Clinical trial NCT04306510
Conditions: Hereditary Transthyretin Amyloidosis With Polyneuropthy
Keywords: Hereditary Transthyretin Amyloidosis hATTR-PN hATTR Amyloidosis
Sponsor: Akcea Therapeutics
Start date: 2021-01-21; Completion date: 2024-03-20
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of the study was to characterize adverse events (AEs) occurring within one day of TEGSEDI administration to adult participants with hATTR-PN overall and in individual participants with respect to time course of AE onset, vital sign changes, preventive measures, treatment required, risk factors, and subsequent adverse outcomes.

Detailed description:

Arms: arm 1: Participants received TEGSEDI 284 milligrams (mg), subcutaneously (SC) once weekly, as prescribed by their physician per the product label.
Interventions: intervention 1: TEGSEDI
Intervention descriptions: intervention 1: SC injection.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
A Phase 4 Safety Study Assessing the Adverse Events Occurring Within One Day of TEGSEDI 
Administration in Patients With Polyneuropathy of Hereditary Transthyretin-mediated 
Amyloidosis (hATTR-PN)   
 
NCT04306510 
 
06 Oct 2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ionis.com 


TEG4004 Protocol  
CONFIDENTIAL 
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Confidential  
Page 1 of 51 
 
 
 
 
 
A Phase 4 Safety Study Assessing the Adverse Events Occurring 
Within One Day of TEGSEDI Administration in Patients with 
Polyneuropathy of Hereditary Transthyretin-mediated 
Amyloidosis (hATTR-PN)   
 
 
 
 
 
Protocol Number: TEG4004 
 
Version: Final v2.0 
Protocol Date: 08 May 2020  
 
 
Compound: TEGSEDI® (inotersen)  
(for injection, for subcutaneous use) 
 
 
Sponsor 
Akcea Therapeutics, Inc. 
 
 
United States  
 
 
The information in this document is the property of Akcea Therapeutics, Inc. and is strictly confidential. 
Neither the document nor the information contained herein may be reproduced or disclosed outside of 
Akcea Therapeutics, Inc. without the prior written consent of the company. 
 


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Title 
A phase 4 safety study assessing the adverse events occurring 
within one day of TEGSEDI administration in patients with 
polyneuropathy of hereditary transthyretin-mediated amyloidosis  
(hATTR-PN) 
Protocol version identifier 
v2.0 
Date of last version of protocol 
20-September-2019  
Active substance 
Inotersen 
Medicinal product 
TEGSEDI 
Product reference 
Not applicable 
Sponsor & license holders 
United States (US) and Canada 
Akcea Therapeutics, Inc.  
 
 
United States  
Research question and objectives 
The objective of the study is to characterize adverse events (AEs) 
occurring within one day of TEGSEDI administration to adult 
patients with hATTR-PN overall and in individual patients with 
respect to time course of AE onset, vital sign changes, preventive 
measures, treatment required, risk factors, and subsequent 
adverse outcomes.   
Regions and countries of study 
US and Canada 
Author 
Akcea Therapeutics, Inc. 
 
Sponsor/License Holder 
Sponsor & License holders 
Akcea Therapeutics, Inc. 
 
United States  
 
Key contact person 
 
Akcea Therapeutics, Inc. 
 
 




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1. Table of Contents 
Cover Page .......................................................................................................................................1 
1. Table of Contents .......................................................................................................................4 
2. List of Abbreviations and Definitions of Terms ........................................................................7 
3. Responsible Parties ....................................................................................................................9 
4. Abstract ....................................................................................................................................10 
5. Amendments and Updates .......................................................................................................14 
6. Milestones ................................................................................................................................19 
7. Rationale and Background .......................................................................................................20 
8. Research Question and Endpoints ...........................................................................................21 
9. Research Methods ....................................................................................................................22 
9.1. Study Design .......................................................................................................................... 22 
9.1.1. Duration of Patient Participation .........................................................................................22 
9.1.2. Study Visits for all Patients While Being Treated With TEGSEDI ....................................22 
9.1.3. ADA Testing and Hypersensitivity ......................................................................................22 
9.1.4. Discontinuation of TEGSEDI ..............................................................................................23 
9.1.5. Withdrawal From Study .......................................................................................................23 
9.1.6. Patients Continuing TEGSEDI After Completing the Study ...............................................23 
9.1.7. Milestones for Study End.....................................................................................................23 
9.2. Setting .................................................................................................................................... 23 
9.2.1. Selection of Study Population ..............................................................................................23 
9.2.2. Study Procedures .................................................................................................................24 
9.2.2.1. Study Schedule..................................................................................................................24 
9.2.3. Schedule of Assessments .....................................................................................................30 
9.2.3.1. Physical Examinations and Vital Signs ............................................................................30 
9.2.3.2. Laboratory Assessments ...................................................................................................30 
9.2.4. Treatment of Patients ...........................................................................................................31 
9.2.4.1. TEGSEDI Administration .................................................................................................31 
9.2.4.2. Treatment Precautions ......................................................................................................31 
9.2.4.3. Safety Monitoring Rules ...................................................................................................31 
9.2.4.4. Discontinuation of Treatment ...........................................................................................31 
9.2.4.5. Withdrawal of Patients From the Study ............................................................................32 
9.2.4.6. Concomitant Therapy ........................................................................................................32 


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9.2.4.7. Treatment Adherence ........................................................................................................32 
9.2.4.8. Study Termination ............................................................................................................32 
9.3. Data Sources .......................................................................................................................... 32 
9.4. Study Size .............................................................................................................................. 33 
9.5. Data Management .................................................................................................................. 33 
9.5.1. Study Documentation and Storage.......................................................................................33 
9.6. Data Analysis ......................................................................................................................... 33 
9.6.1. Analysis Populations ............................................................................................................33 
9.6.2. Definition of Baseline ..........................................................................................................33 
9.6.3. Demographic and Baseline Characteristics .........................................................................34 
9.6.4. Safety Analysis ....................................................................................................................34 
9.6.5. Interim Analyses and Early Stopping Guidelines ................................................................34 
9.7. Quality Control ...................................................................................................................... 34 
9.7.1. Monitoring ...........................................................................................................................34 
9.7.2. Language ..............................................................................................................................35 
9.7.3. Inspection and Auditing Procedures ....................................................................................35 
9.7.4. Source Document Maintenance ...........................................................................................35 
9.7.5. Record Maintenance ............................................................................................................35 
9.8. Limitations of the Research Methods .................................................................................... 36 
9.9. Other Aspects ......................................................................................................................... 36 
9.9.1. Protocol Amendments ..........................................................................................................36 
9.9.2. Compensation for Injury ......................................................................................................36 
10. Protection of Human Patients ..................................................................................................37 
10.1. Informed Consent ................................................................................................................. 37 
10.2. Ethical Conduct of the Study ............................................................................................... 37 
10.3. Independent Ethics Committee/Institutional Review Board ................................................ 37 
10.4. Patient Confidentiality ......................................................................................................... 37 
11. Management and Reporting of Adverse Events/Serious Adverse Events/Adverse Events of 
Special Interest ...............................................................................................................................39 
11.1. Sponsor Review of Safety Information................................................................................ 39 
11.2. Regulatory Requirements ..................................................................................................... 39 
11.3. Definitions ............................................................................................................................ 39 
11.3.1. Adverse Event ....................................................................................................................39 
11.3.2. Adverse Drug Reaction and Unexpected Suspected Adverse Drug Reaction ...................40 
11.3.3. Serious Adverse Event .......................................................................................................40 


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11.3.4. Adverse Events of Special Interest ....................................................................................41 
11.4. Monitoring and Recording Adverse Events ......................................................................... 41 
11.4.1. Serious Adverse Events .....................................................................................................41 
11.4.2. Non-Serious Adverse Events .............................................................................................42 
11.4.3. Evaluation of Adverse Events (Serious and Non-Serious) ................................................42 
11.4.3.1. Relationship to TEGSEDI ...............................................................................................42 
11.4.3.2. Severity ...........................................................................................................................42 
11.4.3.3. Action Taken with TEGSEDI .........................................................................................42 
11.4.3.4. Treatment Given for Adverse Event ...............................................................................43 
11.4.3.5. Outcome of the Adverse Event .......................................................................................43 
11.4.3.6. Follow-up of Adverse Event ...........................................................................................43 
11.5. Procedures for Handling Special Situations ........................................................................ 44 
11.5.1. Abnormalities of Laboratory Tests ....................................................................................44 
11.5.2. Prescheduled or Elective Procedures or Routinely Scheduled Treatments .......................44 
11.5.3. Dosing Errors .....................................................................................................................44 
11.5.4. Contraception and Pregnancy ............................................................................................45 
12. Plans for Disseminating and Communicating Study Results ..................................................46 
13. References ................................................................................................................................47 
14. Investigator Protocol Signature Page .......................................................................................48 
Annex 1 ..........................................................................................................................................49 
 
List of Tables 
Table 1. 
Schedule of Assessments for Patients Who do not Develop a Hypersensitivity 
Reaction ......................................................................................................................25 
Table 2. 
Schedule of Assessments for Patients Who Develop a Hypersensitivity Reaction ....26 


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2. List of Abbreviations and Definitions of Terms 
Abbreviation 
Definition 
ADA 
Anti-drug antibody 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse event 
AESI 
Adverse events of special interest 
ADR 
Adverse drug reaction 
ASO 
Antisense oligonucleotide 
CNS 
Central nervous system 
CPM 
Canadian Product Monograph 
CRO 
Contract research organization 
CRP 
C-reactive Protein 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
ESR 
Erythrocyte sedimentation rate 
ET 
Early termination 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GM-CSF 
Granulocyte-macrophage colony stimulating factor 
hATTR-PN 
Polyneuropathy of hereditary transthyretin-mediated amyloidosis  
HEENT 
Head, eyes, ears, nose and throat 
HLT 
High level term 
ICF 
Informed consent form 
ICH 
International Council For Harmonization 
IEC 
Independent ethics committee 
IFN 
Interferon 
Ig 
Immunoglobulin 
IL 
Interleukin 
IRB 
Institutional review board 
MCP 
Membrane cofactor protein 
MedDRATM 
Medical Dictionary for Regulatory Activities  
MIP 
Macrophage inflammatory protein 
NCS 
Not clinically significant 
NK 
Natural killer 
PT 
Preferred term 
REMS 
Risk Evaluation and Mitigation Strategies 
SAE 
Serious adverse event 
SMQ 
Standardized MedDRA query 
SOC 
System organ class 
TNF-α 
Tumor necrosis factor-alpha 
TRIM21 
Tripartite motif containing 21 


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TTR 
Transthyretin 
US 
United States  
USPI 
United States Prescribing Information 
 


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3. Responsible Parties 
Sponsor 
 
Akcea Therapeutics, Inc. 
 
United States  
Contract research organization 
(CRO)  
UBC 
 
 
United States  


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4. Abstract 
Title 
A Phase 4 Safety Study Assessing the Adverse Events Occurring Within One Day of TEGSEDI 
Administration in Patients with Polyneuropathy of Hereditary Transthyretin-mediated Amyloidosis 
(hATTR-PN). 
Rationale and Background 
Polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) is an inherited, 
progressive, fatal disease caused by misfolded transthyretin (TTR) proteins that accumulate as amyloid 
fibrils predominantly in the peripheral nerves, heart, gastrointestinal tract, and other organs. hATTR-PN 
is a rare disease and there are no large epidemiological studies that reliably provide an indication of its 
prevalence. The worldwide distribution is unequal, with higher rates in Portugal, Japan, Brazil, Northern 
Sweden, and the US. Current estimates suggest there may be 10,000 afflicted patients worldwide 
(Plante-Bordeneuve, V. 2014).  
TEGSEDI (inotersen) is an antisense oligonucleotide (ASO) inhibitor of human TTR protein synthesis. 
In the US, TEGSEDI is indicated for treatment of the polyneuropathy of hATTR in adults. Efficacy has 
been demonstrated in patients with polyneuropathy of hATTR, as reflected by a slowing or reversal of 
disease progression.  
Research Question and Endpoints 
The objective of the study is to characterize adverse events (AEs) occurring within one day of TEGSEDI 
administration to adult patients with hATTR-PN overall and in individual patients with respect to time 
course of AE onset, vital sign changes, preventive measures, treatment required, risk factors, and 
subsequent adverse outcomes.  
The endpoints of the study are the AEs, changes in vital signs and cytokines and inflammatory markers 
24-hour post-injection with additional assessments of: 
x Preventive measures used prior to the injection 
x Treatment of AEs post 24-hour injection 
x Identification of risk factors for AEs 
x Correlation of subsequent adverse outcomes 
Study Design 
An open-label, phase 4, multicenter safety study in at least 75 patients with hATTR-PN prescribed 
284 mg of TEGSEDI in US and Canada.  
Duration patient participation 
For patients with hATTR-PN prescribed TEGSEDI who stay on drug for the duration of the study and 
who do not have any hypersensitivity reactions, participation will be a minimum of 12 months and a 
maximum of 24 months with visits every 4 months. After the first 12 months, visits will continue every 
4 months for a maximum of a further 12 months or until one of the Milestones for Study End is triggered. 


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For patients with hATTR-PN prescribed TEGSEDI who have a hypersensitivity reaction while in the 
study, participation will be a minimum of 12 months and a maximum of 36 months depending upon 
when in their study participation the hypersensitivity reaction occurred. This additional duration is due 
to the additional Post-Treatment Follow-up visits required in response to the hypersensitivity reaction 
which are a minimum of an additional 4 months and maximum of an additional 12 months based upon 
when one of the Milestones for Study End is triggered (see definition of Milestones for Study End  and 
anti-drug antibody (ADA) testing and hypersensitivity below). 
Study visits for all patients while being treated with TEGSEDI 
TEGSEDI (inotersen 284 mg/1.5ml) will be injected subcutaneously once weekly according to product 
label. The dose and dosing regimen of TEGSEDI will follow the approved United States Prescribing 
Information (USPI) (TEGSEDI USPI) or Canadian Product Monograph (CPM) (TEGSEDI CPM). 
During the clinic visits, a scheduled dose of TEGSEDI will be injected and the patients will be 
monitored at 1, 2, 4, and 8 hours post injection for AE assessments, changes in vital signs, and laboratory 
testing. The patient will return to the clinic 20-30 hours post injection for a further assessment of AEs, 
vital signs, and laboratory testing. In addition to these visits, the patient will be monitored according to 
the USPI (TEGSEDI USPI) or CPM (TEGSEDI CPM).  Additional blood samples will be drawn and 
stored for possible non-genetic testing in this study. 
Anti-Drug Antibody testing and hypersensitivity 
All patients will have a minimum of 2 ADA samples taken. One sample will be taken at the first on-
study visit (Month 0) prior to the scheduled dose of TEGSEDI, and the other sample will be taken at 
the end of the patient’s participation in the study, prior to the scheduled dose of TEGSEDI if the patient 
is still on treatment.  
Patients who develop a hypersensitivity reaction during the study will have additional blood samples 
taken for ADA testing on the day of the hypersensitivity reaction at the 20-30 hour time point and again 
at their Post-Treatment Follow-up visits for 12 months or when one of the Milestones for Study End 
has been met, whichever is earliest. All patients who have a hypersensitivity reaction will be followed 
for a minimum of 4 months.  
Discontinuation of TEGSEDI 
If a patient discontinues TEGSEDI for a reason other than a hypersensitivity reaction, the patient will 
have an Early Termination (ET) visit as soon as possible after the decision to end treatment and will be 
followed for 8 weeks after treatment discontinuation for AEs assessments, changes in vital signs and 
laboratory sampling.  
If a patient discontinues TEGSEDI due to hypersensitivity, the patient will undergo an ET visit and an 
8-week follow-up visit. He/she will also return for additional ADA testing at 4 months after the 
hypersensitivity reaction, and then again at 8 months and 12 months after the hypersensitivity reaction, 
if the study is still ongoing  (see definition of Milestones for Study End). 
 


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Withdrawal from study 
Patients who withdraw from the study but continue on treatment with TEGSEDI should return for an 
ET visit as soon as possible after the decision to withdraw from the study. After the ET visit, no further 
follow-up is required for patients who continue treatment on TEGSEDI. 
Patients continuing TEGSEDI after completing the study 
Patients who complete the study and plan to continue TEGSEDI treatment will have the ADA testing 
prior to the scheduled dose of TEGSEDI at their End of Study visit. US patients who complete the study 
will continue on the Risk Evaluation and Mitigation Strategies (REMS) program.  
Population 
Eligibility Criteria: 
1. Satisfy one of the following:  
a. US Patients: Adult patients (≥ 18 years old) diagnosed with hATTR-PN and prescribed 
TEGSEDI according to the USPI (TEGSEDI USPI). 
b. Canadian Patients: Adult patients (≥ 18 years old) diagnosed with stage 1 or stage 2 
hATTR-PN and prescribed TEGSEDI according to the CPM (TEGSEDI CPM).   
2. Must have given written informed consent for participation in this study.  
3. Must provide access to their previous medical records. 
4. Are about to initiate or have recently initiated treatment with TEGSEDI and have not received 
more than 9 doses in total. 
5. Be willing to complete required testing and report any AEs and/or changes in medications.  
6. Satisfy one of the following:  
a. Females:  Non-pregnant and non-lactating; abstinent, or if engaged in sexual relations of 
childbearing potential, patient is using an acceptable contraceptive method from time of 
signing the informed consent form (ICF) until 13 weeks after the last dose of TEGSEDI 
administration. 
b. Males:  Abstinent or if engaged in sexual relations with a female of childbearing potential, 
patient is utilizing an acceptable contraceptive method from the time of signing the ICF until 
13 weeks after the last dose of TEGSEDI administration. 
Data Sources  
Source of the data will be an electronic case report form (eCRF), which will be created for prospective 
data collection. Data will be collected in the eCRF following on-site clinic visits every 4 months.  
Study Size 
A sample size of 75 patients will allow 95% probability to detect an AE occurring as infrequently as 
4% of patients. 
Data Analysis 
Incidence (95% confidence interval), onset, and duration of each AE occurring within 1 day of 
TEGSEDI administration will be summarized by visit and overall in any visits. The rates of AEs 


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occurring after preventive measures will also be summarized. Resolution time with and without 
treatment administered for these AEs will be summarized. 
For each study visit while on treatment, the results and changes from pre dose baseline in vital signs 
and cytokines and inflammatory markers will be summarized using descriptive statistics for patients 
with and without AEs within 1 day of TEGSEDI administration. 
Milestones for Study End 
The last visit of the study will be determined by the last visit date of one of the following scenarios:  
x The date of the last 12 month clinic visit 
x The last 4 month follow up visit of a patient who had a hypersensitivity reaction  
x The last 8-week follow-up visit of a patient who has discontinued TEGSEDI


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4. Abstract/ 
7. Background/ 
9.2.4 Treatment of 
Patients 
US only 
References to USPI 
US and Canada 
References to USPI and CPM 
Study may also be 
performed in Canada 
4. Abstract- Study 
Design/ 9.1 Study 
Design 
An open-label, phase 4, multicenter safety 
study in at least 75 patients with hATTR-PN 
prescribed 284 mg of TEGSEDI who will be 
followed in the protocol for a minimum of 1 
year and a maximum of 2 years with visits 
every 4 months. Patients who have a 
hypersensitivity reaction while participating 
on the study may be followed for up to 1 year 
following the initial event. This may increase 
their participation beyond 2 years. 
 
An open-label, phase 4, multicenter safety study in at least 
75 patients with hATTR-PN prescribed 284 mg of 
TEGSEDI.  
Duration patient participation 
For patients with hATTR-PN prescribed TEGSEDI who 
stay on drug for the duration of the study and who do not 
have any hypersensitivity reactions, participation will be 
a minimum of 12 months and a maximum of 24 months 
with visits every 4 months. After the first 12 months, visits 
will continue every 4 months for a maximum of a further 
To improve clarity 
regarding duration of 
study and follow up for 
patients who do and do 
not experience 
hypersensitivity 


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Section  
Version 1.0 
Version 2.0 
Reason for change 
12 months or until one of the Milestones for Study End is 
triggered. 
For patients with hATTR-PN prescribed TEGSEDI who 
have a hypersensitivity reaction while in the study, 
participation will be a minimum of 12 months and a 
maximum of 36 months depending upon when in their 
study participation the hypersensitivity reaction occurred. 
This additional duration is due to the additional Post-
Treatment Follow-up visits required in response to the 
hypersensitivity reaction which are a minimum of an 
additional 4 months and maximum of an additional 12 
months based upon when one of the Milestones for Study 
End is triggered  
 
4. Abstract- Study 
design/9.1 Study Design 
NA 
Additional multiple edits reflecting above changes 
To improve clarity 
regarding duration of 
study and follow up for 
patients who do and do 
not experience 
hypersensitivity 
4. Abstract: Eligibility 
Criteria/9.2.1 Eligibility 
Criteria 
7. Adult patients (≥ 18 years old) 
diagnosed with polyneuropathy of 
hereditary transthyretin-mediated 
amyloidosis and prescribed TEGSEDI 
according to the USPI. 
 
1. Satisfy one of the following:  
a. 
US Patients: Adult patients (≥ 18 years old) 
diagnosed with hATTR-PN and prescribed 
TEGSEDI according to the TEGSEDI USPI 
b. Canadian Patients: Adult patients (≥ 18 years 
old) diagnosed with stage 1 or stage 2 hATTR-
PN and prescribed TEGSEDI according to the 
TEGSEDI CPM  
 
To allow for potential 
inclusion of Canadian 
patients  
4. Abstract/ 
9.1 Study Design 
Milestones 
Milestones for Study End 
To improve clarity 
regarding Study End 


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Section  
Version 1.0 
Version 2.0 
Reason for change 
9.2.2.1 Study Schedule 
Table 1 Schedule of Assessments included 
schedule for patients who did and did not 
experience a hypersensitivity reaction  
Two separate tables 
Table 1 Schedule of Assessments for Patients Who do 
not Develop a Hypersensitivity Reaction 
Table 2 Schedule of Assessments for Patients Who 
Develop a Hypersensitivity Reaction 
 
To improve clarity with 
respect to differing 
schedules between those 
who do and do not 
experience a 
hypersensitivity reaction  
9.2.2.1 Study Schedule 
Post injection assessment at the following 
intervals 
1-hour ± 15 mins 
2-hour ± 30 mins 
4-hour ± 60 mins 
8-hour ± 120 mins 
20-30 hours 
Post injection assessment at the following intervals 
1-hour ± 15 mins 
2-hour ± 15 mins 
4-hour ± 30 mins 
8-hour ± 30 mins 
20-30 hours 
Correction  
9.2 Study procedures  
The following subsections were in existence 
x 
Screening 
x 
On Treatment 
x 
Contraceptive requirements 
x 
Post Treatment Period 
Amended to the following subsections 
x 
Screening 
x 
Initial Treatment Visit (Month 0) and Every 4 
Months Including End of Study Visit 
x 
End of Study Visit 
x 
Early Termination Visit 
x 
ADA Testing 
x 
Contraception Requirements  
 
Addition of definition of Full Physical Examination and 
Abbreviated Physical Examination 
To improve clarity 
9.2.3.1 Physical 
Examinations and Vital 
Signs 
Weight will be measured at each visit. 
The physical examination and weight do not need to be 
completed at the Month 0 study visit if they occurred 
prior during Screening. 
To clarify that a 
duplication is not 
required at Month 0 if 
performed at screening 
9.2.3.1 Physical 
Examinations and Vital 
Signs 
NA 
Post injection assessments will be made at 1 hour ± 15 
minutes; 2 hour ± 15 minutes; 4 hour ± 30 minutes; 8 
hour ± 30 minutes and 20-30 hours following injection of 
TEGSEDI 
To improve clarity 
9.3 Variables 
Full list of variables  
Removal due to availability in 9.2.2.1 
 
To improve clarity 


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Section  
Version 1.0 
Version 2.0 
Reason for change 
x 
Central nervous system (CNS) vasculitis 
 
11.4.3.6 Follow up of 
Adverse Event 
The investigator 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.  
 
The investigator 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. If the pregnancy results in the birth of a child, 
the mother and infant may continue to be followed for up 
to 8 weeks after birth. 
 
Clarification of follow- 
up period consistent 
with Akcea’s 
pharmacovigilance 
processes 
Annex 1 Laboratory 
Analytes 
NA 
Addition of ADA and rationale for ADA 
To improve clarity 
Annex 1 List of 
MedDRA terms 
Outdated table 
Revised table 
To reflect current 
Akcea’s 
pharmacovigilance 
practices  


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6. Milestones 
Not applicable. 
 
 




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8. Research Question and Endpoints 
The objective of the study is to characterize AEs occurring within one day of TEGSEDI administration 
to adult patients with hATTR-PN overall and in individual patients with respect to time course of AE 
onset, vital sign changes, preventive measures, treatment required, risk factors, and subsequent adverse 
outcomes. 
The endpoints of the study are the AEs, changes in vital signs and cytokines and inflammatory markers 
24-hour post-injection with additional assessments of: 
x Preventive measures used prior to the injection 
x Treatment of AEs post 24-hour injection 
x Identification of risk factors for AEs 
x Correlation of subsequent adverse outcomes 
 
 


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9. Research Methods 
9.1.   Study Design 
This open-label Phase 4, multicenter safety study will enroll at least 75 patients with hATTR-PN in the 
US and Canada.   
9.1.1.  Duration of Patient Participation 
For patients with hATTR-PN prescribed TEGSEDI who stay on drug for the duration of the study and 
do not have any hypersensitivity reactions, participation will be a minimum of 12 months and a 
maximum of 24 months with visits every 4 months. After the first 12 months, visits will continue every 
4 months for a maximum of a further 12 months or until one of the Milestones for Study End is triggered 
(see definition of Milestones for Study End below). 
For patients with hATTR-PN prescribed TEGSEDI who have a hypersensitivity reaction while in the 
study, participation will be a minimum of 12 months and a maximum of 36 months depending upon 
when in their study participation the hypersensitivity reaction occurred. This additional duration is due 
to the additional Post-Treatment Follow-up visits required in response to the hypersensitivity reaction 
which are a minimum of an additional 4 months and maximum of an additional 12 months based upon 
when one of the Milestones for Study End is triggered (see definition of Milestones for Study End  and 
ADA Testing and Hypersensitivity below). 
9.1.2.  Study Visits for all Patients While Being Treated With TEGSEDI 
During the study visits, a scheduled dose of TEGSEDI will be injected and the patients will be monitored 
at 1, 2, 4, and 8 hours post injection for AEs assessments, changes in vital signs and laboratory testing. 
The patient will return to the clinic 20-30 hours post injection for a further assessment of AEs, vital 
signs and laboratory testing. In addition to these study visits, the patient will be monitored according to 
the USPI or CPM. Additional blood samples will be drawn and stored for possible non-genetic testing 
in this study. 
9.1.3.  ADA Testing and Hypersensitivity 
All patients will have a minimum of 2 ADA samples taken. One sample will be taken at the first on-
study visit (Month 0) prior to the scheduled dose of TEGSEDI, and the other sample will be taken at the 
end of the patient’s participation in the study prior to the scheduled dose of TEGSEDI if the patient is 
still on treatment.  
Patients who develop a hypersensitivity reaction during the study will have additional blood samples 
taken for ADA testing on the day of the hypersensitivity reaction at the 20-30 hour time point and again 
at their Post Treatment Follow-up visits for 12 months or when one of the Milestones for Study End has 
been met, whichever is earliest. All patients who have a hypersensitivity reaction will be followed for a 
minimum of 4 months.  


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9.1.4.  Discontinuation of TEGSEDI 
If a patient discontinues TEGSEDI for a reason other than a hypersensitivity reaction, the patient will 
have an ET visit as soon as possible after the decision to end treatment and will be followed for 8 weeks 
after treatment discontinuation for AEs assessments, changes in vital signs and laboratory sampling.  
If a patient discontinues TEGSEDI due to hypersensitivity, the patient will undergo an ET visit and an 
8-week follow-up visit. He/she will also return for additional ADA testing at 4 months after the 
hypersensitivity reaction, and then again at 8 months and 12 months after the hypersensitivity reaction, 
if the study is still ongoing  (see definition of Milestones for Study End). 
9.1.5.  Withdrawal From Study 
Patients who withdraw from the study but continue on treatment with TEGSEDI should return for an 
ET visit as soon as possible after the decision to withdraw from the study. After the ET visit no further 
follow-up is required for patients who continue treatment on TEGSEDI. US patients will continue on 
the REMS program. 
9.1.6.  Patients Continuing TEGSEDI After Completing the Study 
Patients who complete the study and plan to continue TEGSEDI treatment will have the ADA testing 
prior to the scheduled dose of TEGSEDI at their End of Study visit. US patients who complete the study 
will continue on the REMS program.  
9.1.7.  Milestones for Study End  
The last visit of the study will be determined by the last visit date of one of the following scenarios:  
x The date of the last 12 month study visit 
x The last 4-month follow-up visit of a patient who had a hypersensitivity reaction  
x The last 8-week follow-up-visit of a patient who has discontinued TEGSEDI 
9.2.  Setting 
This study will be conducted at multiple study centers in the US and Canada. TEGSEDI will be 
prescribed to the patient by their healthcare provider prior to enrolling in this study. TEGSEDI will be 
administered from approved packaged and labeled packs. Used syringes will be disposed of per the 
product’s instructions for use.  
9.2.1.  Selection of Study Population 
To be eligible to enroll in this study, patients must meet the following eligibility criteria: 
1. Satisfy one of the following:  
a. US Patients: Adult patients (≥ 18 years old) diagnosed with hATTR-PN and 
prescribed TEGSEDI according to the USPI (TEGSEDI USPI) 
b.  Canadian Patients:  Adult patients (≥ 18 years old) diagnosed with stage 1 or stage 
2 hATTR-PN  and prescribed TEGSEDI according to the CPM (TEGSEDI CPM) 


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2. 
Must have given written informed consent for participation in this study  
3. Must provide access to their previous medical records 
4. Are about to initiate or have recently initiated treatment with TEGSEDI and have not 
received more than 9 doses in total 
5. Be willing to complete required testing and report any AEs and/or changes in medications  
6.  Satisfy one of the following:  
a. Females:  Non-pregnant and non-lactating; abstinent, or if engaged in sexual relations 
of childbearing potential, patient is using an acceptable contraceptive method from 
time of signing the ICF until 13 weeks after the last dose of TEGSEDI administration  
b. Males:  Abstinent or if engaged in sexual relations with a female of childbearing 
potential, patient is utilizing an acceptable contraceptive method from the time of 
signing the ICF until 13 weeks after the last dose of TEGSEDI administration 
9.2.2.  Study Procedures 
9.2.2.1.  Study Schedule 
The study will consist of a Screening/Qualification period, a Treatment period and Post-Treatment 
Follow-up period as per Table 1 and Table 2.


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Table 1. 
Schedule of Assessments for Patients Who do not Develop a Hypersensitivity Reaction 
Study Periods   
Screening1 
Treatment Period  
Post-Treatment Follow-up 
 
(Patients who 
discontinued TEGSEDI) 
8-weeks3 
Initial Treatment Visit (Month 0) and 
Every 4 months Visit 
End of Study Visit 
Early 
Termination 
Visit3 
Procedures and  
Testing  
-2 to 0 weeks 
prior to first 
study injection 
Pre-injection 
Post injection 
1-hour ± 15 mins 
2-hour ± 15 mins 
4-hour ± 30 mins 
8-hour ± 30 mins 
20-30 hours 
Pre-injection 
Post injection 
1-hour ± 15 mins 
2-hour ± 15 mins 
4-hour ± 30 mins 
8-hour ± 30 mins 
20-30 hours 
 
Informed Consent  
X  
  
  
 
 
  
 
Demographics 
X 
 
 
 
 
 
 
Medical History  
X  
  
  
 
 
  
 
Full Physical Examination 
X 
 
 
 
 
 
 
Abbreviated Physical Examination  
 
X2  
  
X  
 
X  
X  
Height  
X  
  
  
  
 
  
  
Weight  
X 
X2  
  
X  
 
X  
X  
Vital Signs  
X 
X 
X  
X  
X  
X  
X  
Urine Pregnancy Testing 
X4 
X4 
 
X4 
 
X4 
 
IgE, IgG, IgM  
  
X  
X  
X  
X  
X  
 
Inflammatory Markers  
  
X  
X  
X  
X  
X  
  
Samples for Possible Future Testing  
  
X  
X  
X  
X  
X  
X 
ADA 
 
X5 
X 
 
X6 
 
Adverse Events Since Last Study Visit   
  
X  
  
X  
 
X  
X  
Adverse Events Post Injection at Study Visit  
  
  
X 
  
X  
 
 
Concomitant Medications  
X  
X  
  
X 
 
X  
X  
1. The Screening visit and the Month 0 visit can occur on the same day.  
2. The Physical Examination and Weight does not need to be completed at the Month 0 study visit if they were performed during Screening. 
3. If the patient discontinues the study, the patient will return for an Early Termination visit as soon as possible after the decision to early terminate from the study.  If the patient also discontinues TEGSEDI, they will also 
have one follow-up visit 8-weeks after their last dose of TEGSEDI. 
4. Urine pregnancy testing is only for women of childbearing potential as defined in the protocol. 
5. The baseline ADA sample is only drawn at the Month 0 visit. 
6. An ADA sample will only be taken at the Early Termination visit if the patient does not have an End of Study visit. 
 


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Table 2. 
Schedule of Assessments for Patients Who Develop a Hypersensitivity Reaction 
Study Periods   
Screening1 
Treatment Period  
Post-Treatment Follow-up 
 
(Patients who discontinued 
TEGSEDI) 
8-weeks 
4-month 
8-month3 
12-month3 
Post-Treatment visits 
Initial Treatment Visit (Month 0) and Every 4 
months Visit 
Early Termination 
Visit 
Procedures and  
Testing  
-2 to 0 weeks 
prior to first study 
injection 
Pre-injection 
Post injection 
1-hour ± 15 mins 
2-hour ± 15 mins 
4-hour ± 30 mins 
8-hour ± 30 mins 
20-30 hours 
 
Informed Consent  
X  
  
  
  
 
Demographics 
X 
 
 
 
 
Medical History  
X  
  
  
  
 
Full Physical Examination 
X 
 
 
 
 
Abbreviated Physical Examination  
 
X2  
  
X  
X  
Height  
X  
  
  
  
  
Weight  
X 
X2 
  
X  
X  
Vital Signs  
X 
X 
X  
X  
X  
Urine Pregnancy Testing 
X4 
X4 
 
X4 
 
IgE, IgG, IgM  
  
X  
X  
X  
 
Inflammatory Markers  
  
X  
X  
X  
  
Samples for Possible Future Testing  
  
X  
X  
X  
X 
ADA 
 
X5 
X6 
X 
X6 
Adverse Events Since Last Study Visit   
  
X  
  
X  
X  
Adverse Events Post Injection at Study Visit  
  
  
X 
 
 
Concomitant Medications  
X  
X  
  
X  
X  
1. The Screening visit and the Month 0 visit can occur on the same day.  
2. The Physical Examination and Weight does not need to be completed at the Month 0 study visit if they were performed during Screening. 
3. The 8 month and 12-month follow-up visits will occur only if a Milestone for Study End has not been triggered. 
4. Urine pregnancy testing is only for women of childbearing potential as defined in the protocol. 
5. The baseline ADA sample is only drawn at the Month 0 visit. The ADA sample is only drawn post injection, at the 20-30 hour time point, in the event of a hypersensitivity reaction 
6. A patient who develops  a hypersensitivity reaction during the study will have additional blood samples taken for ADA testing on the day of the hypersensitivity reaction at the 20-30 hour time 
point and again at their Post-Treatment Follow-up visits for 12 months or when a Milestone for Study End has been met, whichever is earliest. All patients who have a hypersensitivity reaction will 
be followed for a minimum of 4 months  


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9.2.2.1.1.  Screening  
Written informed consent/assent for the study will be obtained prior to the performance of any study-
related procedures including screening procedures. A 2-week period is provided for completing 
screening assessments and determining patient eligibility for the study.  However, it is also possible for 
the screening visit and the Initial Treatment Visit (Month 0) to occur at the same time. 
Patients must meet the required laboratory testing referenced in the applicable product label.   
Medical history (including a retrospective chart review for relevant hATTR-PN disease history from the 
onset of the disease) and concomitant medications used within the past 12 months will be collected for 
each patient.  
In addition, the following will be carried out at screening:  
x Full Physical examination including height, weight and vital signs and examination of the 
following body systems: head, eyes, ear, nose throat (HEENT), cardiovascular, respiratory, 
lymphatic, gastrointestinal, musculoskeletal, dermatological, and neurological  
x Urine pregnancy testing for women of childbearing potential 
Demographics, including race & ethnicity, data will be collected for all enrolled patients. 
9.2.2.1.2.  Initial Treatment Visit (Month 0) and Every 4 Months Including End of Study 
Visit 
Pre-injection assessments will be performed prior to administration of each dose of TEGSEDI at study 
visits. Pre-injection assessments will include: 
x Abbreviated Physical examination, i.e. weight and vital signs, general appearance, 
dermatological, respiratory, cardiovascular and abdomen.  (except Month 0 if they were 
performed at Screening)  
x Concomitant Medications  
x Laboratory testing  
o IgE, IgG, IgM (see Annex 1)  
o Inflammatory markers: C-reactive protein (CRP), Erythrocyte sedimentation rate (ESR), 
interferon α (IFN- α), IFN-E, Chemokines (Macrophage inflammatory protein (MIP)-1a 
and membrane cofactor protein (MCP)-1), Granulocyte-macrophage colony stimulating 
factor (GM-CSF), interleukin (IL)-1D, IL-1E, IL-6, IL-8, IL-12. Tumor necrosis factor – 
α (TNF- α) (see Annex 1) 
o ADA sampling at Month 0 visit pre-injection first dose and at End of Study visit, pre-
injection 
o Urine pregnancy testing for women of childbearing potential  
o Additional blood samples will be drawn and stored for possible future non-genetic testing 
in this study.  
x Adverse events since last study visit  
 


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Post injection assessments will be made at 1 hour ± 15 minutes; 2 hour ± 15 minutes; 4 hour ± 30 
minutes; 8 hour ± 30 minutes and 20-30 hours following injection of TEGSEDI. Post-injection 
assessments will include:  
x Vital signs 
x Laboratory testing 
o IgE, IgG, IgM (see Annex 1)  
o Inflammatory markers: CRP, ESR, IFN-α, IFN-E, Chemokines (MIP-1a and MCP-1), 
GM-CSF, IL-1D, IL-1E, IL-6, IL-8, IL-12, TNF- α (see Annex 1) 
o Additional blood samples will be drawn and stored for possible future non-genetic testing 
in this study 
x Adverse events post injection at study visit 
x The ADA sample is only drawn post injection, at the 20-30 hour time point, in the event of a 
hypersensitivity reaction 
In addition to these study visits, the patient will be monitored according to the applicable product label. 
9.2.2.1.3.  End of Study Visit 
Patients who plan to continue TEGSEDI treatment at the end of the study will complete an End of Study 
visit. Assessments as in Section 9.2.2.1.2. will be undertaken and additionally blood for ADA will be 
taken.  
9.2.2.1.4.  Early Termination Visit 
Patients who discontinue TEGSEDI treatment, for reasons other than hypersensitivity, will have an ET 
visit as soon as possible after the decision to end treatment and will return to the study center for a 
Post-Treatment Follow-up visit 8 weeks after their last administration of TEGSEDI. During the visits 
the following procedures will be completed: 
x Abbreviated physical examination including weight, vital signs and an examination of general 
appearance, dermatological, respiratory, cardiovascular and abdomen.  
x Laboratory testing 
o IgE, IgG, IgM (see Annex 1)  
o Inflammatory markers: CRP, ESR, IFN-α, IFN-E, Chemokines (MIP-1a and MCP-1), 
GM-CSF, IL-1D, IL-1E, IL-6, IL-8, IL-12, TNF- α (see Annex 1) 
o Additional blood samples will be drawn and stored for possible future non-genetic testing 
in this study 
x Adverse events since last study visit 
x Concomitant medication  
x Urine pregnancy testing for women of childbearing potential  
x ADA if not taken at End of Study visit 
 


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9.2.2.1.5.  ADA Testing 
All patients will have a minimum of 2 ADA samples taken. One sample will be taken at the first on- 
study (Month 0) clinic visit prior to the scheduled dose of TEGSEDI, and the other sample will be taken 
at the end of patient’s participation in the study prior to the scheduled dose of TEGSEDI if the patient 
is still on treatment. Patients who develop a hypersensitivity reaction during the study will have 
additional blood samples taken for ADA testing on the day of the hypersensitivity reaction at the 20-30 
hour time point and again at their Post-Treatment Follow-up visits for 12 months or when one of the 
Milestones for Study End is triggered, whichever is earliest. All patients who have a hypersensitivity 
reaction will be followed for a minimum of 4 months. 
9.2.2.1.6.  Contraception Requirements  
For the purposes of this study, women of childbearing potential are defined as any female who has 
experienced menarche, and who does not meet 1 of the following conditions:   
x Post-menopausal: 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 post-menopausal range for the laboratory involved 
x 6 weeks after surgical bilateral oophorectomy with or without hysterectomy   
x Post hysterectomy   
All male patients and women of childbearing potential must refrain from sperm/egg donation and either 
be abstinent* or, if engaged in sexual relations, practice effective contraception from the time of signing 
the ICF until at least 13 weeks after their last dose of TEGSEDI administration. Male patients must also 
encourage their female partner to use effective contraception from the time of signing the informed 
consent until 13 weeks after the patient’s last dose of TEGSEDI administration.   
For the purposes of the study, effective contraception is defined as follows:   
x For male patients:  effective male contraception includes a vasectomy with negative semen 
analysis at follow-up, or the use of condoms together with spermicidal foam/gel/film/ 
cream/suppository. Male patients must also encourage their female partner to use effective 
contraception from the time of signing the informed consent until 13 weeks after the patient’s 
last dose of study treatment.  
x For a female partner of a male patient: effective contraception includes surgical sterilization 
(e.g., bilateral tubal ligation), hormonal contraception, intrauterine contraception/device, or 
barrier methods (female condom**, diaphragm, sponge, cervical cap) together with spermicidal 
foam/gel/film/cream/suppository. Male patients with partners that are pregnant must use 
condoms to ensure that the fetus is not exposed to TEGSEDI.   
x For female patients:  effective contraception is using one or more of the following acceptable 
methods of contraception: surgical sterilization (e.g., bilateral tubal ligation), hormonal 
contraception, intrauterine contraception/device, or any two barrier methods (a combination of 
male or female condom** with diaphragm, sponge, or cervical cap) together with spermicidal 
foam/gel/film/cream/suppository.   


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Note:   
*Abstinence is only acceptable as true abstinence, i.e., when this is in line with the preferred and usual 
lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods), declaration of abstinence for the duration of a trial and withdrawal are not acceptable methods 
of contraception. 
**A female condom and a male condom should not be used together as friction between the two can 
result in either product failing.   
9.2.3.  Schedule of Assessments 
9.2.3.1.  Physical Examinations and Vital Signs 
Physical examinations and vital signs will be performed as indicated in the Study Schedule. A full 
physical examination will be performed at the screening visit and an abbreviated physical examination 
will be performed at each subsequent study visit, prior to the TEGSEDI injection.  
The full physical examination comprises a routine medical examination and a neurological exam. The 
following body systems will be examined: HEENT, cardiovascular, respiratory, lymphatic, 
gastrointestinal, musculoskeletal, dermatological, and neurological. 
An abbreviated physical examination consists of an examination of general appearance, dermatological, 
respiratory, cardiovascular and abdomen.  
The physical examination and weight do not need to be completed at the Month 0 study visit if they 
were performed at Screening.  
Vital signs will include blood pressure, pulse rate, respiratory rate and body temperature. Blood pressure 
and pulse rate will be recorded after the patient has been in a sitting position for at least 5 minutes. Semi-
supine systolic and diastolic blood pressure should always be measured on the same arm (preferentially 
on the left arm). Height will be measured at Screening only. 
9.2.3.2.  Laboratory Assessments  
Laboratory analyte samples will be collected and processed throughout the study at the central 
laboratory. ESR will be processed at the local laboratory. During their study visit, IgE, IgG, IgM, and 
inflammatory marker testing will occur at the time points noted in Table 1 and Table 2.  
Samples for ADA will be taken at the Month 0 visit prior to TEGSEDI injection and at the last visit in 
all patients. If the patient experiences a hypersensitivity reaction within 24 hours of any dose of 
TEGSEDI administration during a study visit, the patient will have a further ADA test at the 20-30 hour 
time point and at their Post-Treatment Follow-up visits for 12 months or when one of the Milestones 
for Study End is triggered, whichever is earliest. Additional blood samples will be drawn and stored for 
possible future non-genetic testing in this study. For example, future tests may measure biomarkers or 
other safety parameters. These blood samples will be stored during the study and destroyed upon 
completion of the final study report. 


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9.2.4.  Treatment of Patients 
9.2.4.1.  TEGSEDI Administration 
US 
Please reference the USPI Section 2 – Dosage and Administration, Medication Guide and Instructions 
for Use (TEGSEDI USPI). 
Canada 
Please reference the CPM Section 2- Dosage and Administration (TEGSEDI USPI). 
9.2.4.2.  Treatment Precautions 
US 
Please reference the USPI Section 4 - Contraindication, Section 5 -Warnings and Precautions, Section 
6 - Adverse Reactions, Section 7 - Drug Interactions, and Section 8 - Use in Specific Populations. 
Investigator and patients should refer to the USPI medication guide (TEGSEDI USPI). 
 
Canada 
Please refer to the CPM Section 2- Contraindications, Section 7- Warnings and Precautions, Section 8- 
Adverse Reactions, Section 9- Drug Interactions and Section 7.1- Use in Special Populations (TEGSEDI 
CPM).  
9.2.4.3.  Safety Monitoring Rules 
US 
Please refer to the USPI for safety monitoring (TEGSEDI USPI). 
 
Canada 
Please refer to the CPM for safety monitoring (TEGSEDI CPM). 
9.2.4.4.  Discontinuation of Treatment 
A patient may discontinue treatment for any of the following: 
x The patient withdraws consent to continue treatment. 
x The patient experiences an AE that in the opinion of the investigator necessitates 
discontinuation of TEGSEDI. 
x In the opinion of the investigator, it is in the best interest of the patient that the patient is 
withdrawn from treatment. 
x The patient develops laboratory test abnormalities that meet any of the treatment 
discontinuation requirements listed in USPI Section 2.4 (TEGSEDI USPI) and CPM Section 
4.2 (TEGSEDI CPM). 
The reason for discontinuation from treatment must be recorded in the eCRF and source documentation. 


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9.2.4.5.  Withdrawal of Patients From the Study  
Patients must be withdrawn from the study for any of the following: 
x Patient withdraws consent 
x Patient is unwilling or unable to comply with the required testing outlined in the USPI 
(TEGSEDI USPI) or CPM (TEGSEDI CPM) or the study visits 
Other reasons for withdrawal of patients from the study might include: 
x At the discretion of the investigator for medical reasons 
x At the discretion of the Sponsor for medical reasons or noncompliance 
x 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 to participate in the study will be removed from further study data 
collection immediately upon the date of request. These patients should be encouraged to complete the 
ET study procedures and observations at the time of withdrawal. 
For patients withdrawn for reasons other than withdrawal of consent, every effort should be made to 
complete the ET visit and observations at the time of withdrawal and ideally within 2 weeks from the 
last dose of TEGSEDI. 
9.2.4.6.  Concomitant Therapy 
The use of concomitant therapies defined below must be recorded on the patient’s eCRF. AEs related 
to administration of these therapies must also be documented on the appropriate eCRF. 
A concomitant therapy is any non-protocol specified drug or substance (including over-the-counter 
medications, herbal medications, and vitamin supplements) administered from the time of consent until 
the End of Study visit. 
9.2.4.7.  Treatment Adherence 
Compliance with treatment administration during the study visits will be monitored and recorded in the 
eCRF by study center staff. Compliance with treatment administration between study visits will be 
reported by the patients and recorded in the eCRF. 
9.2.4.8.  Study Termination 
The Sponsor or designee reserves the right to terminate the study. The investigator reserves the right to 
terminate their participation in the study, according to the terms of the site contract. The 
investigator/Sponsor or designee should notify the independent ethics committee (IEC)/institutional 
review board (IRB) in writing of the trial’s completion or ET. 
9.3.  Data Sources 
Data will be collected prospectively into the eCRF at study visits.  


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9.4.  Study Size 
The study will enroll at least 75 patients. 
A sample size of 75 patients will allow 95% probability to detect an AE occurring as infrequently as 
4% of patients. 
9.5.  Data Management 
9.5.1.  Study Documentation and Storage 
An eCRF utilizing an electronic data capture (EDC) application will be used for this study. 
The investigator should ensure that all appropriately qualified persons to whom he/she has delegated 
trial duties are recorded on a Sponsor-approved Delegation of Site Responsibilities Form. 
Source documents are original documents, data, and records from which the patient’s eCRF data are 
obtained. These include but are not limited to hospital records, clinical and office charts, laboratory and 
pharmacy records, diaries, imaging, and correspondence. 
The investigator and study center staff are responsible for maintaining a comprehensive and centralized 
filing system of all study-related (essential) documentation in accordance with International Council 
For Harmonization (ICH) Good Clinical Practice (GCP), suitable for inspection at any time by 
representatives from the Sponsor or designee and/or applicable regulatory authorities. Elements should 
include: 
x Patient files containing, informed consents, and supporting copies of source documentation 
x Study files containing the protocol with all amendments, copies of pre-study documentation and 
all correspondence to and from the IEC/IRB and the Sponsor or designee 
In addition, all original source documents supporting entries in the eCRFs  must be maintained and be 
readily available. 
No study document should be destroyed without prior written agreement between the Sponsor or 
designee and the investigator. Should the investigator wish to assign the study records to another party 
or move them to another location, he/she must notify the Sponsor or designee. 
 
9.6.  Data Analysis 
9.6.1.  Analysis Populations 
Evaluable Set: All patients who have at least one post-dose assessment. 
9.6.2.  Definition of Baseline 
The overall baseline is defined as the last non-missing assessment prior to the Month 0 dose of 
TEGSEDI. 


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On days when serial assessments of vital signs and cytokines/inflammatory markers are performed, the 
pre-dose values will be used as baseline for the analysis of these parameters. 
9.6.3.  Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics for all patients 
who receive TEGSEDI. All patients enrolled will be included in a summary of patient disposition. 
9.6.4.  Safety Analysis 
Patient incidence rates of all AEs will be tabulated by Medical Dictionary for Regulatory Activities 
(MedDRA) system organ class (SOC), and by MedDRA preferred term (PT). Narratives of deaths, all 
discontinuations, serious AEs, pregnancies and AEs of special interest (AESI) will also be provided. 
All treatment emergent AEs, all treatment emergent AEs potentially related to TEGSEDI, all treatment 
emergent serious AEs, and all treatment emergent serious AEs potentially related to TEGSEDI will be 
summarized. 
Incidence (95% confidence interval) of AEs occurring within 1 day of TEGSEDI administration, and 
time to onset from TEGSEDI injection and duration of these AEs will be summarized by visit and 
overall in any visit. The rates of AEs during the 1-day visit occurring after preventive measures will 
also be summarized. Resolution time with and without treatment administered for the AEs will be 
summarized. 
For each study visit on treatment, the result and change from pre-dose baseline in vital signs (body 
temperature, 
heart 
rate, 
respiratory 
rate, 
and 
systolic, 
diastolic 
blood 
pressure) 
and 
cytokines/inflammatory markers will be summarized using descriptive statistics for all patients in the 
Evaluable Set and by presence/absence of AEs within 1 day of TEGSEDI administration. 
9.6.5.  Interim Analyses and Early Stopping Guidelines 
No formal interim analysis is planned; although data related to disposition, exposure, and safety 
considerations will be reported on an annual basis. 
9.7.  Quality Control 
9.7.1.  Monitoring 
The Sponsor representative and regulatory authority inspectors are responsible for contacting and 
visiting the investigator for the purpose of inspecting the facilities and, upon request, inspecting the 
various records of the trial (e.g., eCRFs and other pertinent data) provided that patient confidentiality is 
respected. 
The Sponsor monitor or designee is responsible for inspecting the eCRFs 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 eCRFs. 


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The investigator agrees to cooperate with the monitor to ensure that any problems detected in the course 
of these monitoring visits, including delays in completing eCRFs, are resolved. 
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 investigator will sign and date the indicated places on the case report form. These signatures will 
indicate that the investigator inspected or reviewed the data on the case report form, the data queries, 
and the study center notifications, and agrees with the content. 
9.7.2.  Language 
E-CRFs 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. 
9.7.3.  Inspection and Auditing Procedures 
In accordance with ICH GCP and the Sponsor’s audit plans, this study may be selected for audit by 
representatives from the Sponsor’s Clinical Quality Assurance Department (or designees). Inspection 
of study center facilities (e.g., pharmacy, drug storage areas, laboratories) and review of study-related 
records will occur to evaluate the trial conduct and compliance with the protocol, ICH GCP, and 
applicable regulatory requirements. 
9.7.4.  Source Document Maintenance 
Source documents contain the results of original observations and activities of a clinical investigation. 
Source documents include, but are not limited to, medical records (progress notes), computer printouts, 
screening logs, and recorded data from automated instruments.  
All source documents from this study will be maintained by the site and made available for inspection 
by authorized persons. The original signed ICF for each patient shall be filed with records kept by the 
site and a copy shall be given to the patient. 
9.7.5.  Record Maintenance 
Records will be retained in accordance with the applicable local regulations. All essential study 
documents, including records of patients, source documents, signed ICFs, and eCRFs, must be kept by 
the investigator for at least 15 years from study termination/completion or until instructed in writing by 
the Sponsor that records may be destroyed or forwarded to the Sponsor . The Investigator shall take 
responsibility for maintaining adequate and accurate hard copy source documents of all observations 


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and data generated during this study. Such documentation is subject to inspection by the Sponsor, its 
representatives, and regulatory authorities. 
If an investigator moves, withdraws from the study, or retires, the responsibility for maintaining the 
records must be transferred to another person who will accept responsibility. Notice of transfer must be 
made to and agreed by the Sponsor. 
9.8.  Limitations of the Research Methods 
Patient-selection bias is a consideration, as motivation to consent to join the study can vary between 
patients for different reasons. If prescribers and patients are not willing to participate, selection bias may 
occur, resulting in limited generalizability of the results. However, as TEGSEDI ordering and 
dispensing data will be available to the Sponsor, all patients who will receive TEGSEDI treatment will 
be known at the sites selected to participate in this study. All eligible patients at the study sites who have 
received less than 9 doses will be invited to participate minimizing the selection bias.  
Patients may be enrolled in the study if they have initiated treatment with commercial TEGSEDI prior 
to study enrollment and received less than 9 doses. This approach allows patients who began treatment 
prior to the launch of the study to be included in order to evaluate as large an exposure population as 
possible. The limitation of this approach is that patients who initiate TEGSEDI and discontinue shortly 
thereafter may not be included and could differ in demographic characteristics from those who become 
enrolled, i.e., survivor bias. Also, any AESI that occur shortly after treatment initiation may be 
underrepresented in the study population. Another limitation of this approach is that patients will have 
had TEGSEDI treatment prior to their baseline testing; therefore, it will not be possible to evaluate the 
change in test results from one study visit compared to prior to receiving the patient’s initial dose of 
TEGSEDI. 
9.9.  Other Aspects 
9.9.1.  Protocol Amendments 
Protocol amendments must be made only with the prior approval of the Sponsor or designee. Agreement 
from the investigator must be obtained for all protocol amendments and amendments to the informed 
consent document. The regulatory authority and 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 trial. The 
investigators must send a copy of the approval letter from the IEC/IRB to the Sponsor or designee. 
9.9.2.  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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10. Protection of Human Patients  
10.1.  Informed Consent 
The written informed consent document should be prepared in the language(s) of the potential patient 
population, based on an English version provided by the Sponsor or designee. 
Before a patient’s participation in the trial, the investigator is responsible for obtaining written informed 
consent from the patient or legally acceptable representative after adequate explanation of the aims, 
methods, anticipated benefits, and potential hazards of the study before any data are collected for the 
study. The patient or legally acceptable representative must be given sufficient time to consider whether 
to participate in the study.   
The acquisition of informed consent and the patient’s agreement or refusal to notify his/her primary care 
physician should be documented in the patient’s medical records and the ICF should be signed and 
personally dated by the patient or a legally acceptable representative and by the person who conducted 
the informed consent discussion (not necessarily the investigator). The original signed ICF should be 
retained in the Investigator Site File and in any other locations required by institutional policy, and a 
copy of the signed consent form should be provided to the patient or legally acceptable representative. 
10.2.  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.  
10.3.  Independent Ethics Committee/Institutional Review Board 
A copy of the protocol, proposed ICFs, 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. 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. 
The investigator must submit to and, where necessary, obtain approval from the IEC/IRB for all 
subsequent protocol amendments and changes to the informed consent document. The investigator 
should notify the IEC/IRB of deviations from the protocol in accordance with ICH GCP. The 
investigator should also notify the IEC/IRB of Serious Adverse Events (SAEs) occurring at the study 
center and other AE reports received from the Sponsor or designee, in accordance with local procedures. 
The investigator will be responsible for obtaining annual IEC/IRB approval/renewal throughout the 
duration of the study. 
10.4.  Patient Confidentiality 
The investigator must ensure that the patient’s confidentiality is maintained. On the eCRFs 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 
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In compliance with Federal and local regulations/ICH GCP Guidelines, it is required that the 
investigator and institution permit authorized representatives of the company, of the regulatory 
agency(s), and the 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 
is obligated to inform and obtain the consent of the patient to permit named representatives to have 
access to his/her study-related records without violating the confidentiality of the patient. 


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11. Management and Reporting of Adverse Events/Serious Adverse Events/Adverse Events of 
Special Interest 
11.1.  Sponsor Review of Safety Information 
Safety information will be collected, reviewed, and evaluated by the Sponsor or designee. 
 
11.2.  Regulatory Requirements 
The Sponsor or designee is responsible for regulatory submissions and reporting of AEs, SAEs, AESIs 
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 (IRBs)/IECs will be notified of any SAE according to applicable 
regulations. 
In addition to the investigator’s assessment of relatedness, the Sponsor or designee will evaluate the 
available information and perform an independent assessment of all reported SAEs, AESIs, and 
determine if there is a reasonable possibility that TEGSEDI is causally related to a reported SAE. While 
the Sponsor may upgrade an investigator’s decision, it is not permissible to downgrade the investigator’s 
opinion for the purposes of determining whether the SAE meets the criteria of an Expedited Report. 
The Reference Safety Information for this study will be the USPI, CPM or the respective country label 
as applicable. 
11.3.  Definitions 
11.3.1.  Adverse Event 
An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of medicinal product, whether or not 
the AE is considered related to the medicinal product. 
An AE can therefore be any of the following: 
x 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 
x Any new disease or exacerbation of an existing disease (a worsening in the character, frequency, 
or severity of a known condition)  
x Recurrence of an intermittent medical condition (e.g., headache) not present at baseline 
x Any deterioration in a laboratory value or other clinical test (e.g., electrocardiogram, X-ray) that 
is associated with symptoms or leads to a change in study treatment or concomitant treatment or 
discontinuation from TEGSEDI 
x AEs that are related to a protocol-mandated intervention, including those that occur prior to 
assignment of study treatment (e.g., screening invasive procedures such as biopsies) 


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11.3.2.  Adverse Drug Reaction and Unexpected Suspected Adverse Drug Reaction 
Adverse Drug Reaction (ADR) 
In the clinical experience with a new medicinal product or its new usages, particularly as the therapeutic 
dose(s) may not have been established, ADR is defined as follows: 
All noxious and unintended responses to a medicinal product related to any dose should be considered 
ADRs. 
The phrase "responses to a medicinal product" means that a causal relationship between the medicinal 
product and the AE has been determined by the Sponsor as at least a reasonable possibility, i.e., the 
relationship cannot be ruled out. 
11.3.3.  Serious Adverse Event 
A SAE is any AE that in the view of either the investigator or Sponsor, meets any of the following 
criteria: 
x 
Results in death 
x 
Is life threatening: that is, poses an immediate risk of death at the time of the event 
An AE or suspected adverse reaction is considered “life-threatening” if, in the view of either 
the investigator or Sponsor, its occurrence places the 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 
x 
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 
x 
Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
x 
Results in a congenital anomaly or birth defect in the offspring of the patient (whether the 
patient is male or female) 
x 
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 emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse 
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an AE (e.g., 
rated as mild, moderate, or severe). 
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11.4.  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) should be recorded as Medical History and not recorded as AEs unless 
the pre-existing condition has worsened during study treatment. The investigator should always group 
signs and symptoms into a single term that constitutes a single unifying diagnosis if possible. Before a 
diagnosis is confirmed, all symptoms should be reported as separate AEs. 
11.4.1.  Serious Adverse Events 
In the interest of patient safety, and in order to fulfill regulatory requirements, all SAEs, AESIs, 
(regardless of their relationship to TEGSEDI) 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, AESIs, will begin after 
the patient signs the ICF and stop at the end of the patient’s End of Study visit. When the investigator 
is reporting by telephone, it is important to speak to someone in person versus leaving a message. SAEs 
should be reported using an electronic SAE submission form whenever possible. In situations where the 
electronic SAE submission is unavailable, an Initial SAE Form should be completed, and a copy should 
be faxed or emailed to the Sponsor or designee. The SAE reporting instruction, including the fax number 
and email address can be found in the study safety form completion guidelines. 
Detailed information should be actively sought and included on Follow-Up SAE Forms as soon as 
additional information becomes available. All SAEs will be followed until resolution. SAEs that remain 
ongoing past the patient’s last protocol-specified visit will be evaluated by the investigator and Sponsor.  
If the investigator and Sponsor agree the patient’s condition is unlikely to resolve, the investigator and 
Sponsor will determine the follow-up requirement. 


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11.4.2.  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 end-of-study visit. The investigator will monitor each patient closely and record all 
observed or volunteered AEs (Serious and Non-Serious) on the AE eCRF within 24 hours. 
11.4.3.  Evaluation of Adverse Events (Serious and Non-Serious) 
The investigator’s opinion of the following should be documented on the AE eCRF: 
11.4.3.1.  Relationship to TEGSEDI 
The event’s relationship to TEGSEDI is characterized by one of the following: 
x Related:  There is clear evidence that the event is related to the use of TEGSEDI, e.g., 
confirmation by positive re-challenge test 
x 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 
TEGSEDI administration 
x 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 
TEGSEDI administration and/or exposure suggests that a causal relationship is unlikely (For 
reporting purposes, Unlikely/Remote will be grouped together with Not Related) 
x Not Related:  The event can be readily explained by the patient’s underlying medical condition, 
concomitant therapy, or other causes, and therefore, the investigator believes no relationship 
exists between the event and TEGSEDI 
11.4.3.2.  Severity 
The severity of AEs and SAEs will be graded as follows: 
x Mild:  The event is easily tolerated by the patient and does not affect the patient’s usual daily 
activities 
x Moderate:  The event causes the patient more discomfort and interrupts the patient’s usual daily 
activities 
x Severe:  The event is incapacitating and causes considerable interference with the patient’s usual 
daily activities 
11.4.3.3.  Action Taken with TEGSEDI 
Action taken with TEGSEDI due to the event is characterized by one of the following. 
x None:  No changes were made to TEGSEDI administration  
x Not Applicable:  SAE/AE was reported prior to TEGSEDI administration 
x Permanently Discontinued:  TEGSEDI was discontinued and not restarted 
x Temporarily Interrupted, Restarted – Same Dose:  Dosing and/or dosing frequency was 
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11.4.3.4.  Treatment Given for Adverse Event 
Any treatment (e.g., medications or procedures) given for the AE should be recorded on the AE eCRF. 
Treatment should also be recorded on the concomitant treatment or ancillary procedures eCRF, as 
appropriate. 
11.4.3.5.  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: 
x AE Persists:  Patient terminates from the trial and the AE continues 
x Recovered:  Patient recovered completely from the AE 
x 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) 
x 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: 
x Ongoing:  SAE continuing 
x 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) 
x Recovered:  Patient recovered completely from the SAE (the date of recovery should be entered 
as the SAE resolution date) 
x 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 
x Fatal:  Patient died (the date of death should be entered as the SAE resolution date) 
x Unknown:  The outcome of the reported SAE is not available, e.g., patient is lost to follow-up 
11.4.3.6.  Follow-up of Adverse Event 
Investigator Follow-Up 
During the study period, the investigator should follow each AE until the event has resolved to baseline 
grade or better, the event is assessed as stable, the patient is lost to follow-up, or the patient withdraws 
consent. Every effort should be made to follow all SAEs, AESIs, considered to be related to TEGSEDI 
or related to study procedures until a final outcome can be reported. 
Resolution of AE (with dates) should be documented on the AE eCRF and in the patient’s medical 
record.  
The investigator 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. If the pregnancy results in the birth of a child, the mother and infant 
may continue to be followed for up to 8 weeks after birth. 


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Sponsor Follow-Up 
For SAEs, AESI and pregnancy cases in any patient who has completed or terminated study, the Sponsor 
or a designee should follow-up by telephone, fax, email, and/or a monitoring visit to obtain additional 
case details and outcome information (e.g., from hospital discharge summaries, consultant reports, 
autopsy reports, pregnancy status/outcome, new born status, etc.) in order to perform an independent 
medical assessment of the reported case. 
11.5.  Procedures for Handling Special Situations 
11.5.1.  Abnormalities of Laboratory Tests 
Clinically significant abnormal laboratory test results may, in the opinion of the investigator, constitute 
or be associated with an AE. Examples of these include abnormal laboratory results that are associated 
with symptoms, or require treatment, e.g., bleeding due to thrombocytopenia, tetany due to 
hypocalcemia, or cardiac arrhythmias due to hyperkalemia. Whenever possible, the underlying 
diagnosis should be listed in preference to abnormal laboratory values as AEs. Clinically significant 
abnormalities will be monitored by the investigator until the parameter returns to its baseline value or 
until agreement is reached between the investigator and Sponsor. Laboratory abnormalities deemed not 
clinically significant (NCS) by the investigator should not be reported as AEs. Similarly, laboratory 
abnormalities reported as AEs by the investigator should not be deemed NCS. 
The investigator is responsible for reviewing all laboratory reports. The clinical laboratory reports will 
serve as source documents and should include the investigator’s assessment of clinical significance of 
out of range/abnormal laboratory values. If the lab results are electronically received, the investigator 
should assess clinical significance and document the assessment in the patient medical record. 
11.5.2.  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: 
x 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 to participate in the 
study 
x The condition that required the prescheduled or elective procedure or routinely scheduled 
treatment was present before and did not worsen or progress in the opinion of the investigator 
between the patient’s consent to participate in the study and the timing of the procedure or 
treatment 
x The prescheduled or elective procedure or routinely scheduled treatment is the sole reason for 
the intervention or hospital admission 
11.5.3.  Dosing Errors 
TEGSEDI treatment errors occurring during the study visit (including overdose, underdose, and 
administration error) should be documented as Protocol Deviations. A brief description should be 


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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 TEGSEDI that 
exceeds protocol specifications and the patient is symptomatic, then the symptom(s) should be 
documented as an AE and be reported per Section 11.4.  
Dosing errors occurring between study visits will be reported by the patient and recorded in the eCRF; 
however, these dosing errors will not be considered a protocol deviation. 
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 TEGSEDI should be 
recorded on the AE eCRF. If the associated AE fulfills seriousness criteria, the event should be reported 
to the Sponsor immediately (i.e., no more than 24 hours after learning of the event). 
Should an overdose occur, the investigator or designee should contact the Sponsor or designee within 
24 hours. 
11.5.4.  Contraception and Pregnancy 
Male patients and female patients of childbearing potential must continue to use appropriate 
contraception with their partners or refrain from sexual activity. 
If a patient becomes pregnant or a pregnancy is suspected, or if a male patient makes or believes that he 
has made someone pregnant during the study, then the study center staff must be informed immediately. 
An Initial Pregnancy Form should be submitted to the Sponsor or designee within 24 hours of first 
learning of the occurrence of pregnancy. Follow-up information including delivery or termination is 
reported on Follow-up Pregnancy Forms and reported within 24 hours.  
Payment for all aspects of obstetrical care, child or related care will be the patient’s responsibility.  
Female patients: If a suspected pregnancy occurs while on the study (including follow-up), a pregnancy 
test will be performed. The patient with a confirmed pregnancy will be immediately withdrawn from 
treatment with TEGSEDI. However, the patient will be encouraged to complete the post-treatment 
follow-up period of the study to the extent that study procedures do not interfere with the pregnancy. 
Regardless of continued study participation, 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’s and 
infant’s medical records for an additional 8 weeks after birth.  
Male patients: The progress of the pregnancy in a male patient’s partner should be followed until the 
outcome of the pregnancy is known (i.e., delivery, elective termination, or spontaneous abortion). If the 
pregnancy results in the birth of a child, additional follow-up information may be requested for the 
mother and infant. Follow-up will be performed to the extent permitted by applicable regulations and 
privacy considerations. 


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12. Plans for Disseminating and Communicating Study Results
The results of this study will be summarized in a study report that, after review and approval by the 
sponsor, will be communicated to the US Food and Drug Administration (FDA) and Health Canada 
within the agreed timeframe.  


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13. References
Plante-Bordeneuve, V. (2014). Update in the diagnosis and management of transthyretin familial 
amyloid polyneuropathy. J Neurol, 261(6), 1227-1233. doi: 10.1007/s00415-014-7373-0 
Tegsedi (inotersen) [US Prescribing Information]. Boston, MA. Akcea Therapeutics, Inc. 2018. 
Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211172Orig1s000TOC.cfm 
Tegsedi (inotersen) Canadian Product Monograph. Available from: 
https://www.cadth.ca/sites/default/files/cdr/monograph/Tegsedi-product-monograph.pdf 


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14. Investigator Protocol Signature Page
Protocol Signature Page 
Protocol Number:     TEG4004 
Protocol Title:           A Phase 4 Safety Study Assessing the Adverse Events Occurring Within One 
Day of TEGSEDI Administration in Patients with Polyneuropathy of Hereditary 
Transthyretin-mediated Amyloidosis (hATTR-PN) 
Version: 
Final Protocol (v2.0) 
Date:  
8 May 2020 
I hereby acknowledge that I have read and understand the attached clinical protocol, entitled “A Phase 
4 Safety Study Assessing the Adverse Events Occurring Within One Day of TEGSEDI Administration 
in Patients with Polyneuropathy of Hereditary Transthyretin-mediated Amyloidosis (hATTR-PN)”, 
dated 8 May 2020, and agree to conduct the study as described herein. 
I agree to comply with the International Council For Harmonization Guideline on Good Clinical 
Practice. 
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 Akcea Therapeutics, Inc.  
Investigator’s Signature 
Investigator’s Name (please print) 
Date (DD Month YYYY)