A Phase 2, Double-Blinded, Randomized, Placebo-Controlled, Dose-Escalation Study to Examine the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of ISIS 505358 in Treatment-Naïve Patients With Chronic HBV Infection
Phase: PHASE2
Conditions: Hepatitis B, Chronic Hepatitis B Atypical
Sponsor: GlaxoSmithKline

IONIS PHARMACEUTICALS, INC. 
ISIS 505358-CS3 
A Phase 2, Double-Blinded, Randomized, Placebo-Controlled, 
Dose-Escalation Study to Examine the Safety, Tolerability, 
Pharmacokinetics and Antiviral Activity of ISIS 505358 in 
Treatment-Naïve Patients with Chronic Hepatitis B Virus Infection 
Protocol Amendment 3 – Korea – 29 January 2019 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
2020N429086_00
ISIS 505358-CS3 (205695)
CONFIDENTIAL
1

ISIS 505358-CS3 
Protocol · Korea 
CONFIDENTIAL 
ISIS 505358-CS3 
Amendment 3 
29 January 2019 
A Phase 2, Double-Blinded, Randomized, Placebo-Controlled, 
Dose-Escalation Study to Examine the Safety, Tolerability, 
Pharmacokinetics and Antiviral Activity of ISIS 505358 in 
Treatment-Naive Patients with Chronic Hepatitis B Virus Infection 
Protocol Amendment 3 - Korea - 29 January 2019 
Protocol History: 
Original Protocol: 
Protocol Amendment I: 
Protocol Amendment 2: 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 920 I 0 
, MD 
2 September 2015 
19 February 2016 
22 November 2016 
Vice President and Head of Clinical Development 
Jan 29, 2019 
2 
 
2020N429086_00
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ISIS 505358-CS3 
CONFIDENTIAL 
Amendment 3 
Protocol – Korea 
 
29 January 2019 
 
3 
 
ISIS 505358 
Ionis Protocol Number ISIS 505358-CS3 
Protocol Amendment 3 – Korea 
 
Clinical Phase:  2 
A Phase 2, Double-Blinded, Randomized, Placebo-Controlled, 
Dose-Escalation Study to Examine the Safety, Tolerability, 
Pharmacokinetics and Antiviral Activity of ISIS 505358 in 
Treatment-Naïve Patients with Chronic Hepatitis B Virus Infection 
 
Trial Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA  92010 
Telephone: 
Fax: 
 
Key Sponsor Contact: 
, Ph.D. 
Executive Director, Clinical Development 
Telephone: 
Fax: 
 
Date: 
29 January 2019 
 
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 and 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.
 
2020N429086_00
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ISIS 505358-CS3 
CONFIDENTIAL 
Amendment 3 
Protocol – Korea 
 
29 January 2019 
 
4 
Protocol Signature Page 
 
Protocol Number: 
ISIS 505358-CS3 
Protocol Title: 
A Phase 2, Double-Blinded, Randomized, Placebo-Controlled, Dose 
Escalation Study to Examine the Safety, Tolerability, Pharmacokinetics 
and Antiviral Activity of ISIS 505358 in Treatment-Naïve Patients with 
Chronic Hepatitis B Virus Infection 
Amendment: 
Amendment 3 – Korea 
Date:  
 
29 January 2019 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled 
“A Phase 2, Double-Blinded, Randomized, Placebo-Controlled, Dose Escalation Study to 
Examine the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of ISIS 505358 in 
Treatment-Naïve Patients with Chronic Hepatitis B Virus Infection,” dated 29 January 2019, and 
agree to conduct the Study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice (E6). 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
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CONFIDENTIAL 
Amendment 3 
Protocol – Korea 
 
29 January 2019 
 
5 
TABLE OF CONTENTS 
 
Page 
PROTOCOL AMENDMENT...................................................................................................... 9 
PROTOCOL SYNOPSIS ........................................................................................................... 16 
STUDY DESIGN AND TREATMENT SCHEMA .................................................................. 22 
STUDY GLOSSARY .................................................................................................................. 23 
1. 
OBJECTIVES ................................................................................................................. 25 
1.1 
Primary Objective ..........................................................................................................25 
1.2 
Secondary Objectives ....................................................................................................25 
1.3 
Exploratory Objectives ..................................................................................................25 
2. 
BACKGROUND AND RATIONALE .......................................................................... 25 
2.1 
Overview of Disease ......................................................................................................25 
2.2 
Goals of Therapy for CHB .............................................................................................26 
2.3 
Therapeutic Rationale ....................................................................................................27 
2.4 
ISIS 505358 ...................................................................................................................28 
2.4.1 
Mechanism of Action .............................................................................................28 
2.4.2 
Chemistry ...............................................................................................................29 
2.4.3 
Preclinical Experience ............................................................................................30 
2.4.4 
Clinical Experience ................................................................................................31 
2.4.4.1 
ISIS 505358-CS1 .............................................................................................31 
2.4.4.2 
ISIS 505358-CS3 .............................................................................................32 
2.5 
ISIS 505358 Dose and Schedule of Administration Rationale ......................................33 
2.5.1 
Target Dose Levels .................................................................................................33 
2.5.2 
Treatment Duration ................................................................................................33 
2.5.3 
Loading/Maintenance Dosing ................................................................................33 
2.6 
Combination of ISIS 505358 with Nucleos(t)ide Analogue ..........................................34 
3. 
EXPERIMENTAL PLAN .............................................................................................. 35 
3.1 
Study Design ..................................................................................................................35 
3.2 
Number of Study Centers ..............................................................................................36 
3.3 
Number of Subjects .......................................................................................................36 
3.4 
Overall Study Duration and Follow-up .........................................................................36 
3.4.1 
Screening ................................................................................................................36 
3.4.2 
Treatment ................................................................................................................36 
3.4.3 
Post-Study Drug Treatment Follow-Up .................................................................36 
3.5 
End of Study ..................................................................................................................36 
3.6 
Data and Safety Monitoring Board ................................................................................36 
3.7 
Dose Escalation ..............................................................................................................37 
3.8 
Dose Limiting Toxicity ..................................................................................................38 
4. 
SUBJECT ENROLLMENT ........................................................................................... 38 
 
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4.1 
Screening .......................................................................................................................38 
4.2 
Randomization ...............................................................................................................39 
4.3 
Replacement of Subjects ................................................................................................39 
4.4 
Unblinding of Treatment Assignment ...........................................................................39 
5. 
PATIENT ELIGIBILITY .............................................................................................. 40 
5.1 
Inclusion Criteria ...........................................................................................................40 
5.2 
Exclusion Criteria ..........................................................................................................41 
6. 
STUDY PROCEDURES ................................................................................................ 43 
6.1 
Study Schedule ..............................................................................................................43 
6.1.1 
Screening ................................................................................................................43 
6.1.2 
Treatment Period ....................................................................................................43 
6.1.3 
Post-Treatment Period ............................................................................................43 
6.1.4 
Early Termination ...................................................................................................43 
6.2 
Laboratory Assessments ................................................................................................43 
6.3 
HBV Resistance Mutation Monitoring ..........................................................................44 
6.4 
Restriction on the Lifestyle of Patients ..........................................................................44 
6.4.1 
Contraception Requirements ..................................................................................44 
6.5 
Nucleos(t)ide Analogue Plasma Concentrations ...........................................................45 
7. 
STUDY DRUG ................................................................................................................ 45 
7.1 
Study Drug Description .................................................................................................45 
7.2 
Packaging and Labeling .................................................................................................46 
7.3 
Study Drug Accountability ............................................................................................46 
8. 
TREATMENT OF PATIENTS ..................................................................................... 46 
8.1 
Study Drug Administration ............................................................................................46 
8.2 
Other Protocol-Required Drugs .....................................................................................47 
8.3 
Other Protocol-Required Treatment Procedures ............................................................47 
8.4 
Treatment Precautions ...................................................................................................47 
8.5 
Safety Monitoring Rules ................................................................................................47 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ..............................................48 
8.6 
Study Drug (ISIS 505358 or Placebo) Stopping Rules ..................................................49 
8.6.1 
Stopping Rules for Liver Chemistry Elevations .....................................................49 
8.6.2 
Stopping Rules for Hematologic Test Results .......................................................49 
8.6.3 
Stopping Rules for Renal Function Test Results ....................................................50 
8.6.4 
Stopping Rules for Significant Inflammatory Reaction .........................................50 
8.7 
Adjustment of Dose and/or Treatment Schedule ...........................................................50 
8.8 
Discontinuation of Study Treatment ..............................................................................51 
8.9 
Withdrawal of Patients from the Study ..........................................................................51 
8.10 
Concomitant Therapy and Procedures ...........................................................................52 
8.10.1 
Concomitant Therapy .............................................................................................52 
8.10.2 
Concomitant Procedures .........................................................................................53 
 
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8.11 
Treatment Compliance ...................................................................................................53 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ...................... 53 
9.1 
Sponsor Review of Safety Information .........................................................................53 
9.2 
Regulatory Requirements ..............................................................................................53 
9.3 
Definitions .....................................................................................................................54 
9.3.1 
Adverse Event ........................................................................................................54 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction ..............................................54 
9.3.3 
Serious Adverse Event (SAE) ................................................................................54 
9.4 
Monitoring and Recording Adverse Events ...................................................................54 
9.4.1 
Serious Adverse Events ..........................................................................................55 
9.4.2 
Non-Serious Adverse Events ..................................................................................55 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ....................................55 
9.4.3.1 
Relationship to the Study Drug ........................................................................55 
9.4.3.2 
Severity ............................................................................................................56 
9.4.3.3 
Action Taken with Study Drug ........................................................................56 
9.4.3.4 
Treatment Given for Adverse Event ................................................................56 
9.4.3.5 
Outcome of the Adverse Event ........................................................................57 
9.5 
Procedures for Handling Special Situations ..................................................................57 
9.5.1 
Abnormalities of Laboratory Tests .........................................................................57 
9.5.2 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ............57 
9.5.3 
Dosing Errors .........................................................................................................58 
9.5.4 
Contraception and Pregnancy .................................................................................58 
10. 
STATISTICAL CONSIDERATIONS .......................................................................... 59 
10.1 
Study Endpoints, Subsets, and Covariates .....................................................................59 
10.1.1 
Primary Endpoints ..................................................................................................59 
10.1.2 
Secondary Endpoints ..............................................................................................59 
10.1.3 
Exploratory Endpoints ............................................................................................60 
10.2 
Sample Size Considerations ...........................................................................................60 
10.3 
Populations .....................................................................................................................60 
10.4 
Definition of Baseline ....................................................................................................60 
10.5 
Interim Analysis .............................................................................................................60 
10.6 
Planned Methods of Analysis ........................................................................................61 
10.6.1 
Demographic and Baseline Characteristics ............................................................61 
10.6.2 
Safety Analysis .......................................................................................................61 
10.6.3 
Efficacy Analysis ...................................................................................................61 
10.6.4 
Pharmacokinetic Analysis ......................................................................................62 
10.6.5 
Additional Analyses ...............................................................................................63 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ............................................. 63 
11.1 
Informed Consent ..........................................................................................................63 
11.2 
Ethical Conduct of the Study .........................................................................................64 
 
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11.3 
Institutional Review Board ............................................................................................64 
11.4 
Patient Confidentiality ...................................................................................................64 
12.
ADMINISTRATIVE AND LEGAL OBLIGATIONS ................................................ 65 
12.1 
Protocol Amendments ....................................................................................................65 
12.2 
Study Termination .........................................................................................................65 
12.3 
Study Documentation and Storage ................................................................................65 
12.4 
Study Monitoring ...........................................................................................................66 
12.5 
Language ........................................................................................................................66 
12.6 
Compensation for Injury ................................................................................................67 
13.
REFERENCES ................................................................................................................ 68 
14.
APPENDICES ................................................................................................................. 71 
Appendix A 
Schedule of Procedures ....................................................................................72 
Appendix B 
List of Laboratory Analytes .............................................................................76 
Appendix C 
Plasma PK Sampling Schedules ......................................................................78 
Appendix D 
Division of AIDS Table for Grading Severity of Adult and Pediatric Adverse 
 Events Version 2.0, November 2014 ................................................................81 
TABLE OF TABLES 
Page 
Table 1 
Study Drug Characteristics ....................................................................................46 
Table 2 
Study Drug Dosing Information ............................................................................46 
Table 3 
Study Drug Stopping Rules for ALT or AST Elevations ......................................49 
TABLE OF FIGURES 
Page 
Figure 1 
Structure of 2ʹ-MOE Chimeric Phosphorothioate Oligonucleotides.  Each 
N is either A, G, T, or 5-methyl-C .........................................................................29 
 
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CONFIDENTIAL 
Amendment 3 
Protocol – Korea 
 
29 January 2019 
 
9 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 505358-CS3 
Protocol Title: 
A Phase 2, Double-Blinded, Randomized, Placebo-Controlled, 
Dose-Escalation Study to Examine the Safety, Tolerability, 
Pharmacokinetics and Antiviral Activity of ISIS 505358 in 
Treatment-Naïve Patients with Chronic Hepatitis B Virus Infection 
Amendment Number: 
3 – Korea 
Amendment Date: 
29 January 2019 
 
The main purpose of this amendment is to add Cohort 4 in which patients with chronic hepatitis 
B and already on a stable regimen of tenofovir or entecavir are treated with ISIS 505358 by the 
same regimen used in Cohorts 1–3 to dose treatment-naïve HBV patients.  This represents an 
exploratory examination to obtain results that will be used to guide the design of subsequent 
larger study. 
The table below summarizes the modifications made to the ISIS 505358-CS3 Protocol (deletions 
from Was are underlined; additions in the Now Is are in bold font).  Some minor edits have not 
been listed 
Protocol Section 
Description of Change 
Rationale 
Synopsis:  Exploratory 
Objective(s) 
Section 1.3 Exploratory 
Objectives 
Added: 
To explore antiviral activity, safety/tolerability, and 
PK during concurrent treatment with ISIS 505358 and 
nucleos(t)ide analogue (i.e., tenofovir or entecavir) 
Addition of Cohort 4 
Synopsis:  Study Design 
Synopsis:  Treatment Groups  
Section 3.1 Study Design 
Added to Cohort 3 text: 
(note:  cohort was studied as 300 mg ISIS 505358 or 
placebo based on antiviral activity observed in Cohort 2 per 
Section 3.7) 
Update treatment 
performed in 
Cohort  3 
Synopsis:  Study Design  
Section 3.1 Study Design 
Added: 
One (1) exploratory cohort (Cohort 4) will examine add-on 
treatment of patients already on stable nucleos(t)ide 
analogue (i.e., tenofovir or entecavir) regimen with 300 mg 
ISIS 505358 or placebo (3:1 randomization).  Patients 
enrolled into the study may be either HBeAg positive (+) or 
negative (-). 
The target size of Cohort 4 is approximately 8 patients, but 
size may range from 4 to > 8 depending upon availability of 
participants.  Each patient randomized into Cohort 4 is 
expected to continue their ongoing nucleos(t)ide analogue 
regimen and be treated with Study Drug by the above 
schedule for Cohorts 1–3.  After Day 22, the patients are 
expected to continue their ongoing nucleos(t)ide analogue 
regimen and will be followed until Day 211.  On Day 29, the 
effects of Study Drug treatment will be assessed. 
Addition of Cohort 4 
 
 
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Protocol Section 
Description of Change 
Rationale 
Synopsis:  Inclusion Criteria in 
Study Population 
Section 5.1 Inclusion Criteria 
Was: 
4.  Plasma HBV DNA ≥ 2 x 103 IU/mL 
Now Is:  
4.  Cohort 1–3:  Plasma HBV DNA ≥ 2 x 103 IU/mL 
Cohort 4:  HBV DNA adequately suppressed 
(e.g., plasma or serum HBV DNA below the lower 
limit of quantitation) 
Addition of Cohort 4 
Synopsis:  Inclusion Criteria in 
Study Population 
Section 5.1 Inclusion Criteria 
Added:  
7. Cohort 4 only:  Currently taking and have been taking 
tenofovir or entecavir without changes in drug, dose 
level and/or frequency of administration for 
≥ 12 months and expect to continue taking without 
change through to the end of their participation in this 
study (approximately 8 months) 
Addition of Cohort 4 
Synopsis:  Exclusion Criteria 
in Study Population  
Section 5.2 Exclusion Criteria 
Was:  
1. Current or prior receipt of anti-HBV nucleos(t)ide 
analogue therapy.  Patients who have failed prior 
interferon treatment, greater than 6 months prior to 
Screening, may be evaluated for possible participation 
in the study 
Now Is: 
1. Cohort 1–3 only:  Current or prior receipt of anti-HBV 
nucleos(t)ide analogue therapy.  Patients who have 
failed prior interferon treatment, greater than 6 months 
prior to Screening, may be evaluated for possible 
participation in the study 
Addition of Cohort 4 
Synopsis:  Treatment Groups  
Added:  
Cohort 4:  300 mg ISIS 505358 or placebo (in patients 
already on stable tenofovir or entecavir regimen) 
Addition of Cohort 4 
Dose-Escalation section of 
Synopsis 
Section 3.6 Data and Safety 
Monitoring Board 
Was: 
After completion of Study Drug administration and the last 
Day 29 assessment for Cohort 3, the DSMB will review 
the cumulative safety and antiviral data …. 
Now Is: 
After completion of Study Drug administration and the last 
Day 29 assessments for Cohort 3 and for Cohort 4, 
respectively, the DSMB will review the cumulative safety 
and antiviral data …. 
Addition of Cohort 4 
Synopsis:  Statistical 
Considerations 
Section 4.4 Unblinding of 
Treatment Assignment 
Was 
An unblinded interim analysis may be performed after all 
patients have progressed beyond their Study Day 29 
assessments.  
Now Is: 
An unblinded interim analysis may be performed of 
Cohort 1–3 after all patients within these cohorts have 
progressed beyond their Study Day 29 assessments.  An 
unblinded interim analysis similarly may be performed 
of Cohort 4 after all Cohort 4 patients have 
progressed beyond their Study 29 assessments. 
Addition of Cohort 4 
Dose Escalation Flow in Study 
Design and Treatment 
Schema 
Added:  
Note:  Cohort 3 was 300 mg or placebo (3:1) based on 
antiviral activity observed in Cohort 2 per Section 3.7 
Addition of Cohort 4 
 
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Amendment 3 
Protocol – Korea 
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Protocol Section 
Description of Change 
Rationale 
Patient Participation Flow in 
Study Design and Treatment 
Schema 
Added: 
Cohort 4 only:  treatment with tenofovir or entecavir during 
all periods (i.e., Screen, Treatment, and Post-Study Drug 
Treatment) 
Addition of Cohort 4 
Section 2.4.4 Clinical 
Experience 
Added:  
Section 2.4.4.1 ISIS 505358-CS1 
Added subsection 
header for clarity 
Section 2.4.4 Clinical 
Experience 
Added: 
Section 2.4.4.2 ISIS 505358-CS3 
Interim blinded results from Cohort 1 (150 mg or placebo, 
6:2 ratio), Cohort 2 (300 mg or placebo, 6:2 ratio), and 
Cohort 3 (300 mg or placebo, 6 patients, ratio unknown) 
are available.  There has been one SAE in the study—
Alanine aminotransferase increased.  A patient in Cohort 2 
experienced an ALT elevation that peaked at 781 U/L 
(23.7 x ULN, ULN = 33) on Study Day 38 (15 days after 
last protocol-specified dose of Study Drug).  ALT levels 
declined to < 5 x ULN within 11 days and became 
consistently < 3 x ULN by Day 72.  The patient had a 
lesser concurrent AST elevation.  Her total bilirubin levels 
were stable throughout the study.  This ALT elevation 
temporally coincided with HBsAg and HBV DNA reduction 
to less than the lower limit of quantitation and therefore 
may have been secondary to the clearance of infected 
hepatocytes. 
Three (3) additional patients—2 in Cohort 1 and 1 in 
Cohort 2—experienced treatment-emergent elevations of 
ALT to > 3 x ULN.  None had changes in total bilirubin 
levels.  Like the aforementioned patient with SAE, the 
ALT elevations of these 3 patients were temporally related 
to reductions in HBsAg.  However, there were other 
patients in ISIS 505358-CS3 with HBsAg reductions but 
without ALT elevation.  Therefore, the possibility that the 
ALT elevations are a direct adverse effect (wholly or 
partially) of ISIS 505358 on the liver cannot be entirely 
excluded. 
Some activity against HBV was observed in the 
treatment-naïve patients treated ISIS 505358-CS3.  
Three (3) of the 8 patients in Cohort 1 had HBsAg 
reductions of 0.39, 1.19, and 1.24 log10 IU/mL.  Five of the 
8 patients in Cohort 2 had HBsAg reductions of 0.462, 
1.19, 1.96, 2.57, and 3.80 log10 IU/mL.  A 6th patient in 
Cohort 2 had a 0.81 log10 IU/mL reduction in HBV DNA 
although the patient’s HBsAg reduction was minimal 
(0.12 log10 IU/mL).  Dose-related reductions in HBV DNA 
were also observed in the study.  This antiviral activity was 
observed in both HBeAg positive and negative patients.  
In Cohort 3, one (1) of the patients was observed to have 
developed a 3.33 log10 IU/mL reduction in HBsAg and 
3.53 log10 IU/mL reduction in HBV DNA on Day 29.  Two 
(2) other patients each had 0.43 log10 IU/mL reductions of
HBsAg and a 4th patient had a reduction of HBV DNA of
0.77 log10 IU/mL despite minimal HBsAg reduction.
Overall, continued clinical development of ISIS 505358 is 
supported by the results from ISIS 505358-CS1 and the 
emerging results from ISIS 505358-CS3. 
Update clinical 
experience with 
interim experience 
from CS3 
 
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Protocol Section 
Description of Change 
Rationale 
Added:  
Section 2.6 Combination of 
ISIS 505358 with 
Nucleos(t)ide Analogues 
Added: 
Section 2.6 Combination of ISIS 505358 with 
Nucleos(t)ide Analogues  
The differences in pharmacokinetic behavior between 
drugs like ISIS 505358 and nucleos(t)ide analogues 
indicate drug-drug interaction between the 2 drug types is 
unlikely.  The antiviral and safety results from Cohorts 1-2 
of ISIS 505358-CS3 are consistent with that expectation. 
Drugs of the 2′-MOE ASO class, like ISIS 505358, rapidly 
become highly bound (∼95%) to serum proteins upon 
entry into the blood stream and are then rapidly distributed 
(t1/2 ∼2 hr) to tissues where these drugs enter cells through 
target mediated endocytosis and micropinocytosis 
(Geary et al. 2008; Bennett and Swayze 2010).  2′-MOE 
ASOs are eliminated primarily by nucleolytic degradation 
(Geary et al., 2008).  None of these processes are 
inhibited by small-molecule drugs like nucleos(t)ide 
analogues. 
Conversely, tenofovir, entecavir, and other nucleos(t)ide 
analogues circulated in the blood stream with little binding 
to serum proteins and are eliminated in urine as intact 
drug by a combination of glomerular filtration and active 
secretion (Bristol-Myers Squibb 2018; Gilead 2018).  The 
renal elimination has been shown to be mediated by the 
organic anion transporters OAT1, OAT3 and OCT2 
(Cihlar et al. 2001; Uwai et al. 2007; Xu et al. 2013).  
2′-MOE ASO have been shown to be neither substrates 
nor inhibitors of OAT1, OAT3, or OCT2 (Yu et al. 2016; 
Shemesh et al. 2017). 
In Cohorts 1–2 of ISIS 505358-CS3, tenofovir dosing was 
started on Study Day 29, which is 7-days after the last 
dosing of ISIS 505358.  Since the ASO has a long tissue 
half-life (2–3 weeks based on the non-clinical studies), 
there is a period of at least several weeks during which 
there will be a substantial presence of both drugs in the 
livers and other tissues of treated patients.  For Cohorts 1 
and 2, potent reduction of HBV DNA was observed 
following initiation of tenofovir in all patients.  There were 
no obvious differences in tenofovir potency between the 
cohorts consistent with the different ISIS 505358 dose 
levels of the 2 cohorts nor were there differences within 
cohorts that possibly indicate a difference between ASO 
and placebo-treated patients.  Neither were there any 
adverse event or clinical laboratory results suggestive of a 
safety effect due to drug-drug interaction.  The results 
from Cohort 3 to date are consistent with Cohort 2. 
Addition of Cohort 4 
Section 3.4.1 Screening 
Added: 
Patients in screening for Cohort 4 are expected to 
continue to take their pre-existing ongoing nucleos(t)ide 
analogue therapy. 
Addition of Cohort 4 
Section 3.4.2 Treatment 
Added: 
Patients in Cohort 4 are expected to continue to take their 
ongoing nucleos(t)ide analogue therapy during this period. 
Addition of Cohort 4 
 
 
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Protocol Section 
Description of Change 
Rationale 
Section 3.4.3 Post-Study 
Drug Treatment Follow-Up 
Added:  
Patients in Cohort 4 are expected to continue their 
nucleos(t)ide analogue therapy that was ongoing prior to 
Screening.  Follow-up visits will be performed on 
Study Days 36, 57, 85, 113, and 211.  The final study visit 
will be Study Day 211 
Addition of Cohort 4 
Added: 
Section 6.5 Nucleos(t)ide 
Analogue Plasma 
Concentration 
Added:  
Section 6.5 Nucleos(t)ide Analogue Plasma Concentration 
Cohorts 1–3:  measurement of tenofovir and entecavir 
plasma concentrations will be performed following the 
Study Drug administration period.  The measurement for 
each patient will depend on the nucleos(t)ide analogue 
they are taking.  The specimen collection days are 
Study Days 29, 36, 57, 85, 113, and 211. 
Cohort 4:  measurement of tenofovir and entecavir plasma 
concentrations will be performed to explore whether 
treatment-emergent changes to nucleos(t)ide analogue 
plasma levels occur during ISIS 505358 administration.  
The measurement for each patient will depend on the 
nucleos(t)ide analogue they are taking.  The specimen 
collection days are Study Days 1, 8, 15, 22, 29, 36, 57, 85, 
113 and 211. 
Because there is a known food effect for tenofovir and 
entecavir, subjects will be asked to be consistent in their 
eating habits and when they take their doses before the 
clinic visits on these days.  Sites should make reasonable 
efforts to ensure that the pre-dose blood draws on these 
visit days generally occur at the same time of day 
(± 2 hour) to lessen any day-to-day variability. 
Addition of Cohort 4 
Table 2 Study Drug Dosing 
Information 
Was: 
Cohort 2 
Now Is: 
Cohort 2, Cohort 4 
Addition of Cohort 4 
Table 2 Study Drug Dosing 
Information 
Added footnote: 
*Patients in Cohort 3 were treated with total volume of 
2.0 mL and total dose of 300 mg or placebo 
Addition of Cohort 4 
Section 8.2 Other 
Protocol-Required Drugs 
Was: 
After the conclusion of Study Day 29 assessment, patients 
are required …. 
Now is: 
After the conclusion of Study Day 29 assessments, 
patients in Cohorts 1–3 are required …. 
Addition of Cohort 4 
Section 8.2 Other 
Protocol-Required Drugs 
Added: 
Patients in Cohort 4 are expected to continue throughout 
this study their stable nucleos(t)ide analogue regimen that 
was ongoing prior to their enrollment in this study. 
Addition of Cohort 4 
Section 8.10.1 Concomitant 
Therapy 
Was: 
Entecavir and tenofovir are considered concomitant 
medications in this study.  Their usage should be in 
accordance with the recommendations contained in their 
respective region-specific prescribing information and 
should be recorded in each patient’s CRF. 
Addition of Cohort 4 
 
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Protocol Section 
Description of Change 
Rationale 
Section 8.10.1 Concomitant 
Therapy Continued 
Now Is: 
Entecavir and tenofovir are considered concomitant 
medications in this study.  In Cohort 4, patients should 
be on stable tenofovir or entecavir therapy prior to 
Screening and their nucleos(t)ide analogue usage 
should be in accordance with the recommendations 
contained in their respective region-specific prescribing 
information.  For all cohorts, each patient’s 
nucleos(t)ide analogue usage should be recorded in 
their CRF. 
Addition of Cohort 4 
Section 10.5 Interim Analysis 
Was: 
An unblinded interim analysis may be performed after all 
patients have progressed beyond their Study Day 29 
assessments and the database has been locked.  Details 
of the analysis and controlled access to the unblinded data 
will be specified in the SAP. 
Now Is: 
An unblinded interim analysis for Cohort 1–3 may be 
performed after all Cohort 1–3 patients have progressed 
beyond their Study Day 29 assessments and the database 
has been locked.  An unblinded interim analysis for 
Cohort 4 may be performed similarly after all Cohort 4 
patients have progressed beyond their Study Day 29 
assessments and locking of the data.  Details of the 
analysis and controlled access to the unblinded data will 
be specified in the SAP. 
Addition of Cohort 4 
Section 10.6.4 
Pharmacokinetic Analysis 
Was: 
Plasma levels of tenofovir (and entecavir if administered) 
will be measured on multiple days during the post-Study 
Drug Treatment Follow-Up period of the study (see 
Appendix C).  Only the nucleos(t)ide analogue that is taken 
by each patient will be measured.  Plasma concentrations 
of tenofovir (and entecavir) in patients previously treated 
with ISIS 505358 will be compared to prior treatment with 
placebo.  Details for analysis will be defined in the SAP 
Now Is: 
Cohorts 1–3:  Plasma levels of tenofovir (and entecavir if 
administered) will be measured on multiple days during the 
post-Study Drug Treatment Follow-Up period of the study 
(see Appendix C).  Only the nucleos(t)ide analogue that is 
taken by each patient will be measured.  Plasma 
concentrations of tenofovir (and entecavir) in patients 
previously treated with ISIS 505358 will be compared to 
prior treatment with placebo.  Details for analysis will be 
defined in the SAP 
Cohort 4:  Plasma levels of the tenofovir or entecavir 
taken by each patient will be measured on multiple 
days during the study periods before, during, and after 
Study Drug administration (see Appendix C).  Only the 
nucleos(t)ide analogue that is taken by each patient 
will be measured.  Plasma levels on Day 1 (prior to 
ISIS 505358) will be compared for each patient to 
plasma levels taken concurrently with ISIS 505358, 
matched for time from dose and fed/fasted state, to 
monitor for potential interactions.  Details for analysis 
will be defined in the SAP. 
Addition of Cohort 4 
 
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Protocol Section 
Description of Change 
Rationale 
Section 13 References 
Added: 
Bristol-Myers Squibb et al. 2018 
Cihlar et al. 2007 
Gilead Sciences 2008 
Shemesh et al. 2017 
Uwai et al. 2007 
Xu et al 2013 
Yu et al. 2016 
Addition of Cohort 4 
Added: 
Appendix A Schedule of 
Procedures – Cohort 4 
Added: 
Schedule of Procedures - Cohort 4 
Table differs from Cohort 1–3 table in that the 
Nucleos(t)ide Analogue Concentration row contains 
additional collections at Screen and Days 1, 8, 15 and 22. 
Addition of Cohort 4 
Added: 
Appendix C PK Sampling 
Schedule – Cohort 4 
Added: 
PK Sampling Schedule – Cohort 4 
Schedule differs from Cohort 1–3 in that the Nucleos(t)ide 
Analogue Sampling Schedule displays Screen, D1, D2, 
D4, D8, D15, D22 and D23. 
Addition of Cohort 4 
Synopsis – Pharmacokinetic 
Evaluation 
Added: 
Cohort 4 only: tenofovir and entecavir additionally during 
Screen and Study Drug Treatment periods 
Addition of Cohort 4 
 
 
 
 
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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2, Double-Blinded, Randomized, Placebo-Controlled, Dose Escalation Study 
to Examine the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of 
ISIS 505358 in Treatment-Naïve Patients with Chronic Hepatitis B Virus Infection 
Study Phase 
2 
Indication 
Nucleos(t)ide analogue treatment-naïve patients with chronic HBV infection 
Primary Objective 
To examine the safety and tolerability of ISIS 505358 administration to treatment-naive 
patients with chronic hepatitis B virus infection 
Secondary Objective(s) 
•
To examine the effects of ISIS 505358 administration on plasma HBV DNA
concentration
•
To examine the effects of ISIS 505358 administration on serum HBV surface
antigen (HBsAg) concentration
•
To examine the effect of ISIS 505358 administration on serum HBV e antigen
(HBeAg) concentration in the patients that were HBeAg positive at Baseline
•
To assess plasma pharmacokinetics (PK) of ISIS 505358 in patients with chronic
HBV infection
•
To describe the safety and tolerability of tenofovir (and entecavir if administered)
therapy after conclusion of ISIS 505358 administration
Exploratory Objective(s) 
•
To describe the rate of seroconversion of patients to antibody to HBV surface
antigen (anti-HBs antibody) positivity during treatment with ISIS 505358 and then
during subsequent treatment with tenofovir (or entecavir)
•
To describe the rate of seroconversion of HBeAg positive patients to antibody to
HBV e antigen (anti-HBe antibody) positivity during treatment with ISIS 505358
and subsequent treatment with tenofovir (or entecavir)
•
To explore the effect of prior ISIS 505358 exposure on the plasma concentrations
of tenofovir (and entecavir) administered after the conclusion of ISIS 505358
administration
•
To explore antiviral activity, safety/tolerability, and PK during concurrent treatment
with ISIS 505358 and nucleos(t)ide analogue (i.e., tenofovir or entecavir)
Study Design 
This study examines the effects of ISIS 505358 or placebo (3:1 randomization) 
administered subcutaneously to treatment-naïve patients who are chronically infected 
with HBV and the effects of subsequent nucleos(t)ide analogue treatment on these 
patients. 
Three (3) ISIS 505358 dose levels will be evaluated through the treatment of 
3 sequential cohorts of 8 patients each: 
•
Cohort 1 (150 mg ISIS 505358 or placebo)
•
Cohort 2 (300 mg ISIS 505358 or placebo)
•
Cohort 3 (450 mg ISIS 505358 or placebo) (note:  cohort was studied as 300 mg
ISIS 505358 or placebo based on antiviral activity observed in Cohort 2 per
Section 3.7)
In these cohorts, 6 patients will be randomized to treatment with ISIS 505358 and 
2 patients to treatment with placebo.  Patients enrolled into the study may be either 
HBeAg positive (+) or negative (-). 
 
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PROTOCOL SYNOPSIS Continued 
Study Design Continued 
For each patient, Study Drug (ISIS 505358 or placebo) will be administered twice in 
Weeks 1 and 2 (on Days 1, 4, 8, and 11), and then once weekly during Weeks 3 and 4 
(i.e., on Days 15 and 22).  On Day 29, the effects of Study Drug treatment will be 
assessed.  After these assessments, all patients will then commence chronic daily 
treatment with tenofovir (entecavir if judged more appropriate by the patient or 
Investigator) for 6 months.  Continuation of nucleos(t)ide analogue therapy after 
discontinuation from this study will be the decision of the patient in consultation with 
their physician. 
One exploratory cohort (Cohort 4) will examine add-on treatment of patients already on 
stable nucleos(t)ide analogue (i.e., tenofovir or entecavir) regimen with 300 mg 
ISIS 505358 or placebo (3:1 randomization).  Patients enrolled into the study may be 
either HBeAg positive (+) or negative (-). 
The target size of Cohort 4 is approximately 8 patients, but size may range from 4 to 
> 8 depending upon availability of participants.  Each patient randomized into Cohort 4 
is expected to continue their ongoing nucleos(t)ide analogue regimen and be treated 
with Study Drug by the above schedule for Cohorts 1-3.  After Day 22, the patients are 
expected to continue their ongoing nucleos(t)ide analogue regimen and will be followed 
until Day 211.  On Day 29, the effects of Study Drug treatment will be assessed. 
An independent Data and Safety Monitoring Committee (DSMB) will participate in the 
review of the study results and in the dose-escalation decisions (see below and 
Sections 3.6 and 3.7) 
Number of Patients 
Approximately 32 patients will be treated with Study Drug in this study.  Additional 
patients may be treated due to difficulties of coordinating screening and enrollment from 
multiple sites and/or to replace patients that discontinue from cohorts before Day 29 for 
non-adverse event reasons but the actual number treated will not exceed 48. 
Study Population 
Inclusion Criteria 
1. 
Have given written informed consent (signed and dated) and any authorizations 
required by local law and is able to comply with all study requirements 
2. 
Age 18 to 70 years 
3. 
Chronic HBV infection ≥ 6 months (e.g., positive for serum HBsAg ≥ 6 months) 
4. 
Cohorts 1–3:  Plasma HBV DNA ≥ 2 x 103 IU/mL  
Cohort 4:  HBV DNA adequately suppressed (e.g., plasma or serum HBV DNA 
below the lower limit of quantitation) 
5. 
Serum HBsAg ≥ 50 IU/mL 
6. 
Satisfy the following 
a. 
Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal 
occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy), 
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 
FSH levels in the postmenopausal range for the laboratory involved) or, if 
engaged in sexual relations of childbearing potential, subject is using an 
acceptable contraceptive method (refer to Section 6.4) from the time of 
signing the informed consent form until at least 13 weeks after the last dose 
of Study Drug (ISIS 505358 or placebo) 
b. 
Males:  Surgically sterile or if engaged in sexual relations with a female of 
child-bearing potential, subject is utilizing an acceptable contraceptive 
method (refer to Section 6.4) during treatment with Study Drug and for at 
least 13 weeks after the last dose of Study Drug 
 
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PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
Inclusion Criteria Continued 
7. 
Cohort 4 only:  Currently taking and have been taking tenofovir or entecavir 
without changes in drug, dose level and/or frequency of administration for 
≥ 12 months and expect to continue taking without change through to the end of 
their participation in this study (approximately 8 months) 
Exclusion Criteria 
1. 
Cohorts 1-3 only:  Current or prior receipt of anti-HBV nucleos(t)ide analogue 
therapy.  Patients who have failed prior interferon treatment, greater than 
6 months prior to Screening, may be evaluated for possible participation in the 
study 
2. 
History of liver cirrhosis and/or evidence of cirrhosis as determined by any 1 of 
the following: 
a. 
Liver biopsy (i.e., Metavir Score F4) within 2 years of Screening, or 
b. 
Fibroscan > 12 KPa, within 12 months of Screening, or 
c. 
AST-to-Platelet Index (APRI) > 2 and Fibrosure result > 0.7 within 
12 months of Screening 
For patients without a test for cirrhosis in the above timeframes, Fibroscan, or 
APRI and Fibrosure, may be performed during the screening period to rule out 
cirrhosis 
3. 
History of liver failure as evidenced by ascites, hepatic encephalopathy, and/or 
gastric or esophageal varices 
4. 
History of liver disease other than Hepatitis B 
5. 
Co-infection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), 
or hepatitis D virus (HDV) 
6. 
BMI > 35 kg/m2 
7. 
History of, or suspected presence of vasculitis 
8. 
Received solid organ or bone marrow transplant 
9. 
Currently taking, or took within 3 months of Screening, any immunosuppressing 
drugs (e.g., prednisone).  If the patient received a short course (≤ 1-week), the 
situation may be discussed with the Ionis Medical Monitor, or designee 
10. Diagnosed hepatocellular carcinoma or suspected hepatocellular carcinoma as 
evidenced by screening alpha-fetoprotein ≥ 200 ng/mL.  If the screening 
alpha-fetoprotein is ≥ 50 ng/mL and < 200 ng/mL, the absence of liver mass 
must be documented by imaging within 6 months before randomization  
11. Screening laboratory results as follows, or any other clinically-significant 
abnormalities in screening laboratory values that would render a patient 
unsuitable for inclusion 
a. 
ALT or AST > 5 x ULN 
b. 
Total bilirubin > 1.1 x ULN 
c. 
Serum albumin < 3.5 g/dL 
d. 
INR > 1.2 
e. 
Platelet count < 140 k/mm3 
f. 
Hemoglobin < 12.0 g/dL for males and < 11.0 g/dL for females 
g. 
WBC < 3.0 k/mm3 
h. 
Serum creatinine > 1.1 x ULN 
i. 
Urine protein/creatinine (P/C) ratio ≥ 0.2 mg/mg.  In the event of P/C ratio 
above this threshold, eligibility may be confirmed by a quantitative total urine 
protein measurement of < 150 mg/24-hr 
j. 
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 
 
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PROTOCOL SYNOPSIS Continued 
Study Population 
Continued 
Exclusion Criteria Continued 
12. History of Gilbert’s Syndrome or history of laboratory results consistent with
Gilbert’s Syndrome
13. Clinically-significant abnormalities aside from chronic HBV infection in medical
history (e.g., previous acute coronary syndrome within 6 months of Screening,
major surgery within 3 months of Screening, uncontrolled diabetes) or physical
examination
14. History of bleeding diathesis or coagulopathy
15. History of extrahepatic disorders possibly related to HBV immune complexes
(e.g., glomerulonephritis, polyarteritis nodosa)
16. Active infection other than HBV requiring systemic antiviral or antimicrobial
therapy that will not be completed prior to Study Day 1
17. 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
18. Treatment with another investigational drug, biological agent or device within
4 weeks of Screening or 5 half-lives of Study Drug, whichever is longer
19. Treatment with any non-ISIS oligonucleotide (including siRNA) at any time
20. Prior treatment with an ISIS oligonucleotide within 9 months of Screening
21. History of excess alcohol consumption within 6 months of Screening as defined
as weekly intake of > 14 drinks per week (> 2 drinks per day) for males or
> 7 drinks per week (> 1 drink in a day) for females.  (One [1] drink is equivalent
to 12 g of alcohol, e.g., 12 ounces [360 mL] of beer, 5 ounces [150 mL] of wine
or 1.5 ounces [45 mL] of 80 proof distilled spirits)
22. History of drug abuse or dependence, or recreational use of drugs: within
3 months of Screening for soft drugs (such as marijuana) and within 1-year of
Screening for hard drugs (such as cocaine, phencyclidine [PCP])
23. Unwillingness to comply with study procedures, including follow-up, as specified
by this protocol, or unwillingness to cooperate fully with the Investigator
24. Have any other conditions (medical, social or other), which in the opinion of the
Investigator would make the patient unsuitable for inclusion, or could interfere
with the patient participating in or completing the study
25. Patients with hereditary problems of galactose intolerance, Lapp lactose
deficiency, or glucose-galactose malabsorption, unless the patient will be treated
with the lactose-free formulation of entecavir during the study
Treatment Groups 
Cohort 1:  150 mg ISIS 505358 or placebo 
Cohort 2:  300 mg ISIS 505358 or placebo 
Cohort 3:  450 mg ISIS 505358 or placebo (note: cohort was studied as 300 mg 
ISIS 505358 or placebo based on antiviral activity observed in Cohort 2 per 
Section 3.7) 
Cohort 4:  300 mg ISIS 505358 or placebo (in patients already on stable tenofovir or 
entecavir regimen) 
Study Drug Dosage and 
Administration 
ISIS 505358 (150 mg/mL, 1.0 mL) or placebo (1.0 mL), both supplied in 2-mL 
stoppered glass vials 
150 mg dose:  single 1.0 mL subcutaneous injection 
300 mg dose:  two 1.0 mL subcutaneous injections 
450 mg dose:  two 1.5 mL subcutaneous injections 
 
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PROTOCOL SYNOPSIS Continued 
Dose Escalation 
Following completion of the last Day 29 assessment in each cohort, the cumulative study 
results will be reviewed by a DSMB.  After their review of Cohort 1, the DSMB may 
recommend initiation of Cohort 2 provided the committee found the safety and tolerability 
results to be sufficient and acceptable.  Likewise, after their review of Cohort 2, they may 
recommend initiation of Cohort 3.  After completion of Study Drug administration and the last 
Day 29 assessments for Cohort 3 and for Cohort 4, respectively, the DSMB will review the 
cumulative safety and antiviral data from the study, advise on any notable treatment-emergent 
issues, and make recommendations regarding the continuation of the study and periodicity of 
further DSMB reviews during the remainder of the study.  (See Section 3.6 and 3.7 for 
additional information regarding the DSMB reviews and the dose-escalation criteria.). 
Study enrollment and dose-escalation will cease in the event that any of the following occur 
provided there is no alternative explanation other than  
ISIS 505358 administration as the cause of the event as determined by the DSMB: 
• 
Death of 1 patient 
• 
Occurrence of dose-limiting toxicity (DLT) (see Section 3.8) of the same character in 
2 patients of a dose level (e.g., 2 cases of Division of AIDS (DAIDS) Grade 3 cardiac 
ischemia) 
Discontinuation of enrollment and dose-escalation will occur when 1 of the above criteria is 
met regardless of the number of patients that have been enrolled at the time of the event.  For 
example, enrollment would be discontinued after the second patient to have DAIDS Grade 3 
cardiac ischemia related to ISIS 505358 even if there are only 2 patients that had been 
enrolled into the cohort. 
If enrollment is halted due to the above, the DSMB will make recommendations concerning the 
further treatment of the remaining patients already receiving Study Drug in the study.  The 
options include, but are not limited to, ceasing treatment with Study Drug entirely or continuing 
at reduced or current dose levels (Section 8.7). 
In the above deliberations on dose escalation and expansion of enrollment, the DSMB will also 
consider the results from the HBV serological measurements (e.g., HBsAg, HBeAg, and HBV 
DNA).  For example, the DSMB may recommend against further dose escalations despite 
acceptable safety and tolerability because of obvious attainment of maximum antiviral effect. 
Dose Limiting 
Toxicities 
For consistency in the reporting of adverse events between personnel involved in the conduct 
of this study, adverse events will be described and graded according to the Division of AIDS 
Table for Grading Severity of Adult and Pediatric Adverse Events, Version 2.0, November 
2014 (see Appendix D) except for responses at subcutaneous injection sties.  The occurrence 
of the following adverse events categorized as Possibly Related or Related to Study Drug 
administration will be considered as suspected DLTs: 
1. 
Confirmed (by repeated specimen collection) laboratory result meeting 1 of the 
treatment stopping rules in Section 8.6 
2. 
All DAIDS Grade ≥ 3 non-laboratory adverse events with the exception of flu-like 
symptoms consistent with the typical acute, transient, responses to 2ʹ-MOE ASO 
injection (e.g., fever and/or chills beginning within 6 hours of dosing that resolve 
spontaneously within 36 hours and/or fatigue lasting ≤ 7 days).  See the Guidance to the 
Investigator in the Investigator’s Brochure 
3. 
All DAIDS Grade 4 confirmed (by repeated specimen collection) laboratory adverse 
events other than the test results defined in Section 8.6 
Adverse events and laboratory abnormalities will be considered to be DLTs if there is at least a 
possible association to ISIS 505358 or there is no definite alternative explanation for the safety 
finding.  Since some of the patients will be placebo-treated and adverse events in 
placebo-treated patients cannot be DLTs, the events identified by Investigators will be 
considered suspected DLT.  The DSMB (unblinded to treatment assignment) will be the arbiter 
as to which suspected events are to be considered DLTs.  However, the DSMB will not 
recommend continuation or resumption of Study Drug dosing for any patient so as to not 
potentially make an Investigator aware of a patient’s treatment assignment.  The DSMB will 
not disclose to parties outside of the DSMB which of the suspected DLTs are actual DLTs. 
 
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PROTOCOL SYNOPSIS Continued 
Rationale for Dose and 
Schedule Selection 
The dose levels and treatment schedule replicate those tested previously in healthy 
volunteers in the multiple-dose portion of ISIS 505358-CS1 
Study Visit Schedule 
and Procedures 
Treatment with Study Drug on Study Days 1, 4, 8, 11, 15, and 22 
Additional on-treatment visit on Study Day 2 
Post-Study Drug-treatment follow-up visits on Study Days 23, 29, 36, 57, 85, 113, and 
211 
Safety and Tolerability 
Evaluations 
Adverse events, clinical chemistry, hematology, and urinalysis, concomitant medication 
usage, physical examination, ECG, vital signs 
Efficacy Evaluations 
Quantitative plasma HBV DNA 
Quantitative serum HBsAg 
Quantitative serum HBeAg, where applicable 
Qualitative anti-HBs and anti-HBe antibodies 
Pharmacokinetic 
Evaluations 
ISIS 505358 concentrations in plasma 
Tenofovir and entecavir plasma levels during the post-Study Drug treatment follow-up 
period 
Cohort 4 only: tenofovir and entecavir additionally during Screen and Study Drug 
Treatment periods 
Statistical 
Considerations 
There is no statistical rationale for the selected sample size of 8 subjects per cohort.  The 
sample size was based on prior experience with other members of the drug class to 
ensure an adequate initial assessment of the safety, tolerability and pharmacokinetics of 
ISIS 505358 while minimizing the number of subjects unnecessarily exposed to the drug. 
An unblinded interim analysis may be performed of Cohort 1–3 after all patients within 
these cohorts have progressed beyond their Study Day 29 assessments.  An unblinded 
interim analysis similarly may be performed of Cohort 4 after all Cohort 4 patients have 
progressed beyond their Study 29 assessments. 
Sponsor 
Ionis Pharmaceuticals, Inc. 
 
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STUDY DESIGN AND TREATMENT SCHEMA 
 
Dose Escalation Flow  
Patient Participation Phases 
                
 
 
 
Patient Participation Flow 
 
 
Cohort 1
8 Patients
150 mg or placebo (3:1)
Y
Y
N
N
Discontinue
Dose Escalation
Discontinue
Dose Escalation
Acceptable safety &
tolerability per DSMB
Acceptable safety &
tolerability per DSMB
Cohort 2
8 Patients
300 mg or placebo (3:1)
Cohort 3
8 Patients
450 mg or placebo (3:1)
Dosing with study drug completed
Dosing with study drug completed
Screen
Study Day
-28 to -1
Treatment
Study Days 1 – 29
(Weeks 1 – 4)
Post-Treatment Follow-up
Study Days 29 – 211
(Weeks 5 – 31)
Early Treatment 
Discontinuation
Early Term
Procedures
Study
Complete
Early 
Follow-up 
Discontinuation
or
Treatment
Period
4 Weeks
Post-Study Drug Treatment Period
[Treatment with tenofovir (or entecavir)]
26 Weeks
Screen
Period
Up to 4 Wks
D 1
W 1
D 29
W 4/5
D -28
W -4
Study Drug Administrations
[Days 1, 4, 8, 11, 15, and 22]
2
3
4
W 1
D 211
W 31
Note:  Cohort 3 was 300 mg or placebo (3:1) based on 
antiviral activity observed in Cohort 2 per Section 3.7 
Cohort 4 only:  treatment with tenofovir or entecavir during all 
periods (i.e., Screen, Treatment, and Post-Study Drug Treatment) 
 
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STUDY GLOSSARY 
Abbreviation/Acronym Definition 
2ʹ-MOE 
2ʹ-O-(2-methoxyethyl)-modified ribonucleotides 
AE 
Adverse event 
Anti-HBe antibody 
Antibody to HBV e antigen 
Anti-HBs antibody 
Antibody to HBV surface antigen 
APRI 
AST-to-Platelet Index 
ASO 
Antisense oligonucleotide 
cccDNA 
Covalently closed circular DNA 
Cmax 
Maximum observed drug concentration 
CHB 
Chronic hepatitis B 
CRP 
C-reactive protein 
DAIDS 
Division of AIDS 
DLT 
Dose-limiting toxicity 
DSMB 
Data and Safety Monitoring Board 
eCRF 
Electronic case report form 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B virus 
HBeAg 
HBV e antigen 
HBsAg 
HBV surface antigen 
HCC 
Hepatocellular cancer 
HCV 
Hepatitis C virus 
HDV 
Hepatitis D virus 
HED 
Human equivalent dose 
HIV 
Human Immunodeficiency virus 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IXRS 
Interactive voice/internet response system 
mRNA 
Messenger Ribonucleic Acid 
MRT0-24hr 
Mean plasma residence time 
n/a 
Not applicable 
NCS 
Not clinically-significant 
 
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PBMC 
Peripheral blood mononuclear cell 
PK 
Pharmacokinetic 
RNase H 
Ribonuclease H 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
siRNA 
Small interfering ribonucleic acid 
Study Day 1 
Defined as the first day Study Drug product is administered to the patient 
Study Drug 
ISIS 505358 or Placebo 
SUSAR 
Suspected unexpected serious adverse reaction 
Tenofovir 
Tenofovir disoproxil fumarate 
Tmax 
Time taken to reach Cmax  
ULN 
Upper limit of the laboratory reference range 
WHO 
World Health Organization 
 
 
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1. 
OBJECTIVES 
1.1 
Primary Objective 
To examine the safety and tolerability of ISIS 505358 administration to treatment-naive patients 
with chronic hepatitis B virus infection. 
1.2 
Secondary Objectives 
• To examine the effects of ISIS 505358 administration on plasma HBV DNA 
concentration 
• To examine the effects of ISIS 505358 administration on serum HBV surface antigen 
(HBsAg) concentration 
• To examine the effect of ISIS 505358 administration on serum HBV e antigen (HBeAg) 
concentration in the patients that were HBeAg positive at Baseline 
• To assess plasma pharmacokinetics (PK) of ISIS 505358 in patients with chronic HBV 
infection 
• To describe the safety and tolerability of tenofovir (and entecavir if administered) therapy 
following conclusion of ISIS 505358 administration  
1.3 
Exploratory Objectives 
• To describe the rate of seroconversion of patients to antibody to HBV surface antigen 
(anti-HBs antibody) positivity during treatment with ISIS 505358 and then during 
subsequent treatment with tenofovir (or entecavir) 
• To describe the seroconversion of HBeAg positive patients to antibody to HBV e antigen 
(anti-HBe antibody) positivity during treatment with ISIS 505358 and then during 
subsequent treatment with tenofovir (or entecavir) 
• To explore the effect of prior ISIS 505358 exposure on the plasma concentrations of 
tenofovir (and entecavir) administered after the conclusion of ISIS 505358 administration  
• To explore antiviral activity, safety/tolerability, and PK during concurrent treatment with 
ISIS 505358 and nucleos(t)ide analogue (i.e., tenofovir or entecavir) 
2. 
BACKGROUND AND RATIONALE 
2.1 
Overview of Disease 
Hepatitis B virus (HBV) infection, especially chronic infection, is a significant worldwide 
medical problem.  More than 2 billion of the world’s population has been infected.  Of these, the 
infection became chronic in an estimated 360 million (WHO 2009).  Every year, 1 million 
people die from HBV-related disease complications.  For those with chronic infection, up to 
20% progress to liver cirrhosis (WHO 2002).  Individuals with chronic infection also have a 
heightened risk for hepatocellular cancer (HCC).  It is estimated the lifetime risk for cirrhosis 
and/or HCC is 40-50% for men and about 15% for women with chronic infection (WHO 2002). 
 
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HBV infection is highly endemic in Southeast Asia, the Pacific Basin (except Japan, Australia 
and New Zealand), Sub-Saharan Africa, the Amazon Basin, parts of the Middle East, the 
Central Asian Republics, and some of Eastern Europe.  In these areas, 70-90% of the population 
can become HBV infected before the age of 40 years and 8-20% are chronically infected because 
infection frequently occurs at birth or early in life (WHO 2002).  The probability of developing a 
chronic infection from an acute infection is inversely linked to age at infection (90% chronic 
infection development when infected at birth, 25-50% when infected at ages 1-5 years, and 1-5% 
when infected as older children and adults) (WHO 2002). 
Chronic hepatitis B (CHB) is a spectrum of disease characterized by the presence of detectable 
hepatitis B surface antigen (HBsAg) in the blood or serum for longer than 6 months.  CHB may 
be inactive and cause no significant health problems or may progress to liver fibrosis, cirrhosis 
and HCC.  The progression of liver disease is associated with serum HBV DNA levels, serum 
ALT levels, and the severity of liver disease (EASL 2012).  CHB can be broadly divided into 
2 major forms—namely, hepatitis B virus e antigen (HBeAg) positive and HBeAg negative.  
HBeAg negative CHB is also referred to as anti-HBe-positive and precore mutant hepatitis.  
Patients with HBeAg negative CHB have a naturally occurring mutant form of HBV that does 
not produce HBeAg because of a mutation in the precore or core promoter region of the HBV 
genome.  Without treatment, both forms have a high risk of progression to advanced hepatic 
fibrosis, cirrhosis and subsequent complications if they have indicators of active liver disease 
(Lok and McMahon 2009; EASL 2012). 
2.2 
Goals of Therapy for CHB 
The goal of therapy for CHB is to improve quality of life and survival by preventing progression 
of the disease to cirrhosis, decompensated liver disease, end-stage liver disease, HCC and death.  
This goal can be achieved if HBV replication is suppressed in a sustained manner thereby 
decreasing the histological activity of CHB and reducing the risk of cirrhosis and HCC 
(Liaw et al. 2004; Feld et al. 2009).  Thus, effective therapy for CHB must ensure virological 
suppression that induces normalization of serum ALT levels, resolution of active 
necroinflammatory injury on liver biopsy, and prevention of complications. 
In both HBeAg positive and HBeAg negative CHB, the ultimate treatment endpoint is loss of 
detectable serum HBsAg (Lok and McMahon 2009; EASL 2012).  HBsAg loss is preceded by a 
robust immunological response to HBV infection that results in sustained suppression of serum 
HBV DNA and disease resolution.  Natural history studies of CHB conducted over many 
decades in large patient cohorts have shown that HBsAg loss was durable in most cases and 
associated with improved survival and reduced risk of HCC (Kim et al. 2014).  Patients who 
achieved HBsAg seroconversion had the absolute lowest risk with a cumulative risk for 
HCC < 1% over 9 years (Chen et al. 2006), including patients with compensated cirrhosis who 
had survival of nearly 100% after 14 years (Fattovich et al. 1998). 
In patients with HBeAg positive CHB, clearance of HBeAg is also associated with improved 
outcomes, provided that HBeAg loss is sustained after treatment is discontinued and the patient 
does not subsequently develop HBeAg negative CHB with recurrent disease despite loss of 
HBeAg (Feld et al. 2009).  When HBeAg loss occurs, it is associated with a decrease in 
HBV DNA to low levels, normalization of serum ALT, improved histology, and an increased 
 
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potential for HBsAg seroclearance (Liaw 2009).  Accordingly, HBeAg loss has been a major 
endpoint of antiviral therapy in CHB studies. 
First-line therapy for CHB is treatment with a nucleoside or nucleotide (nucleos(t)ide) analogue.  
At least 6 nucleos(t)ide analogues are available for the treatment of CHB patients 
(Lok and McMahon 2009; EASL 2012).  While these antiviral agents are effective in 
suppressing HBV replication in both HBeAg positive and HBeAg negative CHB, patients 
frequently relapse after treatment is discontinued, particularly if HBsAg loss was not achieved.  
Treatment with a pegylated interferon (PEG-interferon), of which 2 are available, is also 
approved for CHB (Lok and McMahon 2009; EASL 2012) for a defined treatment duration 
(usually up to 48 weeks).  Because of their frequent and sometimes severe side-effects and high 
cost vs. a small gain in treatment response, PEG-interferons are less frequently used than the 
nucleos(t)ide analogues.  Unfortunately, with both the nucleos(t)ides and PEG-interferon, 
HBsAg loss is rarely achieved.  Rates of HBsAg loss following 12 months of treatment with 
either a nucleos(t)ide or PEG-interferon generally ranged from 0-3% in most studies (Lok and 
McMahon 2009; EASL 2012).  HBeAg loss occurs more frequently following treatment with 
either the nucleos(t)ides or PEG-interferon, approximately 15-30% after 1-2 years of therapy, but 
off-treatment durability is variable and questions remain as to whether virologic responses can be 
maintained over an extended follow-up period.  Thus, the majority of patients on treatment fail to 
achieve a sustained off-treatment virological response and require extended and often life-long 
therapy to suppress HBV DNA. 
2.3 
Therapeutic Rationale 
Among the features that distinguish patients that have resolved their HBV infection from patients 
with chronic HBV infections is the latter remain positive for circulating HBsAg and negative for 
free anti-HBs antibody (Robinson 1995).  The HBsAg in the serum of infected patients is found 
in 3 forms:  (1) 42 nm, spherical particles (i.e., infectious virus also known as Dane particles); 
(2) 15-25 nm spherical particles; and (3) 20 x 20-200 nm filaments.  The latter 2 represent 
incomplete virus particles.  The amount of HBsAg in incomplete virus particles is more than 
100 times of that in infectious particles.
It has been proposed that the continued production of viral antigens by infected hepatocytes 
interferes with immune clearance of both the infected cells and circulating virus particles 
(Vanlandschoot and Leroux-Roels 2003).  In vitro studies with human peripheral blood 
mononuclear cells (PBMC) have shown HBsAg impairs the functioning of dendritic cells and 
inhibits the activation of monocytes (Vanlandschoot et al. 2002; Op den Brouw et al. 2009).  
Most chronically infected patients produce antibody to HBsAg, but these can only be detected as 
immune complexes due to the vast excess of circulating antigen (Maruyama et al. 1993).  
HBeAg is also thought to have a role in immune response evasion through down-regulation of 
the innate immune system (Milich et al. 1998; Wu et al. 2009; Walsh and Locarnini 2012).  As 
noted above, since loss of HBsAg expression is rarely achieved while loss of HBeAg expression 
occurs in a higher proportion of the patient population, HBsAg appears to be the main antagonist 
of immune clearance. 
Should the viral antigens be instrumental in preventing clearance of persistent infection by the 
immune system, reducing the expression of these antigens, especially HBsAg, would be 
expected to permit reconstitution of an immune response against HBV (Boni et al. 2007; 
 
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Boni et al. 2012; Bertoletti and Ferrari 2013).  Support for this hypothesis is the observation that 
spontaneous seroconversion and resolution of chronic infection is most likely in patients that 
have lower serum HBsAg levels (Chen et al. 2012; Höner zu Siederdissen and Cornberg 2014).  
Similarly, during treatment with nucleos(t)ide analogues, patients with low HBsAg levels are 
more likely to lose HBsAg and seroconvert to anti-HBs antibody positive than patients with high 
HBsAg levels (Wursthorn et al. 2010; Jaroszewicz et al. 2011; Boni et al. 2012; 
Höner zu Siederdissen and Cornberg 2014). 
In CHB patients treated with PEG-interferon, those that achieved sustained virologic responses 
were observed to have substantially more serum HBsAg reduction than non-responders.  For 
HBeAg-positive CHB patients, a mean HBsAg reduction of 3.3 log at the end of treatment was 
reported for responders compared to 0.69 log for non-responders (Sonneveld et al. 2010).  For 
HBeAg-negative patients, mean HBsAg reductions of 1.1–2.1 log at the end of treatment have 
been described for responders and < 0.3 log for non-responders (Brunetto et al. 2009; 
Moucari et al. 2009; Rijckborst et al. 2010).  These observations are consistent with the 
hypothesis that high HBsAg levels inhibit viral clearance. 
ISIS 505358 is antisense inhibitor that is designed to inhibit the synthesis of viral proteins 
(e.g., HBsAg, HBeAg) without having a direct effect on covalently closed circular DNA 
(cccDNA) or integrated HBV DNA.  ISIS 505358 also is not an immune modulator.  Therefore, 
treatment of CHB subjects with ISIS 505358 will permit examination of whether reduction of 
viral proteins allows resumption of a host immune response against HBV virus and infected cells 
and can induce HBsAg and/or HBeAg seroclearance leading to sustained suppression of HBV 
replication after cessation of all treatments for CHB. 
2.4 
ISIS 505358 
2.4.1 
Mechanism of Action 
ISIS 505358 is a 2ʹ-O-(2-methoxyethyl)-modified chimeric phosphorothioate antisense 
oligonucleotide (2′-MOE chimeric ASO) drug targeted to HBV RNAs.  It is complementary to a 
region present in all 4 of the messenger ribonucleic acid (mRNA) and the pre-genomic RNA 
produced by the virus.  The ISIS 505358 binding site is downstream of the pre-core, core and 
surface antigen (pre-S1, pre-S2, and S) coding sequences and within the coding sequences for 
polymerase and X protein.  The HBV direct repeat 2 sequence (DR2) is contained within the 
ISIS 505358 binding site.  The binding site is highly conserved across all HBV genotypes 
(i.e., complete complementarity to 98% of approximately 2900 HBV genomic sequences 
compiled from publicly available sequences).  ISIS 505358 binds to RNA by Watson and Crick 
base pairing.  The hybridization (binding) of ISIS 505358 to the cognate RNA results in the 
RNase H-mediated degradation of the RNA and thereby prevents the production of the 
proteins translated from the RNA (Figure 1).  Maximal antisense-mediated reduction of 
target mRNA levels is typically greater than 90% of control levels in sensitive tissues 
(Crooke and Bennett 1996; Zhang et al. 2010).  Furthermore, reduction in target mRNA levels 
using this approach correlates directly with a subsequent reduction in target protein levels.  
ISIS 505358 was selected for clinical development based upon its superior potency in inhibiting 
the HBV surface antigen (HBsAg) levels of transgenic mice that produce HBV.  It also reduces 
HBeAg, total HBV RNA, and HBV DNA in these mice. 
 
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2.4.2 
Chemistry 
Chemically, ISIS 505358 is a synthetic oligomer of 20 nucleotides (i.e., a 20-mer) that are 
connected sequentially by phosphorothioate linkages.  The nucleotide sequence of ISIS 505358 
is complementary to a 20-nucleotide sequence present in all 4 mRNAs and the pre-genomic 
RNAs of HBV.  Structurally, the oligonucleotide has 3 regions (Figure 1).  Two (2) of them, the 
5 nucleotides at the 5′-end (N1–N5) and the 5 nucleotides at the 3′-end (N16–N20), are composed 
of MOE-modified ribonucleotides.  These MOE-modified nucleotides confer (1) increased 
affinity to the target mRNA (Altmann et al. 1996; McKay et al. 1999), (2) increased resistance to 
exonucleases and endonucleases (thereby increasing stability in tissue) (Geary et al. 2003), and 
(3) amelioration of some of the high dose toxicities resulting in an improved safety profile 
compared to first generation antisense drugs containing phosphorothioate-modified 
oligodeoxynucleotides (DNA) (Henry et al. 2000).  The third region, the central portion of the 
oligonucleotide (N6–N15), is composed of 10 oligodeoxynucleotides.  ASOs with this chimeric 
design are sometimes referred to as MOE-gapmers.  ISIS 505358 employs this chimeric structure 
to enable use of the RNase H1-mechanism for antisense activity.  This is because while the 
2′-MOE modification confers increased stability and affinity, it does not support RNase H1 
catalysis of RNA hybridized to 2′-MOE-modified nucleotides (McKay et al. 1999).  This is 
caused by conformational changes induced in the heteroduplex by 2′-alkoxy:RNA hybrids that 
are not recognized by RNase H enzymes (Inoue et al. 1987; Monia et al. 1993).  By limiting the 
2′-MOE modification to nucleotides flanking the phosphorothioate oligodeoxynucleotide core, 
the beneficial attributes of the 2′-MOE chemistry are preserved while also retaining RNase H 
recognition. 
 
Figure 1 
Structure of 2ʹ-MOE Chimeric Phosphorothioate Oligonucleotides.  
Each N is either A, G, T, or 5-methyl-C 
 
The 2′-MOE chimeric ASO chemical class is the most advanced class of drugs designed to target 
mRNA.  Clinical studies have been performed for 34 of these drugs.  In aggregate, more than 
130 clinical studies have been performed and approximately 5,600 subjects have been dosed with 
2′-MOE chimeric ASO s by intravenous and/or subcutaneous administration.  These studies 
include treatments with doses as high as 1200 mg.  With several class members, there is a 
substantial 3-month duration treatment experience (approximately 1,700 patients in aggregate) 
and for 1 drug, patients have been treated for more than 4 years.  One (1) class member, 
Kynamro®, received marketing approval from the US Food and Drug Administration in 
January 2013 for the treatment of patients with homozygous familial hypercholesterolemia. 
N1 N2 N3 N4 N5
N6 N7 N8 N9 N10 N11 N12 N13 N14 N15
N16 N17 N18 N19 N20
2ʹ- MOE
2ʹ- MOE
2ʹ- Deoxy
(RNase H Sensitive)
Phosphorothioate
Backbone
 
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Other chemical classes of RNA-targeting oligonucleotide drugs are also in clinical 
development including, but not limited to, locked nucleic acid (LNA) chimeras, fully 
2′-O-methyl-modified phosphorothioates, morpholinos, and small interfering ribonucleic acids 
(siRNAs) (Bennett and Swayze 2010).  While the clinical trial data for these other chemical 
classes is more limited than that for 2′-MOE chimeric ASOs, it is clear that each chemical class 
has a unique profile with regard to efficacy, potency, and adverse events (AEs).  There have been 
reports of renal and hepatic effects for some of these other chemistries that have not been 
observed with 2′-MOE chimeric ASOs (Goemans et al. 2011; van Poelgeest et al. 2013; 
Kakiuchi-Kiyota et al. 2014).  Therefore, the results from these other chemical classes should not 
be extrapolated to 2′-MOE chimeric ASOs or vice versa. 
2.4.3 
Preclinical Experience 
Detailed information concerning the preclinical studies conducted with ISIS 505358 can be 
found in the Investigator’s Brochure. 
The nonclinical toxicology of ISIS 505358 was examined in 13-week and 6-month repeated-dose 
general toxicology studies in mice, 13-week and 9-month studies in monkey, 2 in-vitro 
genotoxicity studies (Ames bacterial reverse mutation assay and chromosomal aberration assay 
in CHO cells), 2 safety pharmacology studies (a combined cardiovascular and respiratory 
function study in monkey and an Irwin’s CNS study in mice) and in segment I and II 
reproductive toxicology studies.  No significant toxicities were observed in the 13-week 
toxicology studies to preclude development of the doses and durations being proposed for 
clinical study.  Most of the observed effects were minimal-to-mild in severity, occurred at doses 
above the anticipated human exposure, and are typical for 2′-MOE chimeric ASOs administered 
at high (30-40 mg/kg) subcutaneous doses (e.g., in monkeys: transient aPTT prolongation, 
transient increases of complement split products such as Bb, uptake and accumulation of 
oligonucleotide in tissues as evidenced by the presence of basophilic granules within liver 
Kupffer cells and kidney proximal tubule epithelial cells, and mild (1.3-1.8 fold) increases in 
spleen weight). 
In the 9-month toxicology study, 6 monkeys were terminated early during the treatment portion 
and 1 animal was discontinued prematurely during the 3-month recovery phase of the study.  
These events were either related to monkey-specific responses to high dose 2′-MOE chimeric 
ASO administration (i.e., related to chronic, repeated, low-level complement pathway activation) 
or to spontaneous, naturally-occurring events (e.g., gastric ulcer, recurrent rectal prolapse, 
spontaneous glomerulosclerosis, and pulmonary embolism).  With other 2′-MOE chimeric 
MOE ASOs where both monkey and human treatment experience exists, the complement 
pathway responses observed in monkeys were not observed in humans (Shen et al. 2014). 
The genotoxicity and reproductive toxicology studies were negative, and no adverse effects were 
observed in the safety pharmacology studies. 
The plasma pharmacokinetics (toxicokinetics) and tissue distribution of ISIS 505358 were also 
investigated in the above general toxicology studies.  The results were consistent with those 
observed for other 2′-MOE chimeric ASOs (Geary et al. 2008).  After subcutaneous injection in 
monkeys, ISIS 505358 rapidly distributed from the injection site to the blood stream and then to 
tissues within 48 hours.  The mean residence time for ISIS 505358 in plasma during this 
 
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distribution phase is 5-8 hours.  While 2′-MOE chimeric ASOs distribute to almost all tissues 
(CNS being a notable exception), liver and kidney are the main organs for ASO distribution.  
The half-life of 2′-MOE chimeric ASO drug class members in tissue is typically 2-4 weeks with 
nucleolytic degradation as the metabolic mechanism.  For monkeys treated with ISIS 505358, the 
half-life of the drug in kidney cortex was 13.3-15.7 days and in liver was 8.7-19.9 days.  
Consistent with slow clearance from tissues, the plasma terminal elimination half-life of 
ISIS 505358 in monkeys was 10.6-43 days. 
2.4.4 
Clinical Experience 
2.4.4.1 
ISIS 505358-CS1 
Clinical results for ISIS 505358 are available from one completed study, ISIS 505358-CS1, a 
Phase 1, blinded, placebo-controlled, dose escalation study designed to assess the safety, 
tolerability and pharmacokinetics of single and multiple doses of ISIS 505358 administered to 
healthy subjects.  A detailed summary of the results from ISIS 505358-CS1 are provided in the 
Investigator’s Brochure. 
Briefly, the trial evaluated single-dose treatments at 4 ISIS 505358 dose levels (75, 150, 300, and 
450 mg) and multiple-dose treatments at 3 dose levels (150, 300, and 450 mg).  For each single 
and multiple-dose treatment dose level, 4 subjects were randomized, 3 to ISIS 505358 and 1 to 
placebo.  All treatments were administered by subcutaneous injection.  For the multiple-dose 
treatments, there was a 2-week loading regimen (2 doses/wk) followed by a 2-week maintenance 
schedule (1 dose/wk) such that subjects were to be dosed on Days 1, 4, 8, 11, 15, and 22.  All 
subjects successfully received all Study Drug doses and completed all follow-up assessments.  A 
total of 28 healthy subjects received treatment – 21 with ISIS 505358.  The subjects were mostly 
male (22 vs. 6) and white (24 vs. 4) with a median age of 53 years (range:  27–62 years). 
The tolerability for treatment with ISIS 505358 was satisfactory across all dose levels.  A total of 
198 adverse events were reported.  Aside from 2 that were of moderate intensity (MedDRA 
preferred terms of (i) Productive Cough and (ii) Face Injury), all were of mild intensity.  The 
bulk of the adverse events (72% for the multiple-dose subjects) involved subcutaneous injection 
sites.  Approximately one-half of these injection site events were symptoms of short duration 
(minutes to hours) including brief muscle twitches, transient discomfort/pain, and short-lived 
erythema.  Local cutaneous reactions at the injection site (LCRIS, defined as those events 
presenting as pain, tenderness, erythema, pruritus or swelling occurring on the day of injection 
and persisting for at least 2 days) were limited to the subjects treated with ISIS 505358 at the 
300 mg and 450 mg doses.  The median duration of an LCRIS was 4 days and subjects varied in 
the number of doses that were followed by an LCRIS (median of 2 out of 6 doses). 
The second most common adverse event was C-Reactive Protein Increased (5 of 12 ISIS 505358 
single-dose subjects and 6 of 9 ISIS 505358 multiple-dose subjects).  From the laboratory results, 
elevated C-reactive protein (CRP) levels were observed associated with the initial ISIS 505358 
doses of 300 mg and 450 mg in ISIS 505358-CS1.  No systemic symptoms consistent with an 
inflammatory response (e.g., fever, chills, body aches) were reported to coincide with the 
elevations.  In the multiple-dose subjects, the prevalence of CRP increases after the 6th dose of 
300 mg and 450 mg ISIS 505358 was much reduced.  Similar transient increases in CRP have 
 
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been observed following the dosing of some other 2′-MOE chimeric ASOs.  The significance of 
asymptomatic transient CRP elevations following early ISIS 505358 doses is unknown. 
There were no serious adverse events (SAEs) or adverse events leading to treatment 
discontinuation.  In the laboratory results, 1 subject in the 300 mg ISIS 505358 dose group had 
2 asymptomatic ALT elevations to 106 and 108 U/L (2.6 x upper limit of the laboratory 
reference range [ULN]) of unknown origin.  Despite this patient, the overall liver chemistry 
results in ISIS 505358-CS1 do not raise a hepatic effect concern.  There were no changes in 
laboratory results to suggest any adverse effects of ISIS 505358 on renal function, hematological 
cell counts, hemoglobin, or the complement pathway.  The known transient non-significant 
effect of 2ʹ-MOE chimeric ASOs on aPTT was observed.  There were no treatment related 
changes in vital signs or ECG results. 
Clinical pharmacokinetics analyses produced results consistent with the profiles of other 2ʹ-MOE 
chimeric ASOs.  The plasma Cmax of ISIS 505358 was dose-related and was approximately 
11.0-15.8 µg/mL following injection of 450 mg.  Tmax occurred 3-8 hour after injection and mean 
plasma residence time (MRT0-24hr) was approximately 8 hours due to the rapid distribution of 
drug from blood to tissue.  In the multiple-dose subjects, the PK characteristics following the 
first dose and the 6th dose were highly similar which reflects the known lack of significant drug 
accumulation in the plasma by 2ʹ-MOE chimeric ASOs. 
Overall, continued clinical development of ISIS 505358 is supported by the results from 
ISIS 505358-CS1.  
2.4.4.2 
ISIS 505358-CS3 
Interim blinded results from Cohort 1 (150 mg or placebo, 6:2 ratio), Cohort 2 (300 mg or 
placebo, 6:2 ratio), and Cohort 3 (300 mg or placebo, 6 patients, ratio unknown) are available.  
There has been one SAE in the study—Alanine aminotransferase increased.  A patient in 
Cohort 2 experienced an ALT elevation that peaked at 781 U/L (23.7 x ULN, ULN = 33) on 
Study Day 38 (15 days after last protocol-specified dose of Study Drug).  ALT levels declined to 
< 5 x ULN within 11 days and became consistently < 3 x ULN by Day 72.  The patient had a 
lesser concurrent AST elevation.  Her total bilirubin levels were stable throughout the study.  
This ALT elevation temporally coincided with HBsAg and HBV DNA reduction to less than the 
lower limit of quantitation and therefore may have been secondary to the clearance of infected 
hepatocytes. 
Three (3) additional patients—2 in Cohort 1 and 1 in Cohort 2—experienced treatment-emergent 
elevations of ALT to > 3 x ULN.  None had changes in total bilirubin levels.  Like the 
aforementioned patient with SAE, the ALT elevations of these 3 patients were temporally related 
to reductions in HBsAg.  However, there were other patients in ISIS 505358-CS3 with HBsAg 
reductions but without ALT elevation.  Therefore, the possibility that the ALT elevations are a 
direct adverse effect (wholly or partially) of ISIS 505358 on the liver cannot be entirely 
excluded. 
Some activity against HBV was observed in the treatment-naïve patients treated in 
ISIS 505358-CS3.  Three (3) of the 8 patients in Cohort 1 had HBsAg reductions of 0.39, 1.19, 
and 1.24 log10 IU/mL.  Five (5) of the 8 patients in Cohort 2 had HBsAg reductions of 0.462, 
 
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1.19, 1.96, 2.57, and 3.80 log10 IU/mL.  A 6th patient in Cohort 2 had a 0.81 log10 IU/mL 
reduction in HBV DNA although the patient’s HBsAg reduction was minimal (0.12 log10 
IU/mL).  Dose-related reductions in HBV DNA were also observed in the study.  This antiviral 
activity was observed in both HBeAg positive and negative patients.  In Cohort 3, one (1) of the 
patients was observed to have developed a 3.33 log10 IU/ml reduction in HBsAg and 3.53 log10 
IU/ml reduction in HBV DNA on Day 29.  Two (2) other patients each had 0.43 log10 IU/mL 
reductions of HBsAg and a 4th patient had a reduction of HBV DNA of 0.77 log10 IU/mL despite 
minimal HBsAg reduction. 
Overall, continued clinical development of ISIS 505358 is supported by the results from 
ISIS 505358-CS1 and the emerging results from ISIS 505358-CS3. 
2.5 
ISIS 505358 Dose and Schedule of Administration Rationale 
2.5.1 
Target Dose Levels 
The dose of ISIS 505358 that produced 90% reduction of HBsAg levels (i.e., the ED90) in the 
preclinical HBV transgenic mouse model was 20 mg/kg.  For 2′-MOE chimeric ASOs, the 
human equivalent dose (HED) is most accurately estimated from the mouse dose based on 
dose-adjusted plasma AUCs (Yu et al. 2015).  By this scaling, the HED is 5-fold lower than the 
mouse dose and therefore the human ED90 for ISIS 505358 is estimated to be 4.0 mg/kg or 
280 mg for a 70 kg human. 
To investigate the role of HBsAg in maintaining the persistence of HBV infection, it is desirable 
to reduce HBsAg levels as much as possible.  Therefore, doses of 300 and 450 mg were included 
for study in ISIS 505358-CS3 because these 2 dose levels (1) are > 280 mg, (2) were repeatedly 
administered for 4 weeks to healthy volunteers with acceptable safety and tolerability in 
ISIS 505358-CS1, (3) are simple multiples of the 150 mg/mL ISIS 505358 drug product, 
(4) were lower than 840 mg for 70 kg human, the human equivalent of the NOAEL level of 
12 mg/kg in monkeys, and (5) are in the range of doses that other 2′-MOE chimeric ASOs have 
been successfully administered by subcutaneous injection for 13-week durations and found to be 
generally safe and well-tolerated.  Doses higher than 450 mg ISIS 505358 were not selected for 
study due to the number of injections necessary for administering more than 3 mL of drug 
product per dose. 
2.5.2 
Treatment Duration 
The 4-week treatment duration of ISIS 505358-CS3 was selected to replicate the 4-week 
duration of the already completed healthy volunteer study.  This duration is less than one-third of 
the duration of the 13-week IND-enabling preclinical general toxicology studies (see 
Section 2.4.3 and the Investigator’s Brochure, Revision 2 dated 17 February 2015). 
2.5.3 
Loading/Maintenance Dosing 
For drugs such as ISIS 505358 that have tissue concentration half-lives of 2-3 weeks, regular 
repeated dosing (e.g., once weekly) for 10-15 weeks (i.e., 5 x half-life) is required to achieve 
steady state drug concentrations in tissues.  Such dosing schedules, therefore, would potentially 
result in prolonged exposure of the resident HBV to sub-therapeutic concentrations of 
ISIS 505358 which, in turn, could promote proliferation of any potential resistance variants.  The 
 
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extended time to steady-state also hinders reaching conclusions about the safety and 
pharmacological effects of ISIS 505358 in short duration studies. 
For the pharmacological activity of ISIS 505358 on HBsAg production, the amount of drug in 
the liver is the important determinant as opposed to the amount of drug in plasma.  From PK 
measurements in monkey, the half-life of ISIS 505358 in the liver was estimated as 
approximately 2 weeks (Section 2.4.3 and the Investigator’s Brochure, Revision 2 dated 
17 February 2015).  The half-life in human liver is expected to be similar to that measured in 
monkeys. 
In order to accelerate reaching steady-state concentrations in tissues and thereby both reduce the 
duration of exposure to sub-therapeutic concentrations of ISIS 505358 and permit fuller 
assessment of the ISIS 505358 effects on safety during this 4-week treatment study, loading 
doses are included in the dosing schedule in ISIS 505358-CS3.  Extra doses are added to 
Weeks 1 and 2 so that Study Drug will be administered twice in Weeks 1 and 2 (on Days 1, 4, 8, 
and 11) before switching to once weekly during Weeks 3 and 4.  Inclusion of the loading 
schedule is predicted to result in achievement of hepatic steady-state concentrations following 
the Week 3 dose (i.e., before the last dose in schedule).  The ISIS 505358-CS3 dosing regimen is 
supported by both the toxicology studies which employed loading regimens and the results from 
the completed healthy volunteer study, ISIS 505358-CS1, which used the same dosing schedule 
as in this protocol.  
2.6 
Combination of ISIS 505358 with Nucleos(t)ide Analogue 
The differences in pharmacokinetic behavior between drugs like ISIS 505358 and nucleos(t)ide 
analogues indicate drug-drug interaction between the 2 drug types is unlikely.  The antiviral and 
safety results from Cohorts 1–2 of ISIS 505358-CS3 are consistent with that expectation. 
Drugs of the 2′-MOE ASO class, like ISIS 505358, rapidly become highly bound (∼95%) to 
serum proteins upon entry into the blood stream and are then rapidly distributed (t1/2 ∼2 hr) to 
tissues where these drugs enter cells through target mediated endocytosis and micropinocytosis 
(Geary et al. 2008; Bennett and Swayze 2010).  2′-MOE ASOs are eliminated primarily by 
nucleolytic degradation (Geary et al. 2008).  None of these processes are inhibited by 
small-molecule drugs like nucleos(t)ide analogues. 
Conversely, tenofovir, entecavir, and other nucleos(t)ide analogues circulated in the blood stream 
with little binding to serum proteins and are eliminated in urine as intact drug by a combination 
of glomerular filtration and active secretion (Bristol-Myers Squibb 2018; Gilead 2018).  The 
renal elimination has been shown to be mediated by the organic anion transporters OAT1, OAT3 
and OCT2 (Cihlar et al. 2001; Uwai et al. 2007; Xu et al. 2013).  2′-MOE ASO have been shown 
to be neither substrates nor inhibitors of OAT1, OAT3, or OCT2 (Yu et al. 2016; 
Shemesh et al. 2017). 
In Cohorts 1–2 of ISIS 505358-CS3, tenofovir dosing was started on Study Day 29, which is 
7-days after the last dosing of ISIS 505358.  Since the ASO has a long tissue half-life (2-3 weeks 
based on the non-clinical studies), there is a period of at least several weeks during which there 
will be a substantial presence of both drugs in the livers and other tissues of treated patients.  For 
Cohorts 1 and 2, potent reduction of HBV DNA was observed following initiation of tenofovir in 
 
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all patients.  There were no obvious differences in tenofovir potency between the cohorts 
consistent with the different ISIS 505358 dose levels of the 2 cohorts nor were there differences 
within cohorts that possibly indicate a difference between ASO and placebo-treated patients.  
Neither were there any adverse event or clinical laboratory results suggestive of a safety effect 
due to drug-drug interaction.  The results from Cohort 3 to date are consistent with Cohort 2.   
3. 
EXPERIMENTAL PLAN 
3.1 
Study Design 
This study examines the effects of ISIS 505358 or placebo (3:1 randomization) administered 
subcutaneously to treatment-naïve patients who are chronically infected with HBV and the 
effects of subsequent nucleos(t)ide analogue treatment of these patients.  Three (3) ISIS 505358 
dose levels will be evaluated through the treatment of 3 sequential cohorts of 8 patients each: 
• Cohort 1 (150 mg ISIS 505358 or placebo) 
• Cohort 2 (300 mg ISIS 505358 or placebo) 
• Cohort 3 (450 mg ISIS 505358 or placebo) (note:  cohort was studied as 300 mg 
ISIS 505358 or placebo based on antiviral activity observed in Cohort 2 per Section 3.7) 
In these cohorts, 6 patients will be randomized to treatment with ISIS 505358 and 2 patients to 
treatment with placebo.  Patients enrolled into the study may be either HBeAg positive (+) or 
negative (-). 
For each patient, Study Drug (ISIS 505358 or placebo) will be administered twice in Weeks 1 
and 2 (on Days 1, 4, 8, and 11), and then once weekly during Weeks 3 and 4 (i.e., on Days 15 
and 22).  On Day 29, the effects of Study Drug treatment will be assessed.  After these 
assessments, all patients will then commence chronic daily treatment with tenofovir disoproxil 
fumarate (tenofovir) (entecavir if judged more appropriate by the patient or Investigator) for 
6 months.  Continuation of nucleos(t)ide analogue after discontinuation from this study will be 
the decision of the patient in consultation with their physician. 
One exploratory cohort (Cohort 4) will examine add-on treatment of patients already on stable 
nucleos(t)ide analogue (i.e., tenofovir or entecavir) regimen with 300 mg ISIS 505358 or placebo 
(3:1 randomization).  Patients enrolled into the study may be either HBeAg positive (+) or 
negative (-). 
The target size of Cohort 4 is approximately 8 patients, but the size may range from 4 to > 8 
depending upon availability of participants.  Each patient randomized into Cohort 4 is expected 
to continue their ongoing nucleos(t)ide analogue regimen and be treated with Study Drug by the 
above schedule for Cohorts 1–3.  After Day 22, the patients are expected to continue their 
ongoing nucleos(t)ide analogue regimen and be followed until Day 211.  On Day 29, the effects 
of Study Drug treatment will be assessed. 
An independent Data and Safety Monitoring Committee (DSMB) will participate in the review 
of the study results and in the dose-escalation decisions (see Sections 3.6 and 3.7). 
 
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3.2 
Number of Study Centers 
This study will be conducted at multiple centers both in and outside of the United States. 
3.3 
Number of Subjects 
Approximately 32 patients will be treated with Study Drug in this study.  Additional patients 
may be treated due to difficulties of coordinating screening and enrollment from multiple sites 
and/or to replace patients that discontinue from cohorts before Day 29 for non-adverse event 
reasons but the actual number treated will not exceed 48. 
3.4 
Overall Study Duration and Follow-up 
The Study will consist of screening, treatment, and post-treatment follow-up periods.  Please 
refer to the Schedule of Procedures in Appendix A. 
3.4.1 
Screening 
Subject eligibility for the Study will be determined within 28 days prior to first Study Drug dose.  
Patients in screening for Cohort 4 are expected to continue to take their pre-existing ongoing 
nucleos(t)ide analogue therapy. 
3.4.2 
Treatment 
Eligible subjects will report to the Study Center for treatment with Study Drug on Study Days 1, 
4, 8, 11, 15, and 22.  They will additionally report to the Study Center for assessment on Study 
Days 2, 23, and 29.  
Patients in Cohort 4 are expected to continue to take their ongoing nucleos(t)ide analogue 
therapy during this period. 
3.4.3 
Post-Study Drug Treatment Follow-Up 
During the Post-Study Drug Treatment Follow-Up period, patients in Cohorts 1–3 will be 
treated with tenofovir (entecavir if judged more appropriate by the patient or Investigator) for 
6 months commencing after the assessments of Day 29.  Subjects are to return to the Study 
Center for follow-up visits on Study Days 36, 57, 85, 113, and 211.  The final study visit will be 
Study Day 211.  
Patients in Cohort 4 are expected to continue their nucleos(t)ide analogue therapy that was 
ongoing prior to Screening.  Follow-up visits will be performed on Study Days 36, 57, 85, 113, 
and 211.  The final study visit will be Study Day 211. 
3.5 
End of Study 
The End-of-Study is defined as last patient, last visit. 
3.6 
Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) will be assembled to review safety, 
tolerability and antiviral activity data collected on during this study.  Based on the DSMB’s 
regular assessments of the safety and tolerability of ISIS 505358, the DSMB will provide 
recommendations to the Sponsor for continuing the study as planned or for modifying or 
stopping cohorts and/or the study. 
 
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Following the completion of the last Day 29 assessment in each cohort, the DSMB will review 
the cumulative safety and tolerability results from the study and make dose-escalation 
recommendations.  Should the committee find the safety and tolerability results to be sufficient 
and acceptable after their review of results from Cohort 1, the committee may recommend 
initiation of Cohort 2.  Likewise, after their review of Cohort 2, the committee may recommend 
initiation of Cohort 3.  For the Cohort 2 through-Day 29 review, the DSMB will also be provided 
with the Cohort 1 post-Study Drug treatment results that have emerged since the Cohort 1 
dose-escalation review.  The DSMB will consider those results in forming their 
recommendations on study continuation. 
After completion of Study Drug administration and the last Study Day 29 assessment for 
Cohort 3 and for Cohort 4, respectively, the DSMB will again review the cumulative study 
results, advise on any notable treatment-emergent issues, and make recommendations regarding 
the continuation of the study and the periodicity of further DSMB reviews during reminder of the 
study.  At any time during the study, the DSMB may also make recommendation regarding the 
frequency of their reviews, increases or decreases to the sizes of Cohorts 1-3, and/or introduction 
of cohorts to evaluated intermediate dose levels. 
Additional details on the assessments, frequency of review, meeting schedules and controlled 
access to unblinded data will be outlined in the DSMB Charter and Statistical Analysis Plan 
(SAP). 
3.7 
Dose Escalation 
Study enrollment and dose-escalation will cease in the event that any of the following occur 
provided there is no alternative explanation other than ISIS 505358 administration as the cause 
of the event as determined by the DSMB: 
• Death of 1 patient 
• Occurrence of dose-limiting toxicity (DLT) (see Section 3.8) of the same character in 
2 patients of a dose level (e.g., 2 cases of Division of AIDS (DAIDS) Grade 3 cardiac 
ischemia) 
Discontinuation of enrollment and dose-escalation will occur when 1 of the above criteria is met 
regardless of the number of patients that have been enrolled at the time of the event.  For 
example, enrollment would be discontinued after the second patient to have DAIDS Grade 3 
cardiac ischemia related to ISIS 505358 even if there are only 2 patients that had been enrolled 
into the cohort. 
If enrollment is halted due to the above, the DSMB will make recommendations concerning the 
further treatment of the remaining patients already receiving Study Drug in the study.  The 
options include, but are not limited to, ceasing treatment with Study Drug entirely or continuing 
at reduced or current dose levels (Section 8.7). 
In the above deliberations on dose escalation and expansion of enrollment, the DSMB will also 
consider the results from the HBV serological measurements (e.g., HBsAg, HBeAg, and 
HBV DNA).  For example, the DSMB may recommend against further dose escalations despite 
acceptable safety and tolerability because of obvious attainment of maximum antiviral effect. 
 
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3.8 
Dose Limiting Toxicity 
For consistency in the reporting of adverse events between personnel involved in the conduct of 
this study, adverse events will be described and graded according to the Division of AIDS Table 
for Grading Severity of Adult and Pediatric Adverse Events, Version 2.0, November 2014 (see 
Appendix D) except for responses at subcutaneous injections sites.  Responses at injection sites 
will be graded according to the mild, moderate, and severe criteria defined in Section 9.4.3.2 to 
allow comparison to the results from this study to those obtained in ISIS 505358-CS1 and to the 
clinical study results from other 2′-MOE chimeric ASOs.  The occurrence of the following 
adverse events categorized as Possibly Related or Related to Study Drug administration will be 
considered as suspected DLTs: 
1. Confirmed (by repeated specimen collection) laboratory result meeting 1 of the treatment 
stopping rules in Section 8.6 
2. All DAIDS Grade ≥ 3 non-laboratory adverse events with the exception of flu-like 
symptoms consistent with the typical acute, transient, responses to 2ʹ-MOE ASO 
injection (e.g., fever and/or chills beginning within 6 hours of dosing that resolve 
spontaneously within 36 hours and/or fatigue lasting ≤ 7 days).  See the Guidance to the 
Investigator in the Investigator’s Brochure. 
3. All DAIDS Grade 4 confirmed (by repeated specimen collection) laboratory adverse 
events except the test results defined in Section 8.6 
Adverse events and laboratory abnormalities will be considered to be DLTs if there is at least a 
possible association to ISIS 505358 or there is no definite alternative explanation for the safety 
finding.  Since some of the patients will be placebo-treated and adverse events in placebo-treated 
patients cannot be DLTs, the events identified by Investigators will be considered suspected 
DLT.  The DSMB (unblinded to treatment assignment) will be the arbiter as to which suspected 
events are to be considered DLTs.  However, the DSMB will not recommend continuation or 
resumption of Study Drug dosing for any patient so as to not potentially make an Investigator 
aware of a patient’s treatment assignment.  The DSMB will not disclose to parties outside of the 
DSMB which of the suspected DLTs are actual DLTs. 
4. 
SUBJECT ENROLLMENT 
4.1 
Screening 
Before patients may be enrolled into the study, the Sponsor or designee requires a copy of the 
Study Center’s written Institutional Review Board (IRB) approval of the protocol, informed 
consent form, and all other patient information and/or recruitment material. 
Patients must sign the consent form before any screening tests or assessments are performed.  At 
the time of consent, the patient 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, patients will be assigned a unique patient 
identification number.  This number will be used to identify the patient throughout the trial and 
must be used on all study documentation related to that patient.  The screening number and 
patient identification number must remain constant throughout the entire trial.  In the event the 
patient is re-consented and re-screened, the patient must be given a new screening number and, if 
 
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re-randomized, a new patient identification number.  Screening numbers and patient 
identification numbers, once assigned, will not be re-used. 
If a patient has an exclusionary result(s) in their Screening laboratory tests, and the Investigator 
has reason to believe the result is erroneous, the Investigator may discuss his reasons with the 
Ionis Medical Monitor or designee.  The Ionis Medical Monitor or designee may give approval 
for retesting and will specify the number of retests, or alternative tests, and the testing schedule 
that must be met in order to qualify the patient for inclusion in the study. 
4.2 
Randomization 
Patients will be randomized prior to the first dose of Study Drug (ISIS 505358 or placebo), after 
all screening assessments have been completed and after the Investigator has verified that they 
are eligible per criteria in Sections 5.1 and 5.2.  No patient may begin treatment prior to 
randomization and assignment of a unique patient identification number. 
The Investigator or designee will obtain the patient’s identification number and cohort, and 
Study Drug kit number from an Interactive Voice/Internet Response System (IXRS).  The system 
will randomize eligible patients 3:1 to receive ISIS 505358 or placebo, respectively. 
A permuted block schedule will be used for the randomizations.  The Sponsor’s Quality 
Assurance department or designee will hold a copy of the randomization lists generated by the 
IXRS vendor. 
4.3 
Replacement of Subjects 
Subjects withdrawn early from the Study before completion of Study Day 29 procedures may be 
replaced at the discretion of the Sponsor.  The additional subjects will be assigned to the same 
Study Drug (ISIS 505358 or placebo) as the subjects who are being replaced. 
Subjects whose randomization code has been broken will not be replaced. 
4.4 
Unblinding of Treatment Assignment 
All patients, study monitors, Study Center personnel and contract research organization (CRO) 
personnel will be blinded to Study Drug assignment (ISIS 505358 or placebo) throughout the 
study.  However, if a patient has suffered a Serious Adverse Event (as defined in Section 9.3.3), 
and/or when knowledge of the treatment assignment will impact the clinical management of the 
patient, the Investigator will have the ability to unblind the treatment assignment for that patient 
using the IXRS.  If time permits, the Investigator may contact the Sponsor’s Medical Monitor, or 
designee, about the situation before unblinding.  Regardless, the Sponsor or designee will be 
informed of the unblinding of a patient within 24 hours.  In addition, all suspected unexpected 
serious adverse reactions (SUSARs) will be unblinded as necessary by the Sponsor’s Drug 
Safety and Quality Assurance personnel 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 Appendices A and B) prior to unblinding, as knowledge of the treatment arm 
could influence patient assessment. 
 
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The DSMB may be unblinded when reviewing safety and tolerability results.  Sponsor and 
contract personnel supporting the DSMB, and not in communication with Investigators and/or 
investigational site staff, may also be unblinded. 
An unblinded interim analysis for Cohorts 1–3 may be performed after all Cohort 1–3 patients 
have progressed beyond their Study Day 29 assessments.  For such an analysis, select Sponsor 
personnel that have no direct communication with the Investigational Centers may become 
unblinded to individual patient treatment assignments.  An unblinded interim analysis for 
Cohort 4 may be performed similarly after all Cohort 4 patients have progressed beyond their 
Study Day 29 assessments. 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 28 days prior to Study Day 1 or at the time-point specified in the individual eligibility 
criterion listed. 
5.1 
Inclusion Criteria 
1. Have given written informed consent (signed and dated) and any authorizations required 
by local law and is able to comply with all study requirements 
2. Age 18 to 70 years 
3. Chronic HBV infection ≥ 6 months (e.g., positive for serum HBsAg ≥ 6 months) 
4. Cohorts 1–3:  Plasma HBV DNA ≥ 2 x 103 IU/mL  
Cohort 4:  HBV DNA adequately suppressed (e.g., plasma or serum HBV DNA below 
the lower limit of quantitation) 
5. Serum HBsAg > 50 IU/mL 
6. Satisfy the following: 
a. Females:  Non-pregnant and non-lactating; surgically sterile (e.g., tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral oophorectomy), 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 FSH levels in the postmenopausal range for the laboratory 
involved) or, if engaged in sexual relations of child-bearing potential, subject is using 
an acceptable contraceptive method (refer to Section 6.4) from the time of signing the 
informed consent form until at least 13 weeks after the last dose of Study Drug 
(ISIS 505358 or placebo) 
b. Males:  Surgically sterile or if engaged in sexual relations with a female of 
childbearing potential, subject is utilizing an acceptable contraceptive method (refer 
to Section 6.4) during treatment with Study Drug and for at least 13 weeks after the 
last dose of Study Drug 
7. Cohort 4 only: Currently taking and have been taking tenofovir or entecavir without 
changes in drug, dose level and/or frequency of administration for ≥ 12 months and 
expect to continue taking without change through to the end of their participation in this 
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5.2 
Exclusion Criteria 
1. Cohort 1–3 only:  Current or prior receipt of anti-HBV nucleos(t)ide analogue therapy.  
Patients who have failed prior interferon treatment, greater than 6 months prior to 
Screening, may be evaluated for possible participation in the study. 
2. History of liver cirrhosis and/or evidence of cirrhosis as determined by any 1 of the 
following: 
a. Liver biopsy (i.e., Metavir Score F4) within 2 years of Screening, or 
b. Fibroscan > 12 KPa, within 12 months of Screening, or 
c. AST-to-Platelet Index (APRI) > 2 and Fibrosure result > 0.7 within 12 months of 
Screening 
For patients without a test for cirrhosis in the above timeframes, Fibroscan, or APRI and 
Fibrosure, may be performed during the screening period to rule out cirrhosis 
3. History of liver failure as evidenced by ascites, hepatic encephalopathy, and/or gastric or 
esophageal varices 
4. History of liver disease other than Hepatitis B 
5. Co-infection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or 
hepatitis D virus (HDV) 
6. BMI > 35 kg/m2 
7. History of, or suspected presence of vasculitis 
8. Received solid organ or bone marrow transplant 
9. Currently taking, or took within 3 months of Screening, any immunosuppressing drugs 
(e.g., prednisone).  If the patient received a short course (≤ 1-week), the situation may be 
discussed with the Ionis Medical Monitor, or designee 
10. Diagnosed hepatocellular carcinoma or suspected hepatocellular carcinoma as evidenced 
by screening alpha-fetoprotein ≥ 200 ng/mL.  If the screening alpha-fetoprotein is 
≥ 50 ng/mL and < 200 ng/mL, the absence of liver mass must be documented by imaging 
within 6 months before randomization 
11. Screening laboratory results as follows, or any other clinically-significant abnormalities 
in screening laboratory values that would render a patient unsuitable for inclusion 
a. ALT or AST > 5 x ULN 
b. Total bilirubin > 1.1 x ULN 
c. Serum albumin < 3.5 g/dL 
d. INR > 1.2 
e. Platelet count < 140 k/mm3 
f. Hemoglobin < 12.0 g/dL for males and < 11.0 g/dL for females 
g. WBC < 3.0 k/mm3 
 
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h. Serum creatinine > 1.1 x ULN 
i. Urine protein/creatinine (P/C) ratio ≥ 0.2 mg/mg.  In the event of P/C ratio above this 
threshold, eligibility may be confirmed by a quantitative total urine protein 
measurement of < 150 mg/24-hr 
j. 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 
12. History of Gilbert’s Syndrome or history of laboratory results consistent with Gilbert’s 
Syndrome 
13. Clinically-significant abnormalities aside from chronic HBV infection in medical history 
(e.g., previous acute coronary syndrome within 6 months of Screening, major surgery 
within 3 months of Screening, uncontrolled diabetes) or physical examination 
14. History of bleeding diathesis or coagulopathy 
15. History of extrahepatic disorders possibly related to HBV immune complexes 
(e.g., glomerulonephritis, polyarteritis nodosa) 
16. Active infection other than HBV requiring systemic antiviral or antimicrobial therapy 
that will not be completed prior to Study Day 1 
17. 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 
18. Treatment with another investigational drug, biological agent or device within 4 weeks of 
screening or 5 half-lives of Study Drug, whichever is longer 
19. Treatment with any non-ISIS oligonucleotide (including siRNA) at any time 
20. Prior treatment with an ISIS oligonucleotide within 9 months of Screening 
21. History of excess alcohol consumption within 6 months of Screening as defined as 
weekly intake of > 14 drinks per week (> 2 drinks per day) for males or > 7 drinks per 
week (> 1 drink in a day) for females.  (One [1] drink is equivalent to 12 g of alcohol, 
e.g., 12 ounces [360 mL] of beer, 5 ounces [150 mL] of wine or 1.5 ounces [45 mL] of 
80 proof distilled spirits) 
22. History of drug abuse or dependence, or recreational use of drugs:  within 3 months of 
Screening for soft drugs (such as marijuana) and within 1-year of Screening for hard 
drugs (such as cocaine, phencyclidine [PCP]) 
23. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator 
24. Have any other conditions (medical, social or other), which in the opinion of the 
Investigator would make the patient unsuitable for inclusion, or could interfere with the 
patient participating in or completing the study 
25. Patients with hereditary problems of galactose intolerance, Lapp lactose deficiency, or 
glucose-galactose malabsorption, unless the patient will be treated with the lactose-free 
formulation of entecavir during the study 
 
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6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
All required study procedures are outlined in Appendices A, B, and C. 
6.1.1 
Screening 
For patients without history of cirrhosis and without liver biopsy within 2 years of Screening or 
Fibroscan or Fibrosure and APRI within 1-year of Screening, Fibroscan, or APRI and Fibrosure, 
may be performed during Screening in order to answer Exclusion Criteria #2 (Section 5.2). 
6.1.2 
Treatment Period 
All reasonable attempts should be made to ensure compliance with the visit schedule as outlined 
in Appendix A.  Aside from Study Day 2 occurring on the day after Day 1, Day 23 occurring on 
the day after Day 22, and Day 29 occurring 7 days after Day 22, occasional variances are 
permitted to accommodate holidays, patient needs, and scheduling conflicts.  A window of 
± 1 day is allowed for the Study Day 4–22 visits.  However, the administration of Study Drug 
doses should be separated by at least 36 hours.  Following a variance, the patient should return to 
the schedule based on elapsed days from the actual Day 1 (i.e., variances do not permanently 
shift the schedule). 
6.1.3 
Post-Treatment Period 
The permitted variance for the Study Day 36 visit is ± 1 day and for the Day 57 visit is ± 3 days.  
For other post-treatment visits (Days 85, 113, and 211), a ± 7 day variance is permitted. 
6.1.4 
Early Termination 
If a decision is made to withdraw a patient from Study Drug treatment, or if a patient on their 
own accord chooses to withdraw from treatment, all reasonable attempts should be made to have 
the patient participate in the post-treatment schedule beginning with the Day 29 (at 7 days after 
the last Study Drug dose or at the earliest time thereafter).  If this is not possible, every attempt 
should be made for the patient to attend an Early Termination visit as soon as possible prior to 
withdrawal. 
If a decision is made to withdraw a patient from post-treatment follow-up, or if a patient on their 
own accord chooses to withdraw from post-treatment follow-up, every attempt should be made 
for the patient to attend an Early Termination visit as soon as possible prior to withdrawal. 
6.2 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B. 
In addition, serum and plasma specimens will be collected at a number of time-points (see 
Appendix A) and stored frozen for retrospective clinical safety, immunologic and/or virologic 
assays.  Examples include, but are not limited to, retrospective LDH or CPK isoform 
measurements, measurement of cytokine, chemokine, and/or autoantibodies, or measurement of 
additional markers of kidney function, or mutation analysis of breakthrough HBV in order to 
follow-up effects observed in the current study or in another study of ISIS 505358.  The selection 
 
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of time points balanced supporting examination of effects that may occur at any time during the 
study against an excessive amount of blood collection.   
Peripheral blood mononuclear cell preparation at selected time points (see Appendix A) stored 
frozen for future cellular immunity investigations. 
6.3 
HBV Resistance Mutation Monitoring 
Serum HBV DNA levels for each patient will be measured throughout the study (see 
Appendix A).  If evidence of virologic failure is observed, patients will be interviewed regarding 
treatment compliance and concomitant usage of medication that might affect virus replication 
(e.g., corticosteroids), and other potentially relevant parameters.  Additional blood samples will 
be collected for measurement of ISIS 505358 concentration in plasma (and nucleos(t)ide 
analogue concentration if applicable) and for HBV resistance mutation analysis where the viral 
genome will be DNA sequenced to determine whether mutations have occurred the ISIS 505358 
binding region (and, if applicable, whether any known the nucleos(t)ide analogue resistance 
mutations are present in the polymerase coding region). 
Virologic failure is defined as the occurrence of either virologic breakthrough (i.e., a confirmed 
increase of ≥ 1 log10 HBV DNA copies/mL above nadir or becoming quantifiable after being 
below the lower limit of quantitation) or virologic nonresponse (i.e., failure to achieve 
HBV DNA levels below 103 copies/mL) 
6.4 
Restriction on the Lifestyle of Patients 
6.4.1 
Contraception Requirements 
All male subjects and women of childbearing potential must refrain from sperm/egg donation 
and practice effective contraception from the time of signing the informed consent form until at 
least 13 weeks after their last dose of study treatment. 
Male subjects must also encourage their female partner to use 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, women of childbearing potential 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 
 
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For the purposes of the Study, effective contraception is defined as follows: 
For male subjects: 
• Effective male contraception includes a vasectomy with negative semen analysis at 
Follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository 
• 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 subjects and female partners of male subjects: 
• Using 1 or more of the following acceptable methods of contraception:  surgical 
sterilization (e.g., bilateral tubal ligation), hormonal contraception, intrauterine 
contraception/device, or any 2 barrier methods (a combination of male or female 
condom* with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository 
*Note: A female condom and a male condom should not be used together as friction 
between the two can result in either or both products failing. 
6.5 
Nucleos(t)ide Analogue Plasma Concentrations 
Cohorts 1–3:  measurement of tenofovir and entecavir plasma concentrations will be performed 
following the Study Drug administration period.  The measurement for each patient will depend 
on the nucleos(t)ide analogue they are taking.  The specimen collection days are Study Days 29, 
36, 57, 85, 113, and 211.   
Cohort 4:  measurement of tenofovir and entecavir plasma concentrations will be performed to 
explore whether treatment-emergent changes to nucleos(t)ide analogue plasma levels occur 
during ISIS 505358 administration.  The measurement for each patient will depend on the 
nucleos(t)ide analogue they are taking.  The specimen collection days are Study Days 1, 8, 15, 
22, 29, 36, 57, 85, 113 and 211.   
Because there is a known food effect for tenofovir and entecavir, subjects will be asked to be 
consistent in their eating habits and when they take their doses before the clinic visits on these 
days.  Sites should make reasonable efforts to ensure that the pre-dose blood draws on these visit 
days generally occur at the same time of day (± 2 hour) to lessen any day-to-day variability. 
7. 
STUDY DRUG 
7.1 
Study Drug Description 
Study Drug (ISIS 505358 or placebo) characteristics are listed in Table 1. 
The Study Drug is contained in 2-mL stoppered glass vials and will be provided to the 
Study Centers by the Sponsor.  The Study Drug storage and preparation instructions will be 
provided by the Sponsor.  For long term storage at clinical sites, the Study Drug must be stored 
securely at 2–8 °Celsius and be protected from light. 
 
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Table 1 
Study Drug Characteristics 
Study Drug 
ISIS 505358 
Placebo 
Strength 
150 mg/mL 
Not Applicable 
Volume/Formulation 
1 mL solution per vial 
1 mL solution per vial 
Route of Administration 
SC 
SC 
 
7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drug labeled in accordance with 
specific country regulatory requirements. 
7.3 
Study Drug Accountability 
The Study Center staff is required to document the receipt, dispensing, and return of Study Drug 
supplies provided by the Sponsor.  The Study Center must return all used and unused Study Drug 
vials to the Sponsor or designee. 
8. 
TREATMENT OF PATIENTS 
8.1 
Study Drug Administration 
Study Drug will be administered by subcutaneous injection by trained study center personnel.  
The recommended sites for injection are the abdomen, upper arm, and thigh. 
The volume of injection for each dose level is shown in Table 2.  For doses ≥ 300 mg, the dose 
will be split into 2 equal injections (i.e., 2 x 1.0 mL for 300 mg dose and 2 x 1.5 mL for 450 mg 
dose) and administered to 2 separate anatomical sites (e.g., upper arm, thigh, abdomen 
quadrants).  The site(s) of injection should be changed administration-to-administration and 
injection into areas with ongoing injection site responses should be avoided. 
Please refer to the Study Drug Manual provided by the Sponsor or designee for more detailed 
instructions for Study Drug preparation and administration. 
Table 2 
Study Drug Dosing Information 
Cohort 
Total Volume to 
Administer 
Total Dose 
Cohort 1 
1.0 mL 
150 mg or placebo 
Cohort 2, Cohort 4 
2.0 mL 
300 mg or placebo 
Cohort 3 
3.0 mL* 
450 mg or placebo* 
*  Patients in Cohort 3 were treated with total volume of 2.0 ml and total dose of 300 mg or placebo 
 
In the event a patient experiences difficulty with the number or volume of the injections or skin 
responses at the injection site, the Investigator should contact the Ionis Medical Monitor to 
 
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discuss possible mitigations that may enable the patient to complete the dosing period.  These 
mitigations include, but are not limited to, subdividing a dose into smaller injection volumes, and 
splitting the administration of a dose to more than 1 day. 
8.2 
Other Protocol-Required Drugs 
After the conclusion of Study Day 29 assessments, patients in Cohorts 1–3 are required to 
commence treatment with tenofovir.  Patients and/or Investigators may opt for treatment with 
entecavir if they deem that more appropriate.  
Patients in Cohort 4 are expected to continue throughout this study their stable nucleos(t)ide 
analogue regimen that was ongoing prior to their enrollment in this study. 
8.3 
Other Protocol-Required Treatment Procedures 
There are no other protocol-required treatment procedures. 
8.4 
Treatment Precautions 
There are no required specific treatment precautions. 
8.5 
Safety Monitoring Rules 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
For the purposes of safety monitoring, Baseline is defined as the pre-dose value on Day 1 or, if 
no pre-dose Day 1 result is available, it is the pre-dose test performed closest to Day 1. 
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 (within 48 hours of receiving initial result).  If the repeat testing collection is not 
performed by 7 days of the initial collection, the initial result will be assumed as confirmed.  If 
the initial laboratory result meeting a stopping rule is observed during the Treatment Period, the 
results from the retest must be available prior to administration of the next dose of Study Drug. 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator and the 
Ionis Medical Monitor (or appropriately qualified designee) should confer as to whether 
additional close monitoring of the patient is appropriate.  If any of the stopping criteria described 
below (refer to Sections 8.6.1 to 8.6.4) are met and are confirmed, treatment of the patient with 
Study Drug will be stopped and patients will be followed as described below. 
 
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8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests 
The following safety monitoring rules for liver chemistry tests 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.  
For a definition of Baseline please refer to guidance in Section 8.5 above. 
In the event of an ALT or AST measurement that is > 3 x ULN or > 2 x Baseline value, 
whichever is greater, at any time during the study (Treatment or Post-Treatment Period), the 
initial measurement(s) should be confirmed as described above (i.e., blood collection for retest 
should be performed within 48 hours of receiving the initial result).  Additional confirmatory 
measurements should also be performed if ALT or AST levels increase to the greater of 5 x ULN 
or 3 x Baseline. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 x ULN or 
> 2 x Baseline value, whichever is greater, that are continuing to rise should have their liver 
chemistry tests (ALT, AST, ALP, INR and total bilirubin) retested twice weekly until levels 
stabilize and begin to recover.  Thereafter, the frequency of further testing will be discussed 
between the Investigator and Ionis Medical Monitor, or designee, and performed as clinically 
indicated.  Once ALT and AST levels become ≤ 1.2 x ULN (or 1.2 x Baseline value if the 
Baseline value was > ULN), the frequency of testing can return to that specified in 
Appendix A - Schedule of Procedures for the relevant Study Day. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or 
AST levels > 3 x ULN or > 2 x Baseline value, whichever is greater, 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 sources other than HBV (HAV IgM, HCV antibody, HDV 
IgM, HEV IgM, CMV IgM, and EBV antibody panel) 
5. Serology for autoimmune hepatitis (i.e., antinuclear antibody (ANA), anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal antibody, total IgG.) 
6. Collect and store plasma sample for PK analysis (of nucleos(t)ide analogue and 
ISIS 505358) as soon as possible following occurrence of an event 
7. Collect and store plasma samples for HBV DNA quantitation and resistance mutation 
analysis 
8. Collect and store serum sample for serum acetaminophen adduct HPLC assay 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic CT or 
MRI scans, may be performed at the discretion of the Investigator, in consultation with the 
 
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Sponsor Medical Monitor.  Repetition of the above evaluations should be considered if a 
patient’s ALT and/or AST levels continue to increase. 
8.6 
Study Drug (ISIS 505358 or Placebo) Stopping Rules 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
Upon receipt of laboratory results meeting stopping criteria, Study Drug administration should 
be suspended while awaiting the results from confirmation testing.  In the event of confirmed 
laboratory results (by testing of new specimens) meeting any of the following criteria, and the 
event is without a probable cause other than Study Drug-induced liver injury as discussed 
with the Ionis Medical Monitor, or designee, dosing of a patient with Study Drug will be stopped 
permanently. 
Table 3 
Study Drug Stopping Rules for ALT or AST Elevations 
Baseline ALT ≤ 2x ULN 
Baseline ALT > 2 x ULN 
If confirmed ALT or AST ≥ 8 x ULN, 
permanently discontinue Study Drug 
If confirmed ALT or AST ≥ 4 x Baseline, or confirmed 
ALT or AST ≥ 20 x ULN permanently discontinue Study 
Drug  
If confirmed ALT or AST ≥ 3 to < 8 x ULN, 
permanently discontinue Study Drug if any of the 
following apply: 
• 
appearance or worsening of symptoms felt by the 
Investigator to be potentially related to worsening 
of hepatic inflammation such as fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or concomitant eosinophilia 
(> ULN) 
• 
total bilirubin > 1.5 x ULN and direct bilirubin 
> 35% 
If confirmed ALT or AST ≥ 2 to < 4 x baseline, 
permanently discontinue Study Drug if any of the 
following apply: 
• 
appearance or worsening of symptoms felt by the 
Investigator to be potentially related to worsening 
of hepatic inflammation such as fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, 
fever, rash, and/or concomitant eosinophilia 
(> ULN) 
• 
total bilirubin > 1.5 x ULN and direct bilirubin 
> 35% 
Note: 
Baseline is latest laboratory result prior to first dose of Study Drug (ISIS 505358 or placebo) 
 
The investigations described above in Section 8.5.1 should be performed as soon as possible for 
any patient meeting 1 of these stopping rules unless the Investigator and Ionis Medical Monitor, 
or designee, agree on another schedule. 
The Investigator and Ionis Medical Monitor, or designee, should discuss the advisability of 
continuing Study Drug administration in situations where ALT or AST are elevated in ways not 
covered by the above rules (e.g., rising ALT levels > 2 x ULN but < 3 x ULN coupled with 
rising total bilirubin > 1.1 x ULN but < 1.5 x ULN).  In situations where alternative probable 
causes exist for the above laboratory results (e.g., Gilbert’s syndrome diagnosis and/or direct 
bilirubin < 35% of total; physical trauma and elevated creatine kinase coincident with elevated 
ALT and/or AST), the Investigator and Ionis Medical Monitor should confer about the 
possibility of continuing/resuming Study Drug treatment. 
8.6.2 
Stopping Rules for Hematologic Test Results 
In the event of a confirmed laboratory results (by testing of new specimens) meeting any of the 
following criteria, and the event is without a probable cause other than Study Drug as 
 
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discussed with the Ionis Medical Monitor, or designee, dosing of a patient with Study Drug will 
be stopped permanently. 
1. Hemoglobin < 9.0 g/dL (i.e., ≥ DAIDS Grade 3) 
2. White Blood Cell count < 1.5 k/mm3 (i.e., ≥ DAIDS Grade 3) 
3. Absolute neutrophil count < 0.75 k/mm3 (i.e., ≥ DAIDS Grade 3) 
4. Platelet count < 75 k/mm3 
The follow-up schedule for events meeting these events will be determined by the Investigator in 
consultation with the Ionis Medical Monitor, or designee.  The Ionis Medical Monitor, or 
designee, should also be consulted as to further investigations into alternative sources for these 
events.  In situations where the hematologic changes are unlikely related to the Study Drug, the 
Investigator and Ionis Medical Monitor, or designee, will conference on the possibility of 
continuing/resuming treatment with Study Drug. 
8.6.3 
Stopping Rules for Renal Function Test Results 
In the event of confirmed laboratory results (by testing of new specimens) for either of the 
following criteria, and the event is without a probable cause other than Study Drug as 
discussed with the Ionis Medical Monitor, or designee, dosing of a patient with Study Drug will 
be stopped permanently. 
1. Confirmed serum creatinine increase that is both ≥ 0.3 mg/dL and ≥ 40% above Baseline 
creatinine values (defined as the average of the Screening and Study Day 1 results) and 
above upper limit of the reference range (i.e., > ULN) 
2. Confirmed urine protein/creatinine ratio ≥ 0.90 
3. Evidence of glomerular injury on urine microscopic exam. 
The follow-up schedule for any events meeting either of these criteria will be determined by the 
Investigator in consultation with the Ionis Medical Monitor, or designee.  The Ionis Medical 
Monitor, or designee, should also be consulted as to further investigations into alternative 
sources for the changes in renal function tests.  In situations where the changes in renal function 
tests are unlikely related to Study Drug alone or in combination with nucleos(t)ide analogues, the 
Investigator and Ionis Medical Monitor, or designee, will confer about the possibility of 
continuing resuming treatment with Study Drug. 
8.6.4 
Stopping Rules for Significant Inflammatory Reaction 
In the event of clinical symptoms (e.g., constellation of symptoms such as severe fever, chills, 
and myalgia) or confirmed laboratory findings (e.g., substantial decrease in serum complement 
protein levels) consistent with a significant inflammatory reaction, and the event is without a 
probable cause other than Study Drug as discussed with the Ionis Medical Monitor, or 
designee, dosing of the patient with Study Drug will be stopped permanently. 
8.7 
Adjustment of Dose and/or Treatment Schedule 
Should one or more Study Drug doses not be administered due to events not or unlikely related 
to Study Drug (e.g., weather prevents travel to the study center, recuperation from rhinovirus 
 
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infection, recovery from injury), the patient will resume dosing with Study Drug at the point in 
the schedule corresponding to the patient’s actual elapsed time from Study Day 1.  Treatment 
will resume at the original assigned dose level.  Missed doses and time off from treatment will 
not be made up.  Treatment will end with the dose on Study Day 22 (see Appendix A – Schedule 
of Procedures). 
After its review of a suspected DLT, the DSMB may determine the event was not an actual DLT 
(e.g., patient treated with placebo) and may recommend resumption of dosing with Study Drug 
be considered.  The DSMB will not disclose the actual treatment assignment of the patient.  Any 
resumption of treatment will be as described above. 
If the number of patients with DLTs exceeds the limits described in Section 3.8 and further 
enrollment to that dose level is halted, 1 of the options available to the DSMB is to recommend 
some or all of the patients already receiving Study Drug have their dose level reduced by 1 dose 
step.  That is, patients on treatment at 450 mg could be reduced to 300 mg, those at 300 mg could 
be reduced to 150 mg, and those on at 150 mg could be reduced to 75 mg. 
8.8 
Discontinuation of Study Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4 
• The patient withdraws consent 
• The patient experiences an adverse event that necessitates permanent discontinuation of 
study treatment 
• The patient experiences an AE that necessitates unblinding of the Investigator to the 
patient’s treatment assignment 
A patient must stop treatment with Study Drug, at least temporarily, if the patient develops 
laboratory test abnormalities that meet any of the stopping rules listed in Sections 8.6.1 to 8.6.4. 
The reason for discontinuation of study treatment must be recorded in the CRF and source 
documentation. 
Patients that are discontinued from treatment with Study Drug will enter the Post-Treatment 
Period (see Section 6.1.4; tenofovir/entecavir treatment omitted if contraindicated) unless 
consent is withdrawn.  Every effort should be made to complete the early termination study 
procedures and observations if the patient does not enter post-treatment follow-up. 
8.9 
Withdrawal of Patients from the Study 
Patients must be withdrawn from the study for any of the following: 
• Withdrawal of consent 
• The patient is unwilling or unable to comply with the protocol 
 
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Other reasons for withdrawal of patients from the study 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 CRF. 
Any patient who withdraws consent to participate in the study will be removed from further 
treatment and study observation immediately upon the date of request.  These patients should be 
encouraged to complete the early termination study procedures and observations at the time of 
withdrawal (Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent every effort should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Appendix A). 
8.10 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
CRF.  AEs related to administration of these therapies or procedures must also be documented on 
the appropriate CRF. 
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 signing 
informed consent and last post-treatment visit. 
Entecavir and tenofovir are considered concomitant medications in this study.  In Cohort 4, 
patients should be on stable tenofovir or entecavir therapy prior to Screening and their 
nucleos(t)ide analogue usage should be in accordance with the recommendations contained in 
their respective region-specific prescribing information.  For all cohorts, each patient’s 
nucleos(t)ide analogue usage should be recorded in their CRF. 
Allowed Concomitant Therapy 
Aside from the disallowed medication described below, Physician Investigators may prescribe 
any concomitant medications or treatments deemed necessary to provide adequate supportive 
care. 
Disallowed Concomitant Therapy 
Immunosuppressive/immunomodulatory therapy (e.g., use of > 5 mg systemic prednisone or its 
equivalent per day) is not permitted at any time during the study. 
 
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Initiation of treatment with additional anti-HBV agents (e.g., additional nucleos(t)ide analogues, 
interferons, vaccines) is not permitted during the study except where necessary in the opinion of 
the Investigator for re-establishing HBV DNA suppression following viral breakthrough. 
Tenofovir and entecavir are principally eliminated by the kidney.  Therefore, the concurrent use 
of drugs that may impair renal function (e.g., high-dose or multiple NSAIDs) should be avoided 
as recommended in the prescribing information for tenofovir. 
Treatments that may increase ALT or AST (e.g., Augmentin, > 2 g acetaminophen/day, initiating 
treatment with an HMG-CoA Reductase Inhibitor [statin]) should be avoided.  The use of these 
drugs, if necessary, should be discussed with the Ionis Medical Monitor, or designee, preferably 
before initiation of their administration. 
Treatment with herbal medicines thought to possess anti-HBV activity is not permitted. 
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 
signing informed consent and last post-treatment visit. 
8.11 
Treatment Compliance 
Treatment dosing is to be performed and recorded 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 Safety Management Plan throughout the conduct of the clinical trial. 
9.2 
Regulatory Requirements 
The Sponsor or designee is responsible for regulatory submissions and reporting to the 
Investigators of serious adverse events (SAEs) including suspected unexpected serious adverse 
reactions (SUSARs) per the International Conference on Harmonization (ICH) guidelines E2A 
and ICH E6.  Country-specific regulatory requirements will be followed in accordance with local 
country regulations and guidelines. 
IRBs will be notified of any SAE according to applicable regulations.  The DSMB will be 
notified of any SAE as specified in the DSMB charter. 
The Sponsor or designee will evaluate the available information and decide if there is a 
reasonable possibility that the Study Drug caused the AE and, therefore, meets the definition of a 
SUSAR.  Appropriate personnel at the Sponsor or designee will unblind SUSARs for the 
purpose of regulatory reporting.  The Sponsor or designee will submit SUSARs to Regulatory 
Agencies in blinded or unblinded fashion according to local law.  The Sponsor or designee will 
submit SUSARs to Investigators in a blinded fashion. 
 
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9.3 
Definitions 
9.3.1 
Adverse Event 
An adverse event is any unfavorable and unintended sign (including a clinically-significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
Study or use of investigational drug product, whether or not the AE is considered related to the 
investigational drug product. 
9.3.2 
Adverse Reaction and Suspected Adverse Reaction 
An adverse reaction is any AE caused by the Study Drug. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the drug 
caused the adverse event.  A suspected adverse reaction implies a lesser degree of certainty about 
causality than an adverse reaction. 
9.3.3 
Serious Adverse Event (SAE) 
A serious adverse event is any adverse event 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 adverse reaction 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 1 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 
9.4 
Monitoring and Recording Adverse Events 
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 
 
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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. 
9.4.1 
Serious Adverse Events 
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 
follow-up period which is defined as the Study Week 30 visit unless the patient withdrew earlier.  
When the Investigator is reporting by telephone, it is important to speak to someone in person vs. 
leaving a message.  An Initial Serious Adverse Event Form should be completed and a copy 
should be faxed to the Sponsor or designee.  The fax number for reporting SAEs can be found in 
the Study Reference Manual provided by the Sponsor to each study center. 
Detailed information should be actively sought and included on Follow-Up Serious Adverse 
Event 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 Adverse Events 
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 follow-up period, which is defined as the Study Week 30 
visit unless the patient withdrew earlier.  The Investigator will monitor each subject closely and 
record all observed or volunteered AEs on the Adverse Event Case Report Form. 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s opinion of the following should be documented on the Adverse Event Case 
Report Form: 
9.4.3.1 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (ISIS 505358 or placebo) is characterized by 1 of the 
following: 
• 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 505358 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 505358 or placebo) administration and/or exposure 
suggests that a causal relationship is unlikely (for reporting purposes, Unlikely/Remote 
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• 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 event’s severity is graded according to the Division of AIDS Table for Grading Severity of 
Adult and Pediatric Adverse Events, Version 2.0, November 2014 (see Appendix D) except for 
responses at subcutaneous injections sites.  Responses at injection sites will be graded according 
to the mild, moderate, and severe criteria defined below.  As noted in the DAIDS criteria, clinical 
adverse events not specifically identified in the table are to be characterized by 1 of the 
following: 
Grade 1 (Mild):  Symptoms causing no or minimal interference with usual social and functional 
activities 
Grade 2 (Moderate):  Symptoms causing greater than minimal interference with usual social 
and functional activities 
Grade 3 (Severe):  Symptoms causing inability to perform usual social and functional activities 
Grade 4 (Potentially Life Threatening):  Symptoms causing inability to perform basic self-care 
functions OR medical or operative intervention indicated to prevent permanent impairment, 
persistent disability or death 
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 505358 or placebo) due to an adverse event is characterized 
by 1 of the following. 
• None:  No changes were made to Study Drug (ISIS 505358 or placebo) administration 
and dose 
• Permanently Discontinued:  Study Drug was discontinued and not restarted 
• Temporarily Interrupted, Restarted – Same Dose:  Dosing was temporarily 
interrupted or delayed due to the AE and restarted at the same dose 
• Reduced Dose:  Dosing was reduced, temporarily interrupted or delayed due to the AE 
and restarted at the next lower dose 
9.4.3.4 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form (treatment should also be recorded on the concomitant 
treatment or ancillary procedures eCRF as appropriate). 
 
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9.4.3.5 
Outcome of the Adverse Event 
If the event is a non-serious AE, then the event’s outcome is characterized by 1 of the following: 
• AE Persists:  Patient terminates from the trial and the AE continues 
• Recovered:  Patient 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):  Patient 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:  Patient recovered completely from the SAE (the date of recovery should be 
entered as the SAE resolution date) 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
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 in preference to abnormal laboratory values as AEs.  
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 (NCS) by the 
Investigator should not be reported as AEs.  Similarly, laboratory abnormalities reported as AEs 
by the Investigator should not be deemed NCS 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: 
 
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• 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 
9.5.3 
Dosing Errors 
Study Drug (ISIS 505358 or placebo) errors 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 505358 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. 
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 patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient 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 on Follow-up Pregnancy Forms and 
reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the subject’s 
responsibility. 
Female patients:  If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be performed.  The patient with a confirmed pregnancy will be immediately 
withdrawn from treatment with Study Drug.  However, the patient will be encouraged to 
complete the post-treatment follow-up portion of the study to the extent that study procedures do 
not interfere with the pregnancy.  Regardless of continued study participation, the study 
physician will assist the patient in getting obstetrical care and the progress of the pregnancy will 
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 
 
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Sponsor may require access to the mother and infant’s medical records for an additional 8 weeks 
after birth. 
Male patients:  The progress of the pregnancy in a male patient’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, additional follow-up information may 
be requested for the mother and infant.  Follow-up will be performed to the extent permitted by 
relevant guidelines (e.g., HIPAA) and privacy considerations. 
10. 
STATISTICAL CONSIDERATIONS 
10.1 
Study Endpoints, Subsets, and Covariates 
10.1.1 
Primary Endpoints 
The safety endpoints include: 
• Adverse events 
• Clinical laboratory tests (e.g., serum chemistry, hematology, urinalysis, coagulation, 
complement, antibodies, pregnancy test for women with childbearing potential) 
• Vital signs and body weight 
• Physical examination 
• ECG 
• Concomitant medication usage 
There is no primary efficacy endpoint. 
10.1.2 
Secondary Endpoints 
The efficacy endpoints include: 
• Change from Baseline to Day 29 in plasma HBV DNA concentration 
• Change from Baseline to Week 31 in plasma HBV DNA concentration 
• Change from Baseline to Day 29 in serum HBsAg concentration 
• Change from Baseline to Week 31 in serum HBsAg concentration 
• Proportion of patients with HBsAg loss at Day 29 and at Week 31 
• Change from Baseline to Day 29 and to Week 31 in serum HBeAg concentration in 
patients that were HBeAg positive at Baseline 
• Proportion of patients with HBeAg loss at Day 29 and at Week 31 in patients that were 
HBeAg positive at Baseline 
• Plasma pharmacokinetics of ISIS 505358 in patients with chronic hepatitis B virus 
infection 
 
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10.1.3 
Exploratory Endpoints 
• Proportion of patients with seroconversion to anti-HBs antibody positivity at Day 29 and 
at Week 31 
• Proportion of patients with seroconversion to anti-HBe antibody positivity at Day 29 and 
at Week 31 in patients that were HBeAg positive at Baseline 
• Plasma concentrations of tenofovir and entecavir 
10.2 
Sample Size Considerations 
There is no statistical rationale for the selected sample size of 8 subjects per cohort.  The sample 
size was based on prior experience with other members of the drug class to ensure an adequate 
initial assessment of the safety, tolerability and pharmacokinetics of ISIS 505358 while 
minimizing the number of subjects unnecessarily exposed to the drug. 
10.3 
Populations 
The Safety Set will include all randomized patients who received at least 1 dose of ISIS 505358 
or placebo. 
The Full Analysis Set (FAS), which represents the practically-feasible intent-to-treat (ITT) 
population as delineated in ICH Guideline E9, will include the subset of the Safety Set with a 
Baseline and at least 1 post-Baseline plasma HBV DNA concentration.   
The Per-Protocol Set will include the subset of the FAS who have: 
• received at least 5 doses of ISIS 505358 or placebo during the 4-week Treatment Period 
• had plasma HBV DNA concentration measure at Day 29, and 
• had no significant protocol deviations that would be expected to affect efficacy 
assessments 
PK Population will include all subjects who were randomized and received at least 1 dose of 
Study Drug. 
10.4 
Definition of Baseline 
Baseline ECG will be the average of the triplicate taken on Day 1 Pre-dose, if only 1 or 
2 assessments are available, the single assessment or average of the 2 assessments will be used. 
Baseline creatinine will be the average of all measurements taken between Screening and Day 1 
Pre-dose. 
For other assessments, baseline will be the last non-missing measurement prior to the first dose 
of Study Drug. 
10.5 
Interim Analysis 
To ensure patient safety, blinded data including the adverse events and safety laboratory data 
will be reviewed by the Sponsor on an ongoing basis. 
 
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An unblinded interim analysis or Cohort 1–3 may be performed after all Cohort 1–3 patients 
have progressed beyond their Study Day 29 assessments and the database has been locked.  An 
unblinded interim analysis for Cohort 4 may be performed similarly after all Cohort 4 patients 
have progressed beyond their Study Day 29 assessments and locking of the data.  Details of the 
analysis and controlled access to the unblinded data will be specified in the SAP. 
10.6 
Planned Methods of Analysis 
All eCRF data, lab data transfers, as well as any outcomes derived from the data, will be 
provided in the patient data listings.  Patient data listings will be presented for all patients 
enrolled into the study.  Descriptive summary statistics including n, mean, median, standard 
deviation, 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.  Where appropriate, p-values will be reported.  All statistical tests will be 
conducted using 2-sided tests with 5% type I error rates unless otherwise stated. 
For data summaries and statistical analyses, the placebo subjects from all 3 cohorts will be 
pooled.  The efficacy endpoints will be assessed on the FAS and Per-Protocol Set.  The safety 
analyses will be performed on the Safety Set. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized descriptively by treatment group.  
All patients enrolled will be included in the summary of patient disposition. 
10.6.2 
Safety Analysis 
The safety analyses will be conducted on the Safety Population. 
Treatment duration and amount of Study Drug received will be summarized by treatment group.  
Subject incidence rates of all adverse events will be tabulated by MedDRA system organ class, 
and by MedDRA preferred term.  Tables of “on-study” deaths, serious and significant adverse 
events, including early withdrawals due to adverse events, 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 will be summarized. 
Laboratory tests 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 administration, as appropriate. 
Vital sign and ECG measures will be tabulated by treatment group.  In addition, the number of 
patients who experience abnormalities in clinical laboratory evaluations will be summarized by 
treatment group. 
10.6.3 
Efficacy Analysis 
There are no formal hypotheses in this study; therefore, all the efficacy endpoints will be 
summarized using descriptive statistics.  Additional analyses for comparison between 
 
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ISIS 505358 groups and pooled placebo group will be performed in an exploratory manner, and 
will be detailed in the SAP. 
The main efficacy analysis will be the changes from Baseline to Day 29 (1-week after last dose 
of Study Drug) for plasma HBV DNA and serum HBsAg, and change from Baseline to Day 29 
in serum HBeAg concentrations for patients that were HBeAg positive at Baseline.  These 
concentrations will be logarithmic transformed in this analysis.  The LOCF method will be used 
to impute missing values in this analysis.  Comparison between the ISIS 505358 and placebo 
treatment groups will be performed using an ANCOVA model with baseline as a covariate, and 
treatment group as a factor (if data departs substantially from normality, the Wilcoxon Rank Sum 
test will be used. 
Additional efficacy analyses will include: 
• Changes from Baseline to Week 31 in plasma HBV DNA (except Cohort 4), serum 
HBsAg, and changes from Baseline to Week 31 in serum HBeAg concentrations for 
patients that were HBeAg positive at Baseline.  These concentrations will be logarithmic 
transformed.  Comparison between the ISIS 505358 and placebo treatment groups will be 
performed using an ANCOVA model with baseline value as a covariate, and treatment 
group as a factor (if data departs substantially from normality, the Wilcoxon Rank Sum 
test will be used). 
• Proportions of patients with at least 1 logarithmic reduction in plasma HBV DNA (except 
Cohort 4), serum HBsAg, and serum HBeAg concentrations (for patients that were 
HBeAg positive at Baseline) at Day 29 and Week 31 by treatment group.  Responder 
analysis with other response thresholds (e.g., 0.5, 1.5, and 2.0 logarithmic reduction) will 
also be conducted.  Comparison between ISIS 505358 and placebo treatment groups will 
be performed using the Pearson’s Chi-square test or Fisher exact test as appropriate. 
Exploratory analyses: 
• Proportion of patients with seroconversion to anti-HBs antibody positivity at Day 29 and 
Week 31.  Comparison between ISIS 505358 and placebo treatment groups will be 
performed using the Pearson’s Chi-square test or Fisher exact test as appropriate. 
• Proportion of patients with seroconversion to anti-HBe antibody positivity at Day 29 and 
Week 31 in patients that were HBeAg positive at Baseline.  Comparison between 
ISIS 505358 and placebo treatment groups will be performed using the Pearson’s 
Chi-square test or Fisher exact test as appropriate. 
10.6.4 
Pharmacokinetic Analysis 
The plasma exposure and PK of ISIS 505358 will be assessed following single (i.e., first dose) 
and multiple SC administrations of ISIS 505358. 
Non-compartmental PK analysis of ISIS 505358 will be carried out for (Day 1) and the end 
(Day 22) of ISIS 505358 treatment.  Calculated PK parameters may include, but may not 
necessarily be limited to, the following: 
 
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• The maximum observed drug concentration (Cmax) will be obtained directly from the 
observed concentration-time profile 
• The time of the Cmax (Tmax) will be obtained directly from the observed 
concentration-time profile 
• Following single or multiple dosing, area under the plasma concentration-time curve 
from zero time (pre-dose) to select selected times (t) after dose administration (AUCt), or 
over the duration of a dosing interval (tau,τ) after the last administered multiple-dose 
(AUCτ), will be calculated using the linear trapezoidal rule 
• Following the last administered multiple-dose, the plasma disposition half-life (t1/2λz) 
associated with the apparent terminal elimination phase will be calculated from the 
equation, t1/2λz = 0.693/λz, where λz is the rate constant associated with the apparent 
terminal elimination phase, when appropriate data exist and at the discretion of the 
PK scientist 
All other plasma PK parameters may be summarized using descriptive statistics. 
Cohorts 1–3:  Plasma levels of tenofovir (and entecavir if administered) will be measured on 
multiple days during the post-Study Drug Treatment Follow-Up period of the study (see 
Appendix C).  Only the nucleos(t)ide analogue that is taken by each patient will be measured.  
Plasma concentrations of tenofovir (and entecavir) in patients previously treated with 
ISIS 505358 will be compared to prior treatment with placebo.  Details for analysis will be 
defined in the SAP.  
Cohort 4:  Plasma levels of the tenofovir or entecavir taken by each patient will be measured on 
multiple days during the study periods before, during, and after Study Drug administration (see 
Appendix C).  Only the nucleos(t)ide analogue that is taken by each patient will be measured.  
Plasma levels on Day 1 (prior to ISIS 505358) will be compared for each patient to plasma levels 
taken concurrently with ISIS 505358, matched for time from dose and fed/fasted state, to 
monitor for potential interactions.  Details for analysis will be defined in the SAP. 
10.6.5 
Additional Analyses 
Additional exploratory analyses could be performed based on observed data determined by the 
study team.  Details for additional analyses will be defined in the SAP. 
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 or designee. 
Before a patient’s participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the patient after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific screening 
procedures or any Study Drug are administered.  The patient must be given sufficient time to 
consider whether to participate in the study. 
 
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The acquisition of informed consent and the patient’s agreement or refusal to notify his/her 
primary care physician should be documented in the patient’s medical records and the informed 
consent form should be signed and personally dated by the patient 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 
patient. 
11.2 
Ethical Conduct of the Study 
The Guidelines of the World Medical Association (WMA) Declaration of Helsinki dated 
October 2002 the applicable regulations and guidelines of current Good Clinical Practice (GCP) 
as well as the demands of national drug and data protection laws and other applicable regulatory 
requirements will be strictly followed. 
11.3 
Institutional Review Board 
A copy of the protocol, proposed informed consent forms, other written patient 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 
or designee before recruitment of patients 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 or designee before recruitment of patients 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 
Section 4.5.2.  The Investigator should also notify the IRB of serious adverse events occurring at 
the Study Center and other adverse event reports received from the Sponsor or designee, 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 or designee. 
11.4 
Patient Confidentiality 
The Investigator must ensure that the patient’s confidentiality is maintained.  On the case report 
forms or other documents submitted to the Sponsor or designee, patients should be identified by 
unique initials and a patient study number only.  Documents that are not for submission to the 
Sponsor or designee (e.g., signed informed consent forms) should be kept in strict confidence by 
the Investigator. 
In compliance with national 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 patient’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 
 
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study.  The Investigator is obligated to inform and obtain the consent of the patient to permit 
named representatives to have access to his/her study-related records without violating the 
confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor or designee.  
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 patients or 
the conduct of the trial.  The Investigator must send a copy of the approval letter from the IRB to 
the Sponsor or designee. 
12.2 
Study Termination 
Both the Sponsor or designee and the Investigator reserve the right to terminate the study, 
according to the terms of the study contract.  The Investigator/Sponsor or designee 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 electronic case report form (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 patient’s case report 
form data are obtained.  These include but are not limited to hospital records, clinical and office 
charts, laboratory and pharmacy records, diaries, imaging, and correspondence.  In this study, 
CRFs 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 
Section 8 of the ICH Guidelines (E6), suitable for inspection at any time by representatives from 
the Sponsor or designee and/or applicable regulatory authorities.  Elements should include: 
• Patient 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 
or designee 
• 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 Statement, and all drug-related correspondence 
 
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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 or 
designee 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 or designee. 
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 or designee 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 (or designees).  
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 or designee.  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 or designee. 
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 for concomitant medications 
should be recorded in English if possible, unless it is a combination drug, then record the trade 
name in English. 
All written information and other material to be used by subjects and investigative staff must use 
vocabulary and language that are clearly understood. 
 
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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. 
 
 
 
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13. 
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methoxyethyl) modified antisense oligonucleotide: comparison across species. Drug Metab Dispos 2003; 31: 
1419-1428. 
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Drug Technology: Principles, Strategies and Applications, 2nd Edition. Boca Raton, FL. Taylor & Francis Group 
2008; 305-326. 
Gilead Sciences Inc. Viread prescribing information (USA). 12/2018 revision. 
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dystrophy. N Engl J Med 2011; 364: 1513-1522. 
Henry SP, Stecker K, Brooks D, Monteith D, Conklin B, Bennett CF. Chemically modified oligonucleotides exhibit 
decreased immune stimulation in mice. J Pharmacol Exp Ther 2000; 292: 468-479. 
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infection. Ann Gastroenterol 2014; 27(2): 105-112. 
 
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Inoue H, Hayase Y, Iwai S, Ohtsuka E. Sequence-dependent hydrolysis of RNA using modified oligonucleotide 
splints and RNase H. FEBS Lett 1987; 215: 327-330. 
Jaroszewicz J, Ho H, Markova A, et al. Hepatitis B surface antigen (HBsAg) decrease and serum interferon-
inducible protein-10 levels as predictive markers for HBsAg loss during treatment with nucleoside/nucleotide 
analogues. Antivir Ther 2011; 16(6): 915-924. 
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ribonucleic acid antisense oligonucleotides: evidence of distinct pathways contributing to non-target mediated 
toxicity in mice. Toxicol Sci 2014; 138: 234-248. 
Kim GA, Lim YS, An J, et al. HBsAg seroclearance after nucleoside analogue therapy in patients with chronic 
hepatitis B: clinical outcomes and durability. Gut 2014 Aug; 63(8): 1325-1332. 
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patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004 Oct 7; 351(15): 1521-1531. 
Liaw YF. HBeAg seroconversion as an important end point in the treatment of chronic hepatitis B. Hepatol Int 
2009 Sep; 3(3): 425-433. 
Lok ASF and McMahon BJ. Chronic hepatitis B: Update 2009. AASLD practice guidelines. Hepatol 2009; 50: 
661-662. 
Maruyama T, McLachlan A, Iino S, Koike, K, Kurokawa K, Milich DR. The serology of chronic hepatitis B 
infection revisited. J Clin Invest 1993; 91: 2586-2595. 
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. 
Milich DR, Chen MK, Hughes JL, Jones JE. The secreted hepatitis B precore antigen can modulate the immune 
response to the nucleocapsid: a mechanism for persistence. J Immunol 1998 Feb 15; 160(4): 2013-2021. 
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. 
Moucari R, Mackiewicz V, Lada O, et al. Early serum HBsAg drop: a strong predictor of sustained virological 
response to pegylated interferon alfa-2a in HBeAg-negative patients. Hepatol 2009 Apr; 49(4): 1151-1157. 
Op den Brouw ML, Binda RS, van Roosmalen MH, et al. Hepatitis B virus surface antigen impairs myeloid 
dendritic cell function: a possible immune escape mechanism of hepatitis B virus. Immunology 2009 Feb; 126(2): 
280-289. 
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HBeAg-negative chronic hepatitis B using HBsAg and HBV DNA levels. Hepatol 2010; 52: 454-461. 
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oligonucleotide -mediated complement activation compared to humans. J Pharmacol Exp Ther 2014; 351: 709-717. 
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Vanlandschoot P, Van Houtte F, Roobrouck A, et al. Hepatitis B virus surface antigen suppresses the activation of 
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hepatitis B virus? Trends Immunol 2003; 24(3): 144-147. 
van Poelgeest EP, Swart RM, Betjes MGH, et al. Acute kidney injury during therapy with an antisense 
oligonucleotides directed against PCSK9. Am J Kidney Dis 2013; 62: 796-800. 
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monkey relative to human for antisense oligonucleotides with 2ʹ-O-(2-methoxyethyl) modifications. Mol Ther 
Nucleic Acids 2015 Jan 20; 4: e218. 
Yu RZ, Warren MS, Watanabe T, et al. Lack of interactions between an antisense oligonucleotide with 2'-O-(2-
methoxyethyl) modifications and major drug transporters. Nucleic Acid Ther 2016; 26: 111-117. 
Zhang H, Löwenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway Factor XI by antisense 
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14. 
APPENDICES 
 
 
 
 
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Appendix A 
Schedule of Procedures 
 
 
 
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Appendix A Schedule of Procedures – Cohorts 1–3 
 
Screen 
Treatment (4 wks) 
Post-Treatment Follow-Up (26 wks) 
Early 
Term 
Study Week (W) and/or Study Day 
S-28 to 
S-1 
W1 
D1 
W1 
D2 
W1 
D4 
W2 
D8 
W2 
D11 
W3 
D15 
W4 
D22 
W4 
D23 
W5 
D29 
W6 
D36 
W9 
D57 
W13 
D85 
W17 
D113 
W31 
D211 
 
Allowed Variance Window * 
n/a 
n/a 
^ 
± 1 
± 1 
± 1 
± 1 
± 1 
^ 
§ 
± 1 
± 3 
± 7 
± 7 
± 7 
n/a 
Study Drug Administration 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
Tenofovir (or entecavir) Daily Administration 
 
 
 
 
 
 
 
 
 
X e 
X 
X 
X 
X 
X 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion, Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body Weight and Height 1 
X 
X a 
 
 
 
 
 
X 
 
Xa 
 
X 
 
X 
X 
X 
Physical Exam 
X 
 
 
 
 
 
 
 
 
Xa 
 
 
 
X 
X 
X 
Vital Signs 2 
X 
Xa 
X 
 
Xa 
Xa 
Xa 
Xa 
X 
Xa 
X 
X 
X 
X 
X 
X 
HIV, Hepatitis C & D 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 3 
X 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
X 
X 
X 
Alpha-fetoprotein 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry, Hematology, Urinalysis 5 
X 
Xa 
X b 
 
Xa 
 
Xa 
 
Xb 
Xa 
X 
X 
X 
X 
X 
X 
Complement C3 
X 
Xa 
 
 
Xa 
 
Xa 
Xa 
 
Xa 
X 
X 
 
X 
X 
X 
Complement split products 
 
X c 
Xb 
 
 
 
 
X c 
Xb 
 
X 
X 
 
X 
X 
X 
PT, INR, aPTT 
X 
Xc 
Xb 
 
 
 
 
Xc 
Xb 
 
X 
X 
 
X 
X 
X 
C-reactive protein 
X 
Xa 
Xb 
Xa 
Xa 
 
Xa 
Xa 
Xb 
Xa 
X 
X 
 
X 
X 
X 
Quantitative HBsAg, HBeAg, HBV DNA  
X 
Xa 
 
 
 
 
Xa 
 
X 
Xa 
X 
X 
X 
X 
X 
X 
Anti-HBs and anti-HBe antibodies 
X 
Xa 
 
 
 
 
 
 
 
Xa 
 
X 
 
X 
X 
X 
HBsAg genotype 
 
Xa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV Drug Binding Sites DNA Sequence  
 
Xa 
 
 
 
 
 
 
 
Xa 
 
 
 
X 
 
X 
Archived Serum & Plasma Samples 6 
X 
Xa 
Xb 
 
Xa 
 
Xa 
Xa 
Xb 
Xa 
X 
X 
X 
X 
X 
X 
Archived PBMC Samples7 
 
Xa 
 
 
 
 
Xa 
 
 
Xa 
 
X 
 
X 
X 
X 
ECG (12-Lead) in triplicate at each time point 
X 
Xc 
Xb 
 
 
 
 
Xc 
Xb 
Xa 
 
 
 
X 
 
X 
Adverse Events 
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 
Tenofovir (or entecavir) concentration 8 
 
 
 
 
 
 
 
 
 
Xa 
X 
X 
X 
X 
X 
X 
ISIS 505358 PK Blood Sampling 9 
 
X d 
Xb 
Xa 
Xa 
 
Xa 
Xd 
Xb 
Xa 
X 
X 
X 
X 
X 
X 
 
 
 
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Appendix A Schedule of Procedures – Cohort 4 
Screen 
Treatment (4 wks) 
Post-Treatment Follow-Up (26 wks) 
Early 
Term 
Study Week (W) and/or Study Day 
S-28 to
S-1
W1 
D1 
W1 
D2 
W1 
D4 
W2 
D8 
W2 
D11 
W3 
D15 
W4 
D22 
W4 
D23 
W5 
D29 
W6 
D36 
W9 
D57 
W13 
D85 
W17 
D113 
W31 
D211 
Allowed Variance Window * 
n/a 
n/a 
^ 
± 1 
± 1 
± 1 
± 1 
± 1 
^ 
§ 
± 1 
± 3 
± 7 
± 7 
± 7 
n/a 
Study Drug Administration 
X 
X 
X 
X 
X 
X 
Nucleos(t)ide Analogue Daily Administration 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X 
X 
X 
X 
X 
Informed Consent 
X 
Inclusion/Exclusion, Medical History 
X 
Body Weight and Height 1 
X 
X a 
X 
Xa 
X 
X 
X 
X 
Physical Exam 
X 
Xa 
X 
X 
X 
Vital Signs 2 
X 
Xa 
X 
Xa 
Xa 
Xa 
Xa 
X 
Xa 
X 
X 
X 
X 
X 
X 
HIV, Hepatitis C & D 
X 
Pregnancy Test 3 
X 
X 
X 
X 
X 
X 
X 
X 
Alpha-fetoprotein 
X 
Chemistry, Hematology, Urinalysis 5 
X
Xa 
X b 
Xa 
Xa 
Xb 
Xa 
X 
X 
X 
X 
X 
X 
Complement C3 
X 
Xa 
Xa 
Xa 
Xa 
Xa 
X 
X 
X 
X 
X 
Complement split products 
X c 
Xb 
X c 
Xb 
X 
X 
X 
X 
X 
PT, INR, aPTT 
X 
Xc 
Xb 
Xc 
Xb 
X 
X 
X 
X 
X 
C-reactive protein
X 
Xa 
Xb 
Xa 
Xa 
Xa 
Xa 
Xb 
Xa 
X 
X 
X 
X 
X 
Quantitative HBsAg, HBeAg, HBV DNA 
X 
Xa 
Xa 
X 
Xa 
X 
X 
X 
X 
X 
X 
Anti-HBs and anti-HBe antibodies 
X 
Xa 
Xa 
X 
X 
X 
X 
HBsAg genotype 
Xa 
HBV Drug Binding Sites DNA Sequence  
Xa 
Xa 
X 
X 
Archived Serum & Plasma Samples 6 
X 
Xa 
Xb 
Xa 
Xa 
Xa 
Xb 
Xa 
X 
X 
X 
X 
X 
X 
Archived PBMC Samples7 
Xa 
Xa 
Xa 
X 
X 
X 
X 
ECG (12-Lead) in triplicate at each time point 
X 
Xc 
Xb 
Xc 
Xb 
Xa 
X 
X 
Adverse Events 
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 
Nucleos(t)ide Analogue concentration 8 
X10
X 
X 
X 
X 
Xa 
X 
X 
X 
X 
X 
X 
ISIS 505358 PK Blood Sampling 9 
X d 
Xb 
Xa 
Xa 
Xa 
Xd 
Xb 
Xa 
X 
X 
X 
X 
X 
X 
 
 
 
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Appendix A Schedule of Procedures Continued 
*
See Section 6.1.2 and 6.1.3 for additional details
^ 
Day 2 and Day 23 visits must occur on the day after the actual Day 1 and Day 22 visits, respectively 
§
Every attempt should be made for the Study Day 29 visit to occur 7 days after the actual occurrence of Study Day 22
n/a Not applicable
Note:  If not specifically labeled, “X” means anytime 
1 
Height measured at Screen visit only 
2 
BP, HR, RR, temp 
3 
Women who are not surgically sterile or post-menopausal 
4 
Women who are post-menopausal and not surgically sterile 
5 
If hematuria or 2 + proteinuria is observed, see confirmation guidance in Section 8.5 
6 
Stored at -80° C for retrospective clinical safety, immunologic, and/or virologic assays (e.g., retrospective LDH or CPK isoform measurements, measurement 
of cytokine and/or chemokine levels, and/or measurement of additional markers of kidney function, or mutation analysis of breakthrough HBV) in this or 
subsequent clinical studies of ISIS 505358 
7 
PBMC samples prepared from whole blood, frozen and stored for analysis at future time to be determined based upon results from HBV tests 
8 
Time of nucleos(t)ide administration and fed/fasted status at time of dose ingestion must be recorded.  Time and fed/fasted status does not need to be 
controlled, but should be similar on each blood draw day 
9 
See also Appendix C 
10 Measurement result not required for Screen pass/fail decision 
Time (time is in reference to Study Drug administration): 
a 
Pre-dose (for Day 29, is before first nucleos(t)ide analogue dose) 
b 
24-hour
c 
Pre-dose and 3 and 5 hours post-dose 
d 
0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours post-dose 
e 
Initiate dosing after specimen collections for Day 29 laboratory tests 
 
 
 
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Appendix B 
List of Laboratory Analytes 
 
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Appendix B List of Laboratory Analytes 
Clinical Chemistry Panel 
•
Sodium
•
Potassium
•
Chloride
•
Bicarbonate
•
Total protein
•
Albumin
•
Calcium
•
Magnesium
•
Phosphorus
•
Glucose
•
BUN
•
Creatinine
•
Cholesterol
•
Uric Acid
•
Total bilirubin
•
Direct (conjugated)
bilirubin
•
Indirect (unconjugated)
bilirubin
•
ALT
•
AST
•
Alkaline phosphatase
•
Creatinine kinase
•
GGT
•
LDH
Screening Tests 
•
Hepatitis D antibody
•
Hepatitis C antibody
•
HIV antibody
•
Serum βhCG
•
Alpha-fetoprotein
Coagulation 
•
aPTT (sec)
•
PT (sec)
•
INR
Complement 
•
C5a
•
Bb
•
C3
Biomarkers 
•
C-reactive protein
Pharmacokinetics1 
•
ISIS 505358 levels in
plasma
•
Tenofovir levels in
plasma
•
Entecavir levels in
plasma
Hematology 
•
Red blood cells
•
Hemoglobin
•
Hematocrit
•
MCV, MCH, MCHC
•
Platelets
•
White blood cells
•
WBC Differential
(% and absolute)
•
Neutrophils
•
Eosinophils
•
Basophils
•
Lymphocytes
•
Monocytes
HBV Tests, Quantitative 
•
HBsAg
•
HBeAg
•
HBV DNA
HBV Tests, Qualitative 
•
Anti-HBs antibody
•
Anti-HBe antibody
•
HBsAg genotype
•
HBV DNA sequence at
drug binding sites
Urinalysis 
•
Color
•
Appearance
•
Specific gravity
•
pH
•
P/C Ratio
•
Protein
•
Blood
•
Ketones
•
Urobilinogen
•
Glucose
•
Bilirubin
•
Leukocyte esterase
•
Nitrate
•
Microscopic examination 
•
Albumin/creatinine ratio
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 505358 with plasma 
constituents 
 
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Appendix C 
Plasma PK Sampling Schedules 
 
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Appendix C PK Sampling Schedules – Cohorts 1–3 
ISIS 505358 Plasma PK Blood Sampling Schedule 
D1 
D2 
D4 
D8 
D15 
D22 
D23 
D29 
Blood: 
Pre-dose, 
0.5, 1, 1.5, 2, 
3, 4, 5, 
6 hours post 
SC Injection 
Blood: 
24-hour
Blood: 
Pre-dose 
Blood: 
Pre-dose 
Blood: 
Pre-dose 
Blood: 
Pre-dose, 
0.5, 1, 1.5, 
2, 3, 4, 5, 
6 hours post 
SC injection 
Blood: 
24-hour
Blood: 
anytime 
D36 
D57 
D85 
D113 
D211 
Blood: 
anytime 
Blood: 
anytime 
Blood: 
anytime 
Blood: 
anytime 
Blood: 
anytime 
Nucleos(t)ide Analogue Sampling Schedule 
D29 
D36 
D57 
D85 
D113 
D211 
Blood: 
before first dose 
Blood: 
anytime 
Blood: 
anytime 
Blood: 
anytime 
Blood: 
anytime 
Blood: 
anytime 
Pre-dose refers to prior to administration of ISIS 505358. 
Time of nucleos(t)ide administration and fed/fasted at time of dose ingestion must be recorded.  
Time and fed/fasted (due to food effect for both nucleos(t)ide analogues) does not need to be 
controlled, but should be similar for each dose on blood draw days, and blood draw time should 
be similar for each day. 
 
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Appendix C PK Sampling Schedules – Cohort 4 
ISIS 505358 Plasma PK Blood Sampling Schedule 
D1 
D2 
D4 
D8 
D15 
D22 
D23 
D29 
Blood: 
Pre-dose, 0.5, 1, 
1.5, 2, 3, 4, 5, 
6 hours post-SC 
Injection 
Blood: 
24-hour
Blood: 
Pre-dose 
Blood: 
Pre-dose 
Blood: 
Pre-dose 
Blood: 
Pre-dose, 0.5, 1, 
1.5, 2, 3, 4, 5, 
6 hours post-SC 
injection 
Blood: 
24-hour
Blood: 
anytime 
D36 
D57 
D85 
D113 
D211 
Blood: 
anytime 
Blood: 
anytime 
Blood: 
anytime 
Blood: 
anytime 
Blood: 
anytime 
Nucleos(t)ide Analogue Sampling Schedule 
Screen 
D1 
D2 
D4 
D8 
D15 
D22 
D23 
Blood: 
anytime 
Blood: 
pre-dose 
--- 
--- 
Blood: 
pre-dose 
Blood: 
pre-dose 
Blood: 
pre-dose 
--- 
D29 
D36 
D57 
D85 
D113 
D211 
Blood: 
anytime 
Blood: 
anytime 
Blood: 
anytime 
Blood: 
anytime 
Blood: 
anytime 
Blood: 
anytime 
Pre-dose and 24-hour refers to administration of ISIS 505358. 
Time of nucleos(t)ide administration and fed/fasted at time of dose ingestion must be recorded.  
Time and fed/fasted (due to food effect for both nucleos(t)ide analogues) does not need to be 
controlled, but should be similar for each dose on blood draw days, and blood draw time should 
be similar for each day. 
 
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Appendix D 
Division of AIDS Table for Grading Severity of 
Adult and Pediatric Adverse Events Version 2.0, November 2014 
 
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Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and 
Pediatric Adverse Events  
Version 2.0 
November 2014 
Division of AIDS 
National Institute of Allergy and Infectious Diseases 
National Institutes of Health 
US Department of Health and Human Services 
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Amendment 3
29 January 2019
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Table of Contents 
Glossary and Acronyms .................................................................................................................. 1 
Introduction..................................................................................................................................... 3 
Instructions for Use ......................................................................................................................... 4 
Major Clinical Conditions............................................................................................................... 7 
Cardiovascular .......................................................................................................................... 7 
Dermatologic............................................................................................................................. 9 
Endocrine and Metabolic ........................................................................................................ 10 
Gastrointestinal ....................................................................................................................... 11 
Musculoskeletal ...................................................................................................................... 13 
Neurologic............................................................................................................................... 14 
Pregnancy, Puerperium, and Perinatal .................................................................................... 16 
Psychiatric ............................................................................................................................... 17 
Respiratory .............................................................................................................................. 18 
Sensory.................................................................................................................................... 19 
Systemic .................................................................................................................................. 20 
Urinary .................................................................................................................................... 22 
Site Reactions to Injections and Infusions .................................................................................... 23 
Laboratory Values......................................................................................................................... 24 
Chemistries ............................................................................................................................. 24 
Hematology............................................................................................................................. 27 
Urinalysis ................................................................................................................................ 29 
Appendix A.  Total Bilirubin Table for Term and Preterm Neonates .......................................... 30 
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Page 1 
Glossary and Acronyms 
AE 
Adverse event; Any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure regardless 
of whether it is considered related to the medical treatment or 
procedure. 
ALT (SGPT) 
Alanine aminotransferase (serum glutamic pyruvic transaminase) 
 ANC  
Absolute neutrophil count 
AST (SGOT) 
Aspartate aminotransferase (serum glutamic-oxaloacetic transaminase) 
 AV  
Atrioventricular 
Basic Self-care Functions 
Adult 
Activities such as bathing, dressing, toileting, transfer or movement, 
continence, and feeding. 
Young Children 
Activities that are age and culturally appropriate, such as feeding one’s 
self with culturally appropriate eating implements. 
BMI z-score 
Body mass index z- score; A body reference norm. Specifically, the 
number of standard deviations a participant's BMI differs from the 
average BMI for their age, sex, and ethnicity. 
BMD t-score 
Bone mineral density t-score; The number of standard deviations above 
or below the mean bone mineral density of a healthy 30 year old adult 
of the same sex and ethnicity as the participant. 
BMD z-score 
Bone mineral density z-score; The number of standard deviations a 
participant's BMD differs from the average BMD for their age, sex, and 
ethnicity. 
BPAP 
Bilevel positive airway pressure; A mode used during noninvasive 
positive pressure ventilation. 
Chemical Pregnancy 
A pregnancy in which a positive pregnancy test is followed by a 
negative pregnancy test without evidence of a clinical pregnancy loss. 
CNS 
Central nervous system 
CPAP 
Continuous positive airway pressure 
DAERS 
DAIDS Adverse Experience Reporting System; An internet-based 
system developed for clinical research sites to report Expedited 
Adverse Events (EAEs) to DAIDS. It facilitates timely EAE report 
submission and serves as a centralized location for accessing and 
processing EAE information for reporting purposes. 
Disability 
A substantial disruption of a person’s ability to conduct normal life 
functions. 
ECG 
Electrocardiogram 
 eGFR 
Estimated glomerular filtration rate 
Hospitalization 
Does not include the following hospital admissions: under 24 hours, 
unrelated to an adverse event (e.g., for labor and delivery, cosmetic 
surgery, social or administrative for temporary placement [for lack of a 
place to sleep]), protocol-specified, and for diagnosis or therapy of a 
condition that existed before the receipt of a study agent and which has 
not increased in severity or frequency. 
 INR 
International normalized ratio 
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Glossary and Acronyms 
Intervention 
Medical, surgical, or other procedures recommended or provided by a 
healthcare professional for the treatment of an adverse event. 
 IV  
Intravenous 
IVIG 
Intravenous immune globulin 
 LDL  
Low density lipoprotein 
LLN 
Lower limit of normal 
Life-threatening AE 
Any adverse event that places the participant, in the view of the 
investigator, at immediate risk of death from the reaction when it 
occurred (i.e., it does not include a reaction that would have caused 
death if it had occurred in a more severe form). 
NA 
Not applicable 
Participant ID 
The identification number assigned to a study participant which is used 
to track study-related documentation, including any reported AEs. 
PR Interval 
The interval between the beginning of the P wave and the beginning of 
the QRS complex of an electrocardiogram that represents the time 
between the beginning of the contraction of the atria and the beginning 
of the contraction of the ventricles. 
 PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QTc Interval 
The measure of time between the onset of ventricular depolarization 
and completion of ventricular repolarization corrected for ventricular 
rate. 
RBC 
Red blood cell 
 SI  
Standard international unit 
ULN 
Upper limit of normal 
Usual Social & Functional Activities 
Activities which adults and children perform on a routine basis and 
those which are part of regular activities of daily living, for example: 
Adults 
Adaptive tasks and desirable activities, such as going to work, 
shopping, cooking, use of transportation, or pursuing a hobby. 
Young Children 
Activities that are age and culturally appropriate, such as social 
interactions, play activities, or learning tasks. 
WBC 
White blood cell 
 WHO 
World Health Organization 
WNL 
Within normal limits 
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Introduction 
The Division of AIDS (DAIDS) oversees clinical trials throughout the world which it sponsors 
and supports.  The clinical trials evaluate the safety and efficacy of therapeutic products, 
vaccines, and other preventive modalities.  Adverse event (AE) data collected during these 
clinical trials form the basis for subsequent safety and efficacy analyses of pharmaceutical 
products and medical devices.  Incorrect and inconsistent AE severity grading can lead to 
inaccurate data analyses and interpretation, which in turn can impact the safety and well-being of 
clinical trial participants and future patients using pharmaceutical products. 
The DAIDS AE grading table is a shared tool for assessing the severity of AEs (including 
clinical and laboratory abnormalities) in participants enrolled in clinical trials.  Over the years as 
scientific knowledge and experience have expanded, revisions to the DAIDS AE grading table 
have become necessary. 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.0 replaces the grading table published in 2004 and updated in 2009.  In version 
2.0, AEs not previously included, but which now are deemed medically important events, are 
included while other AEs have been removed.  Some AE severity grading descriptions have been 
revised to more appropriately reflect the presentation of these events in clinical settings and their 
impact on clinical trials.  For example, DAIDS performed an extensive literature search and 
reviews of select DAIDS clinical trial data in revising certain hematology parameters (i.e., 
hemoglobin, white cell counts, and absolute neutrophil counts).  DAIDS also took into 
consideration the U.S. Food and Drug Administration’s guidance regarding the use of local 
laboratory reference values and ethnic differences among certain healthy adolescent and adult 
populations in defining parameter limits.  Finally, the revised DAIDS AE grading table also 
contains an updated glossary and acronyms section, an expanded instructions for use section, and 
an appendix that provides more age-specific information for an AE of concern to DAIDS. 
DAIDS is grateful to the DAIDS Grading Table Working Group, numerous government and 
non-government affiliated medical subject matter experts and reviewers who were instrumental 
in the revision of the DAIDS AE grading table. 
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Instructions for Use 
General Considerations 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse 
Events, Version 2.0 consists of parameters, or AEs, with severity grading guidance that are to be 
used in DAIDS clinical trials for safety data reporting to maintain accuracy and consistency in 
the evaluation of AEs.  The term “severe” is not the same as the term “serious” in classifying 
AEs.  The severity of a specific event describes its intensity, and it is the intensity which is 
graded.  Seriousness, which is not graded, relates to an outcome of an AE and is a regulatory 
definition. 
Clinical sites are encouraged to report parameters in the DAIDS AE grading table as they are 
written to maintain data consistency across clinical trials.  However, since some parameters can 
be reported with more specificity, clinical sites are encouraged to report parameters that convey 
additional clinical information.  For example, diarrhea could be reported as neonatal diarrhea; 
seizures, as febrile seizures; and pain, as jaw pain. 
The DAIDS AE grading table provides an AE severity grading scale ranging from grades 1 to 5 
with descriptions for each AE based on the following general guidelines: 
•
Grade 1 indicates a mild event
•
Grade 2 indicates a moderate event
•
Grade 3 indicates a severe event
•
Grade 4 indicates a potentially life-threatening event
•
Grade 5 indicates death (Note: This grade is not specifically listed on each page of the
grading table).
Other points to consider include: 
•
Use parameters defined by age and sex values as applicable.
•
Male and female sex are defined as sex at birth.
•
Unless noted, laboratory values are for term neonates.  Preterm neonates should be assessed
using local laboratory normal ranges.
•
Where applicable, Standard International (SI) units are included in italics.
Selecting and Reporting a Primary AE Term 
When selecting a primary AE term to report, sites should select the term that best describes what 
occurred to the participant.  For example, a participant may present with itching, urticaria, 
flushing, angioedema of the face, and dyspnea.  If the underlying diagnosis is determined to be 
an acute allergic reaction, sites should report “Acute Allergic Reaction” as the primary AE term. 
Primary AE terms should be reported using the DAIDS Adverse Experience Reporting System 
(DAERS) only if they meet expedited reporting criteria.  However, all primary AE terms should 
be reported using protocol-specific case report forms (CRFs).  Because the reported information 
is stored in different databases (i.e., safety and clinical), sites should report primary AE terms 
using the same terminology for data consistency. 
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Instructions for Use 
When reporting using DAERS, other clinically significant events associated with a primary AE 
term that more fully describe the nature, severity, or complications of the primary AE term 
should be entered in the “Other Events” section.  However, the severity grade for these events 
must be lower than or equal to the severity grade of the primary AE term.  In the example above, 
dyspnea and angioedema of the face may be entered in the “Other Events” section, because they 
are more descriptive and provide additional information on the severity of the acute allergic 
reaction.  However, their severity grades must be lower than or equal to the severity grade of the 
primary AE term of “Acute Allergic Reaction”. 
Differences exist in the reporting and recording of information (e.g., signs and symptoms, 
clinically significant events) in DAERS and CRFs.  Therefore, sites should refer to their 
protocols and CRF requirements for further instructions. 
Grading Adult and Pediatric AEs 
When a single parameter is not appropriate for grading an AE in both adult and pediatric 
populations, separate parameters with specified age ranges are provided.  If no distinction 
between adult and pediatric populations has been made, the listed parameter should be used for 
grading an AE in both populations. 
Reporting Pregnancy Outcomes 
In the Pregnancy, Puerperium, and Perinatal section, all parameters are pregnancy outcomes 
and should be reported using the mother's participant ID.  If an infant is not enrolled in the same 
study as the mother, any identified birth defects should be reported using the mother's participant 
ID.  However, if an infant is enrolled in the same study as the mother or in another study, any 
identified birth defects should be reported using the infant's participant ID.  Sites should refer to 
the applicable network standards for reporting abnormal pregnancy outcomes on the CRFs. 
Determining Severity Grade for Parameters between Grades 
If the severity of an AE could fall in either one of two grades (i.e., the severity of an AE could be 
either grade 2 or grade 3), sites should select the higher of the two grades. 
Laboratory Values 
General. An asymptomatic, abnormal laboratory finding without an accompanying AE should 
not be reported to DAIDS in an expedited timeframe unless it meets protocol-specific reporting 
requirements.  Sites should refer to the applicable network standards for reporting abnormal 
laboratory findings on the CRFs. 
Values below Grade 1.  Any laboratory value that is between the ULN and grade 1 (for high 
values) or the LLN and grade 1 (for low values) should not be graded or reported as an AE. 
Sites should consult the Manual for Expedited Reporting of Adverse Events to DAIDS, Version 
2.0 and their protocol when making an assessment of the need to report an AE. 
Overlap of Local Laboratory Normal Values with Grading Table Ranges.  When local laboratory 
normal values fall within grading table laboratory ranges, the severity grading is based on the 
ranges in the grading table unless there is a protocol-specific grading criterion for the laboratory 
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Instructions for Use 
value.  For example, “Magnesium, Low" has a grade 1 range of 1.2 to < 1.4 mEq/L, while a 
particular laboratory’s normal range for magnesium may be 1.3 to 2.8 mEq/L.  If a study 
participant’s magnesium laboratory value is 1.3 mEq/L, the laboratory value should be graded as 
grade 1. 
Appendix Usage 
Appendix A takes priority over the main grading table in all assessments of total bilirubin for 
term and preterm neonates. 
Using Addenda 1-3: Grading Tables Used in Microbicide Studies 
In protocols involving topical application of products to the female and male genital tracts or 
rectum, strong consideration should be given to using Addenda 1-3 (see below) as the primary 
grading tables for these areas.  Although these grading tables are used specifically in microbicide 
studies, they may be used in other protocols as adjuncts to the main grading table (i.e., the 
Division of AIDS (AIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.0).  It should be clearly stated in a protocol which addendum is being used as the 
primary grading table (and thus takes precedence over the main grading table) and which 
addendum is being used in a complementary fashion. 
•
Addendum 1 – Female Genital Grading Table for Use in Microbicide Studies – PDF
•
Addendum 2 – Male Genital Grading Table for Use in Microbicide Studies – PDF
•
Addendum 3 – Rectal Grading Table for Use in Microbicide Studies – PDF
Estimating Severity Grade for Parameters Not Identified in the Grading Table 
The functional table below should be used to grade the severity of an AE that is not specifically 
identified in the grading table.  In addition, all deaths related to an AE are to be classified as 
grade 5. 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY LIFE-
THREATENING 
Clinical adverse 
event  NOT 
identified 
elsewhere in the 
grading table 
Mild symptoms 
causing no or 
minimal interference 
with usual social & 
functional activities 
with intervention not 
indicated 
Moderate symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
with intervention 
indicated 
Severe symptoms 
causing inability to 
perform usual social & 
functional activities with 
intervention or 
hospitalization indicated 
Potentially life-threatening 
symptoms causing inability to 
perform basic self-care 
functions with intervention 
indicated to prevent 
permanent impairment, 
persistent disability, or death 
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Major Clinical Conditions 
Cardiovascular 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Arrhythmia 
(by ECG or physical 
examination) 
Specify type, if applicable 
No symptoms AND 
No intervention 
indicated 
No symptoms AND 
Non-urgent 
intervention indicated 
Non-life-threatening 
symptoms  AND 
Non-urgent 
intervention indicated 
Life-threatening 
arrhythmia OR Urgent 
intervention indicated 
Blood Pressure 
Abnormalities 1
Hypertension (with the 
lowest reading taken 
after repeat testing 
during a visit) 
≥ 18 years of age 
140 to < 160 mmHg 
systolic 
OR 
90 to < 100 mmHg 
diastolic 
≥ 160 to < 180 
mmHg systolic 
OR 
≥ 100 to < 110 
mmHg diastolic 
≥ 180 mmHg systolic 
OR 
≥ 110 mmHg diastolic 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
< 18 years of age 
> 120/80 mmHg
≥ 95th to < 99th 
percentile + 5 mmHg 
adjusted for age, 
height, and gender 
(systolic and/or 
diastolic) 
≥ 99th percentile 
+ 5 mmHg adjusted 
for age, height, and
gender (systolic 
and/or diastolic) 
Life-threatening 
consequences in a 
participant not 
previously diagnosed 
with hypertension (e.g., 
malignant hypertension) 
OR Hospitalization 
indicated 
Hypotension 
No symptoms 
Symptoms corrected 
with oral fluid 
replacement 
Symptoms AND IV 
fluids indicated 
Shock requiring use of 
vasopressors or 
mechanical assistance to 
maintain blood pressure 
Cardiac Ischemia or 
Infarction 
Report only one 
NA  
NA 
New symptoms with 
ischemia (stable 
angina) OR New 
testing consistent with 
ischemia 
Unstable angina OR 
Acute myocardial 
infarction 
Heart Failure 
No symptoms AND 
Laboratory or 
cardiac imaging 
abnormalities 
Symptoms with mild 
to moderate activity 
or exertion 
Symptoms at rest or 
with minimal activity 
or exertion (e.g., 
hypoxemia) OR 
Intervention indicated 
(e.g., oxygen) 
Life-threatening 
consequences OR Urgent 
intervention indicated 
(e.g., vasoactive 
medications, ventricular 
assist device, heart 
transplant) 
Hemorrhage 
(with significant acute 
blood loss) 
NA  
Symptoms AND  No 
transfusion indicated 
Symptoms AND 
Transfusion of ≤ 2 
units packed RBCs 
indicated 
Life-threatening 
hypotension OR 
Transfusion of > 2 units 
packed RBCs (for 
children, packed RBCs 
> 10 cc/kg) indicated 
1 Blood pressure norms for children < 18 years of age can be found in: Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk 
Reduction in Children and Adolescents. Pediatrics 2011;128;S213; originally published online November 14, 2011; DOI: 10.1542/peds.2009- 
2107C. 
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Cardiovascular 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Prolonged PR Interval 
or AV Block 
Report only one 
> 16 years  of age 
PR interval 0.21 to < 
0.25 seconds 
PR interval ≥ 0.25 
seconds OR Type I 
2nd degree AV block 
Type II 2nd degree AV 
block OR Ventricular 
pause ≥ 3.0 seconds 
Complete AV block 
≤ 16 years of age 
1st degree AV block 
(PR interval 
> normal for age and
rate) 
Type I 2nd degree AV 
block 
Type II 2nd degree AV 
block OR Ventricular 
pause ≥ 3.0 seconds 
Complete AV block 
Prolonged QTc 
Interval 2
0.45 to 0.47 seconds 
> 0.47 to 0.50 
seconds 
> 0.50 seconds OR 
≥ 0.06 seconds above 
baseline 
Life-threatening 
consequences (e.g., 
Torsade de pointes, other 
associated serious 
ventricular dysrhythmia) 
Thrombosis or 
Embolism 
Report only one 
NA 
Symptoms AND No 
intervention indicated 
Symptoms AND 
Intervention indicated 
Life-threatening embolic 
event (e.g., pulmonary 
embolism, thrombus) 
2 As per Bazett’s formula. 
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Dermatologic 
3 For pruritus associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23). 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 9 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Alopecia (scalp only) 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
NA 
NA 
Bruising 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Cellulitis 
NA  
Non-parenteral 
treatment indicated 
(e.g., oral antibiotics, 
antifungals, 
antivirals) 
IV treatment indicated 
(e.g., IV antibiotics, 
antifungals, antivirals) 
Life-threatening 
consequences (e.g., 
sepsis, tissue necrosis) 
Hyperpigmentation 
Slight or localized 
causing no or 
minimal interference 
with usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Hypopigmentation 
Slight or localized 
causing no or 
minimal interference 
with usual social & 
functional activities 
Marked or 
generalized causing 
greater than minimal 
interference with 
usual social & 
functional activities 
NA 
NA 
Petechiae 
Localized to one 
area 
Localized to more 
than one area 
Generalized 
NA 
Pruritus 3
(without skin lesions) 
Itching causing no 
or minimal 
interference with 
usual social & 
functional activities 
Itching causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Itching causing 
inability to perform 
usual social & 
functional activities 
NA 
Rash 
Specify type, if applicable 
Localized rash 
Diffuse rash OR 
Target lesions 
Diffuse rash AND 
Vesicles or limited 
number of bullae or 
superficial ulcerations 
of mucous membrane 
limited to one site 
Extensive or generalized 
bullous lesions OR 
Ulceration of mucous 
membrane involving two 
or more distinct mucosal 
sites OR Stevens- 
Johnson syndrome OR 
Toxic epidermal 
necrolysis 
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Endocrine and Metabolic 
DAIDS AE Grading Table Version 2.0- November 2014 
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Diabetes Mellitus 
Controlled without 
medication 
Controlled with 
medication OR 
Modification of 
current medication 
regimen 
Uncontrolled despite 
treatment 
modification OR 
Hospitalization for 
immediate glucose 
control indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non- 
ketotic coma, end organ 
failure) 
Gynecomastia 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing pain with 
greater than minimal 
interference with 
usual social & 
functional activities 
Disfiguring changes 
AND Symptoms 
requiring intervention 
or causing inability to 
perform usual social 
& functional activities 
NA 
Hyperthyroidism 
No symptoms AND 
Abnormal laboratory 
value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Thyroid 
suppression therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
thyroid storm) 
Hypothyroidism 
No symptoms AND 
Abnormal laboratory 
value 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR  Thyroid 
replacement therapy 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Uncontrolled 
despite treatment 
modification 
Life-threatening 
consequences (e.g., 
myxedema coma) 
Lipoatrophy 4 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
Lipohypertrophy 5 
Detectable by study 
participant, 
caregiver, or 
physician AND 
Causing no or 
minimal interference 
with usual social & 
functional activities 
Obvious on visual 
inspection AND 
Causing greater than 
minimal interference 
with usual social & 
functional activities 
Disfiguring changes 
NA 
4 Definition: A disorder characterized by fat loss in the face, extremities, and buttocks. 
5 Definition: A disorder characterized by abnormal fat accumulation on the back of the neck, breasts, and abdomen. 
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Gastrointestinal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Anorexia 
Loss of appetite 
without decreased 
oral intake 
Loss of appetite 
associated with 
decreased oral intake 
without significant 
weight loss 
Loss of appetite 
associated with 
significant weight loss 
Life-threatening 
consequences OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
Ascites 
No symptoms 
Symptoms AND 
Intervention indicated 
(e.g., diuretics, 
therapeutic 
paracentesis) 
Symptoms recur or 
persist despite 
intervention 
Life-threatening 
consequences 
Bloating or Distension 
Report only one 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cholecystitis 
NA  
Symptoms AND 
Medical intervention 
indicated 
Radiologic, 
endoscopic, or 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
sepsis, perforation) 
Constipation 
NA  
Persistent 
constipation requiring 
regular use of dietary 
modifications, 
laxatives, or enemas 
Obstipation with 
manual evacuation 
indicated 
Life-threatening 
consequences (e.g., 
obstruction) 
Diarrhea 
≥ 1 year of age 
Transient or 
intermittent episodes 
of unformed stools 
OR Increase of ≤ 3 
stools over baseline 
per 24-hour period 
Persistent episodes of 
unformed to watery 
stools OR Increase of 
4 to  6 stools over 
baseline per 24-hour 
period 
Increase of ≥ 7 stools 
per 24-hour period 
OR IV fluid 
replacement indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
< 1 year of age 
Liquid stools (more 
unformed than 
usual) but usual 
number of stools 
Liquid stools with 
increased number of 
stools OR Mild 
dehydration 
Liquid stools with 
moderate dehydration 
Life-threatening 
consequences (e.g., 
liquid stools resulting in 
severe dehydration, 
hypotensive shock) 
Dysphagia or 
Odynophagia 
Report only one and 
specify location 
Symptoms but able 
to eat usual diet 
Symptoms causing 
altered dietary intake 
with no intervention 
indicated 
Symptoms causing 
severely altered 
dietary intake with 
intervention indicated 
Life-threatening 
reduction in oral intake 
Gastrointestinal 
Bleeding 
Not requiring 
intervention other 
than iron 
supplement 
Endoscopic 
intervention indicated 
Transfusion indicated 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
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Gastrointestinal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Mucositis or Stomatitis 
Report only one and 
specify location 
Mucosal erythema 
Patchy 
pseudomembranes or 
ulcerations 
Confluent 
pseudomembranes or 
ulcerations OR 
Mucosal bleeding 
with minor trauma 
Life-threatening 
consequences (e.g., 
aspiration, choking) OR 
Tissue necrosis OR 
Diffuse spontaneous 
mucosal bleeding 
Nausea 
Transient (< 24 
hours) or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Persistent nausea 
resulting in decreased 
oral intake for 24 to 
48 hours 
Persistent nausea 
resulting in minimal 
oral intake for > 48 
hours OR 
Rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
Pancreatitis 
NA 
Symptoms with 
hospitalization not 
indicated 
Symptoms with 
hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
circulatory failure, 
hemorrhage, sepsis) 
Perforation 
(colon or rectum) 
NA 
NA 
Intervention indicated 
Life-threatening 
consequences 
Proctitis 
Rectal discomfort 
with no intervention 
indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Medical 
intervention indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
OR Operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Rectal Discharge 
Visible discharge 
Discharge requiring 
the use of pads 
NA 
NA 
Vomiting 
Transient or 
intermittent AND 
No or minimal 
interference with 
oral intake 
Frequent episodes 
with no or mild 
dehydration 
Persistent vomiting 
resulting in orthostatic 
hypotension OR 
Aggressive 
rehydration indicated 
(e.g., IV fluids) 
Life-threatening 
consequences (e.g., 
hypotensive shock) 
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Musculoskeletal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Arthralgia 
Joint pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Joint pain causing 
inability to perform 
usual social & 
functional activities 
Disabling joint pain 
causing inability to 
perform basic self-care 
functions 
Arthritis 
Stiffness or joint 
swelling causing no 
or minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Stiffness or joint 
swelling causing 
inability to perform 
usual social & 
functional activities 
Disabling joint stiffness 
or swelling causing 
inability to perform basic 
self-care functions 
Myalgia (generalized) 
Muscle pain causing 
no or minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Muscle pain causing 
inability to perform 
usual social & 
functional activities 
Disabling muscle pain 
causing inability to 
perform basic self-care 
functions 
Osteonecrosis 
NA  
No symptoms but 
with radiographic 
findings AND No 
operative intervention 
indicated 
Bone pain with 
radiographic findings 
OR Operative 
intervention indicated 
Disabling bone pain with 
radiographic findings 
causing inability to 
perform basic self-care 
functions 
Osteopenia 6
≥ 30 years of age 
BMD t-score 
-2.5 to -1 
NA 
NA 
NA 
< 30 years of age 
BMD z-score 
-2 to -1 
NA 
NA 
NA 
Osteoporosis6
≥ 30 years of age 
NA 
BMD t-score < -2.5 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
< 30 years of age 
NA  
BMD z-score < -2 
Pathologic fracture 
(e.g., compression 
fracture causing loss 
of vertebral height) 
Pathologic fracture 
causing life-threatening 
consequences 
6 BMD t and z scores can be found in: Kanis JA on behalf of the World Health Organization Scientific Group (2007). Assessment of osteoporosis 
at the primary health-care level. Technical Report. World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of 
Sheffield, UK. 2007: Printed by the University of Sheffield. 
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Neurologic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Acute CNS Ischemia 
NA  
NA 
Transient ischemic 
attack 
Cerebral vascular 
accident (e.g., stroke 
with neurological 
deficit) 
Altered Mental Status 
(for Dementia, see 
Cognitive, Behavioral, or 
Attentional Disturbance 
below) 
Changes causing no 
or minimal 
interference with 
usual social & 
functional activities 
Mild lethargy or 
somnolence causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Confusion, memory 
impairment, lethargy, 
or  somnolence 
causing inability to 
perform usual social 
& functional activities 
Delirium OR 
Obtundation OR 
Coma 
Ataxia 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with ataxia detected 
on examination 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Disabling symptoms 
causing inability to 
perform basic self-care 
functions 
Cognitive, Behavioral, 
or Attentional 
Disturbance (includes 
dementia and attention 
deficit disorder) 
Specify type, if applicable 
Disability causing 
no or minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources not 
indicated 
Disability causing 
greater than minimal 
interference with 
usual social & 
functional activities 
OR Specialized 
resources on part- 
time basis indicated 
Disability causing 
inability to perform 
usual social & 
functional activities 
OR Specialized 
resources on a full- 
time basis indicated 
Disability causing 
inability to perform 
basic self-care functions 
OR Institutionalization 
indicated 
Developmental Delay 
< 18 years of age 
Specify type, if applicable 
Mild developmental 
delay, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Moderate 
developmental delay, 
either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Severe developmental 
delay, either motor or 
cognitive, as 
determined by 
comparison with a 
developmental 
screening tool 
appropriate for the 
setting 
Developmental 
regression, either motor 
or cognitive, as 
determined by 
comparison with a 
developmental screening 
tool appropriate for the 
setting 
Headache 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
basic self-care functions 
OR Hospitalization 
indicated  OR Headache 
with significant 
impairment of alertness 
or other neurologic 
function 
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Neurologic 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Neuromuscular 
Weakness (includes 
myopathy and 
neuropathy) 
Specify type, if applicable 
Minimal muscle 
weakness causing no 
or minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with decreased 
strength on 
examination 
Muscle weakness 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Muscle weakness 
causing inability to 
perform usual social 
& functional activities 
Disabling muscle 
weakness causing 
inability to perform 
basic self-care functions 
OR  Respiratory muscle 
weakness impairing 
ventilation 
Neurosensory Alteration 
(includes paresthesia and 
painful neuropathy) 
Specify type, if applicable 
Minimal paresthesia 
causing no or 
minimal 
interference with 
usual social & 
functional activities 
OR No symptoms 
with sensory 
alteration on 
examination 
Sensory alteration or 
paresthesia causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Sensory alteration or 
paresthesia causing 
inability to perform 
usual social & 
functional activities 
Disabling sensory 
alteration or paresthesia 
causing inability to 
perform basic self-care 
functions 
Seizures 
New Onset Seizure 
≥ 18 years of age 
NA 
NA 
1 to  3 seizures 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
< 18 years of age 
(includes new or pre- 
existing febrile 
seizures) 
Seizure lasting < 5 
minutes with < 24 
hours postictal state 
Seizure lasting 5 to < 
20 minutes with 
< 24 hours postictal 
state 
Seizure lasting ≥ 20 
minutes OR > 24 
hours postictal state 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
Pre-existing Seizure 
NA 
Increased frequency 
from previous level 
of control without 
change in seizure 
character 
Change in seizure 
character either in 
duration or quality 
(e.g., severity or 
focality) 
Prolonged and repetitive 
seizures (e.g., status 
epilepticus) OR Difficult 
to control (e.g., 
refractory epilepsy) 
Syncope 
Near syncope 
without loss of 
consciousness (e.g., 
pre-syncope) 
Loss of consciousness 
with no intervention 
indicated 
Loss of consciousness 
AND Hospitalization 
or intervention 
required 
NA 
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Pregnancy, Puerperium, and Perinatal 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Fetal Death or Stillbirth 
(report using mother’s 
participant ID) 
Report only one 
NA  
NA 
Fetal loss occurring at 
≥ 20 weeks gestation 
NA 
Preterm Delivery 7 
(report using mother’s 
participant ID) 
Delivery at 34 to 
< 37 weeks 
gestational age 
Delivery at 28 to 
< 34 weeks 
gestational age 
Delivery at 24 to 
< 28 weeks 
gestational age 
Delivery at < 24 weeks 
gestational age 
Spontaneous Abortion or 
Miscarriage 8 (report 
using mother’s participant 
ID) 
Report only one 
Chemical pregnancy 
Uncomplicated 
spontaneous abortion 
or miscarriage 
Complicated 
spontaneous abortion 
or miscarriage 
NA 
7 Definition:  A delivery of a live-born neonate occurring at ≥ 20 to < 37 weeks gestational age. 
8 Definition:  A clinically recognized pregnancy occurring at < 20 weeks gestational age. 
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Psychiatric 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Insomnia 
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
Moderate difficulty 
falling asleep, staying 
asleep, or waking up 
early 
Severe difficulty 
falling asleep, staying 
asleep, or waking up 
early 
NA 
Psychiatric Disorders 
(includes anxiety, 
depression, mania, and 
psychosis) 
Specify disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
intervention indicated 
OR Behavior causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
hospitalization 
indicated OR 
Behavior causing 
inability to perform 
usual social & 
functional activities 
Threatens harm to self or 
others OR Acute 
psychosis OR Behavior 
causing inability to 
perform basic self-care 
functions 
Suicidal Ideation or 
Attempt 
Report only one 
Preoccupied with 
thoughts of death 
AND No wish to kill 
oneself 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or intent 
Thoughts of killing 
oneself with partial or 
complete plans but no 
attempt to do so OR 
Hospitalization 
indicated 
Suicide attempted 
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Respiratory 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Acute Bronchospasm 
Forced expiratory 
volume in 1 second 
or peak flow 
reduced to 
≥ 70 to < 80% OR 
Mild symptoms with 
intervention not 
indicated 
Forced expiratory 
volume in 1 second or 
peak flow 50 to 
< 70% OR Symptoms 
with intervention 
indicated OR 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Forced expiratory 
volume in 1 second 
or peak flow 25 to 
< 50% OR Symptoms 
causing inability to 
perform usual social 
& functional 
activities 
Forced expiratory 
volume in 1 second or 
peak flow < 25% OR 
Life-threatening 
respiratory or 
hemodynamic 
compromise OR 
Intubation 
Dyspnea or Respiratory 
Distress 
Report only one 
Dyspnea on exertion 
with no or minimal 
interference with 
usual social & 
functional activities 
OR Wheezing OR 
Minimal increase in 
respiratory rate for 
age 
Dyspnea on exertion 
causing greater than 
minimal interference 
with usual social & 
functional activities 
OR Nasal flaring OR 
Intercostal retractions 
OR Pulse oximetry 90 
to < 95% 
Dyspnea at rest 
causing inability to 
perform usual social 
& functional 
activities OR Pulse 
oximetry < 90% 
Respiratory failure with 
ventilator support 
indicated (e.g., CPAP, 
BPAP, intubation) 
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Sensory 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Hearing Loss 
≥ 12 years of age 
NA 
Hearing aid or 
intervention not 
indicated 
Hearing aid or 
intervention indicated 
Profound bilateral 
hearing loss (> 80 dB at 
2 kHz and above) OR 
Non-serviceable hearing 
(i.e., >50 dB audiogram 
and <50% speech 
discrimination) 
< 12 years of age 
(based on a 1, 2, 3, 4, 6 
and 8 kHz audiogram) 
> 20 dB hearing loss 
at  ≤ 4 kHz 
> 20 dB hearing loss 
at > 4 kHz 
> 20 dB hearing loss at 
≥ 3 kHz in one ear 
with additional speech
language related 
services indicated 
(where available) OR 
Hearing loss 
sufficient to indicate 
therapeutic 
intervention, 
including hearing aids 
Audiologic indication for 
cochlear implant and 
additional speech- 
language related services 
indicated (where 
available) 
Tinnitus 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
with intervention not 
indicated 
Symptoms causing 
greater than minimal 
interference with 
usual social & 
functional activities 
with intervention 
indicated 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Uveitis 
No symptoms AND 
Detectable on 
examination 
Anterior uveitis with 
symptoms OR 
Medicamylasal 
intervention indicated 
Posterior or pan- 
uveitis OR Operative 
intervention indicated 
Disabling visual loss in 
affected eye(s) 
Vertigo 
Vertigo causing no 
or minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Vertigo causing 
inability to perform 
usual social & 
functional activities 
Disabling vertigo 
causing inability to 
perform basic self-care 
functions 
Visual Changes 
(assessed from baseline) 
Visual changes 
causing no or 
minimal interference 
with usual social & 
functional activities 
Visual changes 
causing greater than 
minimal interference 
with usual social & 
functional activities 
Visual changes 
causing inability to 
perform usual social 
& functional activities 
Disabling visual loss in 
affected eye(s) 
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Acute Allergic 
Reaction 
Localized urticaria 
(wheals) with no 
medical intervention 
indicated 
Localized urticaria 
with intervention 
indicated OR Mild 
angioedema with no 
intervention 
indicated 
Generalized urticaria 
OR Angioedema with 
intervention indicated 
OR Symptoms of mild 
bronchospasm 
Acute anaphylaxis OR 
Life-threatening 
bronchospasm OR 
Laryngeal edema 
Chills 
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
NA 
Cytokine Release 
Syndrome9
Mild signs and 
symptoms AND 
Therapy (i.e., antibody 
infusion) interruption 
not indicated 
Therapy (i.e., 
antibody infusion) 
interruption 
indicated AND 
Responds promptly 
to symptomatic 
treatment OR 
Prophylactic 
medications 
indicated for ≤ 24 
hours 
Prolonged severe signs 
and symptoms OR 
Recurrence of 
symptoms following 
initial improvement 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
Fatigue or Malaise 
Report only one 
Symptoms causing no 
or minimal 
interference with usual 
social & functional 
activities 
Symptoms causing 
greater than 
minimal 
interference with 
usual social & 
functional activities 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Incapacitating symptoms 
of fatigue or malaise 
causing inability to 
perform basic self-care 
functions 
Fever (non-axillary 
temperatures only) 
38.0 to < 38.6°C or 
100.4 to < 101.5°F 
≥ 38.6  to < 39.3°C 
or ≥ 101.5 to 
< 102.7°F 
≥ 39.3 to < 40.0°C or 
≥ 102.7 to < 104.0°F 
≥ 40.0°C or ≥ 104.0°F 
Pain10 (not associated 
with study agent 
injections and not 
specified elsewhere) 
Specify location 
Pain causing no or 
minimal interference 
with usual social & 
functional activities 
Pain causing greater 
than minimal 
interference with 
usual social & 
functional activities 
Pain causing inability 
to perform usual social 
& functional activities 
Disabling pain causing 
inability to perform basic 
self-care functions OR 
Hospitalization indicated 
Serum Sickness 11
Mild signs and 
symptoms 
Moderate signs and 
symptoms AND 
Intervention 
indicated (e.g., 
antihistamines) 
Severe signs and 
symptoms AND 
Higher level 
intervention indicated 
(e.g., steroids or IV 
fluids) 
Life-threatening 
consequences (e.g., 
requiring pressor or 
ventilator support) 
9 Definition: A disorder characterized by nausea, headache, tachycardia, hypotension, rash, and/or shortness of breath. 
10 For pain associated with injections or infusions, see the Site Reactions to Injections and Infusions section (page 23). 
11 Definition: A disorder characterized by fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or dyspnea. 
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PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Underweight12 
> 5 to 19 years of 
age 
NA 
WHO BMI z-score 
< -2 to ≤ -3 
WHO BMI z-score 
< -3
WHO BMI z-score 
< -3 with life-threatening 
consequences 
2 to 5 years of age 
NA 
WHO Weight-for- 
height z-score 
< -2 to ≤ -3 
WHO Weight-for- 
height z-score < -3 
WHO Weight-for-height 
z-score < -3 with life- 
threatening consequences 
< 2 years of age 
NA 
WHO Weight-for- 
length z-score 
< -2 to ≤ -3 
WHO Weight-for- 
length z-score < -3 
WHO Weight-for-length 
z-score < -3 with life- 
threatening consequences 
Weight Loss (excludes 
postpartum weight 
loss) 
NA 
5 to < 9% loss in 
body weight from 
baseline 
≥ 9 to < 20% loss in 
body weight from 
baseline 
≥ 20% loss in body weight 
from baseline OR 
Aggressive intervention 
indicated (e.g., tube 
feeding, total parenteral 
nutrition) 
12 WHO reference tables may be accesed by clicking the desired age range or by accessing the following URLs: 
http://www.who.int/growthref/who2007_bmi_for_age/en/ for participants > 5 to 19 years of age and 
http://www.who.int/childgrowth/standards/chart_catalogue/en/ for those ≤ 5 years of age. 
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Urinary 
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Page 22 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Urinary Tract 
Obstruction 
NA  
Signs or symptoms of 
urinary tract 
obstruction without 
hydronephrosis or 
renal dysfunction 
Signs or symptoms of 
urinary tract 
obstruction with 
hydronephrosis or 
renal dysfunction 
Obstruction causing life- 
threatening 
consequences 
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Site Reactions to Injections and Infusions 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Injection Site Pain or 
Tenderness 
Report only one 
Pain or tenderness 
causing no or 
minimal limitation 
of use of limb 
Pain or tenderness 
causing greater than 
minimal limitation of 
use of limb 
Pain or tenderness 
causing inability to 
perform usual social 
& functional activities 
Pain or tenderness 
causing inability to 
perform basic self-care 
function OR 
Hospitalization indicated 
Injection Site Erythema 
or Redness 13
Report only one 
> 15 years of age 
2.5 to < 5 cm in 
diameter OR 6.25 to 
< 25 cm2 surface 
area AND 
Symptoms causing 
no or minimal 
interference with 
usual social & 
functional activities 
≥ 5 to < 10 cm in 
diameter OR ≥ 25 to 
< 100 cm2 surface 
area OR  Symptoms 
causing greater than 
minimal interference 
with usual social & 
functional activities 
≥ 10 cm in diameter 
OR ≥ 100 cm2 surface 
area OR Ulceration 
OR Secondary 
infection OR Phlebitis 
OR Sterile abscess 
OR Drainage OR 
Symptoms causing 
inability to perform 
usual social & 
functional activities 
Potentially life- 
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
≤ 15 years of age 
≤ 2.5 cm in diameter 
> 2.5 cm in diameter 
with < 50% surface 
area of the extremity 
segment involved 
(e.g., upper arm or 
thigh) 
≥ 50% surface area of 
the extremity segment 
involved (e.g., upper 
arm or thigh) OR 
Ulceration OR 
Secondary infection 
OR Phlebitis OR 
Sterile abscess OR 
Drainage 
Potentially life- 
threatening 
consequences (e.g., 
abscess, exfoliative 
dermatitis, necrosis 
involving dermis or 
deeper tissue) 
Injection Site 
Induration or Swelling 
Report only one 
> 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, > 15 years of 
age 
≤ 15 years of age 
Same as for 
Injection Site 
Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years 
of age 
Same as for Injection 
Site Erythema or 
Redness, ≤ 15 years of 
age 
Injection Site Pruritus 
Itching localized to 
the injection site that 
is relieved 
spontaneously or in 
< 48 hours of 
treatment 
Itching beyond the 
injection site that is 
not generalized OR 
Itching localized to 
the injection site 
requiring ≥ 48 hours 
treatment 
Generalized itching 
causing inability to 
perform usual social 
& functional activities 
NA 
13 Injection Site Erythema or Redness should be evaluated and graded using the greatest single diameter or measured surface area. 
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Laboratory Values 
Chemistries 
14 Direct bilirubin > 1.5 mg/dL in a participant < 28 days of age should be graded as grade 2, if < 10% of the total bilirubin. 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 24 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Acidosis 
NA  
pH ≥ 7.3 to < LLN 
pH < 7.3 without life- 
threatening 
consequences 
pH < 7.3 with life- 
threatening 
consequences 
Albumin, Low 
(g/dL; g/L) 
3.0 to < LLN 
30  to < LLN 
≥ 2.0 to < 3.0 
≥ 20  to < 30 
< 2.0 
< 20 
NA 
Alkaline Phosphatase, 
High 
1.25  to < 2.5 
x ULN 
2.5  to < 5.0 x ULN 
5.0 to < 10.0 x ULN 
≥ 10.0 x ULN 
Alkalosis 
NA  
pH > ULN to ≤ 7.5 
pH > 7.5 without life- 
threatening 
consequences 
pH > 7.5 with life- 
threatening 
consequences 
ALT or SGPT, High 
Report only one 
1.25  to < 2.5 
x ULN 
2.5 to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Amylase (Pancreatic) or 
Amylase (Total), High 
Report only one 
1.1  to < 1.5 x ULN 
1.5  to < 3.0 x ULN 
3.0  to < 5.0 x ULN 
≥ 5.0 x ULN 
AST or SGOT, High 
Report only one 
1.25  to < 2.5 
x ULN 
2.5  to < 5.0 x ULN 
5.0  to < 10.0 x ULN 
≥ 10.0 x ULN 
Bicarbonate, Low 
(mEq/L; mmol/L) 
16.0 to <  LLN 
16.0 to <  LLN 
11.0  to < 16.0 
11.0  to < 16.0 
8.0  to < 11.0 
8.0  to < 11.0 
< 8.0 
< 8.0 
Bilirubin 
Direct Bilirubin14, 
High 
> 28 days of age 
NA 
NA 
> ULN
> ULN with life- 
threatening 
consequences (e.g., signs 
and symptoms of liver 
failure) 
≤ 28 days of age 
ULN to ≤ 1 mg/dL 
> 1 to ≤ 1.5 mg/dL 
> 1.5 to ≤ 2 mg/dL
> 2 mg/dL
Total Bilirubin, High 
> 28 days of age 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥  5.0 x ULN 
≤ 28 days of age 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. 
Total Bilirubin for 
Term and Preterm 
Neonates 
See Appendix A. Total 
Bilirubin for Term and 
Preterm Neonates 
Calcium, High 
(mg/dL; mmol/L) 
≥ 7 days of age 
10.6   to < 11.5 
2.65  to < 2.88 
11.5  to < 12.5 
2.88  to < 3.13 
12.5   to < 13.5 
3.13  to < 3.38 
≥  13.5 
≥  3.38 
< 7 days of age 
11.5  to < 12.4 
2.88  to < 3.10 
12.4  to < 12.9 
3.10  to < 3.23 
12.9  to < 13.5 
3.23  to < 3.38 
≥  13.5 
≥  3.38 
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Chemistries 
15 Use the applicable formula (i.e., Cockroft-Gault in mL/min or Schwatrz in mL/min/1.73m2). 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 25 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Calcium (Ionized), High 
(mg/dL; mmol/L) 
> ULN to < 6.0
> ULN  to < 1.5 
6.0 to < 6.4 
1.5 to < 1.6 
6.4 to < 7.2 
1.6 to < 1.8 
≥ 7.2 
≥ 1.8 
Calcium, Low 
(mg/dL; mmol/L) 
≥ 7 days of age 
7.8  to < 8.4 
1.95  to < 2.10 
7.0   to < 7.8 
1.75  to < 1.95 
6.1  to < 7.0 
1.53  to < 1.75 
< 6.1 
< 1.53 
< 7 days of age 
6.5  to < 7.5 
1.63  to < 1.88 
6.0 to < 6.5 
1.50  to < 1.63 
5.50  to < 6.0 
1.38  to < 1.50 
< 5.50 
< 1.38 
Calcium (Ionized),  Low 
(mg/dL; mmol/L) 
< LLN  to 4.0 
< LLN to 1.0 
3.6 to < 4.0 
0.9 to < 1.0 
3.2 to < 3.6 
0.8 to < 0.9 
< 3.2 
< 0.8 
Cardiac Troponin I, 
High 
NA 
NA 
NA 
Levels consistent with 
myocardial infarction or 
unstable angina as 
defined by the local 
laboratory 
Creatine Kinase, High 
3 to < 6 x ULN 
6 to < 10 x ULN 
10 to < 20 x ULN 
≥ 20 x ULN 
Creatinine, High 
1.1 to 1.3 x ULN 
> 1.3 to 1.8 x ULN 
OR Increase of 
> 0.3 mg/dL above 
baseline 
> 1.8  to < 3.5 
x ULN OR Increase 
of 1.5 to < 2.0 x 
above baseline 
≥ 3.5 x ULN OR 
Increase of ≥ 2.0 x 
above baseline 
Creatinine Clearance 15
or eGFR, Low 
Report only one 
NA 
< 90 to 60 ml/min or 
ml/min/1.73 m2
OR 
10 to < 30% decrease 
from baseline 
< 60 to 30 ml/min or 
ml/min/1.73 m2
OR 
≥ 30 to < 50% 
decrease from 
baseline 
< 30 ml/min or 
ml/min/1.73 m2
OR 
≥ 50% decrease from 
baseline or dialysis 
needed 
Glucose 
(mg/dL; mmol/L) 
Fasting, High 
110 to 125 
6.11 to < 6.95 
> 125 to 250 
6.95 to < 13.89 
> 250 to 500 
13.89 to < 27.75 
> 500
≥ 27.75
Nonfasting, High 
116 to 160 
6.44 to < 8.89 
> 160 to 250 
8.89 to < 13.89 
> 250 to 500 
13.89  to < 27.75 
> 500
≥ 27.75
Glucose, Low 
(mg/dL; mmol/L) 
≥ 1 month of age 
55  to 64 
3.05  to 3.55 
40  to < 55 
2.22  to < 3.05 
30  to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
< 1 month of age 
50 to 54 
2.78  to 3.00 
40 to < 50 
2.22 to < 2.78 
30 to < 40 
1.67 to < 2.22 
< 30 
< 1.67 
Lactate, High 
ULN to  < 2.0 
x ULN without 
acidosis 
≥ 2.0 x ULN without 
acidosis 
Increased lactate with 
pH < 7.3 without life- 
threatening 
consequences 
Increased lactate with 
pH < 7.3 with life- 
threatening 
consequences 
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Chemistries 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 26 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Lipase, High 
1.1  to < 1.5 x ULN 
1.5  to < 3.0 x ULN 
3.0  to < 5.0 x ULN 
≥ 5.0 x ULN 
Lipid Disorders 
(mg/dL; mmol/L) 
Cholesterol, Fasting, 
High 
≥ 18 years of age 
200  to < 240 
5.18  to < 6.19 
240  to < 300 
6.19  to < 7.77 
≥  300 
≥  7.77 
NA 
< 18 years of age 
170  to < 200 
4.40  to < 5.15 
200  to < 300 
5.15  to < 7.77 
≥  300 
≥  7.77 
NA 
LDL, Fasting, High 
≥ 18 years of age 
130  to < 160 
3.37  to < 4.12 
160 to < 190 
4.12  to < 4.90 
≥ 190 
≥ 4.90 
NA 
> 2 to < 18 years of 
age
110  to < 130 
2.85  to < 3.34 
130 to < 190 
3.34  to < 4.90 
≥ 190 
≥ 4.90 
NA 
Triglycerides, Fasting, 
High 
150 to 300 
1.71 to 3.42 
>300  to 500 
>3.42 to 5.7 
>500 to < 1,000 
>5.7 to 11.4 
> 1,000 
> 11.4 
Magnesium16, Low 
(mEq/L; mmol/L) 
1.2   to < 1.4 
0.60  to < 0.70 
0.9  to < 1.2 
0.45  to < 0.60 
0.6  to < 0.9 
0.30  to < 0.45 
< 0.6 
< 0.30 
Phosphate, Low 
(mg/dL; mmol/L) 
> 14 years of age 
2.0 to < LLN 
0.81 to < LLN 
1.4 to < 2.0 
0.65 to < 0.81 
1.0 to < 1.4 
0.32 to < 0.65 
< 1.0 
< 0.32 
1 to 14 years of age 
3.0  to < 3.5 
0.97  to < 1.13 
2.5  to < 3.0 
0.81  to < 0.97 
1.5  to < 2.5 
0.48  to < 0.81 
< 1.5 
< 0.48 
< 1 year of age 
3.5  to < 4.5 
1.13  to < 1.45 
2.5  to < 3.5 
0.81  to < 1.13 
1.5  to < 2.5 
0.48  to < 0.81 
< 1.5 
< 0.48 
Potassium, High 
(mEq/L; mmol/L) 
5.6  to < 6.0 
5.6  to < 6.0 
6.0  to < 6.5 
6.0  to < 6.5 
6.5  to < 7.0 
6.5  to < 7.0 
≥ 7.0 
≥ 7.0 
Potassium, Low 
(mEq/L; mmol/L) 
3.0  to < 3.4 
3.0  to < 3.4 
2.5  to < 3.0 
2.5  to < 3.0 
2.0  to < 2.5 
2.0  to < 2.5 
< 2.0 
< 2.0 
Sodium, High 
(mEq/L; mmol/L) 
146  to < 150 
146  to < 150 
150  to < 154 
150  to < 154 
154  to < 160 
154  to < 160 
≥ 160 
≥ 160 
Sodium, Low 
(mEq/L; mmol/L) 
130  to < 135 
130  to < 135 
125  to < 130 
125  to < 135 
121  to < 125 
121  to < 125 
≤ 120 
≤ 120 
Uric Acid, High 
(mg/dL; mmol/L) 
7.5  to < 10.0 
0.45  to < 0.59 
10.0  to < 12.0 
0.59  to < 0.71 
12.0  to < 15.0 
0.71  to < 0.89 
≥ 15.0 
≥ 0.89 
16 To convert a magnesium value from mg/dL to mmol/L, laboratories should multiply by 0.4114. 
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CONFIDENTIAL
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DAIDS AE Grading Table Version 2.0- November 2014 
Page 27 
Hematology 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Absolute CD4+ Count, 
Low 
(cell/mm3; cells/L) 
> 5 years of age 
(not HIV infected) 
300 to < 400 
300 to < 400 
200 to <  300 
200 to < 300 
100 to < 200 
100  to < 200 
< 100 
< 100 
Absolute Lymphocyte 
Count, Low 
(cell/mm3; cells/L) 
> 5 years of age 
(not HIV infected) 
600  to < 650 
9 
0.600 x 10   to 
< 0.650 x 109 
500  to < 600 
9 
0.500 x 10   to 
< 0.600 x 109 
350 to < 500 
9 
0.350 x 10   to 
< 0.500 x 109 
< 350 
9 
< 0.350 x 10 
Absolute Neutrophil 
Count (ANC), Low 
(cells/mm3; cells/L) 
> 7 days of age 
800 to 1,000 
0.800 x 109 to 1.000 
x 109 
600 to 799 
0.600 x 109 to 0.799 x 
109 
400 to 599 
0.400 x 109 to 0.599 x 
109 
< 400 
< 0.400 x 109 
2 to 7 days of age 
1,250 to 1,500 
1.250 x 109 to 1.500 
x 109 
1,000 to 1,249 
1.000 x 109 to 1.249 x 
109 
750 to 999 
0.750 x 109 to 0.999 x 
109 
< 750 
< 0.750 x 109 
≤ 1 day of age 
4,000 to 5,000 
4.000 x 109 to 
5.000 x 109 
3,000 to 3,999 
3.000 x 109 to 3.999 x 
109 
1,500 to 2,999 
1.500 x 109 to 2.999 x 
109 
< 1,500 
< 1.500 x 109 
Fibrinogen, Decreased 
(mg/dL; g/L) 
100  to < 200 
1.00 to < 2.00 
OR 
0.75 to < 1.00 
x LLN 
75  to < 100 
0.75  to < 1.00 
OR 
≥ 0.50 to < 0.75 
x LLN 
50  to < 75 
0.50  to < 0.75 
OR 
0.25 to < 0.50 
x LLN 
< 50 
< 0.50 
OR 
< 0.25 x LLN 
OR Associated with 
gross bleeding 
Hemoglobin17, Low 
(g/dL; mmol/L)18
≥ 13 years of age 
(male only) 
10.0 to 10.9 
6.19 to 6.76 
9.0 to < 10.0 
5.57 to < 6.19 
7.0 to < 9.0 
4.34 to < 5.57 
< 7.0 
< 4.34 
≥ 13 years of age 
(female only) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
17 Male and female sex are defined as sex at birth. 
18 The conversion factor used to convert g/dL to mmol/L is 0.6206 and is the most commonly used conversion factor.  For grading hemoglobin 
results obtained by an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using the appropriate 
conversion factor for the particular laboratory. 
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CONFIDENTIAL
Amendment 3
29 January 2019
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DAIDS AE Grading Table Version 2.0- November 2014 
Page 28 
Hematology 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
57 days of age to < 13 
years of age 
(male and female) 
9.5 to 10.4 
5.88 to 6.48 
8.5 to < 9.5 
5.25 to < 5.88 
6.5 to < 8.5 
4.03 to < 5.25 
< 6.5 
< 4.03 
36 to 56 days of age 
(male and female) 
8.5 to 9.6 
5.26 to 5.99 
7.0 to < 8.5 
4.32 to < 5.26 
6.0 to < 7.0 
3.72 to < 4.32 
< 6.0 
< 3.72 
22 to 35 days of age 
(male and female) 
9.5 to 11.0 
5.88 to 6.86 
8.0 to < 9.5 
4.94 to < 5.88 
6.7 to < 8.0 
4.15 to < 4.94 
< 6.7 
< 4.15 
8 to ≤ 21 days of age 
(male and female) 
11.0 to 13.0 
6.81 to 8.10 
9.0 to < 11.0 
5.57 to < 6.81 
8.0 to < 9.0 
4.96 to < 5.57 
< 8.0 
< 4.96 
≤ 7 days of age 
(male and female) 
13.0 to 14.0 
8.05 to 8.72 
10.0 to < 13.0 
6.19 to < 8.05 
9.0 to < 10.0 
5.59 to < 6.19 
< 9.0 
< 5.59 
INR, High 
(not on anticoagulation 
therapy) 
1.1  to < 1.5 x ULN 
1.5  to < 2.0 x ULN 
2.0  to < 3.0 x ULN 
≥  3.0 x ULN 
Methemoglobin 
(% hemoglobin) 
5.0  to < 10.0% 
10.0  to < 15.0% 
15.0  to < 20.0% 
≥  20.0% 
PTT, High 
(not on anticoagulation 
therapy) 
1.1  to < 1.66 
x ULN 
1.66 to < 2.33 
x ULN 
2.33 to < 3.00 
x ULN 
≥  3.00 x ULN 
Platelets, Decreased 
(cells/mm3; cells/L) 
100,000  to 
< 124,999 
100.000 x 109  to 
< 124.999 x 109 
50,000  to 
< 100,000 
50.000 x 109  to 
< 100.000 x 109 
25,000  to 
< 50,000 
25.000 x 109  to 
< 50.000 x 109 
< 25,000 
< 25.000 x 109 
PT, High 
(not on anticoagulation 
therapy 
1.1  to < 1.25 
x ULN 
1.25  to < 1.50 
x ULN 
1.50  to < 3.00 
x ULN 
≥  3.00 x ULN 
WBC, Decreased 
(cells/mm3; cells/L) 
> 7 days of age 
2,000 to 2,499 
2.000 x 109 to 2.499 
x 109 
1,500 to 1,999 
1.500 x 109 to 1.999 x 
109 
1,000 to 1,499 
1.000 x 109 to 1.499 x 
109 
< 1,000 
< 1.000 x 109 
≤ 7 days of age 
5,500 to 6,999 
5.500 x 109 to 6.999 
x 109 
4,000 to 5,499 
4.000 x 109 to 5.499 x 
109 
2,500 to 3,999 
2.500 x 109 to 3.999 x 
109 
< 2,500 
< 2.500 x 109 
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DAIDS AE Grading Table Version 2.0- November 2014 
Page 29 
Urinalysis 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Glycosuria (random 
collection tested by 
dipstick) 
Trace to 1+ or 
≤ 250 mg 
2+ or ˃ 250 to 
≤ 500 mg 
> 2+ or > 500 mg
NA 
Hematuria (not to be 
reported based on dipstick 
findings or on blood 
believed to be of 
menstrual origin) 
6  to < 10 RBCs per 
high power field 
≥ 10 RBCs per high 
power field 
Gross, with or 
without clots OR 
With RBC casts OR 
Intervention indicated 
Life-threatening 
consequences 
Proteinuria (random 
collection tested by 
dipstick) 
1+ 
2+ 
3+  or higher 
NA 
ISIS 505358-CS3
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Appendix A. 
DAIDS AE Grading Table Version 2.0- November 2014 
Page 30 
Total Bilirubin Table for Term and Preterm Neonates 
PARAMETER 
GRADE 1 
MILD 
GRADE 2 
MODERATE 
GRADE 3 
SEVERE 
GRADE 4 
POTENTIALLY 
LIFE- 
THREATENING 
Total Bilirubin 19, High 
(mg/dL; µmol/L)20
Term Neonate21 
< 24 hours of age 
4 to < 7 
68.4 to < 119.7 
7 to < 10 
119.7 to < 171 
10  to < 17 
171  to < 290.7 
≥ 17 
≥ 290.7 
24 to < 48 hours of 
age 
5 to < 8 
85.5 to < 136.8 
8 to < 12 
136.8 to < 205.2 
12  to < 19 
205.2  to < 324.9 
≥ 19 
≥ 324.9 
48 to < 72 hours of 
age 
8.5 to < 13 
145.35 to < 222.3 
13 to < 15 
222.3 to < 256.5 
15  to < 22 
256.5  to < 376.2 
≥ 22 
≥ 376.2 
72 hours to < 7 days 
of age 
11 to < 16 
188.1 to < 273.6 
16 to < 18 
273.6 to < 307.8 
18  to < 24 
307.8  to < 410.4 
≥ 24 
≥ 410.4 
7 to 28 days of age 
(breast feeding) 
5 to < 10 
85.5 to < 171 
10 to < 20 
171 to < 342 
20 to < 25 
342 to < 427.5 
≥ 25 
≥ 427.5 
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥  5.0 x ULN 
Preterm Neonate20 
35 to < 37 weeks 
gestational age 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
Same as for Total 
Bilirubin, High, 
Term Neonate (based 
on days of age). 
Same as for Total 
Bilirubin, High, Term 
Neonate (based on 
days of age). 
32 to < 35 weeks 
gestational age and 
< 7 days of age 
NA 
NA 
10 to < 14 
171 to < 239.4 
≥ 14 
≥ 239.4 
28 to < 32 weeks 
gestational age and 
< 7 days of age 
NA 
NA 
6 to < 10 
102.6 to < 171 
≥ 10 
≥ 171 
< 28 weeks 
gestational age and 
< 7 days of age 
NA 
NA 
5 to < 8 
85.5 to < 136.8 
≥ 8 
≥ 136.8 
7 to  28 days of age 
(breast feeding) 
5 to < 10 
85.5 to < 171 
10 to < 20 
171 to < 342 
20 to < 25 
342 to < 427.5 
≥ 25 
≥ 427.5 
7 to 28 days of age 
(not breast feeding) 
1.1 to < 1.6 x ULN 
1.6 to < 2.6 x ULN 
2.6 to < 5.0 x ULN 
≥  5.0 x ULN 
19 Severity grading for total bilirubin in neonates is complex because of rapidly changing total bilirubin normal ranges in the first week of life 
followed by the benign phenomenon of breast milk jaundice after the first week of life.  Severity grading in this appendix corresponds 
approximately to cut-offs for indications for phototherapy at grade 3 and for exchange transfusion at grade 4. 
20 A laboratory value of 1 mg/dL is equivalent to 17.1 µmol/L. 
21 Definitions: Term is defined as ≥ 37 weeks  gestational age; near-term, as ≥ 35 weeks  gestational age; preterm, as < 35 weeks gestational age; 
and neonate, as 0 to 28 days of age. 
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