A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ISIS 721744 in Patients With Hereditary Angioedema (HAE)
Phase: PHASE3
Conditions: Hereditary Angioedema
Sponsor: Ionis Pharmaceuticals, Inc.

 
 
A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of ISIS 
721744 in Patients With Hereditary Angioedema (HAE)   
 
NCT05139810 
 
12 Jul 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ionis.com 

 
WHAT IS HEREDITARY ANGIOEDEMA (HAE)?  
 
WHAT TREATMENT DID REASEARCHERS WANT TO STUDY? 
 
In this study, researchers tested a new medicine called donidalorsen.  
Donidalorsen is a type of medicine called an antisense oligonucleotide (ASO). An ASO 
medication helps reduce the amount of a specific protein in the body called prekallikrein 
by targeting the messenger RNA (mRNA) that contains instructions to make that protein. 
Donidalorsen specifically attaches to the mRNA that contains instructions for making 
PKK and signals the cell to break down that mRNA, reducing the amount of PKK 
produced. This reduction in PKK leads to a decrease in the amount of bradykinin, lowering 
the chance for swelling. 
 
 
 
 
Donidalorsen for Hereditary Angioedema 
 
Hereditary angioedema (HAE) is a rare and very serious disease that causes sudden and sometimes dangerous 
swelling in different parts of the body, like the face, throat, stomach, arms, and legs. The swelling is random, 
painful, comes back again and again, and can be life-threatening, especially if swelling occurs in the throat. These 
episodes of swelling can affect the quality of a patient’s life.  
This long-term illness is due to a problem in a specific gene called SERPING1that encodes a protein called C1 
inhibitor. This protein helps to control other proteins in our blood that manage inflammation and swelling. When 
the SERPING1gene does not work properly, the body either does not make enough of the C1 inhibitor protein 
(this form of the disease is called HAE-C1INH Type 1) or the protein does not work correctly (this form of the 
disease is called HAE-C1INH Type 2). When the body does not have enough working C1 inhibitor protein, it 
produces too much of a molecule called Factor XIIa. Too much Factor XIIa causes another protein called 
prekallikrein (PKK) to become active and turn into kallikrein. Kallikrein is an enzyme, which is a special protein that 
helps speed up reactions in the body. Kallikrein cuts a larger protein called high-molecular-weight kininogen into a 
substance called bradykinin. Large amounts of bradykinin cause blood vessels to widen and cause uncontrolled 
painful swelling of different body parts called HAE attacks. 
WHY WAS THIS STUDY DONE? 
Researchers wanted to know how well 
donidalorsen could effectively and safely help 
people suffering from HAE attacks compared with 
placebo. 
 
© Ionis Pharmaceuticals, Inc. 
Page 1 
What was the main question researchers 
wanted to answer? 
 
What was the number of Investigator-
confirmed HAE attacks (per 4 weeks) 
from Week 1 to Week 25 for participants 
receiving donidalorsen 80 mg every 4 
weeks compared with the pooled 
placebo group? 
HOW WAS THIS STUDY DESIGNED? 
• 
Phase 3: A Phase 3 study is one of the last studies to be conducted 
before a new medicine is submitted to government agencies for 
approval. The study tests the new medicine in participants with the 
disease to be treated by the medicine to see how well it works and to 
check for any medical problems. 
• 
Randomized: Participants were randomly assigned to a treatment in 
the study by chance (like rolling a specific number on a die). 
• 
Placebo-controlled: Patients were randomly assigned to receive 
placebo at the same amount and frequency as the patients receiving 
donidalorsen. All steps of the study were the same for all groups, 
allowing researchers to see differences between the medicine and 
no active treatment. 
• 
Double-Blind: Neither researchers nor participants knew if the 
participant was receiving the real medicine (donidalorsen) or a 
placebo. 
THANK YOU 
 
Ionis Pharmaceuticals, the sponsor, would like to sincerely thank the participants who took part in 
this study, “A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of 
ISIS 721744 in Patients With Hereditary Angioedema (HAE),”  
also known as the OASIS-HAE study. 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      
    
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
What happened during this study? 
 
Page 2 
© Ionis Pharmaceuticals, Inc. 
Participants were 
randomly assigned 
to treatment as 
soon as they 
experienced 
≥ 2 HAE attacks 
during this period 
and completed all 
evaluations that 
ensured they were 
eligible to enroll in 
the study. 
8-WEEK 
SCREENING 
PERIOD 
24-WEEK TREATMENT PERIOD 
13-WEEK FOLLOW 
UP PERIOD 
Participants were randomly assigned to receive 
donidalorsen or placebo: 
 
Donidalorsen Group 1 had 45 participants. 
 
Donidalorsen Group 2 had 23 participants.  
 
Placebo Group: had 22 participants. All patients who 
received placebo either every 4 weeks or every 8 weeks 
were pooled together for data analyses.  
 
Participants had check-up visits at certain weeks to see 
how they were doing and if they had any medical 
problems. They also filled out questionnaires to talk 
about any symptoms they experienced while receiving 
treatment. 
HOW WAS THIS STUDY DONE? 
Participants could  
attend check-up visits at 
the study clinic sites at 
weeks 4, 8, and 13 during 
the 13-week follow-up 
period, or could choose to 
enroll in the open-label 
extension (OLE) study 
(OASISplus, 
NCT05392114).  
 
The OLE study allowed 
participants to receive 
donidalorsen 80 mg even 
if they received placebo 
during this study follow-up 
period. 
WHAT TREATMENT DID PARTICIPANTS GET? 
Donidalorsen Group 1 
80 mg of donidalorsen every 
4 weeks by injection under the skin 
Donidalorsen Group 2 
80 mg donidalorsen every 
8 weeks by injection under the skin 
Placebo Group 
Injection under the skin every 4 
or 8 weeks (pooled together). 
Placebo is an inactive medicine 
used as a control in the study. 
WHO PARTICIPATED IN THIS STUDY? 
DEMOGRAPHICS 
90 total participants, at least 12 years of 
age or older, with a diagnosis of HAE-1 or 
HAE-2 who had at least 2 HAE attacks 
during the Screening Period 
 
Researchers at 39 clinics across 
Belgium, Bulgaria, France, 
Germany, Italy, Netherlands, 
Poland, Spain, United Kingdom, 
United States, Canada, Israel, and 
Turkey enrolled participants in this 
study. 
This study started in December 2021 
and ended in November 2023, so it 
lasted 23 months (almost 2 years). 
WHERE DID THIS STUDY TAKE PLACE AND FOR 
HOW LONG? 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
What were the results of this study? 
Donidalorsen – Group 1 
(donidalorsen 80 mg every 4 weeks) 
The average HAE attack rate (per 4 weeks) from Week 1 to 
Week 25 for Donidalorsen Group 1 (donidalorsen 80 mg 
every 4 weeks) was 0.44 compared with 2.26 for the 
placebo group. 
Answer to the main question asked: 
 
The Donidalorsen Group 1 had an 81% reduction in HAE attacks 
relative to the placebo group. This reduction was considered 
significant. 
The average HAE attack rate (per 4 weeks) from 
Week 1 to Week 25 for Donidalorsen Group 2 
(donidalorsen 80 mg every 8 weeks) was 1.02 
compared with 2.26 for the placebo group. The 
Donidalorsen Group 2 had a 55% reduction in 
HAE attacks relative to the placebo group. This 
reduction was considered significant.  
 
Overall, the results show that donidalorsen 80 
mg administered every 4 weeks or every 8 
weeks significantly reduced the number of HAE 
attacks (per 4 weeks) compared with the 
placebo group. 
Donidalorsen – Group 2 
(donidalorsen 80 mg every 8 weeks) 
WHAT MEDICAL PROBLEMS DID PARTICIPANTS HAVE DURING THE STUDY? 
 
Page 3 
© Ionis Pharmaceuticals, Inc. 
DID PARTICIPANTS HAVE ANY 
SERIOUS MEDICAL PROBLEMS 
RELATED TO THE MEDICINE 
DURING THE STUDY? 
No serious medical problems 
related to donidalorsen were 
experienced by participants. 
 
The most common, not 
serious, medical problems 
reported were injection-site 
reactions and headaches. 
Medically Confirmed Number of HAE Attacks (Per 
4 Weeks) from Week 1 to Week 25 
Average HAE Attack Rate (Per 4 Weeks) from Week 1 to Week 25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Where can I learn more about this study? 
HOW HAS THIS STUDY HELPED PEOPLE WITH HAE AND RESEARCHERS? 
Researchers look at the results of many studies to decide which treatments work and are 
safest for participants. This summary gives the results of 90 participants in a single study. 
Other studies may have more participants and may give different results. 
 
Overall, researchers learned that donidalorsen at a dose of 80 mg taken every 4 weeks or 
every 8 weeks made a difference in reducing HAE attack rates compared with placebo. 
   
Researchers also found no serious safety concerns with donidalorsen under the conditions 
of this study.  
 
The results from this study support the use of donidalorsen as a possible ongoing 
(prophylactic) treatment to reduce the number of HAE attacks for people living with HAE. 
Findings from this study may be used in other studies to learn more about the use of 
donidalorsen in participants with HAE. 
 
ARE THERE PLANS FOR FURTHER STUDIES? 
Further clinical studies with donidalorsen are ongoing at this time. 
You can find them by looking up the following NCT numbers on ClinicalTrials.gov: 
• 
NCT05392114 
• 
NCT04307381 
• 
NCT06415448 
WHERE CAN I LEARN MORE ABOUT THIS STUDY?  
 
Page 4 
© Ionis Pharmaceuticals, Inc. 
Sponsor Ionis Pharmaceuticals, Inc. 
Treatment Studied Donidalorsen 
Protocol Number of Study 
ClinicalTrials.gov Study Number 
European Study Number (EudraCT) 
 
Official Title of this Study 
 
 
 
 
721744-CS5 
NCT05139810 
2021-002571-19 
 
A Phase 3 Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy 
and Safety of ISIS 721744 in Patients 
With Hereditary Angioedema (HAE)   
Dates of this Study 
 
Journal Article of this Study 
December 2021 to November 2023 
Riedl, MA, et al. Efficacy and Safety of 
Donidalorsen for Hereditary 
Angioedema. The New England Journal 
of Medicine. 2024. 
Date of this Report 18 October 2024 
IONIS: A Force For Life 

 
 
 
 
 
IONIS PHARMACEUTICALS, INC. 
 
ISIS 721744-CS5 
 
A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of ISIS 721744 in Patients with Hereditary 
Angioedema (HAE) 
 
Amendment 2 – 12 July 2022 
 
EudraCT No:  2021-002571-19 
 
Trial Sponsor: 
Ionis Pharmaceuticals 
2855 Gazelle Court 
Carlsbad, CA 92010 
Telephone Number:  760-603-4665 
Fax Number:  760-603-2625 
 
Key Sponsor Contact and 
Signatory: 
 
 
 
 
 
 
Sponsor Medical Monitor: 
 
 
 Clinical Development 
2855 Gazelle Court 
Carlsbad, CA 92010 
 
 
 
 
 
Clinical Development 
2855 Gazelle Court 
Carlsbad, CA 92010 
 
 
 

ISIS 721744-CS5 
CONFIDENTIAL 
Amendment 2 
Protocol 
 
12 July 2022 
 
2 
ISIS 721744-CS5 
Protocol Amendment 2 
 
EudraCT No:  2021-002571-19 
 
Clinical Phase:  3 
 
A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of ISIS 721744 in Patients with Hereditary 
Angioedema (HAE) 
 
 
Protocol History 
Original Protocol: 
16 June 2021 
Amendment 1: 
1 October 2021 
 
 
 
 
Sponsor 
Ionis Pharmaceuticals, Inc. 
Carlsbad, CA 92010 
 
See electronic signature and date attached at end of document 
 
  
 Clinical Development 
  
 
Confidentiality Statement 
This document contains confidential information of Ionis Pharmaceuticals, Inc.  that must not be disclosed to anyone 
other than the recipient study staff and members of the independent ethics committee, institutional review board, or 
authorized regulatory agencies.  This information cannot be used for any purpose other than the evaluation or 
conduct of the clinical investigation without the prior written consent of Ionis Pharmaceuticals, Inc. 

ISIS 721744-CS5 
CONFIDENTIAL 
Amendment 2 
Protocol 
 
12 July 2022 
 
3 
Protocol Signature Page 
 
Protocol Number: 
ISIS 721744-CS5 
Protocol Title: 
A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of ISIS 721744 in Patients with Hereditary 
Angioedema (HAE) 
Amendment:  
2 
Date:  
 
12 July 2022 
 
I hereby acknowledge that I have read and understand the attached clinical protocol, identified 
above, and agree to conduct the study as described herein. 
I agree to comply with the International Conference on Harmonization Tripartite Guideline on 
Good Clinical Practice and the Declaration of Helsinki. 
I agree to ensure that the confidential information contained in this document will not be used for 
any purpose other than the evaluation or conduct of the clinical investigation without the prior 
written consent of Ionis Pharmaceuticals, Inc.   
 
 
 
 
 
Investigator’s Signature 
 
 
 
Investigator’s Name (please print) 
 
Date (DD Month YYYY) 
 
 
 

ISIS 721744-CS5 
CONFIDENTIAL 
Amendment 2 
Protocol 
 
12 July 2022 
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT .........................................................................................................9 
EXECUTIVE SUMMARY ...........................................................................................................13 
STUDY DESIGN AND TREATMENT SCHEMA ......................................................................17 
STUDY GLOSSARY ....................................................................................................................18 
1. 
OBJECTIVES AND ENDPOINTS ............................................................................21 
1.1. 
Objectives ...................................................................................................................21 
1.1.1. 
Primary Objective .......................................................................................................21 
1.1.2. 
Secondary Objectives .................................................................................................21 
1.1.3. 
Safety Objectives ........................................................................................................21 
1.1.4. 
Exploratory Objectives ...............................................................................................21 
1.2. 
Study Endpoints ..........................................................................................................21 
1.2.1. 
Primary Endpoint ........................................................................................................21 
1.2.2. 
Secondary Endpoints ..................................................................................................21 
1.2.3. 
Safety Endpoints .........................................................................................................22 
1.2.4. 
Exploratory Endpoints ................................................................................................22 
2. 
BACKGROUND AND RATIONALE .......................................................................22 
2.1. 
Overview of Disease ...................................................................................................22 
2.2. 
Therapeutic Rationale .................................................................................................23 
2.3. 
ISIS 721744 ................................................................................................................23 
2.3.1. 
Mechanism of Action .................................................................................................23 
2.3.2. 
Chemistry ....................................................................................................................24 
2.3.3. 
Preclinical Experience ................................................................................................25 
2.3.4. 
Clinical Experience .....................................................................................................25 
2.4. 
Rationale for Dose and Schedule of Administration ..................................................27 
2.5. 
Benefit-Risk Assessment ............................................................................................28 
2.5.1. 
Overall Assessment of Benefit:Risk ...........................................................................28 
2.5.2. 
Additional Risks During the COVID-19 Pandemic ...................................................28 
3. 
EXPERIMENTAL PLAN ..........................................................................................29 
3.1. 
Study Design ...............................................................................................................29 
3.2. 
Number of Study Centers ...........................................................................................29 
3.3. 
Number of Patients .....................................................................................................29 

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3.4. 
Overall Study Duration and Follow-up ......................................................................29 
3.4.1. 
Screening ....................................................................................................................29 
3.4.2. 
Treatment ....................................................................................................................30 
3.4.3. 
Post-Treatment ............................................................................................................30 
3.5. 
End-of-Study ...............................................................................................................30 
3.6. 
Data and Safety Monitoring Board or Independent Data Monitoring 
Committee ...................................................................................................................30 
4. 
PATIENT ENROLLMENT ........................................................................................31 
4.1. 
Screening ....................................................................................................................31 
4.2. 
Randomization ............................................................................................................31 
4.3. 
Replacement of Patients .............................................................................................31 
4.4. 
Unblinding of Treatment Assignment ........................................................................31 
5. 
PATIENT ELIGIBILITY ...........................................................................................32 
5.1. 
Inclusion Criteria ........................................................................................................32 
5.2. 
Exclusion Criteria .......................................................................................................33 
6. 
STUDY PROCEDURES ............................................................................................35 
6.1. 
Study Schedule ...........................................................................................................35 
6.1.1. 
Screening ....................................................................................................................35 
6.1.2. 
Treatment Period ........................................................................................................35 
6.1.3. 
Post-Treatment Period ................................................................................................36 
6.2. 
Study/Laboratory Assessments ...................................................................................37 
6.2.1. 
Laboratory Assessments .............................................................................................37 
6.2.2. 
Physical Exams and Vital Signs .................................................................................37 
6.2.3. 
Electrocardiography ....................................................................................................38 
6.2.4. 
Pharmacokinetic Sampling .........................................................................................38 
6.2.5. 
Collection of Hereditary Angioedema Attack Details ................................................38 
6.2.6. 
Patient-Reported Outcomes ........................................................................................39 
6.2.6.1. 
Angioedema Quality of Life (AE-QoL) Questionnaire ..............................................39 
6.2.6.2. 
Angioedema Control Test (AECT) Questionnaire .....................................................39 
6.2.6.3. 
Angioedema Activity Score (AAS) ............................................................................39 
6.2.6.4. 
Additional PROs .........................................................................................................40 
6.3. 
Restriction on the Lifestyle of Patients .......................................................................40 
6.3.1. 
Contraception Requirements ......................................................................................40 

ISIS 721744-CS5 
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6.4. 
Emergency Provisions ................................................................................................41 
7. 
STUDY DRUG ...........................................................................................................42 
7.1. 
Study Drug Description ..............................................................................................42 
7.2. 
Packaging and Labeling ..............................................................................................43 
7.3. 
Study Drug Accountability .........................................................................................43 
8. 
TREATMENT OF PATIENTS ..................................................................................43 
8.1. 
Study Drug Administration.........................................................................................43 
8.2. 
Other Protocol-Required Drugs ..................................................................................43 
8.3. 
Other Protocol-Required Treatment Procedures ........................................................44 
8.4. 
Treatment Precautions ................................................................................................44 
8.5. 
Safety Monitoring Rules .............................................................................................44 
8.5.1. 
Safety Monitoring Rules for Liver Chemistry Tests ..................................................44 
8.5.2. 
Safety Monitoring Rules for Renal Function Test Results .........................................46 
8.5.3. 
Safety Monitoring Rules for Platelet Count Results...................................................46 
8.5.4. 
Safety Monitoring for Bleeding Events ......................................................................48 
8.6. 
Stopping Rules ............................................................................................................48 
8.6.1. 
Stopping Rules for Liver Chemistry Elevations .........................................................49 
8.6.2. 
Temporary Stopping Rules for Renal Function Test Results .....................................49 
8.6.3. 
Stopping Rules for Platelet Count Results ..................................................................49 
8.6.4. 
Stopping Rules for Bleeding Events ...........................................................................49 
8.7. 
Adjustment of Dose and/or Treatment Schedule ........................................................50 
8.8. 
Discontinuation of Study Drug/Treatment .................................................................50 
8.8.1. 
Follow-up Visits for Early Termination from Treatment Period or 
Post-Treatment Period ................................................................................................50 
8.8.2. 
Temporary Pause/Safety Review ................................................................................51 
8.9. 
Withdrawal of Patients from the Study Procedures ....................................................51 
8.10. 
Concomitant Therapy and Procedures ........................................................................51 
8.10.1. 
Concomitant Therapy .................................................................................................52 
8.10.2. 
Concomitant Procedures .............................................................................................52 
8.11. 
Treatment Compliance ................................................................................................52 
9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING .....................53 
9.1. 
Sponsor Review of Safety Information ......................................................................53 
9.2. 
Regulatory Reporting Requirements ..........................................................................53 

ISIS 721744-CS5 
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9.3. 
Definitions ..................................................................................................................54 
9.3.1. 
Adverse Event .............................................................................................................54 
9.3.2. 
Adverse Drug Reaction and Suspected Unexpected Adverse Drug Reaction ............54 
9.3.3. 
Serious Adverse Event (SAE) ....................................................................................55 
9.3.4. 
Adverse Event of Special Interest (AESI) ..................................................................55 
9.4. 
Monitoring and Recording Adverse Events ...............................................................56 
9.4.1. 
Serious Adverse Events (SAE) ...................................................................................56 
9.4.2. 
Non-Serious Adverse Events ......................................................................................56 
9.4.3. 
Evaluation of Adverse Events (Serious and Non-Serious) .........................................56 
9.4.3.1. 
Relationship to the Study Drug...................................................................................57 
9.4.3.2. 
Severity .......................................................................................................................57 
9.4.3.3. 
Action Taken with Study Drug ...................................................................................57 
9.4.3.4. 
Treatment Given for Adverse Event ...........................................................................58 
9.4.3.5. 
Outcome of the Adverse Event ...................................................................................58 
9.4.3.6. 
Follow-up of Adverse Event .......................................................................................59 
9.5. 
Procedures for Handling Special Situations ...............................................................59 
9.5.1. 
Abnormalities of Laboratory Tests .............................................................................59 
9.5.2. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments ................59 
9.5.3. 
Dosing Errors ..............................................................................................................60 
9.5.4. 
Contraception and Pregnancy .....................................................................................60 
10. 
STATISTICAL CONSIDERATIONS .......................................................................61 
10.1. 
Stratification, Subsets, and Covariates .......................................................................61 
10.2. 
Sample Size Considerations .......................................................................................61 
10.3. 
Populations .................................................................................................................62 
10.4. 
Definition of Baseline .................................................................................................62 
10.5. 
Interim Analysis, Multiplicity, and Early Stopping Guidelines .................................62 
10.6. 
Planned Methods of Analysis .....................................................................................63 
10.6.1. 
Demographic and Baseline Characteristics ................................................................63 
10.6.2. 
Safety Analysis ...........................................................................................................63 
10.6.3. 
Efficacy Analysis ........................................................................................................64 
10.6.3.1. 
Primary Efficacy Analysis ..........................................................................................64 
10.6.3.2. 
Secondary Efficacy Analysis ......................................................................................64 

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10.6.4. 
Pharmacokinetic Analysis ..........................................................................................65 
10.6.5. 
Pharmacodynamic Analysis ........................................................................................65 
10.6.6. 
Additional Analyses ....................................................................................................65 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS ...........................................66 
11.1. 
Informed Consent and Assent .....................................................................................66 
11.2. 
Ethical Conduct of the Study ......................................................................................66 
11.3. 
Independent Ethics Committee/Institutional Review Board ......................................66 
11.4. 
Patient Confidentiality ................................................................................................67 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS ..............................................67 
12.1. 
Protocol Amendments ................................................................................................67 
12.2. 
Study Termination ......................................................................................................67 
12.3. 
Study Documentation and Storage .............................................................................68 
12.4. 
Study Monitoring ........................................................................................................68 
12.5. 
Language .....................................................................................................................69 
12.6. 
Compensation for Injury .............................................................................................69 
13. 
REFERENCES ...........................................................................................................70 
14. 
APPENDICES ............................................................................................................72 
APPENDIX A.  SCHEDULE OF VISITS AND PROCEDURES ..............................................73 
APPENDIX B.  LIST OF LABORATORY ANALYTES ..........................................................77 
APPENDIX C.  PK SAMPLING SCHEDULE ...........................................................................79 
APPENDIX D.  GRADING SCALE FOR ADVERSE EVENTS RELATING TO 
LABORATORY ABNORMALITIES ..............................................................81 
APPENDIX E.  PATIENT REPORTED OUTCOME ASSESSMENTS ....................................85 
 
 
LIST OF FIGURES 
Figure 1: 
Design of ISIS 721744, a GalNAc-Conjugated Chimeric 2ʹ-MOE 
Phosphorothioate/Phosphate Oligonucleotide (MOE Gapmer) ..................................25 
 
 
LIST OF TABLES 
Table 1: 
Study Drug Characteristics .........................................................................................43 
Table 2: 
Actions in Patients with Confirmed Low Platelet Count ............................................47 

ISIS 721744-CS5 
CONFIDENTIAL 
Amendment 2 
Protocol 
 
12 July 2022 
 
9 
PROTOCOL AMENDMENT 
 
Protocol Number: 
ISIS 721744-CS5 
Protocol Title: 
A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of ISIS 721744 in Patients with Hereditary 
Angioedema (HAE) 
Amendment Number: 
2 
Amendment Date: 
12 July 2022 
 
The following modifications to Protocol ISIS 721744-CS5, dated 12 July 2022, have been made.   
The purpose of this protocol amendment is to implement the following modifications to Protocol 
ISIS 721744-CS5, Amendment 1, dated 1 October 2021, predominantly around contraceptive use 
as well as administrative changes and updates. 
Minor changes (not included in the list of changes below) have been made throughout the 
protocol to correct errors 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 summary list of changes to the protocol.   
Protocol 
Section 
Description of Change  
(Additions in bold, deletions in strikethrough) 
Rationale 
Executive 
Summary 
The hierarchical testing order sequence for the secondary 
endpoints is the order will be specified in which they are 
listed in the secondary endpoints section above SAP. 
Clarification for 
statistical analysis. 
Executive 
Summary 
Section 10.6.3.1  
the time normalized run-in period attack rate (continuous) as 
a covariate, and the logarithm of time in month (days from 
first dose date to 28 days after last dose administration 
divided by 28) that each patient was observed during the 
period from Week 1 to Week 25 will be used as an offset 
variable. 
Clarification for 
statistical analysis. 
Section 1.2.2  
The number of Investigator-confirmed HAE attacks 
requiring acute HAE therapy from Week 5 to Week 25 
compared to placebo 
Correction of 
inconsistency in the 
protocol. 
Section 3.4.1  
A patient may be randomized after fewer than 56 days from 
the screening visit if the patient experiences > ≥ 2 HAE 
attacks 
Clarification on how 
many attacks are 
required for a patient 
to be randomized. 
Section 5.1  
6d).  If engaged in sexual relations of childbearing potential, 
agree to use acceptable highly effective contraceptive 
methods (refer to Section 6.3.1) from the time of signing the 
ICF and, as applicable, assent form until at least 24 weeks 
after the last dose of Study Drug (ISIS 721744 or placebo) 
7.  Male patients must be surgically sterile or, if engaged in 
sexual relations with a female of childbearing potential, the 
patient must agree to use an acceptable highly effective 
contraceptive method (refer to Section 6.3.1) 
The reproductive 
toxicity study 
performed in mice 
(combined Seg I and 
II) indicated no 
ISIS 721744-related 
effects on fertility or 
embryo/fetal 
development. 

ISIS 721744-CS5 
CONFIDENTIAL 
Amendment 2 
Protocol 
 
12 July 2022 
 
10 
Protocol 
Section 
Description of Change  
(Additions in bold, deletions in strikethrough) 
Rationale 
Section 5.2  
14  Recent history (3 years) of, or current drug or alcohol 
abuse 
Clarification to 
exclude patients with 
alcohol or drug abuse 
Section 6.2.2  
Height will be measured at Screening and for pediatric 
patients at Week 25. 
Added collection of 
Height at Treatment 
Study Week 25 for 
pediatric patients.  
Section 6.2.3  
Electrocardiography will be recorded per the standard 
practice of the Study Center.   
Electrocardiography will be performed in triplicate. 
Correction of 
inconsistency in the 
protocol.  
Section 6.3.1  
All male patients and women of childbearing potential 
(WOCBP) must refrain from sperm/egg donation and either 
be abstinent† or practice effective acceptable contraception 
from the time of signing the informed consent and, as 
applicable, assent form until at least 24 weeks after their last 
dose of Study Drug.   
For male patients engaged in sexual relations with a female 
of childbearing potential, if their female partner is using 
acceptable highly effective contraception from the time of 
the patient signing the informed consent and, as applicable, 
assent until at least 24 weeks after the patient’s last dose of 
Study Drug, then it is not required for the male patient to also 
use an highly effective acceptable contraceptive method. 
For the purposes of the study, highly effective acceptable 
contraception is defined as follows: 
For male patients: 
 Acceptable highly effective male contraception 
includes a vasectomy with negative semen analysis at 
Follow-up, surgically sterile via bilateral 
orchidectomy, abstinence†, condom with 
spermicide or the non-pregnant female partner of 
child-bearing potential uses an acceptable highly 
effective contraceptive method (defined below) 
 Male patients with partners that are pregnant must use 
condoms as contraception to ensure that the fetus is 
not exposed to the Study Drug  
For female patients and female partners of male patients, 
highly effective acceptable contraception methods comprise: 
The reproductive 
toxicity study 
performed in mice 
(combined Seg I and 
II) indicated no 
ISIS 721744-related 
effects on fertility or 
embryo/fetal 
development. 
 
 

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Protocol 
Section 
Description of Change  
(Additions in bold, deletions in strikethrough) 
Rationale 
Section 6.3.1  
Surgical sterilization (e.g., bilateral tubal occlusion, 
hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy), hormonal contraception associated with 
inhibition of ovulation (combined estrogen and progestogen 
containing, or progestogen-only [female patients with HAE] 
or combined estrogen and progesterone [female partners 
of male patients]), intrauterine contraception device or 
intrauterine hormone-releasing system or a vaginal ring (as 
long as the patient has been using this contraceptive 
method for at least 3 months before Screening) or 
vasectomized partner with negative semen analysis at 
follow-up, male or female condom with spermicide; or 
cap, diaphragm, or sponge with spermicide.  Female 
patients with HAE cannot use estrogen containing oral, 
subcutaneous, or transdermal contraceptives in this 
study. 
This clarification is to 
note that this 
exclusion was 
intended for oral 
hormonal therapy, 
and not for 
intrauterine or 
intravaginal 
estrogens. There is 
significantly more 
systemic absorption 
with oral therapy and 
the purpose of this 
exclusion criteria was 
to prohibit that use. 
Section 8.6.2  
UPCR >1000 mg/g, Proteinuria, dipstick 2 + (confirmed by 
dipstick retest and then further confirmed a quantitative total 
urine protein measurement of > 1.0 g/24 hours 
Updating to a more 
accurate lab measure. 
Section 10.4  
Run-in period is defined as the period from screening to 
the last day prior to Study Day 1. 
For Investigator-confirmed HAE attacks, the baseline 
rate, i.e., run-in period Investigator-confirmed HAE 
attack rate, will be calculated for each patient as number 
of Investigator-confirmed HAE attacks occurred during 
the run-in period divided by the number of days 
contributed to the run-in period multiplied by 28 days. 
Clarification of 
statistical analysis. 
Section 10.5  
Final analyses will be conducted after the End of 
Treatment period when all patients complete Week 25 
visit, stay in the study for at least 25 weeks since the 
Study Day 1 or withdraw from the study before 25 weeks 
from the Study Day 1. Study results with continuing 
collected post-treatment data will be updated at the End 
of Study. 
Clarification that we 
will perform the final 
analysis before the 
follow-up period is 
completed. 
Footnote 
Table 2  
The suitability of the patient for reduced, interrupted and/or 
continued dosing will be determined by the Investigator or 
designee in consultation with the Medical Monitor 
Dose reduction is not 
allowed per protocol. 
Appendix A  
Study Week 
Screen 
Treatment 
-8 to -1 
25 
Study Day 
-56 to -1 
169/ET-L3 or 
Tx-ET4 
Height 
X 
X20 
20 For pediatric patients only. 
Added collection of 
Height at Treatment 
Study Week 25 for 
pediatric patients.  
Appendix A  
8 C1-INH, C4, and C1q will be obtained at Screening. 
Historical values can be used for the HAE Inclusion 
Criteria, if already collected in the last tested unless 
already collected within 5 years of Screening. 
Clarification of 
eligibility laboratory 
collection. 

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Protocol 
Section 
Description of Change  
(Additions in bold, deletions in strikethrough) 
Rationale 
Appendix B  
3 Samples for C4, C1-INH and C1q assays will be obtained 
at Screening for eligibility assessment unless already 
collected in the last 5 years 
Clarification of 
eligibility laboratory 
collection. 
Appendix C  
See Plasma PK Sampling Schedule for clarifications. 
To ensure the correct 
PK sampling schedule 
and timing of 
assessments is followed 
for each respective 
Cohort, the PK 
Sampling Schedule will 
be presented as two 
separate Cohort-
specific tables in this 
Amendment. 
 
 

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EXECUTIVE SUMMARY 
Title:  A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of 
ISIS 721744 in Patients with Hereditary Angioedema (HAE) 
Phase:  3 
Intended Indication:  Hereditary Angioedema (HAE) 
Investigational Product:  ISIS 721744 
Population:  HAE-Type I and HAE-Type II 
Objectives 
Corresponding Endpoints 
Primary 
The primary objective of the study 
is to evaluate the clinical efficacy of 
ISIS 721744 in patients with HAE. 
 
The primary endpoint is the time-normalized number of 
Investigator-confirmed HAE attacks (per month) from Week 1 
to Week 25 compared to placebo 
Secondary 
Evaluate the effects of ISIS 721744 
on the quality and pattern of HAE 
attacks and their impact on Quality 
of Life. 
Secondary endpoints include the following: 
• 
The time-normalized number of Investigator-confirmed 
HAE attacks (per month) from Week 5 to Week 25 
compared to placebo 
• 
The percentage of Investigator-confirmed HAE attack-free 
patients from Week 5 to Week 25 compared to placebo 
• 
The time-normalized number of moderate or severe 
Investigator-confirmed HAE attacks (per month) from 
Week 5 to Week 25 compared to placebo 
• 
The number of patients with a clinical response defined as 
a ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline 
(i.e., screening rate) in Investigator-confirmed HAE attack 
rate between Week 5 to Week 25 compared to placebo 
• 
The number of Investigator-confirmed HAE attacks 
requiring acute HAE therapy from Week 5 to Week 25 
compared to placebo 
• 
Percent of patients who are well controlled on the 
Angioedema Control Test (AECT) at Week 25 
• 
Change in Angioedema Quality of Life (AE-QoL) 
questionnaire total score at Week 25 
Safety 
To evaluate safety and tolerability 
of ISIS 721744 in patients with 
HAE 
 
The number, type, severity, and dose-relationship of AEs; vital 
signs; ECGs; and clinical laboratory parameters 
Exploratory 
Further characterize the effects of 
ISIS 721744 on health economic 
and utilization parameters and 
additional Patient Reported 
Exploratory endpoints include change or percent change from 
Baseline compared to placebo in the following: 
• 
PKK level in plasma 
• 
GAD-7 questionnaire score 

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Objectives 
Corresponding Endpoints 
Outcomes (PROs) and biomarkers. 
 
• 
EQ-5D-5L 
• 
PGIS 
• 
Work Productivity and Impairment (WPAI) questionnaire 
score 
Also: 
• 
Incidence of all cause emergency room visits, 
hospitalization and total inpatient days 
• 
PGIC 
• 
PK:  Potential exposure-response analysis using relevant 
exposure parameters (such as ISIS 721744 plasma Ctrough) 
and biomarkers (plasma PKK) and/or clinical endpoints, as 
appropriate 
 
Study Design 
This study is a randomized (ISIS 721744:placebo), double-blind, placebo-controlled trial 
conducted in multiple centers to evaluate the efficacy and safety of ISIS 721744 in preventing 
angioedema attacks in patients with HAE-1 (Type I) and HAE-2 (Type II).  Patients will be 
randomized 2:1 to Cohort A (3:1 ISIS 721744 80 mg or placebo every 4 weeks) or Cohort B 
(3:1 ISIS 721744 80 mg or placebo every 8 weeks). 
Inclusion/Exclusion Criteria 
Key Inclusion Criteria 
• Patients must be aged ≥ 12 years at the time of informed consent, and, as applicable, 
assent 
• Patients must have a documented diagnosis of HAE-1/HAE-2 based upon ALL of the 
following: 
a. Documented clinical history consistent with HAE (subcutaneous [SC] or mucosal, 
non-pruritic swelling episodes without accompanying urticaria) (Maurer et al. 2018) 
b. Diagnostic testing results that confirm HAE-1/HAE-2:  C1-INH functional level 
< 40% normal level.  Patients with a functional level of 40% to 50% of normal can be 
enrolled if their complement factor C4 level is below the lower limit of normal (LLN) 
or if a known pathogenic mutation in the SERPING1 gene has been demonstrated 
c. At least 1 of the following:  age at reported HAE onset ≤ 30 years; a family history 
consistent with HAE-1/HAE-2; or complement component 1q within the normal 
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• Patients must: 
a. Experience a minimum of 2 HAE attacks (confirmed by the Investigator) during the 
Screening Period 
b. Be willing to complete the PRO assessments throughout the study as described in 
Section 6.2.6. 
• Patients must have access to, and the ability to use, ≥ 1 acute HAE medication(s) 
(e.g., plasma-derived or recombinant C1-INH concentrate or a BK2-receptor antagonist) 
to treat angioedema attacks 
A full list of inclusion criteria is provided in Section 5.1. 
Key Exclusion Criteria 
• Anticipated use of short-term prophylaxis for angioedema attacks for a pre-planned 
procedure during the Screening, Treatment or Post-Treatment Periods 
• Concurrent diagnosis of any other type of recurrent angioedema, including acquired, 
idiopathic angioedema or HAE with normal C1-INH (also known as HAE Type III) 
• Anticipated change in the use of concurrent androgen prophylaxis used to treat 
angioedema attacks 
• Participation in a prior ISIS 721744 study 
• Exposure to any of the following medications: 
a. Angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing 
medications with systemic absorption (such as oral contraceptive or hormonal 
replacement therapy) within 4 weeks prior to Screening 
b. Chronic prophylaxis with Takhzyro (lanadelumab), Haegarda (C1-Esterase inhibitor 
SQ), Cinryze and Ruconest (C1 esterase inhibitor) or Orladeyo (berotralstat) within 
5 half-lives prior to Screening (i.e., Takhzyro within 10 weeks prior to Screening, 
Haegarda/Cinryze/Ruconest within 2 weeks prior to screening, Orladeyo within 
3 weeks prior to Screening) 
c. Oligonucleotides (including small interfering ribonucleic acid) within 4 months of 
Screening if single dose received, or within 12 months of Screening if multiple doses 
received.  This exclusion does not apply to vaccines 
A full list of exclusion criteria is provided in Section 5.2. 
Statistical Analyses 
The power and sample size estimations were calculated using simulations based on a generalized 
linear model for counting data assuming a Poisson distribution.  The primary analysis of the 
primary endpoint is to compare the time-normalized number of Investigator-confirmed HAE 
attacks (per month) from Week 1 to Week 25 between ISIS 721744 80 mg every 4 weeks and 
pooled placebo.  Assuming an HAE attack rate of 13.26 attacks per 6-month period in the pooled 
placebo group and an HAE attack rate of 1.38 attacks per 6-month period in the ISIS 721744 
80 mg every 4 weeks group, the sample size of 54 patients (2:1 ratio [ISIS 721744:placebo]) will 
provide more than 90% power for the primary endpoint, with a two-sided 0.05 significance level.  

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A total of approximately 84 patients (42 in the ISIS 721744 every 4 weeks group, 21 in the 
pooled placebo group, and 21 in the ISIS 721744 every 8 weeks group) will be enrolled in this 
trial to account for potential early dropouts and to facilitate some general safety evaluations.   
Multiplicity Comparisons/Multiplicity 
The multiplicity for primary and secondary analyses will be controlled by using the hierarchical 
testing procedure at 0.05.  The testing sequence for the secondary endpoints will be specified in 
the SAP. 
Analysis of Primary Endpoint 
The primary analysis of the primary endpoint is to compare the time-normalized number of 
Investigator-confirmed HAE attacks (per month) from Week 1 to Week 25 between ISIS 721744 
80 mg every 4 weeks and pooled placebo using a Poisson regression model and Pearson 
chi-square scaling of standard errors to account for potential overdispersion.  The model will 
include fixed effect for treatment group (categorical), the time normalized run-in period attack 
rate (continuous) as a covariate, and the logarithm of time in month that each patient was 
observed from Week 1 to Week 25 will be used as an offset variable. 
All available data will be included in the analysis.  The logarithm of the length of observation 
time will be included as an offset variable in the Poisson model to adjust for differences in 
follow-up time.  Additional details regarding statistical analyses are provided in Section 10.   
 
 

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STUDY GLOSSARY 
Abbreviation 
Definition 
2′-MOE 
2′-O-(2-methoxyethyl) 
AAS 
Angioedema Activity Score 
ACE 
angiotensin-converting enzyme 
ADA 
Anti-Drug Antibody 
ADR 
adverse drug reaction 
AE(s) 
adverse event(s) 
AECT 
Angioedema Control Test 
AE-QoL 
angioedema quality of life 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
ANA 
antinuclear antibody 
aPTT 
activated partial thromboplastin time 
ASO 
antisense oligonucleotide 
AST 
aspartate aminotransferase (SGOT) 
AUC 
area under the curve 
βhCG 
beta-subunit of human chorionic gonadotropin (pregnancy test) 
BK 
bradykinin 
BUN 
blood urea nitrogen 
C1q 
Complement 1q 
C1-INH 
C1-inhibitor 
C4 
Complement factor 4 
C5a 
Complement Factor C5a (activated complement split product) 
Cmax 
maximum concentration 
cHK 
cleaved high molecular weight kininogen 
CKD-EPI 
Formula for glomerular filtration (> 18 years) 
CRF 
case report form 
CRNMB 
clinically relevant non-major bleeding 
CRP 
C-reactive protein 
CS 
clinically significant 
CTCAE 
Common Terminology Criteria for Adverse Events  
DNA 
Deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ER 
emergency room 
EQ-5D-5L 
EuroQoL-5-Dimensions (5D) quality of life questionnaire 
ET 
Early Termination 
FSH 
follicle-stimulating hormone 
GAD-7 
generalized anxiety disorder 7 
GalNAc3 
N-acetly galactosamine 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
HAE 
hereditary angioedema 

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HAE-1 
hereditary angioedema type 1 
HAE-2 
hereditary angioedema type 2 
HAE-nC1-INH 
hereditary angioedema with normal C1-inhibitor 
Hb 
hemoglobin 
HIV 
human immunodeficiency virus 
HK 
high molecular weight kininogen 
hr, hrs 
hour(s) 
hs-CRP 
CRP measured by high sensitivity assay 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgM 
immunoglobulin M 
IM 
immunogenecity 
INR 
international normalized ratio 
IONIS-PKK-LRx 
ISIS 721744 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISIS 721744 
antisense inhibitor of prekallikrein 
ISIS 721744-CS1 
Phase 1 for ISIS 721744 
ISIS 721744-CS2 
Phase 2 for ISIS 721744 
ISIS 721744-CS3 
OLE for ISIS 721744 
ITT  
Intent-to-Treat 
IVIG 
intravenous immunoglobulin 
LCRIS 
local cutaneous reaction at injection site 
LLN 
lower limit of normal 
MB 
major bleeding 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRATM 
Medical Dictionary for Regulatory Activities  
MMRM 
mixed effects model with repeated measures 
mRNA 
messenger ribonucleic acid 
NCS 
not clinically significant 
OLE 
open-label extension 
PD 
pharmacodynamic(s) 
PGIC 
Patient Global Impression of Change  
PGIS 
Patient Global Impression of Severity 
pH 
measure of the acidity or basicity of a solution 
PK 
pharmacokinetic(s) 
PKa 
plasma kallikrein 
PKK 
prekallikrein 
PLT(s) 
platelet(s) 
Post-Tx-ET 
Post-Treatment Early Termination 
PROs 
Patient Reported Outcomes 
PT 
prothrombin time 
QoL 
quality of life 

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RNA 
ribonucleic acid 
RNase H1 
an ubiquitous endonuclease that specifically hydrolyzes the RNA strand in 
RNA/DNA hybrids 
SAE(s) 
serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SC 
subcutaneous(ly) 
siRNA 
small interfering ribonucleic acid 
Study Day 1 
defined as the first day Study Drug product is administered to the patient 
Study Drug 
ISIS 721744 or placebo 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE(s) 
treatment-emergent adverse event(s) 
Tmax 
time to maximal concentration 
Tx 
treatment 
Tx-ET 
Treatment Early Termination 
ULN 
upper limit of normal 
UPCR 
urine protein/creatinine ratio 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
WPAI 
work productivity and impairment 
 
 

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1. 
OBJECTIVES AND ENDPOINTS 
1.1. 
Objectives 
1.1.1. 
Primary Objective 
The primary objective of the study is to evaluate the clinical efficacy of ISIS 721744 in patients 
with hereditary angioedema (HAE).   
1.1.2. 
Secondary Objectives 
Evaluate the effects of ISIS 721744 on the quality and pattern of HAE attacks and their impact 
on Quality of Life. 
1.1.3. 
Safety Objectives 
To evaluate safety and tolerability of ISIS 721744 in patients with HAE. 
1.1.4. 
Exploratory Objectives 
Further characterize the effects of ISIS 721744 on health economic and utilization parameters 
and additional Patient Reported Outcomes (PROs) and biomarkers. 
1.2. 
Study Endpoints 
1.2.1. 
Primary Endpoint 
The primary endpoint is the time-normalized number of Investigator-confirmed HAE attacks 
(per month) from Week 1 to Week 25 compared to placebo. 
1.2.2. 
Secondary Endpoints 
• The time-normalized number of Investigator-confirmed HAE attacks (per month) 
from Week 5 to Week 25 compared to placebo 
• The percentage of Investigator-confirmed HAE attack-free patients from Week 5 to 
Week 25 compared to placebo 
• The time-normalized number of moderate or severe Investigator-confirmed HAE 
attacks (per month) from Week 5 to Week 25 compared to placebo 
• The number of patients with a clinical response defined as a ≥ 50%, ≥ 70%, or ≥ 90% 
reduction from Baseline (i.e., screening rate) in Investigator-confirmed HAE attack 
rate between Week 5 to Week 25 compared to placebo 
• The number of Investigator-confirmed HAE attacks requiring acute HAE therapy 
from Week 5 to Week 25 compared to placebo 
• Percent of patients who are well-controlled based on the AECT at Week 25 
• Change in AE-QoL questionnaire total score at Week 25 

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1.2.3. 
Safety Endpoints 
The safety and tolerability of ISIS 721744 will be assessed by determining the number, type, 
severity, and dose-relationship of AEs; vital signs; electrocardiogram (ECG); and clinical 
laboratory parameters.  Safety results in patients dosed with ISIS 721744 will be compared to 
safety results in patients dosed with placebo. 
1.2.4. 
Exploratory Endpoints 
Exploratory endpoints include change or percent change from Baseline compared to placebo in 
the following: 
• PKK level in plasma 
• GAD-7 questionnaire score  
• EQ-5D-5L 
• PGIS 
• WPAI questionnaire score 
• Incidence of ER visits, all cause hospitalization and total inpatient days 
• PGIC 
• PK:  Potential exposure-response analysis using relevant exposure parameters (such 
as ISIS 721744 plasma Ctrough) and biomarkers (plasma PKK) and/or clinical 
endpoints, as appropriate  
2. 
BACKGROUND AND RATIONALE 
2.1. 
Overview of Disease 
Hereditary angioedema is a rare genetic disorder that is characterized by disabling recurrent 
episodes of local skin swellings, painful abdominal attacks, and, occasionally, laryngeal attacks 
that can be life-threatening.  The disorder is classified in 3 subtypes.  Hereditary angioedema 
Type I (HAE-1) and Type II (HAE-2) are caused by an autosomal dominant mutation in the 
SERPING1 gene, resulting in either decreased levels of C1-INH (HAE-1) or loss-of-function of 
this protein (HAE-2) (Bissler et al. 1997).  The third form of HAE is associated with normal 
levels and function of C1-INH (HAE-nC1-INH).  This form is currently categorized as 
4 subtypes, with either specific genetic mutations in the factor XII gene, the plasminogen gene, 
or the angiopoietin-1 gene, or due to an unknown cause (Maurer et al. 2018).  Extensive 
evidence from in vitro and in vivo studies supports the key role of bradykinin (BK) in HAE 
attacks, although the data linking HAE-nC1-INH with BK are less strong (Zuraw and 
Christiansen 2016).  Diagnosing HAE-nC1-INH can be challenging given the large heterogeneity 
of this patient population, the lack of diagnostic tests, and the fact that specific genetic mutations 
account only partially for the occurrence of this type of HAE.  Recently, a threshold-stimulated 
kallikrein activity assay was shown to discriminate BK-mediated angioedema from 
histamine-mediated angioedema (Lara‑Marquez et al. 2018).  This technique may, therefore, 

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enhance the identification of HAE-nC1-INH patients that are likely to benefit from inhibition of 
the contact activation pathway. 
Treatment options for HAE include on-demand treatment of attacks and prophylaxis.  
On-demand options include supplementation of C1-INH (either plasma-derived or recombinant 
C1-INH concentrate) and inhibition of BK2 receptor activation (BK2-receptor antagonist).  In 
addition, tranexamic acid may relieve symptoms in non-severe angioedema attacks.  
Prophylactic regimens for HAE include plasma-derived C1-INH concentrate (administered either 
intravenously or subcutaneously [SC]), attenuated androgens, antifibrinolytics and a monoclonal 
antibody directed against plasma kallikrein (PKa) and a small molecule inhibitor of PKa.  
Kallikrein circulates in plasma as a zymogen (i.e., PKK) which is bound to one of its main 
substrates, high molecular weight kininogen (HK).  Prekallikrein (PKK) is cleaved upon contact 
activation, forming the active protease PKa.  Plasma kallikrein cleaves HK in turn, thereby 
releasing BK and the split product cleaved high molecular weight kininogen (cHK).  The binding 
of BK to the BK2 receptor leads to activation of various intracellular signaling pathways 
resulting in vasodilation, chemotaxis of neutrophils, and increased vascular permeability and 
fluid efflux, which typically characterize an angioedema attack (Zuraw and Christiansen 2016). 
2.2. 
Therapeutic Rationale 
ISIS 721744 is a 2-O-(2 methoxyethyl) (2′-MOE) chimeric phosphorothioate (PS)-modified 
second-generation antisense oligonucleotide (ASO) designed to bind to the messenger 
ribonucleic acid (mRNA) of PKK, a protease in the contact system.  By inhibiting expression of 
PKK, ISIS 721744 reduces the release of BK, a potent vasodilator that increases vascular 
permeability resulting in swelling and pain associated with HAE attacks. 
The Phase 1 clinical data show that ISIS 721744 inhibits plasma PKK effectively in a 
dose-dependent manner without safety concerns.  Validation of this mechanism has been 
demonstrated in a recently completed 12-week Phase 2 study of ISIS 721744 in adult HAE 
patients with recurrent attacks, ISIS 721744-CS2, in which once-every-4-weeks ISIS 721744 
administration showed 90% reduction in HAE attacks compared to placebo. 
2.3. 
ISIS 721744 
2.3.1. 
Mechanism of Action 
ISIS 721744 is a chimeric 2ʹ-MOE ASO targeted to PKK mRNA.  The ASO is covalently 
bonded to triantennary GalNAc, a high-affinity ligand for the hepatocyte-specific ASGPR, to 
form an ASO-GalNAc conjugate.  This GalNAc conjugate approach results in enhanced ASO 
delivery to hepatocytes vs. non-parenchymal cells and has increased ASO potency by 
approximately 10-fold in mice (Prakash et al. 2014) and up to 30-fold in humans (Crooke et al. 
2018) compared to unconjugated ASOs.  The ASO portion of ISIS 721744 is fully 
complementary to a base-pair position 1019-1038 of the Genbank NM_000892.3 sequence 
spanning a portion of Exon 9 of the PKK-mRNA and binds to the mRNA by Watson and Crick 
base pairing.  The hybridization (binding) of ISIS 721744 to the cognate mRNA results in the 
ribonuclease H1 (RNase H1)-mediated degradation of the PKK mRNA, thus preventing 
production of the PKK protein.  Antisense-mediated reduction of target mRNA levels is 
predictable and dose-dependent.  Maximal inhibition of greater than 90% of control levels is 

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typically achievable in sensitive tissues (Crooke and Bennett 1996; Zhang et al. 2010).  
Furthermore, reduction in target mRNA levels using this approach correlates directly with a 
subsequent reduction in target protein levels. 
2.3.2. 
Chemistry 
ISIS 721744 is a GalNAc-conjugated 2ʹ-MOE ASO.  The oligonucleotide portion of the drug 
consists of 20 nucleotides (i.e., a 20-mer).  Of the nineteen (19) internucleotide linkages, 15 are 
3′-O to 5′-O phosphorothioate diesters, and 4 are 3′-O to 5′-O phosphate diesters.   
Structurally, the conjugated oligonucleotide has 4 regions.  Within 2 of the regions, the 
5 nucleotides at the 5′ end and the 5 nucleotides at the 3′ end, are composed of 
2′-O-(2-methoxyethyl) (2′-MOE)-modified ribonucleotides.  These MOE-modified nucleotides 
confer (i) increased affinity for the target mRNA (Altmann et al. 1996; McKay et al. 1999), 
(ii) increased resistance to exonucleases and endonucleases (thereby increasing stability in 
tissue) (Geary et al. 2003), and (iii) amelioration of some of the high dose toxicities thereby 
resulting in an improved safety profile compared to first generation antisense drugs containing 
phosphorothioate modified oligodeoxynucleotides (DNA) (Henry et al. 2000).  The third region, 
the central portion of the oligonucleotide, is composed of 10 oligodeoxynucleotides.  This 
chimeric design is called a MOE-Gapmer, and ISIS 721744 employs this chimeric structure to 
enable use of the RNase H1 mechanism for antisense activity.  The 2′-MOE modification confers 
increased stability and affinity but does not support RNase H1 catalyzed cleavage of RNA 
hybridized to 2′-MOE-modified nucleotides (McKay et al. 1999).  This is caused by 
conformational changes induced in the heteroduplex by 2′-alkoxy-RNA hybrids that are not 
recognized by RNase H1 enzymes (Inoue et al. 1987; Monia et al. 1993).  By limiting the 
2′-MOE modification to nucleotides flanking the phosphorothioate oligodeoxynucleotide core, 
the beneficial attributes of the 2′-MOE chemistry are preserved while also retaining RNase H1 
recognition. 
The fourth region is comprised of a triantennary cluster of GalNAc sugars which is linked to the 
5′ end of ISIS 721744 via a phosphodiester linkage.  The GalNAc cluster is a high affinity ligand 
for the ASGPR, a receptor expressed primarily on the surface of liver hepatocytes (Stockert 
1995).  The GalNAc cluster enhances delivery of ISIS 721744 to liver hepatocytes over other 
cell types and enhances potency.  After internalization into cells, the GalNAc cluster is 
metabolized to release “free ASO” inside the cell (Prakash et al. 2014). 
The internucleosidic linkages are a mixture of phosphorothioate and phosphodiester.  The 
phosphorothioate linkages are introduced into the DNA gap region and at both ends of the 
oligonucleotide to protect it from nuclease mediated metabolism.  The mixed backbone design 
reduces the total number of phosphorothioate linkages which reduces non-specific interactions 
with proteins and further enhances the therapeutic index of GalNAc-conjugated ASOs. 

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2ʹ-MOE 
2′-Deoxy 
(RNase H1 sensitive) 
2ʹ-MOE 
GalNAc 
OMeUSGSMeCOAOAS 
GSTSMeCSTSMeCSTSTSGSGSMeCS 
AOAOASMeCSA 
 
GalNAc = trishexylamino GalNAc cluster 
2′-MOE = 2ʹ-methoxyethyl RNA 
2′-Deoxy = DNA 
MeC = 5-methylcytosine 
MeU = 5-methyluridine 
S = phosphorothioate linkage 
O = phosphodiester linkage 
Figure 1: 
Design of ISIS 721744, a GalNAc-Conjugated Chimeric 2ʹ-MOE 
Phosphorothioate/Phosphate Oligonucleotide (MOE Gapmer) 
The sequence of ISIS 721744 is shown.  All of the cytosine bases are methylated at the 5-position.  It should be noted that 
2′-O-(2-methoxyethyl)-5-methyluridine (2′-MOE MeU) nucleosides are sometimes referred to as 2′-O-(2-methoxyethyl) 
ribothymidine (2′-MOE T). 
 
2.3.3. 
Preclinical Experience 
Detailed information concerning the preclinical studies conducted with PKK ASO ISIS 546254 
(parent unconjugated compound), its 5ʹ-GalNAc3-conjugated mixed backbone variant 
ISIS 721744, and mouse surrogate PKK ASOs can be found in the Investigator’s Brochure. 
The results support the concept that inhibition of PKK through antisense mechanism may serve 
as a new and effective strategy for the prophylaxis of HAE.  Results also strongly support that 
GalNAc3-conjugation of PKK ASO significantly increases the potency of ASO for inhibition of 
PKK hepatic mRNA and circulatory protein expression and thus these ASOs should be a useful 
therapeutic strategy for the prophylactic treatment of HAE. 
2.3.4. 
Clinical Experience 
ISIS 721744 has been evaluated in the clinical setting in a Phase 1 safety study 
(ISIS 721744-CS1) and Phase 2 study (ISIS 721744-CS2).   
Phase 1:  ISIS 721744 was studied in 32 healthy volunteers in a double-blind, multiple-dose, 
dose-escalation study.  Of these, 24 subjects received multiple doses of ISIS 721744.  The 
32 subjects were randomized into 4 cohorts (6 subjects each) to receive once-every-4-week SC 
doses of ISIS 721744 20, 40, 60, or 80 mg, or placebo (8 subjects) for a total of 12 weeks (4 total 
doses).  All subjects received all planned doses of Study Drug (ISIS 721744 or placebo).  The 
duration of Study Drug exposure was 84 days for each subject. 
No serious adverse events (SAEs) were reported in the ISIS 721744-CS1 study.  There were no 
early discontinuations from Study Drug or the study, and all subjects in the ISIS 721744 and 
placebo arms completed all study procedures.  Adverse events at the injection site (defined as 

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any preferred term containing “injection site”) were the most commonly reported 
treatment-emergent adverse events (TEAEs) in the ISIS 721744 treatment arms; no injection 
site-related TEAEs were reported in the placebo arm.  There were no flu-like reactions or events 
of local cutaneous reaction at injection site (LCRIS) reported; LCRIS events were defined as 
(A) moderate or severe injection site erythema, swelling, pruritus, pain, or tenderness that started 
on the day of injection and persisted for at least 2 days; or (B) any AE at the injection site, 
regardless of severity, that led to discontinuation of Study Drug, where AE at the injection site 
was the principal reason for discontinuation.  No relationship between incidence of TEAEs and 
the dose administered was observed. 
Thirteen (13) AEs related to study treatment were reported for 4 (16.7%) subjects in the 
ISIS 721744 arm, and for 1 subject (2 events; 12.5%) in the placebo arm.  One (1) subject each 
in the ISIS 721744 and placebo arm reported AEs of ECG T wave inversion (preferred term) that 
were assessed as related.  Nine (9) of the total 13 related events with ISIS 721744 concerned 
Injection site-related events and were reported by 1 subject in the 80 mg arm.  Additional related 
events were Tinnitus (1 subject, 1 event in the 60 mg arm), Headache (1 subject, 1 event in the 
60 mg arm), and Epistaxis (1 subject, 1 event in the 20 mg arm).  All TEAEs related to study 
treatment were mild in severity, and none were serious. 
ISIS 721744 resulted in a dose-dependent reduction of PKK concentration and plasma 
proenzyme activation.  The difference in absolute and percent change from Baseline for 
ISIS 721744 vs. placebo was statistically significant for PKK concentration for 40, 60, and 
80 mg (p ≤ 0.043) starting at Day 15, the first evaluation, and for 20 mg starting at Day 29, and 
for plasma proenzyme activation for all doses (p ≤ 0.002) starting at Day 15.  The nadir was 
generally reached around Day 71, when the percent reduction with the 80 mg dose was -93.2% 
for PKK concentration and -99.6% for plasma proenzyme activation.  The difference in absolute 
and percent change from Baseline in cHK for ISIS 721744 vs. placebo was not statistically 
significant at any visit. 
Phase 2:  ISIS 721744 was evaluated in a double-blind placebo-controlled trial in patient with 
HAE Type I and II in Part A and in an open-label treated patients with HAE-nC1-INH (or 
Type III).  Clinical data demonstrated a significant degree of efficacy of ISIS 721744 80 mg 
administered once every-4-weeks for 4 months in reducing the rate of HAE attacks in Type I and 
Type II HAE patients with recurrent attacks over a 16-week (Week 1-17) period vs. placebo 
(90% reduction in number of HAE attacks compared to placebo; p < 0.001).  The percentage of 
patients who were HAE attack-free from Week 5 to Week 17 was 92.3% as compared to none of 
the patients treated with placebo.  There was also a significant reduction, 95%, in patient treated 
with ISIS 721744 in the need for use of acute therapies to treat HAE attacks vs. placebo treated 
patients.  Additionally, the number of moderate to severe attack was also markedly reduced with 
a 96% reduction in ISIS 721744 treated group vs. placebo.  There was also a statistically 
significant reduction in plasma PKK, plasma proenzyme activation and cHK. 
ISIS 721744 was well-tolerated with most AEs being mild in severity, and similar in frequency 
between active and placebo treated patients.  The most common TEAE was headache.  All the 
TEAEs had resolved by the end of the study.  No LCRIS or flu-like reactions were reported.  No 
deaths or SAEs were reported.  There were no clinically relevant changes in the safety 
laboratories, such as chemistry, hematology, coagulation, complement, inflammatory markers, 
urinalysis, ECG, or vital sign.   

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Overall, ISIS 721744 was efficacious and well-tolerated in these patients with HAE. 
Eligible patients from ISIS 721744-CS2 are continuing to receive the drug for an additional 
2 years in the open-label extension (OLE) study, ISIS 721744-CS3. 
Investigator Initiated Trial:  Additionally, evidence was provided of efficacy in 2 patients in 
the Netherlands with severe BK-mediated forms of angioedema who were administered drug as 
treatment use, first with the unconjugated parent ASO, IONIS-PKKRx, (ISIS 546254) followed by 
treatment with the ligand-conjugated ASO, IONIS-PKK-LRx (ISIS 721744; (Cohn et al. 2020).  
In both patients, IONIS-PKKRx and IONIS-PKK-LRx showed clinical efficacy by markedly 
reducing the rate of breakthrough attacks.   
2.4. 
Rationale for Dose and Schedule of Administration 
The dose level of 80 mg every 4 weeks was selected based on the safety, tolerability, 
pharmacokinetic (PK), and pharmacodynamic (PD) data from the ISIS 721744-CS1 study in 
healthy volunteers and ISIS 721744-CS2 study in patients with HAE as well as the clinical 
efficacy data of the ISIS 721744-CS2 study.  The Phase 1 study evaluated doses of 20, 40, 60, 
and 80 mg ISIS 721744 administered to healthy volunteers once every 4 weeks for a total of 
12 weeks.  All dose levels were generally well-tolerated and induced a dose- and 
exposure-dependent reduction in plasma PKK, a biomarker for BK and vascular permeability.  
The highest dose level of 80 mg produced near complete reduction of plasma PKK levels (a 
mean reduction of 93.6% from Baseline on Day 99 [2 weeks after the last dose]) in healthy 
volunteers.  In the Phase 2 study in HAE patients, the dose level of 80 mg resulted in a mean 
plasma PKK reduction of about 60% from Baseline on Day 113, 4 weeks after a total of 4 doses 
(administered every 28 days) with no corresponding attacks reported for most patients.  This 
suggests that the 80-mg dose administered every 4 weeks results in sufficient target knockdown 
to achieve near-complete prevention of attacks in these patients.  Additionally, the mean plasma 
PKK levels correlated well with the mean attacks/month (clinical endpoint) over time.  A second 
dosing regimen of 80 mg every 8 weeks is included in this study to evaluate the efficacy and 
safety of a reduced dosing frequency.  This dosing schedule was selected based on the 
ISIS721744-CS3 open-label study (open-label study extension of the ISIS 721744-CS2 study) 
that evaluated the same dosing regimen.  In the CS3 study, 5 out of the 17 HAE Type II patients 
that rolled over to the CS3 study switched to 80 mg every 8 weeks.  Currently 4 out of these 
5 patients have remained attack free.  This suggests that patients could potentially benefit from 
this alternative dosing regimen with a reduced dosing frequency.  Both dosing schedules (80 mg 
every 4 weeks and 80 mg every 8 weeks) have been generally well-tolerated in these patients.  
The estimated half-life (t½) of ISIS 721744 is approximately 4 to 5 weeks, thus supporting these 
dosing schedules as well.  Minimal to no correlation was observed between ISIS 721744 
clearance and exposure with body weight across healthy volunteers and patients combined 
suggesting that a flat dose of 80 mg is appropriate across the entire population of this study.  The 
dose and schedule are also supported by sub-chronic and chronic toxicity studies in mice and 
monkeys of up to 6- and 9-months dosing duration, respectively.  For an 80-mg monthly dose in 
adult humans (70 kg), the safety margin is approximately 21-fold and 32-fold based on the dose 
and area under the curve (AUC) respectively at NOAEL in the 9-month monkey study.  
Additionally, the safety margin would still be over 20-fold for patients with lower body weight 

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(~35 kg patients) based on a conservative body weight- based AUC predicted from population 
PK modeling. 
2.5. 
Benefit-Risk Assessment 
2.5.1. 
Overall Assessment of Benefit:Risk 
The preclinical, Phase 1, and Phase 2 studies of ISIS 721744 have demonstrated a favorable 
risk-benefit profile, with no safety signals identified in clinical trials on hematological 
parameters, liver function, or renal function.  In the completed Phase 2 study of ISIS 721744 in 
HAE patients, AEs, including those at the injection site, were balanced between groups and no 
severe AEs were reported and all TEAEs had resolved by the end of the study.  There were no 
clinically relevant changes in the safety laboratories, such as chemistry, hematology, 
coagulation, complement, inflammatory markers, urinalysis, or ECGs, nor in vital signs.  No 
safety or stopping rules were met for renal function, liver or bleeding.  No deaths or SAEs were 
reported.  Overall, in this trial, ISIS 721744 was safe and well-tolerated in patients with HAE.  In 
the ongoing Phase 2 OLE study of ISIS 721744, a continued favorable safety and tolerability 
profile has been demonstrated, with no platelet (PLT), liver function, or renal function signals 
identified. 
The conjugated nature of ISIS 721744 allows specific targeting of ASO to hepatocytes so, that 
for similar hepatocyte exposure, reduced exposure to both non-parenchymal liver cells and 
systemic exposure has the potential to lower PKK with an enhanced tolerability profile over the 
parent molecule, ISIS 546254.   
Nevertheless, regular monitoring of PLT counts, liver chemistry, and renal function, and 
stopping rules will be included in the clinical study as described in Section 8.5 and Section 8.6. 
Taking into account the measures taken to minimize risk to patients participating in this study, 
the potential risks identified in association with ISIS 721744 are justified by the anticipated 
benefits that may be afforded to patients with HAE. 
Detailed information concerning the benefit-risk assessment of ISIS 721744 can be found in the 
Investigator’s Brochure.   
2.5.2. 
Additional Risks During the COVID-19 Pandemic 
HAE patients should continue any approved pharmaceutical interventions for treating acute 
attacks as no risks have been identified that would cause termination of treatment during the 
COVID-19 Pandemic at this time. 
There could be risk however, for patients who are participating in a clinical trial such as 
ISIS 721744-CS5.  There may be risks to patients traveling to research sites.  Sites should follow 
their specific regional guidance (i.e., institutional, local, state, federal, country-level, as 
applicable) with regard to receiving patients for clinical trials.  Visits should continue as long as 
it is deemed safe to do so.  Provision will be available for patients to be treated or evaluated in 
their homes by a home healthcare professional.  Additional mitigation steps and a study pause 
may be necessary as conditions warrant.  If a study patient becomes infected with COVID-19 or 
develops COVID-19-related symptoms, the patient should notify the study staff/Investigator or 

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designee and notify their treating Physician that they are participating in a clinical trial with 
ISIS 721744. 
3. 
EXPERIMENTAL PLAN 
3.1. 
Study Design 
This study is a randomized (ISIS 721744:placebo), double-blind, placebo-controlled trial 
conducted in multiple centers to evaluate the efficacy and safety of ISIS 721744 in preventing 
angioedema attacks in patients with HAE-1 (Type I) and HAE-2 (Type II) HAE.  Patients will be 
randomized in a 2:1 ratio to Cohort A (ISIS 721744 or placebo every-4-weeks) or Cohort B 
(ISIS 721744 or placebo every 8 weeks), respectively.  Within each Cohort, patients will be 
randomized in a 3:1 ratio to receive 80mg of ISIS 721744 or matching volume of placebo.  
Patients who discontinue treatment will attend the Early Termination (ET) Visit and will be 
encouraged to complete the Post-Treatment Period unless consent or assent is withdrawn. 
Detailed information regarding the study procedures is presented in Section 6 and Appendix A.  
Appendix B includes a list of laboratory analytes required for the study. 
3.2. 
Number of Study Centers 
This study will be conducted at multiple Study Centers worldwide. 
3.3. 
Number of Patients 
Approximately 84 patients are planned to be enrolled in the study. 
3.4. 
Overall Study Duration and Follow-up 
The study will consist of Screening, Treatment, and Post-Treatment Periods.  Please refer to the 
Schedule of Procedures in Appendix A. 
Patients may be required to attend additional visits for monitoring of AEs or abnormal 
investigation results.  The frequency of additional monitoring will be determined by the Sponsor 
Medical Monitor in consultation with the Investigator or designee. 
The length of each patient’s participation in the study is approximately 11 months, which 
includes an up to 56-day Screening Period, a 25-week Treatment Period, and an up to 13-week 
Post-Treatment Period, unless the patient chooses to enroll in the OLE study. 
3.4.1. 
Screening 
After the informed consent (ICF) and, in the case of participants not of legal age, assent is 
signed, the patient will be assessed for eligibility according to the Schedule of Procedures in 
Appendix A.  The Screening Period is up to 56 days in duration.  A patient may be randomized 
after fewer than 56 days from the screening visit if the patient experiences ≥ 2 HAE attacks in 
less than 56 days, has completed all other screening activities, and has met all other eligibility 
requirements. 

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3.4.2. 
Treatment 
Eligible patients will report to the Study Center for the first administration of Study Drug on 
Study Day 1 and will continue to receive Study Drug once every 4 (Cohort A) or 8 (Cohort B) 
weeks during the 25-week Treatment Period.  Patients will return to the Study Center (or Home 
Healthcare, if available) for treatment visits to complete assessments and dosing per the Schedule 
of Procedures in Appendix A.  In regions where Home Healthcare is available to patients, a 
training curriculum will be developed with input from the Sponsor and all Home Healthcare 
providers will be trained prior to conducting any study related assessments/procedures.  This 
training will be documented and filed as appropriate. 
3.4.3. 
Post-Treatment 
Patients are to return to the Study Center for post-treatment follow-up visits (or Home 
Healthcare, if available), as arranged by the Study Center personnel, per the Schedule of 
Procedures in Appendix A.  Alternatively, patients who complete Study Visit Week 25, and meet 
eligibility requirements, may enroll in the OLE study any time after the Week 25 visit.  If a 
patient chooses to enroll in the OLE study, the patient will discontinue participation in the CS5 
Post-Treatment Period prior to the first visit in the OLE study.  Patients may be required to 
attend additional visits for monitoring of AEs or abnormal investigation results.  The frequency 
of additional monitoring will be determined by the Sponsor Medical Monitor in consultation 
with the Investigator or designee.   
The final study visit for patients not enrolling in the OLE will be the Week 13 Post-Treatment 
Period Visit.   
Throughout the study including during the Post-Treatment Period, patients may be required to 
attend additional visits for monitoring of AEs or abnormal investigation results.  The frequency 
of additional monitoring will be determined by the Sponsor Medical Monitor in consultation 
with the Investigator or designee.   
3.5. 
End-of-Study 
The End-of-Study is defined as the date of the last visit of the last patient in the study. 
For individual patients, End-of-Study is defined as completion of their last study visit. 
3.6. 
Data and Safety Monitoring Board or Independent Data Monitoring 
Committee 
A Data and Safety Monitoring Board (DSMB) will be assembled to review safety, tolerability, 
and efficacy (as needed) data collected on ISIS 721744 during this study.  Based on its ongoing 
assessment of the safety and tolerability of ISIS 721744, the DSMB will provide 
recommendations to the Sponsor for modifying, stopping, or continuing the study as planned.  
Details on the safety assessments, frequency of review, meeting schedules, and controlled access 
to unblinded data are outlined in the DSMB Charter and Statistical Analysis Plan (SAP). 

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4. 
PATIENT ENROLLMENT 
4.1. 
Screening 
Before patients may be enrolled into the study, the Sponsor or designee requires a copy of the 
Study Center’s written Independent Ethics Committee (IEC)/Institutional Review Board (IRB) 
approval of the protocol, ICF and, as applicable, assent form, and all other patient information 
and/or recruitment material. 
Patients, or their legally appointed and authorized representatives, will sign and date an ICF, and 
when appropriate, an assent form before any screening tests or assessments are performed.  Race 
and Ethnicity data will be collected as part of the demographic information for all screened 
patients during the Screening Period.  At the time of consent and, as applicable, assent, the 
patient will be considered enrolled into the study and will be assigned a unique screening number 
before any study procedures, including screening procedures, are performed.  At the time of 
randomization, patients will be assigned a unique patient identification number.  This number 
will be used to identify the patient throughout the study and must be used on all study 
documentation related to that patient.  The screening number and patient identification number 
must remain constant throughout the entire study.   
In the event the patient is re-consented and as applicable, re-assented and re-screened, the patient 
must be given a new screening number.  Screening numbers, once assigned, will not be re-used. 
4.2. 
Randomization 
Patients will be randomized, after all screening assessments have been completed and after the 
Investigator or designee has verified that they are eligible per the criteria in Section 5.1 and 
Section 5.2.  No patient may begin treatment prior to randomization and assignment of a unique 
patient identification number.   
Approximately 84 patients with HAE-1/HAE-2 will be randomized via the IRT system to SC 
injections of ISIS 721744 80 mg or placebo.  Approximately 56 patients will be randomized to 
every-4-week dosing (Cohort A) and 28 patients will be randomized to every-8-week dosing 
(Cohort B).  Within each Cohort, patients will be randomized in a 3:1 ratio to receive 80 mg of 
ISIS 721744 or matching volume of placebo.  For purposes of planned analyses, the placebo 
patients from each Cohort will be pooled for comparison to ISIS 721744 treated patients. 
Randomization information will be concealed from the Investigators or designees and patients 
until the end of the study, with the exception of an emergency situation involving a patient that 
requires unblinding of the treatment assignment. 
4.3. 
Replacement of Patients 
Patients who withdraw from the study will not be replaced. 
4.4. 
Unblinding of Treatment Assignment 
The Sponsor and all patients, monitors, and Study Center personnel related to the study (except 
for the DSMB, statistical/programming support staff) will be blinded throughout the study until 
all patients have completed the study and the database has been locked.  Representatives from 

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the Sponsor may be unblinded after the last patient has completed the end of the Treatment 
Period (Week 25/Tx-ET) as described in the Unblinding Plan.  Those Sponsor representatives 
will no longer be involved in the conduct of the study after they have been unblinded.  However, 
if a patient has suffered an SAE (as defined in Section 9.3.3), and/or when knowledge of the 
treatment assignment will impact the clinical management of the patient, the Investigator will 
have the ability to unblind the treatment assignment for that patient via the IRT system. 
The Sponsor or designee will be informed of the unblinding of a patient within 24 hours.  An 
unblinded randomization schema will be maintained securely at the Sponsor’s designated 
vendor.  In addition, all suspected unexpected serious adverse reactions (SUSARs) will be 
unblinded by the Sponsor or designee for the purpose of unblinded regulatory reporting (see 
Section 9.2). 
Every reasonable attempt should be made to complete the ET study procedures and observations 
(see Appendix A) prior to unblinding, as knowledge of the treatment arm could influence patient 
assessment. 
5. 
PATIENT ELIGIBILITY 
To be eligible to participate in this study candidates must meet the following eligibility criteria 
within 56 days of the Study Day 1 Visit or at the time point specified in the eligibility criteria 
listed. 
5.1. 
Inclusion Criteria 
1. Patients, or their legally appointed and authorized representatives, must provide written 
and signed ICF, and when appropriate, an assent form and any authorizations required by 
local law and be able to comply with all study requirements for the duration of the study 
2. Patients must be aged ≥ 12 years at the time of informed consent and, as applicable, 
assent 
3. Patients must have a documented diagnosis of HAE-1/HAE-2 based upon ALL of the 
following: 
a. Documented clinical history consistent with HAE (SC or mucosal, non-pruritic 
swelling episodes without accompanying urticaria) (Maurer et al. 2018) 
b. Diagnostic testing results that confirm HAE-1/HAE-2:  C1-INH functional level 
< 40% normal level.  Patients with a functional level of 40% to 50% of normal can be 
enrolled if their complement factor C4 level is below the lower limit of normal (LLN) 
or if a known pathogenic mutation in the SERPING1 gene has been demonstrated 
c. At least 1 of the following:  age at reported HAE onset ≤ 30 years; a family history 
consistent with HAE-1/HAE-2; or complement component 1q within the normal 
range 
4. Patients must: 
a. Experience a minimum of 2 HAE attacks (confirmed by the Investigator) during the 
Screening Period 

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b. Be willing to complete the PRO assessments throughout the study as described in 
Section 6.2.6 
5. Patients must have access to, and the ability to use, ≥ 1 acute medication(s) (e.g., plasma 
derived or recombinant C1-INH concentrate or a BK2-receptor antagonist) to treat 
angioedema attacks 
6. Female patients must be non-pregnant (and not planning a pregnancy during the study) 
and non-lactating, and be either: 
a. Surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy) 
b. Post-menopausal (defined as 12 months of spontaneous amenorrhea in females 
> 55 years of age or, in females ≤ 55 years of age, 12 months of spontaneous 
amenorrhea without an alternative medical cause and follicle-stimulating hormone 
[FSH] levels in the post-menopausal range for the laboratory involved) 
c. Abstinent (only acceptable as true abstinence, i.e., when in line with the preferred and 
usual lifestyle of the patient; periodic abstinence [e.g., calendar, ovulation, 
symptothermal, or post ovulation methods], declaration of abstinence for the duration 
of the study, or withdrawal are not acceptable methods of contraception) 
d. If engaged in sexual relations of childbearing potential, agree to use acceptable 
contraceptive methods (refer to Section 6.3.1) from the time of signing the ICF and, 
as applicable, assent form until at least 24 weeks after the last dose of Study Drug 
(ISIS 721744 or placebo) 
7. Male patients must be surgically sterile or, if engaged in sexual relations with a female of 
childbearing potential, the patient must agree to use an acceptable contraceptive method 
(refer to Section 6.3.1) from the time of signing the ICF until at least 24 weeks after the 
last dose of Study Drug (ISIS 721744 or placebo) 
5.2. 
Exclusion Criteria 
1. Anticipated use of short-term prophylaxis for angioedema attacks for a pre-planned 
procedure during the Screening, Treatment or Post-Treatment Periods 
2. Concurrent diagnosis of any other type of recurrent angioedema, including acquired, 
idiopathic angioedema or HAE with normal C1-INH (also known as HAE Type III) 
3. Anticipated change in the use of concurrent androgen prophylaxis used to treat 
angioedema attacks 
4. Any clinically-significant abnormalities in screening laboratory values that would render 
a patient unsuitable for inclusion in the study.  The following laboratory values are 
exclusionary: 
a. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × upper 
limit of normal (ULN) 
b. Total bilirubin > 1.5 × ULN OR, if due to Gilbert’s syndrome, > 5 mg/dL 
c. Platelet count < 130 K/mm3 

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d. For patients ≥18 years old:  Estimated glomerular filtration rate < 45 mL/min (as 
determined by the CKD-EPI formula for creatinine clearance) 
e. For patients 12 and <18 years old:  Estimated glomerular filtration rate < 60 mL/min 
(as determined by the Bedside Schwartz formula for creatinine clearance) 
5. Patients with a history of acquired coagulopathies or bleeding diathesis (e.g., 
thrombocytopenia, disseminated intravascular coagulation, coagulopathy of liver disease, 
drug-induced PLT dysfunction, hyperfibrinolysis, acquired clotting factor inhibitors) and 
inherited bleeding disorders (e.g., hemophilia A, hemophilia B, other clotting factor 
deficiencies, qualitative PLT disorders, inherited thrombocytopenia, vascular 
abnormalities) and hypercoagulability 
6. Any clinically significant (CS) renal or hepatic diseases 
7. Active infection requiring systemic antiviral or antimicrobial therapy that will not be 
completed prior to Study Day 1 
8. Active infection with human immunodeficiency virus (HIV), hepatitis C or hepatitis B 
diagnosed by initial serological testing and confirmed with RNA testing, or prior 
treatment for hepatitis C.  Patients at Screening who test positive by serology, but 
negative by RNA may be allowed in consultation with the Sponsor Medical Monitor 
9. 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 
10. Treatment with another investigational drug or biological agent within 1 month or 5 half-
lives, whichever is longer, of Screening 
11. Participated in a prior ISIS 721744 study 
12. Exposure to any of the following medications: 
a. Angiotensin-converting enzyme (ACE) inhibitors or any estrogen containing 
medications with systemic absorption (such as oral contraceptive or hormonal 
replacement therapy) within 4 weeks prior to Screening 
b. Chronic prophylaxis with Takhzyro (lanadelumab), Haegarda (C1-esterase inhibitor 
SQ), Cinryze and Ruconest (C1 esterase inhibitor) or Orladeyo (berotralstat) within 
5 half-lives prior to Screening (i.e., Takhzyro within 10 weeks prior to Screening, 
Haegarda/Cinryze/Ruconest within 2 weeks prior to screening, Orladeyo within 
3 weeks prior to Screening) 
c. Oligonucleotides (including small interfering ribonucleic acid [siRNA]) within 
4 months of Screening if single dose received, or within 12 months of Screening if 
multiple doses received.  This exclusion does not apply to vaccines 
13. Any condition that, in the opinion of the Investigator or designee, may compromise the 
patient’s safety or compliance, preclude successful conduct of the study, or interfere with 
the interpretation of results 
14. Recent history (3 years) of, or current drug or alcohol abuse 

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6. 
STUDY PROCEDURES 
6.1. 
Study Schedule 
All required study procedures are outlined in Appendix A. 
The safety of ISIS 721744 will be continually monitored throughout the study by the Investigator 
or designee and the Sponsor Medical Monitor. 
The length of each patient’s participation from Screening to the last study visit is up to 
approximately 11 months. 
6.1.1. 
Screening 
Written and signed informed consent and, as applicable, assent for the study will be obtained 
prior to the performance of any study related procedures including screening procedures.  An up 
to 56-day period is provided for completing screening assessments and determining patient 
eligibility for the study.  Abnormal screening results may be re-tested once for determination of 
patient eligibility after consultation with the Sponsor Medical Monitor.  Patients may have 
laboratory procedures repeated 1 time in order to determine eligibility.   
A list of assessments to be completed during Screening is provided in Appendix A.  All patient-
reported outcomes assessments should be completed at the beginning of each (as appropriate) 
visit. 
During the Screening Period (up to 56 days), patients must experience a minimum of 2 HAE 
attacks (confirmed by the Investigator) to be eligible for the study; patients will be instructed to 
report details of any HAE attack to the study site within 72 hours of the onset of the attack.  
Throughout the Screening Period, site personnel will contact the patient approximately weekly in 
order to inquire about any attack that may have occurred.  The patient should be randomized as 
soon as possible after the second attack occurs, assuming all other screening activities have been 
completed and the patient meets all other eligibility requirements; in such cases, the Screening 
Period may be shorter than 56 days.  Once eligibility has been confirmed, patients will be 
randomized to receive ISIS 721744 80 mg or placebo once every 4 (Cohort A) or 8 (Cohort B) 
weeks for a total Treatment Period of up to 25 weeks. 
6.1.2. 
Treatment Period 
The first dose of ISIS 721744 or placebo will be administered at the Study Center on Day 1.  
Self-administration of Study Drug (ISIS 721744 or placebo), or administration by other qualified 
individuals (e.g., family member), may be allowed after dosing instructions and training have 
been provided by qualified site personnel.  If a dose is to be administered outside the Study 
Center, site personnel must also confirm that a home healthcare nurse is available to complete all 
pre-dosing procedures and that the patient has been instructed not to administer a dose until the 
home healthcare nurse has completed all protocol required pre-dose procedures.  ISIS 721744 or 
placebo will be administered as a SC injection in the abdomen, thigh, or outer area of the upper 
arm.  Study visits will be performed at the Study Center (or by Home Healthcare, if available) 
throughout the Treatment Period approximately every 28 days.  During the study, patients will be 
instructed to report details of any HAE attack to the study site within 72 hours of the onset of the 
attack.  During the Treatment and Post-Treatment Periods, the following data will be collected:  

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Angioedema Activity Score (AAS) and number of HAE attacks (confirmed by the Investigator); 
number of HAE attacks that required on demand treatment; HAE attack details, including 
localization, severity, course, and details of any required treatment (i.e., frequency and dose); 
and vital signs.  Throughout the Treatment and Post-Treatment Periods, site personnel will 
contact the patient approximately weekly in order to inquire about any attack that may have 
occurred.  In addition, during study visits, site personnel will inquire about any new HAE attack 
information that was not provided through patient contact with the site.  See Section 6.2.1 for 
further information on the collection of data surrounding HAE attacks.   
Additional assessments will be performed throughout the study as indicated in the Schedule of 
Procedures table in Appendix A. 
Patients who experience at least 5 attacks/month for 2 consecutive months after Week 5 will 
have the opportunity to terminate from the Treatment Period and either continue in the Post-
Treatment Period or enter into an OLE.  A decision to terminate a patient from the Treatment 
Period for this reason will be made by the Investigator or designee in consultation with the 
Sponsor Medical Monitor.  Patients who complete Study Visit Week 25, and meet eligibility 
requirements, may enroll in an OLE study after the Week 25 visit.  If a patient chooses to enroll 
in the OLE study, the patient will discontinue participation in ISIS 721744-CS5 prior to the first 
visit in the OLE study. 
Patients who discontinue treatment will attend the ET Visit and will be encouraged to complete 
the Post-Treatment Period, unless consent/assent is withdrawn. 
Detailed information regarding the study procedures is presented in Section 6 and Appendix A.  
Appendix B includes a list of laboratory analytes required for the study. 
6.1.3. 
Post-Treatment Period 
Each patient will be followed for safety assessments for up to 13 weeks after completion of, or 
ET from, the Treatment Period.  During the Post-Treatment Period, patients will return to the 
Study Center (or have Home Healthcare, if available), as arranged by the Study Center 
personnel, per the Schedule of Procedures in Appendix A for safety and clinical laboratory 
evaluations and for blood sampling for PK/PD analyses.  Alternatively, after completion of the 
Week 25 visit, eligible patients may elect to enroll in the OLE study, pending study approval by 
the IRB/IEC and the appropriate regulatory authority, and will need to sign the IRB/IEC 
approved informed consent and, as applicable, assent prior to enrollment.  Patients who complete 
Study Visit Week 25, and meet eligibility requirements, may enroll in the OLE study any time 
after the Week 25 visit.  If a patient chooses to enroll in the OLE study, the patient will 
discontinue participation in ISIS 721744-CS5 prior to the first visit in the OLE study. 
Assessments will be performed throughout the Post-Treatment Period as indicated in the 
Schedule of Procedures table in Appendix A. 

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6.2. 
Study/Laboratory Assessments  
6.2.1. 
Laboratory Assessments 
Laboratory analyte samples will be collected throughout the study.  A list of these analytes is 
contained in Appendix B.   
If the PLT value, serum creatinine, or liver enzyme tests are uninterpretable (e.g., due to 
clumping, hemolysis, or quantity not sufficient) or missing, a repeat blood specimen should be 
redrawn as soon as possible (ideally within 7 days) either in clinic or by Home Healthcare (if 
available) or local laboratory. 
All PLT count results, and liver and renal function tests, must be reviewed promptly (within 
48 hours of receipt) by the Investigator, or designee, to ensure that the result has not met the 
stopping rule. 
All lab alerts received, including those related to PLT, liver, or renal function 
monitoring/stopping rules, are also reviewed promptly by the Sponsor and the CRO Medical 
Monitors who will agree on actions to be taken.  Within 24 hours of receiving an actionable lab 
alert the CRO Medical Monitor will communicate instructions to the Investigator or designee 
and the study personnel by emailing them the Safety Surveillance Form that needs to be 
completed and signed by the Investigator or designee /study personnel and promptly returned to 
the Sponsor and CRO Medical Monitor.  In urgent cases, such as PLTs results below 
50,000/mm3, or liver or renal test results reaching a critical stopping rule, the Investigator or 
designee must also be contacted by phone. 
Investigators or designees may, at their discretion, test specific laboratory parameters which may 
be prone to clotting, clumping or hemolysis (e.g., hematology samples) at their local laboratory, 
in addition to the required central laboratory samples.  In these instances, the local laboratory 
results should be recorded by the site into the electronic database.  Assays which are blinded 
should not be locally tested and recorded into the database (e.g., PKK).  All lab sample results 
from the site’s local laboratories are received by the Study Center staff per the local laboratories’ 
standard reporting time, and should be entered as soon as possible (ideally within 1 week) into 
the electronic Case Report Form (eCRF) to inform the Sponsor and CRO study monitoring teams 
Further information on safety monitoring and actions to be taken by the Study Investigator or 
designee in the event of reduced PLT count are provided in Section 8.5.3 and Section 8.6.3. 
6.2.2. 
Physical Exams and Vital Signs 
Physical exams and vital signs will be performed as indicated in the Schedule of Procedures 
(Appendix A).  Vital signs should include weight, blood pressure, pulse rate, respiratory rate and 
body temperature.  Blood pressure and pulse rate will be recorded per the standard practice of the 
Study Center.  Blood pressure should always be measured on the same arm (preferentially on the 
left arm).  Height will be measured at Screening and for pediatric patients at Week 25. 

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6.2.3. 
Electrocardiography 
Electrocardiography will be conducted at Screening, Day 1 (prior to the first dose of Study 
Drug), and again during the Treatment Period and at the Post-Treatment Period visits as outlined 
in Appendix A.   
Electrocardiography will be recorded per the standard practice of the Study Center.   
6.2.4. 
Pharmacokinetic Sampling 
Blood samples for the determination of plasma ISIS 721744 concentrations will be collected 
prior to dosing on Day 1 and at various times throughout the Treatment and Post-Treatment 
Periods as noted in the table in Appendix C. 
6.2.5. 
Collection of Hereditary Angioedema Attack Details 
Historical HAE attack information will be collected at Screening.  During the study, patients will 
be instructed to report details of any HAE attack to the study site within 72 hours of the onset of 
the attack.  Throughout the Screening, Treatment, and Post-Treatment Periods, site personnel 
will contact the patient approximately weekly in order to inquire about any attack that may have 
occurred.  In addition, during study visits, site personnel will inquire about any new HAE attack 
information that was not provided through patient contact with the site. 
During the Screening, Treatment, and Post-Treatment Periods, detailed information on each 
HAE attack will be collected including the number of HAE attacks that required on-demand 
treatment and the details of any on-demand treatment used (frequency and dosing).  For each 
HAE attack, the following data will be collected:   
• Date/time of symptom onset 
• Location and description of symptoms: 
− Peripheral angioedema:  cutaneous swelling involving an extremity, face, neck, 
torso, and/or genitourinary region 
− Abdominal angioedema:  abdominal pain, with or without abdominal distension, 
nausea, vomiting, or diarrhea 
− Laryngeal angioedema:  stridor, dyspnea, difficulty speaking, difficulty 
swallowing, throat tightening, or swelling of the tongue, palate, uvula, or larynx 
• HAE attack severity: 
− Mild:  transient or mild discomfort 
− Moderate:  mild to moderate limitation in activity, some assistance needed 
− Severe:  marked limitation in activity, assistance required 
• Need for assistance, medical intervention, ER visit, or hospitalization 
• Medications to treat the attack 
• HAE attack course, including if the HAE attack(s) in question was a typical attack for 
the patient, or if there was an alternative diagnosis 
• Date/time symptoms resolved 

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The presence of these symptoms, including symptoms in one or more of the above locations, will 
not automatically be considered an HAE attack unless such a diagnosis is confirmed by the 
Investigator.  The investigator may feel that the presence of these symptoms does not represent a 
HAE attack if there are features that strongly refute such a diagnosis.  For example, if the 
reported event is accompanied by symptoms that are not consistent with an HAE attack (e.g., 
urticaria); if the reported event persists well beyond the typical course of time for an HAE attack 
(e.g., greater than 7 days); or if there is a likely alternative etiology for the event (e.g., viral 
gastroenteritis).   
An HAE attack will be defined as an event with signs or symptoms consistent with an attack in at 
least 1 of the locations noted above.  A discrete attack will be counted if there is at least 24-hour 
symptom-free period between attacks. 
6.2.6. 
Patient-Reported Outcomes 
6.2.6.1. 
Angioedema Quality of Life (AE-QoL) Questionnaire 
Quality of life (QOL) will be assessed by the AE-QoL questionnaire during Screening, 
Treatment, and Post-Treatment Periods as outlined in Appendix A.   
The AE-QoL questionnaire is a validated tool to assess symptom-specific health-related QOL 
impairment in patients suffering from recurrent angioedema (Weller et al. 2013).  The AE-QoL 
is a self-administered questionnaire that can be completed in less than 5 minutes; it comprises 
17 questions across 4 domains:  functioning, fatigue/mood, fears/shame, and food.  The AE-QoL 
can be used to calculate scores for the 4 individual domains and can also be used to determine a 
total score.  The AE-QoL will be completed by the patient. 
6.2.6.2. 
Angioedema Control Test (AECT) Questionnaire 
The AECT is a validated patient-reported outcome instrument to assess disease activity in 
patients with recurrent angioedema (Weller et al. 2020) which will be assessed during the 
Treatment and Post-Treatment Periods as outlined in Appendix A.  The AECT is easy to 
administer and fast to complete.  The questionnaire consists of four questions asking about the 
frequency and severity of angioedema experienced in the prior month.  Each question has 
5 response choices.  The AECT can be used to identify patients with poorly controlled disease by 
working with a cutoff value of greater than or equal to 10 points.  Patients who score less than 
10 points (0-9) in the AECT have poorly controlled disease whereas patients with controlled 
disease score 10-16 points.  The AECT will be completed by the patient. 
6.2.6.3. 
Angioedema Activity Score (AAS) 
Patients will be instructed on the use of the AAS questionnaire during Screening and will record 
their HAE attacks using the AAS questionnaire to confirm study eligibility.  The AAS 
questionnaire will be completed by patients daily (minimum of 4 daily assessments per week) 
during the Screening, Treatment, and Post-Treatment Periods.   
During the Screening Period, patients must experience a minimum of 2 HAE attacks (assessed 
by the AAS and confirmed by the Investigator) to be eligible for the study. 

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The AAS is a validated patient-reported outcome instrument to assess disease activity in patients 
with recurrent angioedema.  The AAS was designed as a diary-type tool and is easy to administer 
and fast to complete.  Using the AAS questionnaire, patients score each of 5 key 
symptoms-related factors from 0 to 3, resulting in a total daily score of 0 to 15 (Weller et al. 
2013). 
6.2.6.4. 
Additional PROs 
Additional instruments that will be used to collect information from patients during the 
Treatment and Post-Treatment Periods are summarized in this section.  Timing of these 
assessments is outline in Appendix A.  Generic health-related QOL will be assessed using the 
EQ-5D-5L.  The PGIC and the PGIS scales will also be administered throughout the study.  The 
PGIC and PGIS scales are administered for purposes of PRO validation and estimation of 
minimal important difference (MID).  A Generalized Anxiety Disorder (GAD-7) questionnaire 
will be administered to evaluate anxiety experienced by patients.  The GAD-7 is a self-
administered patient questionnaire, and it is used as a screening tool and severity measure for 
generalized anxiety disorder.  Pharmacoeconomics will be assessed by the Work Productivity 
and Activity Impairment (WPAI) questionnaire.  ER visits, hospitalization and total inpatient 
days will be assessed at each study visit starting at Day 1.   
6.3. 
Restriction on the Lifestyle of Patients 
6.3.1. 
Contraception Requirements  
All male patients and women of childbearing potential (WOCBP) must refrain from sperm/egg 
donation, and either be abstinent† or practice acceptable contraception from the time of signing 
the informed consent and, as applicable, assent form until at least 24 weeks after their last dose 
of Study Drug.   
For male patients engaged in sexual relations with a female of childbearing potential, if their 
female partner is using acceptable contraception from the time of the patient signing the 
informed consent and as applicable, assent until at least 24 weeks after the patient’s last dose of 
Study Drug, then it is not required for the male patient to also use an acceptable contraceptive 
method. 
For the purposes of this study, females 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 amenorrhea in females > 55 years of age 
or, in females ≤ 55 years, 12 months of spontaneous amenorrhea without an 
alternative medical cause and FSH levels in the postmenopausal range for the 
laboratory involved 
• 6 weeks after surgical bilateral oophorectomy with or without hysterectomy 
• Post-hysterectomy 

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For the purposes of the study, acceptable contraception is defined as follows: 
For male patients: 
• Acceptable male contraception includes a vasectomy with negative semen analysis at 
Follow-up, surgically sterile via bilateral orchidectomy, abstinence†, condom with 
spermicide or the non-pregnant female partner of child-bearing potential uses an 
acceptable contraceptive method (defined below) 
• Male patients with partners that are pregnant must use condoms as contraception to 
ensure that the fetus is not exposed to the Study Drug  
For female patients and female partners of male patients, acceptable contraception methods 
comprise: 
• Surgical sterilization (e.g., bilateral tubal occlusion, hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy), hormonal contraception associated with 
inhibition of ovulation (progestogen-only [female patients with HAE] or combined 
estrogen and progesterone [female partners of male patients]), intrauterine 
contraception device or intrauterine hormone-releasing system or a vaginal ring (as 
long as the patient has been using this contraceptive method for at least 3 months 
before Screening) or vasectomized partner with negative semen analysis at follow-up, 
male or female condom with spermicide; or cap, diaphragm, or sponge with 
spermicide.  Female patients with HAE cannot use estrogen containing oral, 
subcutaneous, or transdermal contraceptives in this study. 
†Note: Abstinence (i.e., refraining from heterosexual intercourse throughout the duration of 
study participation) 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 2 can result in either or both products failing 
6.4. 
Emergency Provisions 
During an emergency, such as a pandemic, natural or man-disasters (i.e., earthquake, industrial 
accident), weather events (i.e., hurricanes, typhoons), terrorist acts/acts of war, etc., the 
following changes to this protocol are allowed without formal amendment to the protocol, 
provided all International Conference on Harmonization (ICH), Good Clinical Practice (GCP), 
and regulatory requirements associated with the study are upheld.   
• Remote Assessments and At-Home visits:  Scheduled clinic visits may be replaced by 
remote assessments (via video conference or telephone call), or at-home visits, or a 
combination thereof, provided that these are properly documented.  This may be 
accomplished by at-home visits by Study Center staff or home healthcare providers, with 
incorporation of videoconference or telephone assessments by Study Center staff or 
designee 

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• Randomization:  When a participant is found to be eligible for the study, the decision 
regarding if and when randomization will occur is based on the judgment of the 
Investigator or designee in consultation with the Sponsor.  Randomization may be 
delayed by up to 1 month without rescreening 
• Study Drug Administration:  To support Study Drug administration at home, delivery 
of Study Drug to a participant may be undertaken at the discretion of the Investigator or 
designee, based on local and regional regulations for transporting investigational product 
• Safety Assessments:  Every effort should be made to continue performing safety 
assessments on schedule.  This may require remote assessments (e.g., for adverse events 
and concomitant medications) by Study Center staff, and it may require at home visits 
(e.g., for blood draws, urine samples, physical examination, vital signs) by Study Center 
staff or home healthcare providers.  Which safety assessments are considered critical, for 
example to support a decision on whether to administer the next scheduled dose of Study 
Drug, is to be determined on a case-by case basis by the Investigator or designee in 
consultation with the Sponsor 
• Other Assessments:  Every effort should be made to perform the assessments related to 
primary or secondary endpoints on schedule 
• Reporting of Protocol Deviations:  All protocol deviations that are caused by a public 
health emergency should be documented as such; for example, include in the description 
of the protocol deviation that it is related to COVID-19.  The impact of such protocol 
deviations on the study is to be summarized in the clinical study report.  This summary is 
considered sufficient notification of the EC/IRB for minor protocol deviations that were 
caused by a public health emergency 
• Immunization:  Immunization of participants with a vaccine for an epidemic/pandemic 
may occur while participants are on study, however it is preferable that a separation of at 
least 7 days occurs between administration of the vaccine and administration of Study 
Drug.  Adjustment of the Study Drug schedule may be considered in order to achieve this 
separation in consultation with the Sponsor 
An event requiring institution of emergency provisions is based on the judgement of the 
Investigator or designee in consultation with the Sponsor.  The determination of when an 
emergency has resolved to sufficient extent such that these allowances are no longer needed is 
also based on the judgment of the Investigator or designee in consultation with the Sponsor. 
7. 
STUDY DRUG 
7.1. 
Study Drug Description 
Study Drug (ISIS 721744 or placebo) characteristics are listed in Table 1. 
The Study Drug (ISIS 721744 or placebo) is contained in 2 mL stoppered glass vials.  The Study 
Drug (ISIS 721744 or placebo) and its storage and preparation instructions will be provided by 
the Sponsor or designee.  The Study Drug (ISIS 721744 or placebo) must be stored securely at 
2 °C to 8 °C and be protected from light. 

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During the Treatment Period, Study Drug (ISIS 721744 or placebo) will be administered as a 
single-SC injection once every 4 (Cohort A) or 8 (Cohort B) weeks.   
Table 1: 
Study Drug Characteristics 
Study Drug 
ISIS 721744 
Placebo 
Strength 
100 mg/mL  
Not Applicable 
Volume/Formulation 
0.8 mL solution per vial  
0.8 mL solution per vial 
Route of Administration 
SC 
SC 
 
7.2. 
Packaging and Labeling 
The Sponsor will provide the Investigator or designee with packaged Study Drug (ISIS 721744 
or placebo) labeled in accordance with specific country regulatory requirements. 
7.3. 
Study Drug Accountability 
The study staff is required to document the receipt, dispensing, and return/destruction of Study 
Drug (ISIS 721744 or placebo) supplies provided by the Sponsor according to Sponsor 
instruction and in accordance with institutional policy. 
8. 
TREATMENT OF PATIENTS 
8.1. 
Study Drug Administration 
Study Drug (ISIS 721744 or placebo) will be administered as a single SC injection once every 
4 (Cohort A) or 8 (Cohort B) weeks by blinded study staff during on-site visits at the Study 
Centers or by Home Healthcare professional.  Self-administration of ISIS 721744 or placebo 
may be allowed after dosing instructions and training are provided by qualified site personnel 
and home healthcare nurse is available to complete all pre-dosing procedures. 
Vials of Study Drug (ISIS 721744 or placebo) are for single use only. 
Please refer to the Study Drug Manual provided by the Sponsor or designee for more detailed 
instructions for Study Drug (ISIS 721744 or placebo) preparation and administration. 
8.2. 
Other Protocol-Required Drugs 
Patients must have access to, and the ability to use, ≥ 1 acute HAE medication(s) (e.g., plasma-
derived or recombinant C1-INH concentrate or a BK2-receptor antagonist) to treat angioedema 
attacks.  During the course of the study, the use of acute HAE medications (plasma-derived or 
recombinant C1-INH concentrate, BK2-receptor antagonist, or kallikrein inhibitor) to treat 
angioedema attacks is allowed as medically indicated.  Patients can be treated with on-demand 
therapy as determined by their treating physician. 

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8.3. 
Other Protocol-Required Treatment Procedures 
There are no other protocol-required treatment procedures.   
8.4. 
Treatment Precautions 
There are no specific treatment precautions required.   
8.5. 
Safety Monitoring Rules 
Stopping rules are described below in Section 8.6. 
Please refer also to the ‘Guidance for Investigator’ section of the Investigator’s Brochure. 
• For the purposes of safety monitoring baseline is defined as the average of the pre-dose 
Study Day 1 value and the last value prior to Study Day 1 
• In addition to the standard monitoring of clinical safety parameters, the following 
guidelines are provided for the monitoring of selected parameters chosen based on 
preclinical and clinical observations 
• In case of discrepancy between the test results from 2 sources, such as between the 
central and local lab, safety-mandated action must be initiated based on the more critical 
(lower or higher, as relevant) of the 2 values 
Confirmation Guidance:  At any time during the study (Treatment or Post-Treatment Periods), 
the initial clinical laboratory results meeting the safety monitoring criteria presented below must 
be confirmed by performing measurements (ideally in the same laboratory that performed the 
initial measurement) on new specimens.  All new specimen collections should take place as soon 
as possible (ideally within 3 days of the initial collection).  For stopping rules, if the initial 
laboratory result is observed during the Treatment Period, the results from the retest must be 
available prior to administering the next dose of Study Drug (ISIS 721744). 
Re-dosing Guidance:  Patients with initial laboratory test values that reach a stopping rule must 
not be re-dosed until the re-test results are available.  In general, patients who do not meet the 
stopping rules based upon retest may continue dosing.  However, the Investigator or designee 
and the Sponsor Medical Monitor (or appropriately qualified designee) should confer as to 
whether additional close monitoring of the patient is appropriate.  If any of the stopping criteria 
described in Section 8.6 are met, the patient will be permanently discontinued from further 
treatment with Study Drug (ISIS 721744), evaluated fully as outlined below and in consultation 
with the Sponsor Medical Monitor or appropriately qualified designee, and will be followed up 
in accordance with Section 8.8 of the Protocol.   
8.5.1. 
Safety Monitoring Rules for Liver Chemistry Tests 
The following rules are adapted from the draft guidance for industry, “Drug-Induced Liver 
Injury:  Premarketing Clinical Evaluation,” issued by the U.S.  Department of Health and Human 
Services, Food and Drug Administration, July 2009.  For a definition of Baseline please refer to 
guidance in Section 8.5 above. 

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All patients will have liver chemistry tests monitored every 4 weeks during the Treatment 
Period.  Upon completion of the study Treatment Period, liver chemistry tests should be 
monitored as per visit schedule in Appendix A. 
In the event of appearance of symptoms or signs of hepatic injury (jaundice, fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, abnormal bleeding or bruising, or 
eosinophilia > ULN) liver enzymes and bilirubin should be tested as soon as possible (ideally 
within 3 days).  Testing at a lab that is local to the patient is permissible for this purpose. 
In the event of an ALT or AST measurement that is > 3 × ULN (or the greater of 2 × baseline 
value or 3 × ULN if the baseline value was > ULN) at any time during the study (Treatment or 
Post-Treatment Period), the initial measurement(s) should be confirmed as described above.  
Additional confirmatory measurements should also be performed if ALT or AST levels increase 
to 5 × ULN. 
Frequency of Repeat Measurements:  Patients with confirmed ALT or AST levels > 3 × ULN (or 
the greater of 2 × baseline value or 3 x ULN if the baseline value was > ULN) should have their 
liver chemistry tests (ALT, AST, Alkaline Phosphatase (ALP), international normalized ratio 
[INR], and total bilirubin) retested at least once-weekly until ALT and AST levels become 
≤ 1.2 × ULN or 1.2 × baseline value if the baseline value was > ULN]. 
Further Investigation into Liver Chemistry Elevations:  For patients with confirmed ALT or AST 
levels > 3 × ULN (or the greater of 2 × baseline value or 3 × ULN if the baseline value was 
> ULN), the following evaluations should be performed: 
1. Obtain a more detailed history of symptoms and prior and concurrent diseases 
2. Obtain further history for concomitant drug use (including nonprescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets 
3. Obtain a history for exposure to environmental chemical agents and travel 
4. Serology for viral hepatitis (hepatitis A virus immunoglobulin M [IgM], hepatitis B 
surface antigen [HBsAg], Hepatitis C Virus antibody, cytomegalovirus IgM, and EBV 
antibody panel) 
5. Serology for autoimmune hepatitis (e.g., antinuclear antibody [ANA]) 
Additional liver evaluations, including gastroenterology/hepatology consultations, hepatic 
computerized tomography (CT) or magnetic resonance imaging (MRI) scans, may be performed 
at the discretion of the Investigator or designee, in consultation with the Sponsor Medical 
Monitor.  Repetition of the above evaluations should be considered if a patient’s ALT and/or 
AST levels reach 5 × ULN. 
The Study Drug must be interrupted until all evaluations and consultation with the Sponsor 
Medical Monitor is complete. 
All lab alerts for abnormal liver function tests must be promptly reviewed by the Investigator or 
designee (within 48 hours of receipt) and Medical Monitor(s) (within 24 hours of receipt) as 
described in Section 6.2.1.   

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Lab alerts for abnormal liver chemistry tests will be issued for:  1) ALT or AST > 3 × ULN; 
2) ALT or AST > 2 × baseline; 3) total bilirubin > ULN.  These alert levels are set to anticipate 
the risk of a combined elevation of aminotransferases and bilirubin as per the FDA Guidance 
referenced in Section 8.5 above. 
8.5.2. 
Safety Monitoring Rules for Renal Function Test Results 
While on treatment, all patients will have renal function tests monitored every 4 weeks during 
the Treatment and Follow-up Periods as per visit schedule in Appendix A. 
In the event of appearance of symptoms or signs consistent with renal dysfunction such as 
hematuria, polyuria, anuria, flank pain, new-onset hypertension, nausea and/or anorexia, renal 
function should be tested as soon as possible (ideally within 3 days).  Testing at a lab that is local 
to the patient is permissible for this purpose. 
If a patient’s results meet criteria 1 or 2 below, the Investigator or designee should confirm the 
results and initiate weekly monitoring if confirmed.  If the event a persistent elevation is 
observed over 2 consecutive weeks, then refer to Stopping Rules for Renal Function Test Results 
in Section 8.6.2. 
1. Serum creatinine increase that fulfills all of the following:  ≥ 0.3 mg/dL (26.5 μmol/L) 
and ≥ 40% above baseline creatinine values and > ULN (refer to definition of Baseline in 
Section Stopping Rules Section 8.6) 
2. Proteinuria, urine protein/creatinine ratio (UPCR) > 750 mg/g for baseline values 
≥ 200 mg/g, or 4 × baseline value for baseline values < 200 mg/g that are confirmed by 
repeated urine protein/creatinine ratio or by a quantitative total urine protein 
measurement of > 1.0 g/24 hours 
8.5.3. 
Safety Monitoring Rules for Platelet Count Results 
Platelet count will be monitored at least every 4 weeks during the Treatment and Post-Treatment 
Periods as per visit schedule in Appendix A. 
The Investigator or the designee should review all PLT count results within 48 hours of receipt.  
Any unreportable PLT count result must be rechecked ideally within 7 days and determined not 
to have met a stopping rule before dosing can continue. 
Actions to be taken in the event of reduced PLT count are shown in Table 2. 
 
 

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Table 2: 
Actions in Patients with Confirmed Low Platelet Count 
Platelet count 
(K/mm3) 
Dosing 
Monitoring frequency 
≥ 125  
No action 
At least every 4 weeks. 
> 100 to < 125 
Dosing every 4 (Cohort A) or 
8 (Cohort B) weeks should be 
continued.   
At least every 2 weeks until 2 successive values 
> 125K/mm3. 
≥ 75 to ≤ 100 
Dosing every 4 (Cohort A) or 
8 (Cohort B) weeks may be 
continued if approved by the 
Sponsor Medical Monitor. 
Every week until 2 successive values 
> 100K/mm3. 
Consider more frequent monitoring if additional 
risk factors for bleeding are present.* 
≥ 50 to < 75 
Pause dosing.  When PLT count 
returns to > 100K/mm3, restart 
dosing only if approved by the 
Sponsor Medical Monitor.   
Twice weekly until 2 successive values 
> 75K/mm3, then weekly until 2 successive 
values > 100K/mm3. 
Consider more frequent monitoring if additional 
risk factors for bleeding are present.* 
≥ 25 to < 50 
Permanently discontinue Study 
Drug. 
Consider corticosteroids if 
additional risk factors for 
bleeding are present.**  
Twice weekly until 2 successive values 
> 75K/mm3, then weekly until 2 successive 
values > 100/mm9.   
Consider more frequent monitoring if additional 
risk factors for bleeding are present.* 
< 25 
Permanently discontinue Study 
Drug. 
Corticosteroids strongly 
recommended.** 
Daily until 2 successive values > 25K/mm3, 
then twice weekly until 2 successive values 
> 75K/mm3, then weekly until 2 successive 
values > 100K/mm3.   
Consider more frequent monitoring if additional 
risk factors for bleeding are present.* 
* The suitability of the patient for interrupted and/or continued dosing will be determined by the Investigator or 
designee in consultation with the Medical Monitor and will be based on factors such as the original rate of 
decline in the patient’s PLT count, whether any bleeding events were experienced by the patient, and the speed 
of recovery of PLT count after interruption of dosing. 
** Recovery in platelet count may be accelerated by administration of high-dose glucocorticoids.  Treatment as 
recommended by the American Society of Hematology (ASH) (2019) guidelines for immune thrombocytopenia 
(Blood Advances, 10 DECEMBER 2019, Volume 3, Number 23) includes initial therapy with either 
dexamethasone 40 mg per day for 4 days, or prednisone 0.5 to 2.0 mg/kg per day.  Prednisolone or prednisone 
may be administered for up to 2 to 4 weeks with taper; alternatively, intravenous immunoglobulin (IVIG) may be 
administered at 0.4 g/kg/d for 5 days, or infusions of 1 g/kg/d for 1-2 days (Provan et al. 2010; Provan et al. 
2019). 
 
There will be lab alerts for PLT values under 100,000/mm3. 

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8.5.4. 
Safety Monitoring for Bleeding Events 
Patients will be evaluated for occurrence of bleeding events continuously after the start of Study 
Drug treatment (Day 1) up to the end of the Follow-up Period.  All bleeding events are 
considered AEs and reported on the AE case report form (CRF). 
If an event of major bleeding (MB) or clinically relevant non-major bleeding (CRNMB) event 
occurs (as defined below), the Investigator or designee must notify the Medical Monitor (or 
designee) and the patient should be treated, as needed, immediately and closely monitored (vital 
signs, lab tests such as hemoglobin (Hb), hematocrit, and PLT count, additional visits, overnight 
stays and coagulation tests may be needed if deemed appropriate by the treating physician) 
throughout the Treatment and Post-Treatment Periods and an (S)AE CRF will be completed.  In 
addition, approximately 2 mL of K2 EDTA anticoagulated blood will be collected and resulting 
plasma must be stored allowing for a centralized assessment of ISIS 721744 concentrations. 
If a minor bleeding event occurs, the Investigator or designee should notify the Medical Monitor 
(or designee) and additional testing of coagulation parameters (activated partial thromboplastin 
time [aPTT], prothrombin time [PT], INR), PLT count, and PLT volume may be performed. 
Major bleeding is defined as one of the following (Schulman and Kearon 2005): 
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 pericardial, or 
intramuscular with compartment syndrome 
3. Clinically overt bleeding leading to transfusion of ≥ 2 units of packed RBCs 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 is defined as any sign or symptom of hemorrhage (e.g.  
more bleeding that would be expected for a clinical circumstance, including bleeding found by 
imaging alone) that does not fit the criteria for MB but does meet at least one of the following 
criteria (Kaatz et al. 2015): 
1. Requiring medical intervention by a healthcare professional 
2. Leading to hospitalization or increased level of care 
3. Prompting a face to face (i.e., not just a telephone or electronic communication) 
evaluation 
Minor bleeding events are those that do not fulfill the criteria for MB or CRNMBs (defined 
above), for example excess bruising, petechiae, gingival bleeding on brushing teeth. 
8.6. 
Stopping Rules 
Monitoring rules are described above in Section 8.5. 
For the purposes of the stopping rules, Baseline is defined as the average of the pre-dose Study 
Day 1 value and the last value prior to Study Day 1.   

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8.6.1. 
Stopping Rules for Liver Chemistry Elevations 
In the event of laboratory results meeting the following criteria, and the event is without an 
alternative explanation as discussed with the Sponsor Medical Monitor, dosing of a patient 
with Study Drug (ISIS 721744 or placebo) will be stopped permanently; values that are not 
confirmed due to failure to retest or missing lab values will be presumed confirmed: 
1. ALT or AST > 8 × ULN, which is confirmed 
2. ALT or AST > 5 × ULN, which is confirmed and persists for ≥ 2 weeks 
3. ALT or AST > 3 × ULN (or the greater of 2 x baseline value or 3 × ULN if the baseline 
value was > ULN), which is confirmed and total bilirubin > 1.5 × ULN or INR > 1.5 
4. ALT or AST > 3 × ULN (or the greater of 2 x baseline value or 3 x ULN if the baseline 
value was > ULN), which is confirmed, and the new appearance (i.e., onset coincides 
with the changes in hepatic enzymes) of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or concomitant eosinophilia (> ULN) 
8.6.2. 
Temporary Stopping Rules for Renal Function Test Results 
In the event of a persistent elevation that is observed over 2 consecutive weeks, for either of the 
2 criteria below, dosing of a patient with Study Drug (ISIS 721744 or placebo) may be stopped 
temporarily: 
1. Serum creatinine increase that fulfills all of the following criteria:  ≥ 0.3 mg/dL 
(26.5 μmol/L) and ≥ 40% above baseline creatinine values and > ULN (refer to 
definition of Baseline in Section 8.6) 
2. UPCR >1000 mg/g, confirmed by a quantitative total urine protein measurement of 
> 1.0 g/24 hours 
The possible dosing re-initiation or follow-up schedule for any events meeting either of these 
criteria will be determined by the Investigator or designee in consultation with the Sponsor 
Medical Monitor or designee. 
8.6.3. 
Stopping Rules for Platelet Count Results 
Actions to be taken in the event of a low PLT count are summarized in Table 2 above. 
8.6.4. 
Stopping Rules for Bleeding Events 
In the event of MB or CRNMB (see definitions in Section 8.5.4 as assessed by the Investigator 
or designee, dosing of a patient with Study Drug (ISIS 721744 or placebo) may be stopped 
permanently.  The follow-up schedule for any events meeting this stopping criterion will be 
determined, including the suitability of the patient for resumption of dosing by the Investigator 
or designee in consultation with the Medical Monitor (or designee).   

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8.7. 
Adjustment of Dose and/or Treatment Schedule 
Down-titration of Study Drug (ISIS 721744 or placebo) will not be allowed during the study. 
Dose adjustments for PLT count reduction must be made in accordance with Table 2. 
Other adjustments, including dose interruptions, will be allowed for safety or tolerability after 
consultation with the Sponsor Medical Monitor. 
8.8. 
Discontinuation of Study Drug/Treatment 
A patient must permanently discontinue study treatment for any of the following: 
• The patient becomes pregnant.  Report the pregnancy according to instructions in 
Section 9.5.4  
• The patient withdraws consent or assent 
• The patient withdraws from treatment (but does not withdraw consent or assent) 
• The patient experiences an AE that necessitates permanent discontinuation of Study 
Drug 
• The patient develops laboratory test abnormalities that meet any of the stopping rules 
listed in Section 8.6 
• The patient experiences an AE that necessitates unblinding of the Investigator or 
designee or Sponsor to the patient’s treatment assignment 
The reason for discontinuation of Study Drug must be recorded in the eCRF and source 
documentation. 
Patients who discontinue Study Drug will remain in the study and attend the Tx-ET Visit 
(Week 25 visit assessments), unless consent or assent is withdrawn.  Any patient who 
discontinues early from the Treatment Period should be strongly encouraged to complete the 
Post-Treatment Period study visits, procedures and observations (see Appendix A). 
8.8.1. 
Follow-up Visits for Early Termination from Treatment Period or 
Post-Treatment Period 
If a patient discontinues early from the Treatment Period, Treatment Early Termination (Tx-ET) 
visit assessments should be performed 28 days from the last dose of Study Drug, and patients 
should start the 13 weeks Post-Treatment Period to collect the study assessments in accordance 
with the Schedule of Procedures in Appendix A.  Patients should also be strongly encouraged to 
attend the landmark visit at Week 25 if they discontinue prior to Week 25 to collect HAE attacks 
and conduct safety assessments in accordance with Appendix A.  Depending on the day of 
discontinuation, Post-Treatment visits and the landmark visit may overlap and can be combined.   
Any patient who chooses to discontinue early from the Post-Treatment Period should be strongly 
encouraged to complete safety procedures and observations in accordance with Appendix A.  If 
the patient declines or is unable to participate in the above, final Post-Treatment Early 
Termination (Post-Tx ET) assessments should be performed at the time of withdrawal in 
accordance with Appendix A. 

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8.8.2. 
Temporary Pause/Safety Review 
The trial should be halted for a safety review based on the following criteria: 
• Death in any subject in which the cause of death is judged to be probably or definitely 
related to the study drug by the treating investigator 
• The occurrence in any subject of a life-threatening SAE that is assessed to be related 
to the study drug by the treating investigator 
• Two occurrences of Grade 3 or higher toxicities that are assessed to be related to the 
study drug by the treating investigator 
• Two occurrences of a clinically significant Grade 3 or higher laboratory abnormality 
assessed to be related to the study drug by the treating investigator 
8.9. 
Withdrawal of Patients from the Study Procedures 
Patients must be withdrawn from study procedures for any of the following: 
• Withdrawal of consent or assent 
• The patient is unwilling or unable to comply with the protocol 
• The patient meets any of the Exclusion Criteria (see Section 5.2) after enrolling in the 
study that in the opinion of the Investigator represents a safety risk to the patient 
Other reasons for withdrawal of patients from the study may include the following: 
• At the discretion of the Investigator or designee for medical reasons 
• At the discretion of the Investigator or designee or Sponsor for non-compliance 
• 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 patient who withdraws consent or assent to participate in the study will be removed from 
further treatment and study observation immediately upon the date of request.  These patients 
should be encouraged to complete the respective ET study procedures (Week 25 or Post-
Treatment Week 13 visit assessments) and observations at the time of withdrawal (see 
Appendix A). 
For patients withdrawn for reasons other than withdrawal of consent or assent, every effort 
should be made to complete the ET study procedures and observations at the time of withdrawal 
(see Appendix A) and ideally within 4 weeks from the last dose of Study Drug. 
8.10. 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined below must be recorded on the patient’s 
eCRF.  Adverse events related to administration of these therapies or procedures must also be 
documented on the appropriate eCRF. 

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8.10.1. 
Concomitant Therapy 
A concomitant therapy is any non-protocol-specified drug or substance (including over-the-
counter medications, herbal medications, and vitamin supplements) administered between 
Screening and the end of the Post-Treatment Period. 
Allowed Concomitant Therapy 
During the course of the study, the use of acute HAE medications (plasma-derived or 
recombinant C1-INH concentrate, BK2-receptor antagonist, or kallikrein inhibitor) to treat 
angioedema attacks is allowed as medically indicated.  Patients can be treated with on-demand 
therapy as determined by their treating physician. 
All other stable medications (if not excluded below) are allowed, so long as the dose and type is 
not expected to change during the study. 
Disallowed Concomitant Therapy 
1. Chronic prophylaxis for angioedema attacks, except for a stable dose of androgens or 
tranexamic acid.  Any chronic use of other HAE prophylactic agents such as 
lanadelumab or berotralstat will not be permitted during the Treatment Period. 
NOTE:  The use of acute HAE medications (plasma-derived or recombinant C1-
INH concentrate, BK2-receptor antagonist, or kallikrein inhibitor) to treat 
angioedema attacks is allowed as medically indicated 
2. ACE inhibitors or any estrogen-containing medications with systemic absorption 
(such as oral contraceptive or hormonal replacement therapy) 
3. Any oligonucleotides (including siRNA) other than ISIS 721744 
4. Any other investigational drug or device 
Patients should consult with the Investigator or designee prior to initiating any new medication, 
including non-prescription or herbal compounds or any non-drug therapy. 
8.10.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
Screening and the end of the Post-Treatment Period. 
Disallowed Concomitant Procedures 
Plasma apheresis is not allowed during the study. 
8.11. 
Treatment Compliance 
Compliance with treatment dosing is to be monitored and recorded in the eCRF by Study Center 
staff. 

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9. 
SERIOUS AND NON-SERIOUS ADVERSE EVENT REPORTING  
9.1. 
Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor or designee in 
accordance with the applicable Ionis and/or designee Standard Operating Procedures throughout 
the conduct of the clinical study. 
9.2. 
Regulatory Reporting Requirements 
The Sponsor or designee is responsible for regulatory submissions and reporting to the 
Investigators or designees of SAEs including SUSARs per the ICH guidelines E2A and ICH 
GCP.  Country-specific regulatory requirements will be followed in accordance with local 
country regulations and guidelines. 
Institutional Review Boards/Independent Ethics Committees will be notified of any SAE 
according to applicable regulations.  The DSMB will be notified of any SAE as specified in the 
DSMB charter. 
In addition to the Investigator’s or designee’s assessment of relatedness, the Sponsor or designee 
will evaluate the available information and perform an independent assessment of all reported 
SAEs and determine if there is a reasonable possibility that the Study Drug (ISIS 721744 or 
placebo) is causally related to a reported SAE and, therefore, meets the definition of an SUSAR.  
While the Sponsor’s independent causality assessment may differ from the Investigator’s or 
designee’s assessment, the country-specific regulatory requirements must be followed for 
expedited reporting of SUSAR to local regulatory authorities. 
Appropriate personnel at the Sponsor or designee will unblind SUSARs for the purpose of 
regulatory reporting.  The Sponsor or designee will submit SUSARs to Regulatory Agencies in 
blinded or unblinded fashion according to local law.  The Sponsor or designee will submit 
SUSARs to Investigators or designees in a blinded fashion. 
For the purpose of regulatory reporting of SUSARs, there are not “expected” AEs in this study 
population.  Investigator’s Brochure (provided separately) for expected adverse events. 
SAEs due to HAE attacks will not be reported on an individual basis in an expedited manner 
because they are anticipated to occur in the study population independent of the Study Drug 
(ISIS 721744 or placebo) exposure.  The Investigator or designee still has the responsibility to 
report all SAEs to the Sponsor as described in Section 9.4.1 to Section 9.4.3.5. 
HAE attacks will be reported on a HAE attack CRF page and will not be reported as AEs.   
The Sponsor or designee and DSMB will monitor these protocol-specified SAEs using the 
incidence rate of the event in the study compared to the expected incidence rate in a non-Study 
Drug exposed patient population.  If the aggregate analysis indicates that an event is occurring 
more frequently or at a greater severity than expected, then the event will be reported. 

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9.3. 
Definitions 
9.3.1. 
Adverse Event 
An adverse event (AE) can be any unfavorable and unintended sign (including an abnormal 
laboratory finding, for example), symptom, or disease temporally associated with the use of 
medicinal (investigational) product, whether or not the AE is considered related to the medicinal 
(investigational) product. 
An adverse event can therefore be any of the following: 
• Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product 
• Any new disease or exacerbation of an existing disease (a worsening in the character, 
frequency, or severity of a known condition) 
• Recurrence of an intermittent medical condition (e.g., headache) not present at 
Baseline 
• Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from Study Drug 
• Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive procedures 
such as biopsies) 
9.3.2. 
Adverse Drug Reaction and Suspected Unexpected Adverse Drug Reaction 
Adverse Drug Reaction (ADR) 
In the pre-approval clinical experience with a new medicinal product or its new usages, 
particularly as the therapeutic dose(s) may not have been established, ADR is defined as follows: 
All noxious and unintended responses to a medicinal product related to any dose should 
be considered adverse drug reactions. 
The phrase "responses to a medicinal product" means that a causal relationship between the 
medicinal product and the adverse event has been determined by the Sponsor as at least a 
reasonable possibility, i.e., the relationship cannot be ruled out. 
Suspected Unexpected Adverse Drug Reaction  
A suspected unexpected ADR is any ADR, the nature or severity of which is not consistent with 
the applicable product information, e.g., Investigator's Brochure for an unapproved medicinal 
(investigational) product. 
A suspected adverse reaction implies a lesser degree of certainty about causality than an adverse 
reaction. 

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9.3.3. 
Serious Adverse Event (SAE) 
A SAE is any adverse event that in the view of either the Investigator or designee 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 designee or Sponsor, its occurrence places the patient at 
immediate risk of death.  It does not include an AE or suspected adverse reaction that, 
had it occurred in a more severe form, might have caused death 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
Hospitalization is defined as an admission of greater than 24 hours to a medical 
facility and does not always qualify as an AE 
• Results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
• Results in a congenital anomaly or birth defect in the offspring of the patient (whether 
the patient 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 patient 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 ER or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse. 
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of an 
adverse event (e.g., rated as mild, moderate, or severe, or according to National Cancer Institute 
Common Terminology Criteria for Adverse Events [NCI CTCAE]; OR Toxicity Grading Scale 
for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials; the 
event itself may be of relatively minor medical significance (such as severe headache without 
any further findings). 
Severity and seriousness need to be independently assessed for each adverse event recorded on 
the eCRF. 
9.3.4. 
Adverse Event of Special Interest (AESI) 
For the purpose of this study, severe reductions in PLT count < 50,000/mm3 accompanied by a 
MB event or CRNMB event, or PLT count of < 25,000/mm3 independent of a MB or CRNMB 
event, are considered as AEs of special interest (AESIs) and are subject to 15-day expedited 
reporting by the Sponsor to the regulatory agencies. 

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Adverse events of special interest are required to be reported by the Investigator or designee to 
the Sponsor immediately, within 24 hours of the Study Center’s first knowledge of the event, for 
expedited reporting to Regulatory Authorities. 
9.4. 
Monitoring and Recording Adverse Events 
Any pre-existing conditions or signs and/or symptoms present in a patient prior to the start of the 
study (i.e., before informed consent and, as applicable, assent) should be recorded as Medical 
History and not recorded as AEs unless the pre-existing condition worsened.  The Investigator or 
designee should always group signs and symptoms into a single term that constitutes a single 
unifying diagnosis if possible.  Before a diagnosis is confirmed, all symptoms should be 
reported as separate AEs. 
9.4.1. 
Serious Adverse Events (SAE) 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs 
(regardless of their relationship to Study Drug) should be reported to the Sponsor or designee 
within 24 hours of the Study Center’s first knowledge of the event.  The collection of SAEs will 
begin after the patient signs the ICF and will stop at the end of the patient’s Post-Treatment 
Period, which is defined as completion of the Week 13 Visit of the Post-Treatment Period, or 
patient has Day 1/Week 1 in the OLE study.  Serious adverse events should be reported using 
electronic SAE submission (via Electronic Data Capture [EDC]) whenever possible.  In 
situations where electronic SAE submission is unavailable, a paper Initial Serious Adverse Event 
Form should be completed, and a copy should be faxed or emailed to the Sponsor or designee.  
The SAE reporting instructions, including the fax number and email address, can be found in the 
Investigator Site File for the study.   
Detailed information should be actively sought and included as Follow-Up as soon as additional 
information becomes available.  All SAEs will be followed until resolution.  Serious adverse 
events that remain ongoing past the patient’s last protocol-specified visit will be evaluated by the 
Investigator or designee and Sponsor.  If the Investigator or designee and Sponsor agree that the 
patient’s condition is unlikely to resolve, the Investigator or designee 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 patient signs the ICF and will stop at the 
end of the patient’s Post-Treatment Period, which is defined as completion of the Week 13 Visit 
of the Post-Treatment Period, or patient has Day 1/Week 1 in the OLE study.  The Investigator 
or designee will monitor each patient closely and record all observed or volunteered AEs on the 
eCRF. 
9.4.3. 
Evaluation of Adverse Events (Serious and Non-Serious) 
The Investigator’s or designee’s opinion of the following should be documented on the Adverse 
Event Case Report Form: 

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9.4.3.1. 
Relationship to the Study Drug 
The event’s relationship to the Study Drug (ISIS 721744 or placebo) is characterized by 1 of the 
following: 
• Related:  There is clear evidence that the event is related to the use of Study Drug 
(ISIS 721744 or placebo), e.g., confirmation by positive re-challenge test 
• Possible:  The event cannot be explained by the patient’s medical condition, 
concomitant therapy, or other causes, and there is a plausible temporal relationship 
between the event and Study Drug (ISIS 721744 or placebo) administration 
• Unlikely/Remote:  An event for which an alternative explanation is more likely (e.g., 
concomitant medications or ongoing medical conditions) or the temporal relationship 
to Study Drug (ISIS 721744 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 patient’s underlying medical 
condition, concomitant therapy, or other causes, and therefore, the Investigator or 
designee believes no relationship exists between the event and Study Drug 
(ISIS 721744 or placebo) 
9.4.3.2. 
Severity 
The severity of AEs and SAEs relating to laboratory tests will be graded based on criteria from 
the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive 
Vaccine Clinical Trials, Sept. 2007 (refer to Appendix D).  Any AE not listed in Appendix D 
will be graded as follows: 
• Mild:  The event is easily tolerated by the patient and does not affect the patient’s 
usual daily activities 
• Moderate:  The event causes the patient more discomfort and interrupts the patient’s 
usual daily activities 
• Severe:  The event is incapacitating and causes considerable interference with the 
patient’s usual daily activities 
The severity of AEs and SAEs relating to AEs at the injection site will be graded based on 
criteria from the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled 
in Preventive Vaccine Clinical Trials, Sept 2007 (refer to Appendix D). 
If the event is an SAE, then all applicable seriousness criteria must be indicated (criteria listed in 
Section 9.3.3. 
9.4.3.3. 
Action Taken with Study Drug 
Down-titration of Study Drug (ISIS 721744 or placebo) will not be allowed during the study. 
Action taken with Study Drug (ISIS 721744 or placebo) due to an AE is characterized by 1 of the 
following: 

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• None:  No changes made to Study Drug (ISIS 721744 or placebo) administration and 
dose 
• Not Applicable:  AE reported during the Screening Period prior to Study Drug 
(ISIS 721744 or placebo) administration or during the Post-Treatment Period 
• Permanently Discontinued:  Study Drug (ISIS 721744 or placebo) discontinued and 
not restarted 
• Temporarily Interrupted, Restarted - Same Dose:  Dosing and/or dosing 
frequency temporarily interrupted/changed or delayed due to the AE and restarted at 
the same 
9.4.3.4. 
Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the 
Adverse Event Case Report Form.  Treatment should also be recorded on the concomitant 
treatment or ancillary procedures eCRF, as appropriate. 
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 terminates from the trial and the AE continues 
• Recovered:  Patient recovered completely from the AE 
• Became Serious:  The event became serious (the date that the event became serious 
should be recorded as the Resolution Date of that AE and the Onset Date of the 
corresponding SAE) 
• Change in Severity (if applicable):  AE severity changed 
If the event is an SAE, then the event’s outcome is characterized by one of the following: 
• Ongoing:  SAE continuing 
• Persists (as non-serious AE):  Patient has not fully recovered but the event no longer 
meets serious criteria and should be captured as an AE on the non-serious AE eCRF 
(the SAE resolution date should be entered as the date of onset of that AE) 
• Recovered:  Patient recovered completely from the SAE (the date of recovery should 
be entered as the SAE resolution date) 
• Recovered with Sequelae:  The signs/symptoms of the reported SAE have improved 
but not completely resolved, and a new baseline for the patient is established since 
full recovery is not expected 
• Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
• Unknown:  The outcome of the reported SAE is not available, e.g., patient is lost to 
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9.4.3.6. 
Follow-up of Adverse Event 
Investigator or designee Follow-Up 
During the study, the Investigator or designee should follow each AE until the event has resolved 
to Baseline grade or better, the event is assessed as stable, the patient is lost to follow-up, or the 
patient withdraws consent or assent.  Every effort should be made to follow all SAEs considered 
to be related to Study Drug or related to study procedures until a final outcome can be reported. 
Resolution of AE (with dates) should be documented on the Adverse Event eCRF and in the 
patient’s medical record to facilitate source data verification.   
Investigator or designee should follow-up or support the Sponsor’s effort to follow up with all 
pregnancies reported during the study from either the study patient or the female partner of male 
study patient until pregnancy outcome is available.   
Sponsor Follow-Up 
For SAEs, AESIs, and pregnancy cases in patients who have completed or terminated the study, 
the Sponsor or a designee should follow-up by telephone, fax, email, and/or a monitoring visit to 
obtain additional case details and outcome information (e.g., from hospital discharge summaries, 
consultant reports, autopsy reports) in order to perform an independent medical assessment of 
these case. 
9.5. 
Procedures for Handling Special Situations 
9.5.1. 
Abnormalities of Laboratory Tests 
Clinically significant abnormal laboratory test results may, in the opinion of the Investigator or 
designee, constitute or be associated with an AE.  Examples of these include abnormal laboratory 
results that are associated with symptoms, or require treatment, e.g., bleeding due to 
thrombocytopenia, tetany due to hypocalcemia, or cardiac arrhythmias due to hyperkalemia.  
Whenever possible, the underlying diagnosis should be listed in preference to abnormal 
laboratory values as AEs.  Clinically significant abnormalities will be monitored by the 
Investigator or designee until the parameter returns to its baseline value or until agreement is 
reached between the Investigator or designee and Sponsor Medical Monitor.  Laboratory 
abnormalities deemed not clinically significant (NCS) by the Investigator or designee should not 
be reported as AEs.  Similarly, laboratory abnormalities reported as AEs by the Investigator or 
designee should not be deemed NCS on the laboratory sheet. 
The Investigator is responsible for reviewing and signing all laboratory reports.  The signed 
clinical laboratory reports will serve as source documents and should include the Investigator’s 
or designee’s assessment of clinical significance of out of range/abnormal laboratory values. 
9.5.2. 
Prescheduled or Elective Procedures or Routinely Scheduled Treatments 
A prescheduled or elective procedure or a routinely scheduled treatment will not be considered 
an SAE, even if the patient 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 patient’s 
consent and, as applicable, assent to participate in the study 

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• 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 or designee between the patient’s consent and, as applicable, 
assent to participate in the study and the timing of the procedure or treatment 
• The prescheduled or elective procedure or routinely scheduled treatment is the sole 
reason for the intervention or hospital admission 
9.5.3. 
Dosing Errors 
Study Drug (ISIS 721744 or placebo) dosing errors (including overdose, underdose, and 
administration error) should be documented as protocol deviations.  A brief description should be 
provided in the deviation, including whether the patient was symptomatic (list symptoms) or 
asymptomatic, and the event accidental or intentional. 
Dosing details should be captured on the Dosing eCRF.  If the patient takes a dose of Study Drug 
(ISIS 721744 or placebo) that exceeds protocol specifications and the patient is symptomatic, 
then the symptom(s) should be documented as an AE and be reported per Section 9.4. 
An overdose is the accidental or intentional use of a drug in an amount higher than the dose 
being studied.  An overdose or incorrect administration of study treatment is not itself an AE, but 
it may result in an AE.  All AEs associated with an overdose or incorrect administration of Study 
Drug should be recorded on the Adverse Event eCRF.  If the associated AE fulfills seriousness 
criteria, the event should be reported to the Sponsor immediately (i.e., no more than 24 hours 
after learning of the event). 
Should an overdose occur, the Investigator or designee should refer to the “Guidance for 
Investigator” section of the Investigator’s Brochure and contact the Sponsor or designee within 
24 hours. 
9.5.4. 
Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use acceptable 
contraception with their partners, or refrain from sexual activity, as described in Section 6.3.1. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes 
that he has made someone pregnant during the study, then the Study Center staff must be 
informed immediately.  An Initial Pregnancy Form should be submitted to the Sponsor or 
designee within 24 hours of first learning of the occurrence of pregnancy.  Follow-up 
information including delivery or termination is reported by designating as ‘Follow-up’ on the 
Pregnancy Forms and reported within 24 hours. 
Payment for all aspects of obstetrical care, child or related care will be the patient’s 
responsibility.   
Female patients:  If a suspected pregnancy occurs while on the study (including the 
Post-Treatment Period), a pregnancy test will be performed.  The patient with a confirmed 
pregnancy will be immediately withdrawn from treatment with Study Drug.  However, the 
patient will be encouraged to complete the Post-Treatment Period of the study to the extent that 
study procedures do not interfere with the pregnancy.  Regardless of continued study 
participation, the study physician will assist the patient in getting obstetrical care and the 

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progress of the pregnancy will be followed until the outcome of the pregnancy is known (i.e., 
delivery, elective termination, or spontaneous abortion).  If the pregnancy results in the birth of a 
child, the Study Center and Sponsor may require access to the mother and infant’s medical 
records to obtain additional information relevant to the pregnancy progress and outcome.  A 
longer follow-up may be required if a newborn child experiences a medical condition.  
Follow-up will be performed to the extent permitted by the applicable regulations and privacy 
considerations, e.g., pregnancy ICF may be required. 
Male patients:  The progress of the pregnancy of a male patient’s partner should be followed 
until the outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous 
abortion).  If the pregnancy results in the birth of a child, the Study Center and Sponsor may 
follow-up with the mother and may request access to the mother and infant’s medical records to 
obtain additional information relevant to the pregnancy progress and outcome.  A longer 
follow-up may be required if a newborn child experiences a medical condition.  Follow-up will 
be performed to the extent permitted by the applicable regulations and privacy considerations, 
e.g., partner ICF may be required. 
10. 
STATISTICAL CONSIDERATIONS 
The sections below indicate the overall structure and approach to the analysis of this study.  A 
detailed SAP incorporating these sections below will be prepared separately.  The SAP will 
outline all data handling conventions, including software, and specify additional statistical 
methods to be used for analysis.  The study objectives and endpoints are listed in Section 1.1 and 
Section 1.2, respectively. 
10.1. 
Stratification, Subsets, and Covariates 
There are no stratification factors in this study.  Subset analyses are not planned.  The covariate 
used in the model for the primary efficacy analysis is described in Section 10.6.3.1. 
10.2. 
Sample Size Considerations 
The power and sample size estimations were calculated using simulations based on a generalized 
linear model for count data assuming a Poisson distribution.  The primary endpoint is the time-
normalized- number of Investigator-confirmed HAE attacks (per month) from Week 1 to 
Week 25.  Assuming an HAE attack rate of 13.26 attacks per 6-month period in the placebo 
group and an HAE attack rate of 1.38 attacks per 6-month period in the ISIS 721744 80 mg 
every 4 weeks group, the sample size of 54 patients (2:1 ratio [ISIS 721744:placebo]) will 
provide at least 90% power for the primary endpoint, with a 0.05 significance level.  A total of 
approximately 84 patients (42 in the ISIS 721744 every 4 weeks group, 21 in the pooled placebo 
group, and 21 in the ISIS 721744 every 8 weeks group) will be enrolled in this trial to account 
for potential early dropouts and to facilitate some general safety evaluations. 

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10.3. 
Populations 
The Safety Population will include all randomized patients who receive at least 1 dose of Study 
Drug (ISIS 721744 or placebo). 
The Intent-to-Treat (ITT) Population will include all randomized patients. 
The Per-Protocol (PP) Population will include all patients in the ITT Population who are treated 
according to the protocol without any major deviations that could compromise the interpretation 
of efficacy.  Significant deviations will be determined prior to unblinding for statistical analysis.   
The PK Population will include all patients who are randomized and receive at least 1 dose of 
Study Drug and have at least 1 evaluable PK sample. 
10.4. 
Definition of Baseline 
Run-in period is defined as the period from screening to the last day prior to Study Day 1.   
For Investigator-confirmed HAE attacks, the baseline rate, i.e., run-in period Investigator-
confirmed HAE attack rate, will be calculated for each patient as number of Investigator-
confirmed HAE attacks occurred during the run-in period divided by the number of days 
contributed to the run-in period multiplied by 28 days. 
For PLTs, Baseline will be defined as the average of all non-missing pre-dose assessments. 
For other assessments, if there are 2 or more pre-dose values available, baseline will be defined 
as the average of the pre-dose Study Day 1 value and the last pre-dose value prior to Study 
Day 1.  If there is only 1 pre-dose measurement available, then it will be assigned as Baseline. 
10.5. 
Interim Analysis, Multiplicity, and Early Stopping Guidelines 
No interim analysis is planned for this study.  Final analyses will be conducted after the End of 
Treatment period when all patients complete Week 25 visit, stay in the study for at least 
25 weeks since the Study Day 1 or withdraw from the study before 25 weeks from the Study 
Day 1. Study results with continuing collected post-treatment data will be updated at the End of 
Study. 
The multiplicity for primary and secondary analyses will be controlled by using the hierarchical 
testing procedure at 0.05. 
The following secondary endpoints will be tested if the primary endpoint is statistically 
significant (p < 0.05).  The testing sequence for the secondary endpoints will be specified in the 
SAP. 
• The time-normalized number of Investigator-confirmed HAE attacks (per month) 
from Week 5 to Week 25 compared to placebo 
• The percentage of Investigator-confirmed HAE attack-free patients from Week 5 to 
Week 25 compared to placebo  
• The time-normalized number of moderate or severe Investigator-confirmed HAE 
attacks (per month) from Week 5 and Week 25 compared to placebo 

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• The number of patients with a clinical response defined as a ≥ 50%, ≥ 70%, or ≥ 90% 
reduction from Baseline (i.e., screening rate) in Investigator-confirmed HAE attack 
rate between Week 5 to Week 25 compared to placebo 
• The number of Investigator-confirmed HAE attacks requiring acute HAE therapy 
from Week 5 to Week 25 compared to placebo 
• Percent of patients who are well controlled based on the AECT at Week 25 
• Change in AE-QoL questionnaire total score at Week 25  
The early stopping guidelines are described in Section 8.6. 
10.6. 
Planned Methods of Analysis 
All eCRF data, lab data transfers, and any outcomes derived from the data will be provided in the 
patient listings.  Patient data listings will be presented for all patients enrolled into the study.  
Descriptive summary statistics including n, mean, median, SD, standard error, interquartile range 
(25th percentile, 75th percentile), and range (minimum, maximum) for continuous variables, and 
counts and percentages for categorical variables will be used to summarize most data.  Where 
appropriate, p-values will be reported.  All statistical tests will be conducted using 2-sided tests 
with 5% Type I error rate unless otherwise stated. 
All primary and secondary endpoints will be assessed on ITT and PP Populations, with the 
former being the basis for the primary efficacy analysis.  Placebo patients from Cohort A and 
Cohort B will be pooled for analysis. All safety assessments will be performed on the Safety 
Population. 
10.6.1. 
Demographic and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using descriptive statistics by 
treatment group.  Patient randomization will be summarized by cohort and treatment group.  The 
patient disposition will be summarized.  All patients enrolled will be included in a summary of 
patient disposition. 
10.6.2. 
Safety Analysis 
The safety and tolerability of ISIS 721744 will be assessed by determining the number, type, 
severity, and dose-relationship of AEs; vital signs; ECGs; and clinical laboratory parameters.  
Safety results in patients dosed with ISIS 721744 will be compared to safety results in patients 
dosed with placebo. 
Treatment duration and amount of Study Drug (ISIS 721744 or placebo) received will be 
summarized by treatment group.  Patient incidence rates of all adverse events will be tabulated 
by Medical Dictionary for Regulatory Activities (MedDRA) system organ class, and by 
MedDRA term.  Tables and/or narratives of treatment emergent deaths, serious and significant 
adverse events, including early withdrawals due to adverse events, will also be provided. 
All treatment emergent AEs, all treatment emergent AEs potentially related to Study Drug, all 
treatment emergent serious AEs, and all treatment emergent serious AEs potentially related to 
Study Drug (ISIS 721744 or placebo) will be summarized. 

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Laboratory tests to ensure patient safety including chemistry panel, complete blood count with 
differential, coagulation panel, complement etc., will be summarized by study visits for each 
treatment group.  These safety variables will also be presented as change and percent change 
from Baseline over time after Study Drug (ISIS 721744 or placebo) administration, as 
appropriate.   
Vital sign and ECG measures will be tabulated by treatment group.  In addition, the number of 
patients who experience abnormalities in clinical laboratory evaluations will be summarized by 
treatment group. 
10.6.3. 
Efficacy Analysis 
10.6.3.1. Primary Efficacy Analysis 
The primary endpoint is the time-normalized number of Investigator-confirmed HAE attacks 
(per month) from Week 1 to Week 25. 
The primary analysis of the primary endpoint is to compare the time-normalized number of 
Investigator-confirmed HAE attacks (per month) from Week 1 to Week 25 between ISIS 721744 
80 mg every 4 weeks and pooled placebo using a Poisson regression model and Pearson chi-
square scaling of standard errors to account for potential overdispersion on the ITT population.  
The model will include fixed effect for treatment group (categorical), the time-normalized run-in 
period attack rate (continuous) as a covariate, and the logarithm of time in months that each 
patient was observed from Week 1 to Week 25 will be used as an offset variable. 
All available data, including data after participants received androgens or on demand acute 
medications to manage attacks during the Treatment Period, up to either the start of the 
open-label period or Week 25, whichever is earlier, will be used to account for missing values in 
the primary analysis.  The logarithm of the length of observation time will be included as an 
offset variable in the Poisson model to adjust for differences in follow-up time.  All patients who 
discontinued the Treatment Period early and started OLE, and patients who discontinued the 
Treatment Period early and were lost to follow-up before Week 25, will have the time-adjusted 
attack rate included in the analysis. 
Sensitivity analyses will be conducted for all patients who discontinued the Treatment Period 
early and started OLE, and patients who discontinued the Treatment Period early and were lost to 
follow-up before Week 25, using multiple imputation (MI) to impute the unobserved attack rate.  
A pattern mixture model may be included.  In addition, a tipping-point analysis will be 
conducted to measure the potential effect of missing data on the reliability of the primary 
efficacy analysis. 
10.6.3.2. Secondary Efficacy Analysis 
The secondary endpoints include the time-normalized number of Investigator-confirmed HAE 
attacks (per month) from Week 5 to Week 25; the percentage of Investigator-confirmed HAE 
attack-free patients from Week 5 to Week 25; the time-normalized number of moderate or severe 
Investigator-confirmed HAE attacks (per month) from Week 1 to Week 25; the number of 
patients with a clinical response defined as a ≥ 50%, ≥ 70%, or ≥ 90% reduction from Baseline 
(i.e., screening rate) in Investigator-confirmed HAE attack rate between Week 5 to Week 25 

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compared to placebo; the number of Investigator-confirmed HAE attacks requiring acute therapy 
from Week 5 to Week 25; percent of patients who are well controlled on the AECT at Week 25; 
and change in AE-QoL questionnaire total score at Week 25. 
The time-normalized number of Investigator-confirmed HAE attacks (per month) from Week 5 
to Week 25, the time normalized number of moderate or severe Investigator-confirmed HAE 
attacks (per month) from Week 5 to Week 25, and the time-normalized number of moderate or 
severe Investigator-confirmed HAE attacks (per month) from Week 5 to Week 25 will be 
analyzed in a similar way to the primary efficacy endpoint. 
Continuous variables will be summarized by descriptive statistics (n, mean, median, standard 
deviation, minimum, and maximum) by treatment group.  Continuous variables will also be 
analyzed using a mixed effects model with repeated measures (MMRM).  The least-squares 
means, standard errors, and the 2-tailed 95% confidence intervals for the treatment group and 
placebo group will be presented. 
Categorical variables will be summarized by frequency and percentage for the treatment group 
and placebo group.  Categorical variables will be analyzed using the Chi-squared test or Fisher’s 
Exact test. 
10.6.4. 
Pharmacokinetic Analysis 
The plasma PK of ISIS 721744 will be assessed following SC administration.  For all patients, 
pre-dose (trough) and post-treatment plasma ISIS 721744 concentrations will be determined and 
summarized using descriptive statistics.  Plasma terminal elimination half-life will also be 
calculated using the Post-Treatment Follow-up ISIS 721744 plasma concentrations, if data 
permits. 
Metabolite identification and profiling may be conducted on select plasma samples. 
Plasma PK parameters will be summarized using descriptive statistics.  Additional details 
regarding the PK analysis along with immunogenicity (IM) analysis will be described in the 
SAP. 
Analysis of potential exposure-response relationship between biomarkers and PK measures may 
also be explored. 
Population PK and PK/PD analyses may be performed using PK and PD data from this study, 
and/or combined with other ISIS 721744 clinical PK/PD data in the development timeline. 
10.6.5. 
Pharmacodynamic Analysis 
The change from Baseline in PKK levels at each visit during the Treatment Period will be 
compared between ISIS 721744 80 mg and placebo using the MMRM.  The response variable is 
the change or percent change from Baseline at post-baseline visit up to Week 25.  The MMRM 
model will include effects of treatment (ISIS 721744 or placebo), time (categorical), 
treatment-by-time interaction, and baseline value. 
10.6.6. 
Additional Analyses 
Exploratory efficacy endpoints include change in GAD-7, change in EQ-5D-5L, PGIC, PGIS, 
change in WPAI, and incidence of ER visits, all cause hospitalization, and total inpatient days. 

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The change from Baseline in PGIS will be analyzed using a proportional odds model with 
treatment as a factor and baseline value as covariate. 
The value in PGIC will be analyzed using a proportional odds model with treatment as a factor. 
All other exploratory efficacy endpoints will be analyzed using the same methods as described 
for the secondary efficacy endpoints.  Additional psychometric analyses may be conducted for 
selected PROs. 
11. 
INVESTIGATOR’S REGULATORY OBLIGATIONS 
11.1. 
Informed Consent and Assent 
The written informed consent and, as applicable, assent document should be prepared in the 
language(s) of the potential patient population, based on an English version provided by the 
Sponsor or designee. 
Before a patient’s participation in the study, the Investigator or designee is responsible for 
obtaining written informed consent and, as applicable, assent from the patient or their legally 
appointed and authorized representatives after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol-specific 
screening procedures or any Study Drug (ISIS 721744 or placebo) are administered.  The patient 
must be given sufficient time to consider whether to participate in the study.   
The acquisition of informed consent and, as applicable, assent and the patient’s agreement or 
refusal to notify his/her primary care physician should be documented in the patient’s medical 
records and the ICF should be signed and personally dated by the patient and by the person who 
conducted the informed consent and, as applicable, assent discussion (not necessarily an 
Investigator).  The original signed ICF should be retained in the Study Master File and in any 
other locations required by institutional policy, and a copy of the signed consent and, as 
applicable, assent form should be provided to the patient. 
11.2. 
Ethical Conduct of the Study 
All applicable regulations and guidelines of current GCP as well as the demands of national drug 
and data protection laws and other applicable regulatory requirements must be followed.   
11.3. 
Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed ICF, other written patient information, and any proposed 
advertising material must be submitted to the IEC/IRB for written approval.  A copy of the 
written approval of the protocol and ICF must be received by the Sponsor or designee before 
recruitment of patients into the study and shipment of Study Drug.  A copy of the written 
approval of any other items/materials that must be approved by the Study Center or IEC/IRB 
must also be received by the Sponsor or designee before recruitment of patients into the study 
and shipment of Study Drug.  The Investigator’s Brochure must be submitted to the IEC/IRB for 
acknowledgement. 

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The Investigator or designee must submit to and, where necessary, obtain approval from the 
IEC/IRB, for all subsequent protocol amendments and changes to the informed consent and 
assent document.  The Investigator or designee should notify the IEC/IRB of deviations from the 
protocol in accordance with ICH GCP.  The Investigator or designee should also notify the 
IEC/IRB of SAEs occurring at the Study Center and other AE reports received from the Sponsor 
or designee, in accordance with local procedures. 
The Investigator or designee will be responsible for obtaining annual IEC/IRB approval/renewal 
throughout the duration of the study.  Copies of the Investigator’s reports, all IEC/IRB 
submissions and the IEC/IRB continuance of approval must be sent to the Sponsor or designee. 
11.4. 
Patient Confidentiality 
The Investigator or designee must ensure that the patient’s confidentiality is maintained.  On the 
CRFs or other documents submitted to the Sponsor or designee, patients should be identified by 
initials (if permitted by local law) and a patient identification number only.  Documents that are 
not for submission to the Sponsor or designee (e.g., signed ICFs) should be kept in strict 
confidence by the Investigator or designee. 
In compliance with federal and local regulations/ICH GCP Guidelines, it is required that the 
Investigator or designee and institution permit authorized representatives of the company, of the 
regulatory agency(s), and the IEC/IRB direct access to review the patient’s original medical 
records for verification of study-related procedures and data.  Direct access includes examining, 
analyzing, verifying, and reproducing any records and reports that are important to the evaluation 
of the study.  The Investigator or designee is obligated to inform and obtain the consent and, as 
applicable, assent of the patient to permit named representatives to have access to his/her 
study-related records without violating the confidentiality of the patient. 
12. 
ADMINISTRATIVE AND LEGAL OBLIGATIONS 
12.1. 
Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor or designee.  
Agreement from the Investigator or designee must be obtained for all protocol amendments and 
amendments to the informed consent and assent document.  The regulatory authority and 
IEC/IRB must be informed of all amendments and give approval for any amendments likely to 
affect the safety of the patients or the conduct of the study.  The Investigator or designee must 
send a copy of the approval letter from the IEC/IRB to the Sponsor or designee. 
12.2. 
Study Termination 
The Sponsor or designee reserves the right to terminate the study.  The Investigator or designee 
reserves the right to terminate their participation in the study, according to the terms of the Study 
Center contract.  The Investigator/Sponsor or designee should notify the IEC/IRB in writing of 
the study’s completion or ET and send a copy of the notification to the Sponsor or designee. 

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12.3. 
Study Documentation and Storage 
An eCRF utilizing an EDC application will be used for this study. 
The Investigator or designee should ensure that all appropriately qualified persons to whom 
he/she has delegated study duties are recorded on a Sponsor-approved Delegation of Site 
Responsibilities Form. 
Source documents are original documents, data, and records from which the patient’s CRF data 
are obtained.  These include but are not limited to hospital records, clinical and office charts, 
laboratory and pharmacy records, imaging, and correspondence.  In this study, eCRFs may not 
be used as source documents. 
The Investigator or designee and Study Center staff are responsible for maintaining a 
comprehensive and centralized filing system of all study-related (essential) documentation in 
accordance with ICH GCP, suitable for inspection at any time by representatives from the 
Sponsor or designee and/or applicable regulatory authorities.  Elements should include the 
following: 
• Patient files containing completed CRFs, informed consents and, as applicable, 
assents, and supporting copies of source documentation 
• Study files containing the protocol with all amendments, Investigator’s Brochure, 
copies of pre-study documentation and all correspondence to and from the IEC/IRB 
and the Sponsor or designee 
• If drug supplies are maintained at the Study Center, proof of receipt, Study Drug 
Product Accountability Record, Return of Study Drug Product for Destruction, final 
Study Drug product reconciliation, and all drug-related correspondence 
In addition, all original source documents supporting entries in the CRFs must be maintained and 
be readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
designee and the Investigator or designee.  Should the Investigator or designee wish to assign the 
study records to another party or move them to another location, he/she must notify the Sponsor 
or designee. 
12.4. 
Study Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the Investigator for the purpose of inspecting the facilities and, upon request, inspecting 
the various records of the study (e.g., CRFs and other pertinent data) provided that patient 
confidentiality is respected. 
The Sponsor monitor or designee is responsible for inspecting the CRFs 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 patient medical records and other study-related records 
needed to verify the entries on the CRFs. 

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The Investigator or designee agrees to cooperate with the monitor to ensure that any problems 
detected in the course of these monitoring visits, including delays in completing CRFs, are 
resolved. 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit 
by representatives from the Sponsor’s Clinical Quality Assurance Department (or designees).  
Inspection of Study Center facilities (e.g., pharmacy, drug storage areas, laboratories) and review 
of study-related records will occur to evaluate the study conduct and compliance with the 
protocol, ICH GCP, and applicable regulatory requirements. 
To ensure the quality of clinical data a clinical data management review will be performed on 
patient data received by the Sponsor or designee.  During this review, patient 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 CRF.  These signatures 
will indicate that the Principal Investigator inspected or reviewed the data on the CRF, the data 
queries, and the Study Center notifications, and agrees with the content. 
12.5. 
Language 
Case report forms must be completed in English.  Generic names and trade names are acceptable 
for concomitant medications.  Combination medications should be recorded using their trade 
name. 
All written information and other material to be used by patients and investigative staff must use 
vocabulary and language that are clearly understood. 
12.6. 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws.  Patients will be treated and/or compensated for any study-
related illness/injury in accordance with the information provided in the Compensation for Injury 
section of the Informed Consent document. 
 
 

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13. 
REFERENCES 
Altmann, K-H, Dean NM, Fabbro D, et al. Second generation of antisense oligonucleotides: 
From nuclease resistance to biological efficacy in animals. CHIMIA Int J Chem 1996; 50: 
168‑176. 
Bissler, JJ, Aulak KS, Donaldson VH, et al. Molecular defects in hereditary angioneurotic 
edema. Proc Assoc Am Physicians 1997; 109: 164‑173. 
Cohn, DM, Viney NJ, Fijen LM, et al. Antisense Inhibition of Prekallikrein to Control 
Hereditary Angioedema. N Engl J Med 2020; 383: 1242-1247. 
Crooke, ST, Baker BF, Xia S, et al. Integrated Assessment of the Clinical Performance of 
GalNAc3-Conjugated 2'-O-Methoxyethyl Chimeric Antisense Oligonucleotides: I. Human 
Volunteer Experience. Nucleic Acid Ther 2018; 29: 16-32. 
Crooke, ST, and Bennett CF. Progress in antisense oligonucleotide therapeutics. Annu Rev 
Pharmacol Toxicol 1996; 36: 107-129. 
Geary, RS, Yu RZ, Watanabe T, et al. Pharmacokinetics of a tumor necrosis factor-alpha 
phosphorothioate 2'-O-(2-methoxyethyl) modified antisense oligonucleotide: comparison across 
species. Drug Metab Dispos 2003; 31: 1419-1428. 
Henry, S, Stecker K, Brooks D, et al. Chemically modified oligonucleotides exhibit decreased 
immune stimulation in mice. J Pharmacol 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 Lett 1987; 215: 327-330. 
Kaatz, S, Ahmad D, Spyropoulos AC, et al. Definition of clinically relevant non-major bleeding 
in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-
surgical patients: communication from the SSC of the ISTH. Journal of Thrombosis and 
Haemostasis 2015; 13: 2119-2126. 
Lara‑Marquez, ML, Christiansen SC, Riedl MA, et al. Threshold-stimulated kallikrein activity 
distinguishes bradykinin- from histamine-mediated angioedema. Clin Exp Allergy 2018; 48: 
1429‑1438. 
Maurer, M, Magerl M, Ansotegui I, et al. The international WAO/EAACI guideline for the 
management of hereditary angioedema-The 2017 revision and update. Allergy 2018; 73: 
1575‑1596. 
McKay, RA, Miraglia LJ, Cummins LL, et al. Characterization of a potent and specific class of 
antisense oligonucleotide inhibitor of human protein kinase C-α expression. J Biol Chem 1999; 
274: 1715-1722. 
Monia, BP, Lesnik EA, Gonzalez C, et al. Evaluation of 2'-modified oligonucleotides containing 
2'-deoxy gaps as antisense inhibitors of gene expression. J Biol Chem 1993; 268: 14514-14522. 
Neunert, C, Terrell DR, Arnold DM, et al. American Society of Hematology 2019 guidelines for 
immune thrombocytopenia. Blood Adv 2019; 3: 3829-3866. 
Prakash, TP, Graham MJ, Yu J, et al. Targeted delivery of antisense oligonucleotides to 
hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice. 
Nucleic Acids Res 2014; 42: 8796-8807. 

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Provan, D, Arnold DM, Bussel JB, et al. Updated international consensus report on the 
investigation and management of primary immune thrombocytopenia. Blood Adv 2019; 3: 3780-
3817. 
Provan, D, Stasi R, Newland AC, et al. International consensus report on the investigation and 
management of primary immune thrombocytopenia. Blood 2010; 115: 168-186. 
Schulman, S, and Kearon C. Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692-694. 
Stockert, RJ. The asialoglycoprotein receptor: relationships between structure, function, and 
expression. Physiol Rev 1995; 75: 591-609. 
Weller, K, Donoso T, Magerl M, et al. Validation of the Angioedema Control Test (AECT)-A 
Patient-Reported Outcome Instrument for Assessing Angioedema Control. J Allergy Clin 
Immunol Pract 2020; 8: 2050-2057.e2054. 
Weller, K, Groffik A, Magerl M, et al. Development, validation, and initial results of the 
Angioedema Activity Score. Allergy 2013; 68: 1185-1192. 
Zhang, H, Lowenberg EC, Crosby JR, et al. Inhibition of the intrinsic coagulation pathway factor 
XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk. 
Blood 2010; 116: 4684-4692. 
Zuraw, BL, and Christiansen SC. HAE Pathophysiology and Underlying Mechanisms. Clin Rev 
Allergy Immunol 2016; 51: 216-229. 
 

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14. 
APPENDICES 
 
 

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APPENDIX A. SCHEDULE OF VISITS AND PROCEDURES 
 
 
 

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Appendix A SCHEDULE OF VISITS AND PROCEDURES (CONTINUED) 
15 
Self-administration of Study Drug, or administration by other qualified individuals (e.g., family member), may be allowed after completion of training 
provided by qualified site personnel.  A Home Healthcare professional must be available to complete all pre-dosing procedures prior to Study Drug 
administration. 
16 
Cohort A ONLY:  Measure ECG at pre-dose and at 2-hours post-dose. 
17 
Cohort B ONLY:  Measure ECG at pre-dose and at 2-hours post-dose. 
18 
Targeted physical exam/body assessment which must include examination of the skin (including injection site), chest and mouth following Study Drug 
administration. 
19 
Cohort A ONLY. 
20 
For pediatric patients only. 
 

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APPENDIX B. LIST OF LABORATORY ANALYTES 
 
 

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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 721744 or other similar 
oligonucleotides. 
Clinical Chemistry Panel 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Bicarbonate 
• 
Total protein 
• 
Albumin 
• 
Calcium 
• 
Magnesium 
• 
Phosphorus 
• 
Glucose 
• 
BUN 
• 
Creatinine 
• 
Cholesterol 
• 
Uric Acid 
• 
Total bilirubin 
• 
Direct (conjugated) 
bilirubin 
• 
Indirect (unconjugated) 
bilirubin 
• 
ALT 
• 
AST 
• 
ALP 
• 
Creatinine kinase 
• 
GGT 
Screening Tests 
• 
Hepatitis B surface 
antigen 
• 
Hepatitis C antibody 
• 
HIV antibody 
• 
FSH (only women who 
are not surgically 
sterile) 
• 
Serum βhCG  
(only women who are 
not surgically sterile or 
post-menopausal) 
 
Coagulation 
• 
aPTT (sec) 
• 
PT (sec) 
• 
INR 
• 
D-dimer 
 
Complement 
• 
C5a 
• 
C43 
• 
C1-INH3 
• 
C1q3 
 
Hematology 
• 
Red blood cells 
• 
Hemoglobin 
• 
Hematocrit 
• 
MCV, MCH, MCHC 
• 
Platelets 
• 
White blood cells 
• 
WBC Differential  
(% and absolute) 
• 
Neutrophils 
• 
Eosinophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
 
Pharmacokinetics1 
• 
ISIS 721744 
concentration in plasma 
 
Immunogenicity 
• 
Anti-ISIS 721744 
antibodies (Anti-Drug 
Antibody [ADA]) 
Inflammatory 
• 
hs-CRP  
 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific gravity 
• 
pH 
• 
P/C Ratio 
• 
Protein 
• 
Blood 
• 
Ketones 
• 
Urobilinogen 
• 
Glucose 
• 
Bilirubin 
• 
Leukocyte esterase 
• 
Nitrate 
• 
Microscopic 
examination2 
 
PD Biomarkers 
• 
Plasma PKK levels 
 
1 Plasma and urine PK samples may also be used for profiling of drug binding proteins, bioanalytical method 
validation purposes, stability assessments, metabolite assessments, or to assess other actions of ISIS 721744 with 
plasma constituents. 
2 Will be performed on abnormal findings unless otherwise specified. 
3 Samples for C4, C1-INH and C1q assays will be obtained at Screening. 
 

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APPENDIX C. PK SAMPLING SCHEDULE 
 
 

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Appendix C PK Sampling Schedule  
Blood samples for the determination of plasma ISIS 721744 concentrations will be collected 
prior to dosing, and at various time points throughout the Dosing and Post-Treatment Period as 
noted in the table below.  Plasma PK samples may also be used for profiling of drug binding 
proteins, bioanalytical method validation purposes, stability and metabolite assessments, IM 
testing (or possibly for purposes of IM assay development and/or validation), or to assess other 
actions of ISIS 721744 with plasma constituents. 
Plasma PK Sampling Schedule 
Cohort A:  Plasma PK Sampling Schedule 
Study Week Treatment Period 
Post-Treatment Period 
1 
5 
9 
13 
17 
21 
25 
41 
81 
131 
Study Day 
1 
29 
57 
85 
113 
141 
169/ ET-L 
or Tx-ET 
28 
56 
91 or  
Post-Tx-
ET 
Time Point 
Pre-dose, 
2 hr2 
Pre-dose Pre-dose Pre-dose Pre-dose  Pre-dose, 
2 hr2 
Anytime 
Anytime Anytime Anytime 
1 Weeks/days from end of treatment.  End of treatment is defined as 1 dosing interval (i.e., 4 weeks/28 days post-last 
dose. 
2 2 hrs after dose of Study Drug.  Window of ± 15 minutes.  Record actual time of collection in CRF.  
Cohort B:  Plasma PK Sampling Schedule 
Study Week Treatment Period 
Post-Treatment Period 
1 
5 
9 
13 
17 
21 
25 
41 
81 
131 
Study Day 
1 
29 
57 
85 
113 
141 
169/ ET-L 
or Tx-ET 
28 
56 
91 or  
Post-Tx-
ET 
Time Point 
Pre-dose, 
2 hr2 
Anytime Pre-dose Anytime Pre-dose, 
2 hr2 
Anytime Anytime 
Anytime Anytime Anytime 
1 Weeks/days from end of treatment.  End of treatment is defined as 1 dosing interval (i.e., 8 weeks/56 days) post-
last dose. 
2 2 hrs after dose of Study Drug.  Window of ± 15 minutes.  Record actual time of collection in CRF. 
 
 

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APPENDIX D. GRADING SCALE FOR ADVERSE EVENTS RELATING 
TO LABORATORY ABNORMALITIES 
 
 

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Appendix D Grading Scale for Adverse Events Relating to Laboratory Abnormalities 
The following grading recommendations for adverse events relating to lab test abnormalities are 
based upon the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, Sept.  2007. 
 

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The following grading recommendations for adverse events (AEs) at the injection site are based 
upon the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in 
Preventive Vaccine Clinical Trials, Sept 2007. 
 
 
 

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APPENDIX E. 
PATIENT REPORTED OUTCOME ASSESSMENTS 
Angioedema Activity Score (AAS) 
Angioedema Quality of Life (AE-QoL) 
Angioedema Control Test (AECT) 
Generalized Anxiety Disorder 7 (GAD-7) 
Work Productivity and Impairment (WPAI) 
Patient Global Impression of Change (PGIC) 
Patient Global Impression of Severity (PGIS) 

Version: 1
Version Date: 12 Jul 2022
Title: ISIS 721744-CS5 Protocol Amendment 2: A Phase 3 Double Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of ISIS 721744 in Patients with
Hereditary Angioedema (HAE)
Clinical Development 
12-Jul-2022 23:06:33 GMT+0000
APPROVALS:
Protocol

 
Parexel International 
 
 
 
Ionis Pharmaceuticals, Inc. 
ISIS 721744-CS5 
A Phase 3 Double-Blind, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of ISIS 721744 in Patients with Hereditary 
Angioedema (HAE) 
Statistical Analysis Plan 
Version: 2.0  
Parexel Project Number: 
 
 
 

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TABLE OF CONTENTS 
SPONSOR SIGNATURE PAGE ....................................................................................................2 
PAREXEL SIGNATURE PAGE ....................................................................................................3 
TABLE OF CONTENTS .................................................................................................................4 
REVISION HISTORY.....................................................................................................................7 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
INTRODUCTION ......................................................................................................10 
2. 
STUDY OBJECTIVES ..............................................................................................10 
2.1. 
Primary Objective .......................................................................................................10 
2.2. 
Secondary Objectives .................................................................................................11 
2.3. 
Safety Objectives ........................................................................................................11 
2.4. 
Exploratory Objectives ...............................................................................................11 
3. 
INVESTIGATIONAL PLAN .....................................................................................11 
3.1. 
Overall Study Design and Plan ...................................................................................11 
3.2. 
Study Estimand and Endpoints ...................................................................................12 
3.2.1. 
Intercurrent events ......................................................................................................12 
3.2.2. 
Estimand and Main Estimator/Primary Endpoint for the Primary Objective .............12 
3.2.3. 
Secondary Endpoints ..................................................................................................12 
3.2.4. 
Safety Endpoints .........................................................................................................13 
3.2.5. 
Exploratory Variables .................................................................................................13 
4. 
STATISTICAL METHODS .......................................................................................14 
4.1. 
Data Management and Quality Assurance .................................................................14 
4.1.1. 
Case Report Form Data ..............................................................................................14 
4.1.2. 
Laboratory Data ..........................................................................................................14 
4.1.3. 
Patient Reported Outcome (PRO) Assessments .........................................................14 
4.1.4. 
Plasma Prekallikrein (PKK) Level Data .....................................................................14 
4.1.5. 
Pharmacokinetics (PK) Data and Immunogenicity (IM) Data ...................................15 
4.2. 
General Considerations ...............................................................................................15 
4.2.1. 
Data Presentation ........................................................................................................15 
4.2.2. 
Definition of Study Day and Baseline ........................................................................15 
4.2.3. 
Analysis Visit Window ...............................................................................................16 

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4.3. 
Software ......................................................................................................................19 
4.4. 
Study Patients .............................................................................................................19 
4.4.1. 
Disposition of Patients ................................................................................................19 
4.4.2. 
Protocol Deviations ....................................................................................................19 
4.5. 
Analysis Sets ...............................................................................................................20 
4.6. 
Demographic and Other Baseline Characteristics ......................................................20 
4.7. 
Medical History ..........................................................................................................21 
4.8. 
Prior and Concomitant Medication .............................................................................21 
4.9. 
Efficacy Evaluation ....................................................................................................22 
4.9.1. 
Analysis and Data Conventions ..................................................................................22 
4.9.2. 
Primary Efficacy Variable ..........................................................................................28 
4.9.3. 
Secondary Efficacy Variables .....................................................................................32 
4.10. 
Safety Evaluation ........................................................................................................39 
4.10.1. 
Extent of Exposure .....................................................................................................39 
4.10.2. 
Adverse Events (AEs) .................................................................................................39 
4.10.3. 
Deaths, and Other Serious or Significant Adverse Events .........................................40 
4.10.4. 
Clinical Laboratory Evaluation ...................................................................................41 
4.10.5. 
Vital Signs, Physical Findings and Other Observations Related to Safety ................43 
4.10.6. 
Data Monitoring ..........................................................................................................44 
4.11. 
Pharmacokinetics ........................................................................................................44 
4.12. 
Immunogenicity (IM) Analysis ..................................................................................45 
4.12.1. 
Sample Level ADA Data ............................................................................................45 
4.12.2. 
Subject Level ADA Data ............................................................................................45 
4.12.3. 
Evaluation of IM Impact on PK, PD, Efficacy and Safety .........................................47 
4.13. 
Exploratory Analyses ..................................................................................................48 
4.13.1. 
Change and Percent Change from Baseline in Plasma Prekallikrein (PKK) 
Level ...........................................................................................................................48 
4.13.2. 
Change from Baseline in Generalized Anxiety Disorder (GAD-7) 
Questionnaire Total Score ..........................................................................................48 
4.13.3. 
EuroQoL-5-Dimensions Quality of Life Questionnaire (EQ-5D-5L) and 
Change from Baseline in Visual Analog Scale (EQ VAS) Score ..............................49 

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4.13.4. 
Patient Global Impression of Change (PGIC) Scale at Week 25/Early 
Termination .................................................................................................................50 
4.13.5. 
Change from Baseline in Patient Global Impression of Severity (PGIS) Scale .........50 
4.13.6. 
Change from Baseline in Work Productivity and Impairment (WPAI) .....................51 
4.13.7. 
Incidence of ER Visits, All-Cause Hospitalization, and Total Inpatient Days ...........52 
4.13.8. 
Change in each AE-QoL Questionnaire Domain Scores ............................................52 
4.13.9. 
Time-Normalized Number of Investigator-Confirmed Hereditary 
Angioedema (HAE) Attacks (per Every-4-week) from Week 17 to Week 25 ...........53 
4.13.10. 
Investigator-Confirmed Hereditary Angioedema (HAE) Attacks that 
involves the larynx ......................................................................................................53 
4.13.11. 
Angioedema Activity Score (AAS) ............................................................................54 
4.14. 
Other Analyses ............................................................................................................54 
4.15. 
Determination of Sample Size ....................................................................................54 
4.16. 
Changes in the Conduct of the Study or Planned Analysis ........................................55 
5. REFERENCES ..........................................................................................................................56 
APPENDIX A. SAS SAMPLE CODES .....................................................................................57 
APPENDIX B. EUROQOL-5-DIMENSIONS INDEX SCORE VALUESET FOR SAS 
BY COUNTRIES ..............................................................................................60 
 

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REVISION HISTORY   
 
Version No. 
Effective Date 
Summary of Major Changes 
1.0 
11 Apr 2022 
New document 
2.0 
08 Dec 2023 
• Section 1: Updated the list of Study Protocol and Amendments. 
• Section 3.2.2 (and later related sections):  Updated the primary 
analysis set from intent-to-treat (ITT) population to Full 
Analysis Set (FAS).  
• Section 3.2.5 (and later related sections):  Added the following 
exploratory endpoints and analyses methods: 
o Change in each angioedema quality of life (AE-QoL) 
questionnaire domain scores  
o Time-normalized number of Investigator-confirmed HAE 
attacks from Week 17 to Week 25 
o Investigator-confirmed HAE attacks that involves the larynx 
• Section 4.2.2:  Clarified baseline definitions with more details. 
• Section 4.9.1.3 (and later related sections):  Angioedema Control 
Test (AECT) total score missing data handling is changed to 
LOCF in the main analysis. MI based on J2R will be a 
sensitivity analysis. 
• Section 4.9.1.4:  Adjusted testing hierarchical rank.  
• Section 4.9.2.1:  Added interaction of baseline and treatment 
group as a covariate in efficacy analysis models. 
• Section 4.9.2.6:  Added typical patients as subgroup analyses. 
• Section 4.9.3 (and later related sections):  Updated responder 
analyses methods by using a logistic regression instead of Chi-
square. Added the analysis handling in case the logistic 
regression models with convergence issue. 
Section 4.9.3:  Clarified continuous data analyses methods, i.e., 
mixed effects model with repeated measures (MMRM) or 
Wilcoxon Rank Sum test.   
 

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LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ADA 
Anti-Drug Antibody 
AE(s) 
adverse event(s) 
AECT 
Angioedema Control Test 
AE-QoL 
angioedema quality of life 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase (SGOT) 
BUN 
blood urea nitrogen 
CRP 
C-reactive protein 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
ER 
emergency room 
EQ-5D-5L 
EuroQoL-5-Dimensions quality of life questionnaire 
EQ VAS 
EQ Visual analog scale 
FSH 
follicle-stimulating hormone 
GAD-7 
generalized anxiety disorder 7 
HAE 
hereditary angioedema 
Hb 
hemoglobin 
HIV 
human immunodeficiency virus 
INR 
international normalized ratio 
ISIS 721744 
antisense inhibitor of prekallikrein 
ITT  
Intent-to-Treat 
J2R 
Jump-to-Reference 
LCRIS 
local cutaneous reaction at injection site 
MAR 
Missing at Random 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCMC 
Markov chain Monte Carlo 
MCV 
mean corpuscular volume 
MedDRATM 
Medical Dictionary for Regulatory Activities  
MI 
multiple imputation 
MID 
minimal(ly) important difference 
MMRM 
mixed effects model with repeated measures 
NA 
not applicable 
NB regression 
Negative Binomial regression 
OLE 
open-label extension 
PGIC 
Patient Global Impression of Change  
PGIS 
Patient Global Impression of Severity 
PD 
pharmacodynamics 
PK 
pharmacokinetic(s) 

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PKK 
prekallikrein 
PT 
preferred term 
SAE(s) 
serious adverse event(s) 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SEM 
standard error of the mean 
SOC 
system organ class 
Study Day 1 
defined as the first day Study Drug product is administered to the 
patient 
Study Drug 
ISIS 721744 or placebo 
TEAE(s) 
treatment-emergent adverse event(s) 
ULN 
upper limit of normal 
WBC 
white blood cell 
WPAI 
work productivity and impairment 
WPAI4 
work productivity and impairment every-4-week score 
WS 
Weight of school 
WW 
Weight of work 
 

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1. 
INTRODUCTION  
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing 
study data and outlines the statistical programming specifications for the Tables, Listings, and 
Figures. It describes the variables and analysis sets, anticipated data transformations and 
manipulations and other details of the analyses not provided in the Study Protocol. 
The analyses described in this SAP are based upon the following study documents: 
• Study Protocol, Amendment 1 (1 October 2021) 
• Study Protocol, Amendment 2 (UK only, 29 March 2022) 
• Study Protocol, Amendment 2 (Germany, 11 April 2022) 
• Study Protocol, Amendment 2 (Spain, 21 April 2022) 
• Study Protocol, Amendment 2 (12 July 2022) 
• Study Protocol, Amendment 3 (UK, 22 August 2022) 
• Study Protocol, Amendment 3 (Germany, 24 August 2022) 
• Study Protocol, Amendment 3 (Spain, 22 August 2022) 
• electronic Case Report Form (eCRF) (12 October 2023) 
Additional requests in Study Protocol amendment 3 (UK only) include 1) assessments of growth 
development and sexual maturity (i.e., Tanner Staging) for adolescent patients (12-17 years) and 
2) extending the last post-treatment visits from Week 13 to Week 17.  This SAP describes these 
requests in the corresponding section below. 
Revision(s) of this SAP will be required for any subsequent amendments to the protocol which 
may change the analyses described in this SAP.  The SAP will be finalized prior to database lock 
and describes the statistical analysis as it is foreseen when the study is being planned.  If 
circumstances should arise during the study rendering this analysis inappropriate, or if improved 
methods of analysis should arise, updates to the analyses may be made.  Any deviations from the 
SAP after database lock, reasons for such deviations and all alternative or additional statistical 
analyses that may be performed, will be described in an SAP Addendum and/or documented in 
the final clinical study report. 
2. 
STUDY OBJECTIVES  
2.1. 
Primary Objective  
The primary objective of the study is to evaluate the clinical efficacy of ISIS 721744 in patients 
with Hereditary Angioedema (HAE). 

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2.2. 
Secondary Objectives  
To evaluate the effects of ISIS 721744 on the quality and pattern of HAE attacks and their impact 
on Quality of Life. 
2.3. 
Safety Objectives  
To evaluate safety and tolerability of ISIS 721744 in patients with HAE. 
2.4. 
Exploratory Objectives  
To further characterize the effects of ISIS 721744 on health economic and utilization parameters 
and additional Patient Reported Outcomes (PROs) and biomarkers. 
3. 
INVESTIGATIONAL PLAN  
3.1. 
Overall Study Design and Plan  
This study is a phase 3, randomized (ISIS 721744:placebo), double-blind, placebo-controlled 
trial conducted in multiple centers to evaluate the efficacy and safety of ISIS 721744 in 
preventing angioedema attacks in patients with HAE-1 (Type I) and HAE-2 (Type II).  
Approximately 84 patients are planned to be enrolled in the study.  Patients will be randomized 
in a 2:1 ratio to Cohort A (ISIS 721744 or placebo every 4 weeks) or Cohort B (ISIS 721744 or 
placebo every 8 weeks), respectively.  Within each Cohort, patients will be randomized in a 
3:1 ratio to receive 80 mg of ISIS 721744 or matching volume of placebo.  
Detailed information regarding the study procedures is presented in the Study Protocol. 
The study will consist of Screening, Treatment, and Post-Treatment Periods.  Patients may be 
required to attend additional visits for monitoring of adverse events (AEs) or abnormal 
investigation results.  
The length of each patient’s participation in the study is approximately 11 months (or 12 months 
for UK), which includes an up to 56-day Screening Period, a 24-week Treatment Period, and an 
up to 13-week (or up to 17-week, in UK only) Post-Treatment Period, unless the patient chooses 
to enroll in the open-label extension (OLE) study. 
Patients who experience at least 5 attacks/month for 2 consecutive months after Week 5 will 
have the opportunity to terminate from the Treatment Period and either continue in the 
Post-Treatment Period or enter into an OLE study.  Patients who complete Study Visit Week 25, 
and meet eligibility requirements, may enroll in an OLE study after the Week 25 visit.  If a 
patient chooses to enroll in the OLE study, the patient will discontinue participation in 
ISIS 721744-CS5 prior to the first visit in the OLE study.  
Patients who discontinue treatment will attend the Early Termination Visit and will be strongly 
encouraged to complete the Post-Treatment Period, unless consent/assent is withdrawn.  

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Endpoints related to “Investigator-confirmed HAE attacks (per month)” in the protocol is 
intended to be an attack rate per every-4-week. To be accurate, these endpoints are rephrased as 
“Investigator-confirmed HAE attacks (per every-4-week)” throughout this SAP.  
3.2. 
Study Estimand and Endpoints  
3.2.1. 
Intercurrent events  
The following intercurrent events will be considered when define estimand: 
1. Treatments are early terminated, e.g.  
a. Patients escaping early to the OLE study due to experiencing ≥ 5 recurrent HAE 
attacks per month for 2 consecutive months during the Treatment Period; 
b. Patients discontinuing the study treatment early due to recurrent HAE attacks and not 
enrolling in the OLE study; 
c. Patients discontinuing the study treatment early due to COVID-19 or war-related 
events. 
2. Not allowed concomitant therapy or procedures defined in the Protocol Section 8.10 are 
used.    
3.2.2. 
Estimand and Main Estimator/Primary Endpoint for the Primary Objective  
The estimand for the primary objective is to evaluate the difference between randomized study 
medication of ISIS 721744 80 mg once every 4 weeks and Placebo in the Investigator-confirmed 
HAE attack count from Week 1 to Week 25 irrespective of intercurrent events on the Full 
Analysis Set (FAS).  
The main estimator, i.e. primary endpoint is the time-normalized number of 
Investigator-confirmed HAE attacks (per every-4-week) from Week 1 to Week 25 compared to 
placebo.  
Investigator-confirmed HAE attacks will be continuously collected until Week 25 no matter 
which intercurrent event is occurred.  The primary analysis will be performed based on the 
treatment policy strategy.  
3.2.3. 
Secondary Endpoints  
• The time-normalized number of Investigator-confirmed HAE attacks 
(per every-4-week) from Week 5 to Week 25 compared to placebo 
• The percentage of Investigator-confirmed HAE attack-free patients from Week 5 to 
Week 25 compared to placebo 
• The time-normalized number of moderate or severe Investigator-confirmed HAE 
attacks (per every-4-week) from Week 5 to Week 25 compared to placebo 
• The number of patients with a clinical response defined as a ≥ 50%, ≥ 70%, or ≥ 90% 
reduction from Baseline (i.e., screening rate) in Investigator-confirmed HAE attack 
rate between Week 5 to Week 25 compared to placebo 

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• Percent of patients who are well controlled based on the Angioedema Control Test 
(AECT) at Week 25 
• Change in Angioedema Quality of Life (AE-QoL) questionnaire total score at 
Week 25  
• The number of Investigator-confirmed HAE attacks requiring acute therapy from 
Week 5 to Week 25 
3.2.4. 
Safety Endpoints  
The safety and tolerability of ISIS 721744 will be assessed by determining the number, type, 
severity, and dose-relationship of AEs; vital signs; electrocardiogram (ECG); and clinical 
laboratory parameters.  Safety results in patients dosed with ISIS 721744 will be compared to 
safety results in patients dosed with placebo. 
3.2.5. 
Exploratory Variables  
Exploratory endpoints include change or percent change from Baseline compared to placebo in 
the following: 
• Prekallikrein (PKK) level in plasma 
• Generalized anxiety disorder 7 (GAD-7) questionnaire score  
• EuroQoL-5-Dimensions quality of life questionnaire (EQ-5D-5L) 
• Patient Global Impression of Severity (PGIS) 
• Work productivity and impairment (WPAI) questionnaire score 
• Change in each AE-QoL questionnaire domain score 
• Time-normalized number of Investigator-confirmed HAE attacks (per every-4-week) 
from Week 17 to Week 25 
• Investigator-confirmed HAE attacks that involves the larynx 
• Incidence of emergency room (ER) visits, all cause hospitalization, and total inpatient 
days 
• Patient Global Impression of Change (PGIC) 
• Pharmacokinetic (PK):  Potential exposure response analysis using relevant exposure 
parameters (such as ISIS 721744 plasma Ctrough) and biomarkers (plasma PKK) and/or 
clinical endpoints, as appropriate 

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4. 
STATISTICAL METHODS  
4.1. 
Data Management and Quality Assurance  
An electronic case report form (eCRF) utilizing an Electronic Data Capture (EDC) application 
will be used for this Study. Data will be continuously collected no matter which intercurrent 
events defined in the Section 3.2.1 have occurred. 
4.1.1. 
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).  Ionis (or designee) 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.  Ionis reviews all 
data for accuracy and validity and generates additional queries in the EDC system when 
necessary.  The data is 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. 
4.1.2. 
Laboratory Data  
Ionis and Medpace are responsible for the format of the laboratory electronic data transfers and 
the transfer schedule.  Central laboratory data results are not stored in the EDC system. Medpace 
and Ionis are responsible for the review of the clinical laboratory data.  This process involves 
reviewing the patient and visit identifiers in the central laboratory data results data against the 
central lab data identifiers collected in the EDC system.  Investigator sites have access to the data 
via lab reports sent directly from the laboratory or through the laboratory’s web portal (in which 
case Investigators only have access to data from their site).  
4.1.3. 
Patient Reported Outcome (PRO) Assessments  
The PRO assessments will be captured by YPrime eCOA System.  Patients will enter their 
assessments into the system using a study-dedicated tablet and handheld devices.  Ionis and 
YPrime are responsible for the format of the electronic data transfers and the transfer schedule.  
The PRO assessments will not be stored in the EDC system.  Ionis and YPrime are also 
responsible for the review of the data.  This process involves reviewing the patient and visit 
identifiers in the assessment data against the data identifiers collected in the EDC system.  The 
YPrime system for data collection includes built-in measures to prevent missing items for any 
completed questionnaire. 
4.1.4. 
Plasma Prekallikrein (PKK) Level Data  
PPD is contracted and responsible for analyzing plasma PKK. Ionis is responsible for the 
management and review of the plasma PKK data.  Final data, which has been approved by 
Quality Assurance, will be stored in version-controlled repository. 

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4.1.5. 
Pharmacokinetics (PK) Data and Immunogenicity (IM) Data  
PPD is contracted and responsible for plasma drug concentration and Immunogenicity sample 
analysis.  Ionis is responsible for the management and review of the PK data.  This process 
involves reviewing the patient and visit identifiers with the clinical data collected in the EDC 
system.  The PK data are not stored in the EDC system.  
4.2. 
General Considerations  
4.2.1. 
Data Presentation  
Placebo patients from Cohort A and Cohort B will be pooled for analyses.  
Continuous data will be summarized in terms of the number of patients, mean, standard deviation 
(SD), standard error of mean (SEM), median, interquartile range (25th percentile, 75th 
percentile), minimum, and maximum, unless otherwise stated.  The minimum and maximum will 
be reported to the same number of decimal places as the raw data recorded in the database.  The 
mean, median, lower quartile and upper quartile will be reported to one more decimal place than 
the raw data recorded in the database.  The SD and SEM will be reported to 2 more decimal 
places than the raw data recorded in the database.  In general, the maximum number of decimal 
places reported shall be four for all summary statistic.  Raw values presented in listings will be 
displayed to the measured precision, unless specified. 
Categorical data will be summarized in terms of the number of patients providing data at the 
relevant time point (n), frequency counts and percentages.  Any planned collapsing of categories 
will be detailed in the SAP text and the data displays.  Percentages will be presented to one 
decimal place.  Percentages will not be presented for zero counts.  Changes from baseline in 
categorical data will be summarized using shift tables where appropriate. 
All statistical tests will be conducted using 2-sided tests with 5% Type I error rate unless 
otherwise stated. P-values greater than or equal to 0.001, in general, will be presented to 
3 decimal places. P-values less than 0.001 may be presented as “< 0.001”. 
Confidence intervals will be presented to 2 more decimal place than the raw data. 
4.2.2. 
Definition of Study Day and Baseline  
Study Day will be calculated relative to the date of first dose, i.e.,:  
• For assessments after the first dose date, Study Day = Assessment Date – Date of first 
dose + 1.  Study Day 1 is the first dose date. 
• For assessments before the first dose date, Study Day = Assessment Date – Date of 
first dose. 
Run-in period is defined as the period from screening to the first dose date/time.  The treatment 
period for this summary is defined as the period from the first dose date/time to the last dose 
date/time + 28 days for Cohort A and + 56 days for Cohort B.  
For Investigator-confirmed HAE attacks, the baseline rate, i.e., run-in period 
Investigator-confirmed HAE attack rate, will be calculated for each patient as number of 

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Investigator-confirmed HAE attacks occurred during the run-in period divided by the number of 
days contributed to the run-in period multiplied by 28 days.  
For Angioedema Activity Score (AAS), 2 baseline scores will be calculated.  The daily AAS of 
the last week before the first dose date/time is summed up to 7-day scores (AAS7) baseline.  The 
daily AAS of the last 28 days before the first dose date/time is summed up to 4-week scores 
(AAS28) baseline.  More details are described in Section 4.13.11.  
For questionnaires, including AE-QoL, GAD-7, EQ-5D-5L, PGIS, and AECT, baselines are 
defined as scores collected on Study Day 1.  
For WPAI, the baseline is defined as the score collected before or on Study Day 1.  Additionally, 
a baseline of WPAI every-4-week mean score (WPAI4) will be derived as a mean of 4 
consecutive weekly scores prior to Study Day 1.  The last week WPAI prior to Study Day 1 is 
collected on Study Day 1. 
For platelet count, the baseline is defined as the average of all non-missing assessments prior to 
the first dose. 
For other assessments including chemistry, hematology, urinalysis, coagulation, weight, and 
plasma PKK levels, if there are 2 or more pre-dose values available, Baseline will be defined as 
the average of the pre-dose Study Day 1 value and the last pre-dose value prior to Study Day 1.  
If there is only 1 pre-dose measurement available, then it will be assigned as Baseline.  For ECG, 
if the triplicates are taken, the average of the triplicates will be calculated first before averaging 
assessments from multiple visits.  If only 1 or 2 assessments are available, the single assessment 
or average of the 2 assessments will be calculated first before averaging assessments from 
multiple visits.  
4.2.3. 
Analysis Visit Window  
Data collected by visit, including scheduled and unscheduled visits, will be mapped to analysis 
visit specified in the table below.  The intent of these visit windows is not to align with those 
prescribed for visit scheduling in the clinical study protocol but, rather, based on the protocol-
defined target study day, to delineate mutually exclusive windows so that all assessments 
proximal to a particular study period can be integrated to best represent the patient’s status 
during that period of the study.  If a patient has discontinued early from the treatment period but 
attended Early Termination Post-Treatment follow-up visit to collect assessments, then those 
assessments collected at Early Termination visit and during Post-Treatment Follow-Up Period 
should be mapped to analysis visits as well and included in the analysis and summaries, unless 
otherwise described.  If there are multiple assessments within a visit window, the visit nearest the 
scheduled date will be used unless 2 visits are equally near, in which case the average will be 
used. 

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Assessment 
Analysis Visit1,2 (Week) 
Target Day2 
Study Day Window2 
PKK level, AECT, 
Clinical Laboratory 
Evaluations, Vital Sign, 
Weight 
Tx Week 5 
Tx Day 29 
2-43 
Tx Week 9 
Tx Day 57 
44-71 
Tx Week 13 
Tx Day 85 
72-99 
Tx Week 17 
Tx Day 113 
100-127 
Tx Week 21 
Tx Day 141 
128-155 
Tx Week 25 
Tx Day 169 
156-186  
Post-Tx Week 4 
Post-Tx Day 28 
15-42 
 
Post-Tx Week 8 
Post-Tx Day 56 
43-73 
Post-Tx Week 13 (or Post-Tx 
Week 17 for UK) 
Post-Tx Day 91 (or Post-Tx 
Day 119 for UK) 
74-105 (or 74-127) 
AE-QoL, GAD-7, 
EQ-5D-5L, PGIS, 
Height 
Tx Week 13 
Tx Day 85 
30-127 
Tx Week 25 
Tx Day 169 
128-186 
Post-Tx Week 13 (or Post Tx 
Week 17 for UK) 
Post-Tx Day 91 (or Post-Tx 
Day 119 for UK) 
45-105 (or 45-127) 
PGIC 
Tx Week 25 
Tx Day 169 
128-186 
Post-Tx Week 13 (or Post Tx 
Week 17 for UK) 
Post-Tx Day 91 (or Post-Tx 
Day 119 for UK) 
45-105 (or 45-127) 
12-lead ECG 
Tx Week 13 
Tx Day 85 
72-99 
Tx Week 17 
Tx Day 113 
100-127 
Tx Week 21 
Tx Day 141 
128-155 
Tx Week 25 
Tx Day 169 
156-186 
Post-Tx Week 4 
Post-Tx Day 28 
15-42 
Post-Tx Week 13 (or Post Tx 
Week 17 for UK) 
Post-Tx Day 91 (or Post-Tx 
Day 119 for UK) 
74-105 (or 74-127) 
 

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Assessment 
Analysis Visit1,2 (Week) 
Target Day2 
Study Day Window2 
WPAI 
Tx Week 2 
Tx Day 8 
2-11 
Tx Week 3 
Tx Day 15 
12-18 
Tx Week 4 
Tx Day 22 
19-25 
Tx Week 5 
Tx Day 29 
26-32 
Tx Week 6 
Tx Day 36 
33-39 
Tx Week 7 
Tx Day 43 
40-46 
Tx Week 8 
Tx Day 50 
47-53 
Tx Week 9 
Tx Day 57 
54-60 
Tx Week 10 
Tx Day 64 
61-67 
Tx Week 11 
Tx Day 71 
68-74 
Tx Week 12 
Tx Day 78 
75-81 
Tx Week 13 
Tx Day 85 
82-88 
Tx Week 14 
Tx Day 92 
89-95 
Tx Week 15 
Tx Day 99 
96-102 
Tx Week 16 
Tx Day 106 
103-109 
Tx Week 17 
Tx Day 113 
110-116 
Tx Week 18 
Tx Day 120 
117-123 
Tx Week 19 
Tx Day 127 
124-130 
Tx Week 20 
Tx Day 134 
131-137 
Tx Week 21 
Tx Day 141 
138-144 
Tx Week 22 
Tx Day 148 
145-151 
Tx Week 23 
Tx Day 155 
152-158 
Tx Week 24 
Tx Day 162 
159-165 
Tx Week 25 
Tx Day 169 
166-173 
Post-Tx Week 1 
Post-Tx Day 7 
3-10 
Post-Tx Week 2 
Post-Tx Day 14 
11-17 
Post-Tx Week 3 
Post-Tx Day 21 
18-24 
Post-Tx Week 4 
Post-Tx Day 28 
25-31 
Post-Tx Week 5 
Post-Tx Day 35 
32-38 
Post-Tx Week 6 
Post-Tx Day 42 
39-45 
Post-Tx Week 7 
Post-Tx Day 49 
46-52 
Post-Tx Week 8 
Post-Tx Day 56 
53-59 
Post-Tx Week 9 
Post-Tx Day 63 
60-66 
Post-Tx Week 10 
Post-Tx Day 70 
67-73 
Post-Tx Week 11 
Post-Tx Day 77 
74-80 
Post-Tx Week 12 
Post-Tx Day 84 
81-87 
Post-Tx Week 13 
Post-Tx Day 91 
88-94 
Post-Tx Week 143 
Post-Tx Day 983 
95-1013 
Post-Tx Week 153 
Post-Tx Day 1053 
102-1083 
Post-Tx Week 163 
Post-Tx Day 1123 
109-1153 
Post-Tx Week 173 
Post-Tx Day 1193 
116-1223 
1 Tx = Treatment Period; Post-Tx = Post-Treatment Period    2 For Tx, Weeks/days from the first dose date; for Post-
Tx, Weeks/days from end of treatment.  End of treatment is defined as 1 dosing interval (i.e., 4 weeks for Cohort 
A and 8 weeks for Cohort B) post-last dose.    3 UK only. 

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4.3. 
Software  
All report outputs will be produced using SAS® version 9.4 or higher in a secure and validated 
environment.   
4.4. 
Study Patients  
4.4.1. 
Disposition of Patients  
A clear accounting of the disposition of all patients who enter the study will be provided, from 
screening to study completion. 
The following summaries will be provided: 
• The number and percentage of randomized patients, screen failed patients and major 
screen failure reason will be summarized based on all screened patients.  
Additionally, the number and percentage of patients who failed the screening due to 
COVID-19 related impact will also be provided. 
• The number and percentage of treated patients with at least one dose of Study Drug 
(ISIS 721744 or placebo), patients terminated from the treatment, and major reasons 
of treatment termination will be summarized by treatment group (ISIS 721744 80 mg 
every 4 weeks, ISIS 721744 80 mg every 8 weeks, pooled placebo) and overall based 
on all randomized patients.  Additionally, the number and percentage of patients who 
terminated from treatment due to COVID-19 related impact will also be summarized. 
• The number and percentage of patients completed the post-treatment follow-up, 
terminated from the post-treatment follow-up, and major reasons of termination from 
the post-treatment follow-up will be summarized by treatment group and overall 
based on all randomized patients.  Additionally, the number and percentage of 
patients who terminated from study due to COVID-19 related impact will also be 
summarized. 
• The number and percentage of patients within each analysis population, as defined in 
Section 4.5, by treatment group and overall, will be summarized based on all 
randomized patients. 
A by-patient listing of disposition data will be provided based on the randomized patients. 
A listing of eligibility criteria will also be provided.  A separate by-patient listing for screen 
failures will also be provided. 
4.4.2. 
Protocol Deviations  
After all data are entered, reviewed, and queried, the database is closed and sent to the statistics 
group for review and for identification of protocol deviations.  
Protocol deviations will be classified to major or minor based on the study protocol deviation 
process plan.  Protocol deviations will be provided in the by-patient listing.  Major protocol 
deviations will be summarized by deviation category.  Additional table may be provided to 
summarize the major protocol deviations related to COVID-19 public health emergency.  

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A listing of all patients affected by the COVID-19 public health emergency related study 
disruption by patient number identifier and by investigational site, and a description of how the 
individual’s participation was altered will be provided. 
4.5. 
Analysis Sets  
Screened patients will be defined as those patients who signed informed consent/assent forms. 
The Safety Set will include all randomized patients who received at least 1 dose of Study Drug 
(ISIS 721744 or placebo). Analyses or summaries on the Safety Set will be performed by actual 
treatment group. 
The Full Analysis Set (FAS) will include all randomized patients who received at least 1 dose of 
Study Drug (ISIS 721744 or placebo). Analyses or summaries on FAS will be performed by 
randomized treatment group.  
The Per-Protocol Set (PPS) will include all patients in the FAS who are treated according to the 
protocol without any major deviations that could compromise the interpretation of efficacy.  
Other major deviations that could compromise the interpretation of efficacy will be determined 
prior to unblinding for statistical analyses. Analyses or summaries on the PPS will be performed 
by randomized treatment group.    
The PK Population will include all patients who are randomized and received at least 1 dose of 
Study Drug of ISIS 721744 and have at least 1 evaluable PK sample. 
The FAS is the basis for the primary efficacy analysis. All efficacy and pharmacodynamics (PD) 
endpoints will be assessed based on the FAS. Efficacy endpoints may be analyzed based on the 
PPSs which is specified in the Section 4.9.  
All safety assessments analyses or summaries will be performed on the Safety Population.   
The number of patients in each analysis population will be summarized by treatment group 
(ISIS 721744 80 mg every 4 weeks, ISIS 721744 80 mg every 8 weeks or pooled placebo) and 
overall for all randomized patients.  A summary of reasons for patients to have been excluded 
from the PPS will be provided.  A by-patient listing for analysis populations and reason for 
exclusion will be provided. 
4.6. 
Demographic and Other Baseline Characteristics  
Demographic and baseline characteristics, including regions, age, age category (12 to 17, 18 to 
39, 40-64, ≥ 65), sex, ethnicity, race, weight at baseline, height at screening, and body mass 
index (BMI) at baseline, will be descriptively summarized by treatment group and overall for the 
FAS, PP and Safety Populations.  
For race summary, if multiple races are recorded in database, ‘Multiple Race’ will be used in the 
summary table.  Detailed records will be presented in a by-patient listing. 
Summaries will be provided for HAE attack history, including family history of HAE attacks 
(yes or no), the number of attacks the patient has had in the past 12 months (i.e., the past year), 
historical C1-INH activity (%), years from diagnosis to informed consent, age at onset, HAE 

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type, type of attack(s) experienced, treatment history of lanadelumab, berotralstat, C1-esterase 
inhibitor (yes or no), run-in period Investigator-confirmed HAE attack rate (attacks/4 weeks), 
and run-in period Investigator-confirmed HAE attack rate group (≤ 2, 2–5, > 5 attacks/4 weeks). 
By-patient listings for demographics and baseline characteristics will be presented based on the 
FAS.  Screen failures will also be listed per data availability. 
4.7. 
Medical History  
Medical history will be coded by Medical Dictionary for Regulatory Activities (MedDRA) 
dictionary Version 24.1 or higher and will be summarized by system organ class (SOC) and 
preferred term (PT) by treatment group and overall for the Safety Population.  Medical history 
will also be provided in a by-patient listing. 
4.8. 
Prior and Concomitant Medication  
Prior and concomitant medications will be coded using WHO Drug dictionary version September 
2023 or later. Medications will be summarized by anatomical therapeutic chemical (ATC) class 
and PT by treatment group and overall. 
Prior medications include medications that started prior to the first dose of Study Drug 
(ISIS 721744 or placebo) regardless of whether they continued while on treatment or not. 
Concomitant medications include medications that patients are exposed to (on or after the first 
dose) Study Drug (ISIS 721744 or placebo).  Partial or missing medication start date or end date 
will be imputed by the following imputation rules: 
Start date: 
• If year, month and day are all missing then assign it as the date of Study Day 1 
• If month and day are missing and year is: 
o earlier than the year of Study Day 1 then assign it as December 31 
o otherwise, assign it as January 1 
• If only day is missing, and month-year is: 
o earlier than the month-year of Study Day 1 then assign it as the last day of the 
month 
o otherwise, assign it as the first day of the month 
End date: imputation will be performed for the end date only if the day or month is missing 
(i.e., year is present): 
• If month and day are missing, then assign December 31 
• If only day is missing, then assign the last day of the month 
If the imputed start date is later than the imputed end date, then set the imputed start date to the 
imputed end date. 

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The definitions for prior, concomitant medication defined relative to use of study drug are shown 
schematically in the diagram below.  
Scenario 
First Dose Date 
Prior 
Medication 
Concomitant  
1 
x----------x 
 
Y 
N 
2 
      x------------------------x/* 
Y 
Y 
3 
 
x-------x/* 
N 
Y 
4 
?----------x 
 
Y 
N 
5 
      ?-------------------------x/* 
Y 
Y 
6 
x----------? 
 
Y 
Y 
7 
 
x----------?/* 
N 
Y 
Y = yes 
N = no 
x = start/stop date/time 
? = missing date/time 
*= ongoing 
4.9. 
Efficacy Evaluation  
The FAS is the basis for the primary efficacy analysis and the main efficacy analyses for all 
other efficacy endpoints.  Analyses based on the PPS, if applicable, are described for each 
endpoint within this section.  By-patient listings will be provided. 
4.9.1. 
Analysis and Data Conventions  
4.9.1.1. 
Multicenter Studies  
This study will be conducted at multiple study centers worldwide.  Study centers or regions are 
not stratified during randomization.  No formal adjustments for centers will be conducted.  The 
primary endpoint will be analyzed by adding regions and the interaction of region and treatment 
group as covariates as a subgroup analysis (see Section 4.9.2.6). 
4.9.1.2. 
Adjustments for Covariates  
The primary efficacy endpoint is time-normalized number Investigator-confirmed HAE attacks.  
Run-in period time-normalized attack rate as a baseline as well as the interaction of baseline and 
treatment will be included in the model as a covariate.  
Baselines and the interaction of baseline and treatment may be a covariate in change from 
baseline analyses models for secondary endpoints, if applicable.  
4.9.1.3. 
Handling of Dropouts or Missing Data Dropouts  
Investigator-confirmed HAE attacks will be considered as missing when the study termination 
date for a patient is earlier than 24 weeks since Study Day 1. 
Other endpoints will be considered as missing when assessment is not available at a specific 
visit.  

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Handling of Dropouts 
Missing primary and secondary endpoints data will be handled as following: 
• For time-normalized Investigator-confirmed HAE attack endpoints, the primary 
analysis for the primary endpoint and the main analyses for secondary endpoints will 
have the time-adjusted attack rate included in the analysis; sensitivity analyses will be 
performed based on imputed data by using multiple imputation (MI) methods 
assuming Jump-to-Reference (J2R). 
• For number of patients with a clinical response on HAE and HAE attack-free, 
responder is derived based on time-adjusted Investigator-confirmed HAE attack rate 
per every-4-week.  The main analysis will consider the HAE attack rate per every-4-
week are the same before and after withdrawal; sensitivity analysis will be performed 
based on imputed data by using the MI method assuming J2R. 
• For the AECT total score, the main analysis will be performed based on imputed data 
by last observation carried forward (LOCF).  Additionally, sensitivity analyses will 
be performed based on imputed data by using MI methods assuming J2R.  
• For the AE-QoL total score, main analysis will be performed by using MMRM model 
without missing data imputation; sensitivity analyses will be performed based on 
imputed data by using MI methods assuming J2R.  
For exploratory endpoints, including plasma PKK level, GAD-7, EQ-5D-5L, PGIS, PGIC, 
WPAI, missing data will not be imputed. 
Multiple Imputation – Investigator-confirmed HAE attack  
Patients with the study termination date earlier than 25 weeks since the Study Day 1 will have 
two portions of treatment period, the pre-withdrawal part and the post-withdrawal part.  
Investigator-confirmed HAE attacks observed in the study will be combined with the imputed 
data to estimate the event rates for each treatment group.  Missing data during the 
post-withdrawal part will be imputed by the following methods assuming J2R. 
First, the Poisson regression model used for the primary analysis will be fitted to the data using a 
Bayesian approach, with non-informative priors for the mean and variance-covariance matrix to 
provide a joint posterior for the parameters in this model.   
Second, Independent samples will then be drawn from the posterior distributions of model 
parameters fit using the Bayesian analysis.  For each patient with missing data during the post-
withdrawal part, these sampled values of the model parameters are then used to generate a set of 
values for the expected unobserved attack.  
Last, the expected number of attacks for the post-withdrawal part is added to the number of 
attacks in the pre-withdrawal part to get the total number of attacks over treatment period for 
patients who have missing data.  

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The post-withdrawal part of each pattern-specific distribution may be modelled using 
approaches discussed below:   
Jump-to-Reference (J2R) 
The J2R approach is an extremely conservative imputation approach that assumes that a 
patient receiving active Study Drug (ISIS 721744) does not sustain benefit after 
discontinuing study treatment. In J2R, missing event rate in both the ISIS 721744 
treatment group and the pooled placebo group will be imputed by setting to the event rate 
of the pooled placebo group during the pre-withdraw part.  
Tipping Point 
The tipping point approach is known to progressively shift the imputed analysis results 
towards a point where the analysis conclusion is reversed (i.e., the analysis yields a non-
significant p-value).  The study adopts a two-way tipping point approach where a series 
of shift (denoted as δ) is applied to both active Study Drug (ISIS 721744) and placebo 
treatment arm.  As the underlying distribution of primary endpoint is a Poisson 
distribution, the parameter of Poisson distribution (denoted as λ) is adjusted by δ as 
follows: 
λ (ISIS 721744, tipping point) = λ (ISIS 721744, MAR-imputed) × δ (ISIS 721744) 
λ (Placebo, tipping point) = λ (Placebo, MAR-imputed) × δ (ISIS 721744) 
The sequences of both λ starts at 1, where λ (ISIS 721744, tipping point) is increased by 
0.25 upwards and λ (Placebo, tipping point) goes backwards to 0.  The increment of 0.25 may be 
subject to adjust in case the tipping points are not yet to be discovered.  The upper limit 
may expand further in case the ‘tipping-point’ that yields non-significant conclusion has 
not appeared yet.  Under each combination of λ (ISIS 721744, tipping point) and λ (Placebo, tipping 
point), the same analysis method as Missing at Random (MAR) is applied to acquire the p-
value of the analysis.  For example, if there are 6 numbers (from 1 to 2.25 by 0.25) set as 
δ, there should be in total 36 corresponding p-values in the whole tipping point analysis. 
For each imputation method used, at least 100 imputed datasets will be generated.  
Multiple Imputation Jump-to-Reference (J2R) – AECT Total Score and AE-QoL Total 
Score  
The Markov Chain Monte Carlo (MCMC) method will be used under the multivariate normality 
assumption to impute the missing AE-QoL total score and AECT total score by treatment 
group.  The variable list for imputations will include the baseline score, as well as all available 
post-baseline scores within the treatment period, in the order of protocol defined visits.  The SAS 
procedure PROC MI will be used in the multiple simulation.  EM algorithm will be used to 
derive a set of initial parameter estimates for MCMC method.  A non-informative prior (Jeffreys’ 
prior) will be used to derive the posterior distribution of the parameters.  In case there are 
missing baselines, it will be imputed first by the average of available baselines across all patients 
in the FAS.  In the case of non-monotone missing pattern, MCMC method will be used first so 
that each imputed data set has a monotone missing pattern based on the order of the variable list.  

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The J2R approach is detailed in (Carpenter et al. 2013) and is an extremely conservative 
imputation approach that assumes that a patient receiving active Study Drug (ISIS 721744) does 
not sustain benefit after discontinuing study treatment.  In J2R, missing data in the pooled 
placebo group will be imputed under a within treatment arm MAR assumption.  For a patient 
with missing data in the ISIS 721744 treatment group, their AE-QoL total score or AECT total 
score distribution is set to equal that of the pooled placebo group.  
For each imputation method used, at least 100 imputed datasets will be generated.  
Last Observation Carried Forward (LOCF) – AECT Total Score 
For each subject, the missing AECT total score at Week 25 will be imputed by the available 
value at the nearest previous post-baseline visit.  For example, if a subject early withdraws at 
Week 13, the subject’s Week 25 will be imputed by the available total score at Week 13. 
Missing Dates for Investigator-confirmed HAE attacks 
Missing start or end date and time for Investigator-confirmed HAE attacks will be imputed.  In 
general, missing start time will be imputed as 0:00 and missing end time will be imputed as 
23:59.  However, the following rules will be applied for the attacks satisfying the corresponding 
conditions, in order to conservatively classify the attacks as separate, distinct attacks with at least 
24 hours in between: 
• For Investigator-confirmed HAE attacks with a missing start time and a non-missing 
start date one calendar day after the end date of the previous attack, the start time will 
be imputed using the end time of the previous Investigator-confirmed HAE attack to 
ensure there are 24 hours in between the 2 attacks. 
• For Investigator-confirmed HAE attacks with a missing start time and a non-missing 
end date/time within 24 hours from the end date/time of the previous attack, the 
attack should be considered as one attack with the previous attack 
• For Investigator-confirmed HAE attacks with missing end time and a non-missing 
end date one calendar day before the start date of the next attack, the end time will be 
imputed as the start time of the next Investigator-confirmed HAE attack to ensure 
there are 24 hours in between the 2 attacks. 
• For Investigator-confirmed HAE attacks with a missing end time and non-missing 
start date/time within 24 hours from the start date/time of the next attack, the attack 
should be considered as one attack with the next attack. 
For Investigator-confirmed HAE attacks with a non-missing start date and time and a missing 
stop date and time: 
• The stop date and time will be imputed as the earlier of the following 2 date and time: 
o Start date and time + 48 hours or study completion date and the stop time of 
23:59, whichever is later. 
o 24 hours before the start date and time of the next attack. 
After imputation, in the case of earlier than the start date/time, impute the time to be 
one second after the start date/time. 

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4.9.1.4. 
Multiple Comparisons/Multiplicity  
The multiplicity will be controlled by using a hierarchical ranking strategy in the following 
testing sequence. Should the null hypothesis for the primary efficacy endpoint be rejected, other 
endpoints will be tested in order.  If any test is not statistically significant, the test(s) at the lower 
rank will be considered exploratory.  Other statistical analyses planed in this SAP but not listed 
below are considered as exploratory analyses.  No adjustment will be made.  All tests will be 
conducted at a two-sided alpha level of 0.05.  
1. Primary efficacy endpoint analysis:  Comparison of the time-normalized number of 
Investigator-confirmed HAE attacks (per every-4-week) from Week 1 to Week 25 
between ISIS 721744 80 mg every 4 weeks group and pooled placebo group 
2. Comparison of the time-normalized number of Investigator-confirmed HAE attacks (per 
every-4-week) from Week 5 to Week 25 between ISIS 721744 80 mg every-4-weeks 
group and pooled-placebo group 
3. Comparison of the number of patients with a ≥ 70% reduction from baseline in 
Investigator-confirmed HAE attacks (per every-4-week) from Week 5 and Week 25 
between ISIS 721744 80 mg every-4-weeks group and pooled-placebo group  
4. Comparison of the percentage of Investigator-confirmed HAE attack-free patients from 
Week 5 to Week 25 between ISIS 721744 80 mg every-4-weeks group and 
pooled-placebo group 
5. Comparison of the time-normalized number of moderate or severe 
Investigator-confirmed HAE attacks (per every-4-week) from Week 5 to Week 25 
between ISIS 721744 80 mg every-4-weeks group and pooled-placebo group 
6. Comparison of the number of Investigator-confirmed HAE attacks requiring acute 
therapy (per every-4-week) from Week 5 to Week 25 between ISIS 721744 80 mg 
every-4-weeks group and pooled-placebo group 
7. Comparison of the change in AE-QoL total score at Week 25 between ISIS 721744 
80 mg every-4-weeks group and pooled-placebo group 
8. Comparison of the time-normalized number of Investigator-confirmed HAE attacks (per 
every-4-week) from Week 1 to Week 25 between ISIS 721744 80 mg every-8-weeks 
group and pooled-placebo group  
9. Comparison of the time-normalized number of Investigator-confirmed HAE attacks (per 
every-4-week) from Week 5 to Week 25 between ISIS 721744 80 mg every-8-weeks 
group and pooled-placebo group 
10. Comparison of the number of patients with a ≥ 70% reduction from baseline in 
Investigator-confirmed HAE attacks (per every-4-week) from Week 5 and Week 25 
between ISIS 721744 80 mg every-8-weeks group and pooled-placebo group  
11. Comparison of the percentage Investigator-confirmed HAE attack-free patients from 
Week 5 to Week 25 between ISIS 721744 80 mg every-8-weeks group and 
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12. Comparison of the time-normalized number of moderate or severe 
Investigator-confirmed HAE attacks (per every-4-week) from Week 5 to Week 25 
between ISIS 721744 80 mg every-8-weeks group and pooled-placebo group 
13. Comparison of the number of Investigator-confirmed HAE attacks requiring acute 
therapy (per every-4-week) from Week 5 to Week 25 between ISIS 721744 80 mg 
every-8-weeks group and pooled-placebo group 
14. Comparison of the change in AE-QoL total score at Week 25 between ISIS 721744 
80 mg every-8-weeks group and pooled-placebo group  
15. Comparison of the change in AE-QoL domain score of Functioning at Week 25 between 
ISIS 721744 80 mg every-4-weeks group and pooled-placebo group 
16. Comparison of the change in AE-QoL domain score of Fears/Shame at Week 25 between 
ISIS 721744 80 mg every-4-weeks group and pooled-placebo group 
17. Comparison of the change in AE-QoL domain score of Fatigue/Mood at Week 25 
between ISIS 721744 80 mg every-4-weeks group and pooled-placebo group 
18. Comparison of the change in AE-QoL domain score of Nutrition at Week 25 between 
ISIS 721744 80 mg every-4-weeks group and pooled-placebo group 
19. Comparison of the change in AE-QoL domain score of Functioning at Week 25 between 
ISIS 721744 80 mg every-8-weeks group and pooled-placebo group 
20. Comparison of the change in AE-QoL domain score of Fears/Shame at Week 25 between 
ISIS 721744 80 mg every-8-weeks group and pooled-placebo group 
21. Comparison of the change in AE-QoL domain score of Fatigue/Mood at Week 25 
between ISIS 721744 80 mg every-8-weeks group and pooled-placebo group 
22. Comparison of the change in AE-QoL domain score of Nutrition at Week 25 between 
ISIS 721744 80 mg every-8-weeks group and pooled-placebo group 
23. Comparison of the percent of patients who are well controlled on the AECT at Week 25 
between ISIS 721744 80 mg every-4-weeks group and pooled-placebo group 
24. Comparison of the percent of patients who are well controlled on the AECT at Week 25 
between ISIS 721744 80 mg every-8-weeks group and pooled-placebo group 
4.9.1.5. 
Interim Analyses  
No interim analysis is planned for this study.  Primary analyses will be conducted after the End 
of Treatment period when all patients complete Week 25 visit, stay in the study for at least 166 
days since the Study Day 1 or withdraw from the study before Week 25 visit.  Study results with 
continuing collected post-treatment data will be updated at the End of Study. 
4.9.1.6. 
Examination of Subgroups  
To evaluate the consistency of analysis results in the primary endpoint over parameters such as 
demographic and baseline characteristics, summaries by subgroup will be provided.  Exploratory 

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subgroup analyses may be performed if supported by data.  More details are described in the 
Section 4.9.2.6.  The subgroups include the following: 
• Age Category (12 to 17, 18 to 39, 40–64, ≥ 65) 
• Sex (Male, Female) 
• Race (Caucasian, Other),  
• Regions (North America, Europe, Middle East)  
• Taken any predefined prophylactic therapy, including lanadelumab, berotralstat, C1-
esterase inhibitor? (Yes, No) 
4.9.2. 
Primary Efficacy Variable  
The primary endpoint is the time-normalized number of Investigator-confirmed HAE attacks 
(per every-4-week) from Week 1 to Week 25.  
Hereditary Angioedema Attack (HAE Attack)  
During the study, patients will be instructed to report details of any HAE attack to the study site 
within 72 hours of the onset of the attack.  Throughout the Screening, Treatment, and 
Post-Treatment Periods, site personnel will contact the patient approximately weekly in order to 
inquire about any attack that may have occurred. 
The presence of these symptoms, including symptoms in one or more predefined locations in the 
protocol will not automatically be considered an HAE attack unless such a diagnosis is 
confirmed by the Investigator.   
An Investigator-confirmed HAE attack will be defined as an event with signs or symptoms 
consistent with an attack in at least 1 of the locations noted above.  A discrete attack will be 
counted if there is at least 24-hour symptom-free period between attacks. 
Unique Investigator-confirmed HAE Attacks 
To be counted as a unique Investigator-confirmed attack distinct from the previous attack, there 
must be at least 24 hours between the stop date/ time of the first event and the start date/time of 
the next event, for the attacks to be considered distinct.  If there is less than 24 hours between the 
stop date/time of the first event and the start date/time of the next event, the events will be 
combined and counted as one unique attack.  
When 2 or more events are combined as one unique Investigator-confirmed attack for efficacy 
analysis, parameters of the derived unique attack with combined multiple events will be defined 
in a conservative way.  
• Events:  Investigator-confirmed attacks. 
• Dates:  The start date/time will be the earliest start date/time of those multiple events; 
and the end date/time will be the latest end date/time of those multiple events.  
• The severity will be defined as the highest severity among those multiple events.  

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• The primary location will be determined by the primary location of individual event, 
and by following the hierarchy of laryngeal attack, peripheral attack, and abdominal 
attack.  One primary location will be taken; and all the other primary location(s) and 
secondary locations will be considered as secondary location for the combined attack. 
• Regarding the concomitant (allowed or not allowed) medications for the derived 
unique Investigator-confirmed HAE attack, all records from individual events will be 
included.  
4.9.2.1. 
Primary Analysis  
The primary efficacy endpoint will be tested by the following hypothesis: 
H0: λISIS 721744 / λplacebo = 1 versus H1: λISIS 721744 / λplacebo ≠ 1 
λISIS 721744 refers to the Investigator-confirmed HAE attack rate from Week 1 to Week 25 in the 
ISIS 721744 80 mg every 4 weeks group and λplacebo refers to the Investigator-confirmed HAE 
attack rate during the treatment period in the placebo group.  The null hypothesis is that the 
Investigator-confirmed HAE attack rate ratio from Week 1 to Week 25 is 1 (no difference 
between treatment groups), versus the alternative hypothesis that the Investigator-confirmed 
HAE attack rate ratio is not 1.  Estimated attack rate ratios less than 1 would indicate that 
patients treated with ISIS 721744 80 mg every 4 weeks, on average, have a lower incidence of 
Investigator-confirmed HAE attacks from Week 1 to Week 25.  The hypothesis will be tested 
using a Poisson regression model. 
The primary analysis will be performed using a Poisson regression model and Pearson chi-square 
scaling of standard errors to account for potential overdispersion on the FAS.  The model will 
include fixed effect for treatment group (categorical), baseline (the time-normalized run-in 
period attack rate, continuous), and the treatment-by-baseline interaction as covariates, and the 
logarithm of time in every-4-week that each patient was observed from Week 1 to Week 25 will 
be used as an offset variable.  
All patients who discontinued the Treatment Period early and started OLE, and patients who 
discontinued the Treatment Period early and were lost to follow-up before Week 25, will have 
the time-adjusted attack rate included in the analysis. 
The primary analysis will be performed based on the treatment policy strategy.  Treatment effect 
will be estimated regardless of intercurrent events, which are defined in the Section 3.2.1.  
From this model, the least squares mean rate, the standard error and the corresponding 
95% confidence interval for each treatment group as well as, the model adjusted mean rate ratios 
of ISIS721744 80 mg every 4 weeks relative to the pooled placebo group and the corresponding 
95% confidence interval will be estimated.  These estimates will be reported as mean event rates 
per every-4-week by transforming the estimates using the exponential function.  The p-value of 
the Wald-based chi-square test will be reported for testing the hypothesis. 
The percentage difference in mean Investigator-confirmed HAE attack rate between ISIS 721744 
80 mg every 4 weeks and the pooled placebo will be calculated as 100% × (model adjusted mean 
rate ratio –1).  Similarly, the estimated upper and lower confidence limits for the model adjusted 

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mean rate ratio can be transformed by subtracting 1 and multiplying by 100% to calculate 95% 
confidence intervals for the percentage change. 
In the case when the Poisson regression model cannot be converged, e.g., when all patients 
within one treatment group have 0 post-baseline Investigator-confirmed HAE event, Fisher’s 
Exact Test will be used for the analysis instead of Poisson regression.  The odds ratio, 
corresponding 95% CI, and p-value will be provided.  Sensitivity analyses on FAS described 
below for the primary endpoint analysis may not be performed.  
The comparison between ISIS 721744 80 mg every-8-weeks group and the pooled-placebo group 
in the time-normalized number of Investigator-confirmed HAE attacks (per every-4-week) from 
Week 1 to Week 25 will be analyzed in the same way including sensitivity analyses and 
supportive analyses discussed in sections from 4.9.2.1 to 4.9.2.4 
4.9.2.2. 
Sensitivity Analysis 1 – Negative Binomial (NB) Regression  
The Poisson regression model assumes that the mean and variance are equal.  When the variance 
in the data is larger than the mean, the model is said to be over-dispersed.  The primary analysis 
using Pearson chi-square scaling of standard errors to account for potential overdispersion.  
A sensitivity analysis will be performed by fitting a NB regression (Negative Binomial 
regression) model, which allows the variance in a different function of the mean.  The model will 
include fixed effects for treatment group (categorical), baseline (the time normalized run-in 
period attack rate, continuous), and the treatment-by-baseline interaction as covariates, and the 
logarithm of time in every-4-week that each patient was observed will be used as an offset 
variable.  
All patients who discontinued the Treatment Period early and started OLE, and patients who 
discontinued the Treatment Period early and were lost to follow-up before Week 25, will have 
the time-adjusted attack rate included in the analysis. 
Strategy used for the primary analysis, the treatment policy, will be used for this sensitivity 
analysis.  Treatment effect will be estimated regardless of intercurrent events, which are defined 
in the Section 3.2.1.  
4.9.2.3. 
Supportive Analysis – Per-Protocol Set (PPS)  
Primary analysis and sensitivity analysis 1 described above will be repeated on the PPS.  In the 
case when Poisson regression cannot be converged, e.g., when all patients within one treatment 
group have 0 post-baseline Investigator-confirmed HAE event, Fisher’s Exact Test will be used 
for the analysis instead of Poisson regression.  The odds ratio, corresponding 95% CI, and p-
value will be provided. 
4.9.2.4. 
Sensitivity Analysis 3 – Multiple Imputation Incorporating Pattern Mixture 
Model  
For patients who discontinued the Treatment Period early and started OLE, and patients who 
discontinued the Treatment Period early and lost to follow-up before Week 25, the primary 
analysis assumes that the missing data is MAR.  To evaluate the robustness of inferences made 
on MAR, a sensitivity analysis on FAS will be performed based on imputed data by using MI 

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method assuming J2R which is described in Section 4.9.1.3.  For each imputed data set, the 
Poisson regression model used for the primary analysis will be performed.  Results will be 
combined using Rubin’s rules.  
4.9.2.5. 
Sensitivity Analysis 4 – Tipping-Point Analysis  
A tipping-point analysis will be conducted to measure the potential effect of missing data on the 
reliability of the primary efficacy analysis. 
In this analysis, a range of progressively more conservative assumptions about the number of 
events occurring in the post-withdrawal period will be explored in order to find the assumption 
which will reverse the conclusion (i.e., yield a non-significant p-value) of the primary analysis.  
The assumption that will reverse the conclusion is referred to as the tipping point.  Once the 
tipping point is identified, the clinical plausibility of the assumption can be assessed. 
Missing event rate will be imputed by using the MI method described in Section 4.9.1.3.  In each 
run, the Poisson regression model used for the primary analysis will be performed.  Results will 
be combined using Rubin’s rules. 
The range of assumptions will be determined after treatment unblinding to ensure an appropriate 
range is explored based on the magnitude of treatment effect and pattern of missing data. 
4.9.2.6. 
Supplementary Analyses of Primary Endpoints  
4.9.2.6.1. Subgroup Analyses  
Investigator-confirmed HAE attacks (per every-4-week) from Week 1 to Week 25 will be 
summarized by each subgroup defined in the Section 4.9.1.6.  
Typical Patients Subgroup Analyses  
During the study conduction, patients that have a clinical history and/or screening period which 
is atypical for patients with Type I/II HAE may be found that could compromise the 
interpretation of the efficacy.  The list of atypical patients will be determined prior to unblinding 
for statistical analyses.  
Subgroup analyses based on typical patients, i.e., excluding atypical patients mentioned above, 
will be performed for the following endpoints by using the same methods as described for the 
primary efficacy endpoint in Sections 4.9.2.1. 
• Time-normalized number of Investigator-confirmed HAE attacks (per every-4-week) 
from Week 1 to Week 25 
• Time-normalized number of Investigator-confirmed HAE attacks (per every-4-week) 
from Week 5 to Week 25 
• Time-normalized number of moderate or severe Investigator-confirmed HAE attacks (per 
every-4-week) from Week 5 to Week 25 
• Time-normalized number of Investigator-confirmed HAE attacks requiring acute therapy 
(per every-4-week) from Week 5 to Week 25 

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4.9.2.6.2. Descriptive Summaries  
Investigator-confirmed HAE attack rates as well as change and percent change from baseline in 
the run-in period will be summarized by treatment group.  
The Investigator-confirmed HAE attack rate will be calculated for each patient as the following: 
Rate from Week 1 to Week 25: the number of Investigator-confirmed HAE attacks occurring 
during from Week 1 to Week 25 divided by number of days the patient contributed to the period 
multiplied by 28 days.  
Rate every 4 weeks:  Investigator-confirmed HAE attacks will be grouped into 28-day intervals 
using the start date/time of the Investigator-confirmed HAE attack.  First dose date/time will be 
used as the start of the first interval and end of the interval will be First dose date/time + 28 days.  
Each successive interval will start from the end of the prior interval, exclusively, and end 28 days 
later.  The Investigator-confirmed HAE attack rate will be calculated for each patient as the 
number of Investigator-confirmed HAE attacks occurring during each 28-day intervals.  
Rate standardized to every-4-week per each week:  First, as described above, 
Investigator-confirmed HAE attack rate will be derived for every 7 days.  It then standardized to 
every-4-week rate by multiply by 4. 
4.9.3. 
Secondary Efficacy Variables  
Strategy used for the primary analysis, the treatment policy, will be used for each second 
efficacy endpoint analysis.  Treatment effect will be estimated regardless of intercurrent events, 
which are defined in the Section 3.2.1.   
For secondary endpoints which are count data, i.e., number of HAE related data, in the case 
when Poisson regression models cannot be converged, e.g., when all patients within one 
treatment group have 0 event, Fisher’s Exact Test will be used as the main analysis. Sensitivity 
analyses on FAS described below may not be performed. 
For secondary endpoints which are responder data, e.g., number of patients with a clinical 
response on HAE or AECT or with HAE attack-free, in the case when logistic regression models 
cannot be converged, e.g., when all patients within one treatment group are responders, Fisher’s 
Exact Test will be used as the main analysis.  Sensitivity analyses on FAS described below may 
not be performed. 
In the case of convergence problems with the repeated measures mixed model, Section 4.9.3.7 
provides alternative model options.     
4.9.3.1. 
Time-Normalized Number of Investigator-Confirmed Hereditary Angioedema 
(HAE) Attacks (per Every-4-week) from Week 5 to Week 25  
The time-normalized number of Investigator-confirmed HAE attacks (per every-4-week) from 
Week 5 to Week 25 will be analyzed using the same methods as described for the primary 
efficacy endpoint in sections from 4.9.2.1 to 4.9.2.4.  
Main analysis will be based on Poisson regression model on FAS with the treatment policy 
strategy.  For patients who discontinued the Treatment Period early and started OLE, and 

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patients who discontinued the Treatment Period early and were lost to follow-up before Week 25 
but after Week 5, will have the time-adjusted attack rate included in the analysis.  For patients 
who were lost to follow-up before Week 5, assuming there is no change on the Investigator-
confirmed HAE attack rate, the baseline Investigator-confirmed HAE attack rate in run-in period 
will be used. 
Sensitivity Analyses 
A NB regression on FAS will be performed as a sensitivity analysis.  
To evaluate the robustness of inferences made on MAR, a sensitivity analysis on FAS will be 
performed based on imputed data by using multiple AE) methods assuming J2R which is 
described in Section 4.9.1.3.  For each imputed data set, the Poisson regression model used 
for the primary analysis will be performed.  Results will be combined using Rubin’s rules .  
4.9.3.2. 
Time-Normalized Number of Moderate or Severe Investigator-Confirmed 
Hereditary Angioedema (HAE) Attacks (per Every-4-week) from Week 5 to 
Week 25  
The time-normalized number of moderate or severe Investigator-confirmed HAE attacks (per 
every-4-week) from Week 5 to Week 25 will be analyzed using the same method as described 
for the primary efficacy endpoint in Sections 4.9.2.1, 4.9.2.2 and 4.9.2.4. 
Main analysis will be based on Poisson regression model on FAS with the treatment policy 
strategy.  For patients who discontinued the Treatment Period early and started OLE, and 
patients who discontinued the Treatment Period early and were lost to follow-up before 
Week 25, will have the time-adjusted attack rate included in the analysis.  
Sensitivity Analyses 
A NB regression on FAS will be performed as a sensitivity analysis.  
To evaluate the robustness of inferences made on MAR, a sensitivity analysis based on FAS 
will be performed based on imputed data by using MI methods assuming J2R which is 
described in Section 4.9.1.3.  For each imputed data set, the Poisson regression model used 
for the primary analysis will be performed.  Results will be combined using Rubin’s rules 
(Rubin 1987). 
Similar descriptive summaries described in Section 4.9.2.6 will be provided for this endpoint as 
well. 
4.9.3.3. 
Number of Patients with A Clinical Response between Week 5 and Week 25  
A clinical response is defined as a ≥ 50%, ≥ 70%, or ≥ 90% reduction from baseline in 
Investigator-Confirmed HAE attack rate.  The patient who archives a clinical response is a 
responder.  

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Percentage reduction = (Post-baseline rate - Baseline rate) / Baseline rate × 100%,  
where  
Post-baseline = the Investigator-confirmed HAE attack rate from Week 5 to Week 25 and 
Baseline = run-in period Investigator-confirmed HAE attack rate.  
For each of the clinical response, the odds ratio, corresponding 95% confidence intervals and p-
value will be provided by using a logistic regression model with the baseline, and the treatment-
by-baseline interaction as covariates.  Odds Ratio is showing the strength of the association 
between the treatment effect and the clinical response. 
Odds Ratio = (p1/(1- p1)) / (p2/(1- p2)) 
Where 
 
p1 = proportion of responder of ISIS 721744 80 mg every 4 weeks (or every 8 weeks) 
 
p2 = proportion of responder of the pooled Placebo 
Odds Ratio ranges from 0 to infinity.  When Odds Ratio = 1, there is no association; when Odds 
Ratio > 1, patients in the active treatment group are more likely than patients in the placebo 
group to be responders. 
The responder is derived based on time-adjusted Investigator-confirmed HAE attack rate per 
every-4-week.  For patients who discontinued the Treatment Period early and started OLE, and 
patients who discontinued the Treatment Period early and were lost to follow-up before Week 
25, the HAE attack rate per every-4-week for each treatment group is considered as the same 
before and after withdrawal.  
Main analysis will be based on FAS.  
Sensitivity Analysis 
To evaluate the robustness of inferences made on the main analysis, a sensitivity analysis on 
FAS will be performed based on imputed data by using MI methods assuming J2R which is 
described in Section 4.9.1.3.  For each imputed data set, the percentage reduction will be 
calculated and main analysis described above will be performed.  Results will be combined 
using Rubin’s rules. 
4.9.3.4. 
Percentage of Investigator-Confirmed Hereditary Angioedema (HAE) Attack-
Free Patients from Week 5 to Week 25  
The clinical response of Investigator-confirmed HAE attack-free from Week 5 to Week 25 will 
be analyzed using the same method as described for clinical responses in Section 4.9.3.3. 
For patients who discontinued the Treatment Period early and started OLE, and patients who 
discontinued the Treatment Period early and were lost to follow-up before Week 25, the HAE 
attack rate per every-4-week for each treatment group is considered as the same before and after 
withdrawal.  
Main analysis will be based on FAS and PPS.  

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Sensitivity Analysis 
To evaluate the robustness of inferences made on the main analysis, a sensitivity analysis on 
FAS will be performed based on imputed data by using MI methods assuming J2R which is 
described in Section 4.9.1.3.  For each imputed data set, the percentage reduction will be 
calculated and main analysis described above will be performed.  Results will be combined 
using Rubin’s rules. 
4.9.3.5. 
Number of Investigator-Confirmed Hereditary Angioedema (HAE) Attacks 
Requiring Acute Therapy from Week 5 to Week 25  
HAE attacks requiring acute therapy include those attacks with the following concomitant 
medication. 
C1 Esterase Inhibitors (human) 
 
Berinert 
Cinryze 
C1 Esterase Inhibitor (recombinant) 
Ruconest 
Plasma Kallikrein Inhibitor (human) 
Kalbitor (ecallantide) 
Bradykinin antagonist 
Firazyr (icatibant) 
The time-normalized number of Investigator-confirmed HAE attacks (per every-4-week) 
requiring acute therapy from Week 5 to Week 25 will be analyzed using the same methods as 
described for the primary efficacy endpoint in Sections 4.9.2.1, 4.9.2.2 and 4.9.2.4. 
Main analysis will be based on Poisson regression model on FAS with treatment policy strategy. 
For patients who discontinued the Treatment Period early and started OLE, and patients who 
discontinued the Treatment Period early and were lost to follow-up before Week 25, will have 
the time-adjusted attack rate included in the analysis.  
Sensitivity Analyses 
A NB regression on FAS will be performed as a sensitivity analysis.  
To evaluate the robustness of inferences made on MAR, a sensitivity analysis based on FAS 
will be performed based on imputed data by using multiple imputation (MI) methods 
assuming J2R which is described in Section 4.9.1.3.  For each imputed data set, the Poisson 
regression model used for the primary analysis will be performed.  Results will be combined 
using Rubin’s rules . 
4.9.3.6. 
Percent of Patients who are Well-Controlled on the Angioedema Control Test 
(AECT) at Week 25  
The AECT is a validated patient-reported outcome instrument to assess disease activity in 
patients with recurrent angioedema (Weller et al. 2020) which will be assessed during Treatment 
and Post-Treatment Periods as outlined in Protocol Appendix A.  The questionnaire consists of 
four questions asking about the frequency and severity of angioedema experienced in the last 4 
weeks.  Each question has 5 response choices.  Scored as the following: 

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1. How often have you had 
angioedema? 
Very often = 0, Often = 1, Sometimes = 2, Seldom = 3, Not at all =4 
2. QOL been affected by 
angioedema? 
Very much = 0, Much = 1, Somewhat = 2, A little = 3, Not at all =4 
3. Unpredictability of 
angioedema? 
Very much = 0, Much = 1, Somewhat = 2, A little = 3, Not at all =4 
4. Angioedema been 
controlled? 
Not at all = 0, A little = 1, Somewhat = 2, Well = 3, Very well =4 
The AECT total score is the summation of scores of 4 questions and can be used to identify 
patients with poorly controlled disease by working with a cutoff value of greater than or equal to 
10 points.  Patients with the total score less than 10 points (0–9) in the AECT have poorly 
controlled disease whereas patients with controlled disease score 10–16 points.  The AECT will 
be completed by the patient. 
The number and percentage of patients who are well-controlled on the AECT at Week 25 will be 
summarized by treatment group.  
The clinical response of well controlled patients on AECT at Week 25 will be analyzed on all 
patients with at least one non-missing AECT value at a post-baseline visit, using the same 
method as described for clinical responses in Section 4.9.3.3.  However, the baseline and 
treatment-by-baseline interaction is not included for AECT (i.e., no covariates in the logistic 
regression). 
For patients who discontinued the Treatment Period early and started OLE, and patients who 
discontinued the Treatment Period early and were lost to follow-up before Week 25, before 
calculating the responder of well controlled on the AECT at Week 25, missing AECT total score 
will be imputed by LOCF which is described in Section 4.9.1.3. 
Sensitivity Analyses 
To evaluate the robustness of inferences made on the imputed data using LOCF, a sensitivity 
analysis on all patients with at least one non-missing AECT value at a post-baseline visit will 
be performed based on imputed data by using MI methods assuming J2R which is described 
in Section 4.9.1.3.  For each imputed data set, the responder will be derived, and main 
analysis described above will be performed.  Results will be combined using Rubin’s rules.  
A sensitivity analysis on all patients with at least one non-missing AECT value at a 
post-baseline visit based on imputed data by using LOCF in Section 4.9.1.3 will also be 
performed.  In the sensitivity analysis, the logistic regression will include the baseline AECT 
total score (continuous) as a covariate.  Missing baselines will be imputed first by the average 
of available baselines across all patients in the FAS.  
4.9.3.7. 
Change from Baseline in Angioedema Quality of Life (AE-QoL) Questionnaire 
Total Score at Week 25.  
Quality of life will be assessed by the AE-QoL questionnaire during Screening, Treatment, and 
Post-Treatment Periods as outlined in Protocol Appendix A.   

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The AE-QoL questionnaire is a validated tool to assess symptom specific health-related quality 
of life impairment in patients suffering from recurrent angioedema (Weller et al. 2012).  The 
AEQoL is a self-administered questionnaire that can be completed in less than 5 minutes; it 
comprises 17 questions across 4 domains:  functioning, fatigue/mood, fears/shame, and food.  
Each domain includes the following questions: 
Functioning 
How often have been restricted in the area of Q1. Work; Q2. Physical activity; 
Q3. Leisure time; Q4. Social relations 
Fatigue/mood 
Q6. Difficulty falling asleep; Q7. Wake up during the night; Q8. Tired since not 
sleeping well; Q9. Trouble on concentrating; Q10. Depressed 
Fears/shame 
Q12. Swelling episode burden you; Q13. Afraid swelling could occur suddenly; 
Q14. Afraid frequency of the swelling increase; Q15. Ashamed to go out in public 
because of swelling; Q16. Embarrassed or self-conscious because of swelling; 
Q17. Afraid treatment has negative long-term effects 
Food 
Q5. Restrict eating and drinking; Q11. Limit your choices of food/beverage 
The AE-QoL can be used to calculate scores for the 4 individual domains and can also be used to 
determine a total score.  The AE-QoL will be completed by the patient. 
AE-QoL will be evaluated by determining its four individual domain scores and a total score. 
Each item answered by the patient scores between 0 and 4 points depending on the answer option 
chosen by the patient:  Never = 0, Rarely = 1, Occasionally = 2, Often = 3, Very often = 4.  The 
AE-QoL domain scores and total score are calculated by using the following formula: 
(Sum score of all completed items) / (maximum sum score of all possible items) × 100 
Computation of AE-QoL Total Score 
Example 1:  All items were completed (maximum possible sum:  68 points) 
Sum of all 17 completed items:  41 points 
Total score = 100 × (41/68) = 60 (out of a possible 100 points) 
Example 2: 2 items were not completed (maximum possible sum: 60 points)  
Sum of all 15 completed items:  41 points 
Total score = 100 × (41/60) = 68 (out of a possible 100 points) 
Computation of Domain Scores (Example: Fears/Shame) 
Example: Sum of all 6 completed items:  14 points 
Maximum possible sum:  24 points 
Domain Score = 100 × (14/24) = 58 (out of a possible 100 points) 
Remarks 
Since only answered items are included in the computation (and the calculated domain and total 
scores are not raw scores but linear transformations to a 0-to-100 scale), the calculated scores are 
not or only little influenced by missing items. 
An AE-QoL domain score should not be calculated if more than one item is left unanswered in 
that domain.  The AE-QoL total score should not be calculated if more than 25% of items 

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(>4 items) are left unanswered.  For AE-QoL each derived domain score and total score, missing 
baseline or post-baseline handling are described in the Section 4.9.1.3. 
The minimal and highest possible domain and total scores are 0 and 100, respectively. 
AE-QoL total score, the change, and the percent change from baseline will be summarized by 
visit and treatment group.  
The change from baseline in AE-QoL total score at Week 13 and Week 25 will be compared 
between ISIS 721744 80 mg every 4 weeks and pooled placebo using the MMRM model.  The 
MMRM model will include effects of treatment, time, treatment-by-time interaction, baseline 
value at Study Day 1, and treatment-by-baseline interaction.  Missing baselines will be imputed 
first by the average of available baselines across all patients in the FAS . The analysis will be 
conducted in the FAS.  The unstructured covariance model will be used to model the within 
patient errors, shared across treatment and small sample adjustments to standard errors and tests 
will be made following the Kenward-Roger approach (Kenward and Roger 1997).  If there are 
convergence problems with the repeated measures mixed model, this will be explored with the 
following methods in order:  1) the SCORING = 4 option could be used in the PROC MIXED 
statement in SAS.  This makes SAS use Fisher scoring for the first 4 iterations. 2) If the 
convergence problem cannot be resolved, the unstructured covariance matrix will be replaced by 
the homogeneous compound symmetry covariance matrix (Type = CS in SAS).  
The comparison between ISIS 721744 every 8 weeks and pooled placebo will also be analyzed 
in the same way as above mentioned. 
The least-squares means, standard errors, and the 2-tailed 95% confidence intervals for the 
treatment group and placebo group will be presented. 
Sensitivity Analyses 
To evaluate the robustness of inferences made on MAR, a sensitivity analysis on FAS based 
on imputed data by using MI methods assuming J2R which is described in Section 4.9.1.3 
will be performed.  For each imputed data set, total score will be derived.  The change from 
baseline in AE-QoL total score will be compared between ISIS721744 80 mg every 4 weeks 
and pooled placebo using ANCOVA with baseline as a covariate.  Results will be combined 
using Rubin’s rules.  
In addition, a responder analysis will be performed for AE-QoL total score as an exploratory 
analysis: 
A clinical response is defined as a ≥ 6-point improvement from baseline in AE-QoL total score at 
Week 25, i.e., Post-baseline – Baseline ≤ -6.  The patient who archives a clinical response is a 
responder. Patients with non-missing response will be analyzed.  The odds ratio, corresponding 
95% confidence intervals and p-value will be provided by using a logistic regression model with 
the baseline, and the treatment-by-baseline interaction as covariates. 
For patients who discontinued the Treatment Period early and started OLE, and patients who 
discontinued the Treatment Period early and were lost to follow-up before Week 25, the 
treatment termination reason will be checked.  Due to reasons of adverse events or lack of 
efficacy, patients will be considered as a non-responder; due to other reasons, patient will be 

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categorized as missing and excluded from the analysis.  Patient with missing baseline will also 
be excluded from the analysis.  
Exploratory analysis for each AE-QoL domain score is described in Section 4.13.8.  
4.10. 
Safety Evaluation  
All safety summaries and analyses will be based on the Safety Set as defined in Section 4.5. 
4.10.1. 
Extent of Exposure  
Study drug will be administered as subcutaneous injections.  A descriptive summary of exposure 
variables will be provided for patients who took ISIS 721744 80 mg: 
• Amount of active Study Drug (ISIS 721744) (mg) 
• Duration of active Study Drug (ISIS 721744) exposure (days) from the first dose 
date/time to the last dose date/time + pre-specified duration in days, or to the study 
termination date, which occurred earlier. 
− for cohort A, the pre-specified duration is 28 days 
− for cohort B, the pre-specified duration is 56 days 
4.10.2. 
Adverse Events (AEs)  
AEs will be coded using the MedDRA Version 26.1 or higher.   
Treatment-emergent adverse events (TEAEs) will be tabulated and are defined as those AEs that 
either start or worsen in severity on or after the date/time of first dose of study treatment. 
In addition, if severity of an AE changes during the study, a separate AE will be recorded for 
each severity on the AE CRF. “first” and “second” AE will be identify based on AE start date. 
AE start date of the second record is AE stop date of first record.  AE severity 
(mild/moderate/severe) are compared between these 2 linked records in a pair for further 
defining TEAE.  Consider 2 cases below: 
• Case 1:  The first AE record in the pair occurs before first dosing, and the second AE 
record occurs after first dosing.  
If the AE severity of the second record is worse than that of the first record, then only 
the second AE is deemed as a TEAE.  Otherwise, neither record is considered as 
TEAE. 
• Case 2:  Both AE records in the pair occur after first dosing.   
If the AE severity on the second record is worse than the severity on the first record, 
then count both records as treatment-emergent.  But, if the severity improves, then 
only count the first record as treatment-emergent. 
All TEAEs identified based on the rules above will be summarized in the event number analysis. 

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The most conservative approach will be used to determine if the event occurs after the treatment.  
For example, if the onset date or resolution date of an AE is prior to the first study treatment 
date, it will be considered to have occurred prior to the study period.  If the onset or resolution 
date 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. 
The incidence of AEs will be summarized by MedDRA PT and SOC for: 
• Any TEAEs 
• Potentially Related TEAEs. Related is defined as “Related”, “Possible”, or missing 
relationship to Study Drug (ISIS 721744 or placebo)  
• Any TEAEs by severity.  At each level of patient summarization, a patient is 
classified according to the highest severity if the patient reported one or more events.  
AEs with missing severity will categorized as “Missing” for this summary 
• Related TEAEs by severity 
• Serious AEs (SAEs) 
• Serious and related TEAEs 
AE summaries will be ordered alphabetically for SOC, and PT within SOC and decreasing 
frequency for SOC, and PT within SOC, in the overall column. 
A by-patient listing of all AEs (including non-treatment-emergent events) will be provided. AEs 
that lead to study discontinuation or investigational drug discontinuation will also be listed 
separately.  Non-treatment emergent adverse event will be flagged in the data listing. 
4.10.3. 
Deaths, and Other Serious or Significant Adverse Events  
4.10.3.1. Local Cutaneous Reactions at the Injection Site  
Local cutaneous reaction at injection site (LCRIS) is defined as (A) moderate or severe AEs with 
the PTs including Injection site erythema, Injection site swelling, Injection site pruritus, or 
Injection site pain that started on the day of injection, persisted for at least 2 days or ongoing; 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 PT and by 
treatment group. Patients with moderate, severe and any LCRIS will also be summarized. 
Discontinuations of Study Drug (ISIS 721744 or placebo) due to AE at the injection site will be 
summarized separately. 
Percentage of injections leading to those events will be summarized by PT and overall using the 
descriptive statistics.  Additionally, percentage of injections leading to events will be 
summarized by moderate, severe severity and overall discontinuation of study drug due to AE at 
injection site.  

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Percentage of injections leading to LCRIS will be calculated as follows for each patient: (A/B) × 
100, where A = number of injections with a LCRIS, and B = total number of injections.  Doses 
that are split across multiple injections are counted as a single injection.  
LCRIS will be provided in a subject data listing. 
4.10.3.2. Flu-like Reactions  
Flu-like reactions are defined as adverse events with PTs including either (A) Influenza like 
illness or (B) Pyrexia or Feeling hot or Body temperature increased, plus at least 2 of the 
following symptoms with the PTs:  Chills, Myalgia, or Arthralgia, starting on day of injection or 
the next day. 
Flu-like reactions will also be summarized using the MedDRA coding system, by PT and by 
treatment group. 
Percentage of injections leading to flu-like reactions will be summarized by treatment group 
using the descriptive statistics. 
Percentage of the injections leading to flu-like reactions will be calculated as follows for each 
patient: (A/B) × 100, where A = number of injections leading to flu-like reactions, and B = total 
number of injections. 
Flu-like reactions will also be listed. 
4.10.3.3. Bleeding Adverse Events  
Bleeding AEs will be identified based on the Haemorrhages (SMQ) Export from MedDRA and 
summarized by MedDRA SOC and PT and by treatment group.  A by-patient listing will be 
provided. 
4.10.4. 
Clinical Laboratory Evaluation  
The following is the list of lab analytes that will be collected throughout the study: 
• Chemistry:  sodium, potassium, chloride, bicarbonate, total protein, albumin, calcium, 
magnesium, phosphorus, glucose, BUN, creatinine, cholesterol, uric acid, total 
bilirubin, direct (conjugated) bilirubin, indirect (unconjugated) bilirubin, alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase 
(ALP), creatinine kinase, gamma-glutamyl transferase (GGT) 
• Hematology:  red blood cells, hemoglobin (Hb), hematocrit, platelets, mean 
corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular 
hemoglobin concentration (MCHC), white blood cells (WBC), and WBC differential 
(percentage and absolute count) (basophils, eosinophils, lymphocytes, monocytes and 
neutrophils) 
• Coagulation:  activated partial thromboplastin time (aPTT) (sec), prothrombin time 
(sec), international normalized ratio (INR), D-dimer 

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• Complement:  Complement Factor 5a (C5a).  (At screening, Complement factor 4 
(C4), C1-inhibitor (C1-INH) level and function, Complement 1q (C1q) will be 
collected.) 
• Inflammatory:  C-reactive protein (CRP) measured by high sensitivity assay 
(Hs-CRP) 
• Screening tests:  hepatitis B surface antigen, hepatitis C antibody, human 
immunodeficiency virus (HIV) antibody, follicle-stimulating hormone (FSH) (women 
only, if applicable), and serum beta-subunit of human chorionic gonadotropin (βhCG) 
(women only).  The data will be displayed in by-patient listings. 
• Urinalysis (other):  color, appearance, specific gravity, pH, P/C ratio, protein, blood, 
ketones, urobilinogen, glucose, bilirubin, leukocyte esterase, nitrate, microscopic 
examination.  The data will be displayed in by-patient listings. 
Missing WBC differential absolute counts and percentages will be derived: 
• 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 WBC 
differential absolute counts are missing, and manual count values are available, then 
manual count values will be used.  If neutrophils count 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, if only 
segmented neutrophil result is available, then neutrophils will be set to segmented 
neutrophils result. 
All lab data will be displayed in by-patient listings. 
Chemistry, hematology, coagulation, and complement, (result, change and percent change from 
baseline) will be summarized using descriptive statistics (n, mean, median, standard error, 
standard deviation, 25th percentile, 75th percentile, minimum, and maximum) by treatment 
group and analysis visit.  Only central lab data will be summarized in by-visit summary.  Both 
central and local lab data will be used in the abnormal summaries described below. 
For ALT and AST, the number and percent of patients falling in each of the following categories 
based on the confirmed results (both central and local lab data will be used) will be tabulated by 
treatment group: 
• ALT or AST > 3 × upper limit of normal (ULN), which is confirmed 
• ALT or AST > 3 × ULN (or the greater of 2 × baseline value or 3 × ULN if the baseline 
value was > ULN), which is confirmed  
• ALT or AST > 3 × ULN (or the greater of 2 × baseline value or 3 × ULN if the baseline 
value was > ULN), which is confirmed  
and  

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total bilirubin > 1.5 × ULN or INR > 1.5, where “and” required to be based on the same 
sample 
• ALT or AST > 5 × ULN, which is confirmed 
• ALT or AST > 5 × ULN, which is confirmed 
and  
persists for ≥ 2 weeks 
• ALT or AST > 8 × ULN, which is confirmed 
For platelet (K/mm3), the number and percentage of patients falling in each of the following 
categories based on the confirmed results (both central and local lab data will be used) will be 
tabulated by treatment group for ≥ 125, >100 to <125, ≥75 to ≤ 100, ≥ 50 to < 75, ≥ 25 to < 50, < 
25. 
A confirmed value is based on a consecutive lab value within 7 days.  If that value is in the same 
or worse category the initial value is confirmed.  If the consecutive value is in a better category, 
then the initial value is confirmed using the consecutive value category.  If there is no retest 
within 7 days, then 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. 
Laboratory data will be presented in by-patient listings.  
4.10.5. 
Vital Signs, Physical Findings and Other Observations Related to Safety  
4.10.5.1. Vital Signs  
Vital signs will include heart rate, respiratory rate, body temperature, systolic and diastolic blood 
pressure and pulse pressure.  Summary tables will be created to present the descriptive statistics 
(n, mean, standard error, standard deviation, median, 25th percentile, 75th percentile, minimum, 
and maximum) for vital sign values, weight, and BMI as well as the change and percent change 
from baseline at each analysis visits. 
4.10.5.2. Physical Examinations  
Adverse changes in physical examinations that are deemed clinically significant by the 
Investigator will be classified as AEs.  All physical examination data will be provided in a 
by-patient listing.  Per Study Protocol Amendment 2 (UK only), additionally, assessments of 
growth development and sexual maturity (i.e., Tanner Staging) for adolescent patients 
(12-17 years) will be provided in a by-patient listing.  
4.10.5.3. 12-Lead Electrocardiograms (ECG)  
Safety 12-lead ECG data will include Ventricular Rate, PR Interval, RR Interval, QRS Duration, 
QTc, QTcF (QT corrected using the Fridericia’s formula), QTcB (QT corrected using the 
Bazett’s formula), and Overall interpretation. QTcF and QTcB will be calculated based on the 
patient’s reportable ECG data at each time point using the formula described below: 

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QTcF = QT / (RR) 1/3, where RR = 60/VR 
QTcB = QT / (RR) 1/2, where RR = 60/VR 
For the continuous variables above, descriptive statistics (n, mean, standard error, standard 
deviation, median, 25th percentile, 75th percentile, minimum and maximum) of the results at 
each analysis visit, as well as the changes and percent changes from Baseline to each study visit, 
will be presented in summary tables; for the categorical responses to overall interpretation, the 
results and the associated findings at each visit will be summarized by counts and percentages.  
In the case when triplicate results are collected, for the continuous variables, average of triplicate 
results will be derived before generating the descriptive summary; for the categorical responses, 
the worst of triplicate results will be choosing for the descriptive summary.  
All the ECG data collected will be listed. 
4.10.6. 
Data Monitoring  
4.10.6.1. Safety Data Monitoring  
Ionis (or designee) is responsible for processing all reported AEs.  All serious adverse events 
(SAEs), reported to Ionis (or designee), are reviewed according to standard operating procedures.  
The medical monitor will review all AEs and SAEs on an ongoing basis throughout the study.  
Ionis (or designee) will prepare and submit safety reports to the health authorities worldwide in 
accordance with local requirements.  If it becomes necessary to communicate new safety 
information, Ionis (or designee) will also prepare a safety notification letter and transmit it to 
study site. 
4.10.6.2. Data and Safety Monitoring Board  
An independent Data and Safety Monitoring Board (DSMB) will be established to monitor the 
overall safe conduct of the study.  Based on its ongoing assessment of the safety and tolerability 
of ISIS 721744, the DSMB will provide recommendations to the Sponsor for modifying, 
stopping or continuing the study as planned.  Details on the safety assessments, frequency of 
review, meeting schedules, and controlled access to unblinded data are outlined in the DSMB 
Charter.  
4.11. 
Pharmacokinetics  
Plasma concentrations of ISIS 721744 (measured as total full-length oligonucleotides or 
ISIS 721744-equivalent, i.e., ISIS 721744-eq, including fully conjugated, partially conjugated, 
and unconjugated ISIS 721744, along with the scheduled (nominal) and actual sampling times 
(i.e., time from subcutaneous [SC] dosing) will be listed for each evaluable patient by treatment, 
actual dose, cohort, gender, body weight, age, subject IM status, and study day.  Plasma 
concentrations below the lower limit of quantification (LLOQ) will be indicated by “BLQ”. 
Percent differences between nominal and actual dose, as well as between scheduled and actual 
sampling times will also be listed for all patients. 
For all patients administered with ISIS 721744, ISIS 721744 plasma trough, 2 hours post-dose 
concentrations after the first and last dose and post-treatment concentrations will be summarized 

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using descriptive statistics by treatment, dose, cohort, study day, and scheduled time point, 
without and with age group stratification (12 to < 18-year-old and ≥ 18-year-old patients), 
without and with stratification by subject Anti-Drug Antibody (ADA) status overall (see 
Section 4.12.2).  For the purpose of calculating typical summary descriptive statistics (n, mean, 
SEM/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 
below the LLOQ will be presented as BLQ, and the SD, SEM/SD, %CV, and geometric %CV 
will be reported as not applicable (NA).  Other stratifications may also be performed if deemed 
warranted.  Samples will be excluded from descriptive statistics if there are large deviations 
between scheduled and actual sampling times (percent difference between scheduled and actual 
sampling time greater than 30%), or large deviations between actual dose and nominal dose 
(percent difference 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. 
Population PK, PK/PD or exposure-response analysis may be performed using the PK and PD 
data from this study, and/or combined with other clinical study data and reported separately.  If 
appliable, details of these analyses will be presented in a separate analysis plan.  
4.12. 
Immunogenicity (IM) Analysis  
Samples collected for IM assessment at baseline (Day 1 pre-dose), during treatment and 
post-treatment follow-up period including early termination samples will be analyzed for 
anti-ISIS 721744 antibodies (ADA).  
4.12.1. 
Sample Level ADA Data  
An evaluable sample will be designated ‘Positive’ based on both positive screening and 
confirmation assay results (i.e., confirmed positive result), and otherwise will be deemed 
‘Negative’. Sample ADA results (screen positive/negative, confirmed positive/negative or 
unevaluable, and when applicable, titer of anti-ISIS 721744 antibodies) before, during, and after 
treatment with study drug (ISIS 721744 or placebo) (sample ADA status) will be listed by 
treatment, dose, cohort, and day of collection.  
The sample ADA incidence (number) and incidence rate (percent) at each evaluated study time 
point will be determined and appropriately summarized by treatment, dose, and cohort as the 
total number of and percentage of evaluated subjects with sample ADA negative, positive, and 
unknown status.  Furthermore, titer over time will be also appropriately summarized (using 
descriptive statistics) as median, quartiles (25% and 75%), and range by treatment, dose, and 
cohort.  Summarization of ADA incidence, incidence rate and titer by age group (12 to < 18-
year-old and ≥ 18-year-old patients) may also be reported.  
4.12.2. 
Subject Level ADA Data  
Subject ADA status overall (ADASTAT) will be defined as ‘Positive’ status if they have at least 
one confirmed positive sample result at any time during the treatment or post-treatment 
evaluation periods; ‘Negative’ status if all evaluated ADA sample results during the treatment 

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and post-treatment evaluation periods are ADA negative and they have at least one evaluable 
ADA result collected post study drug treatment.  Otherwise, a study subject will be assigned 
‘Unknown’ ADA status.  
Furthermore, subjects with positive overall ADA status will be further classified into different 
ADA types (ADATYPE) based on their baseline ADA status and change in ADA titer post-
treatment as described below :  
• Treatment-Emergent ADA: sum of treatment-induced ADA and treatment-boosted 
ADA as described below:  
o Treatment-Induced ADA:  ADA developed de novo (seroconversion) following 
biologic drug administration (i.e., formation of ADA any time after the initial 
drug administration in a subject without pre-existing ADA, i.e., baseline negative 
ADA)  
o Treatment-Boosted ADA:  pre-existing ADA that were boosted to a higher level 
following biologic drug administration (i.e., any time after the initial drug 
administration the ADA titer is greater than the baseline titer by a factor of 8-fold 
or more  
• Treatment-Unaffected ADA:  pre-existing ADA that were not affected (boosted) 
following biologic drug administration (i.e., any time after the initial drug 
administration the ADA titer is 4-fold or less)  
• ADATYPE would be not applicable (NA) if the subject overall ADA status is 
negative.  
Other subject level IM parameters to be calculated/defined may include but not limited to: 
• Subject ADA Status at Baseline (ADASTATB):  "Positive" if the subject has Week 1 
Day 1 pre-dose sample (baseline) tested as confirmed positive; "Negative" if the 
subject has Week 1 Day 1 pre-dose sample (baseline) tested as confirmed negative; 
"Unknown" if the subject has Week 1 Day 1 pre-dose sample (baseline) unevaluable. 
• Onset of ADA (TFSTADA):  i.e., the first day ADA positive sample observed, will 
be calculated by: the date of first sample has “positive” sample IM status - first dose 
date +1 
• Last Positive ADA Study Day (TLSTADA):  defined as the last positive ADA sample 
observed from the start of study drug treatment and will be calculated by: the date of 
last sample has “positive” sample IM status - first dose date +1 
• Last IM Sampling Study Day (TLSTSAMP):  defined as the last ADA sample 
collected from the start of study drug treatment and will be calculated by:  the date of 
last sample collected - first dose date +1 
• Peak titer (PEAKTIT):  the highest titer observed for the subject 
• Time to peak titer (TPEAKTIT):  the time to reach peak titer will be calculated by:  
the date of first peak titer observed- first dose date +1 

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• Total number of ADA Positive Samples (NOPOSAMP):  the total number of ADA 
samples being confirmed positive for the subject 
• Total number of ADA Samples evaluated (NOADASAMT):  the total number of 
ADA samples being collected and analyzed successfully with reportable results for 
the subject 
Lastly, subjects with positive ADA status may further be classified as being transient or 
persistent ADA response, if there are sufficient number of subjects with transient ADA status.  
Transient and persistent ADA definitions are defined below and based on : 
Transient ADA response: 
• 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: 
• Treatment-induced ADA detected at 2 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 subject level ADA prevalence, incidence, and positive ADA response being transient or 
persistent (if applicable) will be calculated as the number and the proportion (percent) of the 
study population during the study period by treatment, dose, and cohort.  Subject level IM 
parameters (as described above) will be listed by treatment, dose, and cohort for all evaluable 
subjects, and also appropriately summarized (using descriptive statistics) as median, quartiles 
(25% and 75%), and range by treatment, dose, and cohort.  Summarization of subject level ADA 
response and IM parameters by age group (12 to < 18-year-old and ≥ 18-year-old patients) may 
also be reported. 
4.12.3. 
 Evaluation of IM Impact on PK, PD, Efficacy and Safety   
The impact of IM on PK, PD, and safety will be evaluated by stratifying plasma trough and 
post-treatment ISIS 721744 concentrations, PD biomarker levels, selected clinical efficacy end 
points and safety measures by subject ADA status, summarized using typical descriptive 
statistics, and presented graphically and/or in tables.  Efficacy and PD measures to be stratified 
by subject IM status may include Investigator-confirmed HAE attacks and plasma PKK levels . 
Safety measures to be stratified by subject IM status may include AEs, and lab tests for 

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hematology, liver and kidney functions.  Other efficacy, PD and safety measures stratifications 
with subject IM status may also be conducted, if deemed appropriate.  
Other stratifications (e.g., based on antibody titer, onset of ADA, etc.) of selected PK, PD, 
efficacy and safety assessments may also be performed if deemed warranted at the discretion of 
the pharmacokineticist, medical monitor, and/or biostatistician. 
4.13. 
Exploratory Analyses  
All exploratory analyses will be performed as a reference based on the FAS as defined in 
Section 4.5.  By-patient listings will be provided too.  Missing data will not be imputed. 
For exploratory endpoints which are count data, in the case when Poisson regression models 
cannot be converged, e.g., when all patients within one treatment group have 0 event, Fisher’s 
Exact Test will be used as the main analysis.  
For exploratory endpoints which are responder data, in the case when Logistic regression models 
cannot be converged, e.g., when all patients within one treatment group are responders, Fisher’s 
Exact Test will be used as the main analysis. 
In the case of convergence problems with the repeated measures mixed model, Section 4.9.3.7 
provides alternative model options. 
4.13.1. 
Change and Percent Change from Baseline in Plasma Prekallikrein (PKK) Level  
The change and percent change from baseline in plasma PKK levels will be summarized by visit 
and treatment group.  The change and percent change from baseline in plasma PKK levels at 
each visit during the treatment period will be compared between ISIS 721744 80 mg every 4 
weeks (or every 8 weeks) and pooled placebo using MMRM model based on the FAS.  The 
response variable is the change or percent change from baseline at post-baseline visit up to 
Week 25.  
The MMRM model will include effects of treatment, time, treatment-by-time interaction, and 
baseline value.  The unstructured covariance model will be used to model the within patient 
errors, shared across treatment and small sample adjustments to standard errors and tests will be 
made following the Kenward-Roger approach (Kenward and Roger 1997).  
4.13.2. 
Change from Baseline in Generalized Anxiety Disorder (GAD-7) Questionnaire 
Total Score  
A GAD-7 questionnaire will be administered to evaluate anxiety experienced by patients.  The 
GAD-7 is a self-administered patient questionnaire and it is used as a screening tool and severity 
measure for generalized anxiety disorder (Spitzer et al. 2006). 
The GAD-7 questionnaire includes 7 questions, and the response to each question is scored 
as:  Not at all = 0, Several days =1, More than half the days = 2, Nearly every day = 3. 
The total score is calculated by summing the score of each question and provides a possible score 
from 0-21. GAD-7 total score will be classified into severity stages (Spitzer et al. 2006) as 
shown below, which will be summarized for each visit. 

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Total Score Range 
Symptom 
0–4 
Minimal Anxiety 
5–9 
Mild Anxiety 
10–14 
Moderate Anxiety 
15–21 
Severe Anxiety 
The GAD-7 total score, the change and the percent change from baseline will be summarized by 
visit and treatment group.  The change from baseline in GAD-7 total score will be compared 
between ISIS 721744 80 mg every 4 weeks (or every 8 weeks) and pooled placebo using the 
MMRM model based on the FAS. The MMRM model will include effects of treatment, time, 
treatment-by-time interaction, and baseline value.  The unstructured covariance model will be 
used to model the within patient errors, shared across treatment and small sample adjustments to 
standard errors and tests will be made following the Kenward-Roger approach (Kenward and 
Roger 1997).  
4.13.3. 
EuroQoL-5-Dimensions Quality of Life Questionnaire (EQ-5D-5L) and Change 
from Baseline in Visual Analog Scale (EQ VAS) Score  
EQ-5D-5L is a standardized measure of health status developed by the EuroQoL Group to 
provide a simple, generic measure of health for clinical and economic appraisal (Herdman et al. 
2011).  The EQ-5D-5L consists of the EQ-5D-5L descriptive system and the EQ Visual analog 
scale (EQ VAS). 
The EQ-5D-5L descriptive system comprises five dimensions (mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression), and the response to each dimension is scored 
in 5 levels as:  No problems = 1, Slight problems = 2, Moderate problems = 3, Severe problems 
=4, Unable to/extreme problems = 5.  Each state is referred to by a 5-digit code.  For example, 
the health state, 12121, represents a patient who indicates no problems on mobility, usual 
activities, and anxiety/depression but slights problems on self-care and pain/discomfort.  
EQ-5D health state index score reflects how good or bad a health state is according to the 
preferences of the general population of a country/region.  To derive this index score, the 
response of each dimension from the EQ-5D-5L descriptive system will be first translated into a 
weight based on the value sets issued by EuroQoL group.  Index value = 1 - sum of weights from 
these 5 dimensions’ response.  
The possible best value is 1 and the possible worst value varies by country. Validated weights for 
many countries are available from the EuroQol page of https://euroqol.org/support/analysis-
tools/index-value-set-calculators/.  If there is a missing response from a dimension, then the 
index value will not be calculated and be treated as missing.  For countries without validated 
health state utility values yet, the suggestion from EuroQol group, currently, is using the United 
States EQ-5D-5L value set from (Pickard et al. 2019).  The display of the index value is with 3 
digits of decimal points.   
The EQ VAS is used as a quantitative measure of health outcome as judged by the individual 
respondent. The EQ VAS records a self-rating of health status on a vertical VAS anchored at 
100 (best imaginable health state) at the top and 0 (worst imaginable health state) at the bottom. 

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The index score, its change and it’s percent change from baseline as well as EQ VAS score, its 
change and it’s percent change from baseline will be summarized by visit and treatment group.  
The change from baseline in index score and in EQ VAS will be compared between ISIS 721744 
80 mg every 4 weeks (or every 8 weeks) and pooled placebo using the MMRM model based on 
the FAS.  The MMRM model will include effects of treatment, time, treatment-by-time 
interaction, and baseline value.  The unstructured covariance model will be used to model the 
within patient errors, shared across treatment and small sample adjustments to standard errors 
and tests will be made following the Kenward-Roger approach (Kenward and Roger 1997).  
Health state index score and EQ VAS will be summarized in tables and listed in a by-patient 
listing. 
4.13.4. 
Patient Global Impression of Change (PGIC) Scale at Week 25/Early 
Termination  
The PGIC scales will also be administered throughout the study for purposes of PRO validation 
and its use as an anchor for estimation of minimal important difference (MID) of other PRO 
measures.  PGIC is a single item rated on a 5-point Likert scale (Much better = 1, A little better = 
2, No change = 3, A little worse = 4, Much worse = 5) designed for patients to rate their own 
perceptions of change in HAE-related health status. 
The number and percentage of patients of each scale at Week 25 will be summarized by 
treatment group.  
The PGIC scale will be dichotomized to category of “better” and “no change or worse”.  The 
binary category data be summarized by treatment group and be analyzed by using a logistic 
regression.  The odds ratio, corresponding 95% CI, and p-value will be provided.  
The analysis will be conducted in FAS. 
4.13.5. 
Change from Baseline in Patient Global Impression of Severity (PGIS) Scale  
The PGIS scales will also be administered throughout the study for purposes of PRO validation 
and its use as an anchor for estimation of MID of other PRO measures.  PGIS is a 1-item 
questionnaire rated on a 5-point scale (None = 1, Mild = 2, Moderate = 3, Severe = 4, Very 
severe = 5) designed to assess patient’s impression of disease severity.  
The number and percentage of patients of each scale will be summarized by visit and treatment 
group.  
The change from baseline in PGIS will be summarized by visit and treatment group and be 
analyzed using Wilcoxon Sum Rank test.   
The change from baseline in PGIS will also be dichotomized to category of “better” (change 
from baseline < 0) and “no change or worse” (change from baseline ≥ 0).  The binary category 
data be summarized by visit and treatment group and be analyzed by using a logistic regression 
with baseline as the covariate.  
Both analyses will be conducted in FAS.  

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4.13.6. 
Change from Baseline in Work Productivity and Impairment (WPAI)  
Pharmacoeconomics will be assessed by the WPAI questionnaire plus Classroom Impairment 
Questions (CIQ):  specific health problem (SHP), US Version 2 (WPAI+CIQ:SHP).  Outcomes 
are expressed as impairment percentages, with higher numbers indicating greater impairment and 
less productivity, i.e., worse outcomes. 
Questions: 
During the past seven days (not including today, i.e., the day of answering questions): 
1 = currently employed (No; Yes) 
2 = hours missed work due to HAE symptoms 
3 = hours missed work due to other reasons 
4 = hours actually worked 
5 = degree HAE symptoms affected productivity while working (0–10) with 0 = had no effect on 
my work and 10 = completely prevented me from working 
6 = currently attended classes/school (No; Yes) 
7 = hours missed classes/school due to HAE symptoms 
8 = hours actually attend class or school 
9 = degree HAE symptoms affected productivity while in classes/school (0-10) with 0 = had no 
effect on my class work and 10 = completely prevented me from doing my class working 
10 = degree health affected regular activities (0–10) with 0 = had no effect on my daily activities 
and 10 = completely prevented me from doing my daily activities 
Weight of work/school for each subject and each visit per hours: 
Weight of work (WW) = 0, if Q1 = No; 
= (Q2+Q3+Q4)/(Q2+Q3+Q4+Q7+Q8), if Q1 = Yes and 
Q6 = Yes; 
= 1, if Q1 = Yes and Q6 = No; 
Weight of school (WS) = 0, if Q6 = No; 
= (Q7+Q8)/(Q2+Q3+Q4+Q7+Q8), if Q1 = Yes and Q6 = Yes; 
= 1, if Q1 = No and Q6 = Yes; 
Weekly scores will be derived as following and multiply scores by 100 to express in percentages: 
• Absenteeism Score is percent work/school time missed due to HAE symptoms: 
(Q2+Q7)/(Q2+Q3+Q4+Q7+Q8) 
• Presenteeism Score is percent impairment while working/attending school due to HAE 
symptoms: Q5/10 × WW + Q9/10 x WS 

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• Overall Productivity Impairment Score is percent overall work/school impairment due to 
HAE symptoms: 
{Q2/(Q2+Q3+Q4)+[(1-(Q2/(Q2+Q3+Q4)))x(Q5/10)]}xWW + 
{Q7/(Q7+Q8)+[(1-(Q7/(Q7+Q8)))x(Q9/10)]}xWS 
• Activity Impairment Score is percent activity impairment due to HAE symptoms: 
Q10/10  
WPAI every-4-week mean score (WPAI4):  Weekly WPAI score will be grouped into every-4-
week intervals, incorporating WPAI+CIQ:SHP weekly scores from the 4 weeks immediately 
prior to/ at the assessment point.  The mean of every-4-week WPAI score is to be calculated to 
get WPAI4.  For example, WPAI4 at Week 5 is a mean of 4 consecutive weekly scores prior to 
Week 5 since Study Day 1.  Similarly, each successive interval, i.e., WPAI4 at Week 9, Week 
13, Week 17, Week 21 and Week 25, will start from the end of the prior interval, exclusively, 
and end 4 weeks later.  
WPAI 4 of Absenteeism score, Presenteeism score, overall productivity impairment score and 
activity impairment score and the change from baseline will be summarized by visit and 
treatment group.  Patients (or visits) with both Q1 = No and Q6 = No will be excluded from the 
summary of Absenteeism score, Presenteeism score and overall productivity impairment score.   
All patients are expected to answer Q10 and have the activity impairment score.  The change 
from baseline in WPAI4 of the activity impairment score will be compared between ISIS 721744 
80 mg every 4 weeks (or every 8 weeks) and pooled placebo using the MMRM model based on 
the FAS.  The MMRM model will include effects of treatment, time, treatment-by-time 
interaction, and baseline value.  The unstructured covariance model will be used to model the 
within patient errors, shared across treatment and small sample adjustments to standard errors 
and tests will be made following the Kenward-Roger approach (Kenward and Roger 1997).  
4.13.7. 
Incidence of ER Visits, All-Cause Hospitalization, and Total Inpatient Days  
The incidence of all-cause ER visits and ER visits due to HAE attack, all-cause hospitalization 
and total inpatient days during the treatment period will be summarized using descriptive 
statistics.  
If supported by data, the incidence of all-cause ER visits, ER visits due to HAE attack and 
all-cause hospitalization may be compared between treatment group and pooled placebo group 
using a Poisson regression model and Pearson chi-square scaling of standard errors to account 
for potential overdispersion on the FAS.  The model will include the treatment group as the 
factor.  The logarithm of time in month that each patient observed during the on-treatment period 
will be used as an offset variable.  
The total inpatient days may be compared between treatment group and pooled-placebo group 
using an ANOVA model with the treatment group as the factors. 
4.13.8. 
Change in each AE-QoL Questionnaire Domain Scores  
Scoring of each AE-Qol domain is described in the Section 4.9.3.7.  

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The change and percent change from baseline in each AE-QoL domain score will be summarized 
by visit and treatment group.  
The change from baseline in each AE-QoL domain score at Week 13 and Week 25 will be 
compared between ISIS 721744 80 mg every 4 weeks and pooled placebo using the MMRM 
model.  The MMRM model will include effects of treatment, time, treatment-by-time interaction, 
and baseline value at Study Day 1.  Missing baselines will be imputed first by the average of 
available baselines across all patients in the FAS.  The analysis will be conducted in the FAS.  
The unstructured covariance model will be used to model the within patient errors, shared across 
treatment and small sample adjustments to standard errors and tests will be made following the 
Kenward-Roger approach (Kenward and Roger 1997) .  
The comparison between ISIS 721744 every 8 weeks and pooled placebo will also be analyzed 
in the same way as above mentioned. 
The least-squares means, standard errors, and the 2-tailed 95% confidence intervals for the 
treatment group and placebo group will be presented. 
4.13.9. 
Time-Normalized Number of Investigator-Confirmed Hereditary Angioedema 
(HAE) Attacks (per Every-4-week) from Week 17 to Week 25  
For exploring the dosing effect when administrated every 8 weeks with at least 3 doses of study 
drug, the time-normalized number of Investigator-confirmed HAE attacks (per every-4-week) 
from Week 17 to Week 25 will be analyzed using the same methods as described for the primary 
efficacy endpoint in Sections 4.9.2.1.  
The analysis using Poisson regression model will be performed on a subset of FAS including 
patients in Cohort B who received ISIS 721744 and patients who received Placebo in both 
Cohort A and Cohort B.  
For patients who discontinued the Treatment Period early and started OLE, and patients who 
discontinued the Treatment Period early and were lost to follow-up before Week 25, missing 
HAE count will be imputed by HAE count occurred during the last 56 days.  
4.13.10. 
Investigator-Confirmed Hereditary Angioedema (HAE) Attacks that involves 
the larynx  
For exploring the dosing effect on laryngeal attacks, the time-normalized Investigator-confirmed 
HAE attacks that involves the larynx (per every-4-week) will be summarized by treatment group 
and compared between treatment group and pooled placebo group using a Poisson regression 
model and Pearson chi-square scaling of standard errors to account for potential overdispersion 
on the FAS.  The model will include fixed effect for treatment group (categorical), baseline (the 
time-normalized run-in period attack rate, continuous), and the treatment-by-baseline interaction 
as covariates, and the logarithm of time in every-4-week that each patient was observed during 
the interested periods will be used as an offset variable.  
Analyses on 2 interested periods will be performed, including from Week 1 to Week 25 and from 
Week 5 to Week 25.  Number of patients and percentage per treatment group will also be 
summarized.  

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4.13.11. 
Angioedema Activity Score (AAS)  
The AAS is a PRO measure developed to assess disease activity in patients with recurrent 
angioedema, which includes patients with HAE (Weller et al. 2013).  The AAS consists of an 
opening question as well as 5 questions regarding the swelling episodes. 
Opening question is “Have you had a swelling episode in the last 24 hours?”  It may be used to 
count the number of angioedema affected days during the AAS documentation period but has no 
score. 
5 questions regarding the swelling episodes will be summed up for AAS score calculation. 
A score between 0 and 3 points is assigned to every question as None = 0 and increase the point 
from 1 to 3 per severity for each question.  The question scores are summed up to an AAS daily 
score.  The daily AAS is summed up to AAS7 and AAS28.  Calculation is described as the 
following:  taking the first dose date/time as the start point, sum of daily AAS score during each 
period divided by the number of days contributed to that period multiplied by 7 days as AAS7 or 
multiplied by 28 days as AAS28.  The minimum number of days for a valid AAS7 and AAS28 is 
4 days per week and 3 weeks per 28 days, respectively.  Accordingly, the minimum and 
maximum possible AAS scores are 0–15 for AAS daily score, 0–105 for AAS7, and 0–420 for 
AAS28. 
AAS28 will be compared between ISIS 721744 80 mg every 4 weeks (or every 8 weeks) and 
pooled placebo using the MMRM model based on the FAS.  The MMRM model will include 
effects of treatment, time, treatment-by-time interaction, and baseline value.  The unstructured 
covariance model will be used to model the within patient errors, shared across treatment and 
small sample adjustments to standard errors and tests will be made following the Kenward-Roger 
approach (Kenward and Roger 1997).  
AAS scores will be listed in by-patient listings.  
4.14. 
Other Analyses  
Psychometric analyses will be conducted for selected PRO assessments.  Details will be 
specified in a separate analysis plan. 
4.15. 
Determination of Sample Size  
The power and sample size estimations were calculated using simulations based on a 
generalized linear model for count data assuming a Poisson distribution.  The primary endpoint 
is the time-normalized number of Investigator-confirmed HAE attacks (per every-4-week) from 
Week 1 to Week 25.  Assuming an HAE attack rate of 13.26 attacks per 6-month period in the 
placebo group and an HAE attack rate of 1.38 attacks per 6-month period in the ISIS 721744 80 
mg every 4 weeks group, the sample size of 54 patients (2:1 ratio [ISIS 721744 : placebo]) will 
provide at least 90% power for the primary endpoint, with a 0.05 significance level.  A total of 
approximately 84 patients (42 in the ISIS 721744 every-4-weeks group, 21 in the pooled placebo 
group, and 21 in the ISIS 721744 every-8-weeks group) will be enrolled in this trial to account 
for potential early dropouts and to facilitate some general safety evaluations.  

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4.16. 
Changes in the Conduct of the Study or Planned Analysis  
The FAS represents the practically feasible intent-to-treat (ITT) population as delineated in 
International Conference on Harmonization (ICH) Guideline E9.  This SAP choose to use FAS 
for the primary analysis of efficacy. 
Responder analyses will be performed by using logistic regression with baseline and the 
interaction of baseline and treatment groups as covariates, if specified in the SAP.  Compare to 
the Chi-square requested in the protocol, adjustment for baseline related covariates will generally 
reduce the variability of estimation of treatment effects and thus lead to more powerful 
hypothesis testing.  
Rather than checking the distribution difference between treatment groups as ordinal variables by 
using a proportional odds model, PGIC and PGIS will be dichotomized to “better” and “no 
change or worse” and be analyzed for treatment effect by using logistic regression model.  
Additionally, the change from baseline on PGIS at each visit will be checked for the mean 
difference as continuous variable by using Wilcoxon Rank Sum test. 

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 5. REFERENCES   
Carpenter, JR, Roger, JH, and Kenward, MG (2013) Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
imputation. J Biopharm Stat, 23(6), 1352–71. doi:10.1080/10543406.2013.834911. 
Herdman, M, Gudex, C, Lloyd, A, … Badia, X (2011) Development and preliminary testing of 
the new five-level version of EQ-5D (EQ-5D-5L). Quality of Life Research, 20(10), 1727–1736. 
doi:10.1007/s11136-011-9903-x. 
Kenward, MG, and Roger, JH (1997) Small sample inference for fixed effects from restricted 
maximum likelihood. Biometrics, 53(3), 983–97. 
Pickard, AS, Law, EH, Jiang, R, … Busschbach, JJV (2019) United States Valuation of EQ-5D-
5L Health States Using an International Protocol. Value in Health, 22(8), 931–941. 
doi:10.1016/j.jval.2019.02.009. 
Rubin, DB (1987) Multiple Imputation for Nonresponse in Surveys. John Wiley & Sons, Inc. 
Retrieved from https://onlinelibrary.wiley.com/doi/book/10.1002/9780470316696 
Spitzer, RL, Kroenke, K, Williams, JBW, and Löwe, B (2006) A Brief Measure for Assessing 
Generalized Anxiety Disorder: The GAD-7. Archives of Internal Medicine, 166(10), 1092–1097. 
doi:10.1001/archinte.166.10.1092. 
Weller, K, Donoso, T, Magerl, M, … Maurer, M (2020) Development of the Angioedema 
Control Test—A patient‐reported outcome measure that assesses disease control in patients with 
recurrent angioedema. Allergy, 75(5), 1165–1177. doi:10.1111/all.14144. 
Weller, K, Groffik, A, Magerl, M, … Maurer, M (2012) Development and construct validation 
of the angioedema quality of life questionnaire. Allergy, 67(10), 1289–1298. 
doi:10.1111/all.12007. 
Weller, K, Groffik, A, Magerl, M, … Maurer, M (2013) Development, validation, and initial 
results of the Angioedema Activity Score. Allergy, 68(9), 1185–92. doi:10.1111/all.12209.  
 
 
 
 
 

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APPENDIX A. SAS SAMPLE CODES  
(1) Poisson Regression: 
proc genmod data=adeff; 
    class arm; 
    model no_attks = arm baserate arm*baserate / dist=poisson link=log offset=logmon pscale; 
lsmeans arm/ diff cl exp ilink; 
run; 
 
where  
arm is treatment arm (i.e., ISIS 721744 80 mg every 4 weeks, ISIS 721744 80 mg every 8 weeks 
and pooled placebo); 
no attks is number of Investigator-confirmed HAE attacks during the treatment period; 
baserate is time-normalized Investigator-confirmed HAE attack rate during the run-in period; 
logmon is logarithm of time in months each patient was observed during the treatment period. 
(2) Negative Binomial Regression:  
proc genmod data=adeff; 
    class arm; 
    model no_attks = arm baserate arm*baserate/ dist=negbin link=log offset=logmon; 
lsmeans arm/ diff cl exp ilink; 
run; 
 
where  
arm is treatment arm (i.e., ISIS 721744 80 mg every 4 weeks, ISIS 721744 80 mg every 8 weeks 
and pooled placebo); 
no_attks is number of Investigator-confirmed HAE attacks during the treatment period; 
baserate is time-normalized Investigator-confirmed HAE attack rate during the run-in period; 
logmon is logarithm of time in every-4-weeks each patient was observed during the treatment 
period. 
(3) Mixed Model with Repeated Measures (MMRM): 
proc mixed /*scoring=4*/;  
    class arm visit subject;  
    model endpoint=arm baseline visit arm*visit arm*baseline/ ddfm=kr;  

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    repeated visit / subject=subject type=UN;  
    lsmeans arm*visit / cl diff;  
run; 
where 
arm is treatment arm (i.e., ISIS 721744 80 mg every 4 weeks, ISIS 721744 80 mg every 8 weeks 
and pooled placebo); 
endpoint is change from baseline in AE-QoL total score/each domain score at Week 25; 
baseline is baseline AE-QoL total score/each domain score; 
visit is scheduled visit.  
(4) Jump-to-Reference (J2R) for Recurrent Events:  
Step 1a: 
Draw a series of independent samples from the posterior distribution of model parameters using 
a Bayesian Poisson log-link model with an offset variable which holds the log of the exposure 
time for each patient. 
proc genmod data = input_data; 
    class arm;  
    model no_attks = arm baserate arm*baserate /DIST= poisson LINK = log OFFSET = logmon ; 
    bayes outpost=bayes_out seed=721744 thin=n_thin nmc=n_draws nbi=n_bi; 
run; 
  
where 
arm is treatment arm (i.e., ISIS 721744 80 mg every 4 weeks, ISIS 721744 80 mg every 8 weeks 
and pooled placebo); 
no_attks is number of Investigator-confirmed HAE attacks during the treatment period; 
baserate is time-normalized Investigator-confirmed HAE attack rate during the run-in period; 
logmon is logarithm of time in every-4-weeks each patient was observed during the treatment 
period; 
n_thin is the number of thinning parameters; 
n_draws is the number of draws; 
n_bi is the number of burn-in. 
Step 1b: 
According to the definition of J2R, the event rate in the active treatment arm is expected to shift 
to that of the reference arm.  Post-withdrawal event rate in the reference arm is still under MAR.  

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Then calculate the unobserved event rate to sample the number unobserved events as the 
following: 
rand(‘Poisson’, exp(<unobserved event rate>)*<unobserved exposure period until the study end> 
The imputed unobserved event numbers are added together with no_attks (i.e., observed event 
numbers) to be the final total event numbers for patients who withdraw early from the study. 
Step 2:  
Analyze each imputed dataset using the designated statistical methods in previous sections (e.g., 
Poisson regression, etc.). Sample codes refer to other corresponding sections. 
Step 3: 
Combine the result by using PROC MIANYLIZE. 
proc mianalyze; 
modeleffects estimate;  
stderr std_err; 
run; 
  
where 
estimate is the parameter estimate from Step 2; 
std_err is the standard error for the parameter estimate from Step 2. 
(5) Tipping-Point Analysis for Recurrent Events: 
First three steps are similar with (4) J2R for Recurrent Events multiple imputation mentioned 
above, expect for Step 1b being different: 
Step 1b: 
The unobserved event rate for both reference arm and active treatment arm is added by a series 
of shift parameter (denoted as δ). The number of unobserved events for each discontinued patient 
is then sampled as the following: 
rand(‘Poisson’, exp(<unobserved event rate + δ >)*<unobserved exposure period until the study 
end> 
Step 1b to Step 3 are repeated multiple times, each time with a different δ and thus multiple 
scenario results are generated. 
 

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APPENDIX B. EUROQOL-5-DIMENSIONS INDEX SCORE VALUESET 
FOR SAS BY COUNTRIES  
• Germany 
 
Mobility 
Self-care 
Usual Activities 
Pain/ 
Discomfort 
Anxiety/ 
Depression 
1 
0 
0 
0 
0 
0 
2 
0.026 
0.050 
0.036 
0.057 
0.030 
3 
0.042 
0.056 
0.049 
0.109 
0.082 
4 
0.139 
0.169 
0.129 
0.404 
0.244 
5 
0.224 
0.260 
0.209 
0.612 
0.356 
- 
Index Score = 1 – total of (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) 
 
• Netherlands 
 
Mobility 
Self-care 
Usual Activities 
Pain/ 
Discomfort 
Anxiety/ 
Depression 
1 
0 
0 
0 
0 
0 
2 
0.035 
0.038 
0.039 
0.066 
0.070 
3 
0.057 
0.061 
0.087 
0.092 
0.145 
4 
0.166 
0.168 
0.192 
0.360 
0.356 
5 
0.203 
0.168 
0.192 
0.415 
0.421 
- 
Index Score = 1 – 0.047 – total of (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression) 
- 
If all 5 domains are 1, then index score is 1. 
 
• Italy 
 
Mobility 
Self-care 
Usual Activities 
Pain/ 
Discomfort 
Anxiety/ 
Depression 
1 
0 
0 
0 
0 
0 
2 
0.051 
0.046 
0.050 
0.047 
0.044 
3 
0.064 
0.056 
0.064 
0.088 
0.109 
4 
0.244 
0.216 
0.225 
0.353 
0.318 
5 
0.329 
0.257 
0.255 
0.408 
0.322 
- 
Index Score = 1 – total of (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) 

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• United States 
 
Mobility 
Self-care 
Usual Activities 
Pain/ 
Discomfort 
Anxiety/ 
Depression 
1 
0 
0 
0 
0 
0 
2 
0.096 
0.089 
0.068 
0.060 
0.057 
3 
0.122 
0.107 
0.101 
0.098 
0.123 
4 
0.237 
0.220 
0.255 
0.318 
0.299 
5 
0.322 
0.261 
0.255 
0.414 
0.321 
- 
Index Score = 1 – total of (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) 
 
• United Kingdom, Turkey, Spain, Poland, Israel, France, Denmark, Canada, Bulgaria, 
Belgium 
Follow United States valuesets as there are no pre-defined valuesets for these countries.