actual values and change from 
baseline by visit will be provided for each variable. Vital sign measurements will be presented by 
treatment and patient ID in a data listing, with abnormal vital signs flagged. 
5.11.5. 
Evaluation of Subgroups  
AE summary tables will be separately generated for each of the subgroups as defined for the 
primary efficacy endpoint (except for baseline BP, see Section 5.7.4). 
5.12. 
Interim Analysis 
An analysis of the primary endpoint and secondary endpoints measured at Month 3 will be 
conducted prior to the primary database lock by a small group of designated people who will not 
have direct roles or responsibilities in interacting with study sites. No formal interim analysis is 
planned before the analysis at Month 3 (see Section 4.7.1). 
5.13. 
COVID-19 
Additional data are collected to characterize the impact of the COVID-19 pandemic on general 
study conduct and disposition, and subsequently, additional analyses and summaries will be 
provided in acknowledgement of multiple regulatory guidance (including FDA Guidance on 
Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic: Guidance for 
Industry, Investigators, and Institutional Review Boards, US Food and Drug Administration, 
2020; Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) 
Pandemic, European Medicines Agency, 2020; Points to consider on implications of Coronavirus 
disease (COVID-19) on methodological aspects of ongoing clinical trials, European Medicines 
Agency, 2020; Statistical Considerations for Clinical Trials During the COVID-19 Public Health 
Emergency, US Food and Drug Administration, 2020). 
5.13.1. 
General Impact 
Patients who discontinue treatment or stop study participation due to COVID-19 will be included 
in patient disposition summaries as described in Section 5.1. 


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Impact on study participation due to COVID-19 will be presented in data listings. 
5.13.2. 
Impact on Adverse Events 
An overall summary of AEs mapping to a COVID-19 custom query will be presented. AEs 
mapping to the COVID-19 custom query will be summarized by HLT and PT. Due to the 
evolving nature of COVID-19-related MedDRA terminology, the COVID-19 custom query will 
be based on the latest information available at the specified analysis timepoint. 
AEs mapping to the COVID-19 custom query will also be presented in a data listing. 
6. 
CHANGES FROM PLANNED ANALYSES 
Original SAP  
Section of the SAP Summary of change from protocol 
Rationale 
 
—  
—  
 
Amendment 1  
Section of the SAP Summary of change from original 
SAP 
Rationale 
Section 1   
SAP finalization has been changed to 
prior to treatment unblinding for Month 
6 analysis from Month 3 analysis 
Additional SAP was created for 
Month 3 Interim analysis.  
Section 2.1 
Updated OLE Period definition, Safety 
Follow-up Period definition and study 
design figure 
Updates from protocol amendment. 
Section 2.2 
Updated Exploratory objective “To 
assess the long-term treatment effect of 
zilebesiran” (Changed from Month 18 
to Month 36) 
Updates from protocol amendment. 
Section 2.5, 
Section 4.7.1, 
Section 5.12 
Updated text around the month 3 
analysis  
Additional SAP was created for 
Month 3 Interim analysis. 
Section 3 
 
 
 
 
 
. 
Section 5.1 
Split Patient Disposition into two 
sections  
• 
Six-month double-blind period  
• 
OLE/Safety Follow up period   
Protocol removed the OLE period and 
OLE study. New summarizes required 
for study complexity. 
PPD
PPD
PPD
CCI
CCI


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Section of the SAP Summary of change from original 
SAP 
Rationale 
Section 5.2 
Included urine albumin-to-creatinine 
ratio and diabetes mellitus status 
Requested by study team. 
Section 5.5 
Compliance is calculated as a 
percentage of the number of tablets 
taken over expected number of tablets. 
Requested by study team. 
Section 5.6 
Added analysis for prior and 
concomitant anti-hypertensive 
medications and definitions of escape 
medications 
Requested by study team. 
Section 5.6 
Clarified that background medication 
should not be included in Prior and 
Concomitant Medications analysis  
Requested by study team. 
Section 5.7.1.2, 
Section 5.7.4 
Added texted about model correction 
for observed proportion of black 
patients 
Model was updated to use observed 
proportion of black patients within the 
study. 
Section 5.7.2.1 
Added baseline eGFR as a covariate to 
logistic regression 
Covariate added to match MMRM 
analysis covariates.  
Section 5.7.2.1 
Added sensitivity to key secondary 
endpoints  
Requested by study team. 
Section 5.7.4 
Added additional subgroups of baseline 
BMI and Run-in 1 Plasma renin 
Concentration  
Requested by study team. 
Section 5.11.1 
Added text for TEAE during OLE 
period 
Requested by study team. 
Section 5.11.1 
Added additional AECI of Acute renal 
failure, Hyperkalemia, and Hypotension 
Requested by study team. 
Section 5.11.2 
Added section for Renal Function and 
Serum Potassium  
Requested by study team. 
Section 5.13.1 
Updated to only include listing for 
COVID-19 impact 
Limited data is collected on COVID-
19 impact. 


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7. 
APPENDICES 
7.1. 
List of Escape Antihypertensive Medication ATC Code 
The ATC codes for escape medications are: 
• C02 - Antihypertensives 
• C03 - Diuretics 
• C07 - Beta blocking agents 
• C08 - Calcium channel blockers 
• C09 - Agents acting on the renin-angiotensin system 


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7.2. 
Preferred Terms for Hyperkalemia and Potentially Related to 
Hypotension 
Hyperkalemia: 
Hyperkalemia 
Blood potassium increased 
Blood potassium abnormal 
Potential Hypotension: 
Blood pressure fluctuation 
Labile blood pressure 
Orthostatic intolerance 
Circulatory collapse   
Distributive shock 
Dizziness 
Dizziness exertional 
Dizziness postural 
Hypoperfusion 
Peripheral circulatory failure 
Presyncope 
Procedural shock 
Shock 
Shock symptom 
Syncope 
Cardiovascular insufficiency 
Hypotensive crisis 
Hypotensive transfusion reaction 
Orthostatic hypotension 
Vasolplegia syndrome 
Blood pressure abnormal 
Blood pressure ambulatory abnormal 
Blood pressure ambulatory decreased 
Blood pressure diastolic abnormal 
Blood pressure immeasurable 
Blood pressure orthostatic abnormal 
Blood pressure orthostatic decreased 
Blood pressure systolic decreased 
Blood pressure systolic inspiratory decreased 
Mean arterial pressure decreased 
Loss of consciousness 
 


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7.3. 
Protocol Schedule of Assessments 
Schedule of assessments are listed in Table 2.  










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• 
Patients will be asked to perform Safety Follow-up visits once every 6 months after the last dose of study drug until serum AGT levels return to ≥50% 
of their individual mean baseline level (if known) or 12 months after the last dose of study drug, whichever comes earlier. During this Follow-up period, 
HBPM monitoring may continue at the discretion of the Investigator. The ADA sample should only be collected at the first Follow-up visit during the 
Follow-up period. 
• 
Patients who discontinue study drug prior to the Month 6 visit will also be asked to complete the remainder of scheduled study visits and assessments 
(except for study drug administration) through Month 6. If a patient discontinues study drug after the Month 6 visit, EOT/ET assessments should be 
performed.  
Footnotes: 
a All assessments, except for postdose PK sample collection, are to be performed prior to administration of protocol-specified background 
antihypertensive medications (including Run-In Visit 1) and study drug (as applicable).  
b When applicable, pregnancy test results must be known prior to dosing with study drug at dosing visits.  
c Laboratory assessments at Day 1 do not need to be repeated, per Investigator discretion, if they were collected within 7 days before Day 1 at Run-in Visit 2.  
d Office blood pressure must be measured before the patient takes oral antihypertensive medications or study drug (as applicable).  
e ABPM recordings associated with study drug dosing visits should be obtained within 7 days before the visit and results reviewed before dosing.  
f HBPM should be measured at least 3 times during the week prior to the second randomization to establish baseline. After Day 1, HBPM should be measured at 
least once per week in the morning upon waking and may be increased at the Investigator’s discretion if more frequent measurement is warranted. HBPM is not 
required on days when ABPM is being assessed. In the Safety Follow-up period, the frequency of HBPM assessments can be reduced after the first Safety 
Follow-up visit per Investigator judgement. 
g Neurological evaluation will also be performed as part of the full physical examination. 
h ABPM should only be performed as part of ET assessments if the patient discontinues the study prior to Month 12 and has not had an ABPM within the last 3 
months. ABPM should not be performed at Month 36. 


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7.4. 
Time-Adjusted Change from Baseline 
Time-adjusted change from baseline is the area under the curve (AUC) divided by time interval. 
It leads to a weighted average of all scheduled change from baseline during that time interval.  
E.g., ABPM is assessed at Month 2, 3 and 6. Time-adjusted change from baseline through Month 
6 in 24-hour mean SBP assessed by ABPM is: 
1. AUC is calculated as:  ቂ
1
2 (𝑦𝑦2 + 𝑦𝑦3) ∗1 + 
1
2 (𝑦𝑦3 + 𝑦𝑦6) ∗3 ቃ 
2. Time interval is 4 months, from Month 2 to Month 6. AUC divided by time interval is  
𝐴𝐴𝐴𝐴𝐴𝐴4
⁄
= 0.125 ∗𝑦𝑦2 + 0.5 ∗𝑦𝑦3 + 0.375 ∗𝑦𝑦6 
Where 𝑦𝑦2, 𝑦𝑦3 and 𝑦𝑦6 are the 24-hour mean ABPM at Month 2, 3, and 6.   
Table 3 listed all time-adjusted endpoints and the weights of the assessments. 
Table 3 
Time-Adjusted Endpoints 
Time-adjusted Endpoint 
Weighted average 
Time-adjusted change from baseline 
through Month 3 in 24-hour mean 
SBP/DBP assessed by ABPM 
0.5 ∗𝑦𝑦2 + 0.5 ∗𝑦𝑦3 
Time-adjusted change from baseline 
through Month 3 in office SBP/DBP  
0.25 ∗𝑦𝑦1 + 05 ∗𝑦𝑦2 + 0.25 ∗𝑦𝑦3 
Time-adjusted change from baseline 
through Month 6 in 24-hour mean 
SBP/DBP assessed by ABPM 
0.125 ∗𝑦𝑦2 + 0.5 ∗𝑦𝑦3 + 0.375 ∗𝑦𝑦6 
Time-adjusted change from baseline 
through Month 6 in office SBP/DBP  
0.1 ∗𝑦𝑦1 + 0.2 ∗𝑦𝑦2 + 0.2 ∗𝑦𝑦3 + 0.2 ∗𝑦𝑦4 + 0.2 ∗𝑦𝑦5 + 0.1 ∗𝑦𝑦6 
7.5. 
Missing or Partial Dates 
7.5.1. 
Prior and Concomitant Medications 
For medications with partial start or end dates: the first day/month will be imputed for start date, 
and the last day/month will be imputed for end date. For medications with a completely missing 
start date, the medications will be considered as started one day prior to the first dose of study 
drug. If an imputed start date is after the collected end date, the end date will be used as the 
imputed start date. For medications with a completely missing end date or an imputed end date 
that is after the earliest date of: end of study date, data cutoff date or date of death, the latter (i.e., 
the earliest date of: end of study date, data cutoff date or date of death) will be used as the 
imputed end date. 


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7.5.2. 
Adverse Events 
For records with fully or partially missing AE onset date, conventions for the imputation is as 
below: 
• AE onset dates with missing day and non-missing month will be imputed to occur on 
the first day of the non-missing month, except for AEs occurring in the first month of 
dosing, in which case the date will be the first day of dosing. 
• AE onset dates with missing month will be imputed to occur on the first day of the 
non-missing year (i.e., January 1), except for AEs occurring in the first year of 
dosing, in which case the date will be the first day of dosing.  
• If year of the AE start date is missing, the onset date will be imputed as the first day 
of dosing, except if it can be unequivocally determined (from the partial or complete 
stop date) that the event occurred prior to the first dose of study drug, in which case 
the AE onset date will not be imputed.  
• If an imputed onset date is after the collected AE end date, the end date will be used 
as the imputed onset date.  
7.5.3. 
Others 
For other incomplete dates, unless otherwise specified, the following conventions will be used 
for the calculation of duration (e.g., time in years since diagnosis): 
• Missing day: the first day of the month will be used. 
• Missing month: the January 1 of the non-missing year will be used. 
• Missing year: no duration will be calculated. 


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STATISTICAL ANALYSIS PLAN 
ALN-AGT01-003 (KARDIA-2) 
 
Protocol Title: 
A Randomized, Double-blind, Placebo-
controlled, Multicenter Study to Evaluate the 
Efficacy and Safety of Zilebesiran Used as 
Add-on Therapy in Patients With Hypertension 
Not Adequately Controlled by a Standard of 
Care Antihypertensive Medication 
Short Title: 
Zilebesiran as Add-on Therapy in Patients 
With Hypertension Not Adequately Controlled 
by a Standard of Care Antihypertensive 
Medication (KARDIA-2) 
Study Drug: 
Zilebesiran (ALN-AGT01) 
Protocol Date: 
Original protocol, 25 August 2021 
Amendment 1, 22 March 2022 
SAP Date: 
Original SAP: 29 March 2022 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA 02142 USA 
Telephone: +1-617-551-8200 
 
 
 
 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without expressed written 
authorization of Alnylam Pharmaceuticals, Inc. 
 


Statistical Analysis Plan, ALN-AGT01-003 (KARDIA-2)  
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APPROVAL SIGNATURE PAGE 
 
 
 
 
 
 
This document has been authored, approved, and signed electronically on the final page by 
the following: 
 
 
 
Alnylam Pharmaceuticals, Inc. 
 
 
This document has been approved and signed electronically on the final page by the 
following: 
 
 
 
 
Alnylam Pharmaceuticals, Inc. 
 
 
 
 
Alnylam Pharmaceuticals, Inc. 
PPD
PPD
PPD
PPD
PPD
PPD


Statistical Analysis Plan, ALN-AGT01-003 (KARDIA-2)  
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TABLE OF CONTENTS 
APPROVAL SIGNATURE PAGE .................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY DESIGN .........................................................................................................8 
2.1. 
General Study Design ...................................................................................................8 
2.2. 
Objectives and Endpoints ...........................................................................................10 
2.3. 
Study Procedure ..........................................................................................................11 
2.4. 
Randomization Methodology .....................................................................................11 
2.5. 
Blinding ......................................................................................................................12 
2.6. 
Determination of Sample Size ....................................................................................12 
3. 
ANALYSIS POPULATIONS ....................................................................................13 
3.1. 
Randomization and Treatment Errors .........................................................................13 
4. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................14 
4.1. 
General Considerations ...............................................................................................14 
4.2. 
Blood Pressure Collection and Handling ....................................................................14 
4.2.1. 
24-Hour Ambulatory Blood Pressure Monitoring ......................................................14 
4.2.2. 
Office Blood Pressure .................................................................................................15 
4.2.3. 
Home Blood Pressure Monitoring ..............................................................................15 
4.3. 
Multiple Comparison/Testing Procedure ....................................................................15 
4.4. 
Handling of Missing Data ...........................................................................................16 
4.5. 
Baseline Definitions ....................................................................................................16 
4.6. 
Randomization Stratification Factors .........................................................................16 
4.7. 
Planned Analyses and Data Cutoffs ...........................................................................16 
4.7.1. 
Month 3 Analysis ........................................................................................................16 
4.7.2. 
Month 6 Analysis ........................................................................................................17 
4.7.3. 
Final Analysis .............................................................................................................17 
5. 
STATISTICAL ANALYSES .....................................................................................17 
5.1. 
Patient Disposition ......................................................................................................17 
5.2. 
Demographics and Baseline Characteristics ...............................................................18 
5.3. 
Medical History ..........................................................................................................18 
5.4. 
Protocol Deviations ....................................................................................................18 


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5.5. 
Study Drug Exposure and Compliance .......................................................................18 
5.6. 
Prior and Concomitant Medications ...........................................................................19 
5.7. 
Efficacy Analyses .......................................................................................................19 
5.7.1. 
Primary Endpoint ........................................................................................................19 
5.7.1.1. 
Definition of Estimand ...............................................................................................19 
5.7.1.2. 
Primary Analysis ........................................................................................................20 
5.7.1.3. 
Sensitivity Analyses ....................................................................................................20 
5.7.1.4. 
Other Analyses ............................................................................................................20 
5.7.2. 
Secondary Endpoints ..................................................................................................20 
5.7.2.1. 
Key Secondary Endpoints ...........................................................................................20 
5.7.2.2. 
Other Secondary Endpoints ........................................................................................21 
5.7.3. 
Exploratory Endpoints ................................................................................................22 
5.7.4. 
Evaluation of Subgroups .............................................................................................22 
5.8. 
Pharmacodynamic Analyses .......................................................................................23 
5.9. 
Pharmacokinetic Analyses ..........................................................................................23 
5.10. 
Anti-Drug Antibody ....................................................................................................23 
5.11. 
Safety Analyses ..........................................................................................................23 
5.11.1. 
Adverse Events ...........................................................................................................23 
5.11.2. 
Laboratory Data ..........................................................................................................25 
5.11.3. 
Electrocardiogram .......................................................................................................26 
5.11.4. 
Vital Signs ..................................................................................................................26 
5.11.5. 
Evaluation of Subgroups .............................................................................................26 
5.12. 
Interim Analysis ..........................................................................................................26 
5.13. 
COVID-19 ..................................................................................................................27 
5.13.1. 
General Impact ............................................................................................................27 
5.13.2. 
Impact on Adverse Events ..........................................................................................27 
6. 
CHANGES FROM PLANNED ANALYSES............................................................27 
7. 
APPENDICES ............................................................................................................27 
7.1. 
Protocol Schedule of Assessments .............................................................................27 
7.2. 
Time-Adjusted Change from Baseline .......................................................................32 
7.3. 
Missing or Partial Dates ..............................................................................................32 
7.3.1. 
Prior and Concomitant Medications ...........................................................................32 
7.3.2. 
Adverse Events ...........................................................................................................33 


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7.3.3. 
Others ..........................................................................................................................33 
 
LIST OF TABLES 
Table 1  
Multiplicity Procedure ................................................................................................15 
Table 2 
Schedule of Assessments ............................................................................................28 
Table 3 
Time-Adjusted Endpoints ...........................................................................................32 
 
LIST OF FIGURES 
Figure 1 
Study Design .................................................................................................................9 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation  
Definition 
ABPM 
Ambulatory blood pressure monitoring 
ADA 
Anti-drug antibody(ies) 
AE 
Adverse event 
AGT 
Angiotensinogen 
ALT 
Alanine aminotransferase 
AngI/II 
Angiotensin I/II 
AST 
Aspartate aminotransferase 
AUC 
Area under the curve 
DB 
Double-blind 
DBP 
Diastolic blood pressure 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
eDISH 
Evaluation of drug-induced serious hepatotoxicity 
EOT 
End of treatment 
ET 
Early termination 
ECG 
Electrocardiogram 
FAS 
Full analysis set 
HbA1c 
Hemoglobin A1c 
HBPM 
Home blood pressure monitoring 
HLT 
High level term 
IRT 
Interactive Response Technology 
ISR 
Injection site reaction 
LFT 
Liver function test 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measurements 
OLE 
Open-label extension 


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Abbreviation  
Definition 
PD 
Pharmacodynamic(s) 
PK 
Pharmacokinetic(s) 
PT 
Preferred term 
Q6M 
Once every 6 months 
RAAS 
Renin-angiotensin-aldosterone system 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SBP 
Systolic blood pressure 
SC 
Subcutaneous(ly) 
SD 
Standard deviation 
SOC 
System Organ Class 
ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantification 
 


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1. 
INTRODUCTION 
This statistical analysis plan (SAP) details comprehensive specifications of the efficacy, safety, 
pharmacokinetic (PK) and pharmacodynamic (PD) data summaries and statistical analyses in 
support of the clinical study report (CSR) for Study ALN-AGT01-003 (KARDIA-2). This SAP 
is finalized prior to treatment unblinding for conducting the analysis of the primary and 
secondary endpoints measured at Month 3, which will occur after all patients complete the 
Month 3 visit or withdraw from the study prior to the Month 3 visit. Changes to planned analyses 
specified in this SAP made after database lock will be documented in the CSR. 
Table, figure, and listing (TFL) mocked shells and specifications are contained in a separate 
document. 
2. 
STUDY DESIGN  
2.1. 
General Study Design  
This is a Phase 2 randomized, double-blind, placebo-controlled, multicenter study to evaluate the 
efficacy, safety, and PD of zilebesiran administered SC as an add-on therapy in patients with 
hypertension despite treatment with a standard of care antihypertensive medication. A schematic 
of the study design is provided in Figure 1. 
Run-in Period 
Patients who complete the Screening period and meet all inclusion/exclusion criteria for 
enrollment will be randomized to receive open-label therapy with olmesartan (40 mg orally once 
daily [or 20 mg orally once daily for patients with creatinine clearance ≤60 mL/min enrolled at 
sites outside of the US, consistent with local labeling for olmesartan]), amlodipine (5 mg orally 
once daily), or indapamide (2.5 mg orally once daily) as their protocol-specified background 
antihypertensive medication during a Run-in period of at least 4 weeks. Prior antihypertensive 
medications (if taking) will be discontinued upon the start of this Run-in period (Run-in Visit 1) 
for at least 4 weeks before Run-in Visit 2 to washout their effects. 
DB Period 
Patients who meet all inclusion/exclusion criteria will be randomized 1:1 to receive 600 mg 
zilebesiran SC or placebo SC on Day 1 of a 6-month DB period as add-on therapy to their 
protocol-specified background antihypertensive medication (olmesartan, amlodipine, or 
indapamide). Randomization on Day 1 will be stratified by race (black or all other races), 
baseline blood pressure (24-hour mean SBP < or ≥145 mmHg), and screening eGFR (<60 or 
≥60 mL/min/1.73m2). 
Starting at Month 3, additional conventional oral antihypertensives (“escape antihypertensive 
medications”) may be added to the patient’s protocol-specified background antihypertensive 
medication per Investigator judgement.  


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OLE Period 
After the 6-month DB period, protocol-specified background antihypertensive medications will 
be discontinued, and patients may be eligible to participate in a separate zilebesiran OLE study. 
If an individual patient reaches Month 6 prior to availability of the separate OLE study, they may 
receive open-label zilebesiran at 600 mg SC once every 6 months for up to 12 additional months 
until the separate OLE study is open and then transition. Once the separate OLE study is open for 
enrollment, eligible patients may rollover into that OLE study at Month 6, 12, or 18 (first visit 
after the separate OLE study is open). 
Safety Follow-up Period 
Patients who discontinue study drug or do not enroll in the separate zilebesiran OLE study will 
be asked to complete Safety Follow-up visits once every 6 months after their last dose of study 
drug until serum AGT levels return to ≥50% of their individual mean baseline level (if known) or 
12 months, whichever comes earlier. 
Patients who discontinue study drug prior to the Month 6 visit will also be asked to complete the 
remainder of scheduled study visits and assessments (except for study drug administration) 
through Month 6. If a patient discontinues study drug after the Month 6 visit, end of treatment 
(EOT)/early termination (ET) assessments should be performed. 
 
Figure 1 
Study Design 
 
Abbreviations: aHTN=antihypertensive medication; BL=baseline; DB=double-blind; M=month; OLE=open-label 
extension; PBO=placebo; PO=per os (oral); qd=once daily; q6M=once every 6 months; R=randomization; 
SC=subcutaneous. 
Note: Patients may be eligible to participate in a separate zilebesiran OLE study upon completion of the Month 6 
predose assessments. If an individual patient reaches Month 6 prior to availability of the separate OLE study, they 
may receive open-label zilebesiran once every 6 months in the OLE period for up to 12 additional months until the 
OLE study is open and then transition. Once the separate OLE study is open for enrollment, eligible patients may 
rollover into the separate OLE study at Month 6, 12, or 18 (first visit after the separate OLE study is open). 
Patients who were previously taking antihypertensives at screening should undergo a washout of these medications 
for at least 4 weeks during the Run-in period. 






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At Day 1, patients will be randomized 1:1 to receive zilebesiran or placebo as an add-on to their 
protocol-specified background antihypertensive medication using the IRT. Randomization at 
Day 1 will be stratified by race (black or all other races), baseline blood pressure (24-hour mean 
SBP < or ≥145 mmHg), and screening eGFR (<60 or ≥60 mL/min/1.73m2). 
2.5. 
Blinding  
The Sponsor, all site personnel and patients will be blinded to study drug treatment through 
Month 3 of the 6-month DB period. After the database lock to support the analysis of the primary 
endpoint and secondary endpoints measured at Month 3 is complete, Sponsor staff members who 
will not have direct roles or responsibilities in interacting with study sites will be unblinded to 
the analysis results according to the prespecified blinding plan. Site personnel, patients, and 
Sponsor staff members who have direct roles or responsibilities in interacting with study sites 
will remain blinded to treatment assignment until after the analysis of Month 6 data is complete. 
All Sponsor and site personnel and patients will be blinded to any clinical laboratory result that 
could potentially unblind them (e.g., AGT levels) until unblinding 
Details about the specifics of the blinding aspects throughout the entire study are available in the 
Randomization and Blinding Plan.  
Any unplanned/emergency unblinding occurring during the DB Period will be documented and 
reported in the CSR. 
Refer to the study Randomization and Blinding Plan for more details. 
2.6. 
Determination of Sample Size 
Approximately 630 patients will be randomized to receive either zilebesiran or placebo, with 
sample sizes in each of the patient cohorts with protocol-specified background antihypertensive 
medication as follows:  
• Olmesartan cohort: 300 patients  
• Amlodipine cohort: 210 patients 
• Indapamide cohort: 120 patients 
Assuming a common standard deviation of 16 mmHg in change from baseline in 24-hour mean 
SBP assessed by ABPM and 15% dropout rate from baseline to Month 3, with 2-sided 
significance level of 0.05 for each of the comparisons (zilebesiran versus placebo as add-on to 
olmesartan; zilebesiran versus placebo as add-on to amlodipine; zilebesiran versus placebo as 
add-on to indapamide), these sample sizes will provide at least 80% power to detect the 
following difference between zilebesiran versus placebo: 
• 5 mmHg as add-on to olmesartan  
• 6 mmHg as add-on to amlodipine 
• 8 mmHg as add-on to indapamide  
The power is assessed by mixed model with repeated measurements (MMRM), with change 
from baseline in 24-hour mean SBP assessed by ABPM at Month 3 as response variable and 


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treatment, time, treatment-by-time as fixed factors and corresponding baseline value as a 
covariate. 
3. 
ANALYSIS POPULATIONS 
The populations (analysis sets) are defined as follows: 
• Full Analysis Set (FAS): All randomized patients who received any amount of study 
drug. All by-treatment analyses based on the FAS will be grouped according to the 
randomized treatment arm. 
• Safety Analysis Set: All patients who received any amount of study drug. All by-
treatment analyses based on the Safety Analysis Set will be grouped according to the 
treatment actually received. 
• PK Analysis Set: All patients who received at least 1 full dose of zilebesiran and have 
at least 1 non-missing post-dose PK assessment. 
• PD Analysis Set: All patients who received at least 1 full dose of study drug. All by-
treatment analyses based on the PD Analysis Set will be grouped according to the 
treatment actually received. 
• All Zilebesiran Treated Set: All patients who received any amount of zilebesiran, 
including patients who took zilebesiran during the 6-month DB period, and patients 
who initially took placebo and then switched to zilebesiran after Month 6 Visit.  
For the analyses for 6-month DB period, the primary population used to evaluate efficacy will be 
the FAS. Safety will be analyzed using the Safety Analysis Set. The PK and PD Analysis Sets 
will be used to conduct PK and PD analyses, respectively.  
The All Zilebesiran Treated Set will be used to summarize the efficacy and safety of zilebesiran 
throughout the 6-month DB period and the OLE period.  
3.1. 
Randomization and Treatment Errors 
The study has two randomizations. The first randomization is to assign patients to receive one of 
the three protocol specified background antihypertensive medication. The second randomization 
is to randomize patients to receive either zilebesiran or placebo on top of each backgrouup 
antihypertensive medication. This section mainly focuses on the second randomization. 
For patients who were not treated, not randomized, or received incorrect treatment, the following 
rules will be used:  
• Randomized but not treated: they will be excluded from the FAS and Safety Analysis 
Set for efficacy and safety evaluations as actual treatment is missing.  
• Treated but not randomized: they will be excluded from the efficacy analyses since 
randomized treatment is missing but will be reported under the treatment actually 
received for all safety analyses.  
• Randomized but took incorrect treatment: they will be reported under their 
randomized treatment arm for all efficacy analyses. But for safety analyses, a patient 


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will be reported under the active treatment arm if the patient is randomized to placebo 
arm and received an active dose by mistake. 
4. 
GENERAL STATISTICAL CONSIDERATIONS 
4.1. 
General Considerations 
In general, data will be summarized for each planned analysis defined in Section 4.7 separately. 
All analyses will be performed within each of the 3 protocol-specified background 
antihypertensive medication cohorts. 
Categorical variables will be summarized using counts and percentages. Continuous variables 
will be summarized using the following descriptive summary statistics: number of patients (n), 
mean, standard deviation (SD), median, first quartile (Q1), third quartile (Q3), minimum, and 
maximum. 
Study drug is zilebesiran 600mg Q6M or placebo. 
The day of the first dose of study drug administered is defined as Day 1. The Study Day of a 
time point of interest is calculated as follows: 
• If on or after Day 1, Study Day = date of interest – date of the first dose of study drug 
+ 1 
• If prior to Day 1, Study Day = date of interest – date of the first dose of study drug 
There is no Day 0. For example, the day before the first study drug dose is defined as Day -1. 
For laboratory parameters, assessments collected and recorded as lower than the lower limit of 
quantification/detection (LLOQ) will be replaced by the LLOQ. Any assessment collected and 
recorded as greater than the upper limit of quantification (ULOQ) will be replaced by the ULOQ. 
All descriptive summaries will be presented by treatment arm. 
Statistical analyses will be conducted using SAS software Version 9.4 or newer or R version 3.6 
or newer. 
4.2. 
Blood Pressure Collection and Handling 
4.2.1. 
24-Hour Ambulatory Blood Pressure Monitoring 
24-hour ambulatory blood pressure monitoring (ABPM) is programmed to take readings every 
20 minutes during the day (6 am to 9:59 pm) and every 30 minutes during the night (10 pm to 
5:59 am). An ABPM will be considered adequate if (1) the number of successful daytime 
readings is ≥33, (2) the number of successful nighttime readings is ≥11, and (3) no more than 3 
hours are not represented (i.e., 3 sections of 60 minutes where 0 valid readings were obtained). If 
the ABPM recording is inadequate, the patient will be provided 1 opportunity to repeat the study 
within 4 days.  
To summarize the 24-hour ABPM, hourly adjusted mean will be calculated. Hourly adjusted 
mean will be calculated by two steps:  


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1. Calculate the hourly mean of BP by each hour of the day (e.g., mean of BP measurements 
from 16:00 to 16:59). If there is no reading in a specific hour, this hourly mean will be 
considered as missing.    
2. Calculate the 24-hour mean SBP/DBP, daytime and nighttime means of the SBP/DBP 
based on the hourly means.  
4.2.2. 
Office Blood Pressure 
The office BP in the sitting position will be used for the analysis. Office BP will be collected 
with a set of 4 replicates. The average of the last 3 replicates will be calculated and used for 
analysis. Office BP collected in standing position will be listed only.   
4.2.3. 
Home Blood Pressure Monitoring 
Home blood pressure will be measured both pre and post randomization. To establish baseline, 
each patient should measure HBPM during the week (with at least 3 successful readings) 
immediately prior to randomization. After Day 1, HBPM will be measured at least once per 
week. 4 sequential blood pressure measurements at 1-minute intervals will be recorded. The 
seated blood pressure for the visit will be defined by the average of the last 3 individual 
measurements. HBPM will be summarized by weekly average.  
Details of the blood pressure collection are in Study Protocol Section 10. 
4.3. 
Multiple Comparison/Testing Procedure 
All analyses will be performed within each of the 3 protocol-specified background 
antihypertensive medication cohorts. To control the overall Type I error at α=0.05 within each 
cohort, the primary endpoint and the key secondary endpoints will be tested in hierarchical order.  
Table 1  
Multiplicity Procedure 
Test 
Step a 
Endpoint 
Success criteria 
1 
Primary: Change from baseline at Month 3 in 24-hour mean SBP, 
assessed by ABPM 
Nominal p-value < 0.05 
2 
Key secondary: Change from baseline at Month 3 in office SBP 
Nominal p-value < 0.05 
3 
Key secondary: Time-adjusted change from baseline through Month 
6 in 24-hour mean SBP, assessed by ABPM  
Nominal p-value < 0.05 
4 
Key secondary: Time-adjusted change from baseline through Month 
6 in office SBP  
Nominal p-value < 0.05 
5 
key secondary: 24-hour mean SBP assessed by ABPM <130 mmHg 
and/or reduction from baseline ≥ 20 mmHg without escape 
antihypertensive medication at Month 6 
Nominal p-value < 0.05 
a If the success criterion is satisfied in a given step, the hypothesis test is deemed statistically significant and the 
next step will be evaluated; otherwise all hypotheses in the given and subsequent steps are deemed not statistically 
significant 


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4.4. 
Handling of Missing Data 
No imputation will be done for missing values for the primary analysis of the primary endpoint. 
A sensitivity analysis of the primary endpoint will be performed (details described in Section 
5.7.1.3). For all analyses using mixed model repeated measures, no explicit imputation of 
missing values will be done. 
4.5. 
Baseline Definitions 
For the analyses of 6-month DB period, for office BP, baseline is the average of the office BP 
value on Day 1 prior to receiving the first dose of study drug and last non-missing value prior to 
Day 1 during run-in period. For 24-hour ABPM, baseline is the measurement used for eligibility 
for randomization to study drug. For HBPM, baseline will be the average of all assessments 
during the last week prior to receiving the first dose of study drug. For all other endpoints, 
baseline is the last non-missing value (including unscheduled visit) prior to receiving the first 
dose of study drug. 
For the final analyses, patients initially randomized to placebo and switched to zilebesiran at 
Month 6 will be summarized in two ways:  
• From Day 1. Baseline is the same as the one for the primary analysis 
• From the start of zilebesiran dosing at Month 6. Baseline will be the last assessment 
prior to Month 6 dosing.  
For patients initially randomized to zilebesiran, baseline remains the same as the one for the 
primary analysis.  
4.6. 
Randomization Stratification Factors 
Stratification factors are recorded in the IRT database. Key data is integrated into the clinical 
database. In statistical analyses that use randomization stratification factors as covariates, the 
stratum assignment will reflect the values as recorded in the clinical database (EDC). In the 
presence of stratification errors, the stratification used in analysis may not match that in the IRT. 
A comparison of the number and percentage of patients in each randomization stratification 
factor in IRT versus the clinical database will be summarized by randomized treatment arm and 
overall. 
4.7. 
Planned Analyses and Data Cutoffs 
4.7.1. 
Month 3 Analysis 
The analysis of the primary endpoint and secondary endpoints measured at Month 3 will be 
performed after the last randomized patient has completed Month 3 Visit or otherwise 
discontinued the study. For the Month 3 analysis, as this study will be ongoing with some 
patients in the 6-month DB period, OLE period or safety follow-up period, the study database 
will undergo an interim database lock at the Month 3 cutoff dates (i.e., data in EDC will be 
cleaned, frozen and electronically signed by investigators; external laboratory data will be 
cleaned and will undergo quality assurance). Additional details regarding the interim database 
locks will be documented in the study Data Management Plan. 


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The analysis will include data on, or prior to, this prespecified cutoff date. For assessments with 
starting/ending dates (e.g., adverse events [AEs], medications), the starting date will be 
compared with the pre-specified cutoff date. Data records with starting dates after the specified 
data cutoff date will be excluded. 
4.7.2. 
Month 6 Analysis 
The analysis after the end of double-blind period is the Month 6 analysis. The analysis will be 
performed after all randomized patients have completed the Month 6 Visit or otherwise 
withdrawn from the study.  
The database will undergo an interim database lock, and the data will be summarized in a CSR. 
4.7.3. 
Final Analysis 
After all patients reach the end of the study, the database will undergo a final database lock, and 
the data will be summarized in a CSR.  
A patient is considered to have reached the end of the study if the patient: 
• has completed at least the Month 6 visit and enrolled in the OLE study, or 
• has completed the Safety Follow-up visits for patients who discontinue study drug, 
withdraw from the study, or do not enroll in the OLE study. 
5. 
STATISTICAL ANALYSES 
5.1. 
Patient Disposition 
The number and percentage of patients in the following categories will be summarized by 
randomized treatment arm and overall: 
• Randomized to study drug 
• Treated with study drug 
• Completed the 6-month double-blind (DB) treatment period 
• Discontinuation and primary reason during 6-month DB period 
• Withdrawal from study and primary reason for withdrawal from study 
• Completed the OLE period 
• Completed the study 
• Rollover to the separate OLE study 
In addition to the primary reason for discontinuation of treatment and withdrawal from study, 
patients will also be categorized if discontinuation/withdrawal was due to COVID-19. 


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5.2. 
Demographics and Baseline Characteristics 
Demographic and baseline disease characteristics will be summarized by treatment arm and 
overall for Full Analysis Set, and also presented in listings. 
Age at consent, height, weight, body mass index (BMI), 24-hour ABPM and OBP, eGFR will be 
summarized using descriptive statistics. Sex, race, ethnicity, and country will be summarized by 
presenting the frequencies and percentages of patients in each category.   
5.3. 
Medical History 
Medical history and prior procedures reported will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA), Version 23.1 or newer. Unique patients who report medical 
history events will be summarized by MedDRA system organ class (SOC), high level term 
(HLT) and preferred term (PT). 
5.4. 
Protocol Deviations 
Protocol deviations will be classified by medical review prior to each planned analysis database 
lock, and major protocol deviations will be identified. A major protocol deviation is a deviation 
that may significantly impact the completeness, accuracy, and/or reliability of the trial data; that 
may significantly affect a subject's rights, safety, or well-being. (ICH E3 R1 Structure and 
Contents of Clinical Study Reports Guidance for Industry, 2013). 
The Sponsor or designee will be responsible for producing the protocol deviation file. This file 
will include a description of each protocol deviation and classification as major or minor. The 
protocol deviations will be reviewed and finalized prior to the planned analysis database lock. 
All protocol deviations and major protocol deviations will be summarized and listed. 
5.5. 
Study Drug Exposure and Compliance 
The following variables will be summarized by descriptive statistics and/or frequency tabulation: 
• Duration of exposure, defined as: date of last exposure – date of first dose of study 
drug +1. Date of last exposure is the earliest date of the following: 
− date of last dose of study drug + the length of dosing interval (169 days)  
− date of end of study 
− date of analysis data cutoff 
• Number of doses received; as continuous and/or categorical variable 
• Number of missed doses; as a categorical variable 
• Compliance to background medication: number of pills taken/number of pills 
dispensed 
• Total exposure (patient years) 


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5.6. 
Prior and Concomitant Medications 
Medications will be coded using the World Health Organization (WHO) Drug Dictionary, 
version WHO-DD Global B3, March 2021 or newer. Unique patients who reported medications 
will be summarized by Anatomical Therapeutic Chemical (ATC) level 3 class (or level 2 if not 
available) and PT. Summaries will be provided for prior and concomitant medications separately. 
Prior medications are those medications with start date prior to the first dose of study drug. 
Concomitant medications are medications, other than the study drug or protocol-specified 
background antihypertensive medication, administered at or after the first dose of study drug, as 
well as medications that started prior to the first dose of study drug and are ongoing after the first 
dose of study drug.  
If the medication start date is on or after the date of first dose of study drug, the medication will 
be summarized as a concomitant medication even if the medication end date is missing.  
If the end date of a medication is missing or incomplete, such that it cannot be determined 
whether it is after the first dose of study drug, it will be counted as a concomitant medication. 
For missing or partial dates for medications, the imputation of start and end dates is described in 
Section 7.2  
5.7. 
Efficacy Analyses 
5.7.1. 
Primary Endpoint 
5.7.1.1. 
Definition of Estimand 
The primary objective of the study is to evaluate the add-on effect of zilebesiran on SBP as 
assessed by ABPM at Month 3. Primary estimand is defined as: 
• Treatment condition: add-on therapy: placebo or zilebesiran 600 mg Q6M in addition 
to one of the protocol-specified background antihypertensive medication (olmesartan, 
amlodipine, or indapamide)  
• Target population: patients with hypertension not adequately controlled by a standard 
of care antihypertensive medication 
• Endpoint: Change from baseline at Month 3 in 24-hour mean SBP assessed by ABPM 
• Population-level summary: Least square mean difference between zilebesiran and 
placebo in change from baseline at Month 3 in 24-hour mean SBP assessed by 
ABPM, on top of each background antihypertensive medication 
• Intercurrent events strategy: Hypertensive escape medication taken before Month 3 
visit will be considered as an intercurrent event. For patients who require escape 
antihypertensive medication, given the expected number of such patients at Month 3 
is low, hypothetical strategy will be used, i.e., ABPM assessed while patients are on 
and within 2 weeks after stopping any escape antihypertensive medication will be 
excluded for analysis. This will provide the estimated treatment effect of zilebesiran 
compared with placebo on top of each background antihypertensive medication. 


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5.7.1.2. 
Primary Analysis  
For each background antihypertensive medication cohort, the hypothesis to be tested for the 
primary endpoint is: 
• H0: µ1 =µ0 (there is no add-on effect of zilebesiran) 
• Ha: µ1 ≠ µ0 (there is add-on effect of zilebesiran) 
where µ0 and µ1 are the mean change from baseline at Month 3 in 24-hour mean SBP in placebo 
and zilebesiran arm, respectively.     
MMRM model will be used as primary analysis. The model will include treatment, time, 
treatment-by-time, and race (black, all other races) as fixed factors; baseline 24-hour mean SBP 
assessed by ABPM and screening eGFR as covariates. 
5.7.1.3. 
Sensitivity Analyses  
For the sensitivity analysis, treatment policy strategy will be used for patients who require escape 
antihypertensive medication. All collected blood pressure measurements will be analyzed by the 
same MMRM model as the primary analysis, regardless of the hypertensive escape medication. 
Due to the expected long-acting effect of zilebesiran, the commonly used control-based Pattern 
Mixture Model (PMM) will not be used to assess the missing not at random (MNAR) 
assumption. 
5.7.1.4. 
Other Analyses  
To demonstrate zilebesiran consistently controls blood pressure over the 24-hour period, change 
from baseline at Month 3 in SBP assessed by ABPM at each clock hour will be plotted for each 
treatment group. 
5.7.2. 
Secondary Endpoints 
5.7.2.1. 
 Key Secondary Endpoints 
Secondary objectives of the study are to evaluate the add-on effect of zilebesiran on blood 
pressure assessed by ABPM and office blood pressure through Month 6. The estimand is defined 
as: 
• Treatment condition: add-on therapy: placebo or zilebesiran 600 mg Q6M in addition 
to one of the protocol-specified background antihypertensive medication (olmesartan, 
amlodipine, or indapamide)  
• Target population: patients with hypertension not adequately controlled by a standard 
of care antihypertensive medication 
• Endpoint:  
− Change from baseline at Month 3 in office SBP  
− Time-adjusted change from baseline through Month 6 in 24-hour mean SBP 
assessed by ABPM 
− Time-adjusted change from baseline through Month 6 in office SBP 


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−  24-hour mean SBP assessed by ABPM <130 mmHg and/or reduction from 
baseline ≥ 20 mmHg without escape antihypertensive medication  
• Population-level summary: Least square mean difference between zilebesiran and 
placebo of the change from baseline in SBP on top of each background 
antihypertensive medication. Odds ratio for BP response rate. 
• Intercurrent events strategy:  
− For Month 3 endpoint: Given the expected number of such patients at Month 3 is 
low, hypothetical strategy will be used. 
− For Month 6 endpoint: Protocol allows escape antihypertensive medication from 
Month 3 through Month 6. Given the expected proportion of such patients may be 
large, the treatment policy strategy will be used. 
Time-adjusted change is defined as the area under the curve (AUC) of BP change from baseline 
divided by the duration of the time period. It leads to the weighted average of change from 
baseline to each scheduled visit. Details of the definition and calculation are in Section 7.2.  
Multiplicity adjustment will be applied across primary and the key secondary endpoints. Details 
of multiplicity control are in Section 4.3 . 
MMRM model will be used as the primary analysis. The model will include treatment, visit, 
treatment-by-visit interaction, race (black, all other races) as fixed factors, baseline eGFR and 
corresponding baseline BP as covariates. Least square (LS) mean difference, 95% CI and p-value 
will be generated. 
For the proportion of patients with 24-hour mean SBP assessed by ABPM <130 mmHg and/or 
reduction ≥20 mmHg without escape antihypertensive medication at Month 6, logistic regression 
will be used. The model will include treatment as a factor and baseline 24-hour mean SBP as a 
covariate. 
5.7.2.2. 
Other Secondary Endpoints  
Other blood pressure related secondary endpoints are: 
• Change from baseline at Month 3in 24-hour mean DBP, assessed by ABPM 
• Change from baseline at Month 3 in office DBP.  
• Time adjusted change from baseline through Month 3 in 24-hour mean SBP/DBP, 
assessed by ABPM  
• Time adjusted change from baseline in office SBP/DBP through Month 3  
• Change from baseline at Month 6 in 24-hour mean SBP/DBP, assessed by ABPM 
• Change from baseline at Month 6 in office SBP/DBP 
• Time adjusted change from baseline through Month 6 in 24-hour mean DBP, assessed 
by ABPM  
• Time adjusted change from baseline through Month 6 in office DBP  


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• Change from baseline in daytime/nighttime SBP and DBP by ABPM by each visit. 
Daytime is defined as 6 am to 9:59 pm and nighttime is defined as 10 pm to 5:59 am.  
In general, the BP related endpoints will be summarized using all collected BP data regardless of 
the use of escape antihypertensive medication. The same MMRM model will be used with 
treatment, visit, treatment-by-visit interaction, race (black, all other races) as fixed factors, 
corresponding baseline as a covariate. Least square (LS) mean difference of each zilebesiran 
dose group compared with placebo dose group, 95% CI and p-value will be generated. 
The secondary endpoint of percent change in serum AGT at each visit will be summarized using 
descriptive statistics. 
5.7.3. 
Exploratory Endpoints  
The blood pressure related exploratory endpoints through Month 6 are: 
• BP response rate by each visit, defined as 
− Office SBP < 140 mmHg and/or reduction from baseline ≥ 20 mmHg without 
escape antihypertensive medication 
− 24-hour mean DBP assessed by ABPM < 85 mmHg and/or reduction from 
baseline ≥ 10 mmHg without escape antihypertensive medication 
− Office DBP < 90 mmHg and/or reduction from baseline ≥ 10 mmHg without 
escape antihypertensive medication 
• Proportion of patients with escape antihypertensive medication use by each visit 
• Change from baseline in pulse pressure by each visit, assessed by ABPM and office 
BP 
• Change from baseline in SBP/DBP by HBPM 
To assess the long-term treatment effect of zilebesiran through Month 18, change from baseline 
in SBP/DBP assessed by ABPM, office BP and HBPM will be summarized.  
Body weight, metabolic related exploratory endpoints are: 
• Change from baseline in body weight/body mass index (BMI)/waist 
circumference/waist-to-hip ratio by each visit 
• Change from baseline in HbA1c/fasting glucose/insulin/serum lipids by each visit  
Exploratory endpoints will be summarized using descriptive statistics based on all observed data. 
Missing data will not be imputed.  
5.7.4. 
Evaluation of Subgroups 
Subgroup analyses will be conducted to assess the consistency of treatment effect within various 
subgroups defined by the following baseline characteristics: 
• Age (<65; >=65) 
• Sex 


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• Race (black; all other races) 
• Baseline 24-hour mean SBP assessed by ABPM (<145 mmHg, >=145 mmHg) 
• Baseline eGFR (<60; >=60 mL/min) 
Subgroup analyses will be performed for the primary endpoint and key-secondary endpoints 
using the MMRM within each subgroup. Model will include treatment, visit, treatment-by-visit 
interaction, race ([black, all other races], when race is not the subgroup to be analyzed) as fixed 
factors, baseline eGFR and corresponding baseline BP measurement as covariates. Point estimate 
of treatment effect and 95% confidence interval are to be generated for each subgroup. A forest 
plot will be generated to illustrate the estimated treatment effect along with 95% CI within each 
subgroup. 
5.8. 
Pharmacodynamic Analyses 
In addition to serum AGT, the PD parameters include plasma renin concentration, aldosterone, 
AngI and AngII. Summary tables may be provided for observed values, changes and percentage 
changes from baseline for each scheduled time point by treatment group. In addition to serum 
AGT percent reduction analyses, the AGT maximum and mean percentage reductions over the 6-
month DB period will be summarized using descriptive statistics.  
5.9. 
Pharmacokinetic Analyses 
Plasma concentrations of zilebesiran and its metabolite will be summarized descriptively. 
Descriptive statistics for zilebesiran and its metabolite plasma concentrations will include the 
number of patients, mean, SD, coefficient of variation, geometric mean, geometric mean 
coefficient of variation, median, minimum, and maximum.  
Additional analysis may be done as needed.  
5.10. 
Anti-Drug Antibody 
The number and percentage of patients with confirmed positive anti-drug antibody (ADA) assay 
results at baseline and at any time during the 6-month DB period, as well as treatment-emergent 
ADA during the OLE period, will be summarized. Treatment-emergent ADA consist of 
treatment-induced ADA and treatment-boosted ADA, as defined below: 
• Treatment-induced ADA: Confirmed positive ADA developed de novo after drug 
administration in patients without preexisting (baseline) confirmed positive ADA 
• Treatment-boosted ADA: Confirmed positive ADA after drug administration with 
ADA titer > 4x baseline ADA titer in patients with preexisting (baseline) confirmed 
positive ADA 
5.11. 
Safety Analyses 
5.11.1. 
Adverse Events 
Adverse events (AEs) will be classified by the MedDRA coding system (Version 23.1 or newer) 
and displayed in tables and data listings using SOC and PT. 


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Treatment-emergent AEs (TEAEs) will be summarized for the 6-month DB period and for the 
duration of zilebesiran exposure (defined in Section 5.5) separately.  
For the 6-month DB period, TEAE is defined as any AE occurring or worsening on or after the 
first dose of study drug and through Month 6 Visit (prior to Month 6 dosing).  
For the summary of duration of zilebesiran exposure, TEAE is defined as any AE occurring or 
worsening on or after the first dose of zilebesiran and through the last date of zilebesiran 
exposure.  
AEs that occurred or worsened during safety follow-up period will be listed and may be 
summarized if needed. 
Because any worsening AE is reported as a new AE with higher severity, programmatical 
comparison of severity is not needed for the classification of TEAE. For missing or partial dates 
for AEs, the imputation of start and end date can be found in Section 7.2. Events with a fully or 
partially missing onset date will be assumed to be treatment emergent unless it can be 
unequivocally determined (from the partial onset date and/or a partial or complete stop date) that 
the event occurred prior to the first dose of study drug. 
AEs will be summarized by the numbers and percentages of patients reporting a given AE. An 
overall table of TEAEs will include: 
• any AE, 
• any AE related to study drug, 
• any serious AE (SAE), 
• any SAE related to study drug, 
• any AE leading to study drug discontinuation, 
• any drug-related AE leading to study drug discontinuation, 
• any AE leading to death.  
Tabulations by SOC and PT will be produced for the following:  
• AEs, 
• Treatment-related AEs, 
• AEs by maximum severity, 
• Treatment-related AEs by maximum severity, 
• Severe AEs, 
• SAEs, 
• AEs leading to treatment discontinuation. 
Tabulations by PT will be produced for the following: 
• AEs, 
• Treatment-related AEs, 


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• SAEs. 
A patient contributes only once to the count for a given AE (overall, by SOC, by preferred term). 
Patients who report multiple occurrences of the same AE (preferred term) will be classified 
according to the most severe occurrence. An AE with missing severity will be assumed to be 
severe. An AE with missing study drug relatedness will be assumed to be related. 
Listings of all deaths (if any), SAEs, and AEs leading to treatment discontinuation will be 
provided.  
In addition, AE during run-in period will be summarized and listed by each background 
antihypertensive medication cohort. 
AEs of Clinical Interest 
AEs of special interest or AEs mapping to certain standardized MedDRA queries (SMQs) will be 
summarized by SOC and PT. Other SMQs or AE groupings may be evaluated.  
Injection Site Reactions [ISRs]: AEs mapping to the High-Level Term (HLT)= “Injection Site 
Reactions” using MedDRA dictionary will be included in the summary. Frequency (percentages) 
of ISRs by HLT and PT will be generated. A separate listing will be generated to display all 
patients who reported ISRs. In addition, a table of the number of patients with at least 1 ISR, 
total number of doses (any dose split into multiple injections will be considered 1 dose), total 
number of doses with ISRs and corresponding % of injections with ISR with the most common 
signs and symptoms reported due to ISRs will be generated. 
Hepatic AEs, including Liver Function Test (LFT) abnormalities: Analysis of hepatic AEs 
will include AEs mapping to the Standardized MedDRA Query (SMQ) Drug-related hepatic 
disorders - comprehensive search (includes all narrow and broad terms). Frequency (percentages) 
of hepatic AEs will be summarized by SOC and PT.  A separate listing will be generated of all 
patients reporting these events. 
All AEs will be presented in patient data listings. AEs mapping to the SMQs as described above 
will also be listed. 
Additional summaries of AEs mapping to a COVID-19 custom query are described in Section 
5.13.2. 
5.11.2. 
Laboratory Data 
Clinical laboratory values will be expressed in SI units. Missing laboratory data will not be 
imputed. 
For each continuous clinical laboratory parameter (including hematology, serum chemistry, liver 
function tests and coagulation studies), descriptive statistics will be presented for the actual 
values, change from baseline, and percent change from baseline by visit. These by-visit tables 
will use central laboratory data only. 
Select clinical laboratory parameters may be graded according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 or above. Shift 
summary from baseline CTCAE grade to maximum (worst) post-baseline grade will be presented 
for all graded parameters with directionality specified (e.g., hyper or hypo). To determine the 
worst post-baseline value, all scheduled and unscheduled test results will be used. For 


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hematology and serum chemistry, frequency tables of potentially clinically significant (PCS) 
abnormalities will be provided. 
All laboratory data (both central and local) will be provided in data listings.  Out-of-range 
laboratory results will be presented in a separate listing with proper flags. Local laboratory data, 
if available, will also be flagged. 
Liver Function Tests 
A frequency table and a shift table will be produced to summarize the number and percentage of 
patients in each of the below categories at any post-baseline time point.  
• ALT >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20×ULN, 
• AST >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20×ULN, 
• ALT or AST >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20×ULN, 
• ALP > 1.5×ULN, 
• Total Bilirubin >1.5 & ≤2, >2 & ≤3, >3 & ≤5 and >5×ULN, 
• Total Bilirubin > 2×ULN concurrent with ALT or AST > 3×ULN 
In separate evaluation of drug-induced serious hepatotoxicity (eDISH) figures, the peak total 
bilirubin (as multiple of ULN) at any time post-baseline will be plotted against the peak ALT, 
AST, ALT or AST level and at any time post-baseline. 
A listing for all patients with abnormal liver function tests, defined as an ALT >3×ULN, AST 
>3×ULN, or total bilirubin >2×ULN at any time point, will also be provided. 
5.11.3. 
Electrocardiogram 
Electrocardiogram (ECG) findings will include rhythm and overall interpretation.  
Post-baseline overall interpretation (normal vs. abnormal) will be summarized in frequency table 
by treatment and visit. 
All ECG data for each patient will be provided in a data listing. 
5.11.4. 
Vital Signs 
For vital signs except blood pressure, descriptive statistics for actual values and change from 
baseline by visit will be provided for each variable. Vital sign measurements will be presented by 
treatment and patient ID in a data listing, with abnormal vital signs flagged. 
5.11.5. 
Evaluation of Subgroups  
AE summary tables will be separately generated for each of the subgroups as defined for the 
primary efficacy endpoint (except for baseline BP, see Section 5.7.4). 
5.12. 
Interim Analysis 
No interim analysis is planned for this study. 


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5.13. 
COVID-19 
Additional data are collected to characterize the impact of the COVID-19 pandemic on general 
study conduct and disposition, and subsequently, additional analyses and summaries will be 
provided in acknowledgement of multiple regulatory guidance (including FDA Guidance on 
Conduct of Clinical Trials of Medical Products during COVID-19 Pandemic: Guidance for 
Industry, Investigators, and Institutional Review Boards, US Food and Drug Administration, 
2020; Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) 
Pandemic, European Medicines Agency, 2020; Points to consider on implications of Coronavirus 
disease (COVID-19) on methodological aspects of ongoing clinical trials, European Medicines 
Agency, 2020; Statistical Considerations for Clinical Trials During the COVID-19 Public Health 
Emergency, US Food and Drug Administration, 2020). 
5.13.1. 
General Impact 
Patients who discontinue treatment or stop study participation due to COVID-19 will be included 
in patient disposition summaries as described in Section 5.1. 
Impact on study participation due to COVID-19, including missing visits, visit location changes, 
study drug dosing changes and missing doses, will be summarized descriptively overall and by 
visit on the patient level, and overall on the event level. Patient- and event-level summaries of 
the impact on study participation due to COVID-19 may also be generated by site and/or region. 
Impact on study participation due to COVID-19 will be presented in data listings at patient and 
visit level. 
5.13.2. 
Impact on Adverse Events 
An overall summary of AEs mapping to a COVID-19 custom query will be presented. AEs 
mapping to the COVID-19 custom query will be summarized by HLT and PT. Due to the 
evolving nature of COVID-19-related MedDRA terminology, the COVID-19 custom query will 
be based on the latest information available at the specified analysis timepoint. 
AEs mapping to the COVID-19 custom query will also be presented in a data listing. 
6. 
CHANGES FROM PLANNED ANALYSES 
Original SAP 
Section of the SAP Summary of change from protocol 
Rationale 
— 
—  
— 
7. 
APPENDICES 
7.1. 
Protocol Schedule of Assessments 
Schedule of assessments are listed in Table 2.  








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Notes:  
• 
When scheduled at the same time points and where feasible, the assessments of vital signs and blood sample collections should be performed before 
physical examinations and 12-lead ECGs. 
• 
Run-in Visit 2 should occur at least 4 weeks after Run-in Visit 1. 
• 
Patients may be eligible to participate in a separate zilebesiran OLE study upon completion of the Month 6 predose assessments. If an individual patient 
reaches Month 6 prior to availability of the separate OLE study, they may receive open-label zilebesiran beginning at the Month 6 visit and continue for 
up to 12 additional months until the separate OLE study is open and then transition at Month 12 or 18 (first visit after the separate OLE study is open). 
Patients who rollover at Month 6 should complete all assessments scheduled for the Month 6 visit except for study drug administration. Patients who 
rollover at Month 12 should complete the EOT visit instead of the assessments scheduled at Month 12. 
• 
Patients who discontinue study drug at any time during the study or do not enroll in the separate OLE study will be asked to perform Safety Follow-up 
visits once every 6 months after the last dose of study drug until serum AGT levels return to ≥50% of their individual mean baseline level (if known) or 
12 months, whichever comes earlier. During this Follow-up period, HBPM monitoring may continue at the discretion of the Investigator. The ADA 
sample should only be collected at the first Follow-up visit during the Follow-up period. 
• 
Patients who discontinue study drug prior to the Month 6 visit will also be asked to complete the remainder of scheduled study visits and assessments 
(except for study drug administration) through Month 6. If a patient discontinues study drug after the Month 6 visit, EOT/ET assessments should be 
performed.  
Footnotes: 
a All assessments, except for postdose PK sample collection, are to be performed prior to administration of protocol-specified background 
antihypertensive medications (including Run-In Visit 1) and study drug (as applicable).  
b When applicable, pregnancy test results must be known prior to dosing with study drug at dosing visits.  
c Laboratory assessments at Day 1 do not need to be repeated, per Investigator discretion, if they were collected within 7 days before Day 1 at Run-in Visit 2.  
d Office blood pressure must be measured before the patient takes oral antihypertensive medications or study drug (as applicable).  
e ABPM recordings associated with study drug dosing visits should be obtained within 7 days before the visit and results reviewed before dosing. In the Safety 
Follow-up period, ABPM assessments may be reduced and are optional per Investigator judgement.  
f HBPM should be measured in the morning upon waking. HBPM must be collected daily for at least 1 week during the Run-in period starting at 3 weeks of run-
in (1 week prior to Run-in Visit 2). HBPM is not required at times when ABPM is being assessed. In the Safety Follow-up period, the frequency of HBPM 
assessments can be reduced after the first Safety Follow-up visit per Investigator judgement. 
g Neurological evaluation will also be performed as part of the full physical examination. 
h ABPM should only be performed as part of ET assessments if the patient discontinues the study prior to Month 12 and has not had an ABPM within the last 3 
months. ABPM should not be performed at Month 18. 


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7.2. 
Time-Adjusted Change from Baseline 
Time-adjusted change from baseline is the area under the curve (AUC) divided by time interval. 
It leads to a weighted average of all scheduled change from baseline during that time interval.  
E.g., ABPM is assessed at Month 2, 3 and 6. Time-adjusted change from baseline through Month 
6 in 24-hour mean SBP assessed by ABPM is: 
1. AUC is calculated as:  ቂ
1
2 (𝑦𝑦2 + 𝑦𝑦3) ∗1 + 
1
2 (𝑦𝑦3 + 𝑦𝑦6) ∗3 ቃ 
2. Time interval is 4 months, from Month 2 to Month 6. AUC divided by time interval is  
𝐴𝐴𝐴𝐴𝐴𝐴4
⁄
= 0.125 ∗𝑦𝑦2 + 0.5 ∗𝑦𝑦3 + 0.375 ∗𝑦𝑦6 
Where 𝑦𝑦2, 𝑦𝑦3 and 𝑦𝑦6 are the 24-hour mean ABPM at Month 2, 3, and 6.   
Table 3 listed all time-adjusted endpoints and the weights of the assessments. 
Table 3 
Time-Adjusted Endpoints 
Time-adjusted Endpoint 
Weighted average 
Time-adjusted change from baseline 
through Month 3 in 24-hour mean 
SBP/DBP assessed by ABPM 
0.5 ∗𝑦𝑦2 + 0.5 ∗𝑦𝑦3 
Time-adjusted change from baseline 
through Month 3 in office SBP/DBP  
0.25 ∗𝑦𝑦1 + 05 ∗𝑦𝑦2 + 0.25 ∗𝑦𝑦3 
Time-adjusted change from baseline 
through Month 6 in 24-hour mean 
SBP/DBP assessed by ABPM 
0.125 ∗𝑦𝑦2 + 0.5 ∗𝑦𝑦3 + 0.375 ∗𝑦𝑦6 
Time-adjusted change from baseline 
through Month 6 in office SBP/DBP  
0.1 ∗𝑦𝑦1 + 0.2 ∗𝑦𝑦2 + 0.2 ∗𝑦𝑦3 + 0.2 ∗𝑦𝑦4 + 0.2 ∗𝑦𝑦5 + 0.1 ∗𝑦𝑦6 
7.3. 
Missing or Partial Dates 
7.3.1. 
Prior and Concomitant Medications 
For medications with partial start or end dates: the first day/month will be imputed for start date, 
and the last day/month will be imputed for end date. For medications with a completely missing 
start date, the medications will be considered as started one day prior to the first dose of study 
drug. If an imputed start date is after the collected end date, the end date will be used as the 
imputed start date. For medications with a completely missing end date or an imputed end date 
that is after the earliest date of: end of study date, data cutoff date or date of death, the latter (i.e., 
the earliest date of: end of study date, data cutoff date or date of death) will be used as the 
imputed end date. 


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7.3.2. 
Adverse Events 
For records with fully or partially missing AE onset date, conventions for the imputation is as 
below: 
• AE onset dates with missing day and non-missing month will be imputed to occur on 
the first day of the non-missing month, except for AEs occurring in the first month of 
dosing, in which case the date will be the first day of dosing. 
• AE onset dates with missing month will be imputed to occur on the first day of the 
non-missing year (i.e., January 1), except for AEs occurring in the first year of 
dosing, in which case the date will be the first day of dosing.  
• If year of the AE start date is missing, the onset date will be imputed as the first day 
of dosing, except if it can be unequivocally determined (from the partial or complete 
stop date) that the event occurred prior to the first dose of study drug, in which case 
the AE onset date will not be imputed.  
• If an imputed onset date is after the collected AE end date, the end date will be used 
as the imputed onset date.  
7.3.3. 
Others 
For other incomplete dates, unless otherwise specified, the following conventions will be used 
for the calculation of duration (e.g., time in years since diagnosis): 
• Missing day: the first day of the month will be used. 
• Missing month: the January 1 of the non-missing year will be used. 
• Missing year: no duration will be calculated.