Conditions: Hypertension
Keywords: Hypertension Hypertensive AGT Angiotensinogen Blood Pressure
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 26
Healthy volunteers: no

Brief summary:
This study evaluated the effect of ISIS 757456 (IONIS-AGT-LRx) on plasma angiotensinogen (AGT) and systolic blood pressure (SBP) in uncontrolled hypertensive participants who were on two to three antihypertensive medications.

Detailed description:
This study was a Phase 2, double-blind, randomized, placebo-controlled study in 26 participants. Participants were randomized in a 2:1 ratio and received a once-weekly subcutaneous (SC) treatment with either IONIS-AGT-LRx or placebo, with an additional loading dose administered on Study Day 3. The treatment lasted for 8 weeks and the post-treatment period lasted for 13 weeks.

Arms:
arm 1: Participants received ISIS 757456-matching placebo, subcutaneous (SC) injection, once-weekly for 8 weeks and an additional loading dose on Day 3. arm 2: Participants received ISIS 757456 80 mg, SC injection, once-weekly for 8 weeks and an additional loading dose on Day 3.

Interventions: intervention 1: Placebo intervention 2: ISIS 757456
Intervention descriptions: intervention 1: ISIS 757456-matching placebo solution administered as SC injection. intervention 2: ISIS 757456 administered as SC injection.

Protocol document:
Prot_SAP_000.pdf: 
 
 
A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, 
Tolerability and Efficacy of IONIS-AGT-LRx, an Antisense Inhibitor 
Administered Subcutaneously for 8 Weeks to Hypertensive Subjects With 
Uncontrolled Blood Pressure  
NCT04083222  
4-December-2019 


Official Title: 
A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the Safety, 
Tolerability and Efficacy of IONIS-AGT-LRX, an Antisense Inhibitor 
Administered Subcutaneously for 8 Weeks to Hypertensive Subjects with 
Uncontrolled Blood Pressure 
NCT Number: 
NCT04083222 
Document Date: 
Protocol Version 1.0: 15 July 2019 




ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
2
ISIS 757456-CS3 
Original Protocol 
Clinical Phase:  2 
A Double-Blind, Placebo-Controlled, Phase 2 Study to Assess the 
Safety, Tolerability and Efficacy of IONIS-AGT-LRX, an Antisense 
Inhibitor Administered Subcutaneously for 8 Weeks to 
Hypertensive Subjects with Uncontrolled Blood Pressure
Sponsor 
Ionis Pharmaceuticals, Inc. 
Carlsbad, CA  92010 
See electronic signature and date attached at end of document 
 MD, FACC 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc. that must not be disclosed to anyone 
other than the recipient study staff and members of the institutional review board or authorized regulatory agencies.  
This information cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Pharmaceuticals, Inc. 




ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
4
TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ................................................................................................................9 
STUDY DESIGN AND TREATMENT SCHEMA ......................................................................15 
STUDY GLOSSARY ....................................................................................................................16 
1.
OBJECTIVES AND ENDPOINTS ............................................................................18 
1.1. 
Objectives ...................................................................................................................18 
1.1.1. 
Primary Objective .......................................................................................................18 
1.1.2. 
Secondary Objectives .................................................................................................18 
 
 
1.1.4. 
Safety Objective ..........................................................................................................18 
1.2. 
Study Endpoints ..........................................................................................................18 
1.2.1. 
Primary Endpoint ........................................................................................................18 
1.2.2. 
Secondary Endpoints ..................................................................................................18 
 
 
1.2.4. 
Safety Endpoint ..........................................................................................................19 
2.
BACKGROUND AND RATIONALE .......................................................................19 
2.1. 
Overview of Disease ...................................................................................................19 
2.2. 
Therapeutic Rationale .................................................................................................19 
2.3. 
ISIS 757456 ................................................................................................................20 
 
 
 
 
 
 
2.3.4. 
Clinical Experience .....................................................................................................22 
 
 
2.5. 
Benefit-Risk Assessment ............................................................................................22 
2.5.1. 
Benefit Assessment .....................................................................................................23 
 
 
3.
EXPERIMENTAL PLAN ..........................................................................................23 
3.1. 
Study Design ...............................................................................................................23 
3.2. 
Number of Study Centers ...........................................................................................24 
3.3. 
Number of Subjects ....................................................................................................24 
3.4. 
Overall Study and Post-Treatment Duration ..............................................................24 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
5
3.4.1. 
Screening ....................................................................................................................24 
3.4.2. 
Treatment ....................................................................................................................24 
3.4.3. 
Post-Treatment ............................................................................................................25 
3.5. 
End-of-Study ...............................................................................................................25 
4.
SUBJECT ENROLLMENT .......................................................................................25 
4.1. 
Screening ....................................................................................................................25 
4.2. 
Randomization ............................................................................................................25 
4.3. 
Replacement of Subjects .............................................................................................25 
4.4. 
Unblinding of Treatment Assignment ........................................................................25 
5.
SUBJECT ELIGIBILITY ...........................................................................................26 
5.1. 
Inclusion Criteria ........................................................................................................26 
5.2. 
Exclusion Criteria .......................................................................................................28 
6.
STUDY PROCEDURES ............................................................................................30 
6.1. 
Study Schedule ...........................................................................................................30 
6.1.1. 
Screening ....................................................................................................................30 
6.1.1.1. 
Seated Blood Pressure Measuring Instructions at Each Visit .....................................30 
6.1.1.2. 
Orthostatic Blood Pressure Assessment .....................................................................31 
6.1.2. 
Treatment Period ........................................................................................................31 
6.1.3. 
Post-Treatment Period ................................................................................................32 
6.2. 
Laboratory Assessments .............................................................................................32 
6.3. 
Restriction on the Lifestyle of Subjects ......................................................................32 
6.3.1. 
Contraception Requirements ......................................................................................32 
6.3.2. 
Other Requirements ....................................................................................................33 
7.
STUDY DRUG ...........................................................................................................33 
 
 
7.2. 
Packaging and Labeling ..............................................................................................34 
7.3. 
Study Drug Accountability .........................................................................................34 
8.
TREATMENT OF SUBJECTS ..................................................................................34 
8.1. 
Study Drug Administration.........................................................................................34 
8.2. 
Other Protocol-Required Drugs ..................................................................................34 
8.3. 
Other Protocol-Required Treatment Procedures ........................................................35 
8.4. 
Treatment Precautions ................................................................................................35 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
6
8.5. 
Safety Monitoring Rules .............................................................................................35 
8.5.1. 
Safety Monitoring Rules for Liver Chemistry Tests ..................................................35 
8.5.2. 
Safety Monitoring Rules for Platelet Count Results...................................................36 
8.5.3. 
Safety Monitoring for Minor Bleeding Events ...........................................................37 
8.5.4. 
Safety Monitoring for Potassium ................................................................................38 
8.5.5. 
Safety Monitoring for Blood Pressure ........................................................................38 
8.6. 
Stopping Rules ............................................................................................................38 
8.6.1. 
Stopping Rules for Liver Chemistry Elevations .........................................................38 
8.6.2. 
Stopping Rules for Renal Function Test Results ........................................................39 
8.6.3. 
Stopping Rule for Platelet Count Results ...................................................................39 
8.6.4. 
Stopping Rule for Potassium ......................................................................................41 
8.6.5. 
Stopping Rules for Blood Pressure .............................................................................41 
8.7. 
Adjustment of Dose and/or Treatment Schedule ........................................................42 
8.8. 
Discontinuation of Study Drug ...................................................................................42 
8.9. 
Withdrawal of Subjects from the Study Procedures ...................................................43 
8.10. 
Concomitant Therapy and Procedures ........................................................................43 
8.10.1. 
Concomitant Therapy .................................................................................................43 
8.10.2. 
Concomitant Procedures .............................................................................................44 
8.11. 
Treatment Compliance ................................................................................................44 
9.
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .....................44 
9.1. 
Sponsor Review of Safety Information ......................................................................44 
9.2. 
Regulatory Requirements ...........................................................................................44 
9.3. 
Definitions ..................................................................................................................45 
9.3.1. 
Adverse Event .............................................................................................................45 
9.3.2. 
Adverse Drug Reaction and Suspected Unexpected Adverse Drug Reaction ............45 
9.3.3. 
Serious Adverse Event ................................................................................................46 
9.3.4. 
AE of Special Interest (AESI) ....................................................................................47 
9.4. 
Monitoring and Recording AEs ..................................................................................47 
9.4.1. 
Serious AEs ................................................................................................................47 
9.4.2. 
Non-Serious AEs ........................................................................................................47 
9.4.3. 
Evaluation of AEs (Serious and Non-Serious) ...........................................................47 
9.4.3.1. 
Relationship to the Study Drug...................................................................................47 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
7
9.4.3.2. 
Severity .......................................................................................................................48 
9.4.3.3. 
Action Taken with Study Drug ...................................................................................48 
9.4.3.4. 
Treatment Given for AE .............................................................................................49 
9.4.3.5. 
Outcome of the AE .....................................................................................................49 
9.4.3.6. 
Follow-up of Adverse Event .......................................................................................49 
9.5. 
Procedures for Handling Special Situations ...............................................................50 
9.5.1. 
Abnormalities of Laboratory Tests .............................................................................50 
9.5.2. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................50 
9.5.3. 
Dosing Errors ..............................................................................................................51 
9.5.4. 
Contraception and Pregnancy .....................................................................................51 
10.
STATISTICAL CONSIDERATIONS .......................................................................52 
10.1. 
Stratification, Subsets, and Covariates .......................................................................52 
 
 
10.3. 
Populations .................................................................................................................52 
10.4. 
Definition of Baseline .................................................................................................52 
10.5. 
Interim Analysis ..........................................................................................................52 
10.6. 
Planned Methods of Analysis .....................................................................................52 
10.6.1. 
Demographic and Baseline Characteristics ................................................................53 
10.6.2. 
Safety Analysis ...........................................................................................................53 
10.6.3. 
Efficacy Analysis ........................................................................................................53 
10.6.4. 
Pharmacokinetic Analysis ..........................................................................................54 
 
 
11.
INVESTIGATOR’S REGULATORY OBLIGATIONS ...........................................54 
11.1. 
Informed Consent .......................................................................................................54 
11.2. 
Ethical Conduct of the Study ......................................................................................55 
11.3. 
Institutional Review Board .........................................................................................55 
11.4. 
Subject Confidentiality ...............................................................................................55 
12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS ..............................................56 
12.1. 
Protocol Amendments ................................................................................................56 
12.2. 
Study Termination ......................................................................................................56 
12.3. 
Study Documentation and Storage .............................................................................56 
12.4. 
Study Monitoring ........................................................................................................57 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
8
12.5. 
Language .....................................................................................................................57 
12.6. 
Compensation for Injury .............................................................................................58 
13.
REFERENCES ...........................................................................................................59 
14.
APPENDICES ............................................................................................................60 
APPENDIX A. SCHEDULE OF PROCEDURES .....................................................................61 
APPENDIX B. LIST OF LABORATORY ANALYTES ..........................................................64 
APPENDIX C. PK SAMPLING SCHEDULE ...........................................................................66 
APPENDIX D. GRADING SCALE FOR AES RELATING TO LABORATORY 
ABNORMALITIES ....................................................................................................68 
APPENDIX E. STRATIFICATION CRITERIA ........................................................................72 
LIST OF TABLES 
Table 1: 
Known Risks Associated with RAAS Blockade ........................................................23 
Table 2: 
Orthostatic Hypotension Assessment .........................................................................31 
Table 3: 
Study Drug Characteristics .........................................................................................34 
Table 4: 
Study Drug Dosing Information .................................................................................34 
Table 5: 
Additional Labs to be Performed in the Event of a Platelet Count 
< 75,000/mm3 .............................................................................................................37 
Table 6: 
Actions in Subjects with Low Platelet Count .............................................................39 
Table 7: 
Blood Pressure Monitoring and Stopping Rules Reference Table .............................42 




ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
10 
PROTOCOL SYNOPSIS (CONTINUED) 
Study Population 
(Continued) 
Inclusion Criteria (Continued) 
* True abstinence (i.e., refraining from heterosexual intercourse throughout
the duration of study participation) is only acceptable.  Periodic abstinence
(e.g., calendar, ovulation, symptothermal, post-ovulation methods),
declaration of abstinence for the duration of a trial and withdrawal are not
acceptable methods of contraception
4. BMI ≤ 35.0 kg/m2
5. Brachial circumference ≥ 22 and ≤ 37 cm (8.7 and 14.6 inches)
6. Subject must have been diagnosed with essential hypertension (HTN) for a
minimum of 3 months prior to screening
7. At Screening, the subject must have a plasma AGT concentration
≥ 20 µg/mL.  Up to 1 additional repeat test may be allowed in order to
qualify with consultation of the Sponsor Medical Monitor
8. At Screening, the subject must have been on a stable regimen of 2 to
3 antihypertensive medications for at least 1 month prior to screening and
will be required to maintain this regimen throughout the Study, using either
an angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin II
receptor blocker (ARB), as well as one or two additional antihypertensive
medications in the following categories:
a. beta blocker
i.
acebutolol
ii.
atenolol
iii.
betaxolol
iv.
bisoprolol
v.
carvedilol
vi.
labetalol
vii. metoprolol
viii. nadolol
ix.
nebivolol
x.
propranolol
xi.
pindolol
b.
calcium channel blocker or,
c.
non-potassium sparing diuretic
9. At Screening and pre-dose Study Day 1, the average office seated
blood pressure (BP) must be within > 140 – ≤ 170 mmHg SBP and
> 80 mmHg DBP.  The average is to be derived from 3 assessments taken
within 10 minutes.  Up to 2 additional tests at each timepoint are allowed in
order to qualify.
10. Agree to abstain from alcoholic beverages for at least 24 hours prior to clinic
visits
11. Agree to maintain adequate hydration and adhere to a low sodium diet
throughout the study (from the Screening Visit onward)


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
11 
PROTOCOL SYNOPSIS (CONTINUED) 
Study Population 
(Continued) 
Exclusion Criteria 
1. Clinically significant abnormalities in medical history (e.g., previous acute
coronary syndrome within 6 months of screening, major surgery within
3 months of screening, type I diabetes mellitus) or physical examination
2. History of secondary HTN
3. Subject with borderline orthostatic hypotension (assessed at Screening),
when they assume a standing position (within 3 minutes of standing up),
defined as:
a. A decrease in SBP of ≥ 17 mmHg or
b. A decrease in DBP of ≥ 7 mmHg
4. The use of the following at time of screening and during the course of the
study:
a. Other medications for the treatment of HTN (e.g., clonidine, guanfacine,
guanabenz, alpha-methyldopa, hydralazine, minoxidil, diazoxide, renin
inhibitors)
b. Medications that may cause hyperkalemia (e.g., cyclosporine or
tacrolimus, pentamidine, trimethoprim-sulfamethoxazole, all heparins)
c. Oral or subcutaneous (SC) anticoagulants (e.g., warfarin, rivaroxaban,
apixaban, heparin, lovenox)
d. Organic nitrate preparations (e.g., nitroglycerin, isosorbide mononitrate,
isosorbide dinitrate, or pentaerythritol)
e. Phosphodiesterase 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil,
avanafil)
f. Potassium sparing diuretics (e.g. eplerenone, spironolactone, amiloride,
triamterene)
5. Treatment with another Study Drug, biological agent, or device within
1 month of screening, or 5 half-lives of study agent, whichever is longer
6. Previous treatment with an oligonucleotide or other RNA therapeutic
(including siRNA) within 4 months of screening if single dose received, or
within 12 months of screening if multiple doses received
7. Active infection with HIV, hepatitis C or hepatitis B diagnosed by initial
serological testing and confirmed with RNA testing, or prior treatment for
hepatitis C.  Patients at Screening who test positive by serology, but negative
by RNA may be allowed in consultation with the Sponsor Medical Monitor
8. Malignancy within 5 years, except for basal or squamous cell carcinoma of
the skin or carcinoma in situ of the cervix that has been successfully treated.
Subjects with a history of other malignancies that have been treated with
curative intent and which have no recurrence within 5 years may also be
eligible if reviewed by the Sponsor Medical Monitor
9. History of bleeding diathesis, coagulopathy, immune thrombocytopenic
purpura, thrombotic cytopenic purpura, or any qualitative or quantitative
platelet defect


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
12 
PROTOCOL SYNOPSIS (CONTINUED) 
Study Population 
(Continued) 
Exclusion Criteria (Continued) 
10. Recent history of, or current drug or alcohol abuse
11. Unstable/underlying cardiovascular disease defined as:
a.
Any history of congestive heart failure (NYHA class II-IV)
b.
Any history of previous stroke, transient ischemic attack, unstable or
stable angina pectoris, or myocardial infarction prior to screening
c.
12-lead electrocardiogram (ECG) demonstrating a QT interval
(corrected using Fridericia's formula [QTcF]) > 450 msec in males and
> 470 msec in females at Screening, or a history or evidence of long QT
syndrome
d.
Any clinically significant active atrial or ventricular arrhythmias
e.
Any history of coronary bypass or percutaneous coronary intervention
12. Active infection requiring systemic antiviral or antimicrobial therapy that
will not be completed prior to Study Day 1
13. Show evidence of uncorrected hypothyroidism or hyperthyroidism hormone
results at Screening.  Subjects receiving dose-stable thyroid replacement
therapy for at least 3 months prior to screening will be allowed to participate
as long as thyroid tests (TSH/T3/T4) show that subject is euthyroid
14. Screening laboratory results as follows, or any other clinically significant
abnormalities in screening laboratory values that would render a subject
unsuitable for inclusion
a. Urine protein/creatinine (P/C) ratio ≥ 0.3 mg/mg.  In the event of P/C
ratio above this threshold eligibility may be confirmed by a quantitative
total urine protein measurement of ˂ 300 mg/24 hr
b. Positive test (including trace) for blood on urinalysis.  In the event of a
positive test eligibility may be confirmed with urine microscopy showing
≤ 5 red blood cells per high power field
c. Alanine aminotransferase (ALT), aspartate aminotransferase, bilirubin,
alkaline phosphatase (ALP), serum creatinine, blood urea nitrogen
(BUN) > 1.5 x upper limit of normal (ULN)
d. Platelet count ˂ lower limit of normal (LLN)
e. Serum potassium > 4.9 mmol/L
f. Estimated glomerular filtration rate (eGFR) of less than
45 mL/min/1.73 m2 using the Chronic Kidney Disease (CKD)
Epidemiology Collaboration formula
15. Clinically-significant abnormalities upon physical examination which in the
Investigator’s opinion should exclude the subject from study participation
16. Subject works night time shifts (e.g., 11 PM to 7 AM)
17. Blood donation of 50 to 499 mL within 30 days of screening or of > 499 mL
within 60 days of screening






ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
15 
STUDY DESIGN AND TREATMENT SCHEMA 
TREATMENT PERIOD
Study Days 1, 3, 8, 15, 22, 29,
36, 43, 50
POST-TREATMENT
EVALUATION PERIOD
Study Days 57-141
EARLY TREATMENT
TERMINATION
POST-TREATMENT
EVALUATION
PERIOD
13 Wks
(ET/ Study Days 57,
64, 78, 92, 120,141)
Subject Withdrawn
from Study or
Consent Withdrawn
WITHDRAWAL
FROM STUDY
Early Term Visit
(Study Day 57)
SCREEN
Study Day -28 to -1
END-OF-STUDY
PROCEDURES
Study Day 141
Screen Failure
Treatment
Terminated; Consent
Not Withdrawn


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
16 
STUDY GLOSSARY 
Abbreviation 
Definition 
2′-MOE 
2′-O-(2-methoxyethyl) 
A/C 
albumin/creatinine 
ACE 
angiotensin-converting enzyme 
ACEi 
angiotensin-converting enzyme inhibitor 
AE 
adverse event 
AGT 
angiotensinogen 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
aPTT 
activated partial thromboplastin time 
ARB 
angiotensin receptor blockers  
ARC 
active renin mass concentration 
ARF 
acute renal failure 
ASGPR 
asialoglycoprotein receptor  
ASO 
antisense oligonucleotide 
BMI 
body mass index 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CKD 
chronic kidney disease 
CMV 
cytomegalovirus 
CRF 
case report form 
CRNMB 
clinically relevant non-major bleeding 
CRP 
C-reactive protein 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
trough concentration 
DBP 
diastolic blood pressure 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
ED50 
50% effective dose 
eGFR 
estimated glomerular filtration rate 
FAS 
full analysis set 
FSH 
follicle stimulating hormone 
GalNAc 
N-acetyl galactosamine 
GCP 
Good Clinical Practice 
HAV 
hepatitis A virus 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HepB 
hepatitis B 
HIV 
human immunodeficiency virus 
HR 
heart rate 
hsCRP 
CRP measured by high sensitivity assay 
HTN 
hypertension 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
17 
Abbreviation 
Definition 
ICH 
International Conference on Harmonization 
IgM 
immunoglobulin M 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
KIM-1 
kidney injury molecule 1 
LLN 
lower limit of normal  
MB 
major bleeding 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA™ 
Medical Dictionary for Regulatory Activities  
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for AEs 
MRI 
magnetic resonance imaging 
mRNA 
messenger ribonucleic acid 
NGAL 
neutrophil gelatinase-associated lipocalin 
NOAEL 
no observed adverse effect level 
NYHA 
New York Heart Association 
on study 
The subject is ‘on study’ from signing of the informed consent until their last 
study visit 
P/C 
protein/creatinine 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PPS 
per protocol set  
PRA 
plasma renin activity 
PT 
prothrombin time 
RAAS 
renin-angiotensin-aldosterone system 
RHTN 
resistant hypertension 
RNase H1 
an ubiquitous endonuclease that specifically hydrolyzes the RNA strand in 
RNA/DNA hybrids 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
siRNA 
small interfering ribonucleic acid 
SC 
subcutaneous(ly) 
Study Day 1 
defined as the first day Study Drug product is administered to the subject 
Study Drug 
ISIS 757456 or placebo 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
UACR 
urine albumin-creatinine ratio 
ULN 
upper limit of normal 
UPCR 
urine protein-creatinine ratio  
WBC 
white blood cell 
WOCBP 
woman of child-bearing potential 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
18 
1.
OBJECTIVES AND ENDPOINTS
1.1.
Objectives 
1.1.1.
Primary Objective 
To evaluate the effect of ISIS 757456 on plasma angiotensinogen (AGT) in uncontrolled 
hypertensive subjects on 2 to 3 antihypertensive medications 
1.1.2.
Secondary Objectives 
To evaluate the effect of ISIS 757456 on systolic blood pressure (SBP) in uncontrolled 
hypertensive subjects on 2 to 3 antihypertensive medications 
1.1.4.
Safety Objective 
To evaluate the safety and tolerability of ISIS 757456 vs. placebo 
1.2.
Study Endpoints 
1.2.1.
Primary Endpoint 
Percent change in plasma AGT from Baseline to Study Day 57 (Study Week 9) compared to 
placebo 
1.2.2.
Secondary Endpoints 
•
Change on SBP from Baseline to each scheduled, post-Baseline visit
•
Change and percent change in plasma AGT from Baseline to each scheduled,
post-Baseline visit


19 
1.2.4.
Safety Endpoint 
Incidence and severity of treatment-emergent adverse events (TEAE) (including hypotension and 
orthostatic hypotension), use of concomitant medications, abnormal findings in laboratory 
assessments, electrocardiogram (ECG), and vital signs 
2.
BACKGROUND AND RATIONALE
2.1.
Overview of Disease 
Resistant hypertension (RHTN) is defined as failure to achieve blood pressure (BP) goal 
of ˂ 140/90 in patients adherent to adequate doses of ≥ 3 medications (1 of which is diuretic) 
(Judd and Calhoun 2014).  Some patients have pseudo-resistance hypertension (HTN) and they 
are not compliant with their medications or they have white coat HTN. 
In US alone, 70 million adults have HTN, of which 12–15% have RHTN.  Among these patients 
33% of them have uncontrolled RHTN (Judd and Calhoun 2014).  In an analysis of National 
Health and Nutrition Examination Survey database, these patients are more likely to be black, 
with diabetes, with chronic kidney disease (CKD) Stage 3, with proteinuria and congestive heart 
failure compared to patients with HTN and without resistant HTN. 
2.2.
Therapeutic Rationale 
Renin-angiotensin-aldosterone system (RAAS) inhibition is well established as a mode of 
improving HTN (Te Riet et al. 2015) and complications of HTN.  While ACEi, angiotensin 
receptor blockers (ARB) and renin inhibitors are widely used, escape mechanisms are common 
and lead to incomplete RAAS blockade.  Efforts to provide better RAAS blockade using 2 or 
more agents in this pathway have been complicated by hyperkalemia, hypotension, and acute 
renal failure (ARF).  The effect of this antisense oligonucleotide (ASO) occurs upstream of all 
the known targets for RAAS inhibitors used in clinical practice, and therefore will potentially 
reduce escape mechanisms.  The hyperkalemia and ARF of RAAS blockade could be secondary 
to renal specific reduction of these pathways.  The N-acetyl galactosamine (GalNAc) ASOs have 
more prominent effect in the liver.  As such, the renal sparing effects of this ASO may result in 
an improved therapeutic index compared with RAAS inhibitors, especially important in subjects 
with CKD and/or those at submaximal RAAS blockage. 








ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
23 
2.5.1. 
Benefit Assessment 
This compound has been administered to healthy volunteers, and is currently being studied in 
hypertensive subjects washed out of their antihypertensive medications.  Based on its MOA of 
blocking the RAAS pathway it is expected to lower the BP in subjects with HTN.  While there 
are other compounds (ACEi, ARB, aldosterone blockers, renin inhibitors) that block different 
components of this pathway, this compound blocks AGT, the most upstream factor in the 
pathway.   
3. 
EXPERIMENTAL PLAN 
3.1. 
Study Design 
This will be a Phase 2, double-blind, randomized, placebo-controlled study of ISIS 757456 
conducted in uncontrolled hypertensive subjects on 2 to 3 antihypertensive medications (see 
Section 5.1 Inclusion Criteria).  Subjects will be stratified based on low Screening ACE/ARB 
dose or high Screening ACE/ARB dose (see Section 10.1 and Appendix E).  The subjects will be 
randomized in a 2:1 ratio to receive a once-weekly SC treatment and an additional loading dose 




ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
25 
3.4.3. 
Post-Treatment 
Subjects are to return to the Study Center for Post-Treatment visits on Study Days 57, 64, 78, 92, 
120, and 141.  The final study visit will be Study Day 141 (Study Week 21). 
3.5. 
End-of-Study 
The End-of-Study is defined as the date of the last visit of the last subject.   
4. 
SUBJECT ENROLLMENT 
4.1. 
Screening 
Before subjects may be enrolled into the study, the Sponsor requires a copy of the Study Center’s 
written institutional review board (IRB) approval of the protocol, informed consent form, and all 
other subject information and/or recruitment material. 
Subjects must sign the consent form before any screening tests or assessments are performed.  
At the time of consent, the subject will be considered enrolled into the study and will be assigned 
a unique screening number before any study procedures, including Screening procedures, are 
performed.  At the time of randomization, subjects will be assigned a unique subject 
identification number.  This number will be used to identify the subject throughout the trial and 
must be used on all study documentation related to that subject.  The screening number and 
subject identification number must remain constant throughout the entire trial.  Screening 
numbers and subject identification numbers, once assigned, will not be re-used. 
4.2. 
Randomization 
Subjects will be randomized at Study Day 1, after all screening assessments have been 
completed and after the Investigator has verified that they are eligible per criteria in Section 5.1 
and Section 5.2.  No subject may begin treatment prior to randomization and assignment of a 
unique subject identification number. 
Subjects will be stratified based on low Screening ACE/ARB dose or high Screening ACE/ARB 
dose (see Section 10.1 and Appendix E) and then subjects will be randomized 2:1 to receive 
ISIS 757456 or placebo as outlined in Section 3.1. 
The Sponsor or designee will prepare the randomization list and utilize an automated IRT 
(Interactive Response Technology) system. 
4.3. 
Replacement of Subjects 
Subjects who withdraw from the study or whose randomization code has been broken will not be 
replaced. 
4.4. 
Unblinding of Treatment Assignment 
The Sponsor and all subjects, monitors, and Study Center personnel will be blinded throughout 
the study.  However, if a subject has suffered a Serious Adverse Event ([SAE])as defined in 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
26 
Section 9.3.3), and/or when knowledge of the treatment assignment will impact the clinical 
management of the subject, the Investigator will have the ability to unblind the treatment 
assignment for that subject using the automated IRT system.  The Sponsor or designee will be 
informed of the unblinding of a subject within 24 hours.  An unblinded randomization schema 
will be maintained securely at the Sponsor’s designated vendor.  In addition, all suspected 
unexpected serious adverse reactions (SUSARs) will be unblinded by the Sponsor or designee 
for the purpose of regulatory reporting (see Section 9.2). 
Every reasonable attempt should be made to complete the early termination study procedures and 
observations (see Appendix A and Appendix B) prior to unblinding, as knowledge of the 
treatment arm could influence subject assessment. 
5. 
SUBJECT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 28 days of Study Day 1 or at the time point specified in the individual eligibility criterion 
listed. 
5.1. 
Inclusion Criteria 
1. Must have given written informed consent (signed and dated) and any authorizations 
required by local law and be able to comply with all study requirements 
2. Males or females aged 18–75 inclusive and weighing ≥ 50 kg at the time of informed 
consent 
3. Satisfy the following: 
a. Females:  must be non-pregnant and non-lactating, and either: 
i. 
surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy) or,  
ii. 
post-menopausal (defined as 12 months of spontaneous amenorrhea in females 
> 55 years of age or, in females ≤ 55 years, 12 months of spontaneous 
amenorrhea without an alternative medical cause and follicle stimulating 
hormone (FSH) levels in the postmenopausal range for the laboratory involved) 
b. Males:  Surgically sterile (i.e., bilateral orchidectomy) or abstinent*, if engaged in 
sexual relations with a woman of child-bearing potential (WOCBP), the subject or 
subject’s non-pregnant female partner must be using a highly effective contraceptive 
method from the time of signing the informed consent form until at least 13 weeks 
after the last dose of Study Drug (ISIS 757456 or placebo) 
* True abstinence (i.e., refraining from heterosexual intercourse throughout the 
duration of study participation) is only acceptable.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of 
abstinence for the duration of a trial and withdrawal are not acceptable methods of 
contraception 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
27 
4. BMI ≤ 35.0 kg/m2 
5. Brachial circumference ≥ 22 and ≤ 37 cm (8.7 and 14.6 inches) 
6. Subject must have been diagnosed with essential HTN for a minimum of 3 months prior 
to screening   
7. At Screening, the subject must have a plasma AGT concentration ≥ 20 µg/mL.  Up to 
1 additional repeat test may be allowed in order to qualify with consultation of the 
Sponsor Medical Monitor  
8. At Screening, the subject must have been on a stable regimen of 2 to 3 antihypertensive 
medications for at least 1 month prior to screening and will be required to maintain this 
regimen throughout the Study, using either an angiotensin-converting enzyme inhibitor 
(ACEi) or an angiotensin II receptor blocker (ARB), as well as 1 or 2 additional 
antihypertensive medications in the following categories:  
a. beta blocker 
i. 
acebutolol  
ii. 
atenolol  
iii. 
betaxolol  
iv. 
bisoprolol  
v. 
carvedilol  
vi. 
labetalol  
vii. metoprolol  
viii. nadolol  
ix. 
nebivolol 
x. 
propranolol  
xi. 
pindolol  
b. calcium channel blocker or, 
c. non-potassium sparing diuretic 
9. At Screening and pre-dose Study Day 1, the average office seated BP must be within 
> 140 – ≤ 170 mmHg SBP and > 80 mmHg DBP.  The average is to be derived from 
3 assessments taken within 10 minutes.  Up to 2 additional tests at each time point is 
allowed in order to qualify. 
10. Agree to abstain from alcoholic beverages for at least 24 hours prior to clinic visits 
11. Agree to maintain adequate hydration and adhere to a low sodium diet throughout the 
study (from the Screening visit onward) 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
28 
5.2. 
Exclusion Criteria 
1. Clinically significant abnormalities in medical history (e.g., previous acute coronary 
syndrome within 6 months of screening, major surgery within 3 months of screening, 
type I diabetes mellitus) or physical examination 
2. History of secondary HTN 
3. Subject with borderline orthostatic hypotension (assessed at Screening), when they 
assume a standing position (within 3 minutes of standing up), defined as: 
a. A decrease in SBP of ≥ 17 mmHg or 
b. A decrease in DBP of ≥ 7 mmHg  
4. The use of the following at time of screening and during the course of the study: 
a. Other medications for the treatment of HTN (e.g., clonidine, guanfacine, guanabenz, 
alpha-methyldopa, hydralazine, minoxidil, diazoxide, renin inhibitors)  
b. Medications that may cause hyperkalemia (e.g., cyclosporine or tacrolimus, 
pentamidine, trimethoprim-sulfamethoxazole, all heparins) 
c. Oral or SC anticoagulants (e.g., warfarin, rivaroxaban, apixaban, heparin, lovenox) 
d. Organic nitrate preparations (e.g., nitroglycerin, isosorbide mononitrate, isosorbide 
dinitrate, or pentaerythritol) 
e. Phosphodiesterase 5 inhibitors (e.g., sildenafil, tadalafil, vardenafil, avanafil) 
f. Potassium sparing diuretics (e.g., eplerenone, spironolactone, amiloride, triamterene)  
5. Treatment with another Study Drug, biological agent, or device within 1 month of 
screening, or 5 half-lives of study agent, whichever is longer 
6. Previous treatment with an oligonucleotide or other RNA therapeutic (including siRNA) 
within 4 months of screening if single dose received, or within 12 months of screening if 
multiple doses received  
7. Active infection with human immunodeficiency virus (HIV), hepatitis C (HCV) or 
hepatitis B (HBV) diagnosed by initial serological testing and confirmed with RNA 
testing, or prior treatment for hepatitis C.  Patients at Screening who test positive by 
serology, but negative by RNA may be allowed in consultation with the Sponsor Medical 
Monitor 
8. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated.  Subjects with a history 
of other malignancies that have been treated with curative intent and which have no 
recurrence within 5 years may also be eligible if reviewed by the Sponsor Medical 
Monitor 
9. History of bleeding diathesis, coagulopathy, immune thrombocytopenic purpura, 
thrombotic cytopenic purpura, or any qualitative or quantitative platelet defect 
10. Recent history of, or current drug or alcohol abuse 
11. Unstable/underlying cardiovascular disease defined as:  
a. Any history of congestive heart failure (NYHA class II-IV) 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
29 
b. Any history of previous stroke, transient ischemic attack, unstable or stable angina 
pectoris, or myocardial infarction prior to screening 
c. 12-lead ECG demonstrating a QT interval (corrected using Fridericia's formula 
[QTcF]) > 450 msec in males and > 470 msec in females at Screening, or a history or 
evidence of long QT syndrome 
d. Any clinically significant active atrial or ventricular arrhythmias 
e. Any history of coronary bypass or percutaneous coronary intervention 
12. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
13. Show evidence of uncorrected hypothyroidism or hyperthyroidism hormone results at 
Screening.  Subjects receiving dose-stable thyroid replacement therapy for at least 
3 months prior to screening will be allowed to participate as long as thyroid tests 
(TSH/T3/T4) show that subject is euthyroid  
14. Screening laboratory results as follows, or any other clinically significant abnormalities 
in screening laboratory values that would render a subject unsuitable for inclusion 
a. Urine protein/creatinine (P/C) ratio ≥ 0.3 mg/mg.  In the event of P/C ratio above this 
threshold eligibility may be confirmed by a quantitative total urine protein 
measurement of ˂ 300 mg/24 hr 
b. Positive test (including trace) for blood on urinalysis.  In the event of a positive test 
eligibility may be confirmed with urine microscopy showing ≤ 5 red blood cells per 
high power field 
c. Alanine aminotransferase (ALT), aspartate aminotransferase, bilirubin, alkaline 
phosphatase (ALP), serum creatinine, blood urea nitrogen (BUN) > 1.5 x upper limit 
of normal (ULN) 
d. Platelet count ˂ lower limit of normal (LLN) 
e. Serum potassium > 4.9 mmol/L 
f. Estimated glomerular filtration rate (eGFR) of < 45 mL/min/1.73 m2 using the CKD 
Epidemiology Collaboration formula 
15. Clinically significant abnormalities upon physical examination which in the 
Investigator’s opinion should exclude the subject from study participation 
16. Subject works night time shifts (e.g., 11 PM to 7 AM) 
17. Blood donation of 50 to 499 mL within 30 days of screening or of > 499 mL within 
60 days of screening 
18. Have any other conditions, which, in the opinion of the Investigator or Sponsor would 
make the subject unsuitable for inclusion, or could interfere with the subject participating 
in or completing the study 
19. Unwilling to comply with study procedures, including the Post-Treatment Period, as 
specified by this protocol, or unwillingness to cooperate fully with the Investigator 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
30 
6. 
STUDY PROCEDURES 
6.1. 
Study Schedule 
All required study procedures are outlined in Appendix A, Appendix B and Appendix C. 
The length of each subject’s participation in the study is approximately 6 months that includes a 
4-week Screening Period, 8-week Treatment Period, and a 13-week Post-Treatment Evaluation 
Period.   
All BP assessments will be conducted according to Section 6.1.1.1 (Seated BP Measuring 
Instructions at Each Visit) and Section 6.1.1.2 (Orthostatic BP Assessment). 
The safety of ISIS 757456 will be continually monitored throughout the trial by the Investigator 
and the Sponsor Medical Monitor. 
6.1.1. 
Screening 
Written informed consent for the study will be obtained prior to the performance of any 
study-related procedures including screening procedures.  A 4-week period is provided for 
completing screening assessments and determining subject eligibility for the study.  Safety labs 
may be re-tested up to 2 additional times for determination of subject eligibility after 
consultation with the Sponsor Medical Monitor.  AGT may be re-tested up to 1 additional time 
for determination of subject eligibility after consultation with the Sponsor Medical Monitor.  
During the Screening Period, subjects will undergo a medical history (including cardiovascular 
disease risk factors) and physical examination including vital signs, orthostatic hypotension 
assessment, 12-lead ECG, and have blood and urine samples taken for clinical laboratory testing.  
Subjects will be screened for HIV, HepB, and HCV. 
During the Screening Period the study site will also education subjects regarding a low sodium 
diet.  
The study site will record basic personal details about you, including your name, contact details, 
gender, height, weight, date of birth, age, ethnicity, and racial origin (to be used only for clinical 
purposes), as well as information on your medical history, and clinical data collected about your 
participation in the study. 
6.1.1.1. 
Seated Blood Pressure Measuring Instructions at Each Visit 
Subject Instructions 
• Subject should have abstained from smoking, exercise and caffeine use at least 
30 minutes prior to BP measurements 
• Subject should be wearing a loose, short-sleeved top.  If subject is wearing a 
long-sleeved or tight garment around the arm, provide a gown or remove the arm 
from the sleeve 
• Subject should be comfortably seated (e.g., with his/her back against the chair, feet 
flat on the floor) 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
31 
• Subject’s arm should be bent at the elbow and supported by a table 
Observer Instructions 
• Confirm with that the subject has abstained from smoking, exercise and caffeine use 
at least 30 minutes prior to measurement 
• Place the cuff on the subject’s upper arm at the level of the heart and centered at the 
midpoint of the humerus 
• Leave subject alone for 5 minutes in a quiet setting 
• After 5 minutes, return and take 3 readings, with 60 seconds between readings 
• Document the average of the 3 readings 
BP Results 
At the screening visit, measure the BP per instructions above with both the right and left arm.  
The arm with the highest BP (that meets inclusion/exclusion criteria) will be used at each 
subsequent visit. 
6.1.1.2. 
Orthostatic Blood Pressure Assessment 
An orthostatic BP assessment will be done at Screening.  BP and pulse rate will be assessed 2 
times (Table 2).  The subject will lie down (supine) for at least 5 minutes, then BP and pulse rate 
will be measured.  The subject will then change to a standing position and the BP and pulse rate 
measurements will be repeated after standing greater than 1 minute, but less than or equal to 3 
minutes. 
Borderline orthostatic hypotension will be defined as a confirmed (sequence must be repeated to 
confirm) decrease in SBP ≥ 17 mmHg and/or a decrease in DBP of ≥ 7 mmHg from BP at 
supine position.  During the study, orthostatic hypotension will be defined as a confirmed 
(sequence must be repeated to confirm) decrease in SBP of ≥ 20 mmHg and/or a decrease in 
DBP of ≥ 10 mmHg after standing greater than 1 minute, but less than or equal to 3 minutes.  
The diagnosis will be made specific to each visit with no comparison to Baseline (Study Day 1 
pre-dose) values. 
Table 2: 
Orthostatic Hypotension Assessment 
Position 
Time in Position 
Vital Signs Assessed 
Supine 
5 minutes 
BP and pulse rate after 5 minutes 
Standing 
> 1 to ≤ 3 minutes 
BP and pulse rate assessed within > 1 to ≤ 3 minutes of standing  
 
6.1.2. 
Treatment Period 
Eligible subjects will be administered Study Drug (ISIS 757456 or placebo) on a weekly basis 
(8 weeks) as well as an additional dose on Study Day 3 for a total of 9 doses.  Review of the 
in-clinic BP should be performed prior to administering the Study Drug. 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
32 
Safety and clinical laboratory evaluations as well as blood sampling for PK analysis will be 
performed periodically throughout the Treatment Period (Appendix A, Appendix B and 
Appendix C).  Any AEs and concomitant medications will be recorded.  All safety data including 
AEs, BP, and concomitant medications will be reviewed by the Sponsor’s Medical Monitor or 
designee on an ongoing basis throughout the trial.   
The subject is expected to maintain a low sodium diet throughout the study.  The study site will 
counsel and ask the subject at each in-clinic visit if (s)he is maintaining a low sodium diet. 
Subjects who discontinue the Treatment Period early will continue in the study following the 
post-treatment evaluations (Section 6.1.3). 
6.1.3. 
Post-Treatment Period 
After the last dose (Study Day 50) or last dose for early termination subjects, subjects will return 
to the clinic once weekly for the first 2 weeks (Study Days 57, 64) and then on Study Days 78, 
92, 120, and 141 for safety assessments.   
The study site will continue to counsel and ask the subject at each visit if (s)he is maintaining a 
low sodium diet in the Post-Treatment Period.  
All safety data including AEs, in-clinic BP, and concomitant medications will be reviewed by the 
Sponsor’s Medical Monitor or designee on an ongoing basis throughout the trial. 
6.2. 
Laboratory Assessments  
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B.  Blood chemistry should be taken be taken after fasting for at least 
8 hours.  During this time the subject can drink water and they should ensure that they consume 
sufficient water in order to not become dehydrated. 
If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to 
clumping, hemolysis or quantity not sufficient) or missing a repeat blood specimen should be 
re-drawn as soon as possible (ideally within 7 days).  Any uninterpretable platelet count result 
must be rechecked and determined not to have met a stopping rule before dosing can continue.  
Due to time constraints, a local lab draw is recommended if a repeat blood specimen is necessary 
to continue dosing at any time after Study Day 1 to Study Day 8.  If there is suspicion of EDTA 
mediated platelet clumping, a repeat platelet count should be collected in a sodium citrate tube as 
soon as possible. 
6.3. 
Restriction on the Lifestyle of Subjects 
6.3.1. 
Contraception Requirements 
All male subjects must refrain from sperm donation and either be abstinent† or use highly 
effective contraception from the time of signing the informed consent form until at least 
13 weeks after their last dose of study treatment.   


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
33 
For male subjects engaged in sexual relations with a WOCBP either the subject or their female 
partner must use highly effective contraception from the time of signing the informed consent 
until 13 weeks after the subject’s last dose of study treatment. 
For the purposes of this study, WOCBP are defined as any female who has experienced 
menarche, and who does not meet 1 of the following conditions: 
• Postmenopausal:  12 months of spontaneous amenorrhea in females > 55 years of age 
or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an 
alternative medical cause and FSH levels in the postmenopausal range for the 
laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post-hysterectomy 
For the purposes of the study, highly effective contraception is defined as follows: 
For male subjects: 
• Highly effective male contraception includes a vasectomy with negative semen 
analysis at follow-up, or the non-pregnant female partner of WOCBP uses a highly 
effective contraceptive method (defined below) 
• Male subjects with partners that are pregnant must use condoms as contraception to 
ensure that the fetus is not exposed to the Study Drug 
For female partners of male subjects, highly effective female contraception methods comprise: 
• Surgical sterilization (e.g., bilateral tubal occlusion), hormonal contraception 
associated with inhibition of ovulation (combined estrogen and progestogen 
containing, or progestogen-only), intrauterine contraception device or intrauterine 
hormone-releasing system  
†Note: Only true abstinence (i.e., refraining from heterosexual intercourse throughout the 
duration of study participation) is acceptable.  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of a trial and withdrawal are not acceptable methods of contraception. 
Note: A female condom and a male condom should not be used together as friction between the 
2 can result in either or both products failing. 
6.3.2. 
Other Requirements 
All subjects will be required to fast for at least 8 hours before visits requiring fasted blood 
sampling. 
7. 
STUDY DRUG 


34 
 
7.2. 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug (ISIS 757456 or placebo) 
labeled in accordance with specific country regulatory requirements.  
7.3. 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of Study 
Drug (ISIS 757456 or placebo) supplies provided by the Sponsor according to Sponsor 
instruction and in accordance with institutional policy.   
8. 
TREATMENT OF SUBJECTS 
8.1. 
Study Drug Administration 
Blinded vials of Study Drug will be provided by the Sponsor.  Vials are for single use only.  
Study staff blinded to the identity of the drug will administer the Study Drug.  Doses of 80 mg 
will be administered as a single SC injection at the Study Center.  Volume to be administered is 
shown in Table 4.  Please refer to the Study Drug Manual provided by the Sponsor for more 
detailed instructions for Study Drug (ISIS 757456 or placebo) preparation and administration. 
Table 4: 
Study Drug Dosing Information 
Volume to Administer 
Total Dose 
0.80 mL  
80 mg ISIS 757456 or placebo SC 
8.2. 
Other Protocol-Required Drugs 
Per eligibility criteria, subjects must be on a stable regimen of 2 to 3 antihypertensives for at 
least 1 month prior to screening evaluations and will be required to continue the stable regimen 
throughout the duration of the study (Refer to Inclusion Criteria Section 5.1).  


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
35 
8.3. 
Other Protocol-Required Treatment Procedures 
There are no other protocol-required treatment procedures.   
8.4. 
Treatment Precautions 
There are no treatment precautions required. 
8.5. 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of the renal and platelet safety monitoring rules, Baseline is defined as:  
• The last non-missing measurement prior to the first dose 
In addition to the standard monitoring of clinical safety parameters, the following guidelines are 
provided for the monitoring of selected parameters chosen based on preclinical and clinical 
observations. 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring criteria presented below must 
be confirmed by performing measurements (ideally in the same laboratory that performed the 
initial measurement) on new specimens.  All new specimen collections should take place as soon 
as possible (ideally within 3 days of the initial collection).  For stopping rules, if the initial 
laboratory result is observed during the Treatment Period, the results from the retest must be 
available prior to administering the next dose of Study Drug (ISIS 757456 or placebo). 
Re-dosing Guidance:  Subjects with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, subjects who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Sponsor Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the subject is appropriate.  If any of the stopping criteria described 
below (refer to Section 8.6.1 to Section 8.6.5) are met, the subject will be permanently 
discontinued from further treatment with Study Drug (ISIS 757456 or placebo), evaluated fully 
as outlined below and in consultation with the Sponsor Medical Monitor or appropriately 
qualified designee, and will be followed up in accordance with Section 8.8 of the protocol.   
8.5.1. 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury:  Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.   
In the event of an ALT or AST measurement that is > 3 x ULN at any time during the Study 
(Treatment or Post-Treatment Period), the initial measurement(s) should be confirmed as 
described above ideally within 48 to 72 hours.  Liver chemistry tests (ALT, AST, ALP, INR, and 
total bilirubin) should be tested ideally within 48 to 72 hours as well.  Additional, confirmatory 
measurements should also be performed if ALT or AST levels increase to 5 x ULN. 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
36 
Frequency of Repeat Measurements:  Subjects with confirmed ALT or AST levels > 3 x ULN 
should have their liver chemistry tests (ALT, AST, ALP, international normalized ratio (INR) 
and total bilirubin) retested 2 to 3 times weekly.  The frequency of retesting may decrease to 
once a week or less until ALT or AST levels become ≤ 1.2 x ULN or return to baseline levels or 
Study Drug has been discontinued and the subject is asymptomatic.  
Further Investigation into Liver Chemistry Elevations:  For subjects with confirmed ALT or AST 
levels > 3 x ULN, the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (HAV IgM, HBsAg, HCV antibody, Cytomegalovirus 
(CMV), immunoglobulin M (IgM), and Epstein-Barr Virus antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
6. Additional tests may be conducted to rule out: 
• Nonalcoholic steatohepatitis 
• Hypoxic/ischemic hepatopathy 
• Biliary tract disease 
• Hepatitis types D and E 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic 
computed tomography (CT) or magnetic resonance imaging (MRI) scans, may be performed at 
the discretion of the Investigator, in consultation with the Sponsor Medical Monitor.  Repetition 
of the above evaluations should be considered if a subject’s ALT and/or AST levels reach 
5 x ULN. 
8.5.2. 
Safety Monitoring Rules for Platelet Count Results 
Platelet count will be monitored at least every week during the Treatment Period and at the 
following visits in the Post-Treatment Period, Study Day 57/Study Week 9, Study Day 64/ Study 
Week 10, Study Day 78/Study Week 12, Study Day 92/Study Week 14, Study Day 120/Study 
Week 18, and Study Day 141/Study Week 21.  The Investigator should review all platelet count 
results within 48 hours of receipt.  In case of platelet reduction to below 75,000/mm3, the platelet 
monitoring rule defined in Stopping rules (Section 8.6.3) should be followed and additional 
laboratory investigations may be conducted Table 5. 
Please refer also to Table 6. 
Any uninterpretable platelet count result must be rechecked and determined not to have met a 
stopping rule before dosing can continue. 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
37 
Table 5: 
Additional Labs to be Performed in the Event of a Platelet Count 
< 75,000/mm3 
To Be Performed at Local Lab 
Peripheral smear (should be performed locally, fixed and sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To be performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes and mean platelet volume (MPV) 
Serum B12 and folate 
Fibrinogen 
von Willebrand factor 
Total globulins, total IgA, IgG and IgM 
Complement:  total C3, total C4, Bb, C5a 
To Be Performed at Local Lab 
hsCRP 
Serology for: 
HBV, HCV, HIV (if not done for screening) 
Rubella 
CMV 
EBV 
Parvo B19 
Helicobacter pylori (IgG serum test) 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
Note: 
The above labs may change as additional data is assessed, and sites will be updated regarding any changes. 
 
8.5.3. 
Safety Monitoring for Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for major bleeding (MB) or 
clinically relevant, non-major bleeding events (which are defined in Section 8.6.3), for example 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
38 
excess bruising, petechiae, gingival bleeding on brushing teeth.  If a minor bleeding event 
occurs, additional testing of coagulation parameters (aPTT, PT, INR) and platelet count should 
be performed. 
8.5.4. 
Safety Monitoring for Potassium 
In the event of a potassium measurement ≥ 5.5 mmol/L at any time during the study (Treatment 
or Post-Treatment Period), the initial measurement(s) should be confirmed.  If the initial 
potassium measurement is confirmed to be ≥ 5.5 mmol/L study drug is to be held.  An ECG 
evaluation should be performed if the value is confirmed and signs of hyperkalemia should be 
assessed (delayed conduction, heart block, arrhythmias).  If new signs consistent with 
hyperkalemia are present, proceed to stopping rules.  The subject will start oral hydration with 
1-liter fluids not containing potassium to induce diuresis.  Measure potassium frequently until 
documented to be < 5.5 mmol/L.  Dosing with study drug may continue after a confirmed 
potassium measurement < 5.5 mmol/L with Investigator and Sponsor Medical Monitor or 
designee consultation.  
8.5.5. 
Safety Monitoring for Blood Pressure 
Should a subject experience a BP measurement of ≤ 90 mmHg (systolic) a second measurement 
must be done within a 30-minute period.  If the subject is symptomatic (i.e., dizziness, 
light-headedness, clammy skin, fatigue, blurry vision), at any point in the study, the subject 
should contact the Study Center immediately.  If the confirmed SBP is ≤ 90 mmHg and/or the 
subject remains symptomatic, dosing of a subject with Study Drug will be paused.  Oral and/or 
IV hydration should be instituted.  The suitability of the subject for continued dosing will be 
determined by the Investigator in consultation with the Sponsor Medical Monitor after the SBP 
has normalized and/or subject is no longer symptomatic and will be based on the reversibility of 
initiating factors (e.g., decreased oral intake, cold/flu, other illness).  If the subject remains 
symptomatic or if the SBP does not normalize Study Drug should be permanently discontinued 
(refer to Stopping Rules for BP Section 8.6.5).  
8.6. 
Stopping Rules 
For the purposes of the renal and platelet stopping rules, Baseline is defined as:  
• The last non-missing measurement prior to the first dose 
8.6.1. 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a subject 
with Study Drug (ISIS 757456 or placebo) will be stopped permanently; values that are not 
confirmed due failure to retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 x ULN, which is confirmed 
2. ALT or AST > 5 x ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 x ULN, which is confirmed and total bilirubin > 2 x ULN or INR > 1.5 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
39 
4. ALT or AST > 3 x ULN which is confirmed, and the new appearance (i.e., onset 
coincides with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or concomitant eosinophilia (> ULN) 
8.6.2. 
Stopping Rules for Renal Function Test Results  
In the event of laboratory results for either of the following criteria, dosing of a subject with 
Study Drug (ISIS 757456 or placebo) will be stopped permanently: 
1. Confirmed serum creatinine increase that is both ≥ 0.3 mg/dL (26.5 µmol/L) and 
≥ 40% above Baseline creatinine values (refer to Section 8.6) 
2. Confirmed 30% decline in eGFR from Baseline eGFR values 
3. Confirmed proteinuria (UPCR ≥ 0.5 mg/mg)  
The follow-up schedule for any events meeting either of these stopping criteria will be 
determined by the Investigator in consultation with the Sponsor Medical Monitor or designee.  
At the discretion of the Investigator, a decision to hold or permanently stop study drug may be 
made based on lesser changes in these parameters observed in isolation or in association with 
other renal-related abnormalities. 
8.6.3. 
Stopping Rule for Platelet Count Results 
In the event of any platelet count less than 75,000/mm3, monitoring frequency and dosing should 
be adjusted as recommended in Table 6 below. 
Table 6: 
Actions in Subjects with Low Platelet Count 
Confirmed 
Platelet Count 
Dosing 
AESI? 
Monitoring  
≥ 75,000/mm3 
Yes 
No 
• 
Monitor weekly 
< 75,000/mm3 to 
50,000/mm3, in the 
absence of MB or 
clinically relevant 
non-major bleeding 
(CRNMB) (defined 
below) 
Pause 
No 
• 
Monitor at least twice per week until 3 successive 
values above 75,000/mm3.  Then monitor weekly 
until values normalize.   
• 
The suitability of the subject for continued dosing 
will be determined by the Investigator in 
consultation with the Sponsor Medical Monitor and 
will be based on factors such as the original rate of 
decline in the subject’s platelet count, whether any 
bleeding events were experienced, and the speed of 
recovery of platelet count after interruption of 
dosing.  The subject must have 3 successive values 
above 100,000/mm3 before continued dosing is 
considered. 
• 
Perform additional labs in Table 5   


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
40 
Table 6: 
Actions in Subjects with Low Platelet Count (Continued) 
Confirmed 
Platelet Count 
Dosing 
AESI? 
Monitoring  
< 50,000/mm3 to 
25,000/mm3 
Permanently 
Discontinue 
Yes, if only 
accompanied by a 
MB event or 
CRNMB event, 
subject to 15-day 
expedited reporting 
• 
Monitor at least twice per week until 3 successive 
values above 75,000/mm3.  Then monitor weekly 
until values normalize 
• 
A hematologist consultation may be considered at 
the discretion of the Investigator and Sponsor 
Medical Monitor 
• 
Perform additional labs in Table 5 
< 25,000/mm3 
Permanently 
Discontinue 
Yes, subject to 
15-day expedited 
reporting 
• 
Monitor daily until 2 successive values above 
25,000/mm3.  Then monitor twice per week until 
3 successive values above 75,000/mm3.  Then 
monitor weekly until values normalize.   
• 
Administration of steroids* and a hematologist 
consultation is recommended  
• 
Perform additional labs in Table 5 
< 10,000/mm3 
Permanently 
Discontinue 
Yes, subject to 
15-day expedited 
reporting 
• 
Monitor daily until 2 successive values above 
25,000/mm3.  Then monitor twice per week until 
3 successive values above 75,000/mm3.  Then 
monitor weekly until values normalize.   
• 
Hospitalize subject and expedite a hematologist 
consultation.  
• 
Administer platelet transfusions and steroids*, if 
deemed necessary.  
• 
Perform additional labs in Table 5  
* Treatment guidelines for immune thrombocytopenia (Provan et al. 2010) recommend Dexamethasone 40 mg daily 
for 4 days every 2–4 weeks for 1–4 cycles; Prednis(ol)one 0.5–2 mg/kg/d for 2–4 weeks then taper; or 
methylprednisolone 30 mg/kg/day for 7 days.  (Note:  Subject may require continuation with oral steroids after 
methylprednisolone). 
 
Definition of Major Bleeding Events (Schulman and Kearon 2005) 
1. Fatal bleeding, and/or 
2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarterial or pericardial, or intramuscular with 
compartment syndrome 
3. Clinically overt bleeding leading to transfusion of ≥ 2 units of packed red blood cells or 
whole blood or a fall in hemoglobin of 2.0 mg/dL (1.24 mmol/L) or more within 24 hours 
Definition of Clinically Relevant Non-Major Bleeding Events 
Clinically-relevant non-major bleeding is defined as overt bleeding not meeting the criteria for 
MB but that resulted, for example, in medical examination, intervention, or had clinical 
consequences for a subject. 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
41 
Definition of Minor Bleeding Events 
Minor bleeding events are those that do not fulfill the criteria for MB or CRNMB (defined 
above), for example excess bruising, petechiae, gingival bleeding on brushing teeth. 
8.6.4. 
Stopping Rule for Potassium 
In the event of confirmed potassium of ≥ 6.0 mmol/L or ≥ 5.5 mmol/L with new ECG changes 
consistent with hyperkalemia at any time during the study, dosing of a subject with Study Drug 
will be stopped permanently.  The subject should stop any medications (e.g., ACE/ARB) or high 
K+ diet/supplements affecting potassium levels.  Measure potassium frequently until 
documented to be < 5.5 mmol/L.  If there are ECG changes consistent with hyperkalemia or 
muscle weakness the subject should be admitted to the hospital.  The Investigator may consider 
obtaining a nephrology consultation with consideration for dialysis to treat hyperkalemia.  
Additional consultation of the Investigator with the Sponsor Medical Monitor may be considered 
to individualize treatment plan. 
8.6.5. 
Stopping Rules for Blood Pressure 
1. In the event of a confirmed BP measurement ≤ 90 mmHg (systolic) and/or the subject 
remains symptomatic (i.e., dizziness, light-headedness, clammy skin, fatigue, blurry 
vision) after instituting oral or IV hydration, Study Drug should be permanently 
discontinued, and the subject should be referred to urgent care or the emergency room. 
Any other antihypertensives or other medications that could affect BP should be stopped, 
if feasible.  The use of IV angiotensin II or vasopressors should be considered in subjects 
that remain symptomatic and are hemodynamically unstable.  The subject will continue 
to be followed per protocol in the study.  Follow-up for subjects that screen fail due to BP 
inclusion criteria (see Section 5.1) will not be necessary. 
2. Should a subject experience a BP measurement > 180 mmHg (systolic) or > 110 mmHg 
(diastolic) a second measurement must be done within a 30-minute period.  If the subject 
then experiences a second BP measurement > 180 mmHg (systolic) or > 110 mmHg 
(diastolic), they will then be withdrawn from further blinded, randomized treatment.  
Study Drug is to be permanently discontinued unless the hypertensive event is transient 
and dependent on reversable initiating factors (e.g., stressful event).  The suitability of the 
subject for continued dosing will be determined by the Investigator in consultation with 
the Sponsor Medical Monitor after the subject's BP has normalized.  Additional 
antihypertensive medication(s) may be added per Investigator and Sponsor Medical 
Monitor judgement if the subject has discontinued Study Drug.  If the subject has not 
discontinued Study Drug, changes to the stable regimen of antihypertensives may result 
in withdrawal of the subject from the Treatment Period.  The subject will continue to be 
followed per protocol in the study.  Follow-up for subjects that screen fail due to BP 
inclusion criteria (see Section 5.1 ) will not be necessary. 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
42 
Table 7: 
Blood Pressure Monitoring and Stopping Rules Reference Table 
Confirmed Blood 
Pressure 
Dosing 
Additional Actions 
SBP ≤ 90 mmHg* and/or 
subject is symptomatic 
(e.g., decreased oral intake, 
cold/flu, other illness).   
Pause 
Institute oral and/or IV hydration.  If hypotension or symptoms 
of hypotension persist proceed to stopping rules below 
The suitability of the subject for continued dosing will be 
determined by the Investigator in consultation with the 
Sponsor Medical Monitor after the SBP has normalized and/or 
subject is no longer symptomatic and will be based on the 
reversibility of initiating factors (e.g., decreased oral intake, 
cold/flu, other illness)  
SBP ≤ 90 mmHg* and/or the 
subject remains symptomatic 
after instituting oral and/or IV 
hydration and there is no 
other reason contributing to 
hypotensive event 
Permanently 
Discontinue 
The subject should be referred to urgent care or the emergency 
room 
Any other antihypertensives or other medications that could 
affect BP should be stopped, if feasible 
The use of IV angiotensin II or vasopressors should be 
considered in subjects that remain symptomatic and are 
hemodynamically unstable 
The subject will continue to be followed per protocol in the 
study.  Follow-up for subjects that screen fail due to BP 
inclusion criteria (see Section 5.1) will not be necessary 
SBP > 180 mmHg* or 
DBP > 110 mmHg* 
Pause if BP 
elevation is thought 
to be transient, 
reversible and 
related to external 
initiating factors 
(e.g., stressful event) 
Permanently 
discontinue if no 
other reason 
contributing to 
hypertensive event  
The suitability of the subject for continued dosing will be 
determined by the Investigator in consultation with the 
Sponsor Medical Monitor after the subject's BP has normalized 
Additional antihypertensive medication(s) may be added per 
Investigator and Sponsor Medical Monitor judgement if the 
subject has discontinued Study Drug.  If the subject has not 
discontinued Study Drug, changes to the stable regimen of 
antihypertensives may result in withdrawal of the subject from 
the Treatment Period 
The subject will continue to be followed per protocol in the 
study.  Follow-up for subjects that screen fail due to BP 
inclusion criteria (see Section 5.1) will not be necessary 
* BP measurements must be confirmed by a second measurement within 30 minutes  
 
8.7. 
Adjustment of Dose and/or Treatment Schedule 
If the safety profile warrants, and subjects have not met a stopping rule, Study Drug may be 
adjusted downward in consultation with the Sponsor Medical Monitor or designee. 
8.8. 
Discontinuation of Study Drug 
A subject must permanently discontinue study treatment for any of the following: 
• The subject withdraws consent 
• The subject experiences an AE that necessitates permanent discontinuation of Study 
Drug  


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
43 
• The subject develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6.1 to Section 8.6.5  
• The subject experiences an AE that necessitates unblinding of the Investigator 
The reason for discontinuation of Study Drug must be recorded in the electronic Case Report 
Form (eCRF) and source documentation. 
For subjects withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination of study procedures and observations at the time of withdrawal 
(see Appendix A) and ideally within 2 weeks from the last dose of Study Drug. 
8.9. 
Withdrawal of Subjects from the Study Procedures 
Subjects must be withdrawn from study procedures for any of the following: 
• Withdrawal of consent 
• The subject is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of subjects from study procedures might include: 
• At the discretion of the Investigator for medical reasons 
• At the discretion of the Investigator or Sponsor for noncompliance 
• Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal.  All information, including the reason for withdrawal from study, must be 
recorded in the eCRF. 
Any subject who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These subjects should be 
encouraged to complete the early termination study procedures and observations at the time of 
withdrawal (Appendix A). 
For subjects withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination of study procedures and observations at the time of withdrawal 
(see Appendix A) and ideally within 2 weeks from the last dose of Study Drug. 
8.10. 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the subject’s 
eCRF.  AEs related to administration of these therapies or procedures must also be documented 
on the appropriate eCRF. 
8.10.1. 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-
counter medications, herbal medications and vitamin supplements) administered between 
Screening and the Post-Treatment Evaluation Period. 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
44 
Allowed Concomitant Therapy 
Any other medications deemed necessary by the Investigator are allowed except those listed in 
the disallowed concomitant therapy. 
Disallowed Concomitant Therapy 
The following are disallowed concomitant therapies: 
• Other medications for the treatment of HTN (e.g., clonidine, guanfacine, guanabenz, 
alpha-methyldopa, hydralazine, minoxidil, diazoxide, renin inhibitors) 
• Medications that may cause hyperkalemia (e.g., cyclosporine or tacrolimus, 
pentamidine, trimethoprim-sulfamethoxazole, all heparins) 
• Oral or SC anticoagulants (e.g., warfarin, rivaroxaban, apixaban, lovenox, heparin) 
• Organic nitrate preparations (e.g., nitroglycerin, isosorbide mononitrate, isosorbide 
dinitrate, or pentaerythritol) 
• Sildenafil, tadalafil, vardenafil  
• Potassium sparing diuretics (e.g., eplerenone, spironolactone, amiloride, triamterene) 
Changes to the stable regimen of antihypertensives allowed at Screening may result in 
withdrawal of the subject from the Treatment Period. 
8.10.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
Screening and the Post-Treatment Evaluation Period. 
8.11. 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded in the eCRF by Study Center 
staff.   
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING  
9.1. 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor or designee in 
accordance with the applicable Ionis and/or designee SOPs throughout the conduct of the clinical 
trial. 
9.2. 
Regulatory Requirements 
The Sponsor is responsible for regulatory submissions and reporting to the Investigators of SAEs 
including SUSARs per the International Conference on Harmonization (ICH) guidelines E2A 
and ICH Good Clinical Practice (GCP).  Country-specific regulatory requirements will be 
followed in accordance with local country regulations and guidelines. 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
45 
IRBs will be notified of any SAE according to applicable regulations.  
The Sponsor will evaluate the available information for all reported SAEs and decide if there is a 
reasonable possibility that the Study Drug (ISIS 757456 or placebo) caused the AE and, 
therefore, meets the definition of a SUSAR. 
Appropriate personnel at the Sponsor will unblind SUSARs for the purpose of regulatory 
reporting.  The Sponsor will submit SUSARs to Regulatory Agencies in blinded or unblinded 
fashion according to local law.  The Sponsor will submit SUSARs to Investigators in a blinded 
fashion. 
For the purpose of regulatory reporting of SUSARs, there are no “expected” AEs in this study 
population.  For Study Drug (ISIS 757456 or placebo) “expected” AEs, refer to the Investigator’s 
Brochure. 
9.3. 
Definitions 
9.3.1. 
Adverse Event 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of medicinal 
(investigational) product, whether or not the AE is considered related to the medicinal 
(investigational) product. 
An AE can therefore be any of the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition) 
• Recurrence of an intermittent medical condition (e.g., headache) not present at 
Baseline 
• Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from Study Drug 
AEs that are related to a protocol-mandated intervention, including those that occur prior to 
assignment of study treatment (e.g., screening invasive procedures such as biopsies). 
9.3.2. 
Adverse Drug Reaction and Suspected Unexpected Adverse Drug Reaction 
Adverse Drug Reaction (ADR) 
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not have been established, ADR is defined as follows: 
All noxious and unintended responses to a medicinal product related to any dose should 
be considered ADRs. 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
46 
The phrase "responses to a medicinal product" means that a causal relationship between the 
medicinal product and the AE has been determined by the Sponsor as at least a reasonable 
possibility, i.e., the relationship cannot be ruled out. 
Suspected Unexpected Adverse Drug Reaction  
A suspected unexpected ADR is any ADR, the nature or severity of which is not consistent with 
the applicable product information, e.g., Investigator's Brochure for an unapproved medicinal 
(investigational) product. 
A suspected adverse reaction implies a lesser degree of certainty about causality than an adverse 
reaction. 
9.3.3. 
Serious Adverse Event  
A SAE is any AE that in the view of either the Investigator or Sponsor, meets any of the 
following criteria: 
• Results in death 
• Is life threatening:  that is, poses an immediate risk of death at the time of the event 
• An AE or suspected AE is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the subject at immediate risk of death.  
It does not include an AE or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an admission of greater than 24 hours to a medical 
facility and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
• Results in a congenital anomaly or birth defect in the offspring of the subject 
(whether the subject is male or female) 
• Important medical events that may not result in death, are not life-threatening, or do 
not require hospitalization may also be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of an AE 
(e.g., rated as mild, moderate, or severe, or according to National Cancer Institute Common 
Terminology Criteria for AEs [NCI CTCAE]); the event itself may be of relatively minor 
medical significance (such as severe headache without any further findings). 
Severity and seriousness need to be independently assessed for each AE recorded on the eCRF. 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
47 
9.3.4. 
AE of Special Interest (AESI)  
For the purpose of this study, severe reductions in platelet count < 50,000/mm3 accompanied by 
a MB event or CRNMB event, or platelet count of < 25,000/mm3 independent of a MB or 
CRNMB event are considered as AEs of special interest and should be subject to 15-day 
expedited reporting by the Sponsor to the regulatory agencies. 
9.4. 
Monitoring and Recording AEs 
Any pre-existing conditions or signs and/or symptoms present in a subject prior to the start of the 
study (i.e., before informed consent) should be recorded as Medical History and not recorded as 
AEs unless the pre-existing condition worsened.  The Investigator should always group signs and 
symptoms into a single term that constitutes a single unifying diagnosis if possible.  Before a 
diagnosis is confirmed, all symptoms should be reported as separate AEs. 
9.4.1. 
Serious AEs 
In the interest of subject safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to Study Drug) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the subject signs the informed consent form and stop at the end of the subject’s Post-
Treatment Period which is defined as Study Day 141/ Study Week 21.  When the Investigator is 
reporting by telephone, it is important to speak to someone in person vs. leaving a message.  
SAEs should be reported using a paper SAE submission form.  An Initial Serious AE Form 
should be completed, and a copy should be faxed or emailed to the Sponsor or designee.  The 
SAE reporting instruction, including the fax number and email address can be found in the Study 
Reference Manual for the study. 
Detailed information should be actively sought and included on Follow-Up Serious AE Forms as 
soon as additional information becomes available.  All SAEs will be followed until resolution.  
SAEs that remain ongoing past the subject’s last protocol-specified Follow-Up visit will be 
evaluated by the Investigator and Sponsor.  If the Investigator and Sponsor agree the subject’s 
condition is unlikely to resolve, the Investigator and Sponsor will determine the follow-up 
requirement. 
9.4.2. 
Non-Serious AEs 
The recording of non-serious AEs will begin after the subject signs the informed consent form 
and will stop at the end of the subject’s Post-Treatment Period, which is defined as Study Day 
141/ Study Week 21.  The Investigator will monitor each subject closely and record all observed 
or volunteered AEs on the AE Case Report Form. 
9.4.3. 
Evaluation of AEs (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the AE Case Report Form: 
9.4.3.1. 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (ISIS 757456 or placebo) is characterized by 1 of the 
following: 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
48 
• Related:  There is clear evidence that the event is related to the use of Study Drug, 
e.g., confirmation by positive re-challenge test 
• Possible:  The event cannot be explained by the subject’s medical condition, 
concomitant therapy, or other causes, and there is a plausible temporal relationship 
between the event and Study Drug (ISIS 757456 or placebo) administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely 
(e.g., concomitant medications or ongoing medical conditions) or the temporal 
relationship to Study Drug (ISIS 757456 or placebo) administration and/or exposure 
suggests that a causal relationship is unlikely (for reporting purposes, 
Unlikely/Remote will be grouped together with Not Related) 
• Not Related:  The event can be readily explained by the subject’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator 
believes no relationship exists between the event and Study Drug 
9.4.3.2. 
Severity 
The severity of AEs and SAEs relating to laboratory tests and AEs at the injection site will be 
graded based on criteria from the Common Terminology Criteria for AEs (CTCAE) Version 5.0, 
November 2017 (refer to Appendix D).  Any AE not listed in Appendix D will be graded as 
follows: 
• Mild:  The event is easily tolerated by the subject and does not affect the subject’s 
usual daily activities 
• Moderate:  The event causes the subject more discomfort and interrupts the subject’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
subject’s usual daily activities 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3. 
Action Taken with Study Drug 
Action taken with Study Drug (ISIS 757456 or placebo) due to the event is characterized by 1 of 
the following. 
• None:  No changes were made to Study Drug (ISIS 757456 or placebo) 
administration and dose 
• Not Applicable:  SAE/AE was reported during the Screening Period prior to Study 
Drug administration or during the Post-Treatment Period 
• Permanently Discontinued:  Study Drug was discontinued and not restarted 
• Temporarily Interrupted, Restarted – Same Dose:  Dosing and/or dosing 
frequency was temporarily interrupted/changed or delayed due to the AE and 
restarted at the same dose 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
49 
• Reduced Dose:  Dosing was reduced, temporarily interrupted or delayed due to the 
AE and restarted at the next lower dose or reduced dosing frequency  
9.4.3.4. 
Treatment Given for AE 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the AE 
Case Report Form.  Treatment should also be recorded on the concomitant treatment or ancillary 
procedures eCRF, as appropriate. 
9.4.3.5. 
Outcome of the AE 
If the event is a non-serious AE, then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Subject terminates from the trial and the AE continues 
• Recovered:  Subject recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is an SAE, then the event’s outcome is characterized by 1 of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Subject has not fully recovered but the event no 
longer meets serious criteria and should be captured as an AE on the non-serious AE 
eCRF (the SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Subject recovered completely from the SAE (the date of recovery should 
be entered as the SAE resolution date) 
• Recovered with Sequelae:  The signs/symptoms of the reported SAE have improved 
but not completely resolved, and a new baseline for the subject is established since 
full recovery is not expected 
• Fatal:  Subject died (the date of death should be entered as the SAE resolution date) 
• Unknown:  The outcome of the reported SAE is not available, e.g., subject is lost to 
follow-up 
9.4.3.6. 
Follow-up of Adverse Event 
Investigator Follow-Up 
During the Study Period, the Investigator should follow each AE until the event has resolved to 
baseline grade or better, the event is assessed as stable, the subject is lost to follow-up, or the 
subject withdraws consent.  Every effort should be made to follow all SAEs considered to be 
related to Study Drug or related to study procedures until a final outcome can be reported. 
Resolution of AE (with dates) should be documented on the AE eCRF and in the subject’s 
medical record to facilitate source data verification.  


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
50 
Investigator should follow-up or support the Sponsor’s effort to follow up with all pregnancies 
reported during the study from either the study subject or the female partner of male study 
subject until pregnancy outcome is available.  
Sponsor Follow-Up 
For SAEs, AESI and pregnancy cases in subjects who has completed or terminated study, the 
Sponsor or a designee should follow-up by telephone, fax, email, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge summaries, 
consultant reports, autopsy reports) in order to perform an independent medical assessment of the 
reported case. 
9.5. 
Procedures for Handling Special Situations 
9.5.1. 
Abnormalities of Laboratory Tests 
Clinically significant abnormal laboratory test results may, in the opinion of the Investigator, 
constitute or be associated with an AE.  Examples of these include abnormal laboratory results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  Whenever possible, the 
underlying diagnosis should be listed as AEs rather than as abnormal laboratory values.  
Clinically significant abnormalities will be monitored by the Investigator until the parameter 
returns to its baseline value or until agreement is reached between the Investigator and Sponsor 
Medical Monitor.  Laboratory abnormalities deemed not clinically significant by the Investigator 
should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs by the 
Investigator should be deemed CS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the subject is hospitalized; the Study Center must document all of the following: 
• The prescheduled or elective procedure or routinely scheduled treatment was 
scheduled (or was on a waiting list to be scheduled) prior to obtaining the subject’s 
consent to participate in the study 
• The condition that required the prescheduled or elective procedure or routinely 
scheduled treatment was present before and did not worsen or progress in the opinion 
of the Investigator between the subject’s consent to participate in the study and the 
timing of the procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
51 
9.5.3. 
Dosing Errors 
Study Drug (ISIS 757456 or placebo) errors (including overdose, underdose, and administration 
error) should be documented as Protocol Deviations.  A brief description should be provided in 
the deviation, including whether the subject was symptomatic (list symptoms) or asymptomatic, 
and the event accidental or intentional. 
Dosing details should be captured on the Dosing Case Report Form.  If the subject takes a dose 
of Study Drug (ISIS 757456 or placebo) that exceeds protocol specifications and the subject is 
symptomatic, then the symptom(s) should be documented as an AE and be reported per 
Section 9.4. 
An overdose is the accidental or intentional use of a drug in an amount higher than the dose 
being studied.  An overdose or incorrect administration of study treatment is not itself an AE, but 
it may result in an AE.  All AEs associated with an overdose or incorrect administration of Study 
Drug should be recorded on the AE eCRF.  If the associated AE fulfills seriousness criteria, the 
event should be reported to the Sponsor immediately (i.e., no more than 24 hours after learning 
of the event). 
Should an overdose occur, the Investigator or designee should refer to the Guidance to 
Investigator’s section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4. 
Contraception and Pregnancy 
Male subjects must continue to use appropriate contraception with their partners, or refrain from 
sexual activity, as described in Section 6.3.1. 
If a male subject makes or believes that he has made someone pregnant during the study, then the 
Study Center staff must be informed immediately.  An Initial Pregnancy Form should be 
submitted to the Sponsor or designee within 24 hours of first learning of the occurrence of 
pregnancy.  Follow-up information including delivery or termination is reported by designating 
as ‘Follow-up’ on the Pregnancy Forms and reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the subject’s 
responsibility.   
Male subjects:  The progress of the pregnancy of a male subject’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
follow-up with the mother and may request access to the mother and infant’s medical 
records to obtain additional information relevant to the pregnancy progress and outcome.  A 
longer follow-up may be required if a newborn child experiences a medical condition.  
Follow-up will be performed to the extent permitted by the applicable regulations and privacy 
considerations; e.g., partner ICF may be required. 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
52 
10. 
STATISTICAL CONSIDERATIONS 
10.1. 
Stratification, Subsets, and Covariates 
Subjects will be stratified based on either low Screening ACE/ARB dose or high Screening 
ACE/ARB dose.  The total dose of the ACE or ARB taken per day is to be calculated based off 
their stable regimen of antihypertensive medications at Screening.  Please refer to Appendix E 
for stratification criteria.  
10.3. 
Populations 
Full Analysis Set (FAS):  All randomized subjects who have received at least 1 injection of 
Study Drug (ISIS 757456 or placebo) and who have at least 1 post-Baseline efficacy or 
exploratory measurements. 
Per Protocol Set:  All FAS subjects who received at least 7 of the 9 doses of Study Drug, did not 
alter Screening antihypertensive medications during the Treatment Period and prior to 
Study Day 57, and have no significant protocol deviations that would be expected to affect 
efficacy or exploratory assessments. 
Safety Set:  All subjects who are randomized and receive at least 1 dose of Study Drug. 
PK Set:  All subjects who are randomized and receive at least 1 dose of Study Drug and have at 
least 1 evaluable PK sample. 
10.4. 
Definition of Baseline 
The baseline for plasma AGT will be define as the average of all values prior to the first dose of 
Study Drug.  The baseline for all other assessments will be defined as the last non-missing 
measurement prior to the first dose.   
10.5. 
Interim Analysis  
An interim analysis may be conducted after at least 50% of the subjects have been enrolled. 
10.6. 
Planned Methods of Analysis 
All case report form (CRF) data, lab data transfers, and any outcomes derived from the data may 
be provided in the subject data listings.  Subject data listings will be presented for all subjects 
randomized in the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, standard error, interquartile range (25th percentile, 75th percentile), and range 
(minimum, maximum) for continuous variables, and counts and percentages for categorical 
variables will be used to summarize most data.   


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
53 
10.6.1. 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using descriptive statistics by 
treatment group.  Subject randomization will be summarized by treatment group.  The subject 
disposition will be summarized.  All subjects enrolled will be included in a summary of subject 
disposition. 
10.6.2. 
Safety Analysis 
The safety analysis will be conducted on the Safety Population. 
Treatment duration and amount of Study Drug (ISIS 757456 or placebo) received will be 
summarized by treatment group.  Subject incidence rates of all AEs will be tabulated by Medical 
Dictionary for Regulatory Activities (MedDRA™) system organ class, and by MedDRA™ term.  
Narratives of treatment emergent deaths, serious and AEs of special interest, including early 
withdrawals due to AEs, will also be provided. 
All treatment emergent AEs, all treatment emergent AEs potentially related to Study Drug, all 
treatment emergent serious AEs, and all treatment emergent serious AEs potentially related to 
Study Drug (ISIS 757456 or placebo) will be summarized. 
Laboratory tests to ensure subject safety including chemistry panel, complete blood count with 
differential, coagulation panel, complement etc., will be summarized by study visits for each 
treatment group.  These safety variables will also be presented as change and percent change 
from Baseline over time after Study Drug (ISIS 757456 or placebo) administration, as 
appropriate.  
Vital sign and ECG measures will be tabulated by treatment group.  In addition, the number of 
subjects who experience abnormalities in clinical laboratory evaluations will be summarized by 
treatment group. 
10.6.3. 
Efficacy Analysis 
The primary analysis will be the comparison of percent change from Baseline to Study Day 57 
(Study Week 9) in plasma AGT between ISIS 757456 80 mg group and placebo group in the 
Per Protocol Set.  The data will be analyzed using analysis of variance (ANOVA) with treatment 
and randomization stratification factor (low ACE/ARB dose regimen vs. high ACE/ARB dose 
regimen) as independent variables.  In the case data departs substantially from normality, the 
nonparametric van Elteren test will be employed instead.   
The secondary efficacy analyses will be performed in a similar way to the primary analysis, 
which include: 
• Comparison of change and percent change from Baseline to each schedule 
post-Baseline visit in AGT between ISIS 757456 80 mg group and placebo group in 
Per Protocol Set (PPS) and FAS 
• Comparison of change from Baseline to each schedule post-Baseline visit in in-clinic 
SBP and DBP between ISIS 757456 80 mg group and placebo group in PPS and FAS 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
54 
10.6.4. 
Pharmacokinetic Analysis 
Plasma ISIS 757456 concentrations at trough during the Treatment Period and concentrations 
observed during the Post-Treatment Evaluation Period will be listed by dose, study day, time 
point, and summarized using descriptive statistics. 
Other plasma PK parameters, as appropriate, may be determined or calculated at the discretion of 
the PK scientist. 
Metabolite identification and profiling may be conducted on select plasma samples. 
Additional details regarding the PK analysis will be described in the Statistical Analysis Plan 
(SAP). 
Analysis of potential exposure-response relationship between plasma AGT and ISIS 757456 
exposure (such as Ctrough) will be conducted.  Relationships between other relevant biomarkers 
and clinical endpoints with PK measures may also be explored, if deemed appropriate.   
Population PK and PK/PD analysis may be performed using PK data from this Study, and/or 
combined with other ISIS 757456 clinical PK/PD data later in the development timeline. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1. 
Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential 
patient population, based on an English version provided by the Sponsor. 
Before a subject’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the subject after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific screening 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
55 
procedures or any Study Drug (ISIS 757456 or placebo) are administered.  The subject must be 
given sufficient time to consider whether to participate in the study.   
The acquisition of informed consent and the subject’s agreement or refusal to notify his/her 
primary care physician should be documented in the subject’s medical records and the informed 
consent form should be signed and personally dated by the subject and by the person who 
conducted the informed consent discussion (not necessarily an Investigator).  The original signed 
informed consent form should be retained in the Study Master File and in any other locations 
required by institutional policy, and a copy of the signed consent form should be provided to the 
subject. 
11.2. 
Ethical Conduct of the Study 
All applicable regulations and guidelines of current GCP as well as the demands of national drug 
and data protection laws and other applicable regulatory requirements must be followed.  
11.3. 
Institutional Review Board 
A copy of the protocol, proposed informed consent form, other written subject information, and 
any proposed advertising material must be submitted to the IRB for written approval.  A copy of 
the written approval of the protocol and informed consent form must be received by the Sponsor 
before recruitment of subjects into the study and shipment of Study Drug.  A copy of the written 
approval of any other items/materials that must be approved by the Study Center or IRB must 
also be received by the Sponsor before recruitment of subjects into the study and shipment of 
Study Drug.  The Investigator’s Brochure must be submitted to the IRB for acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IRB, for all 
subsequent protocol amendments and changes to the informed consent document.  The 
Investigator should notify the IRB of deviations from the protocol in accordance with ICH GCP.  
The Investigator should also notify the IRB of SAEs occurring at the Study Center and other AE 
reports received from the Sponsor, in accordance with local procedures. 
The Investigator will be responsible for obtaining annual IRB approval/renewal throughout the 
duration of the study.  Copies of the Investigator’s reports, all IRB submissions and the IRB 
continuance of approval must be sent to the Sponsor. 
11.4. 
Subject Confidentiality 
The Investigator must ensure that the subject’s confidentiality is maintained.  On the case report 
forms or other documents submitted to the Sponsor, subjects should be identified by initials (if 
permitted by local law) and a subject identification number only.  Documents that are not for 
submission to the Sponsor (e.g., signed informed consent forms) should be kept in strict 
confidence by the Investigator. 
In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the IRB direct access to review the subject’s original medical records for 
verification of study-related procedures and data.  Direct access includes examining, analyzing, 
verifying, and reproducing any records and reports that are important to the evaluation of the 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
56 
study.  The Investigator is obligated to inform and obtain the consent of the subject to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the subject. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1. 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor.  Agreement 
from the Investigator must be obtained for all protocol amendments and amendments to the 
informed consent document.  The regulatory authority and IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the subjects or 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the IRB to 
the Sponsor. 
12.2. 
Study Termination 
The Sponsor reserves the right to terminate the study.  The Investigator reserves the right to 
terminate their participation in the study, according to the terms of the site contract.  The 
Investigator should notify the IRB in writing of the trial’s completion or early termination and 
send a copy of the notification to the Sponsor or designee. 
12.3. 
Study Documentation and Storage 
An eCRF utilizing an Electronic Data Capture (EDC) application will be used for this study. 
The Investigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the subject’s case report 
form data are obtained.  These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, imaging, and correspondence.  In this study, eCRF may 
not be used as source documents. 
The Investigator and Study Center staff are responsible for maintaining a comprehensive and 
centralized filing system of all study-related (essential) documentation in accordance with ICH 
GCP, suitable for inspection at any time by representatives from the Sponsor and/or applicable 
regulatory authorities.  Elements should include: 
• Subject files containing completed case report forms, informed consents, and 
supporting copies of source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre-study documentation and all correspondence to and from the IRB and 
the Sponsor. 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
57 
• If drug supplies are maintained at the Study Center, proof of receipt, Study Drug 
Product Accountability Record, Return of Study Drug Product for Destruction, final 
Study Drug product reconciliation, and all drug-related correspondence 
In addition, all original source documents supporting entries in the case report forms must be 
maintained and be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor 
and the Investigator.  Should the Investigator wish to assign the study records to another party or 
move them to another location, he/she must notify the Sponsor. 
12.4. 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the trial (e.g., case report forms and other pertinent data) provided that 
subject confidentiality is respected. 
The Sponsor monitor is responsible for inspecting the case report forms at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical research.  
The monitor should have access to subject medical records and other study-related records 
needed to verify the entries on the case report forms. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing case report forms, are resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department.  Inspection of 
Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of 
study-related records will occur to evaluate the trial conduct and compliance with the protocol, 
ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
subject data received by the Sponsor.  During this review, subject data will be checked for 
consistency, omissions, and any apparent discrepancies.  In addition, the data will be reviewed 
for adherence to the protocol and GCP.  To resolve any questions arising from the clinical data 
management review process, data queries and/or Study Center notifications will be sent to the 
Study Center for completion and return to Sponsor. 
The Principal Investigator will sign and date the indicated places on the case report form.  These 
signatures will indicate that the Principal Investigator inspected or reviewed the data on the case 
report form, the data queries, and the Study Center notifications, and agrees with the content. 
12.5. 
Language 
Case report forms must be completed in English.  Generic names and trade names are acceptable 
for concomitant medications.  Combination medications should be recorded using their trade 
name. 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
58 
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6. 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Subjects will be treated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injury section of the Informed Consent document. 
 
 
 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
59 
13. 
REFERENCES 
Altmann K-H, Dean NM, Fabbro D, et al. Second generation of antisense oligonucleotides: From 
nuclease resistance to biological efficacy in animals. CHIMIA Int J Chem 1996; 50: 168‑176. 
Crooke ST, and Bennett CF. Progress in antisense oligonucleotide therapeutics. Annu Rev 
Pharmacol Toxicol 1996; 36: 107-129. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha 
phosphorothioate 2'-O-(2-methoxyethyl) modified antisense oligonucleotide: comparison across 
species. Drug Metab Dispos 2003; 31: 1419-1428. 
Henry SP, Kim T-W, Kramer-Strickland K, et al. Toxicologic Properties of 2'-O-Methoxyethyl 
Chimeric Antisense Inhibitors in Animals and Man. In In Antisense Drug Technology, 
Principles, Strategies and Applications, 2008. 327-364. Boca Ratan, FL: Taylor & Francis 
Group. 2 
Inoue H, Hayase Y, Iwai S, et al. Sequence-dependent hydrolysis of RNA using modified 
oligonucleotide splints and RNase H. FEBS Lett 1987; 215: 327-330. 
Judd E, and Calhoun DA. Apparent and true resistant hypertension: definition, prevalence and 
outcomes. J Hum Hypertens 2014; 28: 463-468. 
McKay RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of 
antisense oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 
274: 1715-1722. 
Monia BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2'-modified oligonucleotides containing 
2'-deoxy gaps as antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Prakash TP, Graham MJ, Yu J, et al. Targeted delivery of antisense oligonucleotides to 
hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. 
Nucleic Acids Res 2014; 42: 8796-8807. 
Provan D, Stasi R, Newland AC, et al. International consensus report on the investigation and 
management of primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Schulman S, and Kearon C. Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692-694. 
Stockert RJ. The asialoglycoprotein receptor: relationships between structure, function, and 
expression. Physiol Rev 1995; 75: 591-609. 
Te Riet L, van Esch JH, Roks AJ, et al. Hypertension: renin-angiotensin-aldosterone system 
alterations. Circ Res 2015; 116: 960-975. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway factor 
XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. 
Blood 2010; 116: 4684-4692. 
 
 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
60 
14. 
APPENDICES 
.


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
61 
APPENDIX A. SCHEDULE OF PROCEDURES 
 
 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
62 
Appendix A Schedule of Procedures 
Screen Treatment Period 
(8 Weeks) 
Post-Treatment Period  
(13 Weeks) 
Study Week 
 
Wk1 
Wk2 
Wk3 
Wk4 
Wk5 
Wk6 
Wk7 
Wk8 
Wk9 
Wk10 
Wk12 Wk14 
Wk18 
Wk21 
Study Day 
D-28 to 
D-1 
D1 
D3 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
Treatment 
Early 
Term9/ 
D57 
D64 
 
D78 
D92 
D120 
PT 
Early 
Term9/ 
D141 
Visit Window (Days) 
NA 
NA 
+2  
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 5 
± 5 
± 5 
Scheduled Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
Informed Consent 
X 
Inclusion/Exclusion 
X 
Xa 
Medical History 
X 
  
Low Sodium Diet Education 
X 
Continuous Counseling & Monitoring 
CVD Risk Factors 
X 
Body Weight and Height8 
X 
X 
X 
X 
Physical Exam1 
X 
X 
X 
X 
ECG (12-Lead) 
X 
X 
Vital Signs (clinic)2 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
HIV, Hep B & C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test4 
X 
Chemistry Panel (Fasting)7, 10 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
Renal Urine Biomarkers and 
Archived Urine Sample6 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
TSH, FT3, FT4 
X 
Hematology7 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
Urinalysis10 
X 
Xa 
 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
Plasma AGT 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
Exploratory  
X 
Xa 
Xa 
X 
X 
X 
X 
X 
hsCRP 
Xa 
X 
X 
PT, INR, aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
63 
Appendix A Schedule of Procedures (Continued) 
Screen Treatment Period 
(8 Weeks) 
Post-Treatment Period  
(13 Weeks) 
Study Week 
 
Wk1 
Wk2 
Wk3 
Wk4 
Wk5 
Wk6 
Wk7 
Wk8 
Wk9 
Wk10 
Wk12 Wk14 
Wk18 
Wk21 
Study Day 
D-28 to 
D-1 
D1 
D3 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
Treatment 
Early 
Term9/ 
D57 
D64 
 
D78 
D92 
D120 
PT 
Early 
Term9/ 
D141 
Visit Window (Days) 
NA 
NA 
+2  
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 2 
± 5 
± 5 
± 5 
Scheduled Visit # 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Blood Sampling5 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
X 
Immunogenicity Testing 
Xa 
X 
X 
Archived Serum Sample6 
 
X 
 
X 
 
 
X 
 
 
X 
X 
 
 
X 
 
X 
Note: 
D = Day  
W = Week 
1 
Full physical exam to be given at Screening and abbreviated physical exam to be given during Treatment and Post-Treatment Period as indicated to assess 
changes from Screening 
2 
Vital Signs (clinic):  Blood Pressure (SBP/DPB; sitting), Orthostatic assessment (supine and standing, required at Screening), HR, RR, T.  Vital sign 
assessments will be reviewed by the study doctor at each visit prior to dosing. 
3 
Women who are not surgically sterile, as confirmation of menopause 
4 
Women who are not surgically sterile.  Serum test to be done 
5 
Refer to Appendix C for PK sampling schedule 
6 
Stored at -80 °C for follow-up exploration of laboratory findings and/or AEs (e.g., measurement of cytokine and/or chemokine levels, measurement of 
additional markers of kidney function, measurement of antibodies, etc.) in this or subsequent clinical studies of ISIS 757456 
7 
If the platelet value, serum creatinine or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) a repeat blood 
specimen; should be re-drawn as soon as possible (ideally within 7 days) and not meet a stopping rule prior to next dose.  Due to time constraints, a local lab 
draw is recommended if a repeat blood specimen is necessary to continue dosing at any time after Study Day 1 to Study Day 8. 
8 
Height at Screening only 
9 
Subjects who terminate treatment or post-treatment early from the study should be encouraged to participate in an early termination visit, at which time the 
Study D57 or Study D141 assessments should be conducted, respectively 
10 Fasting is not required at Screening visit.  Fasted samples should be taken after fasting for at least 8 hours.  During this time the subject can drink water and 
they should ensure that they consume sufficient water in order to not become dehydrated. 
Time (time is in reference to Study Drug (ISIS 757456 or placebo) administration) 
a 
Pre-dose 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
64 
APPENDIX B. LIST OF LABORATORY ANALYTES 
 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
65 
Appendix B List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of ISIS 757456 or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Creatinine Clearance  
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
Alkaline phosphatase 
• 
Creatinine kinase 
• 
GGT 
 
Thyroid Panel 
• 
TSH 
• 
Free T4 
• 
Free T3 
Screening Tests 
• 
Hepatitis B surface antigen 
• 
Hepatitis C antibody 
• 
HIV antibody 
• 
FSH 
(women only, if applicable) 
• 
Serum beta-subunit of 
human chorionic 
gonadotropin (βhCG) 
(women only, if applicable) 
 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
 
Efficacy 
• 
Plasma AGT 
 
Pharmacokinetics1 
• 
ISIS 757456 levels in 
plasma 
 
Immunogenicity 
• 
Anti-ISIS 757456 
antibodies3 
 
Renal Urine Biomarkers 
• 
NGAL3 
• 
NAG3 
• 
KIM-1 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential (% and 
absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Exploratory 
• 
Angiotensin II 
• 
Renin (PRA) 
• 
Renin (ARC) 
• 
Plasma Aldosterone  
• 
Angiotensin I3 
• 
Angiotensin (1-7)3 
• 
Angiotensin III3 
• 
Angiotensin IV3 
• 
B-type natriuretic 
peptide3 
• 
Atrial natriuretic peptide3  
• 
Plasma Neprilysin3 
• 
Endothelin I3 
Inflammatory 
• 
Hs-CRP  
 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
P/C Ratio (UPCR) 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination2 
• 
Angiotensinogen3 
• 
Albumin3 
• 
Creatinine3 
• 
Protein3  
• 
Sodium3 
• 
Cortisol3 
• 
Aldosterone3  
• 
A/C Ratio (UACR)3 
 
1 Plasma PK samples may also be used for profiling of drug binding proteins, bioanalytical method validation 
purposes, stability assessments, metabolite assessments, immunogenicity testing (or possibly for purposes of 
immunogenicity assay development and/or validation) or to assess other actions of ISIS 757456 with plasma 
constituents 
2 Will be performed on abnormal findings unless otherwise specified 
3 May be analyzed 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
66 
APPENDIX C. PK SAMPLING SCHEDULE 
 
 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
67 
Appendix C PK Sampling Schedule 
 
PK Sampling Schedule 
D1 
D3 
D8 
D15 
D22 
D29 
D36 
D43 
D50 
D57 
D64 
D78 
D92 
D120 
D141 
Pre-dose  
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Pre-dose 
Anytime 
Anytime 
Anytime 
Anytime 
Anytime 
Anytime 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
 SC = subcutaneous 
D = Day 
 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
68 
APPENDIX D. GRADING SCALE FOR AES RELATING TO 
LABORATORY ABNORMALITIES 
 
 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
69 
Appendix D Grading Scale for AEs Relating to Laboratory Abnormalities 
The following grading recommendations for AEs relating to lab test abnormalities and AEs at the 
injection site are based upon the CTCAE Version 5.0, November 2017. 
 
 
 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
70 
Appendix D Grading Scale for AEs Relating to Laboratory Abnormalities (Continued) 
 
 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
71 
Appendix D Grading Scale for AEs Relating to Laboratory Abnormalities (Continued) 
 
 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
72 
APPENDIX E. STRATIFICATION CRITERIA 
 


ISIS 757456-CS3 
CONFIDENTIAL 
Original Protocol
Protocol 
15 July 2019
 
73 
The total dose of the ACE or ARB taken per day is to be calculated based off the subject’s stable 
regimen of antihypertensives at Screening.  The stratification criteria are as follows: 
ACE/ARB 
Low Dose Stratum 
(total mg per day) 
High Dose Stratum 
(total mg per day) 
ACE 
 
 
benazepril 
≤ 20 
> 20  
captopril 
≤ 75 
> 75  
enalapril 
≤ 10 
> 10 
fosinopril 
≤ 20 
> 20 
lisinopril 
≤ 20 
> 20 
perindopril 
< 8 
≥ 8 
quinapril 
< 40 
≥ 40 
ramipril 
≤ 10 
> 10 
trandolapril 
≤ 4 
> 4 
ARB 
 
 
azilsartan 
≤ 40 
> 40 
candesartan 
< 16 
≥ 16 
eprosartan 
≤ 400 
> 400 
irbesartan 
≤ 150 
> 150 
losartan 
≤ 50 
> 50 
olmesartan 
≤ 20 
> 20 
telmisartan 
≤ 40 
> 40 
valsartan 
≤ 160 
> 160 
Should a subject be on a stable regimen of an ACE/ARB at Screening that is not listed in the above table the 
Sponsor Medical Monitor or designee must be consulted prior to stratification.  


Official Title: 
A Double-Blind, Placebo-controlled, Phase 2 Study to Assess the 
Safety, Tolerability 
and 
Efficacy 
of 
IONIS-AGT-LRX, 
an 
Antisense 
lnhibitor Administered Subcutaneously for 8 Weeks to Hypertensive 
 
 
Uncontrolled Blood Pressure 
NCT Number: 
NCT04083222 
Document Date: 
SAP Version 1.0: 04 December 2019