Clinical trial NCT03358030
Conditions: End-stage Renal Disease (ESRD)
Sponsor: Ionis Pharmaceuticals, Inc.
Start date: 2017-12-26; Completion date: 2019-07-10
Enrollment: 213 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Evaluation of safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of ISIS 416858 for up to 204 participants with ESRD receiving chronic hemodialysis as assessed by FXI activity reduction.

Detailed description:
Evaluation of safety, PK, and PD of ISIS 416858 (Dose # 1, Dose #2 and Dose #3 once weekly) as compared to placebo as assessed by FXI activity reduction.

Arms: arm 1: Participants received placebo, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period. arm 2: Participants received ISIS 416858, 200 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period. arm 3: Participants received ISIS 416858, 250 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period. arm 4: Participants received ISIS 416858, 300 mg, subcutaneously, within 2 hours post-dialysis, once weekly from Week 1 (Day 1) through Week 26 of treatment period.
Interventions: intervention 1: ISIS 416858 intervention 2: Placebo
Intervention descriptions: intervention 1: Subcutaneous injection intervention 2: Subcutaneous injection

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the 
Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of ISIS 
416858 (IONIS-FXIRX, an Antisense Inhibitor of Factor XI), Administered 
Subcutaneously to Patients With End-Stage Renal Disease on Hemodialysis 
 
NCT03358030 
 
14-June-2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Official Title:  A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of 
the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple 
Doses of ISIS 416858 (IONIS-FXIRX an Antisense Inhibitor of Factor 
XI), Administered Subcutaneously to Patients with End-Stage Renal 
Disease on Hemodialysis 
 
NCT Number: NCT03358030 
 
 
Document Date: SAP Version 2: 30 May 2019 


Statistical Analysis Plan 30 May 201912.0 
416858-CS0S 
Jonis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
May 30, 2019 
ISIS 416858-CSS 
CONFIDENTIAL 
 
 
 
 
 
 
IONIS" 
 
 
 
Statistical Analysis Plan 
 
 
 
ISIS 416858-CSS 
 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
of the Safety, Pharmacok.inetics, and Pharmacodynamics of 
Multiple Doses of ISIS 416858 (IONIS-FXIRX an Antisense 
Inhibitor of Factor XI), Administered Subcutaneously to Patients 
with End-Stage Renal Disease on Hemodialysis 
 
Date: May 30, 2019 
 
Version: 2.0 
 
 
 
 
CONFIDENTIAL 
 
Confidential/Trade Secret information subject to 18-USC-1905 and to which all claims of privilege and 
confidentiality are asserted in both statutory and common law. Further dissemination may be made 
only with the express written permission of lonis Pharmaceuticals, Inc. 


Statistical Analysis Plan 30 May 201912.0 
416858-CS0S 
Jonis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
May 30, 2019 
ISIS 416858-CSS 
CONFIDENTIAL 
 
 
Statistical Analysis Plan Signature Page 
 
 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court Carlsbad, CA 92010 
 
 
Compound Name: 
ISIS 416858 
 
 
Protocol: 
ISIS 416858-CSS 
 
 
Study Title: 
 A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of 
the Safety, Phannacokinetics, and Pharmacodynamics of Multiple 
Doses ofISIS 416858 (IONIS-FXfaxan Antisense Inhibitor of 
Factor XI), Administered Subcutaneously to Patients with End-Stage 
Renal Disease on Hemodialysis 
 
 
Protocol Version: 
14 June 2018 (Protocol Amendment l) 
 
 
 
Signature: 
 
 
Jonis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
 
 
Signature: 
 
 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 920l0 
 
 
 
 
ii 


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Date: 
 
Ionis Phannaceuticals, Inc. 
Statistical Analysis Plan 
 
 
 
 
Signature: 
 
CONFIDENTIAL 
May 30, 2019 
ISIS 416858-CSS 
 
 
 
Jonis Pharmaceuticals, Inc. 
2855 Gazelle Court 
Carlsbad, CA 92010 
 
 
 
 
Signature:  
 
 
 
2855 Gazelle Court 
Carlsbad, CA 92010 


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ISIS 416858-CS5 
 
 
Table of Contents 
ABB REVIATIONS ....................................................................................................................... 6 
1 
INTRODUCTION ..........................................................................................................9 
1.1 
Study Overview ..................................................................................................... 9 
1.2 
Objectives ............................................................................................................... 9 
1.2.1 
Primary Objectives ............................................................................................ 9 
1.2.2 
Exploratory Objectives .................................................................................... 10 
1.3 
Planned Method of Analysis ............................................................................... ]0 
1.3. l 
Safety and Tolerability Outcomes .................................................................. 10 
1.3.2 
Pharmacodynamic Outcomes ........................................................................... 10 
1.3.3 
Exploratory Outcomes ..................................................................................... 10 
1.3.4 
Other Study Outcomes and Evaluations ......................................................... 10 
1.3.5 
Platelet Function Testing ................................................................................. 11 
1.4 
Randomization & Treatment Allocation ............................................................ 11 
1.5 
Conduct ................................................................................................................. 11 
1.6 
Data Monitoring .................................................................................................... 11 
1.6.1 
Safety Data Monitoring ................................................................................... 11 
1.7 
Data Management ................................................................................................. 11 
1.7.1 
Case Report Form Data ................................................................................... 12 
1.7.2 
Laboratory Data ............................................................................................... 12 
2.5.3 
Pharmacokinetic Data and Immunogenicity (IM) Data ................................ 12 
2 
ANALYTICAL PLAN ........................................................................................... 1. 2 
2.1 
General Overview of Analyses ........................................................................... 12 
2.1.1 
General Statistical Methods ............................................................................ 12 
2.1.2 
Populations ....................................................................................................... 18 
2.1.3 
Sample Size Consideration .............................................................................. 19 
2.1.4 
Planned Interim Analysis ................................................................................. 19 
2.1.5 
Incomplete or Missing Data ............................................................................ 19 
2.2 
Demographic and Baseline Characteristics ........................................................ 19 


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2.3 
Safety Analyses .....................................................................................................21 
2.3.l 
Exposure ........................................................................................................... 21 
2.3.2 
Compliance ...................................................................................................... 21 
2.3.3 
Adverse Events .................................................................................................21 
2.3.4 
Laboratory Measurements ............................................................................... 25 
2.3.5 
Vital Signs ........................................................................................................ 26 
2.3.6 
Physical Examinations .................................................................................... 26 
2.3.7 
12-Lead Electrocardiograms (ECG) ............................................................... 26 
2.3.8 
Concomitant Medications ............................................................................... 26 
2.3.9 
Ancillary procedures ....................................................................................... 27 
2.3.10 Changes in Dialysis Access ............................................................................ 27 
2.4 
Pharmacodynamic Analyses ............................................................................... 27 
2.5 
Exploratory Outcomes ......................................................................................... 29 
2.6 
Other Study Outcomes and Evaluations ............................................................. 29 
2.6.1 
Platelet Function tests ...................................................................................... 30 
2.7 
Pharmacokinetic Analysis ................................................................................... 30 
2.7.1 
Plasma Concentration Data ............................................................................. 30 
2.7.2 
Plasma Phannacokinetic Parameters ............................................................... 31 
2.8 
lmmunogenicity (IM) Analysis .......................................................................... 33 


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ABBREVIATIONS 
Abbreviation 
Definition 
 
AE 
AF 
ALT 
aPTT 
AST 
AUC 
AUCo-4hr 
AUCo-24hr 
BP 
BUN 
 
CRNMB 
CV 
ECG 
eCRF 
EDC 
ESRD 
FLRs 
GCP 
HIV 
HR 
HRL 
hr, hrs 
ICH 
INR 
ISIS 416858 
IXRS 
 
adverse event 
atrial fibrillation 
alanine aminotransferase 
activated partial thromboplastin time 
aspartate aminotransferase 
area under the plasma concentration-time curve 
area under the plasma concentration-time curve from time 
zero to 4 hours 
area under the plasma concentration-time curve from time 
zero to 24 hours 
blood pressure 
blood urea nitrogen 
maximum concentration 
clinically relevant non-major bleeding 
coefficient of variation 
Electrocardiogram 
electronic Case Report Form 
electronic data capture 
end-stage renal disease 
Flu-like reactions 
Good Clinical Practice 
human immunodeficiency virus 
heart rate 
Hemostasis Reference Laboratory 
hour(s) 
International Conference on Harmonization 
international nonnalized ratio 
antisense inhibitor of Factor XI 
automated randomization system 


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Statistical Analysis Plan 
CONFlDENTlAL 
 
May 30, 2019 
ISIS 416858-CSS 
Kg 
Kilogram 
LCRIS 
local cutaneous reaction at injection site 
MB 
major bleeding 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
Mg 
Milligram 
mL 
Milliliter 
MRL 
Medpace Reference Laboratories 
PD 
phannacodynamic(s) 
PK 
pharmacokinetic(s) 
PT 
prothrombin time 
QI 
25th percentile 
Q3 
75th percentile 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(!y) 
Study Drug 
ISIS 416858 or placebo 
TEAE 
treatment emergent adverse event 
Tmax 
time to maximal concentration 
ULN 
upper limit of normal 
VR 
ventricular rate 
WBC 
white blood cell 
WHO 
World Health Organization 


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List of Modifications: 
The following modifications have been made to SAP, version 1.0, dated August 20, 2018. 
 
Section 
Title 
Change 
1.3.5 
Platelet Function Testing 
Details ofBCH data added. 
2.1 
General Overview of 
Procedures 
Blood centers of Wisconsin data added. 
2.5.2 
Laboratory Data 
Clarification of data availability of immunogenicity 
3.1.l 
General Statistical 
Methods 
visit windows added 
3.1.4 
Planned Interim Analysis 
Added details that no unblinding interim analyses were 
conducted until final database lock. 
3.3.3.3 
Bleeding 
Added details on minor bleeding summary. 


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reduction in ESRD patients on hemodialysis; 
 
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Statistical Analysis Plan 
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1 INTRODUCTION 
 
This document provides a description of the study organization, study procedures, and the 
plan for the statistical analysis of the study data. Section 1 discusses study design, 
objectives, and endpoints; Section 2 provides the study procedures; Section 3 provides the 
detailed plan for the statistical analyses. 
The purpose of this plan is to provide specific guidelines from which the analysis will 
proceed. Any deviations from these guidelines will be documented in the clinical study 
report (CSR). 
 
1.1 Study Overview 
 
This is a Phase 2 multicenter, double-blind, randomized, stratified, placebo-controlled study 
in end-stage renal disease (ESRD) subjects receiving hemodialysis at least 3 times per week 
for a minimum of 9 hours per week. Subjects will be stratified based on the diagnosis of 
documented atrial fibrillation (AF) at Screening (Yes/No), enrolled in PK substudy (Yes/No), 
enrolled in Platelet substudy (Yes/No), and then subjects will be randomized to l of 3 dose 
cohorts in a l: l:l ratio (Cohort A, Cohort B, and Cohort C). Within each dose cohort, 
subjects will be randomized in a 3:1 ratio to receive treatment with Study Drug (either ISIS 
416858 or placebo). 
Cohort A: 
Cohort B: 
Cohort C: 
200 mg ISIS 416858 or placebo SC (3:1) 
250 mg ISIS 416858 or placebo SC (3:1) 
300 mg ISIS 416858 or placebo SC (3:1) 
All cohorts will consist of up to 4-week screening period for procedures and a 26-week 
treatment period followed by a 12-week post-treatment evaluation period. 
Approximately 204 subjects are planned to be enrolled in parallel in this study. 
1.2 Objectives 
 
1.2.1 
Primary Objectives 
To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ISIS 416858 
(200, 250, and 300 mg once weekly) as compared to placebo as assessed by FXI activity 


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ISIS 416858-CSS 
 
1.2.2 
Exploratory Objectives 
To evaluate the incidence of myocardial infarction (MI), stroke, systemic embolism, and 
cardiovascular mortality. 
 
1.3 Planned Method of Analysis 
 
1.3.J 
Safety and Tolerability Outcomes 
 
The primary safety outcome is the combination of major bleeding (MB) and clinically- 
relevant non-major bleeding (CRNMB) during the treatment period (or early study 
termination). 
The safety and tolerability of ISIS 416858 will be accessed by determining the incidence and 
severity of adverse events (AEs) and will be evaluated by reviewing: 
• 
AEs (including venous thrombocmbolism (VTE) and bleeding events) 
• 
Vital signs and weight 
• 
ECG 
• 
Physical examination 
• 
Clinical laboratory tests 
• 
Coagulation parameters 
• 
Use of concomitant medications including transfusions 
 
1.3.2 Pharmacodynamic Outcomes 
 
• 
Change from baseline in FXI antigen and activity 
• 
Change from baseline in activated partial thromboplastin time (aPTT) 
• 
The extent and frequency of clotting on the dialysis filters and circuit 
 
1.3.3 Exploratory Outcomes 
 
• 
Incidence of myocardial infarction (MI), stroke, systemic embolism, and 
cardiovascular mortality 
 
1.3.4 Other Study Outcomes and Evaluations 
 
• 
Dialysis adequacy (Urea Reduction Ratio and single pool Kt/v), changes in dialysis 
prescription (vascular access, time on dialysis, dry weight) 
• 
PK 


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1.3.5 Platelet Function Testing 
For the subgroup of subjects evaluated for platelet function and/or activation, an analysis of 
pre- and post-treatment results with ISIS 416858 may be conducted overtime and compared 
to treatment with placebo 
 
1.4 Randomization & Treatment Allocation 
 
Subjects will be randomized on Study Day l after all screening assessments have been 
completed and after the Investigator has verified that they are eligible. No subject may begin 
treatment prior to randomization and assignment of a unique subject identification number. 
All subjects will be randomized using an automated system (IXRS). Subjects will be 
stratified based on the diagnosis of documented atrial fibrillation (AF) at Screening 
(Yes/No), enrolled in PK substudy (Yes/No), enrolled in Platelet substudy (Yes/No), and 
then subjects will be randomized to 1 of 3 dose cohorts in a 1:1:1 ratio (Cohort A, Cohort B, 
and Cohort C). Within each dose cohort, subjects will be randomized in a 3:l ratio to receive 
treatment with Study Drug (either ISIS 416858 or placebo). 
 
1.5 Conduct 
 
The study will be conducted in accordance with current Good Clinical Practice (GCP) and 
International Conference on Harmonization (ICH) guidelines, the World Medical Association 
Declaration of Helsinki guidelines, the Food and Drug Administration (FDA) Code of 
Federal Regulations, and all other local regulatory requirements. 
 
1.6 Data Monitoring 
 
1.6.1 
Safety Data Monitoring 
 
Safety data will be monitored as indicated in the ISIS 416858-CSS Medical Monitoring Plan 
with monthly or more frequent reviews during the treatment and follow-up periods by the 
Sponsor Medical Monitor (or appropriately qualified designee) and PPD Medical Monitor (or 
appropriately qualified designee) throughout the study. Safety data to be reviewed will 
include selected chemistries, hematology, coagulation, ECG, vital signs and adverse events. 
 
1.7 Data Management 
 
An eCRF utilizing an Electronic Data Capture (EDC) application will be used for this Study. 


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I.7.1 Case Report Form Data 
 
BioClinica (or designee) is responsible for creating the EDC data entry screens, database and 
edit checks using definitions developed by Ionis Pharmaceuticals, Inc. Ionis 
Pharmaceuticals, Inc. is responsible for the review, data management querying and locking 
of the database. 
Data are single-entered into the EDC system by the investigator site staff. Programmed edit 
checks (computer logic that checks the validity of the data entered and also prompts for 
missing data that is expected to be entered) are run and automatic queries are generated. 
lonis Pharmaceuticals, Inc. reviews all data for accuracy and validity and generates 
additional queries in the EDC system when necessary. The data arc corrected or an 
explanation concerning the query is provided in the EDC system. After all data are entered, 
reviewed (by Data Management and Clinical Development) and queried, and all queries 
resolved, the database is locked. 
 
1.7.2 Laboratory Data 
 
Jonis Pharmaceuticals, Inc. is responsible for the format of the laboratory electronic data 
transfers, transfer schedule and review of the clinical laboratory data. This lab data will be 
stored as SAS data sets. Data from BCH may be stored in an Excel spreadsheet. 
Immunogenicity results will be available after final database lock. 
 
2.5.3 
Pliarmacoki11etic Data and Immunogenicity (IM) Data 
 
Jonis Pharmaceuticals, Inc. is responsible for the management and review of the PK plasma 
concentration data and IM data. This process involves reviewing the patient and visit 
identifiers (i.e., patient demographics) with the clinical data collected in the EDC system. 
The PK and IM data are not stored in the EDC system. 
 
2 ANALYTICAL PLAN 
 
2.1 General Overview of Analyses 
 
2.1.J General Statistical Methods 
 
Descriptive summary statistics including number of patients, mean, standard deviation, 
median, and range (minimum, maximum) for continuous variables, and counts and 
percentages for categorical variables will be used to summarize most data. All statistical tests 
will be conducted using 2-sided tests with 5% Type I error rate unless otherwise stated. 


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PK parameters will be summarized using number of patients, mean, standard deviation, 
coefficient of variation (CV), geometric mean, median, minimum, and maximum. 
All analyses and tabulations will be performed using SAS® Version 9.2 or higher and 
Phoenix/WinNonlin version 6.1 or higher on a PC platform. 
A separate analysis for on-treatment period might be provided if deemed necessary. 
 
 
Pooled groups: 
Patients who are placebo-treated will be pooled and analyzed as a single placebo group. 
Patients who are ISIS 416858-treated may be pooled and summarized as the ISIS 416858 
total group. 
Baseline definition: 
Unless otherwise specified, baseline for all safety laboratory results will be defined as the last 
non-missing measurement prior to the first dose. For post-dialysis Blood Urea Nitrogen 
(BUN) measures for Urea Reduction Ratio (URR) determination, post-dialysis baseline will 
be defined as the last non-missing post-dialysis measurement prior to the first dose 
Analytical visits: 
All post-baseline data will be summarized according lo the visit windows in the table below. For 
patients who have multiple visits within a window, the average will be used in the summary for 
continuous variable and the worst case result will be used for categorical variable. 
Table I Visit window for Clotting 
 
Analysis visit 
Visit window 
Screening 
<l 
Baseline 
last non-missing measurement 
prior to the first dose 
Day8 
[2, 11] 
Day 15 
[12, 21] 
Day29 
(22, 35] 
Day43 
[36, 49] 
Day 57 
[50, 63] 
Day71 
[64, 77] 
Day 85 
[78, 91] 
Day99 
(92, 105] 


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Day 113 
[106, 116) 
Day 120 
[117, 126) 
Day 134 
(127, 140) 
Day 148 
(141, 154) 
Day 162 
[155, 168) 
Day 176 
[169, 182] 
Day 190 
(183, 196] 
Day 204 
[197,210] 
Day 218 
[2 I1, 224] 
Day 232 
[225, 238] 
Day 246 
(239, 252] 
Day 260 
[253, 266] 
 
 
Table 2 Visit window for Vital Signs 
 
Analysis visit 
Visit window 
Baseline 
last non-missing measurement 
prior to the first dose 
Day 5 
(2, 6) 
Day8 
[7, 9] 
Day 12 
[10, 13] 
Day 15 
[14, 17] 
Day22 
[18,25) 
Day29 
[26, 32) 
Day36 
[33, 39) 
Day43 
[40, 46] 
Day 50 
[47, 53] 
Day 57 
[54, 60] 
Day64 
[61, 67] 
Day71 
[68, 74] 
Day78 
[75, 81) 


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Day85 
[82, 88] 
Day92 
[89, 95] 
Day99 
[96, 102] 
Day 106 
[103, 109] 
Day 113 
[110, 116] 
Day 120 
[117, 123] 
Day 127 
[124, 130] 
Day 134 
[131, 137] 
Day 141 
[138, 144] 
Day 148 
[145, 151] 
Day 155 
[152, 158) 
Day 162 
[159, 165] 
Day 169 
[166, 172] 
Day 176 
--- 
[173, 182] 
Day 190 
[183, 196) 
Day 204 
[197,210] 
Day 218 
[211,224] 
Day 232 
[225,238] 
Day 246 
[239, 252] 
Day260 
[253, 266] 
 
 
Table 3 Visit window for Electrocardiogram 
 
Analysis visit 
Visit window 
Baseline 
last non-missing measurement 
prior to the first dose 
Day29 
[2, 53] 
Day78 
[54, 126] 
Day 176 
[127,217] 
- 
Day260 
[218,273] 


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Table 4 Visit window for Chemistry panel, Hematology, and Coagulation Panel 
 
Analysis visit 
Visit window 
Baseline 
last non-missing measurement 
prior to the first dose 
Day5 
(2, 8] 
Day 12 
(9, 13] 
Day 15 
[14, 18] 
Day22 
[19, 25) 
Day29 
[26, 32] 
Day36 
[33, 42] 
Day 50 
[43, 56] 
Day64 
[57, 70] 
Day78 
(71,84] 
Day92 
- 
[85, 98] 
Day 106 
[99, 112] 
Day 120 
[113, 126] 
Day 134 
[127, 140] 
Day 148 
(141, 154] 
Day 162 
[155, 168] 
Day 176 
[169, 182] 
Day 190 
[183, 196] 
Day 204 
[197,210] 
Day 218 
[211, 224] 
Day 232 
[225, 238] 
Day 246 
[239, 252] 
Day 260 
[253, 266] 
 
 
Table 5 Visit window for Blood Urea Nitrogen, Post-Dialysis BUN, Urea Reduction Ratio 
I Analysis visit 
I Visit window 


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Baseline 
last non-missing measurement 
prior to the first dose 
Day36 
[2, 49] 
Day64 
[50, 77] 
Day92 
- 
[78, 105] 
Day 120 
[106,133] 
Day 148 
(134, 161] 
Day 176 
[162, 189] 
Day 204 
[190, 217] 
Day 232 
[218,245] 
Day260 
[246, 273] 
 
 
Table 6 Visit window for Inflammatory Markers 
 
-Analysis visit 
- 
Visit window 
Baseline 
Day 15 
last non-missing measurement 
prior to the first dose 
[2, 21] 
Day29 
[22, 39] 
Day50 
[40, 63] 
Day78 
- 
Day 106 
[64, 91] 
[92, 119] 
Day 134 
[120, 147] 
Day 162 
[148, 168] 
Day 176 
Day 204 
[169, 189] 
[190,217] 
Day 232 
[218, 245] 
Day 260 
[246,273] 


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2.J.2 
Populations 
 
The following populations will be used in this study, and any exclusion of patients from the 
populations will be documented and decided upon by appropriate medical, clinical, data 
management, and statistical personnel at Ionis Pharmaceuticals prior to unblinding. 
Intent-to-Treat Population (ITT) 
All subjects randomized who have received at least 1 dose of Study Drug (ISIS 416858 or 
placebo). Results will be summarized under the treatment to which patients were 
randomized. 
Per Protocol Population (PPS): 
All subjects who are randomized without missing more than 2 doses during the first 12 
weeks or more than 5 doses over the 26-week Treatment Period and who do not have any 
major protocol violations that would affect the interpretation or integrity of the study results. 
Safety Population: 
AH subjects randomized who have received at least I dose of Study Drug. Results for 
Cohorts A and B will be summarized under the treatment to which patients received. 
 
Atrial Fibrillation (AF) Substudy population: 
All randomized subjects who were reported at baseline as having a documented history of 
atrial fibrillation and have received at least 1 dose of Study Drug (ISIS 416858 or placebo). 
PK Substudy Population: 
All randomized subjects who participated in the PK subgroup and have received at least l 
dose of active Study Drug (ISIS 416858) and had at least 1 PK sample collected and 
analyzed with evaluable results for ISIS 416858 concentration. 
PK Population: 
All randomized subjects who have received at least 1 dose of active Study Drug 
(ISIS 416858) and had at least 1 PK sample collected and analyzed with evaluable results for 
ISIS 416858 concentration. 
Platelet Function/Activation Substudy Population: 
All subjects who participated in the Platelets Function/Activation substudy by having at least 
I evaluable sample assessed for flow cytometry and have received at least 1 dose of active 
Study Drug (ISIS 416858 or placebo). 
In addition to the above analysis populations, it is recognized that some data displays will be 
provided for "All Screened" and "Screening Failures" patients. 


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2.1.3 Sample Size Co11sideration 
 
The sample size was selected based on prior experience to ensure that the safety, tolerability 
and PK/PD relationships will be adequately assessed while minimizing unnecessary patient 
exposure. There is no statistical rationale for the selected sample size. 
 
2.1.4 Planned Interim Analysis 
 
No interim analysis is planned. However, during the study, an unblinded primary database 
lock analysis may be conducted after an patients complete the treatment period to assess the 
safety and PK/PD, and exploratory efficacy of the results. The analysis will be executed with 
controlled dissemination to ensure the integrity of ongoing data collection while maintaining 
sufficient blinding in the study. All the post-baseline coagulation panel data and unblinded 
interim analysis will be conducted by unblinded team members including a clinician and 
biostatistician who will not be associated with the direct conduct of the study after the 
unblinding occurs with interim analysis. The individuals involved in the unblinded interim 
analysis will be identified and docwnented at the time of unblinded interim analysis 
according to lonis SOP. 
The Investigator, study staff, patients, blinded monitors, and members of the Sponsor's 
clinical operations team and data management team will remain blinded throughout the 
study. 
 
2.1.5 Incomplete or Missing Data 
 
In general, missing data values will not be imputed. Incomplete data handling rules will be 
described in the specified section if needed. 
2.2 Demographic and Baseline Characteristics 
 
Demographic and Baseline characteristics (including dialysis and ESRD disease 
characteristics e.g., age, gender, ethnicity, race, weight, height, BMI, Primary Cause of 
ESRD, Time Since the Start Date for Renal Replacement Therapy (First Ever)/ESRD First 
Transplant or First Dialysis Ever, Time since the Start Date for Hemodialysis (Most Recent)) 
obtained before the first study drug administration will be summarized using descriptive 
statistics by treatment group and all patients for ITT population, Safety Population. 
Additional summaries will be provided for each substudy if there are adequate number of 
patients enrolled. 
Age for each patient is defined as number of years between informed consent date and birth 
date. 


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For summarizing race, if multiple races are recorded in the database, then 'Multiple Race' is 
used in the summary table. 
The study sample sizes will be summarized by trial unit (site) for enrolled patients. All 
patients with signed inform consent will be included in the enrolled patients. 
Dialysis prescription characteristics (Days of the week dialysis is scheduled, prescribed 
number of sessions, prescribed duration, dry weight total, type of dialyzer to be used, type of 
vascular access, Location of Arteriovenous Fistula/Graft and Location of Catheter) will be 
summarized for ITT population, Safety Population. Additional summaries will be provided 
for each substudy population if there are adequate number of patients enrolled. 
Medical history will be coded by Medical Dictionary for Regulatory Activities (MedDRA) 
Version 21.0. Medical history will be summarized by System Organ Class (SOC) and 
Preferred Term (PT). In addition, the frequency and percentage of patients with CHAOS 
score (0, 1, 2, ... , 6) will be provided for AF substudy population. The CHADS score is the 
total of the scores per the risk criteria below with data collected from Targeted Medical 
History CRF. 
 
Score 
CHADS2 Risk Criteria 
1 point 
Congestive heart failure 
1 point 
Hypertension 
1 point 
Age 75 years 
1 point 
Diabetes mellitus 
Stroke/transient ischemic attack 
2 points 
 
 
Patient randomization and disposition will be summarized by treatment group and all 
patients. All patients enrolled will be included in the summary. The summaries will include: 
the total number of patients were screened, randomized, dosed and included in each 
population, the number of patients completed treatment, the primary reason for terminating 
treatment, the number of patients completed post-treatment evaluation period, and the 
primary reason for terminating post-treatment evaluation period. 
In addition, the disposition will be summarized by treatment group and all patients for AF 
substudy population, PK substudy population, and Platelets Function/Activation substudy 
population. 
All protocol deviations will be listed. Protocol deviations will also be summarized by region, 
trial unit, and treatment group. 


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2.3 Safety Analyses 
 
Safety analyses will be based on the safety population. Safety summary tables will be 
presented by treatment group and ISIS 416858 total. 
2.3.1 
Exposure 
 
Treatment duration, time on study, number of doses and amount and total volume of Study 
Drug (ISIS 416858 or placebo) received will be summarized by treatment group and ISIS 
416858 total. 
The treatment duration (days) for each patient is defined as last dose date - first dose date +1. 
The time on study will be defined as the total number of days a patient is known to be 
followed on study calculated as follows: 
Time on study = Last date on study - Date of first dose+ 1. 
Where the last date on study is defined as the date of the latest visit with evaluation, or time 
of death from all available data for a given patient. Visits with refused or unable to contact 
are not visits with evaluation. 
The amount of Study Drug received (mg) for each patient is defined as the total volume 
(mL) administered from the 200 mg/mL stock solution. 
 
2.3.2 
Complia11ce 
 
Percentage of compliance will be calculated and summarized by treatment groups and ISIS 
416858 total. 
Study drug compliance = 100 x (Total number of doses with injections given I Total number 
of doses with injections expected). 
If a patient discontinued the study treatment, the total number of doses with injections 
expected is counted, per the schedule of injections, up to the last attended study visit during 
the treatment period. 
2.3.3 
Adverse Events 
 
The treatment emergent adverse events (TEAE) are defined as those AEs that occurred after 
dosing and those existing pre-dose AEs that worsened post-dose during the study. 
The most conservative approach will be used to detennine if the event occurs during the 
treatment or follow-up periods: 
• 
AEs that have onset dates or resolution dates prior to the first study treatment dates will 
be considered to have occurred prior to the study period. If the onset or resolution date 


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of an AE is a partial date with only month or year available or complete missing, then 
the event is assumed to be within the study period unless the year is prior to the year of 
the first study treatment date, or if in the same year, the month is prior to the month of 
the first study treatment date. 
• 
AEs that have onset dates after study termination date for the post-treatment evaluation 
period will be assumed to have occurred after the study period. If the onset of an AE is a 
partial date with only month or year available or complete missing, then similar 
approach as above will be used 
The ESRD related adverse event is defined as TEAE with "Related", "Possible" relationship 
to ESRD. If the AE relationship to ESRD is missing or it has been defined as 
"Unlikely/remote", it will be considered as a Non-ESRD/Procedure-related AE. 
All adverse event summaries will be restricted to treatment-emergent adverse events (TEAE). 
The incidence of treatment-emergent adverse events will be summarized by treatment group 
and ISIS 416858 total, by MedDRA preferred term and system organ class for the 
followings: 
• 
AE Overview 
• 
AE Overview for ESRD/Procedure-related adverse events 
• 
AE Overview for non-ESRD/Procedure-related adverse events 
• 
TEAEs 
• 
TEAE for ESRD/Procedure-related adverse events 
• 
TEAE for non-ESRD/Procedure-related adverse events 
• 
TEAEs potentially related to study drug. Potentially related is defined as "Related", 
"Possible", or missing relationship to study drug 
• 
Serious TEAEs 
• 
Serious TEAEs potentially related to study drug 
• 
TEAEs resulting in permanently discontinuation of study drug 
• 
Subjects with non-serious AE. The subjects with non-serious AE are those subjects 
having at least one non-serious adverse event, but no SAE. 
• 
TEAE by maximum severity. At each level of patient summarization, a patient is 
classified according to the highest severity if the patient reported one or more events. 
Adverse events with missing severity will categorized as "Missing" for this summary. 
Event counts will also be provided for each level of severity. 
• 
TEAEs potentially related to study drug by maximum severity 


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• 
Serious TEAEs potentially related to study drug by maximum severity 
Events will be sorted by total incidence of each System Organ Class then by total incidence 
of each Preferred Term within each System Organ Class. For incidence counts, each patient 
will be counted only once within each Preferred Term and within each SOC. Percentages 
will be based on the nwnber of patients in a particular treatment ann. 
2.3.3 .J 
Local Cutaneous Reactions at the Injection Site 
Local cutaneous reaction at injection site (LCRJS) is defined as (A) moderate or severe 
Injection Site Erythema, Swelling, Pruritus, Pain or Tenderness that started on the day of 
injection, persisted for at least two days; or (B) any AE at the Study Drug injection site, 
regardless of severity, that leads to discontinuation of study drug, where AE at the Study 
Drug injection site is the principal reason for discontinuation. 
LCRIS will be summarized using the MedDRA coding system, by preferred term. Patients 
with moderate, severe and any LCRIS will also be swnmarized. Discontinuations due to AE 
at the injection site will be summarized separately. 
Percentage of injections leading to LCRIS will be summarized by preferred terms and overall 
using the descriptive statistics. Additionally, percentage of Study Drug injections leading to 
LCRIS will be summarized by the moderate, severe severity and overall discontinuation of 
study drug due to AE at Study Drug injection site. 
Percentage of Study Drug injections leading to LCRIS will be calculated as follows for each 
subject: (A/B)*l00, where A=number of Study Drug injections with a LCRIS, and B=total 
number of Study Drug injections. Doses that are split across multiple Study Drug injections 
are counted as a single injection. 
2.3.3.2 Flu-like Reactio11s 
Flu-like reactions (FLRs) will also be summarized using the MedDRA coding system, by 
preferred term. 
Flu-like reactions are defined as either (A) flu-like illness or (B) Pyrexia or feeling hot or 
body temperature increased, plus at least two of the following: Chills, Myalgia, and 
Arthralgia, starting on day of injection or the next day. 
Percentage of injections leading to flu-like reactions will be sun1marized using the 
descriptive statistics. 
Percentage of the injections leading to flu-like reactions will be calculated as follows for each 
subject: (A/B)*100, where A=number of injections leading to flu-like reactions, and B=total 
number of injections. 
2.3.3.3 Bleedi11g 
Major bleeding (MB) is defined as one of the following: 


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1. Fatal bleeding 
2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, retroperitoneal, intraarticular if in a major joint, or pericardia!, or 
intramuscular with compartment syndrome 
3. Clinically overt bleeding leading to transfusion of 
units of packed red blood cells 
or whole blood or a fall in hemoglobin of20 g/L(1.24 mmol/L) or more within 24 
hours 
Clinically relevant non-major bleeding (CRNMB) is defined as overt bleeding not meeting 
the criteria for major bleeding but that resulted, for example, in medical examination, 
intervention, or had clinical consequences for a patient. 
Minor bleeding: 
All other acute clinically ove11 bleeding events not meeting the criteria for either major or 
clinically relevant non-major bleeding will be classified as minor. Minor bleeding will be 
further categorized as injection site and non-injection site bleeding events. 
The incidence of any bleeding event after first dose of study drug will be summarized by 
treatment group for the Safety Population for all bleeding events except minor bleeding at the 
injection site. Minor bleeding at the injection site will be summarized separately. The 
summary will include the following outcomes: 
• 
MB 
• 
CRNMB 
• 
Minor bleeding (Non-injection site and injection site events) 
• 
Combination of MB and CRNMB (with either MB or CRNMB) 
The cumulative rate of first major bleeding events after first dose of study drug will be 
displayed using Kaplan-Meier curves for the safety population. Patients without major 
bleeding event will be censored at the last visit date with evaluation. Additional information 
on the Bleeding CRF will also be summarized and/or listed. 
2.3.3.4 AE of Interests 
Adverse events of interest additionally include the following categories from CRFs: 
• 
Cerebrovascular Accident/Transient Ischemic Attack 
• 
Coronary Ischemia 
• 
Venous Thromboembolism 
AE listing will be provided for each AESI category including the seriousness of the AE. 


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2.3.4 Laboratory Measurements 
 
The following is the list ofroutine lab analytes that may be collected throughout the study: 
• 
Chemistry: Total protein, Albumin, Glucose, Blood urea nitrogen (BUN) for urea 
reduction ratio (URR) determination, Total bilirubin, Direct bilirubin, Indirect 
bilirubin, ALT, AST, GGT 
• 
Hematology: Red blood cells, Hemoglobin, Hematocrit, MCV, MCH, MCHC, 
Platelets, Mean Platelet Volume, WBC, and WBC differential (percentage and 
absolute) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Neutrophils) 
• 
Inflammatory Markers: Hs-CRP, D-climer, Beta-2-M, Cardiac troponin I and T, NT- 
proBNP 
• 
Screening Tests: Hepatitis B surface antigen, Hepatitis C antibody, HIV antibody, 
FSH (women only, if applicable) and Serum PhCG (women only). This data will only 
be displayed in patient listings. 
Missing WBC differential absolute counts and percentages will be derived as needed: 
If WBC differential absolute counts are missing, and percentages are available, then absolute 
counts will be calculated by multiplying the percentage by total WBC count. Conversely, if 
absolute count is available, and percentage is missing, then percentage will be calculated by 
dividing absolute count by the total WBC count. If neutrophils counts and percentages are 
missing, and segmented neutrophil and band neutrophil results are available, then neutrophils 
will be calculated by adding segmented neutrophils and band neutrophils. 
Chemistry and hematology panel results, change and percent change from baseline will be 
summarized by treatment group and study visit. 
For ALT and AST, the number and percent of patients falling in each of the following 
categories for central laboratory data will be tabulated by treatment group: 
• 
Confirmed ALT>= 3x ULN 
• 
Confirmed ALT>= 5x ULN 
• 
Confirmed AST>= 3x ULN 
• 
Confirmed AST>= 5x ULN 
A confirmed laboratory value is based on consecutive lab values within 7 days. If that value 
is in the same or worse category, then the initial value is confirmed. If the consecutive value 
is in a better category, then the initial value is confirmed using consecutive value category. If 
there is no retest within 7 days, the initial value is presumed confirmed. If there are multiple 
results on the same day (no matter from the same lab vendor or different lab vendors), then 
the worst value will be utilized in the analysis. 


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BCH flow cytometry data for platelet function will be summarized separately. The Versiti 
(Blood Centers of Wisconsin) data will be listed. 
All patients meeting safety monitoring and stopping rules will be listed. 
 
2.3.5 
Vital Signs 
 
Vital signs will include heart rate, respiratory rate, body temperature, and systolic and 
diastolic blood pressure. For continuous parameters scheduled to be measured in duplicate 
or triplicate, the mean will be presented in tables and figures. 
Summary tables will be created to present the descriptive statistics for vital sign values as 
well as the change and percent change from baseline at each study visit. 
 
2.3.6 
Physical Examinations 
 
Adverse changes in physical examinations that are deemed clinically significant by the 
Investigator will be classified as adverse events. All physical examination data will be 
provided in a data listing. 
 
2.3.7 
12-Lead Electrocardiograms (ECG) 
 
The ECG data will include ventricular rate (VR), PR interval, QRS duration, QT, QTC 
(recorded from ECG machine). 
Summary tables will be created to present the descriptive statistics for ECG parameters as 
well as the change and percent change from baseline at each study visits. For continuous 
parameters scheduled to be measured in duplicate or triplicate, the mean will be used for 
tables and figures. 
For the categorical responses to overall interpretation, counts and percentages will be 
provided. If multiple results are available, the worst case result will be used in the summary. 
2.3.8 
Co1tcomita11t Medications 
 
Concomitant medications will be coded using WHO Drug dictionary Version Mar 2018 and 
summarized by ATC class, generic name and treatment group. Prior medications and 
Concomitant medications will be summarized by treatment group for the Safety population. 
Prior medications include medications started and stopped prior to study drug administration 
(Day 1). Concomitant medications include medications (1) started prior to, and continued 
after Day l, or (2) medications started on or after Day 1. 
All transfusions will be summarized and listed for all patients as recorded on the transfusion 
logCRF. 


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2.3.9 
Ancillary procedures 
 
Ancillary procedures will be provided in the listing. 
 
2.3.10 Changes in Dialysis Access 
 
Changes in dialysis access prescription will be listed. 
 
2.4 Pharmacodynamic Analyses 
 
The pharmacodynamic analysis will be conducted on the Per Protocol Population and will be 
presented according to treatment group and ISIS 416858 total. The baseline is defined as the 
latest- assessment prior to first dose of study drug. 
Change and percent change from baseline FXI activity and antigen levels and aPTT will be 
summarized by treatment and visit separately. Individual results will be presented in data 
listings by treatment. Figures of the mean FXI activity and antigen levels and aPTT results 
as well as change and percent change from baseline will be provided by treatment group, and 
scheduled visit. 
Change and percent change from baseline in FXl activity and antigen levels and aPTT will 
be compared between each of the ISJS-416858 treated group and pooled placebo group using 
the ANOVA or Wilcoxon Rank Sum test, as appropriate. The normality will be tested by 
applying Kolmogorov-Smimov test on the residuals (difference between individual values 
and group mean). Numeric values will be rounded to 5 decimal places when applying 
Wilcoxon Rank Sum test or Kolmogorov-Smirnov test. 
Frequency and percent of patients with average FXI activity .l, -2, s>.3, ..., :9.0U/mL 
during Day 50 to Day 176 (inclusive) up to last dose+ 7 days will also be provided. 
 
The incidence and events for any aPTT>160s will be summarized by treatment and visit. 
The clotting assessment will be conducted on the Per Protocol Population and will be 
presented according to treatment group and ISIS 416858 total. 
The clotting assessment will consist of a quantitative scale by descriptive category (see 
details in table 1) and will be performed by trained personnel. 


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Table 1 
Clotting Scale 
 
Inspection site 
Category 1 
Category 2 
Category 3 
Category4 
Air Trap 
No clotting 
Fibrinous ring with no 
clot formation on 
venous chamber filter 
Clot formation on 
venous chamber 
Coagulated system 
(treatment cannot 
continue without 
new setup) 
Dialyzer 
Clean dialyzer 
Blood stripes affecting 
less than 5% of the 
fibers seen al the 
surface of the dialyzer 
Blood stripes 
affecting 5% or 
more of the fibers 
seen at the surface 
Coagulated filter 
of the dialyzer 
Overall score Is the highest of the Individual component scores 
 
Individual Category Summary 
The frequency and percentage of patients in each clotting category will be summarized by 
inspection site (air trap, dialyzer) for each visit including screening visit. The overall score 
for individual clotting category, which is the highest of the inspection site Air Trap and 
Dialyzer score, will also be summarized. 
In addition, the frequency and percentage of patients for overall score in each clotting 
category will be summarized by the following visits: 
Week 26 or ET results for patients completed Week 8. 
The denominator is the number of patients with at least one non-missing clotting assessment 
for each specific period above. The overall score for individual clotting category (1, 2, 3, or 
4) will be analyzed for treatment comparison between each of the ISIS-416858Treated group 
and placebo group using the Wilcoxon Rank Sum test. 
Tn addition, the overall score for individual clotting category (1, 2, 3, or 4) will be analyzed 
using the proportional odds model with treatment as main effect. The proportional odds 
model with treatment as main effect and baseline clotting category as covariate will also be 
provided. P-value, odds ratio, and 95% confidence interval will be provided. 
At least one clotting category >= 3 
The frequency and percentage of patients with at least one post-baseline clotting category 3 
or greater event after Week 8 (Day 50) and up to last dose+ 7 days will be summarized by 
treatment group for each of the following periods for subjects on treatment: 
• 
Before Week 8 
• 
After Week 8 and up to last dose + 7 days 


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The denominator is the number of patients with at least one non-missing clotting assessment 
after Week 8 and up to last dose+ 7 days. The corresponding Ex.act Binomial 95% 
confidence interval will be provided. 
A logistic regression model with treatment as main effect will be used to test the treatment 
difference between ISIS 416858 versus placebo in the proportion of patients with at least one 
clotting category 3 or greater. An estimate of the odds ratio, p-value and two-sided 95% 
confidence interval will be computed from the model using Wald's test. The logistic 
regression model with treatment as main effect and baseline clotting category as covariate 
will also be provided. 
In addition, the number of events across all subjects of dialysis circuit will be summarized by 
treatment group. 
 
Patient percentage of events greater or equal to 3 will be summarized for 2 periods (before 
Week 8, after Week 8 and up to last dose+ 7 days). The change of the percentages will be 
summarized and analyzed by ANOVA. 
Most severe clotting category 
In order to examine the correlation of FXI activity level and clotting, a separate summary on 
the most severe clotting category will be provided for patients with average Pre-dialysis FXI 
activity :::{). l, :::{).2, :::{).3, ... , :::1.0 U/mL during Week 8 and Week 26 (Day 176) (inclusive) 
for ISIS 416858 treated patients only. 
 
Additional summary for frequency and percent of events with >=3 clotting category with 
average Pre-dialysis FXI activity ::0.1, :::{).2, :::{).3, ... , :::1.0 U/mL during Week 8 and Week 
26 (Day 176) (inclusive) will also be provided. 
 
2.5 Exploratory Outcomes 
 
The incidence of myocardial infarction (MI), stroke, systemic embolism, and cardiovascular 
(CV) mortality will be summarized by treatment group. In addition, information from the 
specific CRFs will be summarized for each treatment group. 
 
2.6 Other Study Outcomes and Evaluations 
 
Blood Urea Nitrogen (BUN) will be used for Urea Reduction Ratio (URR) analysis in the 
Safety population. 
URR =(Upre - Upost)/Upre) X 100% 


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where Upre is the pre-dialysis blood urea nitrogen (BUN) level in serum and Upos1 is the post- 
dialysis blood urea nitrogen (BUN) level in serum. The URR generated from Lab will be 
used. 
URR and sp Kt/v values as well as the change and percent change from baseline will be 
summarized for each visit by treatment group for the safety population. Single pool dialyzer 
clearance of urea (sp Kt/v) from CRF will be used in the summary. 
Change and percent change from baseline will be compared between each of the ISIS 
416858-treated groups and the pooled placebo group using the ANOVA or Wilcoxon Rank 
Sum test, as appropriate. The normality will be tested by applying Kolmogorov-Smirnov test 
on the residuals (difference between individual values and group mean). 
Changes in dialysis prescription will be listed. 
 
2.6.J 
Platelet Function tests 
All Flow cytometry and PFA results will be summarized by visit and treatment for Platelet 
Function/Activation Substudy population. 
Flow cytometry results (and potentially a report with interpretation of the results) will be 
provided directly by Boston Children's hospital. Flow cytometry results of platelet-monocyte 
and platelet-neutrophil aggregates and platelet surface P-selectin and platelet surface 
activated GPIIb-Illa will be compared between each of the ISIS 416858-treated groups and 
the pooled placebo group. 
The PFA results of duplicate closure times for each evaluated cartridges of collagen/EPI, 
collagen/ADP, and INNOVANCE PFA®P2Y (optional cartridge) for change and percent 
change from baseline will be compared between each of the ISIS 416858-treated groups and 
the pooled placebo group for subjects that have the PFA tests performed. 
 
2.7 Pharmacokinetic Analysis 
 
For pharmacokinetic (PK) assessment, plasma trough PK samples during the 26-week 
treatment period and post-treatment samples during the 12-week post-treatment follow up 
period will be collected from all patients in the study. Additionally, extensive plasma PK 
samples will be collected in the PK subgroup following the first (Day 1) and last (Day 176) 
SC administration. 
PK analysis will be conducted for the PK Population only. 
 
2.7.1 
Plasma Concentration Data 
Plasma concentrations of ISIS 416858 over time, along with the scheduled (nominal) and 
actual sampling times (i.e., time from SC dosing) will be listed (when applicable) for each 


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subject, by group/subgroup, cohort, treatment, and nominal dose. In addition, percent 
differences between scheduled and actual sampling times, and between nominal dose and 
actual dose received will also be listed for all patients. 
For all patients who receive ISIS 416858 treatment, ISIS 416858 plasma trough and post- 
treatment concentrations will be summarized using descriptive statistics by cohort, nominal 
dose, study day, and scheduled time point, without and/or with stratification by subject IM 
status (see Section 3.8). ISIS 416858 plasma concentrations from the PK subgroup will also 
be similarly summarized. Plasma concentrations below the lower limit of quantification 
(LLOQ) will be presented as "BLQ". For the purpose of calculating typical descriptive 
statistics (n, mean, SD, %CV, geometric mean, geometric %CV, median, minimum, and 
maximum) for plasma concentrations, all BLQ values will be set to zero. Mean plasma 
concentrations that are BLQ will be presented as BLQ, and the SD and %CV will be reported 
as "NA" (not applicable). At the discretion of the PK scientist and/or biostatistician,samples 
may be excluded from descriptive statistics ifthere are large deviations between scheduled 
and actual sampling times, or large deviations between actual dose and nominal dose (e.g., 
percent difference between scheduled and actual sampling times, or between nominal and 
actual dose greater than 30%). Any samples excluded from the summary descriptive 
statistics, if deemed necessary, will be listed separately along with the reason for exclusion. 
For all evaluable patients, ISIS 416858 plasma trough (predose) and post-treatment 
concentrations versus time (actual) profiles for each individual patient, as well as 
corresponding mean (±SD) plasma concentration versus time (scheduled) profiles will be 
presented graphically on linear and semilogarithmic scales, without and with stratification by 
subject immunogenicity status (see Section 3.8). For the PK subgroup, ISIS 416858 plasma 
concentration versus time (actual) profiles (up to 24 hours post dose and/or full profiles) 
following the dose on Days 1 and 176, as well as the mean(± SD) plasma concentrations 
versus time (scheduled) profiles without and/or with stratification by subject IM status, will 
be presented graphically on linear and semilogarithmic scales. At the discretion of the PK 
scientist and/or biostatistician, samples may be excluded from the mean plots if there are 
large deviations between scheduled and actual sampling times, or large deviations between 
actual dose and nominal dose (e.g., percent difference between scheduled and actual 
sampling times, or between nominal and actual dose greater than 30%). 
 
2.7.2 
Plasma Pharmacokinetic Parameters 
Noncompartmental PK analysis of ISIS 416858 will be carried out on each individual patient 
data set where full PK sampling profiles and/or post-treatment profiles are collected using 
Phoenix WinNonLin Version 8.0 or higher (Pharsight Corp., Mountain View, CA). Plasma 
pharmacokinetic parameters in each subject (when applicable) will be determined. For 
calculation of PK parameters, all BLQ values will be set to zero. The following plasma PK 


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parameters will be calculated (when applicable and not necessarily limited to) and based on 
actual sampling times: 
1. Cmax: the maximum observed ISIS 416858 concentration in plasma will be detennined 
on Day 1 and Day 176 for patients in the PK subgroup only. 
2. Tmax: the time at which Cmax occurs will be determined on Day 1 and Day 176 for the PK 
subgroup only. 
3. AUCo-24hr: partial area under the plasma concentration-time curve (AUC) from time 
zero to 24 hours will be calculated using the linear-up log-down trapezoidal rule on Day 
1 and Day 176 for patients in the PK subgroup only. 
4. AUCo-4Shr: partial area under the plasma concentration-time curve (AUC) from time zero 
to 48 hours will be calculated using the linear-up log-down trapezoidal rule on Day 176 
for patients in the PK subgroup only. 
5. AUCo.t6Shr (AUCt): partial area under the plasma concentration-time curve (AUC) from 
time zero to 168 hours wilJ be calculated using the linear-up log-down trapezoidal rule 
on Day 176 for patients in the PK subgroup only. 
6. CLsslF (L/hr): Plasma clearance at steady-state will be calculated from CLsJF = Actual 
Dose/AUC0.16&hr for dosing on Study Day 176 for patients in the PK subgroup only. 
7. Vz/F (L): Apparent volume of distribution in the tenninal phase will be calculated from 
Vz/F = CLsslF/ AZ for dosing on Study Day 176 for patients in the PK subgroup only. 
8. tl/21z: apparent terminal elimination half-life will be calculated from the equation, t1mz= 
0.693/Az, where J.z is the rate constant associated with the apparent terminal elimination 
phase. A minimum of three data points in the elimination phase will be used to define J.vz. 
and the correlation of determination values (r2) has to be at or greater than 0.8 for the 
estimate to be accepted. This parameter will only be calculated following the dose on 
Day 176 for all evaluable patients (including subjects participating in the PK subgroup) 
receiving active study drug ISIS 416858 (i.e. PK set). 
Plasma pharmacokinetic parameters (if applicable) will be summarized using descriptive 
statistics (n, mean, SD, %CV, geometric mean, geometric %CV, median, minimum, and 
maximum) by cohort, nominal dose, and day (as deemed appropriate). 
Plasma pharmacokinetic parameters will be listed by cohort, dose, subject ID, subject IM 
status, and study day; and appropriately summarized (separately for the PK subgroup and all 
evaluable ISIS 416858 treated patients) using descriptive statistics (n, mean, SD, SE, %CV, 
geometric mean, geometric %CV, median, minimum, and maximum) by study day. 
Additionally, subject IM status stratified (see Section 3.8) plasma pharmacokinetic 
parameters will be similarly summarized (again separately for the PK Subgroup and all 


416858-CS0S Statistical Analysis Plan 30 May 201912.0 
33 
 
 
 
Ionis Phannaceuticals, Inc. 
Statistical Analysis Plan 
CONFIDENTIAL 
May 30, 2019 
ISIS 416858-CS5 
 
evaluable ISIS 416858 treated patients). Other stratifications may also be performed if 
deemed warranted at the discretion of the pha1macokineticist and/or biostatistician. 
Exposure-response relationships between selected pharmacodynamic (including but not 
limited to FXI antigen level and FXI activity) and pharmacokinetic measures (including but 
not limited to plasma trough concentrations) may also be explored (including with and 
without stratification by IM status), where appropriate. 
2.8 Immunogenicity (IM) Analysis 
 
Samples collected at pre-dialysis/pre-dose on Days 1, 15, 29, 85, 176, and anytime on Day 
260, including early termination samples for IM assessment will be analyzed for anti-ISIS 
416858 antibodies (ADA). However, plasma samples collected at other time points (for PK 
purposes) may also be potentially evaluated if deemed of further interest and warranted by 
the pharmacokinetic scientist. An evaluable sample will be designated 'IM positive' based 
on both positive screening and confirmation assay results (i.e., confirmed positive result), and 
otherwise will be deemed 'IM negative'. Sample IM results (screen positive/negative, 
confirmed positive/negative or unevaluable, and when applicable, titer of anti-ISIS 416858 
antibodies) before, during, and after treatment with study drug (ISIS 416858 or placebo) 
(sample IM status) will be listed by treatment and dose. 
Study subjects will be given 'lM positive' status if they have at least one confirmed positive 
sample result at any time during the treatment or post-treatment evaluation periods. Study 
subjects will be given 'IM negative' status if all evaluated IM sample results during the 
treatment and post-treatment evaluation periods are IM negative and they have at least one 
evaluable IM result collected post study drug treatment. Otherwise, a study patient will be 
given 'unknown' IM status. Subject IM results will be listed by treatment and dose for all 
evaluable patients, which will include but may not be limited to: subject JM status (positive, 
negative or unknown), the study day associated with the first positive TM status emerged 
(T1ii-s1, i.e., onset of ADA development), the last positive IM status observed (T1as1), the time 
of last evaluable IM sample collected (T1as1 sampling), peak titer, and time to reach peak titer. 
The onset of ADA and time to reach peak titer will be calculated by: 
• 
Onset in days= The date of first sample has "positive" sample IM status - first dose 
date +1; 
• 
Time to reach peak titer in days= Thedate of first peak titer observed- first dose date 
+1; 
Other immunogenicity data analysis (e.g. classification as transient or persistent status for IM 
positive subjects) if there is sufficient number of patients with transient IM status. Transient 
and Persistent ADA definitions are defined below and based on Shankar et al. (2014). 
Transient ADA response will be defined as: 


416858-CS0S Statistical Analysis Plan 30 May 201912.0 
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Ionis Pharmaceuticals, Inc. 
Statistical Analysis Plan 
CONFIDENTIAL 
 
May 30, 2019 
ISIS 416858-CSS 
 
• 
Treatment-induced ADA detected only at one sampling time point during the 
treatment or follow-up observation period (excluding the last sampling time point, 
which will be considered persistent unless shown to be undetectable at a later time) or 
• 
Treatment-induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period 
less than 16 weeks, and the subject's last sampling time point is ADA-negative. 
Persistent ADA response will be defined as: 
• 
Treatment-induced ADA detected at two or more sampling time points during the 
treatment (including follow-up period if any), where the first and last ADA-positive 
samples (irrespective of any negative samples in between) are separated by a period 
of 16 weeks or longer or 
• 
Treatment-induced ADA detected only at the last sampling time point of the study 
treatment period or at a sampling time point with less than 16 weeks before an ADA- 
negative last sample. 
The sample IM incidence (number) and incidence rate (percent) at each evaluated study time 
point, and for the overall treatment and post-treatment evaluation period, as well as subject 
IM incidence and incidence rate, will be determined and appropriately summarized by 
treatment, as the total number of and percentage of evaluated subjects with IM negative, 
positive, and unknown status. Subjects with positive IM status may further be classified as 
transient or persistent status if applicable, and incidence and incidence rate for being transient 
or persistent will be appropriately summarized. Furthermore, onset, titer over time, and peak 
titer of the ADA response, if applicable, will be also appropriately summarized (using 
descriptive statistics) as median, quartiles (25% and 75%), and range and presented 
graphically, if deemed appropriate, by treatment at the discretion of the designated study 
pharmacokineticist and/or statistician (e.g., summarized at each evaluated study time point 
and overall; summarized by observed peak titer values from the individual IM positive 
subjects; etc.). 
In addition to PK assessments (Section 3.7), selected safety (Section 3.3) and efficacy 
(Sections 3.4 to 3.5) assessments may be further stratified by subject IM status (i.e., subject 
IM status being positive, negative or unknown) and presented in tables and/or graphically, as 
deemed appropriate or warranted by the designated study pharmacokineticist, medical 
monitor, and/or biostatistician. Other stratifications (e.g., based on antibody titer, onset of 
ADA, etc.) of selected PK, efficacy and safety assessments may also be performed if deemed 
warranted at the discretion of the pbarmacokineticist, medical monitor, and/or biostatistician. 


 
Official Title:  A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of 
the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple 
Doses of ISIS 416858 (IONIS-FXIRX an Antisense Inhibitor of Factor 
XI), Administered Subcutaneously to Patients with End-Stage Renal 
Disease on Hemodialysis 
 
NCT Number: NCT03358030 
 
 
Document Date: Protocol Version 2: 14 June 2018 


Clinical Study Rep011 
Study Number: ISIS 416858-CSS 
16. Appendices 
Ionis Pharmaceuticals, hie. 
20 February 2020 
CONFIDENTIAL 
1 of271 
 
 
 
 
1. 
STUDY INFORMATION 
 
1.1. 
Protocol and Protocol Amendments 
The protocol was amended 1 time. The latest versions of the protocol (Protocol Amendment 1) 
are provided along with the change summary for the revisions. 
 
Prntocol Version 
Date 
Document Prnvided 
Original 
01 June 2017 
None 
Protocol Amendment 1 
14 June 2018 
Protocol and change summaiy 
Protocol Amendment 1 for Czech Republic 
15 June 2018 
Protocol and change summaiy 
Protocol Amendment 1 for Austria 
18 June 2018 
Protocol and change summaiy 
 
 
Notes to File 
Date 
Pregnancy Test will be Perfmmed Once Every Month for Females of Childbearing 
Potential in Austria 
31 July 2017 
Protocol Clarification for Exclusion Crite1ia #2 and Day 2 Schedule of Procedures 
ISIS 416858-CSS - Blinded Safety Data Reviews 
18 December 2017 
21 June 2018 
ISIS 416858-CSS Randomization of Subject- 
Period for Procedures 
with> 28-day Screening 
26 June 2018 
Subject Data: Start Time and End Time of Dialysis Sessions 
9 July 2018 
ISIS 416858-CSS Protocol Clarification for Pregnancy Re-Testing 
16 July 2018 
ISIS 416858-CSS Protocol Clarification for Continuing on Study when Study Drng 
is Discontinued 
1 August 2018 
Dosing Etrnr Subject- 
(Randomization-)   atSite- 
3 August 2018 
ISIS 416858-CSS Clar·ification for Re-Testing of Subjects that have Platelets 
< 150,000/mm3 During Screening 
22 August 2018 
ISIS 416858-CSS FXI Rainin Pipette Calibration Validation Pe1iods 
 6 September 2018 
ISIS 416858-CSS and Emollment ofMYTEMP Patients in Canada 
 10 September 2018 
Unblinding of Lab Data for ISIS 416858-CSS Patient- 
(Rand-) 
11September 2018 
Clarification of Aspirin and/or NSAID Use in Subjects in the Platelet Substudy 
 24 September 2018 
ISIS 416858-CSS FXI Activity and Antigen Levels 
 
 19 October 2018 
· 
re of Hematology Samples 
28 December 2018 
ISIS 416858-CSS Unblinded Local Lab Entiy 
4 March 2019 


Clinical Study Rep011 
Study Number: ISIS 416858-CSS 
16. Appendices 
Ionis Pharmaceuticals, hie. 
20 February 2020 
CONFIDENTIAL 
2 of271 
 
 
 
Notes to File 
Date 
Additional Medical Monitoring Requests in Study ISIS 416858-CSS 
5 April 2019 
ISIS 416858-CSS Per-Protocol Set (PPS) 
7 June 2019 
ISIS 416858-CSS Disallowed Concomitant Medication and Per-Protocol Set (PPS) 
Analysis 
4 September 2019 
ISIS 416858-CSS Study Dmg Intem1ption or Discontinuation Due to Low Platelets 
4 September 2019 
ISIS 416858-CSS Data Enny Enors: Date of Dosing 
8 October 2019 


3 of271 
 
 
ION IS™ 
s 
PHARMACEUTICALS 
 
 
IONIS PHARMACEUTICALS, INC. 
 
 
ISIS 416858-CSS 
 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of 
the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple 
Doses of ISIS 416858 (IONIS-FXIRXan Antisense Inhibitor of 
Factor XI), Administered Subcutaneously to Patients with 
End-Stage Renal Disease on Hemodialysis 
 
 
Protocol Amendment 1-14 June 2018 
 
 
EudraCT No:  2017-002165-21 
 
 
Sponsor: 
Ionis Pha1maceuticals, Inc. 
2855 Gazelle Comt 
Carlsbad, CA 92010 
••  - 


ISIS 416858-CSS 
Protocol 
CONFIDENTIAL 
Amendment 1 
14 June 2018 
2 
4 of271 
 
 
 
 
 
ISIS 416858-CSS 
 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of 
the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple 
Doses of ISIS 416858 (IONIS-FXIRX an Antisense Inhibitor of 
Factor XI), Administered Subcutaneously to Patients with 
End-Stage Renal Disease on Hemodialysis 
 
 
 
Protocol Amendment 1-14 June 2018 
 
 
 
Protocol History: 
Original Protocol: 
I JWie 2017 
 
 
 
 
 
Sponsor: 
Ionis Pharmaceuticals, Inc. 
2855 GazeJJe Court 
 


ISIS 416858-CSS 
Protocol 
CONFIDENTIAL 
Amendment 1 
14 June 2018 
3 
5 of271 
 
 
 
ISIS 416858 
(BAY 230 6001) 
lonis Protocol Number ISIS 416858-CSS 
Protocol Amendment 1 
EudraCT No: 2017-002165-21 
 
 
Clinical Phase: 2 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of 
the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple 
Doses of ISIS 416858 (IONIS-FXIRX an Antisense Inhibitor of 
Factor XI), Administered Subcutaneously to Patients with 
End-Stage Renal Disease on Hemodialysis 
 
Trial Sponsor: 
 
 
 
 
Key Sponsor Contact: 
Ionis Pharmaceuticals, Inc. 
2855 Gazelle CoUI1 
Cru.-Isbad, CA 92010 
Telephone: +1 760-931-9200 
 
 MD,PhD 
2855 Gazelle CoUii 
Carlsbad, CA 92010 
 
 
 
Date: 
14 June 2018 
 
 
Confidentiality Statement 
This doclllllent contains confidential information oflonis Pharmaceuticals, Inc., that must not be 
disclosed to anyone other than the recipient study staff and members of the independent ethics 
committee, institutional review board, or authorized regulato1y agencies. This info1mation 
cannot be used for any purpose other than the evaluation or conduct of the clinical investigation 
without the prior written consent of Ionis Phrumaceuticals, Inc. 


ISIS 416858-CS5 
Protocol 
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Protocol Signature Page 
 
 
Protocol Number: 
ISIS 416858-CS5 
Protocol Title: 
 A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the 
Safety, Pha1macokinetics, and Pharmacodynamics of Multiple Doses of 
ISIS 416858 (IONIS-FXfax an Antisense Inhibitor of Factor XI), 
Administered Subcutaneously to Patients with End-Stage Renal Disease 
on Hemodialysis 
Amendment: 
Protocol Amendment 1 
Date: 
14 June 2018 
 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled "A 
Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, Phaimacokinetics, 
and Phaimacodynamics of Multiple Doses ofISIS 416858 (IONIS-FXfax an Antisense Inhibitor 
of Factor XI), Administered Subcutaneously to Patients with End-Stage Renal Disease on 
Hemodialysis" dated 14 June 2018, and agree to conduct the study as described herein. 
I agree to comply with The International Council for Harmonisation of Technical Requirements 
for Pha1maceuticals for Human Use (ICH) 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 Jonis Pha1maceuticals, Inc. 
 
 
 
 
 
 
 
Investigator's Signature 
 
 
 
Investigator's Name (please print) 
Date (DD Month YYYY) 


ISIS 416858-CSS 
Protocol 
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TABLE OF CONTENTS  
 
Page 
 
PROTOCOL AMENDMENT ............................................................................................................ 9 
PROTOCOL SYNOPSIS .................................................................................................................. 11 
STUDY DESIGN AND TREATMENT SCHEMA ...................................................................... 16 
STUDY GLOSSARY ........................................................................................................................ 17 
1. 
OBJECTIVES ....................................................................................................................... 20 
1.1 
Primaiy Objectives .............................................................................................................. 20 
1.2 
Explorat01y Objectives ....................................................................................................... 20 
2. 
BACKGROUND AND RATIONALE .............................................................................. 20 
2.1 
Ove1view of Disease ............................................................................................................ 20 
2.2 
Therapeutic Rationale ......................................................................................................... 20 
2.3 
ISIS 416858 ......................................................................................................................... 21 
2.3.1 
Mechanism of Action .................................................................................................. 21 
2.3.2 
Chemistry ..................................................................................................................... 22 
2.3.3 
Preclinical Experience ................................................................................................. 23 
2.3.3.1 
Phaimacology .......................................................................................................23 
2.3.3.2 
Phaimacokinetics and Toxicology ....................................................................... 23 
2.3.3.3 
Bleeding Risk Evaluation .....................................................................................24 
2.3.4 
Clinical Experience ......................................................................................................24 
2.4 
Rationale for Dose and Schedule of Administration ......................................................... 25 
2.5 
Benefit-Risk Assessment ..................................................................................................... 26 
3. 
EXPERIMENTAL PLAN ................................................................................................... 27 
3.1 
Study Design ...................................................................................................................... 27 
3.1.1 
Platelet Function/Activation Subgroup ....................................................................... 28 
3.1.2 
Pha1macokinetic Subgroup ......................................................................................... 28 
3.2 
Number of Study Centers ................................................................................................... 28 
3.3 
Number of Subjects ............................................................................................................. 28 
3.4 
Overall Study Duration and Follow-up .............................................................................. 28 
3.4.1 
Screening ...................................................................................................................... 29 
3.4.2 
Treatment. .................................................................................................................... 29 
3.4.3 
Post-Treatment ............................................................................................................. 29 
3.5 
End-of-Study ........................................................................................................................ 29 
4. 
SUBJECT ENROLLMENT ..................................................................................................29 
4.1 
Screening ............................................................................................................................ 29 
4.2 
Randomization .................................................................................................................... 30 
4.3 
Unblinding of Treatment Assignment ................................................................................ 30 
5. 
SUBJECT ELIGIBILITY ................................................................................................... 31 
5.1 
Inclusion Criteria ................................................................................................................. 31 


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5.2 
Exclusion Criteria ................................................................................................................ 31 
6. 
STUDY PROCEDURES ..................................................................................................... 33 
6.1 
Study Schedule .................................................................................................................... 33 
6.1.1 
Screening ..................................................................................................................... 33 
6.1.2 
Baseline (Day l) .......................................................................................................... 34 
6.1.3 
Treatment Period (Day 1 to Day 176) ........................................................................ 34 
6.1.4 
Post-Treatment Evaluation Period .............................................................................. 35 
6.2 
Study Assessments ............................................................................................................... 35 
6.2.1 
Laborato1y Assessments.............................................................................................. 35 
6.2.2 
Safety .......................................................................................................................... 35 
6.2.3 
Clotting Assessments .................................................................................................. 36 
6.3 
Restriction on the Lifestyle of Subjects ............................................................................. 36 
6.3.1 
Contraception Requirements ....................................................................................... 36 
7. 
STUDY DRUG ...................................................................................................................... 37 
7.1 
Study Dmg Description ...................................................................................................... 37 
7.2 
Packaging and Labeling ..................................................................................................... 38 
7.3 
Study Dmg Accountability ................................................................................................. 38 
8. 
TREATMENT OF SUBJECTS .......................................................................................... 38 
8.1 
Study Drng Administration ................................................................................................. 38 
8.2 
Other Protocol-Required Drngs ......................................................................................... 38 
8.3 
Other Protocol-Required Treatment Procedures ............................................................... 38 
8.4 
Treatment Precautions ........................................................................................................ 39 
8.5 
Safety Monitoring Rules .................................................................................................... 39 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests ................................................ 39 
8.5.2 
Safety Monitoring Rules for Platelet Count Results ................................................. 40 
8.5.3 
Safety Monitoring for Bleeding Events ..................................................................... 41 
8.6 
Stopping Rules for Study Drug .......................................................................................... 42 
8.6.1 
Stopping Rules for Liver Chemistiy Elevations ........................................................42 
8.6.2 
Stopping Rule for Platelet Count Reduction .............................................................. 43 
8.6.3 
Stopping Rule for Bleeding ......................................................................................... 43 
8.7 
Discontinuation of Study Drug ...........................................................................................44 
8.8 
Withdrawal of Subjects from the Study ............................................................................. 45 
8.9 
Concomitant Therapy and Procedures ............................................................................... 45 
8.9.1 
Concomitant Therapy .................................................................................................. 45 
8.9.2 
Concomitant Procedures ............................................................................................. 46 
8.10 
Treatment Compliance ......................................................................................................... 46 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING ......................... 46 
9.1 
Sponsor Review of Safety Info1mation ............................................................................. 46 
9.2 
Regulato1y Requirements .....................................................................................................46 
9.3 
Definitions ........................................................................................................................... 47 


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9.3.1 
Adverse Event ............................................................................................................. 47 
9.3.2 
Adverse Drng Reaction and Unexpected Adverse Drng Reaction .......................... 47 
9.3.3 
Serious Adverse Event (SAE) .................................................................................... 47 
9.3.4 
Adverse Event of Interest ............................................................................................ 48 
9.4 
Monitoring and Recording Adverse Events ...................................................................... 48 
9.4.1 
Repmting Requirements for Serious Adverse Events Using Electronic Case 
Repmt Fonns (eCRFs) ............................................................................................... 48 
9.4.2 
Non-Serious Adverse Events ..................................................................................... 49 
9.4.3 
Evaluation of Adverse Events (Serious and Non-Serious) ...................................... 49 
9.4.3.1 
Relationship to the Study Drng ........................................................................... 50 
9.4.3.2 
Severity ................................................................................................................. 50 
9.4.3.3 
Action Taken with Study Drng ........................................................................... 50 
9.4.3.4 
Treatment Given for Adverse Event .................................................................... 51 
9.4.3.5 
Outcome of the Adverse Event ............................................................................. 51 
9.5 
Procedures for Handling Special Situations ...................................................................... 51 
9.5.1 
Abno1malities of Laborato1y Tests ............................................................................. 51 
9.5.2 
Prescheduled or Elective Procedmes or Routinely Scheduled Treatments ............ 52 
9.5.3 
Dosing Enors ................................................................................................................ 52 
9.5.4 
Contraception and Pregnancy ...................................................................................... 52 
10. 
STATISTICAL CONSIDERATIONS ............................................................................ 53 
10.1 
Study Endpoints, Subsets, and Covariates ........................................................................ 53 
10.1.1 
Safety and Tolerability ............................................................................................... 53 
10.1.2 
Pha1macodynamic Outcomes ...................................................................................... 54 
10.1.3 
Exploratmy Outcomes ................................................................................................ 54 
10.1.4 
Other Study Outcomes and Evaluations ..................................................................... 54 
10.2 
Sample Size Considerations ................................................................................................. 54 
10.3 
Populations ......................................................................................................................... 54 
10.4 
Definition ofBaseline ......................................................................................................... 54 
10.5 
Interim Analysis .................................................................................................................. 54 
10.6 
Planned Methods of Analysis ............................................................................................. 55 
10.6.1 
Demographic and Baseline Characteristics ............................................................... 55 
10.6.2 
Safety Analysis ........................................................................................................... 55 
10.6.3 
Pha1macokinetic and Immunogenicity Analysis ....................................................... 56 
10.6.3.1 
Phaimacokinetic Analysis .................................................................................... 56 
10.6.3.2 
Immunogenicity Analysis .................................................................................... 56 
10.6.4 
Pha1macodynamic Analysis ........................................................................................ 57 
10.6.5 
Additional Exploratmy Analyses ............................................................................... 57 
11. 
INVESTIGATOR'S REGULATORY OBLIGATIONS ................................................ 57 
11.1 
Info1med Consent ................................................................................................................ 57 
11.2 
Ethical Conduct of the Study .............................................................................................. 58 


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11.3 
Independent Ethics Committee/Institutional Review Board ............................................ 58 
11.4 
Subject Confidentiality ....................................................................................................... 58 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ......................................................59 
12.1 
Protocol Amendments ........................................................................................................ 59 
12.2 
Study Termination .............................................................................................................. 59 
12.3 
Study Documentation and Storage ...................................................................................... 59 
12.4 
Study Monitoring ............................................................................................................... 60 
12.5 
Language ............................................................................................................................. 60 
12.6 
Compensation for Injmy ..................................................................................................... 60 
13. 
REFERENCES ..................................................................................................................... 61 
14. 
APPENDICES....................................................................................................................... 63 
Appendix A 
Appendix B 
Appendix C 
Appendix D 
Schedule of Procedures ....................................................................................... 64 
List ofLaborato1y Analytes ................................................................................ 69 
PK Sampling Schedule ........................................................................................ 71 
Grading Scale for Adverse Events Relating to Laboratory Abnmmalities ....... 73 
TABLE OF TABLES 
 
 
 
 
 
Page 
 
Table 1 
Table 2 
Table 3 
Table 4 
 
Table 5 
Summa1y ofISIS 416858 Clinical Studies ................................................................ 25 
Study Drng Characteristics ........................................................................................ 37 
Study Drng Dosing Information ................................................................................. 38 
Additional Labs to be Perfo1med in the Event of a Platelet Count 
<  75,000/mm3..•....•...•..•....•...•..•....•...•..•....•...•..•....•...•..•....•...•..•....•...•..•....•...•..•....•.41 
Clotting Scale ............................................................................................................. 57 
 
 
 
 
 
 
 
 
Figure 1 
 
 
 
 
TABLE OF FIGURES 
 
 
Design of Chimeric 2'-MOE Phosphorothioate Oligonucleotides 
 
 
 
 
 
 
Page 
(MOE-Gapmer) ........................................................................................................... 22 


ISIS 416858-CSS 
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PROTOCOL AMENDMENT 
Protocol Number: 
Protocol Title: 
 
 
 
Amendment Number: 
Amendment Date: 
 
 
ISIS 416858-CSS 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study 
of the Safety, Phannacokinetics, and Pharmacodynamics of 
Multiple Doses ofISIS 416858 (IONIS-FXhx an Antisense 
Inhibitor of Factor XI), Administered Subcutaneously to Patients 
with End-Stage Renal Disease on Hemodialysis 
I 
14 June 2018 
 
 
 
The prima1y pmpose of this amendment is to fmther clarify ce1tain aspects of the protocol and to 
simplify procedmes for the study site. Other changes will allow study sites to better prepare 
subjects for the study and provide added flexibility for study subjects with a longer timeframe for 
signing of the info1med consent and greater visit windows, respectively. 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to conect e1rnrs and/or to improve the overall clarity of the original protocol but these 
changes do not impact subject safety, exposure, or the overall study design. 
The following table provides a summa1y list of major changes to the protocol: 
 
Protocol Section(s) 
Description of Change 
Rationale 
Synopsis 
Study Design Schema 
Section 3.4 
Section 8.3 
Section 8.6 
Section 8.7 
Clarified that subjects are encouraged to 
complete the entire treatment and post- 
treatment evaluation periods, even if Study 
Drug (ISIS 416858 or placebo) has been 
discontinued. 
In this safety study, it is important to 
obtain a complete safety set in order to 
complete an intent to treat analysis. 
Additional text provides clear 
expectations for subject and sites. 
Exclusion Criteria 
(Synopsis 
Section 5.2) 
Added to Exclusion Criteria #3 to include 
FXI activity< 0.3 U/ml atScreening. 
Provides clarification on screening 
laboratory procedures to be evaluated for 
subject eligibility. 
Exclusion Criteria 
(Synopsis, 
Section 5.2) 
Synopsis 
Section 8.9.1 
Concomitant Therapy 
For subjects in the optional platelet function 
substudy, aspirin or NSAIDs use is now 
allowed. 
Removing the disallowed concomitant 
therapy of aspirin and NSAIDS for the 
platelet function subgroup will improve 
recruitment into the substudy with 
minimal effects expected for study 
results based on the requirements of the 
primary platelet function assays selected. 


ISIS 416858-CSS 
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Protocol Section(s) 
Description of Change 
Rationale 
Synopsis 
Study Schema 
Section 3.4 
Section 4.1 
Section 6.1.1 
Appendix A 
Extended the screening period for signing of 
the Informed Consent from 28 days to 
49 days 
Allows study sites to prepare subjects for 
the study screening procedures in a 
timely manner at the convenience of the 
sites and subjects. 
Synopsis 
Section 3.4.1 
Section 8.1 
Appendix A 
Provided additional clarification on the 
expected completion of dialysis and Study 
Drug administration. 
Provides more details on dialysis 
completion and when it is appropriate to 
administer Study Drug. 
Synopsis 
Section 3.1 
Section 4.2 
Clarified that subjects are also stratified 
based on their participation in either or both 
of the substudies (pharmacokinetic and/or 
platelet substudy) as applicable. 
Added language provides necessary 
details by which stratification is occurring 
for substudy participants. 
Section 2.3.3.2 
Added the preclinical toxicology 
assessments with respect to the proposed 
dose levels in the study. 
Added details of the relative exposures 
for humans in preclinical toxicology 
studies. 
Section 6.1.3 
Section 6.1.4 
Appendix A 
Added increased window time for visits 
occurring in the treatment and post- 
treatment periods. 
Reduces subject burden to increase 
flexibility without affecting subject safety. 
Section 9: Serious and 
Non-Serious Adverse 
Event Reporting 
• Clarified Adverse Event (AE) definition in 
Section 9.3.1 
• Added adverse drug reaction (ADR) in 
Section 9.3.2 
• Added Adverse Event of Interest (AEOI) 
as Section 9.3.4 
• Clarified in Section 9.4.1 that an SAE 
should be reported electronically 
whenever possible 
Clarifies terms used in the Safety 
sections of the protocol and required 
reporting. 
Section 9.5.4 
Contraception and 
Pregnancy 
Clarification of the expected pregnancy 
follow-up period was provided. 
Clarifies the follow-up for an outcome of 
pregnancy for subjects. 
Appendix A 
Clarified that KW assessments will also be 
recorded on study visits determining URR. 
Ensures that 2 measures of dialysis 
adequacy are evaluated during the 
study. 
Appendix A 
Clarified that the 2 additional ECG measures 
at specified visits are not required. 
Only 1 ECG measure is required per 
timepoint for the study. 
Reduces subject burden without affecting 
study results. 
Appendix A 
Removed the repeat pregnancy testing 
during screening of women determined to 
not be of child bearing potential and clarified 
the testing of women of child-bearing 
potential. 
Reduces subject burden during 
screening without affecting subject safety 
and clarifies for site staff the recurrent 
testing of women of child-bearing 
potential. 


ISIS 416858-CS5 
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PROTOCOL SYNOPSIS 
Protocol Title 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of the Safety, 
Pharmacokinetics, and Pharmacodynamics of Multiple Doses of ISIS 416858 
(IONIS-FXIRXan Antisense Inhibitor of Factor XI), Administered Subcutaneously to 
Patients with End-Stage Renal Disease on Hemodialysis. 
Study Phase 
2 
Indication 
Evaluation of the antithrombotic effects of ISIS 416858 in patients with end-stage renal 
disease (ESRD) receiving chronic hemodialysis. 
Primary Objectives 
To evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of 
ISIS 416858 (200,250, and 300 mg once-weekly) as compared to placebo. 
Exploratory Objectives 
Incidence of myocardial infarction (Ml), stroke, systemic embolism, and cardiovascular 
(CV) mortality 
Study Design 
This is a Phase 2, multi-center, stratified, randomized, double-blind, placebo-controlled 
study of ISIS 416858 (IONIS-FXIRXan Antisense Inhibitor of Factor XI) treatment for up 
to 26 weeks in ESRD patients receiving hemodialysis at least 3 times a week. 
Subjects included in this study will maintain all of their standard of care dialysis 
treatments (including heparins) as determined by their treating practitioners. 
Subjects will be stratified based on the diagnosis of documented atrial fibrillation at 
Screening, and then subjects will be randomized to 1 of 3 dose cohorts in a 1:1:1 ratio 
(Cohort A, Cohort B, and Cohort C). Additionally, the subjects will also be stratified 
based on their participation in the substudies (pharmacokinetic and/or platelet 
substudy) as applicable. Within each dose cohort, subjects will be randomized in a 
3:1 ratio to receive subcutaneous treatment with Study Drug (either ISIS 416858 or 
placebo). 
Cohorts A. B. and C 
Patients in Cohort A will be randomized to receive once-weekly either 200 mg 
ISIS 416858 or placebo, subjects in Cohort B will be randomized to receive either 
250 mg ISIS 416858 or placebo, and Cohort C will be randomized to receive either 
300 mg ISIS 416858 or placebo. 
The study will include a 4-week screening period for procedures and a 26-week 
treatment period followed by a 12-week post-treatment evaluation period. Subjects are 
encouraged to complete the entire treatment and post-treatment evaluation periods, 
even if Study Drug (ISIS 416858 or placebo) has been discontinued. 
Upon completion of screening evaluations, including SC tolerability assessments with 
0.9% sterile saline injections, eligible subjects will receive Study Drug weekly for the 
26-week treatment period. All doses of Study Drug will be administered 
subcutaneously (SC) after completion of the hemodialysis treatment, Study Drug can 
be administered immediately after dialysis is completed when blood is returning to the 
subject but must be within 2 hours (preferably within 15 minutes of the conclusion of 
dialysis). 
Number of Subjects 
Approximately 204 patients are planned to be enrolled in parallel in this study and 
randomized equally across Cohorts A, B, and C. 


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PROTOCOL SYNOPSIS Continued 
 
Study Population 
Inclusion Criteria 
1. Must have given written informed consent (signed and dated) and any 
authorizations required by local law and be able to comply with all study 
requirements. 
2. Males or females aged 18 to 85 years old at the time of informed consent. 
a. 
Females: must be non-pregnant and non-lactating and either: 
i. 
surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy); 
ii. 
post-menopausal (defined as 12 months of spontaneous amenorrhea in 
females> 55 years of age or, in females :S 55 years, 12 months of 
spontaneous amenorrhea without an alternative medical cause and FSH 
levels in the postmenopausal range for the laboratory involved); or, 
iii. if engaged in sexual relations and of child-bearing potential, agree to use 
highly effective contraceptive methods (refer to Section 6.3.1) from the time 
of signing the informed consent form until at least 84 days (approximately 
5 half-lives of ISIS 416858) after the last dose of Study Drug (ISIS 416858 
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 6.3.1) from the time of signing the informed consent form 
until at least 84 days (approximately 5 half-lives of ISIS 416858) after the last 
dose of Study Drug (ISIS 416858 or placebo). 
3. End stage renal disease maintained on outpatient hemodialysis at a healthcare 
center for> 3 months from screening with hemodialysis at least 3-times per week 
for a minimum of 9 hours per week of prescribed treatment time and plan to 
continue this throughout the study. 
Exclusion Criteria 
1. Subjects with a history of a major medical event (e.g., previous acute coronary 
syndrome, stroke or transient ischemic attack, or systemic thromboembolic event) 
within 3 months of screening, major surgery within 3 months of screening, or new 
major physical examination finding (not accounted for by past medical history), 
except for documented atrial fibrillation. 
2. Active bleeding (as judged clinically-significant by the Investigator) within the past 
3 months from screening or documented bleeding diathesis (excluding uremia), 
coagulopathy, or recent history of prolonged compression time at arteriovenous 
fistula. 
3. Screening laboratory results as follows: 
Platelet count< 150,000 cells/mm3 
o 
< 180,000 cells/mm3 for platelet function/activation subgroup 
INR > 1.4 
aPTT > upper limit of normal (ULN) 
FXI activity< 0.3 U/ml 
ALT or AST > 2 x ULN 
Total bilirubin > ULN 


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Study Population 
Continued 
Exclusion Criteria Continued 
4. Subject is not willing to have weekly subcutaneous injections over the study period 
as assessed during screening. 
5. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 (first dose) or IV antibiotic use at the time of 
Screening. 
6. Unwillingness to comply with study procedures, including follow-up, as specified by 
this protocol, or unwillingness to cooperate fully with the Investigator. 
7. Known history of or positive test at Screening for human immunodeficiency virus 
(HIV), hepatitis C or chronic hepatitis B. 
8. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin 
or carcinoma in situ of the cervix that has been successfully treated. Subjects with 
a history of other malignancies that have been treated with curative intent and 
which have no recurrence within 5 years may also be eligible if approved by the 
Sponsor Medical Monitor (or designee). 
9. Treatment with another investigational drug, biological agent, or device within 
1 month of screening, or 5 half-lives of investigational agent, whichever is longer. 
10. Any history of previous treatment with an oligonucleotide (including siRNA). 
Subjects that have previously received only a single-dose of an 
ISIS-oligonucleotide as part of a clinical study may be included as long as a 
duration ;;: 4 months has elapsed since dosing. 
11. Attending nephrologist answers "no" to the question, 'Would you be surprised if this 
patient died in the next year?" 
12. Within 6 months prior to screening, have any of the following: 
• 
More than 3 episodes of severe hypoglycemia requiring the assistance of 
another person to actively administer carbohydrate, glucagon or other 
resuscitative actions 
• 
One (1) event of hypoglycemia in which the patient required hospitalization 
• 
Recurrent syncope and recurrent hypotension in the inter-dialytic period 
requiring intervention 
13. Planned major surgery in the next 6 months, including subjects receiving a kidney 
transplant or subjects that anticipate changing dialysis modality (i.e. hemodialysis 
to peritoneal dialysis). 
14. Recent history of, or current drug or alcohol abuse as detennined by the 
Investigator. 
15. Concomitant use of anticoagulant/antiplatelet agents (e.g., warfarin, dabigatran, 
rivaroxaban, clopidogrel) that may affect coagulation (except low dose aspirin 
(:5100 mg/day)) during Treatment and Post-treatment Evaluation Periods is not 
allowed. Stable doses of heparins during dialysis are permitted. 
16. Uncontrolled hypertension as judged by the Investigator. For example, subjects 
with a pre- or post-dialysis blood pressure (BP) that is > 180 mmHg on at least 3 of 
the last 5 dialysis treatments. 
17. Have any other conditions, which, in the opinion of the Investigator or Sponsor 
would make the subject unsuitable for inclusion, or could interfere with the subject 
participating in or completing the study. 


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Treatment Groups 
There will be 3-dose cohorts that will run concurrently. Subjects will be stratified based 
on the diagnosis of documented atrial fibrillation and then randomized to 1 of 3 dose 
cohorts in a 1:1:1 ratio (Cohort A, Cohort B, and Cohort C). Within each dose cohort, 
subjects will be randomized in a 3:1 ratio to receive subcutaneous treatment with either 
ISIS 416858 or placebo that is added to standard of care hemodialysis therapies as 
prescribed by their providers, including heparin. 
Cohort A: 
 Approximately 68 dialysis subjects will be randomized 3:1 to either 200 mg 
ISIS 416858 or placebo 
Cohort B: 
 Approximately 68 dialysis subjects will be randomized 3:1 to either 250 mg 
ISIS 416858 or placebo 
Cohort C: 
 Approximately 68 dialysis subjects will be randomized 3:1 to either 300 mg 
ISIS 416858 or placebo 
Study Drug Dosage and 
Administration 
The SC Tolerability assessments using 0.9% sterile saline should be administered as 
two 0.75 ml noncontiguous injections on Study Days S-14 (± 3) and S-7 (± 3). 
For Cohort A, B and C, the Sponsor will provide ISIS 416858 (200 mg/ml, 1.0 ml) and 
Placebo (1.0 ml). All doses are given by SC injection. 
Study Drug will be administered SC post-dialysis at any time from when blood is being 
returned to the subject but must be within 2 hours (preferably within 15 minutes of 
dialysis conclusion) for a total of 26 consecutive weeks of treatment in all cohorts. 
The injection volume will be 1.0 ml for Cohort A (200 mg), 1.25 ml for Cohort B 
(250 mg) and 1.5 ml for Cohort C (300 mg). Cohorts B and C will be administered 
Study Drug (ISIS 416858 or placebo) as 2 noncontiguous SC injections. 
Rationale for Dose and 
Schedule Selection 
Based on the PK/PD profile of ISIS 416858 in the previous Phase 1 (ISIS 416858-CS1) 
and Phase 2 (ISIS 416858-CS3 and ISIS 416858-CS4) studies, doses up to 300 mg of 
ISIS 416858 have demonstrated significant reduction in FXI activity and consequent 
anti-thrombotic effects without an increased bleeding risk. 
Study Visit Schedule 
and Procedures 
Detailed information regarding the study procedures is outlined in protocol Section 6, 
and Appendices A and C. 
The study period for an individual patient consists of signing the informed consent up to 
7-weeks (Day -49) prior to randomization, an approximately 4-week screening period 
for procedures, a 26-week treatment period during which Study Drug (ISIS 416858 or 
placebo) will be administered SC once-weekly, and a 12-week post-treatment 
evaluation period. 
During the screening period, subjects who give written informed consent will undergo a 
medical history and comprehensive physical examination and have blood samples 
taken for clinical laboratory testing. Additional tests include a coagulation panel 
consisting of aPTT, PT/INR, FXI antigen and activity levels. For Screening Days S-14 
(± 3 days) and S-7 (± 3 days), subjects shall receive 2 noncontiguous SC injections of 
0.75 ml saline to determine tolerability to SC injections. 
During the treatment period, Study Drug (ISIS 416858 or placebo) will be administered 
as a SC injection once during Weeks 1 (Day 1), 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 
15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, and 26. 
Collection and measurement of vital signs, clinical laboratory parameters (including 
hematology, serum chemistry, coagulation, immunogenicity, and inflammatory 
markers), adverse events (including bleeding events), and concomitant medication will 
be performed according to the schedule of procedures in Appendix A for both treatment 
and post-treatment evaluation periods. Following the Week 26 visit, subjects will enter 
the 12-week post-treatment evaluation period. 


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Study Visit Schedule 
and Procedures 
Continued 
In a subgroup of approximately 12 subjects in each cohort, whose platelet counts are 
:?: 180,000/mm3 at Screening, and who are not taking any anticoagulants or antiplatelet 
agents (other than aspirin), at selected visits during Weeks 1 (pre-dose), 12, 26, and 
38, platelet function/activation tests will also be performed (Section 3.1.1, Appendix A). 
In another subgroup of approximately 12 subjects in each cohort, additional PK 
sampling will be conducted at their Day 1, Day 2, Week 26 (Day 176, Day 177 and 
Day 178), and Week 27 (Day 183) visits in order to determine the peak (Cmax), extent of 
exposure (AUCo-t and AUCo-168), and clearance at steady-state (CLss1F) parameters 
(Section 3.1.2, Appendix C). 
Subjects in the platelet function/activation subgroup may also participate in the 
pharmacokinetic subgroup and may withdraw consent for the subgroup specific 
procedures (e.g., blood draws for PK) without being withdrawn from dosing or from the 
study. If a subject withdraws consent from the subgroup procedures, he/she should 
remain on study and continue to follow all the non-subgroup assessments and 
procedures as outlined in Appendix A. 
Subjects who discontinue Study Drug are encouraged to remain in the study. Subjects 
in whom Study Drug treatment should be stopped e.g., when hemodialysis is held for 
> 2 weeks or stopped, or if there is a change of dialysis modality (i.e., hemodialysis to 
peritoneal dialysis) including those that receive a renal transplant (See Section 6.2.2) 
are encouraged to complete the treatment and post-treatment evaluation periods even 
in the absence of Study Drug administration. 
Safety and Tolerability 
Evaluations 
The safety and tolerability of ISIS 416858 will be assessed by determining the 
incidence and severity of adverse events (including bleeding events) and changes in 
laboratory evaluations. 
The primary safety outcome is the combination of major bleeding (MB) and 
clinically-relevant non-major bleeding (CRNMB) during the treatment period (or early 
study termination). 
Other safety parameters including (S)AEs, deaths, vital signs, ECG and laboratory 
parameters will also be recorded. This may include additional information regarding 
events of interest (i.e. bleeding events, thrombotic events). 
Pharmacokinetic 
Evaluations 
Plasma pharmacokinetics will be assessed following the first and last dose in the PK 
subgroup, whenever possible. Additionally, plasma trough and post-treatment samples 
will be collected during treatment and post-treatment evaluation period, respectively, for 
the measurement of ISIS 416858 concentrations. 
Pharmacodynamic 
Evaluations 
Coagulation parameters such as FXI activity and antigen, aPTT, PT and INR will be 
collected and analyzed in a blinded manner throughout the treatment and post- 
treatment evaluation period visits. 
The rate/frequency of clotting on the dialysis filters and circuit will be measured as an 
exploratory analysis. 
Statistical 
Considerations 
The sample size was selected based on prior experience to ensure that the safety, 
tolerability and PK/PD relationships will be adequately assessed while minimizing 
unnecessary patient exposure. There is no statistical rationale for the selected sample 
size. 
Sponsor 
lonis Pharmaceuticals, Inc. 


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! 
Randomize within each Cohort 
3:1 (ISIS 416858 Placebo) 
Cohort A (200 mg ISIS 416858 or Placebo) 
Cohort B (250 mg ISIS 416858 or Placebo) 
Cohort C (300 mg ISIS 416858 or Placebo) 
STRATIFY BASED ON ATRIAL FIBRILLATION 
HISTORY STATUS 
Randomize 1:1:1 in parallel to Cohorts A, B, or C 
 
 
 
 
 
-------- 
SCREEN FAIL 
 
 
 
 
 
 
 
 
 
 
 
 
 
- ----- ► 
TREATMENT PERIOD 
Weeks 1 to 26 
Once-Weekly, SC 
 
 
 
 
 
POST-TREATMENT 
EVALUATION PERIOD 
Weeks 27 to 38 
 
, ----- ► 
 
 
 
 
 
- ------------------ ♦ 
TREATMENT 
TERMINATION AND 
CONSENT WITHDRAWN 
 
and 
 
Early Termination from 
Treatment Period 
Procedures Visit 
 
or 
 
Early Termination from 
Post-Treatment Period 
Procedures Visit 
 
 
 
 
END-OF-STUDY 
PROCEDURES 
Week 38, Day 260 
TREATMENT 
TERMINATION 
CONSENT NOT 
WITHDRAWN 
Subjects continue with 
regularly scheduled 
Visits through 
Treatment Period and 
Post-Treatment Period 
INFORMED 
CONSENT 
Day-49 to -14 
Must be signed before any 
screening procedures 
conducted 
SCREENING 
PROCEDURES 
-28 to -1 days before Baseline 
(Including tolerability assessments) 


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STUDY GLOSSARY 
2'-MOE 
ADA 
AE 
AEoI 
AF 
ALT 
aPTT 
ASO 
AST 
AUC 
AUCo-t 
AUC0-16shr 
Beta-2-M 
BP 
BUN 
CRNMB 
CLsJF 
Cinax 
CMV 
CRO 
Dialysis/hemodialysis 
Dialyzer 
 
 
 
ECG 
eCRF 
EDC 
 
2'-0-(2-methoxyethyl) 
anti-drug antibody 
adverse event 
adverse events of interest 
atrial fibrillation 
alanine an1inot:ransferase 
activated pariial thromboplastin time 
antisense oligonucleotide 
aspartate aminotransferase 
area under the plasma concentration-time curve 
area under the plasma concentration-time curve from time 
zero to the last observable concentration 
area under the plasma concentration-time cmve from time 
zero to 168 hours 
beta-2-microglobulin 
blood pressure 
blood urea nitrogen 
Clinically-Relevant Non-Major Bleeding 
apparent systemic (plasma) clearance at steady state after SC 
administration 
maximum concentration 
cytomegalovirus 
contract research organization 
process where blood is filtered using a dialyzer and dialysis 
machine 
ruiificial kidney designed to provide controllable transfer of 
solutes and water across a semi permeable membrane 
separating flowing blood and dialysate streams. The transfer 
processes are diffusion (dialysis) and convection 
(ultrafiltration) 
electrocru·diogram 
electronic Case Repori Form 
electronic data capture 


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ESRD 
FFP 
FSH 
FXI 
GCP 
GLP 
HAV 
Hb 
HBsAg 
Hct 
HCV 
HIV 
HR 
ICH 
IEC 
INR 
IRB 
ISIS 416858 
IV 
IXRS 
kg 
MB 
MCH 
MCHC 
MCV 
MedDRA™ 
mg 
MI 
mL 
MPV 
mRNA 
NCS 
end-stage renal disease 
fresh frozen plasma 
follicle-stimulating h01mone 
Factor XI 
Good Clinical Practice 
Good Laboratory Practices 
hepatitis A virus 
hemoglobin 
hepatitis B smface antigen 
hematocrit 
hepatitis C vims 
human immunodeficiency vims 
heart rate 
International Conference on Harmonization 
Independent Ethics Committee 
international n01malized ratio 
Institutional Review Board 
antisense inhibitor of Factor XI 
intravenous(ly) 
automated randomization system 
kilogram 
major bleeding 
mean corpuscular hemoglobin 
mean corpuscular hemoglobin concentration 
mean corpuscular volume 
Medical Dictionary for Regulatory Activities 
milligram 
myocardial infarction 
milliliter 
mean platelet volume 
messenger ribonucleic acid 
not clinically-significant 


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NT-proBNP 
PD 
PK 
PT 
RNase Hl 
 
SAE 
SAP 
siRNA 
SC 
Study Day 1 
 
Study Drng 
SUSAR 
Tmax 
ULN 
VTE 
WBC 
WHO 
W,wk 
WMA 
N-tenninal pro-brain natriuretic peptide 
pha1macodynamic(s) 
pharrnacokinetic(s) 
prothrombin time 
ribonuclease Hl (a non-specific endonuclease that catalyzes 
the cleavage of RNA via a hydrolytic mechanism) 
serious adverse event 
Statistical Analysis Plan 
small interfering ribonucleic acid 
subcutaneous(ly) 
defined as the first day Study Drng is administered to the 
subject 
ISIS 416858 or placebo 
suspected unexpected serious adverse reaction 
time to maximal concentration 
upper linlit of normal 
venous thromboembolism 
whlte blood cell 
World Health Organization 
week 
World Medical Association 


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(200, 250, and 300 mg once-weekly) as compared to lacebo as assessed b FXI activi 
reduction in ESRD atients on hemodial sis; 
 
1. 
OBJECTIVES 
 
1.1 
Primary Objectives 
To evaluate the safety, phaimacokinetics (PK), and phaimacodynamics (PD) of ISIS 416858 
 
1.2 
Exploratory Objectives 
To evaluate the incidence of myocardial infai·ction (MI), stroke, systemic embolism, and 
cardiovasculai·(CV) m01tality. 
 
2. 
BACKGROUND AND RATIONALE 
 
2.1 
Overview of Disease 
ISIS 416858 is a 2'-methox eth l chimeric antisense inhibitor of the molecular tai·get Factor XI 
(FXI). 
Preclinical studies 
suggest that FXI inhibitors can prevent venous and a1terial thrombosis without affecting 
hemostasis, and congenital FXI-deficient patients have a low incidence of ischemic stroke and 
venous thromboembolism (VTE) (Schumacher et al. 2010). Thus, selective inhibition ofFXI 
may represent a novel approach for the prevention of undesired thrombotic events such as VTE 
and ischemic stroke as well as clotting of hemodialysis circuits which limits the effectiveness of 
hemodialysis. 
 
2.2 
Therapeutic Rationale 
Approximately 2 million individuals receive dialysis for end-stage renal disease (ESRD) globally 
and this number is increasing rapidly as both the incidence of ESRD rises and access to dialysis 
as a life sustaining therapy increases (Caskey et al. 2011). Dialysis patients are at high risk of 
thrombotic events due to their high degree of comorbid conditions and because they have a 
hypercoagulable state. This hypercoagulable state appears to be driven by widely used diugs 
(e.g., erythropoiesis stimulating agents), inflammation and endothelial dysfunction from uremia, 
and contact between blood and the extracorporeal circuit. The hypercoagulable state results in 
clinically meaningful negative outcomes. The risk of stroke in dialysis patients may be 10-times 
higher than the general population (Sood et al. 2009). Dialysis patients have a 5-fold higher risk 
of myocai·dial infai·ction than the general population and even moderate chronic kidney disease 
alone is considered the risk equivalent of diabetes mellitus for cardiovasculai·thrombotic events 
(Go et al. 2004; Tonelli et al. 2012). Fwthe1more, dialysis patients depend on patent vascular 
access to receive hemodialysis. Dialysis patients have a high chance, approximately 10% chance 
per year of having their vasculai· access compromised by thrombosis resulting in a potentially 
life-threatening situation requiring urgent intervention (Jean-Baptiste et al. 2008; Schild et al. 
2008). Finally, dialysis patients ai·e hospitalized an average of 3 times per yeai· and ai·e at high 
1isk of VTE (Tveit et al. 2002). Despite this high 1isk ofVTE, there remains considerable 
unce1tainty as to the benefit-to-risk ratio ofVTE prophylaxis. This is of particulai· importance 
when considering the optimal treatment for ESRD, renal transplantation, in which VTE can 
compromise the ability to receive a transplant, the function of an ah·eady transplanted kidney, 


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and/or the life expectancy of a patient who recently received a transplant (i.e., post-operative 
VTE) (Irish 2004). 
While dialysis patients suffer numerous thrombotic events, they also are at increased risk of 
bleeding events. ESRD is associated with attenuated platelet aggregation and adhesion, and 
altered blood rheology. In ESRD patients, blood vessels tend to be compromised from chronic 
comorbid medical diseases such as diabetes and hypertension, age, repeated phlebotomy and 
need for vascular access, and chronic exposure to anticoagulants such as hepaiin and antiplatelet 
agents that are given to maintain vascular access patency and reduce the risk of arterial 
thrombotic events. Contemporai·y estimates suggest that 1 out of eve1y 7 chronic dialysis 
patients will be hospitalized for a hem01Thagic event within 3 years of starting dialysis and the 
risk of major bleeding doubles with the use of anticoagulants (Sood et al. 2014). Patients 
receiving dialysis are therefore at both high risk of thrombotic events and high risk of bleeding 
events. This has resulted in a clinical dilemma as the management of dialysis patients at the 
highest risk for thrombotic events. For example, patients receiving dialysis with concomitant 
atrial fibrillation are anticoagulated only 37% of the time in North America and only 1% of the 
time in Germai1y (Wizemann et al. 2010; Tan et al. 2017). Furthermore, the use of vitamin K 
antagonists in such patients has resulted in a 2-fold increase in the risk of major bleeding and 
even low-dose anticoagulation (tai·get INR 1.5-1.9) resulted in a 1.5-fold increased risk of major 
bleeding (Elliott et al. 2007). 
In summruy, while the number of patients with chronic renal disease on hemodialysis keeps 
growing, anticoagulation treatment options to prevent the sequelae ofESRD remain limited. 
Traditional therapies such as warfruin and aspirin have limited efficacy, perhaps in part due to 
the mechanisms for thrombosis in ESRD, and expose patients to undue bleeding risk. Therefore, 
a therapy like ISIS 416858 that is being developed to provide anticoagulation without increased 
risk of bleeding could effectively reduce thrombosis which may positively affect the morbidity 
and m011ality in these high-risk patients. Initial data demonstrating that treatment with 
ISIS 416858 for 12 weeks reduced FXI activity levels up to 80% without any increase in 
clinically-relevant non-major or major bleeding support this notion. The development of 
ISIS 416858 will ultimately determine whether the need for hepa1-in during the dialysis 
procedure could be reduced or eliminated which could reduce the risk of major hemorrhage and 
improve the dialysis procedure. This concept is supported by a report in the literature of a 
dialysis patient with severe congenital FXI deficiency (less than 3% of normal) who received 
hemodialysis for several months without hepru·in or any other anticoagulant and did not exhibit 
clotting in the extracorporeal circuit or any bleeding complications (Takamizawa et al. 2014). 
Results from an initial study in 43 ESRD subjects on hemodialysis (ISIS 416858-CS4) indicated 
that ISIS 416858 significantly reduced the incidence of severe clotting events in the dialyzer 
circuit at doses of 200 mg and 300 mg per week without increased major or Clinically-Relevant 
Non-Major Bleeding (CRNMB), providing further supp011 to this finding. 
2.3 
ISIS 416858 
 
2.3.1 
Mechanism of Action 
 


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es Inoue et al. 1987; Monia et al. 1993 . 
 
 
 
2.3.2 
Chemistry 
 
 
 
 
 
ased 
a 1mty to the target mRNA Altmann et al. 1996; McKay et a. 1999 ; 2 mcrease resistance to 
exonucleases and endonucleases (thereby increasing stability in tissue) (Geaiy et al. 2003); and 
(3) amelioration of some of the high dose toxicities resulting in an improved safety profile 
com a.red to first en · · 
· ense dm s co 
• ••••• 
• • •• 
I  
• I 
, ·I ·I • I I I 
 
I I I  I 
I ·I ,  • 
I I I · 
• I 
 
 
This is because while the 2'-MOE modification confers 
increased stability and affmity, it does not support RNase Hl catalysis of RNA hybridized to 
2'-MOE-modified nucleotides (McKay et al. 1999). This is caused by conf01mational changes 
induced in the heteroduplex by 2'-alkoxy:RNA h brids that are not reco ized b RNase Hl 
 
 
 
 
 
 
- 


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2.3.3 
Preclinical Experience 
Detailed info1mation concerning the preclinical studies conducted with ISIS 416858 can be 
found in the Investigator's Brochure. A summa1y is included below. 
2.3.3.1 
Pharmacology 
ISIS 416858 and other FXI ASOs have been studied in several species including mice and 
primates. FXI ASOs have demonstrated antithrombotic activity in FeCb -induced venous and 
arterial thrombosis mouse models, a stenosis-induced inferior vena cava (IVC) thrombosis 
mouse model, and a baboon thrombosis model as well as anticoagulant activity in normal mice 
and monkeys. In all species, FXI ASOs produced 
80% reduction of liver FXI mRNA 
expression and plasma FXI activity as well as prolonged activated partial thromboplastin time 
(aPTT) (up to 2-fold) in expe1iments ranging from 3 weeks to 12 weeks of treatment without 
causing spontaneous bleeding or increasing surgically induced bleeding. 
 
2.3.3.2 
Pharmacokinetics and Toxicology 
Nonclinical PK and toxicology studies oflSIS 416858 in mice and monkeys, conducted in 
accordance with Good Laborato1y Practices (GLP) standards, have been perfo1med for up to 
26 and 39 weeks of treatment in mice and monkeys, respectively. In preclinical studies, 
ISIS 416858 has shown a similar PK profile (given subcutaneously [SC] or intravenously [IV]) 
in both mice and monkeys in which drng is cleared within hours from plasma and distributed to 
tissues with the kidneys having the highest concentration followed by the liver. Subsequently, 
ISIS 416858 is cleared slowly in tissues via nuclease-mediated metabolism with an elimination 
half-life of approximately 2 to 4 weeks in both mice and monkeys, which suppmts an infrequent 
clinical dosing regimen. 
In preclinical toxicology studies, the primary findings in the 26-week study in mice were similar 
to those obse1ved in the 13-week study and were related to the uptake and accumulation of the 
ASO in tissue and proinflammatmy effects of the ASO treatment. There were also minimal to 
mild decreases in platelet counts in males at all doses and females at 30 mg/kg/wk 
ISIS 416858, with a statistically significant reduction only seen in females at 60 mg/kg/wk 
(ranged from 16 to 44% reduction in group mean compared to control), likely con-elated with 
increased spleen weights in males at 10 mg/kg/wk and females at 
30 mg/kg/wk ISIS 416858 
(1.3- to 1.5-fold of control). 
In monkeys, the prima1y finding at 6 weeks was the presence of basophilic granules in multiple 
tissues, which is reflective of cellular uptake of oligonucleotide. The effect was dose-dependent 
and more prominent at doses of 40 mg/kg/wk. For the chronic 39-week treatment study of 
ISIS 416858 in the monkey the most notewo1thy finding was the severe reduction in platelet 
counts in 2/16 monkeys in the 10 and 18 mg/kg/wk groups. These types of platelet reductions 
were not obse1ved in the 13-week study with doses up to 40 mg/kg/wk. Gradual reductions in 
mean platelet counts (up to 44%) were also obse1ved at doses 6mg/kg/wk at the end of the 
39 weeks dosing with group mean platelet counts still approximately 250,000/mm3• Up to a 24% 
reduction in mean platelet counts was also seen in the control group. There was no evidence of 
bleeding or abnmmality in bone manow hematopoietic cell morphology (including 
megakaryocytes) associated with either moderate or severe platelet reduction. Minimal to mild 


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sternal bone manow megakaryocytic hyperplasia (increased numbers of megakaryocytes) was 
observed in a few animals as a likely response to the decreased platelet counts in these animals. 
Plasma and tissue PK observed in monkeys for this class of compounds predict the observed 
plasma (and expected tissue) exposure levels in humans on the basis of mg/kg equivalent doses. 
The dose range to be examined in the cmTent clinical study of 200 to 300 mg per week is 
equivalent to approximately 2.8 to 4.3 mg/kg, respectively, for a 70-kg participant. In our 
previous clinical trial with ESRD participants on hemodialysis (ISIS 416858-CS4), the mean 
peak (Cmax) and total exposure (AUC0.24hr) in plasma were 12.0 µg/mL and 150 µg*hr/mL, 
respectively, following single-dose of 300 mg ISIS 416858 administered SC. In non-human 
primates, exposure levels ranged from near equivalent Cmax and AUC at 300 mg/wk dose to high 
multiples depending on the dose level administered. Most systemic toxicities including severe 
thrombocytopenia were observed at doses 2: 10 mg/kg, and the highest observed mean Cmax 
values were 206 and 173 µg/mL, while mean AUCo-4shr values were 2150 and 2280tg*hr/mL, 
onDays 1 and 91, respectively, following 40 mg/kg per week SC dose studied in the 13-week 
sub-chronic monkey study (Study No. 416858-AS02PK). 
2.3.3.3 
Bleeding Risk Evaluation 
Cynomolgus monkeys were administered ISIS 416858 (4, 8, 12 and 40 mg/kg/wk, SC) for up to 
13 weeks with no spontaneous bleeding events. ISIS 416858 produced a dose-dependent 
reduction in systemic FXI activity and a concomitant increase in aPTT. Plasma FXI activity was 
reduced by 80% at 4 weeks of treatment (40 mg/kg/wk) that resulted in a 33% prolongation of 
aPTT by 13 weeks. No effects on prothrombin time (PT) or platelet counts were observed 
during this time period, confuming that the effects ofISIS 416858 on FXI inhibition were 
limited to the intrinsic coagulation cascade. Bleeding parameters were assessed at a 20 mg/kg 
dose ofISIS 416858 as this dose reduced plasma FXI activity by 50% and 70% after 2 and 
6 weeks of treatment, respectively. ISIS 416858 did not increase the risk of bleeding when 
evaluated in models of bleeding under a surgical setting following partial tail amputation and 
gum and skin laceration, while positive control enoxaparin at a single-dose of2 mg/kg produced 
a 2- and 3-fold increase in bleeding time and blood volume loss, respectively, following a pa11ial 
tail amputation. Bleeding time following gum laceration was also increased by 60% following 
enoxaparin treatment, while there were no changes in skin laceration bleeding time. These 
studies suggest that even in tissues with relatively high capacity for fibrinolysis (oral mucosa) 
ISIS 416858 does not cause bleeding. Thus, it is anticipated that reduction ofFXI levels by 
administration ofISIS 416858 will not increase bleeding risk. Data from the previous study in 
ESRD subjects (ISIS 416858-CS4) suppm1 this and demonstrated no increase in CRNMB or MB 
events despite mean FXI activity reduction by up to 80%. 
2.3.4 
Clinical Experience 
Detailed information regarding the clinical studies conducted with ISIS 416858 can be found in 
the Investigator's Brochure. ISIS 416858 has been evaluated in 4 clinical studies. The design 
and status of these studies ar·e summar-ized in Table 1. 


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Table 1 
Summary of ISIS 416858 Clinical Studies 
 
Study 
Phase 
Study Description 
ISIS 416858 Dosage (SC) 
Total# 
Subjects 
Center(s) 
I Country 
Study 
Status 
CS1 
1 
Double-blind, 
randomized, 
placebo-controlled, 
dose-escalation 
Single-Dose: 4 dose levels of 
50, 100, 200, and 300 mg 
ISIS 416858 
Multiple-Dose: 4 dose levels of 
50, 100, 200, and 300 mg of 
ISIS 416858, 8 doses over 
6weeks 
Week 1: 3 doses on Days 1, 3, 
and 5, Weeks 2 to 6: once- 
weekly 
88 
Single/ 
Canada 
Completed 
CS2 
1 
Drug-Drug 
Interaction study 
Multiple-dose drug 
interaction study 
with enoxaparin 
200 mg ISIS 416858, total of 
6 injections during 4 weeks of 
treatment. A single-dose of 
40 mg enoxaparin. 
administered SC alone or in 
combination with ISIS 416858 
on Day 1 and 1 week after the 
last dose of ISIS 416858 
15 
Single/ 
Canada 
Completed 
CS3 
2 
A Phase 2, open- 
label, randomized, 
active comparator- 
controlled, adaptive 
parallel-group 
dosing, 
international 
multiple-center 
study in subjects 
undergoing primary 
unilateral total knee 
arthroplasty 
200 or 300 mg ISIS 416858 
once on Days 1, 3, 5, 8, 15, 22, 
29, 36 (6 hours post-surgery) 
and Day 39 (3 days after 
surgery) 
Enoxaparin 40 mg administered 
SC the evening prior to surgery 
(optional), 6 to 8 hours after 
surgery followed by daily 
injections for at least 
8 additional days post-surgery 
314 
3/Bulgaria 
2/Canada 
3/Latvia 
5/Russia 
6/Ukraine 
Completed 
CS4 
2 
A Phase 2, 
double-blind, 
randomized, 
placebo-controlled 
study in ESRD 
subjects receiving 
a minimum of 
3 hours of 
hemodialysis 
3 times a week 
PK Cohort: 300 mg, 2 doses on 
Days 1 and Day 29 
Cohort A: 200 mg ISIS 416858 
Cohort B: 300 mg ISIS 416858 
Cohorts A and B were 
administered ISIS 416858 on 
Study Days 1, 5, 8, 12, 15, 22, 
29,36,43,50,57,64, 71,and 
78 
49 
8/Canada 
Completed 
 
 
2.4 
Rationale for Dose and Schedule of Administration 
The cunently proposed 200,250, and 300 mg ISIS 416858 dosing regimens were selected based 
on results from the previous Phase 1 and Phase 2 clinical studies that showed a satisfactory 
safety profile and significant PD effect with these regimens. Specifically, significant efficacy 
was observed in the ISIS 416858-CS3 study at both the 200 mg and 300 mg doses of 
ISIS 416858, which resulted in FXI activity reductions to 0.38 ± 0.01 and 0.20 ± 0.01 U/mL, 
respectively. Treatment duration of 12 weeks in ESRD subjects with both 200 mg and 300 mg 
dose levels ofISIS 416858 demonstrated an acceptable safety and tolerability profile. Therefore, 


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the treatment duration in the cmTent study has been extended to 26 weeks to evaluate the safety 
of ISIS 416858 at clinically efficacious levels for an additional 14 weeks at steady-state in a 
larger number of patients. 
At the doses and treatment duration proposed, FXI activity levels are expected to reach maximal 
reduction of approximately 80%, with absolute FXI activity being reduced to :'.S 0.2 U/mL. The 
proposed target level of :'.S 0.2 U/mL FXI activity is fmiher supported by the following safety 
observations: (i) Patients with severe congenital FXI deficiency (FXI activity levels 
:'.S 0.2 U/mL) have a low repmted incidence ofVTE and do not appear to have an increased 
bleeding risk (Asakai et al. 1991; Salomon et al. 2006); (ii) Healthy subjects treated with 
ISIS 416858 (ISIS 416858-CSl) did not exhibit spontaneous bleeding or any other target related 
safety concern despite reductions in plasma FXI activity of :'.S 0.2 U/mL; (iii) No increase in 
bleeding has been obse1ved in the Phase 2 studies for ESRD subjects (ISIS 416858-CS4) or 
patients undergoing knee a1ihroplasty after FXI reduction with ISIS 416858 compared to 
standard treatment of 40 mg/day of enoxaparin (ISIS 416858-CS3), despite FXI activity levels of 
:'.S 0.1 U/mL (Buller et al. 2014). 
Fmihe1more, based on nonclinical and Phase 1 and Phase 2 clinical data, approximately 4 to 
6 weeks of once-weekly dosing is required to achieve a reduction in FXI activity that will result 
in clinically meaningful anticoagulation activity after ISIS 416858 treatment. 
The safety data obtained in the Phase 1 study (ISIS 416858-CSl) and Phase 2 studies 
(ISIS 416858-CS3 and ISIS 416858-CS4), as well as the clinical experience with several other 
2'-MOE-modified ASOs (Sewell et al. 2002; Chi et al. 2005; Kastelein et al. 2006), suppo1is the 
dosing regimen planned for this Phase 2 study. The planned regimen has been employed safely 
in previous clinical studies with a number of other ASOs. This class of ASOs has been safely 
administered IV and SC in multiple clinical studies at doses up to 1000 mg (Kwoh 2008) and 
treatment durations that exceed 24 months. 
 
2.5 
Benefit-Risk Assessment 
The known potential risks to study participants associated with ISIS 416858 are elaborated on in 
the Guidance to Investigator section of the Investigator's Brochme. Additional study associated 
potential safety considerations include thrombocytopenia and increased major or CRNMB, 
which will be monitored closely. 
Thrombocytopenia is a potential safety consideration based on preclinical GLP studies of 
ISIS 416858 in monkeys in which 4 of 32 monkeys in the> 10 mg/kg/wk dose groups developed 
severe thrombocytopenia (< 50,000/mm3). Grade 4 (< 25,000/mm3) thrombocytopenia has also 
been observed clinically with 2 other second generation ASOs in 2 different rare disease 
populations within the same chemical class as ISIS 416858 at doses> 200 mg/wk. If platelet 
count is :'.S 100,000/mm3, then weekly monitoring will be implemented (see Section 8.5.2). In the 
event of a platelet count< 75,000/mm3, additional laboratory investigations will be conducted 
(see Section 8.5.2). Short-term steroid use will be recommended if platelet count< 50,000/mm3. 
This is based on data from other programs at lonis demonstrating that sho1i-te1m steroid use 
improves recove1y from thrombocytopenia. Additionally, no dose of Study Dmg will be 
administered before reviewing a valid platelet result. Valid platelet counts must be conducted 
eve1y 2 weeks and reviewed prior to dosing. If the platelet result is unavailable (e.g., due to 


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hemolysis, clumping, etc.) from the central lab, a repeat local lab will be conducted and reviewed 
prior to dosing. 
fucreased major or CRNMB is also a potential safety consideration given the antithrombosis 
effects ofISIS 416858 investigated in this study. Clinical findings in Hemophilia C patients 
have demonstrated increased bleeding in the complete absence of FXI activity (seen mostly in 
high fibrinolytic tissues and at absolute FXI concentrations< 0.3 U/mL). However, increased 
major or CRNMB has not been obse1ved to date with ISIS 416858 in the clinic or in preclinical 
studies. If bleeding were to occur, it can be rapidly reversed with infusion of plasma-derived 
FXI concentrate (Zhang et al. 2010) as well as specific FXI antidote (where available). Specific 
instrnctions for its use will be provided to site staff. 
Based on the experience from previous clinical studies, it is anticipated that study subjects may 
benefit (anticoagulation) during the study although long te1m benefit cannot be assessed due to 
relatively sholi duration of the study. 
 
3. 
EXPERIMENTAL PLAN 
 
3.1 
Study Design 
This is a Phase 2 multicenter, double-blind, randomized, stratified, placebo-controlled study in 
ESRD subjects receiving hemodialysis at least 3 times per week for a minimum of9 hours per 
week. Subjects will be stratified based on the diagnosis of documented atrial fibrillation (AF) at 
Screening (Yes/No), and then subjects will be randomized to 1 of 3 dose coholis in a 1:1:1 ratio 
(Coholi A, Cohmt B, and Cohmi C). Additionally, subjects will be stratified by pa1ticipation in 
the substudies. Within each dose cohmi, subjects will be randomized in a 3:1 ratio to receive SC 
treatment with either ISIS 416858 or placebo (See Study Design and Treatment Schema). All 
standard of care hemodialysis therapies as prescribed by their providers, including heparins, will 
be continued. 
 
CoholiA: 
Coho1t B: 
Coholi C: 
200 mg ISIS 416858 or placebo SC (3:1) 
250 mg ISIS 416858 or placebo SC (3:1) 
300 mg ISIS 416858 or placebo SC (3:1) 
All cohmts will consist of up to 4-week screening period for procedures and a 26-week treatment 
period followed by a 12-week post-treatment evaluation period. 
The SC Tolerability assessments using 0.9% sterile saline should be administered as 
2 noncontiguous injections during the screening period on Study Days S-14 (± 3) and S-7 (± 3). 
Emolled subjects will receive a SC dose of Study Drng (200 mg, 250 mg, or 300 mg 
ISIS 416858, or placebo) approximately weekly from Week 1 (Day 1) through Week 26. 
The windows for study visits are specified in the Schedule of Procedures (Appendix A); please 
note that the Study Drng (ISIS 416858 or placebo) dose may not be administered more than once 
on the same day. Any questions on study procedures and visit windows may be directed to the 
Sponsor (or designee). 


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3.1.1 
Platelet Function/Activation Subgroup 
fu a subgroup of approximately 12 subjects in each coho1t, platelet function and/or activation 
will be assessed. These subjects must have platelet counts that are 180,000/mm3 at Screening 
and who are not taking any anticoagulants or antiplatelet agents (other than aspirin). 
At regularly scheduled visits during Weeks 1 (pre-dose), 12, 26, and 38, additional blood 
samples will be collected and processed for platelet function and/or activation tests as shown in 
Appendix A. 
3.1.2 
Pharmacokinetic Subgroup 
fu a subgroup of approximately 12 subjects in each coho1t, additional Oto 24-hour PK sampling 
will be conducted following the first (Day 1, Week 1) and last dose (Day 176, Week 26) in order 
to dete1mine the plasma PK parameters ofISIS 416858 in ESRD subjects, e.g., peak maximum 
concentration (Cmax) and total plasma exposure (AUCo-t and AUC0-16shr), as well as clearance at 
steady-state (CLsslF). Subjects in this subgroup will have additional visits to the clinic to collect 
blood after dosing on Day 1, including a 24-hour (Day 2), and post-dose blood draw after 
Day 176 dose (Week 26) at 24-hours (Day 177), 48-hour (Day 178), and 7 days (Day 183). fu 
the event that dialysis is perfo1med on these days, the blood draw should occur pre-dialysis. For 
more details of PK sampling schedule, see Appendix C. 
Subjects in the platelet function/activation subgroup may also pa1ticipate in the PK subgroup and 
may withdraw consent for the subgroup specific procedures (e.g., blood draws for PK) without 
being withdrawn from dosing or from the study. If a subject withdraws consent from the 
subgroup procedures, he/she should remain on study and continue to follow all the non-subgroup 
assessments and procedures as outlined in Appendix A. 
 
3.2 
Number of Study Centers 
This study will be conducted at multiple centers worldwide. 
 
3.3 
Number of Subjects 
Approximately 204 subjects are planned to be enrolled in parallel in this study and randomized 
equally across Coho1ts A, B, and C. 
The 3 multiple-dose cohol1s are designed to assess the safety, tolerability, PK/PD of 
ISIS 416858. The sample size has been selected to ensure that the PK/PD, safety, and 
tolerability ofISIS 416858 will be adequately assessed while minimizing unnecessary subject 
exposure. 
3.4 
Overall Study Duration and Follow-up 
For all coho1ts, the Study will consist of a 4-week screening pe1iod for procedures after the 
inf01med consent is signed. An additional 21 days is pe1mitted p1ior to screening period for 
signing of the inf01med consent. All cohol1s will consist of a 26-week Treatment Period, and a 
12-week Post-Treatment Evaluation Period. For all coho11s, please refer to the Schedule of 
Procedures in Appendix A. 


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Subjects may be required to attend additional visits for monitoring of adverse events (AE) or 
abnormal investigation results. The frequency of additional monitoring will be determined by 
the Investigator in consultation with the Sponsor. 
If Study Drug is discontinued for any reason, subjects are encouraged to continue their regular 
assessments for the duration of the treatment period and post-treatment evaluation period, unless 
subject informed consent is withdrawn. 
 
3.4.1 
Screening 
After signing the infmmed consent fmm, subject eligibility for the study will be dete1mined 
within 4 weeks prior to Study Day 1. 
During the screening period, at Study Days S-14 (± 3) and S-7 (± 3), subjects should receive 
2 noncontiguous SC injections of 0.75 mL saline. As with Study Drug, these may be 
administered immediately after dialysis is completed when blood is returning to the subject but 
must be within 2 hours after dialysis (within 15 minutes is prefen-ed) to determine tolerability to 
SC injections. 
All women will have a serum pregnancy test done between Study Days S-28 and S-14 that must 
be resulted prior to dosing on Study Day 1. 
All screening lab re-tests should be resulted by the central lab prior to randomization on Study 
Day 1. 
3.4.2 
Treatment 
Eligible subjects will receive study treatment every week for 26 weeks. The treatment period 
consists of the period from the first Study Drug (ISIS 416858 or placebo) injection to the last 
injection on Day 176 (Week 26), or early study termination. 
3.4.3 
Post-Treatment 
Subjects will have follow-up evaluation visits on Study Week 27 (PK Subgroup only), and for 
Shrdy Weeks 28, 30, 32, 34, 36, 38 (all subjects), or early study termination. The final study 
visit will be Study Day 260. 
 
3.5 
End-of-Study 
The End-of-Study is defined when the la.st subject has had their la.st visit. 
 
4. 
SUBJECT ENROLLMENT 
 
4.1 
Screening 
Before subjects may be enrolled into the Study, the Sponsor or designated contract research 
organization (CRO) 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. 
Subjects must sign the consent fmm before any screening tests or assessments are performed, 
this can be done up to 49 days prior to randomization. At the time of consent, the patient will be 


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considered enrolled into the Study and will be assigned a unique screening number before any 
study procedures, including screening procedures, are performed. 
Screening labs must be perf01med within 28 days before Study Day 1. If screening labs are to be 
perf01med outside of this window, then additional samples should normally be drawn prior to 
Study Day 1 to ensure that labs still fulfill the eligibility criteria. A single re-test of abn01mal 
screening labs may be done at the central lab to evaluate subject eligibility. 
During the screening period, at Study Day S-14 (±3) and S-7 (±3), subjects should receive 
2 noncontiguous SC injections of0.75 mL saline as described in Section 3.4.1. 
At the time of randomization, subjects will be assigned a unique subject identification number. 
This number will be used to identify the subject throughout the trial and must be used on all 
study documentation related to that subject. The screening number and subject identification 
number must remain constant throughout the entire trial. In the event the subject is re-consented 
and re-screened, the subject must be given a new screening number. Screening numbers and 
subject identification numbers, once assigned, will not be re-used. 
4.2 
Randomization 
Subjects will be randomized on Study Day 1 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 subject may begin treatment prior to randomization and assignment of a unique 
subject identification number. 
All subjects will be randomized using an automated system (IXRS). Subjects will be stratified 
based on the diagnosis of documented AF at Screening (Yes/No). Additionally, subjects will be 
stratified by paiiicipation in the substudies. Then, subjects will be randomized in parallel to 1 of 
3 dose cohorts in a 1:1:1 ratio (Coh01i A, Coh01t B, and Coh01t C). Within each dose cohort, 
subjects will be randomized in a 3:1 ratio to receive SC treatment with either ISIS 416858 or 
placebo. 
4.3 
Unblinding of Treatment Assignment 
The Sponsor and all subjects, monitors, and Study Center personnel related to the Study, will be 
blinded throughout the Study. However, if a subject 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 subject, the Investigator will have the ability to unblind the treatment 
assignment for that subject using the automated system. The Sponsor or designee must be 
inf01med of the unblinding of a subject within 24 hours. All SUSARs will be unblinded by the 
Sponsor or designee for the purpose ofregulat01y rep01ting (see Section 9.2). 
Eve1y reasonable attempt should be made to complete the early te1mination study procedures and 
observations (see Appendices A and B) prior to unblinding, as knowledge of the treatment ai·m 
could influence subject assessment. 
In addition, the safety team assigned to review relevant Study Drng safety and tolerability data 
during the study in a blinded fashion will also have the ability to request the Ionis Drng Safety 


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Oversight Committee, chaired by the Chief Medical Officer, for unblinding the treatment 
assignment if needed for safety and data interpretation. 
During the study, an unblinded interim analysis may be conducted to assess the safety and 
PK/PD results. The analysis will be executed with controlled dissemination of data to ensure the 
integrity of ongoing data collection while maintaining sufficient blinding in the study. Details of 
these controls will be described in the Statistical Analysis Plan (SAP). 
 
5. 
SUBJECT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
during the Screening Period and must continue to meet up to prior to dosing on Study Day 1. 
 
5.1 
Inclusion Criteria 
1. Must have given written informed consent (signed and dated) and any authorizations 
required by local law and be able to comply with all study requirements 
2. Males or females aged 18 to 85 years old at the time of info1med consent 
a 
Females: must be non-pregnant and non-lactating and either: 
1. surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy); 
11.  post-menopausal (defined as 12 months of spontaneous amenoIThea in females 
> 55 years of age or, in females :S 55 years, 12 months of spontaneous amenoIThea 
without an alternative medical cause and FSH levels in the postmenopausal range 
for the laborato1y involved); or, 
iii. if engaged in sexual relations and of child-beaTing potential, agree to use effective 
contraceptive methods (refer to Section 6.3.1) from the time of signing the infmmed 
consent form until at least 84 days (approximately 5 half-lives ofISIS 416858) after 
the last dose of Study Drng (ISIS 416858 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 6.3.1) from the time of signing the info1med consent form until at least 
84 days (approximately 5 half-lives ofISIS 416858) after the la.st dose of Study Drng 
(ISIS 416858 or placebo). 
3. End-stage renal disease maintained on outpatient hemodialysis at a healthcare center for 
> 3 months from screening with hemodialysis at least 3 times per week for a minimum of 
9 hours per week of prescribed treatment time and plan to continue this throughout the 
study. 
 
5.2 
Exclusion Criteria 
1. Subjects with a histo1y of a major medical event (e.g., previous acute corona1y syndrome, 
stroke or transient ischemic attack, or systemic thromboembolic event) within 3 months 
of screening, major surge1y within 3 months of screening, or new major physical 
examination finding (not accounted for by past medical history), except for documented 
AF. 


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2. Active bleeding (as judged clinically-significant by the Investigator) within the past 
3 months from screening or documented bleeding diathesis (excluding uremia), 
coagulopathy, or recent history of prolonged compression time at arteriovenous fistula. 
3. Screening laboratory results as follows: 
• 
Platelet count< 150,000 cells/mm3 
o < 180,000 cells/mm3 for platelet function/activation subgroup 
• 
INR > 1.4 
• 
aPTT > upper limit of normal (ULN) 
• 
FXI activity< 0.3 U/mL 
• 
ALTorAST>2xULN 
• 
Total bilirnbin > ULN 
4. Subject is not willing to have weekly SC injections over the study period as assessed 
during screening. 
5. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 (first dose) or IV antibiotic use at the time of screening. 
6. Unwillingness to comply with study procedures, including follow-up, as specified by this 
protocol, or unwillingness to cooperate fully with the Investigator. 
7. Known histo1y of or positive test at Screening for human immunodeficiency virus (HIV), 
hepatitis C or chronic hepatitis B. 
8. Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or 
carcinoma in situ of the cervix that has been successfully treated. Subjects with a hist01y 
of other malignancies that have been treated with curative intent and which have no 
recunence within 5 years may also be eligible if approved by the Sponsor Medical 
Monitor (or designee). 
9. Treatment with another investigational drug, biological agent, or device within one 
month of screening, or 5 half-lives of investigational agent, whichever is longer. 
10. Any hist01y of previous treatment with an oligonucleotide (including siRNA). Subjects 
that have previously received only a single-dose of an ISIS-oligonucleotide as part of a 
clinical study may be included as long as a duration 2: 4 months has elapsed since dosing. 
11. Attending nephrologist answers "no" to the question, "Would you be surprised if this 
patient died in the next year?" 
12. Within 6 months prior to screening, 
• 
More than 3 episodes of severe hypoglycemia requiring the assistance of another 
person to actively administer carbohydrate, glucagon or other resuscitative actions 
• 
One (1) event of hypoglycemia in which the patient required hospitalization 
• 
Recunent syncope and recmTent hypotension in the inter-dialytic period requiring 
inte1vention 


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13. Planned major surgery in the next 6 months, including subjects receiving a kidney 
transplant or subjects that anticipate changing dialysis modality (i.e., hemodialysis to 
peritoneal dialysis). 
14. Recent history of, or curTent drug or alcohol abuse as determined by the Investigator. 
15. Concomitant use of anticoagulant/antiplatelet agents (e.g., warfarin, dabigatran, 
rivaroxaban, clopidogrel) that may affect coagulation (except low dose aspirin 
(:'.S 100 mg/day) during Treatment and Post-treatment Evaluation Periods is not allowed. 
Stable doses of heparins during dialysis are permitted. 
16. Uncontrolled hypertension as judged by the Investigator. For example, patients with a 
pre- or post-dialysis blood pressure (BP) that is> 180 mmHg on at least 3 of the last 
5 dialysis treatments. 
17. Have any other conditions, which, in the opinion of the Investigator or Sponsor would 
make the subject unsuitable for inclusion, or could interfere with the subject participating 
in or completing the study. 
6. 
STUDY PROCEDURES 
6.1 
Study Schedule 
The study period for an individual patient consists of a :'.S 4-week Screening Period for 
procedures followed by a 26-week Treatment Period, and a 12-week Post-Treatment Evaluation 
Period. Additional outpatient visits may be scheduled if required for further evaluation of an 
abnormal laboratory value or reported AE. 
For patients participating in the PK substudy, there are 4 additional visits than those in the main 
study, occuning on Study Days 2, 177, 178, and 183. On Study Day 1 and at the end of the 
treatment period on Study Day 176, PK blood sampling is required at 1, 2, 3, 4, 6, and 10 hours 
after Study Drug administration. Two (2) of the 4 additional visits may be on non-dialysis days 
(Study Days 2 and 177). 
For patients participating in the platelet subgroup, no additional visits are required. Any AEs, 
concomitant medications, and other safety and tolerability profiling data will be promptly 
reported and reviewed by Sponsor's Medical Monitor (or designee). 
All required study procedures are outlined in Appendices A, B, and C. 
 
6.1.1 
Screening 
Day -49 to Day -14: Written informed consent for the study will be obtained prior to the 
performance of any study-related procedures. 
Day-28 to Day-I: A:'.S 4-week period is provided to complete Screening assessments and 
procedures and to determine subject eligibility for the study. Subjects will be questioned for 
medical hist01y, and undergo physical examination, confomation of their ESRD status, 12-lead 
electrocardiogram (ECG), vital signs, body weight, and height. Race and ethnicity data will be 
collected as part of the demographic inf01mation for all screened subjects during the screening 
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Subjects will also be screened for infections of HIV, Hepatitis B and C, and for blood 
coagulation abnormalities including prolonged aPTT, PT, and international normalized ratio 
(INR), and low FXI activity levels(< 0.3 U/mL). All women will have a serum pregnancy test 
done between S-28 and S-14 that must be resulted prior to dosing on Study Day 1. Follicle- 
stimulating ho1mone (FSH) will be measured to confom menopause in women< 55 years of age 
that have 12 months of spontaneous amenonhea without an alternative medical cause. 
Additional blood samples will be taken for routine clinical laborato1y testing (Appendix A). 
In order to reduce the burden of unnecessary procedures on subjects who subsequently elect not 
to paliicipate in the study or continue with study procedures, all subjects will confom tolerance 
of SC administration prior to randomization. This injection will follow the same procedures as 
injections of the Study Drug (ISIS 416858 or placebo) during the treatment period. Specifically, 
during the screening period on Study Days S-14 (± 3) and S-7 (± 3), subjects should receive 
2 noncontiguous SC injections of 0.75 mL saline within 2 hours after dialysis as described in 
Section 3.4.1. 
The Screening results will be made available to decide individual subject's eligibility against 
inclusion/exclusion criteiia (Section 5.1 and 5.2). Individual subjects will be disqualified if 
results of any laborat01y test are clinically-significant as judged by the Investigator or Sponsor's 
Medical Monitor (or designee). Eligible subjects will be emolled into the study. 
6.1.2 
Baseline (Day 1) 
Baseline for the routine clinical assessments of chemistiy and hematology, PD markers, 
assessment of clotting, PK assessments, vital signs and ECG for the study will be the time-point 
prior to the first administi·ation of Study Drng and prior to dialysis on Day 1 (Appendix A). If 
Day 1 values are not available, screening values will be used. For Urea Reduction Ratio, the 
blood collections for blood urea niti·ogen (BUN) piior to dialysis as well as the post-dialysis 
sample on Day 1 will be used. 
6.1.3 
Treatment Period (Day 1 to Day 176) 
Emolled subjects may be administered ISIS 416858 or placebo immediately after dialysis is 
completed (when blood is returning to the subject) but must be within 2 hours (preferably within 
15 minutes) approximately once each week for a total of26 weeks ofb"eatment. 
Once-weekly SC adminisb"ation will occur during Weeks 1 to 26 (Days 1, 8, 15, 22, 29, 36, 43, 
50, 57, 64, 71, 78, 85, 92, 99, 106, 113, 120, 127, 134, 141, 148, 155, 162, 169, and 176). 
For Study Drug administi-ation on Study Day 1, no dosing window is allowed. For Weeks 2 to 
26, a± 3-day window may be utilized but Study Drug should be administered each week. 
Study Drug doses should be administered at least 72 hours apart. 
Additionally, no dose of Study Drug will be administered before reviewing a valid platelet result. 
Valid platelet counts must be conducted eve1y 2 weeks and reviewed prior to dosing. If the 
platelet result is unavailable (e.g., due to hemolysis, clumping, etc.) from the centi·al lab, a repeat 
local lab will be conducted and reviewed piior to dosing. 


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Any questions on study procedmes and visit windows may be directed to the Sponsor (or 
designee). 
During all subject contacts, Investigators will check for and record: 
• 
Bleeding events 
• 
AEs 
• 
Concomitant medication changes 
Safety and clinical laboratory evaluations as well as PD markers, assessment of clotting, blood 
sampling, including those for routine PK as well as PK substudy analysis will be perfo1med as 
indicated in Appendices A, B, and C. Subjects pa1ticipating in the platelet substudy will have 
additional blood sampling and processing on Study Days 1, 78, and 176 during the Treatment 
Period. 
Any AEs, including bleeding events, will be recorded. This may include additional info1mation 
regarding events of interest (i.e., thrombotic events). 
6.1.4 
Post-Treatment Evaluation Period 
After completing the 26 weeks of the Treatment Pe1iod, subjects will return for follow-up visits 
as indicated in Appendix A. Patients will be followed until the Study Center visit on Day 260. 
Dming the Post-Treatment Evaluation Period, a visit window of± 3 days is allowed for 
Days 183, 190, and a visit window of± 7 days is allowed for visits between Days 204 and 260. 
For all coho1ts, at all subject contacts, Investigators and staff will check for and record: 
• 
Bleeding events 
• 
AEs 
• 
All concomitant medication changes 
Safety and clinical laboratory evaluations as well as PD markers, assessment of clotting, blood 
sampling, including those for routine PK as well as PK substudy analysis, will be perfom1ed as 
indicated in Appendices A, B, and C. Subjects pa1ticipating in the platelet substudy will have 
additional blood sampling and processing on Study Day 260, the last day of the Post-Treatment 
Evaluation Period. 
6.2 
Study Assessments 
 
6.2.1 
Laboratory Assessments 
Blood samples for clinical laboratory and PK assessments will be collected throughout the Study 
as detailed in Appendices A and C. A list of laboratory and PK analytes is contained in 
Appendix B. 
6.2.2 
Safety 
Subjects with a suspected bleeding event will undergo additional testing if deemed appropriate 
by the treating physician and an (S)AE case report form will be completed. In addition, if 


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bleeding is considered significant, hemoglobin (Hb), hematocrit (Hct), aPTT, PT, INR, and 
platelet count are to be obtained, and approximately 2 mL of K2EDTA anticoagulated blood will 
be collected. The resulting plasma must be stored allowing for a centralized assessment of 
ISIS 416858 concentrations. 
If the platelet value or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or 
quantity not sufficient) or missing, a repeat blood specimen must be re-drawn as soon as possible 
(ideally within 7 days). 
Subjects that withdraw from the study due to a change in dialysis modality or to undergo renal 
transplantation should notify the Sponsor Medical Monitor (or designee) and conduct the early 
termination procedures identified in Appendices A and C prior to the change or the surgery as 
appropriate. Whenever possible, a coagulation panel and PK blood sample should be collected 
prior to the initiation of renal transplant surgery. Additionally, at approximately 48 hours 
post-transplant, additional blood samples should be collected for Coagulation Panel 
(Appendix B) and ISIS 416858 plasma concentration (Appendix C). Any clinically-significant 
bleeding such as CRNMB and MB should be recorded and reported to the Sponsor Medical 
Monitor (or designee). 
 
6.2.3 
Clotting Assessments 
Clotting assessments of the dialysis filter will be conducted throughout the Study as indicated in 
Appendix A. The clotting assessment will consist of a semi-quantitative scale by descriptive 
category (See Section 10.6.4) and will be performed by trained personnel. 
 
6.3 
Restriction on the Lifestyle of Subjects 
 
6.3.1 
Contraception Requirements 
All male subjects and women of childbearing potential must refrain from sperm/egg donation 
and either be abstinentt or practice highly effective contraception from the time of signing the 
informed consent form until at least 12 weeks after their last dose of study treatment. 
Male subjects engaged in sexual relations with a female of child-bearing potential must also 
encourage their female partner to use highly effective contraception from the time of signing the 
informed consent until 12 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 one of the following conditions: 
• 
Postmenopausal: 12 months of spontaneous amenonhea in females > 55 years of age or, 
in females :S 55 years, 12 months of spontaneous amenonhea 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 spennicidal foam/gel/film/ 
cream/supposito1y 
• 
Male subjects with pa1tners that are pregnant must use condoms as contraception to 
ensure that the fetus is not exposed to the Study Drng 
For female subjects and female pa1tners 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 ce1vical cap) together with spermicidal 
foam/gel/film/cream/suppositmy 
tNote: Abstinence is only acceptable as true abstinence, i.e., when this is in line with the 
preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of a trial and withdrawal are not acceptable methods of contraception. 
*Note: A female condom and a male condom should not be used together as friction 
between the two can result in either or both products failing. 
7. 
STUDY DRUG 
 
7.1 
Study Drug Description 
Study Drug (ISIS 416858 or placebo) characteristics are listed in Table 2. 
The Study Drug (ISIS 416858 or placebo) is contained in 2 mL stoppered glass vials. The Study 
Drng (ISIS 416858 or placebo) and its storage and preparation instrnctions will be provided by 
the Sponsor or designee. The Study Drug (ISIS 416858 or placebo) must be stored securely at 
2-8 °Celsius and be protected from light. 
Table 2 
Study Drug Charactel'istics 
 
Study Drug 
ISIS 416858 
Placebo 
Strength 
200 mg/ml 
Not Applicable 
Volume 
1 ml solution per vial 
1 ml solution per vial 
Route of Administration 
Subcutaneous (SC) 
Subcutaneous (SC) 


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7.2 
Packaging and Labeling 
The Sponsor will provide the Investigator with packaged Study Drng (ISIS 416858 or placebo) 
labeled in accordance with specific count1y regulato1y requirements. 
7.3 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return of Study Drng 
(ISIS 416858 or placebo) supplies provided by the Sponsor. The Study Center must return all 
used and unused Study Drng (ISIS 416858 or placebo) to the Sponsor or designee. 
8. 
TREATMENT OF SUBJECTS 
 
8.1 
Study Drug Administration 
Study Drng (ISIS 416858 or placebo) will be administered SC by trained personnel at the Study 
Center. Volumes to be administered are shown in Table 3. All doses of Study Drng will be 
administered after the completion of the hemodialysis treatment which can be while blood is 
returning to the patient but must be within 2 hours (preferably within 15 minutes of the 
conclusion of dialysis). Vials are for single use only. Please refer to the Study Drng Manual 
provided by the Sponsor (or designee) for more detailed instrnctions for Study Drng 
(ISIS 416858 or placebo) preparation and administration. 
Table 3 
Study Drug Dosing Information 
 
Cohort 
Volume to 
Administer 
Number of Injections 
Total Dose* 
Cohort A 
(200 mg ISIS 416858 or placebo) 
1.0 ml 
1 of 1.0 ml 
5200 mg ISIS 416858 or placebo 
Cohort B 
(250 mg ISIS 416858 or placebo) 
1.25 ml 
1 of 0.75 ml and 
1 of 0.5 ml 
6500 mg ISIS 416858 or placebo 
Cohort C 
(300 mg ISIS 416858 or placebo) 
1.5 ml 
2 of 0.75 ml 
7800 mg ISIS 416858 or placebo 
* Total dose of ISIS 416858 based on completed treatments for each cohort 
 
 
8.2 
Other Protocol-Required Drugs 
A 0.9% sterile saline will be used for the SC tolerability injections pe1f01med during screening. 
At screening period Study Day S-14 (± 3) and S-7 (± 3), subjects should receive 2 noncontiguous 
SC injections of 0.75 mL saline to be administered following procedures for Study Drng as 
desclibed in Section 8.1. 
8.3 
Other Protocol-Required Treatment Procedures 
Subjects are required to be receiving in center hemodialysis at least 3 times a week for a 
minimum of 9 hours per week while receiving Study Drng during the treatment period. Subjects 
no longer receiving the required in center hemodialysis should continue in the study with the 
regularly scheduled assessments, but will no longer receive Study Drng. 


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8.4 
Treatment Precautions 
Please refer also to the 'Guidance for Investigator' section of the Investigator's Brochure. 
 
8.5 
Safety Monitoring Rules 
Please refer also to the 'Guidance for Investigator' section of the Investigator's Brochure. 
Baseline for the routine clinical assessments of chemist:Iy and hematology, PD markers, 
assessment of clotting, PK assessments, vital signs and ECG for the study will be the last 
non-missing value prior to the first administt·ation of Study Drng and prior to dialysis on Day 1 
(Appendix A). If Day 1 values are not available, screening values will be used. 
For baseline Urea Reduction Ratio deternlination, the BUN blood collection prior to dialysis as 
well as the post-dialysis sample on Day 1 will be used. 
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. 
Confumation Guidance: At any time during the study (Treatment or Post-Treatment Evaluation 
Periods), any clinical laborat01y results meeting the safety monitoring criteria presented below 
must be confirmed by perfo1ming measurements (ideally in the same laborat01y that performed 
the initial measurement) on new specimens. All new specimen collections should take place as 
soon as possible (ideally witllin 7 days of the initial collection). For stopping rnles, if the initial 
laborato1y result is observed during the Treatment Period, the results from the retest must be 
available prior to administering the next dose of Study Drng (ISIS 416858 or placebo). 
Re-dosing Guidance: Subjects with initial laboratory test values that reach a stopping rnle must 
not be re-dosed until the re-test results are available. In general, subjects who do not meet the 
stopping rnles based upon retest may continue dosing. However, the Investigator and the 
Sponsor Medical Monitor (or designee) should confer as to whether additional close monitoring 
of the subject is appropriate. If any of the stopping criteria described in Sections 8.6.1, 8.6.2, or 
8.6.3 are met, the subject will be permanently discontinued from further treatment with Study 
Drng (ISIS 416858 or placebo), evaluated fully as outlined below and in consultation with the 
Sponsor Medical Monitor or designee, and will be followed up in accordance with Section 8.8 of 
the protocol. 
 
8.5.1 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rnles are adapted from the draft guidance for industry, "Drng-Induced Liver 
Injury: Premarketing Clinical Evaluation," issued by the U.S. Department of Health and Human 
Services, Food and Drng Administt·ation, July 2009. For a defirlition of Baseline, please refer to 
guidance in Section 8.5 above. 
In the event of an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
measurement that is> 3 x ULN, or 3 x baseline value if the baseline value was> ULN at any 
time during the study (treatment and post-treatment evaluation periods), the initial 
measurement(s) should be confomed as described above. Additionally, confomat01y 
measurements should also be perfo1med if ALT or AST levels increase to 5 x ULN. 


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Frequency of Repeat Measurements: 
If the patient has confamed post-baseline ALT or AST levels> 3 x ULN, or 2 x baseline value, 
if the baseline value was> ULN at any time dming the study (treatment or post-treatment 
evaluation periods) that are continuing to rise, they should have their liver chemistry tests (ALT, 
AST, INR and total bilimbin) retested at least once-weekly until ALT and AST levels become 
:::; 1.2 x ULN or:::; 1.2 x baseline if the baseline value was> ULN. 
Fmiher Investigation into Liver Chemistry Elevations: 
For patients with confi1med ALT or AST levels> 3 x ULN (or the greater of 2 x baseline value 
or 3 x ULN if baseline value was> ULN), the following evaluations should be perfo1med: 
1. Obtain a more detailed history of symptoms and prior and concunent diseases 
2. Obtain fmiher histo1y for concomitant dtug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational dtug use, and 
special diets 
3. Obtain a histo1y for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (hepatitis A vims [HAV] IgM, hepatitis B surface antigen 
[HBsAg], hepatitis C vims [HCV] antibody, cytomegalovims [CMV] lgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic 
computed tomography (CT) or magnetic resonance imaging (MRI) scans, may be perfmmed at 
the discretion of the Investigator, in consultation with the Sponsor Medical Monitor (or 
designee). Repetition of the above evaluations should be considered if a patient's ALT and/or 
AST levels reach 2: 5 x ULN. 
8.5.2 
Safety Monitoring Rules for Platelet Count Results 
If a subject's absolute platelet count is 100,000/mm3 or less, then the subject's platelet counts 
should be monitored weekly. In the event of a platelet count< 75,000/mm3, additional 
laborato1y investigations may be conducted (Table 4). The frequency of monitoring and 
additional lab tests will be dete1mined by the Investigator in consultation with the Sponsor 
Medical Monitor (or designee). 


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Table 4 
Additional Labs to be Performed in the Event of a Platelet Count 
< 75,000/mm3 
 
To Be Performed at Local Lab 
Peripheral smear (should be perfom,ed locally, fixed and sent to central lab for review) 
Fibrinogen split products or D-dimer on fresh blood 
To Be Performed at Central Lab 
Citrated sample for platelets 
Coagulation panel (PT/INR, aPTT) 
CBC with reticulocytes and mean platelet volume (MPV) 
Fibrinogen 
von Willebrand factor 
Total globulins, total lgA, lgG and lgM 
Complement: total C3, total C4, Bb, C5a 
hsCRP 
Serology for: 
HBV, HCV, HIV (if not done for screening) 
Rubella 
CMV 
EBV 
Parvo 819 
Helicobacter pylori 
Auto-antibody screen: 
Antiphospholipid 
Rheumatoid factor 
Anti-dsDNA 
Anti-thyroid 
To Be Performed at Specialty Lab(s) 
Antiplatelet antibodies and Anti-PF4 assay 
Anti-ASO antibody 
Note: 
 The following labs may change as additional data is assessed, and sites will be updated regarding any 
changes. 
 
 
8.5.3 
Safety Monitoring for Bleeding Events 
Subjects will be evaluated for occunence of bleeding events continuously after the start of 
Study Drug treatment (Day 1) up to Day 260 for all cohorts. All bleeding events are considered 
AEs and reported on adverse event case report form. 
Bleeding events that are either major or CRNMB (as defined below) will need to be monitored 
and treated immediately. Subjects with a suspected bleeding event will undergo additional 
testing if deemed appropriate by the treating physician and an (S)AE case report form will be 
completed. fu addition, if bleeding is considered significant, Hb, HCT, aPTT, PT, INR, FXI 
activity and antigen, and platelet count are to be obtained. fu addition, approximately 2 mL of 


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K2EDTA anticoagulated blood will be collected and resulting plasma must be stored allowing for 
a centralized assessment ofISIS 416858 concentrations. 
In addition, if a minor bleeding event occurs, the Investigator should notify the Sponsor Medical 
Monitor (or designee) and additional testing of coagulation parameters (aPTT, PT, INR), platelet 
count, and platelet volume may be perfmmed. 
Definitions: 
Major bleeding (MB) is defined as one of the following: 
1. Fatal bleeding 
2. Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, 
intraocular, ret:roperitoneal, intraaiiicular if in a major joint, or pericardia!, or 
intramuscular with compaiiment syndrome 
3. Clinically ove11 bleeding leading to transfusion of 2 units of packed red blood cells or 
whole blood or a fall in Hb of 20 g/L (1.24 mmol/L) or more within 24 hours 
Clinically-Relevant Non-Major Bleeding (CRNMB) is defined as ove1t bleeding not meeting the 
critelia for MB but that resulted, for example, in medical examination, inte1vention, or had 
clinical consequences for a subject (Biiller et al. 2007). 
Minor bleeding events are those that do not fulfill the cliteria for MB or CRNBM events (defined 
above), for example excess bruising, petechiae, gingival bleeding on brnshing teeth. 
 
8.6 
Stopping Rules for Study Drug 
When stopping rnles are met for liver chemistry elevations, platelet count reductions, or bleeding 
events, then Study Drng administr·ation must be discontinued. However, subjects are encouraged 
to continue with study assessments through the tr·eatment and post-tr·eatment evaluation periods, 
but will no longer receive Study Drng. 
 
8.6.1 
Stopping Rules for Liver Chemistry Elevations 
In the event of confamed laboratory results meeting the following criteria, and the event is 
without an alternative explanation as discussed with the Sponsor Medical Monitor (or 
designee), dosing of a patient with Study Drng (ISIS 416858 or placebo) will be stopped 
permanently; values that are not confirmed due to failure to retest or missing lab values will be 
presumed confamed: 
1. ALT or AST> 8 x ULN, which is confi1med 
2. ALT or AST> 5 x ULN, which is confi1med and persists for 2weeks 
3. ALT or AST> 3 x ULN (or the greater of2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confi1med and total bilirnbin > 2 x ULN or INR > 1.5) 


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4. ALT or AST> 3 x ULN (or the greater of2 x baseline value or 3 x ULN if the baseline 
value was> ULN), which is confi1med, and with the new appearance (i.e., onset 
coincides with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or concomitant eosinophilia (> ULN) 
8.6.2 
Stopping Rule for Platelet Count Reduction 
In the event of a confi1med platelet count less than 75,000/mm3, dosing of a subject with Study 
Drng (ISIS 416858 or placebo) will be stopped permanently. Fmthe1more, additional laborato1y 
investigations will be conducted as outlined in Table 4. The platelet count should be tested 
weekly until it is above 100,000/mm3. The subsequent follow-up schedule for any events 
meeting this stopping criterion will be dete1mined by the Investigator in consultation with the 
Sponsor Medical Monitor (or designee). 
In the event of a platelet count< 50,000/mm3, the Sponsor must be notified within 24 hours and 
platelets are to be monitored daily until 2 successive values show improvement, then monitored 
every 2-3 days until the platelet count is stable. A stable platelet count is considered when at 
least 6 consecutive values measured are> 100,000/mm3 with no downward trend as dete1mined 
by the Sponsor Medical Monitor (or designee). It is recommended that the subject receive 
glucoco1ticoid therapy to accelerate the recovery in the platelet decline (strongly recommended if 
platelet count< 25,000/mm3). To optimize patient treatment, a discussion between the 
Investigator and the Sponsor Medical Monitor (or designee) must occur. Treatment guidelines 
for inllllune thrombocytopenia (Provan et al. 2010) recommend dexamethasone 40 mg daily for 
4 days eve1y 2-4 weeks for 1-4 cycles; prednisolone 0.5-2 mg/kg/day for 2-4 weeks then taper; 
or methylprednisolone 30 mg/kg/day for 7 days (note: may require continuation with oral 
cmticosteroids after methylprednisolone). 
 
8.6.3 
Stopping Rule for Bleeding 
If an event of Major Bleeding or CRNMB event occurs, the Investigator must notify the Sponsor 
Medical Monitor (or designee) and the subject should be closely monitored (vital signs, lab tests 
such as Hb, HCT and platelet count, additional outpatient visits, overnight stays and coagulation 
tests may be needed) throughout the treatment and during the post-treatment evaluation period. 
In the event of Major Bleeding or CRNMB (see definitions in Section 8.5.3) as assessed by the 
Investigator, dosing of a subject with Study Drng (ISIS 416858 or placebo) may be stopped 
permanently. The follow-up schedule for any events meeting this discontinuation criterion will 
be dete1mined, including the suitability of the subject for resumption of dosing by the 
Investigator in consultation with the Sponsor Medical Monitor (or designee). 
Treatment Precautions: 
Recommendations to manage bleeding in a patient will be provided to all study sites: 
Specifically, if a patient has Major Bleeding or Clinically Relevent Non-Major Bleeding during 
the trial, the following measures are to be considered by the Investigators to control that 
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1. Delay of the next injection or discontinuation of treatment in consultation with 
Sponsor Medical Monitor (or designee) per Section 8.6.3. 
2. Review and discontinue concomitant medications that could exacerbate bleeding. 
3. Mechanical compression/ Surgical inte1vention/haemostasis. 
4. General volume management: fluid replacement & hemodynamic suppo1t. 
5. Transfusion (whole blood/packed cells/FFP/platelets). 
If bleeding cannot be controlled by these measures, consider administration of one of the 
following procoagulants (according to the dosages advised in the package inse1t), FXI 
concentrate (Hemoleven®), Recombinant Factor Vila (NovoSeven®), or 4-factor concentrate 
(prothrombin complex concentrate). 
ISIS 416858 treatment does not directly inhibit circulating FXI, only production of this clotting 
factor in the liver. Therefore, the dose of fresh frozen plasma (FFP) or factor concentrate given 
should aim to increase FXI activity above 0.3 U/mL and should recognize that the half-life of 
circulating FXI is approximately 50 hours when considering the potential need for re- 
administration. Additionally, the time necessa1y to obtain a FXI concentration locally and to 
infuse FFP should be taken into consideration. 
8.7 
Discontinuation of Study Drug 
A subject must pe1manently discontinue Study Drug (ISIS 416858 or placebo) for any of the 
following: 
• 
The subject becomes pregnant. Repo1t the pregnancy according to instmctions in 
Section 9.5.4 
• 
The subject withdraws consent 
• 
The subject experiences an AE that necessitates permanent discontinuation of Study Drug 
• 
The subject develops laborato1y test abnormalities that meet any of the stopping rules 
listed in Sections 8.6.1 to 8.6.3 
• 
The subject experiences an AE that necessitates unblinding of the Investigator to the 
subject's treatment assignment 
• 
The subject is no longer on maintenance hemodialysis of at least 3-times per week for a 
minimum of 9 hours per week which includes a change in dialysis modality or renal 
transplantation 
• 
The subject begins treatment with a disallowed concomitant medication as described in 
Section 8.9.1 
The reason for discontinuation of Study Drug must be recorded in the electronic Case Rep01t 
F01m (eCRF) and source documentation. Every effort should be made to complete the early 
termination study procedures and obse1vations as detailed in Appendix A at the time of 
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Subjects who discontinue Study Drug are encouraged to remain in the study. Subjects that 
discontinue treatment such as in cases where hemodialysis is held for > 2 weeks or stopped, or 
there is a change of dialysis modality (i.e., hemodialysis to peritoneal dialysis) or receive a renal 
transplant (See Section 6.2.2) are encouraged to complete the treatment and the post-treatment 
evaluation period visits unless consent is withdrawn. 
If the subject declines or is unable to participate in the post-treatment evaluation period, the 
fuvestigator should clarify what type of follow-up the subject is agreeable to, such as by 
telephone or through their treating physicians. At the very least, the subject's status at the end of 
the protocol defined study period should be asce1tained and documented wherever possible. The 
agreed means of follow-up should be documented in the subject's records and notified to the 
Sponsor. 
8.8 
Withdrawal of Subjects from the Study 
Subjects must be withdrawn from the study for any of the following: 
 
• 
Withdrawal of consent 
• 
The subject is unwilling or unable to comply with the protocol 
Other reasons for withdrawal of patients from the Study might include: 
• 
At the discretion of the fuvestigator for medical reasons 
• 
At the discretion of the fuvestigator or Sponsor for noncompliance 
• 
Significant protocol deviation 
All efforts will be made to complete and report the observations as thoroughly as possible up to 
the date of withdrawal. All information, including the reason for withdrawal from study, must be 
recorded in the eCRF. Any subject who withdraws consent to pa1ticipate in the study will be 
removed from further treatment and study obse1vation immediately upon the date of request. 
These subjects should be encouraged to complete the early termination study procedures and 
obse1vations at the time of withdrawal (Appendix A). 
For subjects withdrawn for reasons other than withdrawal of consent every effo1t should be made 
to complete the early termination study procedures and observations at the time of withdrawal 
(see Appendix A). 
 
8.9 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the subject's 
eCRF. Adverse events related to administration of these therapies or procedures must also be 
documented on the appropriate eCRF. 
8.9.1 
Concomitant Therapy 
A concomitant therapy is any non-protocol specified mug or substance (including over-the- 
counter medications, herbal medications and vitamin supplements) administered between the 
signing of informed consent and the last protocol specified Post-Treatment Evaluation Period 
visit (Appendix A). 


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Allowed Concomitant Therapy 
Any medications deemed necessary by the Investigator are allowed except those listed in the 
disallowed concomitant therapy. The use of stable doses of unfractionated heparin and low- 
molecular weight heparin during hemodialysis is allowed. 
Disallowed Concomitant Therapy 
Concomitant use of anticoagulant/antiplatelet agents (e.g., warfarin, dabigatran, rivaroxaban, 
clopidogrel) that may affect coagulation (except low dose aspirin(:::;100 mg/day) during 
Treatment and Post-treatment Evaluation Periods is not allowed. 
For subjects in the platelet function/activation subgroup, use of any anticoagulants or antiplatelet 
agents (other than aspirin) is not allowed. 
8.9.2 
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 of informed consent and last protocol-specified Post-Treatment Evaluation visit 
(Appendix A). 
 
8.10 
Treatment Compliance 
Compliance with Study Drng dosing is to be monitored and recorded in the eCRF by Study 
Center staff. 
 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING 
 
9.1 
Sponsor Review of Safety Information 
Safety infom1ation will be collected, reviewed, and evaluated by the Sponsor or designee in 
accordance with the Safety Management Plan and Medical Monitoring 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 ICH E6. Country-specific regulatory requirements will be followed 
in accordance with local country regulations and guidelines. 
Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) will be notified of 
any SAE according to applicable regulations. 
In addition to the Investigator's assessment of relatedness of SAEs to the Study Drug, the 
Sponsor or designee will evaluate the available information and perform an independent 
causality assessment of all reported SAEs. While the Sponsor may upgrade an Investigator's 
decision it is not permissible to downgrade the Investigator's opinion for the purposes of 
determining whether the SAE meets the definition of a SUSAR. 


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Appropriate personnel at the Sponsor or designee will unblind SUSARs for the pmpose 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. 
9.3 
Definitions 
 
9.3.1 
Adverse Event 
An adverse event (AE) can be any unfavorable and unintended sign (including an abn01mal 
laborato1y finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the AE is considered related to the medicinal 
(investigational) product. 
Adverse events are to be identified between study visits by evaluating components of the medical 
record that contain valid and verifiable claims about a medically untoward event. For 
hemodialysis subjects, this includes a complete review of changes in the dialysis prescription in 
the dialysis chaii orders section or inf01mation provided to the study staff directly by the subject. 
Dialysis treatment summaries (rnn-sheets) should be reviewed for pertinent information when 
indicated. 
9.3.2 
Adverse Drug Reaction and Unexpected Adverse Drug Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered adverse drug reactions (ADR). 
An unexpected ADR is any ADR, the nature or severity of which is not consistent with the 
applicable product information, e.g., Investigator's Brochure for an unapproved medicinal 
(investigational) product. 
 
9.3.3 
Serious Adverse Event (SAE) 
A SAE is any AE that in the view of either the Investigator or Sponsor, meets any of the 
following criteria: 
• 
Results in death 
• 
Is life threatening: that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered "life-threatening" if, in the view of 
either the Investigator or Sponsor, its occmTence places the subject at immediate risk of 
death. It does not include an AE or suspected adverse reaction that, had it occuned in a 
more severe fo1m, might have caused death 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
Hospitalization is defined as an admission of greater than 24 homs to a medical facility 
and does not always qualify as an AE 
• 
Results in a persistent or significant incapacity or substantial disrnption of the ability to 
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• 
Results in a congenital anomaly or bi.Ith defect in the offspring of the subject (whether 
the subject is male or female) 
• 
Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may also be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse 
 
9.3.4 
Adverse Event of Interest 
Adverse events of interest (AEol) includes both serious and non-serious events of MB and 
CRNMB, defined in Section 8.5.3 (Safety Monitoring for Bleeding Events). 
AEol are required to be reported by the Investigator to the Sponsor immediately, no more than 
24 hours of the Investigator's first knowledge of the event. 
 
9.4 
Monitoring and Recording Adve1·se 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 
AEs unless the pre-existing condition worsened to an extent not consistent with the natural 
history of the condition. 
In subjects with ESRD requiring dialysis, events due to abnormalities of serum electrolytes such 
as sodium, potassium, chloride, bicarbonate, calcium, and phosphorus, the anemia of chronic 
disease, and hypertension are considered pa1t of their underlying condition. In addition, 
mechanical complications of vascular accesses are common in subjects that requiI·e dialysis. 
Events that are consistent with the natural history ofESRD and the need for dialysis will not be 
considered AEs unless theiI·course or severity is atypical for this population or thought 
potentially due to the Study Drug (e.g., due to bleeding) in the opinion of the Investigator. The 
Investigator should always group signs and symptoms into a single term that constitutes a single 
unifying diagnosis if possible. 
9.4.1 
Reporting Requirements for Serious Adverse Events Using Electronic Case Report 
Forms (eCRFs) 
In the interest of subject safety, and in order to fulfill regulato1y requiI·ements, all SAEs 
(regardless of their relationship to Study Drug) should be repo1ted to the Sponsor or designee 
within 24 hours of the Study Center's first knowledge of the event. Similarly, all events that 
meet the criteria for Major or CRNMB (see definitions in Section 8.5.3) must also be repo1ted 
within 24 hours of the Study Center's first knowledge of the event. 
The collection of SAEs and Clinically-Relevant Bleeding events will begin after the subject 
signs the info1med consent fo1m and stops at the end of the subject's follow-up period which is 
defined as the last protocol specified Post-Treatment Evaluation Period visit. A SAE should be 
repo1ted using the electronic SAE submission fo1m whenever possible. In situations where the 


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electronic SAE submission is unavailable and the Investigator is reporting by telephone, it is 
important to speak to someone in person vs. leaving a message. 
For events that occur prior to Study Drng initiation, the Serious Adverse Event Reporting Form 
provided to Investigators should be completed and submitted to Ionis or its designee immediately 
(i.e., no more than 24 hours after learning of the event), either by faxing (using the fax cover 
sheet provided to Investi ators with countr -s ecific fax numbers) or by scanning and emailing 
the form to 
 
For events that occur after Study Drng initiation, Investigators should record all case details that 
can be gathered immediately (i.e., within 24 hours after learning of the event) on the Adverse 
Event eCRF and submit the report via the electronic data capture (EDC) system. A report should 
be automatically generated and sent to Ionis or designee by the EDC system. 
In the event that the EDC system is unavailable, the Serious Adverse Event Reporting Form 
provided to Investigators should be completed and submitted to Ionis or its designee immediately 
(i.e., no more than 24 hours after learning of the event), either by faxing (using the fax cover 
sheet provided to Investi ators with countr -s ecific fax numbers) or by scanning and emailing 
the form to 
Once the EDC system is available, all 
information will need to be entered and submitted via the EDC system. 
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 
Post-Treatment Evaluation visit will be evaluated by the Investigator and Sponsor. If the 
Investigator and Sponsor agree that 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 last protocol 
specified Post-Treatment Evaluation Period visit. 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 
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9.4.3.1 
Relationship to the Study Drug 
The event's relationship to the Study Drng (ISIS 416858 or placebo) is characterized by one of 
the following: 
• 
Related: There is clear evidence that the event is related to the use of Study Drng, 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 Drng (ISIS 416858 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 Drng (ISIS 416858 or placebo) administration and/or exposure suggests that a 
causal relationship is unlikely (For reporting purposes, Unlikely/Remote will be grouped 
together with Not Related) 
• 
Not Related: The event can be readily explained by the subject's underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator believes 
no relationship exists between the event and Study Drng (ISIS 416858 or placebo) 
 
9.4.3.2 
Severity 
The severity of AEs and SAEs will be graded based on criteria from the Common Te1minology 
Criteria for Adverse Events (CTCAE) Version 4.03, June 2010 (refer to Appendix D). Any AE 
not listed in Appendix D will be graded as follows: 
• 
Mild: The event is easily tolerated by the subject and does not affect the subject's usual 
daily activities 
• 
Moderate: The event causes the subject more discomfo1t and intenupts the subject's 
usual daily activities 
• 
Severe: The event is incapacitating and causes considerable interference with the 
subject's usual daily activities 
If the event is a SAE, then all applicable seriousness cliteria must be indicated (criteria listed in 
Section 9.3.3). 
9.4.3.3 
Action Taken with Study Drug 
Action taken with Study Drng (ISIS 416858 or placebo) due to the event is characterized by one 
of the following. 
• 
None: No changes were made to Study Drng (ISIS 416858 or placebo) administration 
and dose 
• 
Permanently Discontinued: Study Drng was discontinued and not resta1ted 
• 
Temporarily Interrupted, Restarted- Same Dose: Dosing was temporarily 
intenupted or delayed due to the AE and restarted at the same dose 


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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 Repo11 Fonn. Treatment should also be recorded on the concomitant 
treatment or ancilla1y procedures eCRF, as appropriate. 
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 one of the 
following: 
• 
AE Persists: Patient te1minates from the trial and the AE continues 
• 
Recovered: Patient recovered completely from the AE 
• 
Became Serious: The event became se1ious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
conesponding SAE) 
• 
Change in Severity (if applicable): AE severity changed 
If the event is a SAE, then the event's outcome is characterized by one of the following: 
• 
Ongoing: SAE continuing 
• 
Persists (as non-serious AE): Patient has not fully recovered but the event no longer 
meets serious c1iteria 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 recove1y 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 abno1mal laborato1y test results may, in the opinion of the Investigator, 
constitute or be associated with an AE. Examples of these include abno1mal laborat01y results 
that are associated with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, 
tetany due to hypocalcemia, or cardiac anhythmias due to hyperkalemia. Whenever possible, the 
underlying diagnosis should be listed in preference to abno1mal laborat01y values as AEs. 
Clinically-significant abn01malities 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 (or designee). Laboratory abn01malities deemed not clinically-significant 
(NCS) by the Investigator, or those associated with hemodialysis or ESRD (e.g., asymptomatic 
inild to moderate hyperkalemia, hyperphosphateinia, etc.) should not be repoded as AEs. 
Siinilarly, laborato1y abno1malities repoded as AEs by the Investigator should not be deemed 
NCS on the laborato1y sheet. 


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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/abn01mal laborat01y 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 a 
SAE, even if the subject is hospitalized; the Study Center must document all of the following: 
• 
The prescheduled or elective procedure or routinely scheduled treatment was scheduled 
(or was on a waiting list to be scheduled) prior to obtaining the subject's consent to 
participate in the study 
• 
The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the 
Investigator between the subject's consent to paiticipate in the study and the timing of the 
procedure or t1eatment 
• 
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 Drng (ISIS 416858 or placebo) enorsshould 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 Rep01t F01m. If the subject takes a dose 
of Study Drng (ISIS 416858 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 
Subjects must continue to use appropriate highly effective contraception with their paitners, or 
refrain from sexual activity, as described in Section 6.3.1. 
If a subject becomes pregnant or a pregnancy is suspected, or if a male subject makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately. An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first leaining of the occmTence of pregnancy. Follow-up 
inf01mation including delivery or termination is reported by designating as 'Follow-up' on the 
Pregnancy F01ms and rep01ted within 24 hours. 
Payment for all aspects of obstetrical cai·e, child or related care will be the subject's 
responsibility. 


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Female subjects: If a suspected pregnancy occurs while on the study (including follow-up), a 
pregnancy test will be perf01med. The subject with a confamed pregnancy will be immediately 
withdrawn from treatment with Study Drng. However, the subject will be encouraged to 
complete the post-treatment follow-up p01iion of the study to the extent that study procedures do 
not interfere with the pregnancy. Regardless of continued study pa1iicipation, the study 
physician will assist the subject in getting obstetrical care and the progress of the pregnancy will 
be followed until the outcome of the pregnancy is known (i.e., delive1y, elective te1mination, or 
spontaneous abo1iion). If the pregnancy results in the bilih of a child, the Study Center and 
Sponsor may require access to the mother and infant's medical records to obtain additional 
info1mation relevant to the pregnancy outcome. Follow-up will be performed to the extent 
pe1mitted by the applicable regulations and privacy considerations; e.g., pregnancy ICF may be 
required. 
Male subjects: The progress of the pregnancy of a male subject's paiiner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abo1iion). If the pregnancy results in the bi1ih of a child, the Study Center and Sponsor may 
follow-up with the mother and may request access to the mother and infant's medical 
records to obtain additional information relevant to the pregnancy and the newborn child. 
Follow-up will be perf01med to the extent permitted by the applicable regulations and privacy 
considerations, e.g., paliner ICF may be required. 
10. 
STATISTICAL CONSIDERATIONS 
 
10.1 
Study Endpoints, Subsets, and Covariates 
 
10.1.1 
Safety and Tolerability 
The primaiy safety outcome is the combination of MB and CRNMB during the treatment period 
(or early study terniination). For the subgroup of subjects evaluated for platelet function and/or 
activation, an analysis of pre- and post-treatment results with ISIS 416858 may be conducted and 
compared to treatment with placebo. 
The safety and tolerability of ISIS 416858 will be accessed by dete1mining the incidence and 
severity of AEs and will be evaluated by reviewing: 
• 
AEs (including bleeding events) 
• 
Vital signs and weight 
• 
Physical examination 
• 
Clinical laboratory tests 
• 
Coagulation parameters 
• 
Use of concomitant medications 


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10.1.2 
Pharmacodynamic Outcomes 
• 
Change from Baseline in FXI antigen and activity 
• 
Change from Baseline in aPTT 
• 
The extent and frequency of clotting on the dialysis filters and circuit 
 
10.1.3 
Exploratory Outcomes 
• 
Incidence of myocardial infarction (MI), stroke, systemic embolism, and cardiovascular 
(CV) mortality 
 
10.1.4 
Other Study Outcomes and Evaluations 
• 
Urea Reduction Ratio 
• 
PK 
 
10.2 
Sample Size Considerations 
The sample size was selected based on prior experience to ensure that the safety, tolerability and 
PK/PD relationships will be adequately assessed while minimizing unnecessary patient exposure. 
There is no statistical rationale for the selected sample size. 
 
10.3 
Populations 
Intent to Treat Population: All subjects randomized who have received at least 1 dose of Study 
Drng. 
Per Protocol Population: All subjects who are randomized without missing more than 2 doses 
during the first 12 weeks or more than 5 doses over the 26-week Treatment Period and who do 
not have any major protocol violations that would affect the interpretation or integrity of the 
study results. 
Safety Population: All subjects randomized who have received at least 1 dose of Study Drng. 
PK Population: All subjects who have received at least 1 dose of active Study Drng 
(ISIS 416858), and have at least 1 PK sample collected and analyzed with evaluable results. 
 
10.4 
Definition of Baseline 
Baseline for the routine clinical assessments of chemist:Iy and hematology, PD markers, 
assessment of clotting, PK assessments, vital signs and ECG for the study will be the last 
non-missing value prior to the first administration of Study Drug (ISIS 416858 or placebo) and 
prior to dialysis on Day 1 (Appendix A). If Day 1 values are not available, screening values will 
be used. For Urea Reduction Ratio, the BUN blood collections prior to dialysis as well as the 
post-dialysis sample on Day 1 will be used to establish baseline. 
 
10.5 
Interim Analysis 
No interim analysis is planned. However, dming the study, an unblinded interim analysis may 
be conducted to assess the safety, PK/PD, and explorato1y efficacy of the results. The analysis 
will be executed with conti·olled dissemination to ensme the integiity of ongoing data collection 


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while maintaining sufficient blinding in the study. Details of these controls will be described in 
the SAP. 
10.6 
Planned Methods of Analysis 
Descriptive summary analysis including 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. 
Safety and PD assessments will be performed on the Safety population. Exploratory efficacy 
and clotting assessment measures may be assessed on the Per Protocol population. 
10.6.1 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using descriptive statistics by 
tTeatment group. Subject randomization will be summarized by treatment group. The subject 
disposition will be summarized. All subjects emolled will be included in a summa1y of subject 
disposition. 
10.6.2 
Safety Analysis 
Treatment duration and amount of Study Drng (ISIS 416858 or placebo) received will be 
summarized by treatment group. Subject incidence rates of all AEs will be tabulated by the 
Medical Dictionary for Regulato1y Activities (MedDRA™) system organ class, and by 
MedDRA™ te1m. Tables and/or nanatives of treatment-emergent deaths, serious and significant 
AEs, including early withdrawals due to AEs, will also be provided. 
All treatment-emergent AEs, all treatment-emergent AEs potentially related to Study Drng, all 
treatment-emergent serious AEs, and all treatment-emergent serious AEs potentially related to 
Study Drng (ISIS 416858 or placebo) will be summarized. 
Laborato1y tests to ensure subject safety including chemistly panel, complete blood count with 
differential, coagulation panel, complement etc., will be summarized by study visits for each 
ti·eatment group. These safety va1iables will also be presented as change and percent change 
from Baseline over time after Study Drng (ISIS 416858 or placebo) administi·ation, as 
approp1iate. 
Vital sign and ECG measures will be tabulated by ti·eatment group. In addition, the number of 
subjects who experience abn01malities in clinical laboratory evaluations will be summarized by 
ti·eatment group. 
Incidence of bleeding events including the following will be tabulated by treatment: 
 
• 
MB 
• 
CRNMB 
• 
Minor bleeding 
• 
Combination of MB and CRNMB 


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Physical examination data will be provided in the data listing. Concomitant medications will be 
coded using World Health Organization (WHO) Drng dictionruy and summarized by treatment, 
ATC class and generic name. 
10.6.3 
Pharmacokinetic and lmmunogenicity Analysis 
10.6.3.1 
Pharmacokinetic Analysis 
Noncompa1tmental PK analysis ofISIS 416858 will be catTied out on each individual subject 
data set in the PK subgroup where plasma PK will be assessed following the first dose 
(single-dose PK) and last dose (steady-state PK) ofISIS 416858, whenever possible. The 
maximum observed mug concentration (Cmax) and the time taken to reach Cinax (Tmax) will be 
obtained directly from the concentration-time data. Partial areas under the plasma 
concentration-time curve from time zero (pre-dose) to the last observable concentration (AUCo-t) 
and dosing interval (AUC0-16shr) after SC administration of ISIS 416858 will be calculated using 
the linear-up log-down trapezoidal rnle. Apparent systemic (plasma) clearance at steady state 
after SC administration (CL.JP) will be calculated from CL.JP= Actual Dose/AUC0-16shr- 
For all evaluable subjects receiving ISIS 416858, plasma ISIS 416858 concentrations at trough 
during the Treatment Period and concentrations observed during the Post-Treatment Evaluation 
Period will be listed by dose, study day, time point, subject ID, anti-drug antibody (ADA) status, 
and summru·ized using descriptive statistics. The apparent plasma terminal elimination half-life 
ofISIS 416858 following the last administered dose will be calculated in each evaluable subject 
(when deemed possible by the PK scientist). 
Plasma PK parameters will be summarized using descriptive statistics. Other PK parameters, as 
appropriate, may be determined or calculated at the discretion of the PK scientist. Additional 
details regru·ding the PK analysis will be described in the SAP. 
Potential relationships between selected PD and plasma exposure measures (e.g., trough 
concentrations) may also be explored, where deemed appropriate. 
10.6.3.2 
lmmunogenicity Analysis 
Immunogenicity results (screen positive/negative, confirmed positive/negative or not evaluable, 
and when applicable, titer of anti-ISIS 416858 antibodies) before, during, and after treatment 
with Study Drug (ISIS 416858) (i.e., sample ADA status) will be listed. Subject ADA status 
(positive/negative or not evaluable) for all evaluable subjects, along with the study day that the 
first positive immunogenicity status emerged (Ttust, i.e., onset of ADA development), the last 
positive immunogenicity status observed (T1ast), the last ADA sample collection day, and subject 
- peak titer if applicable, will be listed by their treatment and study day. Subjects with positive 
anti-ISIS 416858 antibody status may be further classified (where applicable) as being either 
'persistent', 'transient', or 'not determinable', if deemed appropriate. 
Additionally, the sample and subject immunogenicity incidence (number) and incidence rate 
(percent) will be summarized as the total number and percent of evaluated subjects with antibody 
negative, positive, and unknown status by treatment and dose. Fmthermore, onset, titer over 
time, and peak titer of the ADA response, if applicable, will be summa1ized as median, quartiles 
(25% and 75%), and range by treatment and dose. 


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Additional details regarding the IM data analysis will be described in the SAP. 
 
10.6.4 
Pharmacodynamic Analysis 
Pharrnacodynamic analyses will be perfmmed in the safety population. Change and percent 
change in FXI activity and antigen levels, aPTT, PT, and INR will be tabulated over time. 
The extent and occmrence of clotting on the dialysis filters and circuit will be summarized 
descriptively by categmy scoring. 
Table 5 
Clotting Scale 
 
Inspection Site 
Category 1 
Category 2 
Category 3 
Category4 
Air Trap 
No clotting 
Fibrinous ring with no clot 
formation on venous 
chamber filter 
Clot formation on venous 
chamber 
Coagulated system 
(treatment cannot 
continue without new
setup) 
Dialyzer 
Clean dialyzer
Blood stripes affecting less 
than 5% of the fibers seen at 
the surface of the dialyzer 
Blood stripes affecting 5% or 
more of the fibers seen at the 
surface of the dialyzer 
Coagulated filter 
Note: 
Overall score is the highest of the individual component scores 
 
 
The relative occmTence of each clotting category will also be summarized from all obtained 
clotting assessments, whenever possible. Further details on the analysis of clotting assessments 
will be contained in the SAP. 
10.6.5 
Additional Exploratory Analyses 
Incidence of myocardial infarction (MI), stroke, systemic embolism, and cardiovascular (CV) 
mmtality will be explored. 
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 subject's participation in the trial, the Investigator is responsible for obtaining written 
informed consent from the subject after adequate explanation of the aims, methods, anticipated 
benefits, and potential hazards of the study and before any protocol-specific screening 
procedures or any Study Drng (ISIS 416858 or placebo) are administered. The subject must be 
given sufficient time to consider whether to pa1ticipate in the study. 
The acquisition of informed consent and the subject's agreement or refusal to notify his/her 
primary care physician should be documented in the subject's medical records and the infmmed 
consent form should be signed and personally dated by the subject and by the person who 
conducted the infmmed 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 


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required by institutional policy, and a copy of the signed consent form should be provided to the 
subject. 
11.2 
Ethical Conduct of the Study 
All applicable regulations and guidelines of cunent Good Clinical Practice (GCP) as well as the 
demands of national drug and data protection laws and other applicable regulatmy requirements 
must be followed. 
11.3 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed infonned consent fo1ms, other written subject info1mation, and 
any proposed adve1tising material must be submitted to the IRB for written approval. A copy of 
the written approval of the protocol and informed consent fo1m must be received by the Sponsor 
or designee before recruitment of subjects into the study and shipment of Study Drug 
(ISIS 416858 or placebo). 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 subjects into the study and shipment of Study Drug. The Investigator's Brochure 
must be submitted to the IRB for acknowledgement. 
The Investigator must submit to and, where necessary, obtain approval from the IRB for all 
subsequent protocol amendments and changes to the inf01med consent document. The 
Investigator should notify the IRB of deviations from the protocol in accordance with ICH E6 
Section 4.5.2. The Investigator should also notify the IRB of SAEs occmTing at the Study 
Center and other AE repmts 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 repmts, all IRB submissions and the IRB 
continuance of approval must be sent to the Sponsor or designee. 
11.4 
Subject Confidentiality 
The Investigator must ensure that the subject's confidentiality is maintained. On the case repmi 
fmms or other documents submitted to the Sponsor or designee, subjects should be identified by 
initials (if pe1mitted by local law) and a subject identification number only. Documents that are 
not for submission to the Sponsor or designee (e.g., signed info1med consent fmms) should be 
kept in strict confidence by the Investigator. 
In compliance with ICH E6, it is required that the Investigator and institution permit authorized 
representatives of the company, of the regulatory agency(s), and the IRB direct access to review 
the subject's original medical records for verification of study-related procedures and data. 
Direct access includes examining, analyzing, verifying, and reproducing any records and repo1ts 
that are impo1tant to the evaluation of the study. The Investigator is obligated to info1m and 
obtain the consent of the subject to pe1mit named representatives to have access to his/her 
study-related records without violating the confidentiality of the subject. 


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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 fuvestigator must be obtained for all protocol amendments and amendments 
to the infonned consent document. The regulat01y authority and IRB must be informed of all 
amendments and give approval for any amendments likely to affect the safety of the subjects or 
the conduct of the trial. The fuvestigator must send a copy of the approval letter from the IRB to 
the Sponsor or designee. 
12.2 
Study Termination 
The Sponsor or designee reserves the right to terminate the study. The fuvestigator reserves the 
right to terminate their participation in the study, according to the terms of the site contract. The 
fuvestigator/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 eCRF utilizing an EDC application will be used for this Study. 
 
The fuvestigator should ensure that all appropriately qualified persons to whom he/she has 
delegated trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities 
Form. 
Source documents are original documents, data, and records from which the subject's case rep01t 
form data are obtained. These include but are not limited to hospital records, clinical and office 
charts, laborat01y and pharmacy records, imaging, and conespondence. 
The fuvestigator 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 E6, suitable for inspection at any time by representatives from the Sponsor 
or designee and/or applicable regulat01y authorities. Elements should include: 
• 
Subject files containing completed case report forms, informed consents, and supp01ting 
copies of source documentation 
• 
Study files containing the protocol with all amendments, fuvestigator's Brochure, copies 
of pre-study documentation and all conespondence to and from the IEC/IRB and the 
Sponsor or designee 
• 
If drug supplies are maintained at the Study Center, proof of receipt, Sh1dy Drug Product 
Accountability Record, Return of Study Drug Product for Destruction, final Study Drug 
product reconciliation, and all drug-related coITespondence 
fu addition, all original source documents supporting entries in the case rep01i 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 fuvestigator. Should the Investigator wish to assign the study records to 
another pa1ty or move them to another location, he/she must notify the Sponsor or designee. 


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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 va1ious records of the hial (e.g., case report fo1ms and other pe1tinent data) provided that 
subject confidentiality is respected. 
The Sponsor monitor or designee is responsible for inspecting the case repo1t fo1ms 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 ve1ify the entries on the case repmt 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 repmt fo1ms, are resolved. 
In accordance with ICH E6 and the Sponsor's audit plans, this study may be selected for audit by 
representatives from the Sponsor's Clinical Quality Assurance Depa1tment (or designees). 
Inspection of Study Center facilities (e.g., pha1macy, drng storage areas, laboratolies) and review 
of study-related records will occur to evaluate the h"ial conduct and compliance with the 
protocol, ICH E6, and applicable regulato1y requirements. 
To ensure the quality of clinical data a clinical data management review will be perfo1med 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 repo1t fo1m. These 
signatures will indicate that the Principal Investigator inspected or reviewed the data on the case 
report fmm, the data queries, and the Study Center notifications, and agrees with the content. 
 
12.5 
Language 
Case report fo1ms must be completed in English. Generic and ti·ade names are acceptable for 
concomitant medications. Combination medications should be recorded using their trade name 
in English if possible. 
All wlitten info1mation and other material to be used by subjects and investigative staff must use 
vocabulaiy and language that are clearly understood. 
 
12.6 
Compensation for Injury 
The Sponsor maintains approp1iate insurance coverage for clinical h"ials and will follow 
applicable local compensation laws. Subjects will be ti·eated and/or compensated for any 
study-related illness/injury in accordance with the information provided in the Compensation for 
Injmy section of the Infmmed Consent document. 


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13. 
REFERENCES 
Altmann KH, Dean NM, Fabbro D, et al. Second generation of antisense oligonucleotides: from nuclease resistance 
to biological efficacy in animals. Chimia 1996; 50: 168-176. 
Asakai CR, Chung DW, Davie EW, et al. Factor XI deficiency in Ashkenazi Jews in Israel. N Engl J Med 191; 325: 
153-158. 
Biiller HR, Cohen AT, Davidson B, et al. Idraparinux versus standard therapy for venous thromboembolic disease. 
N Eng J Med 2007; 357: 1094-1104. 
Biiller HR, Bethune C, Bhanot S, et al. Factor XI antisense oligonucleotide for prevention of venous thrombosis. 
N Eng J Med 2014; 372: 232-240. 
Caskey FJ, Kramer A, Elliott RF, et al. Global variation in renal replacement therapy for end-stage renal disease. 
Nephrol Dial Transplant 2011; 26(8): 2604-2610. 
Chi KN, Eisenhauer E, Fazli L, et al. A Phase I pharmacokinetic and pharmacodynamic study of Ogx-011, a 
2'-methoxyethyl antisense oligonucleotide to clusterin, in patients with localized prostate cancer. J Natl Cancer Inst 
2005; 97: 1287-1296. 
Crooke ST arid Bennett CF. Progress in antisense oligonucleotide therapeutics. Ann Rev Pharmacol Toxicol 1996; 
36: 107-129. 
Elliott MJ, Zimme1man D, Holden RM. Warfarin anticoagulation in hemodialysis patients: A systematic review of 
bleeding rates. Am J Kidney Dis 2007; 50: 433-440. 
Geary RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis Factor-a phosphorothioate 2'-O-(2- 
methoxyethyl) modified ar1tisense oligonucleotide: comparison across species. Drng Metab Dispos 2003; 31: 
1419-1428. 
Go AS, Che11ow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular·events, and 
hospitalization. N Eng J Med 2004; 351: 1296-305. 
Herny SP, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased immune stimulation 
in nlice. J Pha1macol Exp Ther 2000; 292: 468-479. 
Inoue H, Hayase Y, Iwai S, et al. Sequence-dependent hydrolysis of RNA using modified oligonucleotide splints 
and RNase H. FEBS Letters 1987; 215: 327-330. 
Irish A. Hypercoagulability in renal transplant recipients. Identifying patients at tisk of renal allograft thrombosis 
and evaluating strategies for prevention. 2004; 4(3): 139-149. 
Jean-Baptiste E, Hassen-Khodja R, Haudebourg P, et al. Axillary loop grafts for hemodialysis access: nlidte1m 
results from a single-center study. J Vase Surg 2008; 47(1): 138-143. 
Kastelein JJP, Wedel MK, Baker BF, et al. Potent reduction of apolipoprotein Band low-density lipoprotein 
cholesterol by sh01t-te1m administration of an antisense inhibitor of apolipoprotein B. Circ 2006; 1729-1735. 
Kwoh TJ. An overview of the clinical safety expe1ience of first and second generation antisense oligonucleotides. 
In: Crooke ST, editor. Antisense Drug Technology: Principles, Strategies and Applications, 2nd Ed. Boca Raton, FL. 
Taylor & Francis Group 2008; 365-400. 
McKay RA, Miraglia LJ, Cummins LL, et al. Char·acte1ization of a potent and specific class of antisense 
oligonucleotide inhibitor of human protein kinase C-u expression. J Biol Chem 1999; 274: 1715-1722. 
Monia BP, Les1lik EA, Gonzalez C, et al. Evaluation of2'-modified oligonucleotides contaitling 2'-deoxy gaps as 
antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Provan D, Stasi R, Newland AC, et al. International consensus rep01t on the investigation and management of 
prima1y itnmune thrombocytopenia. Blood 2010; 115 (2): 168-196. 


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Salomon0, Steinberg DM, Seligsohn U. Vaiiable bleeding manifestations chai·acte1ize different types of surge1y in 
patients with severe Factor XI deficiency enabling pai·simonious use ofreplacement therapy. Haemophilia 2006; 12: 
490-493. 
Schild AF, Perez E, Gillaspie PE, et al. Atteriovenous fistulae vs. a1teriovenous grafts: a retrospective review of 
1,700 consecutive vasculai· access cases. J Vase Access 2008; 9(4): 231-235. 
Schumacher WA, Luettgen JM, Qua.ii ML, Seiffe1t DA. Inhibition of Factor XIa as a new approach to 
anticoagulation. Atterioscler Thromb Vase Biol 2010; 30(3): 388-392. 
Sewell KL, Geaiy RS, Baker BF, et al. Phase I trial ofISIS 104838, a 2'-methoxyethyl modified antisense 
oligonucleotide tai·geting tumor necrosis Factor-a. J Phaimacol Exp Ther 2002; 303(3): 1334-1343. 
Sood MM, Komenda P, Sood AR, et al. The intersection of 1isk ai1d benefit: Is wa1farin anticoagulation suitable for 
atrial fibrillation in patients on hemodialysis? Chest 2009; 136: 1128-1133. 
Sood MM, Bota SE, McAtthur E, et al. The three-year incidence of major hemonhage among older adults initiating 
chronic dialysis. Canadian J Kidney Health Dis 2014; 1: 21. 
Takamizawa Y, At·aki M, Yoshida N, et al. A case of sever Factor XI deficiency in patient undergoing hemodialysis 
without use of heparin. Blood Coagulation and Fib1inolysis 2014; 25: 898-899. 
Tan J, Bae S, Segal JB et al. Treatment of attial fib1illation with warfarin among older adults with end stage renal 
disease. J Nephrol 2017; Jan 24. 
Tonelli M, Muntner P, Lloyd A, et al. Risk of coronaiy events in people with chronic kidney disease compared with 
those with diabetes: a population-level coh01t study. Lancet 2012; 380: 807-814. 
Tveit DP, Hypolite IO, Hshieh P, et al. Chronic dialysis patients have high risk for pulmona1y embolism. Am J 
Kidney Dis 2002; 39(5): 1011-1017. 
Wizemann V, Tong L, Satayathum S, et al. Att·ial fib1illation in hemodialysis patients: clinical features and 
associations with anticoagulant therapy. Kidney Intl 2010; 77: 1098-1106. 
Zhang H, Lowenberg EC, Crosby JR, et al. Inhibition of the inttinsic coagulation pathway Factor XI by antisense 
oligonucleotides: a novel antitluombotic stt·ategy with lowered bleeding tisk. Blood 201O; 116: 4684-4692. 


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14. 
APPENDICES 


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Appendix A 
Schedule of Procedures 


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Appendix A Schedule of Procedures 
 
SCREENING 
Informed Consent 
(Must be signed before any 
Screening Procedures) 
Screening Period Procedures 
(28 Days) 
S-49 to S-14 
S-28 to S-14 
S-14 
S-7 
Visit Window (Days) 
±3 
Informed Consent 
X 
Inclusion/Exclusion 
X 
Medical History 
X 
HIV, Hepatitis B & C 
X 
FSH1 
X 
Serum Pregnancy2 
X 
Body Weight and Height 
(Height at Screening only) 
X 
Physical Exam 
X 
Vital Signs3•4 
X 
ECG (12-Lead) 
X 
Chemistry Panel5 
X 
Hematology5 
X 
Coagulation Panel 
X 
Inflammatory Panel 
X 
Adverse Events 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
Assessment of clotting6 
X 
SC Tolerability Assessment7 
X 
X 


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Treatment Period (26 Weeks) 
W1 
D1 
W1 
02• 
W1
D5
W2 
D8 
W2 
D12 
W3 
D15 
W4 
D22 
W5 
D29
W6 
D36 
W7 
D43 
W8 
D50 
W9 
D57 
W10 
D64 
W11 
D71 
W12 
D78 
W13 
D85 
W14 
D92 
W15 
D99 
W16 
D106
W17 
D113
Visit Window (Days) 
0 
±3 
Inclusion/Exclusion 
X 
Serum Pregnancy2 
X 
Body Weight and Height 
(Height at Screening only) 
X 
Physical Exam 
X 
X 
X 
Vital Signs3•4 
X 
x•.11
X 
X 
X 
X 
X 
X 
X4 
X 
X 
X 
X 
X 
X4 
X 
X 
X 
X 
X 
ECG (12-Lead) 
X 
X 
X 
Chemistry Panel5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urea Reduction Ratio, Kt/VS 
XA,B
XA,B 
XA,B
XA,B 
Hematology5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inflammatory Panel 
X 
X 
X 
X 
X 
X 
Platelet Function/Activation Test9 
X 
X 
Study Drug Administration10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
x•.11
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
x•.11
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of clotting6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Blood Sampling11 
XA,11X*.A.1
XA 
XA 
XA 
XA 
XA 
lmmunogenicity 
XA 
XA 
XA 
XA 


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Treatment Period (26 Weeks) Continued 
Post-Treatment Evaluation Period (12 Weeks) 
W18 
D120
W19 
D127
W20 
D134
W21 
D141 
W22 
D148
W23 
D155
W24 
D162
W25 
D169
W26 
D176
W26 
D177
W26 
D178
Early 
Term 
Tx 
W27 
D183
W28 
D190 
W30
D204
W32 
D218
W34 
D232
W36 
D246
W38 
D260
Early 
Term 
FU 
Visit Window {Days) 
±3 
±3 
±7 
Serum Pregnancy2 
X 
X 
X 
X 
Body Weight 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
Vital Signs3•4 
X4 
X 
X 
X 
X 
X 
X4 
X 
X 
X 
X 
X4 
X 
X 
X4 
X 
X 
ECG (12-Lead) 
X 
X 
X 
X 
Chemistry Panel5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urea Reduction Ratio, KW8 XA,B
XA,B
XA,B
XA,B
XA,B
XA,B
XA,B
XA,B 
Hematology5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inflammatory Panel 
X 
X 
X 
X 
X 
X 
X 
X 
Platelet Function/Activation 
Test9 
X 
X 
X 
Study Drug Administration10 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x·,11 x•.11
X 
x•.11
X 
X 
X 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
x•.11 x•.11
X 
x•.11
X 
X 
X 
X 
X 
X 
X 
Assessment of clotting6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK Blood Sampling11 
XA 
XA X*,A,11X*,A,1
XA X*,A,11
XA 
XA 
XA 
XA 
XA 
lmmunogenicity 
XA 
XA 
XA 
XA 


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Notes:  -If not specifically labeled, "X" means Pre-dialysis. Please refer to Appendix C for PK blood sampling procedures. A 10-minute time window applies to all 
procedures to allow for flexibility where multiple procedures are scheduled at the same time-Subjects who terminate the study early should complete the 
procedures indicated for the early term visit (Treatment or Post-Treatment Evaluation Period). For subjects that undergo renal transplant, please refer to 
Section 6.2.2. 
* 
Only applies to PK subgroup participants 
 
 
1 
Women!, 55 years who are not surgically sterile and have 12 months of spontaneous amenorrhea as confirmation of menopause 
2 
For all women, to be done once at S-28 to S-14. For women of child bearing potential who are not surgically sterile, a serum test at all time points after Day 1 
3 
BP, HR, RR, temp 
4 
BP at selected visits will be assessed 3 times, approximately 5 minutes apart 
5 
If the platelet value or liver enzyme tests are uninterpretable (e.g., due to clumping, hemolysis or quantity not sufficient) or missing a repeat blood specimen 
should be re-drawn as soon as possible (ideally within 7 days) and reviewed prior to dosing. Valid platelet counts must be conducted every 2 weeks and 
reviewed prior to dosing 
6 
The rate/frequency of clotting on the dialysis filters and circuit will be measured as an exploratory PD analysis 
7 
At screening Study Day S-14 (± 3) and S-7 (± 3), subjects should receive 2 noncontiguous SC injections of 0.75 ml saline. This injection will follow the same 
procedures as injections of the Study Drug (ISIS 416858 or placebo) during the treatment period. Specifically, during the screening period on Study Days 
S-14 (± 3) and S-7 (± 3), subjects should receive 2 noncontiguous SC injections of 0.75 ml saline immediately after dialysis when blood is returning to the 
subject but must be within 2 hours after dialysis (preferably within 15 minutes of the conclusion of dialysis) 
8 
Urea Reduction Ratio is a measure of serum BUN, collected before and just after dialysis, and is used to estimate the reduction in urea as a result of dialysis 
as a measure of efficiency of the dialysis procedure. In addition, the subject's most recent KW value, preferably single-pooled Kt/v if possible will be collected 
directly from the subject's chart 
9 
Platelet Function/Activation Subgroup Subjects only (approximately 12 subjects selected from each cohort), please refer to Section 3.1.1 
10 Study Drug will be administered SC after completion of hemodialysis which can be as soon as blood is returning to the patient but must be within 2 hours 
(preferably within 15 minutes of the conclusion of dialysis) 
11 Please refer to Appendix C for PK sampling procedures. For PK Subgroup Subjects (approximately 12 subjects selected from each cohort), please refer to 
Section 3.1.2 and Appendix C for PK subgroup sampling procedures 
 
 
Time: 
A 
Pre-dialysis 
B 
Post-dialysis 


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Appendix B 
List of Laboratory Analytes 


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Chemistry Panel 
Total protein 
Albumin 
Glucose 
Total bilirubin 
Direct (conjugated) bilirubin 
Indirect (unconjugated) bilirubin 
ALT 
AST 
GGT 
Other Tests 
Hepatitis B surface antigen 
Hepatitis C antibody 
HIV antibody 
FSH (women 
55 years with 
12 months of spontaneous 
amenorrhea only) 
Serum Pregnancy test 
Hematology 
Red blood cells 
Hemoglobin 
Hematocrit 
MCV, MCH, MCHC 
Platelets 
• 
• 
Count and Volume (MPV) 
(All Subjects) 
Function and/or Activation 
(Subgroup Subjects only) 
Urea Reduction Ratio 
BUN 
Inflammatory Markers1 
Hs-CRP 
D-dimer 
Beta-2-M 
Cardiac troponin I and T 
NT-proBNP 
Coagulation PaneP 
aPTT (sec) 
PT (sec) 
INR 
FXI antigen level and activity 
White blood cells (WBC) 
WBC Differential 
(% and absolute) 
Neutrophils 
Eosinophils 
Basophils 
Lymphocytes 
Monocytes 
Pharmacokinetics and 
lmmunogenicity 
ISIS 416858 levels in plasma2 
Anti-lSIS 416858 antibodies 
 
Appendix B 
List of Laboratory Analytes 
Based on emerging data from this or future studies, additional tests not listed below may be 
performed on stored samples to better characterize the profile of ISIS 416858 or other similar 
oligonucleotides. 
Additional Labs that May Be Perfo1med in the Event of a Platelet Count< 75,000/mm3 are listed 
in Section 8.5.2. 
 
1 
Other biomarkers may be measured, as needed; at the discretion of the Sponsor, samples will be collected and 
stored 
2 
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 !SIS 416858 with plasma 
constituents or PD biomarkers 
3 
Coagulation panel analytes are to be blinded except at Screening 


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Appendix C 
PK Sampling Schedule 


 
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PK Sampling Schedule for All Subjects: 
 
Period 
Treatment 
(26 Weeks) 
Post-Treatment Evaluation 
(12 Weeks) 
Week 
W1 
W2 
W5 
W9 
W13 
W17 
W22 
W26 
W28 
W30 
W34 
W38 
Study Day 
D1 
D8 
D29 
D57 
D85 
D113 
D148 
D176 
D190 
D204 
D232 
D260 
Blood 
Sampling 
Time 
Pre- 
dialysis 
Pre- 
dialysis 
Pre- 
dialysis 
Pre- 
dialysis 
Pre- 
dialysis 
Pre- 
dialysis 
Pre- 
dialysis 
Pre- 
dialysis 
Pre- 
dialysis 
Pre- 
dialysis 
Pre- 
dialysis 
Pre- 
dialysis 
 
 
Additional PK Sampling Schedule for PK Subgroup Only: 
 
D1 
D2 
D176 
D177 
D178 
D183 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
Blood: 
First sample Pre-dose (taken pre-dialysis) 
24-hour post the D1 First sample Pre-dose (taken pre-dialysis) 
24-hour post 
48-hour post 
168-hour post 
and rest of samples Post SC injection at 1, 
dose (pre-dialysis) 
and rest of samples Post SC injection at 1, D176dose 
D176dose 
D176dose 
2, 3, 4, 6, and 10 hours Post SC Injection 
2, 3, 4, 6, and 10 hours Post SC Injection 
(pre-dialysis) 
(pre-dialysis) 
(pre-dialysis) 
Note: 
PK Subgroup subjects will also complete all the regularly scheduled visits and PK sampling schedule 
The regular visit Day 8 PK sample constitutes the 168-hour sample for Day 1 of the PK Subgroup 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Amendment 1 
14 June 2018 
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Appendix D 
Grading Scale for Adverse Events Relating to 
Laboratory Abnormalities 


ISIS 416858-CS5 
Protocol 
CONFIDENTIAL 
Amendment 1 
14 June 2018 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
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76 of271 
 
 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Common Te1minology Criteria for Adverse Events (CTCAE) Version 4.03, 
June 2010. 
 
Adve.-se Event 
Mild 
Moderate 
Seve.-e 
Hematology 
aPTT prolonged 
>Ll..N - 1.5 X U...N 
>1.5 - 2.5 X U...N 
> 2 5 x ULN; hemorrhage 
Eosinophils increased• 
650 - 1,500 cell/mm3 
1,501 - 5,000 cell/rrrn3 
>5 000 cell/mni3 
Fibr"inogen decreased 
<1.0 - 0.75 x LLN or <25% decrease 
from baseline 
<O.75 - 0.5 x LLN or 25 - <50% 
decrease from baseline 
<O 5 x LLN or ::!::50% decrease 
from baseline 
Hemoglobin decreased 
(Anemia) 
Hemoglobin (Hgb) <LLN- 10.0 g/dL; 
<LLN - 6.2 nvnol/L; <LLN - 100 g/L 
Hgb <10.0 - 8.0 g/dL; 
<6.2 - 4.9 mmoVL; 
<100 - 80g/L 
Hgb<8.0 g/dL; 
<4 9 mmoVL; <80 g/L; 
transfusion indicated 
Hemoglobin inc,.eased 
Increase in >0 - 2 g/dL abo. .... e l.LNor 
aboYe baseline ifbaseline is abo\oe 
ULN 
Increase in >2 -4 g/dL above 
LLN or above baseline if 
baseline is aboveLLN 
lncr-ease in >4 g/dL above 
u..N or above baseline if 
baseline is abo'lle U...N 
11\R increased 
>1 - 1.5 X lJLN; 
> 1 - 1.5 times abovebaseline if on 
anticoagulation 
>1.5 - 2.5 X ULN; 
>1.5 - 2.5 times above baseline 
if on anticoagt.Jation 
>25xl.LN; 
>2 5 times above baseline if 
on anticoagulation 
L hocyte colllt 
decreased 
<LLN - 800/rrn.3; 
<LLN- 0.8 X 109/L 
<800 - 500/rr.-rl; 
<0.8 - 0.5 x 1o-9 /L 
<500 /mm3; 
<O 5 X 109 /L 
L hocyte colrlt 
increased 
- 
>4000/rrvn3 - 20,000/rrvn3 
>20,000/mm3 
Neutrophil coo..nt 
decreased 
<LLN - 1500/mm3; 
<LLN- 1.5 x 109 /L 
<1500 - 1OOO/mm3; 
<1.5- 1.0 x 1()9 /L 
<1000/mm3; 
<1 0 X 109 /L 
Platelet cotn: 
decreased 
<LLN - 75,000/rrvn3; 
<LLN- 75.0 x 109 /L 
<75,000 - 50,000/mm3; 
<75.0 - 50.0 X 109 /L 
<50,000/mm3; 
<50.0 X 109 /L 
White blood cell 
decreased 
<LLN - 3000/mm3; 
<LLN- 3.0 x 109 IL 
<3000 -2000/mm3; 
<3.0 - 2.0 X 109 /L 
<2000/mm3; 
<2 0 X 109 /L 
Chemistry 
Aciclosis 
pH <normal, but >=7.3 
- 
pH <7.3 
Alarine 
aminotransferase 
increased 
>Ll..N - 3.0 X U..N 
>3.0 - 5.0 X U..N 
>5 0 X Ll..N 
Alkaline phosphatase 
increased 
>LILN -2.5 x U..N 
>2.5 - 5.0 X U..N 
>5 0 X l.lLN 
Alkalosis 
pH >normal, but :!i:7.5 
- 
pH >7.5 
Aspartate 
aminotransferase 
increased 
>Ll..N - 3.0 X U..N 
>3.0 - 5.0 X U..N 
>5 0 X Ll..N 
Blood bilirubWl 
increased 
>LILN - 1.5 x U..N 
>1.5 - 3.0 X U..N 
>3 0 X l.lLN 
cardiac troponin I 
increased 
Levels above the upper limit of 
normal an::t below the level of 
myocardial ir,-arction as defined by 
the marufactl.rer 
- 
Levels consistent with 
myocardial infarctionas 
defined by the marufactlM"er 
cardiac troponin T 
increased 
Levels above the upper limit of 
normal an::t below the level of 
myocardial ir,-arction as defined by 
the marufactlM"er 
- 
Levels consistent with 
myocardial infarction as 
defined by the marufactlM"er 
CPI< inc.-eased• 
>U...N- <6 ULN 
6-10xl1-N 
>10 X ll_N 
GGT
increased 
>Ll..N -2.5 X U..N 
>2.5 - 5.0 X l.A..N 
>5 0 X Ll..N 
Hyperglycemia 
Fasting glucose value >LLN - 160 
mg/dL; Fasting glucose value >Ll..N - 
8.9 rrrnoVL 
Fasting glucose value >160 - 
250 mg/dL; Fasting glucose 
value >8.9 - 13.9 mmoVL 
>250 mg/dL; >13.9 mmoVL; 
hospitalization indicated 
Hypenricemia 
>ULN - 10 mg/dL (0.59 mmoVL) 
withol.i physiologic consequences 
- 
>ULN - 10 mg/dL (0.59 
rnnoVL) withphysiologic 
consequences 
Hypoalblnlinemia 
<LLN - 3 g/dL; 
<LLN- 30 g/L 
<3 - 2 g/dL; 
<30 - 20 g/L 
<2 g/dL; 
<20 g/L 
Hypoglycemia 
<LLN - 55 mg/dL; 
<LLN - 3.0 nvnol/L 
<55 mg/dL; 
<3.0 nvnol/L 
<40 mg/dL (<2.2 rrrnol/L) 
At-0 requires assistance of 
another person to actively 
administer carbohydrates, 
glucagon, or take other 
COrTective actionst: 
Lipase increased 
>U....N - 1 .5 x U..N 
>1.5- 2.0 x U..N 
>20xU...N 
Serunamylase 
increased 
>Ll..N - 1.5 x U..N 
>1.5- 2.0 X l.A..N 
>20xU...N 


ISIS 416858-CS5 
Protocol 
CONFIDENTIAL 
Amendment 1 
14 June 2018 
Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
75 
76 of271 
 
 
Continued 
 
Hyperglycemia 
Fastilg glucose value >ULN - 160 
mg/dl; Fasting glucose value >ULN - 
8.9 mmoVL 
Fasting glucose value >160 - 
250 mg/dl; Fasting glucose 
value>8.9- 13.9 rmiol/L 
>250mgldl;>13.9 mmol/L; 
hospitalizationindicated 
Hyperuricemia 
>ULN - 10 mg/dl (0.59 mmoVL) 
witoout physiologic car-sequences 
- 
>ULN - 10 mgldl (0.59 
mmol/L) with physiologic 
consequences 
Hypoalb1mioomia 
<LLN - 3 g/dl; 
<LLN-30g/L 
<3- 2 g/dl; 
<30 - 20 g/L 
<2g/dl; 
<20 g/L 
Hypoglycemia 
<LLN - 55 mg/dl; 
<LLN - 3.0 mmoVL 
<55mg/dl; 
<30 mmoVL 
<40 mg/dl (<2.2 mmoVL) 
All[)reqLires assistance of 
another personto actively 
admnster carbohydrates, 
glocagon, or take other 
correcti\e actions' 
Lpase increased 
>ULN- 1.5 x ULN 
>1 5-2.0 x ULN 
>2 0 x ULN 
Ser1mamylase 
increased 
>ULN- 1.5 x ULN 
>1 5-2.0 x ULN 
>2 0 x ULN 
 
'Grading for tt-isparameter is derived from theToxicity Grading Scale for Healthy Adut and Adolescent Vollllleers E..-olled in 
Preventive Vaccine Clinical Trials, Sept 2007 
•Grading for this parameter is derived from the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events Version 2.0, Nov 2014 
'Modified for consistency withthe ADAand Endocrine Society GLidelines (SeaqList ER, Anderson J, Ct-ilds B, et al. 
Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society. 
Diabetes Care 2013;36:1384-95)