Open-Label Extension Study to Evaluate the Long-term Safety and Efficacy of Efgartigimod in Adult Patients With Post-COVID-19 Postural Orthostatic Tachycardia Syndrome (PC-POTS) Who Completed Study ARGX-113-2104
Phase: PHASE2
Conditions: Post-COVID Postural Orthostatic Tachycardia Syndrome Postural Orthostatic Tachycardia Syndrome
Sponsor: argenx

Clinical Study Protocol ARGX-113-2105 v2.0 
 
23 Feb 2024 
Efgartigimod IV 
 
argenx 
Confidential 
1 
TITLE PAGE 
Protocol Title: 
Open-Label Extension Study to Evaluate the Long-term Safety and 
Efficacy of Efgartigimod in Adult Patients with Post-COVID-19 
Postural Orthostatic Tachycardia Syndrome (PC-POTS) who 
Completed Study ARGX-113-2104 
Protocol Number: 
ARGX-113-2105 
Version Number: 
2.0 (Amendment 1) 
Compound: 
Efgartigimod (ARGX-113) 
Study Phase: 
2 
Sponsor Name: 
argenx BV 
Legal Registered  
Address: 
Industriepark Zwijnaarde 7 
9052 Zwijnaarde (Ghent) 
Belgium 
Phone: +32 9 310 34 00  
Fax: +32 9 310 34 99 
Regulatory Agency 
Identifier Number(s): 
IND
 
Approval Date: 
23 Feb 2024 
 
 
 
System Version: 1.0, Status: Approved, Document ID: VV-TMF-168543

Clinical Study Protocol ARGX-113-2105 v2.0 
 
23 Feb 2024 
Efgartigimod IV 
 
argenx 
Confidential 
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Sponsor’s Medical 
Contact: 
, MD 
Global Clinical Trial Physician 
argenx BV 
33 Arch St 
Boston, MA 
United States 
e-mail: 
 
Contract Research 
Organization: 
IQVIA 
24-Hour Urgent 
Medical Helpline:  
IQVIA’s Medical Emergency Contact Center can be accessed 24/7 by 
the calling the relevant telephone number(s) 
Americas: +1 (973) 659-6677 (main) or +1 (512) 652-0191 (back-up) 
Serious Adverse 
Event Reporting: 
e-mail Address:  safety@argenx.com 
Fax: +1 833 874 7325 
 
 
System Version: 1.0, Status: Approved, Document ID: VV-TMF-168543

Clinical Study Protocol ARGX-113-2105 v2.0 
 
23 Feb 2024 
Efgartigimod IV 
 
argenx 
Confidential 
3 
SIGNATURE OF SPONSOR 
 
Protocol Title: 
Open-Label Extension Study to Evaluate the Long-term Safety and 
Efficacy of Efgartigimod in Adult Patients with Post-COVID-19 
Postural Orthostatic Tachycardia Syndrome (PC-POTS) who 
completed Study ARGX-113-2104 
Protocol Number: 
ARGX-113-2105 
Sponsor Signatory: 
 
 
See appended signature page 
 
 
, MD PhD 
Chief Medical Officer, argenx BV 
 
Date 
 
 
 
 
System Version: 1.0, Status: Approved, Document ID: VV-TMF-168543

Clinical Study Protocol ARGX-113-2105 v2.0 
 
23 Feb 2024 
Efgartigimod IV 
 
argenx 
Confidential 
4 
SIGNATURE OF THE INVESTIGATOR 
Investigator’s Acknowledgment 
I have read the protocol for study ARGX-113-2105. 
Title: Open-Label Extension Study to Evaluate the Long-term Safety and Efficacy of 
Efgartigimod in Adult Patients with Post-COVID-19 Postural Orthostatic Tachycardia Syndrome 
(PC-POTS) who completed Study ARGX-113-2104 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor’s representative.  
I understand that the information in this protocol is confidential and will not be disclosed, except 
to those directly involved in the execution or the scientific/ethical review of the study, without 
written authorization from the sponsor. It is, however, permissible to provide the information 
contained herein to a participant in order to obtain their consent to participate.  
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use guidelines on Good Clinical Practice and with 
the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol can lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor can decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, if 
I decide to withdraw from execution of the study, I will communicate my intention immediately 
in writing to the sponsor. 
 
 
 
Investigator Name 
Institution 
Address 
(please handprint or type) 
 
 
 
 
Signature 
 
 
 
Date 
 
System Version: 1.0, Status: Approved, Document ID: VV-TMF-168543

Clinical Study Protocol ARGX-113-2105 v2.0 
 
23 Feb 2024 
Efgartigimod IV 
 
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Protocol Amendment Summary of Changes 
Global protocol document history 
Date 
Amendment 1 v2.0 
23 Feb 2024 
Original v1.0 
11 Dec 2022 
Amendment 1 (23 Feb 2024) 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The rationale for this amendment is to align the study with the current safety requirements for 
efgartigimod, including moving information on Infusion/injection related reactions and Infusion 
site reactions to AEs of Clinical Interest (previously included under AESIs, in error), as well as 
to align the contraception requirements between Study ARGX-113-2104 and this open-label 
extension study ARGX-113-2105. 
Section  
Description of change 
Brief rationale 
Throughout 
Changed all references to 
“sponsor/designee” to “sponsor” 
To be consistent across the 
efgartigimod program. 
Cover page 
Sponsor’s Medical Contact details 
updated from 
, MD 
to 
, MD. 
To reflect change in personnel for 
this study role. 
Section 1.1, Synopsis 
Updated study duration from: 
“The maximum length of time a 
participant can be in the study is 
approximately 56 weeks (48 weeks 
treatment plus 56 days follow-up).” 
to: 
“The maximum length of time a 
participant can be in the study is 
approximately 55 weeks. 
This includes 46 weeks of 
treatment (Q2W dosing) or 
47 weeks of treatment (QW 
dosing) plus the safety follow-up 
period, with a safety follow-up 
visit approximately 56 days after 
the last dose of IMP 
administration).” 
Updated to clarify the intended 
process, with safety follow-period 
starting from date of last dose 
rather than from end of treatment 
visit. 
Total study duration updated 
accordingly: end of treatment visit 
occurs during safety follow-up 
period rather than after it. 
System Version: 1.0, Status: Approved, Document ID: VV-TMF-168543

Clinical Study Protocol ARGX-113-2105 v2.0 
 
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Section  
Description of change 
Brief rationale 
Section 1.2, Schema; 
Section 1.3, Schedule of 
Activities 
Study day removed for Safety 
Follow-up Visit. 
Updated for clarity as the 
appropriate study day for this visit 
varies depending on multiple 
factors, including dosing and 
discontinuation of IMP. 
Section 2.3.1, Risk 
Assessment 
Updated Infusion/injection-related 
reactions mitigation strategy text to 
reflect that infusion/ 
injection-related reactions are 
considered AEs of Clinical 
Interest, instead of AESIs. 
Correction of error in original 
protocol. 
Removal of list of AEs associated 
with infusion/injection-related 
reactions as these are now listed 
under infusion/injection-site 
reactions. 
To be consistent across the 
efgartigimod program. 
Added separate row for 
Infusion/injection-related site 
reactions, including summary of 
data/rationale for risk and 
mitigation strategy. 
Section 1.1, Synopsis, 
Section 1.2, Schema, 
Section 1.3, Schedule of 
Activities, 
Section 4.1, Overall design. 
Clarified that:  
- The treatment period is 
48 weeks in duration; 
- The maintenance dosing 
period is 42 weeks in duration 
(weeks 4 to 46); 
- The end of treatment visit on 
week 48 (day 337) marks the 
end of the treatment period; 
- The safety follow-up period is 
from the final IMP dose to the 
safety follow-up visit. 
Updated to reflect that IMP will 
only be received for a maximum 
of 47 weeks, but the treatment 
period includes end of treatment 
visit and is therefore 48 weeks 
long. 
Updated to clarify the intended 
process, with safety follow-period 
starting from date of last dose 
rather than from end of treatment 
visit. 
 
System Version: 1.0, Status: Approved, Document ID: VV-TMF-168543

Clinical Study Protocol ARGX-113-2105 v2.0 
 
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Section  
Description of change 
Brief rationale 
Updated from: 
“Participants will return for a 
follow-up visit approximately 56 
days after the week 48 visit. The 
total planned duration of the study 
is 393 days.” 
to: 
“Participants will return for a 
safety follow-up visit 
approximately 56 days after the 
last dose of IMP administration. 
The total planned duration of the 
study is 386 days.” 
Updated to clarify the intended 
process, with safety follow-period 
starting from date of last dose 
rather than from end of treatment 
visit. 
 
56-day time period for Safety 
Follow-Up period removed, as 
time window may vary depending 
on when last IMP dose is given. 
Updated to clarify the intended 
process. 
Section 7.1.1, Permanent 
Discontinuation 
Updated requirements to clarify 
that attendance at scheduled study 
visits is encouraged but not 
mandatory for participants who 
permanently discontinue IMP. 
Updated for consistency across 
the efgartigimod program. 
Included options for 
teleconferencing or telephone visits 
for participants who have 
discontinued IMP.  
Removed requirement that 
participants who permanently 
discontinue IMP will complete the 
IMP discontinuation visit and will 
be encouraged to remain in the 
study. 
Not applicable for open-label 
extension studies. 
Removed requirement that any 
SAE of infection that are 
considered related to IMP will 
result in permanent discontinuation 
of IMP. 
Updated as SAEs of infection are 
only considered a reason for 
permanent discontinuation when 
life-threatening and considered 
related to IMP by the sponsor. 
Added to circumstances which will 
result in permanent discontinuation 
of IMP: 
“The participant develops a new or 
recurrent malignancy except for 
basal cell carcinoma of the skin, 
regardless of relationship to IMP.” 
To ensure study participants' 
safety. 
System Version: 1.0, Status: Approved, Document ID: VV-TMF-168543

Clinical Study Protocol ARGX-113-2105 v2.0 
 
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Section  
Description of change 
Brief rationale 
Section 1.3, Schedule of 
Activities, 
Section 7.1.1, Permanent 
Discontinuation 
Updated requirements for date of 
EDV from within 7 days after the 
participant’s final IMP 
administration to within 7 days of 
last contact with the participant. 
Updated for consistency across 
the efgartigimod program. 
Section 7.2, Participant 
Discontinuation/Withdrawal 
from the Study 
Removed statement that 
participants withdrawing from the 
study can request the destruction of 
collected untested samples. 
Updated for clarity around what 
use of samples are permitted or 
disallowed following participant 
withdrawal from the study. 
Change of process from 
“participants withdrawing from the 
study can request the destruction of 
collected untested samples” to 
“If the participant withdraws 
consent to participate in the study, 
the sponsor can retain and continue 
to use any data collected before 
such consent was withdrawn. 
Future research on samples 
collected from participants who 
have withdrawn consent from the 
study is not impacted unless the 
participant also withdraws the 
consent for future research.” 
Updated for clarity around what 
use of samples are permitted or 
disallowed following participant 
withdrawal from the study. 
Section 8.1, Administrative 
and General/Baseline 
Procedures 
Removal of statement “except the 
postdose PK blood sample”. 
Updated to align with PK blood 
sampling schedule; PK blood 
samples are not taken postdose in 
this study. 
Section 8.2, Efficacy 
Assessments 
Replaced “study manual” with 
“Investigator Site File”. 
The study does not use a formal 
study manual; instead, the 
information is included in 
Investigator Site File. 
Section 1.3, Schedule of 
Activities 
Section 8.3.5, Pregnancy 
testing 
Added following statement on 
timing of pregnancy testing: 
“On visits where both pregnancy 
testing and IMP administration will 
be performed, all pregnancy testing 
must be performed predose. 
Dosing should not begin until a 
negative pregnancy test result has 
been confirmed.” 
Updated to clarify the intended 
process. 
System Version: 1.0, Status: Approved, Document ID: VV-TMF-168543

Clinical Study Protocol ARGX-113-2105 v2.0 
 
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Section  
Description of change 
Brief rationale 
Section 8.3.5, Pregnancy 
testing 
Addition of the following 
requirement: 
Any pregnancy reported during a 
clinical research study, including 
the safety follow up period, is 
routinely monitored as standard 
practice. The pregnancy could have 
arisen from a female clinical study 
participant or a male participant's 
female partner. In either situation, 
consent will be requested to collect 
medical information about the 
pregnancy and the baby's health for 
up to 12 months after the baby’s 
birth. 
Updated for consistency across 
the efgartigimod program. 
Section 8.4, Adverse 
Events, Serious Adverse 
Events, and Other Safety 
Reporting 
Added in definition of AESI: 
An AESI is an AE of scientific and 
medical concern specific to the 
sponsor’s product or program. 
Clarified that SAEs, AESIs, and 
AEs of clinical interest will be 
reported by the participant, as 
types of AE. 
Updated for consistency across 
the efgartigimod program. 
Section 8.4.6, AESIs 
Removal of Section 8.4.6.1 
(Infections) and Section 8.4.6.2 
(Infusion/Injection Related 
Reactions), as these are now 
categorized as AEs of Clinical 
Interest for efgartigimod rather 
than AESIs.  
Addition of detail that events under 
the MedDRA SOC Infections and 
Infestations are considered AESIs 
in this study.  
Updated for consistency across 
the efgartigimod program. 
Section 8.4.7, AEs of 
Clinical Interest 
Addition of new section on AEs of 
Clinical Interest for the study, 
including “Infusion/ 
Injection-Related Reactions”.  
Updated based on the current 
safety profile of efgartigimod and 
for consistency across the 
efgartigimod program. 
Section 1.3, Schedule of 
Activities, Table 1 and 
Table 2; 
Section 8.8, Biomarkers 
References to "plasma" samples 
are removed throughout the 
protocol. 
Corrected as no plasma samples 
will be taken. 
Section 9, Statistical 
Considerations 
Clarified that the SAP will be 
finalized before the first interim 
analysis database lock. 
Updated to clarify the intended 
process. 
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Clinical Study Protocol ARGX-113-2105 v2.0 
 
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Section  
Description of change 
Brief rationale 
Section 9.3.3.3, 
Pharmacokinetics 
Addition of the following 
information: 
“Efgartigimod serum trough 
concentrations will be calculated, 
in line with the secondary endpoint 
assessing exposure to 
efgartigimod. Details will be 
provided in SAP.” 
Updated to clarify the intended 
process, as serum trough 
concentrations are calculated 
values, whereas other serum 
concentrations are summarized 
data. 
Section 10.4.2.2, Male 
Contraception 
Requirements for male 
contraception removed. 
Updated due to non-clinical 
studies results showing no effect 
on reproduction or fertility. 
Efgartigimod falls in the 
“unlikely” risk category and 
therefore does not require 
contraception measures in males 
or nonpregnant WOCBP partners. 
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Clinical Study Protocol ARGX-113-2105 v2.0 
 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
SIGNATURE OF SPONSOR ..........................................................................................................3 
SIGNATURE OF THE INVESTIGATOR ......................................................................................4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................5 
TABLE OF CONTENTS ...............................................................................................................11 
LIST OF TABLES .........................................................................................................................14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................15 
1. 
PROTOCOL SUMMARY ..........................................................................................17 
1.1. 
Synopsis ......................................................................................................................17 
1.2. 
Schema ........................................................................................................................20 
1.3. 
Schedule of Activities .................................................................................................21 
2. 
INTRODUCTION ......................................................................................................26 
2.1. 
Study Rationale ...........................................................................................................26 
2.2. 
Background .................................................................................................................26 
2.3. 
Benefit/Risk Assessment ............................................................................................28 
2.3.1. 
Risk Assessment .........................................................................................................28 
2.3.2. 
Benefit Assessment .....................................................................................................29 
2.3.3. 
Overall Benefit-Risk Conclusion ................................................................................29 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ..................................................30 
4. 
STUDY DESIGN .......................................................................................................32 
4.1. 
Overall Design ............................................................................................................32 
4.2. 
Scientific Rationale for Study Design ........................................................................33 
4.3. 
Justification for Dose ..................................................................................................34 
4.4. 
End-of-Study Definition .............................................................................................34 
5. 
STUDY POPULATION .............................................................................................35 
5.1. 
Inclusion Criteria ........................................................................................................35 
5.2. 
Exclusion Criteria .......................................................................................................35 
5.3. 
Lifestyle Considerations .............................................................................................35 
5.4. 
Screen Failures ............................................................................................................35 
5.5. 
Criteria for Temporarily Delaying Enrollment ...........................................................35 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ........................36 
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6.1. 
Investigational Medicinal Product Administered .......................................................36 
6.2. 
Preparation, Handling, Storage, and Accountability ..................................................36 
6.3. 
Assignment to Study Intervention ..............................................................................37 
6.4. 
Blinding ......................................................................................................................37 
6.5. 
Study Compliance .......................................................................................................37 
6.6. 
Dose Modification ......................................................................................................37 
6.7. 
Continued Access to IMP After the End of the Study ................................................38 
6.8. 
Treatment of Overdose ...............................................................................................38 
6.9. 
Prior and Concomitant Therapy ..................................................................................38 
6.9.1. 
Prohibited Medication ................................................................................................38 
7. 
DISCONTINUATION OF IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................39 
7.1. 
Discontinuation of IMP ..............................................................................................39 
7.1.1. 
Permanent Discontinuation .........................................................................................39 
7.1.2. 
Temporary Discontinuation ........................................................................................39 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................39 
7.3. 
Lost to Follow-up .......................................................................................................40 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................41 
8.1. 
Administrative and General/Baseline Procedures ......................................................41 
8.1.1. 
Use and Storage of Biological Samples ......................................................................41 
8.2. 
Efficacy Assessments .................................................................................................41 
8.2.1. 
Questionnaires ............................................................................................................42 
8.2.2. 
43 
8.2.3. 
43 
8.3. 
Safety Assessments .....................................................................................................43 
8.3.1. 
Physical Examinations ................................................................................................44 
8.3.2. 
Vital Signs ..................................................................................................................44 
8.3.3. 
Electrocardiograms .....................................................................................................44 
8.3.4. 
Protocol-Required Laboratory Tests...........................................................................44 
8.3.5. 
Pregnancy Testing ......................................................................................................44 
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Reporting .....................45 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................45 
8.4.2. 
Method of Detecting AEs and SAEs ..........................................................................45 
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Clinical Study Protocol ARGX-113-2105 v2.0 
 
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8.4.3. 
Follow-up of AEs and SAEs .......................................................................................46 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................46 
8.4.5. 
Pregnancy ...................................................................................................................46 
8.4.6. 
AESIs ..........................................................................................................................47 
8.4.7. 
AEs of Clinical Interest ..............................................................................................47 
8.5. 
Pharmacokinetics ........................................................................................................47 
8.6. 
Pharmacodynamics .....................................................................................................47 
8.7. 
Genetics ......................................................................................................................48 
8.8. 
Biomarkers ..................................................................................................................48 
8.8.1. 
48 
8.8.2. 
48 
8.8.3. 
48 
8.9. 
Immunogenicity Assessments ....................................................................................49 
8.10. 
Health Economics or Medical Resource Utilization and Health Economics .............49 
9. 
STATISTICAL CONSIDERATIONS .......................................................................50 
9.1. 
Statistical Hypothesis ..................................................................................................50 
9.2. 
Analysis Sets ...............................................................................................................50 
9.3. 
Statistical Analyses .....................................................................................................50 
9.3.1. 
General Considerations ...............................................................................................50 
9.3.2. 
Primary Endpoint Analysis .........................................................................................51 
9.3.3. 
Secondary Endpoint Analysis .....................................................................................51 
9.3.4. 
Exploratory Endpoint Analysis...................................................................................52 
9.4. 
Interim Analysis ..........................................................................................................52 
9.5. 
Sample Size Determination ........................................................................................52 
10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................53 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations ....................53 
10.1.1. 
Regulatory and Ethical Considerations ......................................................................53 
10.1.2. 
Financial Disclosure ...................................................................................................53 
10.1.3. 
Informed Consent Process ..........................................................................................54 
10.1.4. 
Recruitment Strategy ..................................................................................................54 
10.1.5. 
Data Protection ...........................................................................................................54 
10.1.6. 
Committees Structure .................................................................................................55 
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10.1.7. 
Dissemination of Clinical Study Data ........................................................................55 
10.1.8. 
Data Quality Assurance ..............................................................................................55 
10.1.9. 
Source Documents ......................................................................................................56 
10.1.10. 
Study and Site Start and Closure ................................................................................56 
10.1.11. 
Publication Policy .......................................................................................................57 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................58 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ........................................................................59 
10.3.1. 
Definition of AE .........................................................................................................59 
10.3.2. 
Definition of SAE .......................................................................................................60 
10.3.3. 
Recording and Follow-Up of AE and/or SAE ............................................................61 
10.3.4. 
Reporting of SAEs and AESIs ....................................................................................62 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ......................................................64 
10.4.1. 
Women of Childbearing Potential Definition .............................................................64 
10.4.2. 
Contraception Guidance .............................................................................................64 
10.5. 
Appendix 5: Operational Considerations for COVID-19 Risk Mitigation .................65 
10.6. 
Appendix 6: Home Study Visits .................................................................................66 
11. 
REFERENCES ...........................................................................................................67 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities: Baseline to Week 48 (Treatment Period) ..............................21 
Table 2: 
Schedule of Activities: Unscheduled, IMP Discontinuation, Early 
Discontinuation, and Safety Follow-up Visits ............................................................24 
Table 3: 
Study ARGX-113-2105 Objectives and Endpoints ....................................................30 
Table 4: 
Study Intervention(s) Administered ...........................................................................36 
Table 5: 
Protocol-Required Laboratory Tests...........................................................................58 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
List of Abbreviations 
Abbreviation 
Expansion 
 
 
AChR 
acetylcholine receptor 
ADA 
antidrug antibody(ies) 
AE 
adverse events 
AESI(s) 
adverse event(s) of special interest 
COMPASS 31 
Composite Autonomic Symptom Score 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDV 
early discontinuation visit 
FcRn 
neonatal Fc receptor 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
gMG 
generalized myasthenia gravis 
GPCR 
G-protein coupled receptor 
 
 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC/IRB 
independent ethics committee/institutional review board 
Ig 
immunoglobulin 
IL 
interleukin 
IMP 
investigational medicinal product 
IRR 
infusion/injection related reaction 
ITP 
immune thrombocytopenia 
IV 
intravenous 
MaPS 
Malmö POTS symptom score 
MedDRA 
Medical Dictionary for Regulatory Activities 
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Abbreviation 
Expansion 
OLE 
open-label extension 
PC-POTS 
post-COVID-19 postural orthostatic tachycardia syndrome 
PD 
pharmacodynamic(s) 
PGI-C 
Patient Global Impression – Change 
PGI-S 
Patient Global Impression – Severity 
PK 
pharmacokinetic(s) 
POTS 
postural orthostatic tachycardia syndrome 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
Q2W 
every 2 weeks 
QW 
once weekly 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SFV 
safety follow-up visit 
SoA 
schedule of activities 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
WOCBP 
women of childbearing potential 
 
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Clinical Study Protocol ARGX-113-2105 v2.0 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: 
Open-Label Extension Study to Evaluate the Long-term Safety and Efficacy of Efgartigimod in 
Adult Patients with Post-COVID-19 Postural Orthostatic Tachycardia Syndrome (PC-POTS) 
who Completed Study ARGX-113-2104 
Regulatory Agency Identifier Number(s): IND
 
Rationale: 
Efgartigimod is a first-in-class antibody fragment that binds to FcRn. This binding prevents 
FcRn from recycling IgG and leads to a reduction in circulating disease-causing autoantibodies. 
This open-label extension study will evaluate the long-term safety of efgartigimod in participants 
with PC-POTS who have completed the 24-week treatment period of the parent study 
ARGX-113-2104. 
Objectives, Endpoints, and Estimands: 
Objectives 
Endpoints 
Primary 
• 
Evaluate the long-term safety of 
efgartigimod in patients with PC-POTS 
• 
Incidence and severity of AEs and AESIs, incidence 
of SAEs, changes in clinically significant laboratory 
test results (per investigator judgment), vital signs, 
and ECG results 
Secondary 
• 
Evaluate the long-term efficacy of 
efgartigimod in reducing the severity of 
PC-POTS symptoms 
• 
Change from baseline to week 24 and week 48 in 
COMPASS 31 (modified) 
• 
Change from baseline to week 24 and week 48 in 
MaPS 
• 
Evaluate the long-term efficacy of 
efgartigimod on patient global assessment 
of symptom experience, fatigue, and 
cognitive function 
• 
Change from baseline to week 24 and week 48 in 
PGI-S 
• 
PGI-C at week 24 and week 48 
• 
Change from baseline to week 24 and 48 in the 
PROMIS Fatigue Short Form 8a 
• 
Change from baseline to week 24 and 48 in the 
PROMIS Cognitive Function Short Form 6a 
• 
Assess the PD effect of efgartigimod 
• 
Absolute values, changes from baseline, and percent 
reduction from baseline in total IgG levels over the 
48-week treatment period 
• 
Assess the exposure to efgartigimod 
• 
Efgartigimod serum trough concentrations over the 
48-week treatment period 
• 
Assess the immunogenicity of efgartigimod 
• 
Incidence and prevalence of ADA against 
efgartigimod over the 48-week treatment period 
ADA=antidrug antibodies; AE=adverse event; AESI=adverse events of special interest; COMPASS=Composite 
Autonomic Symptom Score; ECG=electrocardiogram; IgG=immunoglobulin G; MaPS=Malmö POTS Symptom 
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Score; PC-POTS=post-COVID-19 postural orthostatic tachycardia syndrome; PD=pharmacodynamic; 
PGI-C=Patient Global Impression of Change; PGI-S=Patient Global Impression of Severity; 
PROMIS=Patient-Reported Outcomes Measurement Information System; SAE=serious adverse event 
No estimands have been defined for this study. 
Overall Design: 
Study ARGX-113-2105 is a long-term, single-arm, open-label, multicenter extension of the 
ARGX-113-2104 study, designed to evaluate the long-term safety of efgartigimod IV in adult 
patients with PC-POTS. Participants will be enrolled from both active and placebo arms of the 
ARGX-113-2104 study and will receive efgartigimod IV 10 mg/kg in the extension study 
without knowledge of their prior treatment arm. To be eligible to enroll in this study, participants 
must have completed the 24-week treatment period of the ARGX-113-2104 study and must not 
have permanently discontinued the IMP in that study. 
Brief Summary: 
The treatment period of this study is 48 weeks. Participants will receive efgartigimod (10 mg/kg) 
by IV infusion QW for the first 4 weeks (induction dosing period), and then Q2W for 42 weeks 
(maintenance dosing period).  Participants will return for a safety follow-up visit approximately 
56 days after the last dose of IMP administration. The total planned duration of the study is 
386 days. 
Efgartigimod will be administered during the treatment period in an approximately 1-hour IV 
infusion by site staff or a home nurse. If clinically indicated, the participant and investigator 
(based on the participant-reported reason for the request and physical examination) can jointly 
decide to return the participant to QW dosing during the maintenance dosing period.  
IMP infusions must occur at the site for a minimum of 3 consecutive visits (baseline visit and the 
week 1 and 2 visits) before home infusions are allowed. If doses are missed at 1 or more of these 
visits, then dosing at subsequent visits will also be on-site. IMP administration at home will not 
commence until after 3 doses have been administered on-site. 
The study’s primary objective is to assess the long-term safety of efgartigimod in participants 
with PC-POTS. Additional assessments will be conducted, and blood samples collected to assess 
the effectiveness of efgartigimod at treating PC-POTS, the PD effect of efgartigimod, and the 
immunogenicity of efgartigimod. Blood samples will also be collected to monitor the 
concentration of efgartigimod in blood over time. 
A minimum of 8 study site visits over the 48-week treatment period and safety follow-up period 
is planned; all other visits may be conducted by a home health care service, or a telemedicine 
visit. 
Health Measurement/Outcome: 
The primary outcome of this study will be the incidence and severity of AEs and AESIs, the 
incidence of SAEs, changes in laboratory test results, vital signs, and ECG results. 
Study Intervention and Intervention Form: Efgartigimod IV. 
Condition/Disease: PC-POTS. 
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Study Duration: 
The maximum length of time a participant can be in the study is approximately 55 weeks. This 
includes the 48-week treatment period plus the safety follow-up period, with a safety follow-up 
visit approximately 56 days after the last dose of IMP administration).  
Treatment Duration: 
Total treatment duration will be 46 weeks (Q2W dosing) or 47 weeks (QW dosing), with the end 
of treatment visit on week 48 (total treatment period of 48 weeks).  
 
Visit Frequency: 
A minimum of 8 study site visits over the 48-week treatment period and safety follow-up period 
is planned (baseline, weeks 1, 2, 4, 12, 24, 48, and the SFV); all other visits may be conducted by 
a home health care service, or a telemedicine visit. 
Number of Participants: 
Approximately 38 participants are expected to roll over to this OLE study and receive 
efgartigimod IV 10 mg/kg, assuming approximately 90% of participants in the parent study 
(ARGX-113-2104) will be eligible to enroll in the OLE study. 
Note: Enrolled means the participant agrees to participate in the clinical study by completing the 
informed consent process, and having fully completed the parent study (ARGX-113-2104). 
Study Arms and Duration: 
Each participant will participate in the following study periods:  
• Treatment period of 48 weeks: 
− Induction dosing period: 4-week period of QW efgartigimod IV dosing from 
day 1 (baseline) to day 22 (week 3) 
− Maintenance dosing period: 42-week period from day 29 (week 4) to day 323 
(week 46) Q2W. Participants will receive efgartigimod IV doses Q2W, with the 
first dose of this period administered on day 29 (week 4). If clinically indicated 
(eg, the participant loses PC-POTS symptom control), the participant and 
investigator, based on the participant-reported reason for the request and physical 
examination, can jointly decide to return to QW dosing. Participants who switch 
back to QW dosing will not be allowed to switch back to Q2W dosing during the 
study. Participants who switch must attend an unscheduled visit. The decision to 
switch to QW dosing and the date of the switch should be recorded in the eCRF. 
− End of treatment visit on week 48. 
• Safety follow-up period starting after last dose of IMP, with a safety follow-up visit 
approximately 56 days after the last dose of IMP administration. 
Data Monitoring/Other Committee: No 
 
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b Questionnaires will be administered in the following order: MaPS, PGI-S past week recall, PROMIS Fatigue, PROMIS Cognitive Function, COMPASS 31, 
PGI-S 2-week recall, PGI-C.  
c Procedure performed as part of the ARGX-113-2104 study week 24 assessments 
d These assessments may be performed over 1 to 2 days at each time point, as long as all testing is completed prior to dosing scheduled for that time point. 
e The physical examination will comprise a full assessment of systems at baseline and a brief assessment at all other time points.  
f The 10 mg/kg efgartigimod dose is based on body weight, and the maximum total dose per efgartigimod infusion is 1200 mg for participants who weigh 
≥120 kg. The dose level will be recalculated if a participant’s weight has changed (increased or decreased) by more than 10% from baseline. 
g Vital signs will be measured before collecting any blood sample or administering IMP infusions.  
h A urine pregnancy test will be conducted for WOCBP at baseline and during the study, including during the follow-up period. On visits where both pregnancy 
testing and IMP administration will be performed, all pregnancy testing must be performed predose. Dosing should not begin until a negative pregnancy test 
result has been confirmed. 
i Blood samples to be collected predose (except for week 48, where no IMP is administered and the sample can be taken at any time during the visit). 
j If participants switch from Q2W to QW dosing during the maintenance phase, they must attend an unscheduled visit (see Table 2). The decision to switch to 
QW dosing and the date of the switch should be recorded in the electronic case report form. 
k Day 1 IMP infusion to occur following eligibility and baseline assessments. 
l During the maintenance dosing phase, IMP infusions will be administered Q2W (weeks 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 
44, 46). If clinically indicated, the participant and investigator (based on the participant-reported reason for the request and physical examination) can jointly 
decide to return the participant to QW dosing during the maintenance dosing period, with the final QW dose administered on day 330 (week 47). 
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; ADA=antidrug antibodies; AE=adverse event; COMPASS=composite autonomic symptom scale; EDV=early discontinuation visit; 
 IMP=investigational medicinal product; MaPS=Malmö POTS Symptom Score; NA=not applicable; PD=pharmacodynamics; PGI-C=Patient 
Global Impression – Change; PGI-S=Patient Global Impression – Severity; PK=pharmacokinetics; PROMIS=Patient-Reported Outcomes Measurement 
Information System; QW = once weekly; Q2W = every 2 weeks; SFV=safety follow-up visit; WOCBP=women of childbearing potential. 
a If participants switch from Q2W to QW dosing during the maintenance phase, they must attend an unscheduled visit. The decision to switch to QW dosing and 
the date of the switch should be recorded in the electronic case report form. 
b The IMP Discontinuation Visit will be performed at the earliest opportunity (within 7 days) after permanent IMP discontinuation and applies for participants 
who discontinue IMP but remain in the study. 
c Within 7 days of last contact with participant. The EDV applies for participants who discontinue the study. 
d Participants will attend a safety follow-up visit 56 ±3 days after their final IMP dose. 
e Questionnaires will be administered in the following order: MaPS, PGI-S past week recall, PROMIS Fatigue, PROMIS Cognitive Function, COMPASS 31, 
PGI-S 2-week recall, PGI-C.  
f These assessments may be performed over 1 to 2 days at each time point, as long as all testing is completed prior to dosing scheduled for that time point. 
g The physical examination will comprise a full assessment of systems at baseline and a brief assessment at all other time points.  
h Vital signs will be measured before collecting any blood sample or administering IMP infusions.  
i A urine pregnancy test will be conducted for WOCBP at baseline and during the study, including during the follow-up period.  
j Blood for PK analyses will be collected at the same time of the immunogenicity sample. 
k Blood sample for PK analysis will not be collected if the IMP Discontinuation Visit is more than 4 weeks since the last dose of efgartigimod. 
l In participants that discontinue study treatment, ADA will be assessed 56 days after the last dose administered. 
 
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2. 
INTRODUCTION 
In Study ARGX-113-2104, the efficacy and safety of efgartigimod IV in adult patients with 
PC-POTS is evaluated using a randomized, double-blinded, placebo-controlled study design. 
Participants are randomized to receive efgartigimod IV 10 mg/kg or matching placebo in a 
2:1 ratio. The IMP (efgartigimod or matching placebo) is administered during the treatment 
period in an approximately 1-hour IV infusion QW by site staff or a home nurse. The final dose 
is administered at week 23. At week 24, eligible participants from ARGX-113-2104 may roll 
over into the present single-arm OLE study: ARGX-113-2105. 
2.1. 
Study Rationale 
Efgartigimod is a first-in-class antibody fragment that binds to FcRn. This binding prevents 
FcRn from recycling IgG and leads to a reduction in circulating disease-causing autoantibodies. 
Efgartigimod may be a viable treatment option for individuals diagnosed with PC-POTS because 
it has been shown to reduce IgG levels, including IgG autoantibodies, which may underlie some 
of the autonomic disease manifestations in these patients. 
This open-label extension study will evaluate the long-term safety of efgartigimod in participants 
with PC-POTS who have completed the 24-week treatment period of the parent study 
ARGX-113-2104. 
2.2. 
Background 
The novel SARS-CoV-2 and resulting COVID-19 emerged in late 2019, becoming an ongoing 
global pandemic in 2022.1 Because of COVID-19, many patients develop chronic, debilitating 
symptoms after recovery from the acute infection.2 Multiple terms have been used to describe the 
constellation of symptoms, including long-COVID, long-haul COVID, and post-acute sequelae 
of SARS-CoV-2 syndrome. Typical symptoms of long-COVID include breathlessness, fatigue, 
cognitive impairment (eg, brain fog), orthostatic intolerance, and palpitations.2 These symptoms 
are often debilitating, and most patients receive disability or modified independence.3 Evidence 
is emerging that autonomic dysfunction underlies the symptoms that persist after the acute 
SARS-CoV-2 infection resolves.4 
POTS in patients who continue to have long-lasting symptoms after recovery from the initial 
SARS-CoV-2 infection has been identified in several case reports.5,6 A POTS diagnosis is based 
on evaluations for excessive orthostatic tachycardia (sustained HR increment of ≥30 bpm within 
10 minutes of standing or head-up tilt ≥40 bpm in 12 to 19 years old); absence of orthostatic 
hypotension; frequent symptoms of orthostatic intolerance during standing; duration of 
symptoms for ≥3 months; and absence of other conditions explaining sinus tachycardia.7 Patients 
who develop POTS after COVID-19 are designated in this study as having PC-POTS. 
Currently, the underlying pathophysiology and effective treatments are unknown for PC-POTS. 
Pharmacologic therapy mainly focuses on orthostatic symptoms, targeting blood volume 
expansion and stabilizing HR and blood pressure; however, POTS may be related to immune 
dysfunction and autoimmunity preceded by infection.7 Several infectious pathogens may be 
associated with the development of POTS, including SARS-CoV-2.8,9,10 Patients with POTS 
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have a higher prevalence of autoantibodies, including ganglionic AChR antibody GPCR 
antibodies, which could increase sympathetic tone by activating adrenergic receptors.11 Patients 
with POTS have been shown to have higher levels of these autoantibodies than healthy 
subjects.12 The binding of these autoantibodies to adrenergic receptors has been hypothesized to 
cause tachycardia in some patients.13,14 These autoantibodies, acting as partial agonists, are 
thought to decrease the effectiveness of peripheral norepinephrine leading to an increased 
sympathetic response to posture resulting in postural tachycardia in the absence of hypotension.15 
Collectively, these data suggest that PC-POTS could be caused by IgG autoantibodies that 
induce autonomic dysfunction. The aim of this phase 2 study is to evaluate the long-term safety 
of efgartigimod in participants with PC-POTS who have completed the 24-week treatment period 
of the parent study ARGX-113-2104. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of efgartigimod is 
provided in the IB. 
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2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks of efgartigimod is 
provided in the current efgartigimod IB. 
2.3.1. 
Risk Assessment 
Overall, available data confirm that efgartigimod IV has been well-tolerated across studies in 
different indications and has an acceptable safety profile.  
Potential clinically 
significant risk  
Summary of data/rationale for risk 
Mitigation strategy 
Serious infection 
Efgartigimod reduces IgG levels, 
potentially hindering immune response 
and increasing the risk for infection. 
Exclude participants with 
clinically significant active 
infection not sufficiently resolved 
in the investigator's opinion 
(Section 5.2).  
Infections are considered AESIs 
(Section 8.4.6). Monitor for 
infections and temporarily 
interrupt IMP dosing as specified 
in Section 7.1. 
Infusion/injection- 
related reactions 
All therapeutic proteins can elicit immune 
responses, potentially resulting in 
hypersensitivity or allergic reactions such 
as rash, urticaria, angioedema, serum 
sickness, and anaphylactoid or 
anaphylactic reactions. 
 
Monitor participants during 
administration and for 30 minutes 
thereafter for clinical signs and 
symptoms of infusion reactions. 
Infusion/injection-related 
reactions are considered AEs of 
clinical interest (Section 8.4.7).  
If an infusion reaction occurs, 
interrupt the infusion and institute 
appropriate supportive measures. 
Once resolved, the infusion can 
be resumed and at a slower rate, if 
necessary. 
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Potential clinically 
significant risk  
Summary of data/rationale for risk 
Mitigation strategy 
Infusion/injection-
site reactions 
Most AEs have been mild, transient 
injection site reactions, including 
erythema, pain, bruising, pruritus, 
burning, tenderness, edema, induration, 
irritation, paresthesia, numbness, and 
rash. Moderate injection site reactions 
occurring less frequently include burning, 
erythema, pain, and numbness. Mild to 
moderate headache is commonly reported. 
Continuously monitor participants 
for injection site reactions.  
Infusion/injection-site reactions 
are AEs of clinical interest 
(Section 8.4.7). 
 
AE=adverse event; AESI=adverse event of special interest; IgG=immunoglobulin G; IMP=investigational medicinal 
product 
2.3.2. 
Benefit Assessment 
Efgartigimod has been investigated in nonclinical studies, phase 1 clinical pharmacology studies 
in healthy subjects, and phase 2 to 3 clinical studies in patients with IgG-driven autoimmune 
diseases, including gMG, primary ITP, chronic inflammatory demyelinating polyneuropathy, 
myositis, and pemphigus.  
In clinical studies, efgartigimod effectively reduces IgG antibody levels, including pathogenic 
autoantibodies. The efficacy of efgartigimod to improve clinical outcomes in gMG and reduce 
pathogenic autoantibodies was confirmed in a pivotal phase 3 study in participants with gMG 
(ARGX-113-1704). In addition, clinical benefit was observed in phase 2 studies in primary ITP 
(ARGX-113-1603) and pemphigus (ARGX-113-1701), in which pathogenic autoantibodies 
underlie the disease pathology (see current efgartigimod IB). The available clinical data support 
the clinical benefit of efgartigimod for reducing pathogenic IgG autoantibodies, which may 
mitigate autonomic dysfunction and improve symptoms and the ability to function in patients 
with PC-POTS. 
2.3.3. 
Overall Benefit-Risk Conclusion 
The potential risks associated with efgartigimod are justified by the anticipated benefits possibly 
afforded to participants with PC-POTS in this study and considering the measures implemented 
to minimize risks. The favorable balance between risks and anticipated efficacy/benefit supports 
the use of efgartigimod in the clinical development for PC-POTS. 
More detailed information about the known and expected benefits and risks of efgartigimod can 
be found in the current version of the efgartigimod IB. 
.
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3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
Table 3: 
Study ARGX-113-2105 Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
Evaluate the long-term safety of 
efgartigimod in patients with PC-POTS 
• 
Incidence and severity of AEs and AESIs, incidence 
of SAEs, changes in clinically significant laboratory 
test results (per investigator judgment), vital signs, 
and ECG results 
Secondary 
• 
Evaluate the long-term efficacy of 
efgartigimod in reducing the severity of 
PC-POTS symptoms 
• 
Change from baseline to week 24 and week 48 in 
COMPASS 31 (modified) 
• 
Change from baseline to week 24 and week 48 in 
MaPS 
• 
Evaluate the long-term efficacy of 
efgartigimod on patient global assessment 
of symptom experience, fatigue, and 
cognitive function 
• 
Change from baseline to week 24 and week 48 in 
PGI-S 
• 
PGI-C at week 24 and week 48 
• 
Change from baseline to week 24 and 48 in the 
PROMIS Fatigue Short Form 8a 
• 
Change from baseline to week 24 and 48 in the 
PROMIS Cognitive Function Short Form 6a 
• 
Assess the PD effect of efgartigimod 
• 
Absolute values, changes from baseline, and percent 
reduction from baseline in total IgG levels over the 
48-week treatment period 
• 
Assess the exposure to efgartigimod 
• 
Efgartigimod serum trough concentrations over the 
48-week treatment period 
• 
Assess the immunogenicity of efgartigimod 
• 
Incidence and prevalence of ADA against 
efgartigimod over the 48-week treatment period 
Exploratory 
• 
 
 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
 
• 
 
o 
 
 
o 
 
 
o 
 
 ADA=antidrug antibodies; AE=adverse event; AESI=adverse events of special interest; 
COMPASS=Composite Autonomic Symptom Score; ECG=electrocardiogram; 
; 
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IgG=immunoglobulin G; MaPS=Malmö POTS Symptom Score; PC-POTS=post-COVID-19 postural orthostatic 
tachycardia syndrome; PD=pharmacodynamic; PGI-C=Patient Global Impression of Change; PGI-S=Patient 
Global Impression of Severity; PROMIS=Patient-Reported Outcomes Measurement Information System; 
; SAE=serious adverse event 
No estimands have been defined for this study. 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
Study ARGX-113-2105 is a long-term, single-arm, open-label, multicenter extension of the 
ARGX-113-2104 study, designed to evaluate the long-term safety of efgartigimod IV in adult 
patients with PC-POTS. Participants will be enrolled from both active and placebo arms of the 
ARGX-113-2104 study and will receive efgartigimod IV 10 mg/kg in the extension study 
without knowledge of their prior treatment arm. To be eligible to enroll in this study, participants 
must have completed the 24-week treatment period of the ARGX-113-2104 study and must not 
have permanently discontinued the IMP in that study. 
The treatment period of this study is 48 weeks. Participants will receive efgartigimod (10 mg/kg) 
by IV infusion QW for the first 4 weeks (induction dosing period), and then Q2W for 42 weeks 
(maintenance dosing period). Efgartigimod will be administered during the treatment period in 
an approximately 1-hour IV infusion by site staff or a home nurse. If clinically indicated (eg, the 
participant loses PC-POTS symptom control), the participant and investigator, based on the 
participant-reported reason for the request and physical examination, can jointly decide to return 
the participant to QW dosing during the maintenance dosing period. Participants who switch 
back to QW dosing will not be allowed to switch back to Q2W dosing during the study. 
Participants who switch must attend an unscheduled visit (see Table 2). The decision to switch to 
QW dosing and the date of the switch should be recorded in the eCRF. The final dose for 
participants who remain on Q2W dosing will be administered at week 46 (day 323). The final 
dose for participants who switch back to QW dosing during the maintenance dosing period will 
be administered at week 47 (day 330). The end of treatment visit occurs on week 48 (day 337). 
Participants will return for a safety follow-up visit approximately 56 days after the last dose of 
IMP administration. The total planned duration of the study is 386 days. 
IMP infusions must occur at the site for a minimum of 3 consecutive visits (baseline visit and the 
week 1 and 2 visits) before home infusions are allowed. If doses are missed at 1 or more of these 
visits, then dosing at subsequent visits will also be on-site. IMP administration at home will not 
commence until after 3 doses have been administered on-site. 
The study’s primary objective is to assess the long-term safety of efgartigimod in participants 
with PC-POTS. The primary outcome of this study will be the incidence and severity of AEs and 
AESIs, the incidence of SAEs, changes in clinically significant laboratory test results (per 
investigator judgment), vital signs, and ECG results. Additional assessments will be conducted, 
and blood samples collected to assess the effectiveness of efgartigimod at treating PC-POTS, the 
PD effect of efgartigimod, and the immunogenicity of efgartigimod. Blood samples will also be 
collected to monitor the concentration of efgartigimod in blood over time. 
A minimum of 8 study site visits over the 48-week treatment period and safety follow-up period 
is planned (baseline, weeks 1, 2, 4, 12, 24, 48, and the SFV); all other visits may be conducted by 
a home health care service, or a telemedicine visit. 
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4.2. 
Scientific Rationale for Study Design 
In the present OLE study (ARGX-113-2105), the long-term safety, efficacy, PD, and PK of 
efgartigimod IV will be evaluated in participants with PC-POTS. 
The study includes a 48-week treatment period in which all patients will initially receive QW 
doses of efgartigimod (10 mg/kg) by IV infusion, ie, at the same dose, mode, and frequency of 
administration as in the preceding parent study ARGX-113-2104. After 4 weeks of this induction 
dosing period, participants will be switched to a less frequent dosing regimen (Q2W), for the 
maintenance dosing period, although if clinically indicated the participant can be returned to QW 
dosing. 
The blinded treatment allocation (efgartigimod or placebo) from Study ARGX-113-2104 will be 
maintained. 
The primary outcome measure is the ongoing safety of efgartigimod IV for approximately 1 year 
after completing Study ARGX-113-2104. The endpoints aim to demonstrate that efgartigimod IV 
is a safe long-term treatment option for PC-POTS. The safety endpoints selected for this study 
are those considered to be standard for any clinical study evaluating the safety of an IMP. 
Efficacy is assessed as a secondary objective as assessed by change from baseline to weeks 24 
and 48 in the modified version of COMPASS 31 (2-week recall) and the MaPS. 
COMPASS 31 is a quantitative measure of autonomic symptoms developed for use in autonomic 
research and clinical practice.16 It is a self-rated questionnaire with 31 questions in 6 domains 
(orthostatic intolerance, vasomotor, secretomotor, gastrointestinal, bladder, and pupillomotor) 
(Section 8.2.1.1). 
The MaPS score, recently reported by Fedorowski and colleagues, is a dedicated POTS symptom 
scoring questionnaire.17 The score consists of 12 questions that assess symptom burden related 
and unrelated to orthostatic intolerance (related: tachycardia, palpitations, dizziness, presyncope; 
unrelated: gastrointestinal (GI) symptoms, insomnia, concentration difficulties) (Section 8.2.1.2). 
The COMPASS 31 and MaPS questionnaires were chosen to provide a comprehensive 
assessment of autonomic (COMPASS 31) and POTS-specific symptoms (MaPS). COMPASS 31 
is a validated measure of autonomic symptoms in a common disease of dysautonomia, small 
fiber polyneuropathy.18 Prior studies in patients with POTS support the ability of this assessment 
to measure autonomic symptom burden in patients relative to controls and over time.19,20 
Elevations in COMPASS 31 have also been found in patients post–COVID-19 with evidence of 
POTS and other forms of dysautonomia.21,22 The MaPS questionnaire was developed specifically 
for patients with POTS by investigators at the Skåne University Hospital, Lund University in 
Malmö, Sweden. The 12-item evaluation score is being evaluated in a case-control study in 
patients with POTS compared to healthy controls.23 MaPS is expected to provide an accurate 
assessment of POTS symptoms over time. Further validation of the score will be accomplished 
by its comparison to COMPASS 31 and the other measures included in this study. 
All other secondary efficacy endpoints complement the primary efficacy endpoints and provide 
additional information on efficacy, including measures of patients’ assessment of disease 
severity and change over time (PGI-S and PGI-C) and an established assessment of fatigue 
(PROMIS Fatigue), which is a common symptom among patients with POTS.15 
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4.3. 
Justification for Dose 
Doses of efgartigimod IV 10 mg/kg (QW) will be administered to achieve a maximal total IgG 
reduction (PD effect), thereby ensuring maximal clinical response on the efficacy outcomes. The 
dosing frequency will be reduced to Q2W (but the dose level will not be reduced) after 4 weeks, 
and this dosing frequency will be maintained for the remainder of the study unless a return to 
QW dosing is clinically indicated. 
As the hypothesis for treating PC-POTS with efgartigimod is to reduce the pathogenic 
autoreactive IgG, the selected dose and dose regimen target a nearly maximal PD effect (ie, 
reduction of pathogenic IgGs). The chronic nature of PC-POTS reflects the need for chronic 
treatment to maintain pathogenic IgG autoantibody suppression and symptom reduction. 
The cumulative data from a phase 1 study in healthy adult subjects; phase 2 studies in 
participants with gMG, ITP, and pemphigus; phase 3 studies in gMG; and PK/PD modeling 
results demonstrate that a 10 mg/kg efgartigimod dose administered QW through IV infusion 
achieved approximately 70% IgG reduction, including pathogenic autoantibodies. Data 
furthermore demonstrated that once maximum IgG reduction was achieved following weekly IV 
administration, a 45% or greater IgG reduction was maintained for at least 2 weeks following the 
last efgartigimod dose. Maximal IgG reduction was associated with clinical efficacy observed in 
gMG, ITP, and pemphigus studies. Furthermore, this dose has been safe and well-tolerated in all 
study populations and has demonstrated similar PK and PD profiles across indications. 
Accordingly, the 10 mg/kg IV dose regimen (QW then Q2W) was selected for this study. 
4.4. 
End-of-Study Definition 
The end-of-study is defined as the date of the last participant’s last visit. 
A participant will have completed the study if the SFV has been completed.  
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5. 
STUDY POPULATION 
Prospective approvals of protocol deviations to enrollment criteria, also known as protocol 
waivers or exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. The participant has completed the ARGX-113-2104 study without permanent 
discontinuation of IMP and agrees to directly roll over into the extension study without 
discontinuation of IMP. 
2. The participant signs the informed consent form, as described in Section 10.1.3, and can 
comply with OLE study (ARGX-113-2105) protocol requirements. 
3. The participant agrees to use contraceptives consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. Contraceptive 
requirements are provided in Section 10.4.2. 
4. Female participants of childbearing potential (defined in Section 10.4.1) must have a 
negative urine pregnancy test at baseline before receiving IMP. 
5.2. 
Exclusion Criteria  
Participants will be excluded from the study if any of the following criteria apply: 
1. The participant has a clinically significant condition, based on the judgement of the Study 
Investigator, eg, laboratory abnormalities, 12-lead ECG readings, concomitant medical 
disease(s), etc., which may place them at undue risk or confound interpretation of study 
data. 
2. The participant intends to become pregnant or start breastfeeding during the study. 
5.3. 
Lifestyle Considerations 
Not applicable. 
5.4. 
Screen Failures 
Eligibility to roll over must be verified at the last visit of the preceding study ARGX-113-2104. 
Participants who consent to participate in the clinical study but fail to meet the inclusion and 
exclusion criteria before IMP administration will be considered screen failures and will be 
captured as “enrollment failures.” 
Individuals who do not meet the criteria for participation in this study (screen failures), based on 
the results from assessments in the preceding study, may not be rescreened. 
5.5. 
Criteria for Temporarily Delaying Enrollment 
Not applicable. 
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6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
Efgartigimod is the IMP in this OLE study and is manufactured according to Good 
Manufacturing Practice regulations.  
6.1. 
Investigational Medicinal Product Administered 
Table 4: 
Study Intervention(s) Administered 
Intervention label 
Efgartigimod IV 
Intervention name 
Efgartigimod IV 
Intervention description 
Sterile, colorless, clear concentrate solution for IV infusion. Efgartigimod 
20 mg/mL, administered IV 
Type  
Biologic 
Dose formulation 
Infusion 
Unit dose strength(s) 
20 mg/mL 
Dosage level(s) 
10 mg/kg QW or Q2Wa 
Route of administration 
IV infusion 
Use 
Experimental 
IMP and NIMP/AxMP 
IMP 
Sourcing 
Centrally by the sponsor 
Packaging and labeling 
IMP will be provided in glass vials. Each vial will be labeled per country 
requirements. 
Former name 
ARGX-113 
AxMP=auxiliary medicinal product; IMP=investigational medicinal product; IV=intravenous; 
NIMP= noninvestigational medicinal product; Q2W=every 2 weeks; QW=once weekly 
a QW dosing during the induction dosing period followed by Q2W dosing during the maintenance dosing period. 
6.2. 
Preparation, Handling, Storage, and Accountability 
• The IMP will be supplied to the investigational site by the sponsors' designated IMP 
supply vendor. 
• The pharmacy manual and home guide provide detailed instructions on the 
preparation, handling, storage, and accountability. 
• The investigator or designee is responsible for the correct and safe storage of the 
IMP. All IMP must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area following the labeled storage conditions, with access 
limited to the investigator and authorized site staff.  
• The investigator or designee must confirm that appropriate temperature conditions 
have been maintained for all IMP received during transit. Any discrepancies are 
reported and resolved before using the IMP. The home nurse will be trained to 
evaluate the maintenance of appropriate temperature conditions during IMP transit. 
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• Only participants enrolled in the study are permitted to receive IMP, and only 
authorized site staff or designee are allowed to supply IMP. 
• Appropriate dilutions in a 0.9% saline solution in an infusion bag will be prepared 
before administration with an IV pump. 
• IMP must be stored refrigerated (2°C to 8°C) and protected from direct sunlight in 
secondary packaging. Do not shake IMP or expose it to freezing temperatures. 
• Participants will be observed for at least 30 minutes after the end of IMP infusion for 
routine safety monitoring. 
• The pharmacy manual and home guide provide further guidance and information for 
the final disposition of unused IMP. 
• Accountability of home-administered IMP will be documented as instructed in the 
home guide. 
6.3. 
Assignment to Study Intervention 
All participants will receive efgartigimod (10 mg/kg) by IV infusion. 
6.4. 
Blinding 
ARGX-113-2105 is an open-label study. The blinded treatment allocation (efgartigimod or 
placebo) from the double-blind Study ARGX-113-2104 will be maintained until the database 
lock of that antecedent study. 
6.5. 
Study Compliance 
For some visits, participants will receive IMP under medical supervision at the site. The infusion 
start date/time and infusion end date/time of each dose administered will be recorded in the 
source documents, as well as the total dose administered at each visit.  
IMP may be administered at home (by a health care professional [nurse]) for other visits. 
Participant compliance with IMP administration at home will be assessed by direct questioning 
during the site visit and documented in the source documents and relevant forms. The date and 
time of each dose administered will be recorded. Deviation(s) from the prescribed dosage 
regimen will be recorded. 
IMP infusions must occur at the site for a minimum of 3 consecutive visits (baseline visit and the 
week 1 and 2 visits) before home infusions are allowed. If doses are missed at 1 or more of these 
visits, then dosing at subsequent visits will also be on-site. IMP administration at home will not 
commence until after 3 doses have been administered on-site. 
6.6. 
Dose Modification 
The maximum total efgartigimod dose per efgartigimod infusion is 1200 mg for participants 
weighing ≥120 kg. The IMP weight-based dose will be recalculated if a participant’s weight has 
changed (increased or decreased) by more than 10% from baseline. Otherwise, dose 
modifications are not permitted. 
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6.7. 
Continued Access to IMP After the End of the Study 
Not applicable. 
6.8. 
Treatment of Overdose 
An overdose is defined as a deliberate or accidental administration of IMP to a study participant 
at a dose greater than that assigned to that participant under the study protocol. 
For this study, a variation of more than 10% of the intended weekly amount of IMP will be 
considered an overdose. 
The sponsor does not recommend specific treatment for an overdose.  
In the event of an overdose, the investigator will: 
• Evaluate the participant to determine if IMP will be interrupted. 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities (as 
medically appropriate and at least until the next scheduled follow-up). 
• Immediately report the overdose and the quantity of the excess dose as well as the 
duration of the overdose. 
6.9. 
Prior and Concomitant Therapy 
Participants must maintain a stable regimen of medications throughout the study. Any 
medication or vaccine (including over-the-counter or prescription medicines, recreational drugs, 
vitamins, and/or herbal supplements [including Chinese traditional medicine]) or other specific 
categories of interest that the participant is receiving at the time of enrolment or receives during 
the study must be recorded and include the following information: 
• Reason for use 
• Dates of administration, including start and end dates 
• Dosage information (ie, dose and frequency) 
All available vaccination history should be recorded as part of the participant’s prior medications 
or as concomitant medication for vaccinations received during the study. 
6.9.1. 
Prohibited Medication 
The following medications or treatments are not permitted while the participant receives IMP: 
• Subcutaneous or IV Ig 
• Plasma exchange/plasma electrophoresis 
• Live or live-attenuated vaccines (this restriction also applies for up to 28 days after 
the final dose of IMP) 
• IV saline bolus treatments for volume expansion for treating POTS symptoms 
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7. 
DISCONTINUATION OF IMP AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
Discontinuation of specific sites or the entire study are described in Appendix 1 (Section 10.1). 
7.1. 
Discontinuation of IMP 
7.1.1. 
Permanent Discontinuation 
Permanent discontinuation of IMP occurs when the participant stops receiving the IMP before 
the end of the study, does not resume receiving IMP, and does not withdraw informed consent. 
The investigator will document the primary reason for early discontinuation of IMP. 
Unless consent from the study has been withdrawn, the participant will attend an EDV and an 
SFV. Study sites will attempt to perform the EDV within 7 days of last contact with the 
participant. The SFV will occur 56 ±3 days after the participant’s final IMP administration.  
The following circumstances will result in the permanent discontinuation of IMP: 
• The participant becomes pregnant or intends to become pregnant (see Section 8.3.5). 
• The investigator decides that discontinuing IMP is in the participant’s best interest 
(the sponsor will be informed). 
• The participant develops an SAE or AE that contraindicates further administration of 
IMP in the investigator’s opinion or an AE of NCI-CTCAE severity grade 4 that is 
considered related to IMP by the sponsor. 
• The participant develops a new or recurrent malignancy except for basal cell 
carcinoma of the skin, regardless of relationship to IMP. 
• The participant receives a prohibited medication or substance (Section 6.9.1). 
7.1.2. 
Temporary Discontinuation 
Temporary discontinuation of IMP occurs when the participant discontinues receiving IMP 
before the end of the study and resumed once the cause for the discontinuation has been 
resolved. 
Reasons requiring temporary interruption may include an AE that meets the following criteria: 
• Any SAE considered related to IMP by the sponsor 
• Clinically significant active infection considered related to the IMP by the sponsor 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
Withdrawal from the study is defined as the permanent cessation of further participation in any 
study assessment before its planned completion. 
The primary reason for permanent withdrawal from the study will be recorded. 
The following circumstances will result in the permanent discontinuation and withdrawal from 
the study: 
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• The participant withdraws consent 
• At the request of the sponsor 
The participant will be permanently discontinued from IMP and the study. 
If the participant also withdraws consent to participate in future research, the sponsor may retain 
and continue to use any data collected before such consent was withdrawn.  
• If the participant withdraws consent to participate in the study, the sponsor can retain 
and continue to use any data collected before such consent was withdrawn. 
• Future research on samples collected from participants who have withdrawn consent 
from the study is not impacted unless the participant also withdraws the consent for 
future research. 
Attempts will be made to determine vital status (as a minimum) for participants who withdraw 
consent to participate in the study. 
7.3. 
Lost to Follow-up 
A participant will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and is unable to be contacted by the study site. 
The following actions must be completed if a participant fails to complete a required study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible, counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether the participant wishes to continue in the 
study. 
• Before a participant is considered lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (when possible, 3 phone calls, 
and if necessary, a certified letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts will be documented in the 
participant’s medical record. 
− Participants who continue to be unreachable will be considered to have withdrawn 
from the study. 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
• Study procedures and their timing are summarized in the SoAs (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoAs, is 
required for study conduct. 
• Visits that must be attended on-site are baseline, weeks 1, 2, 4, 12, 24, 48, IMP 
discontinuation visit, EDV, and SFV. All other visits may occur at the participant’s 
home (Appendix 6, Section 10.6)  
• All baseline evaluations must be completed and reviewed to confirm that participants 
meet all eligibility criteria before first dose. The investigator will maintain a log to 
record details of all participants who performed a baseline visit and confirm eligibility 
or record reasons for not being eligible, as applicable. 
• Operational considerations due to the COVID-19 pandemic are provided in 
Section 10.5. 
8.1. 
Administrative and General/Baseline Procedures 
The baseline visit for Study ARGX-113-2105 will be conducted after the participant has 
completed Study ARGX-113-2104. All baseline assessments will be performed before first 
administration of efgartigimod IV in ARGX-113-2105, if applicable. Assessments do not need to 
be repeated if they are performed as part of ARGX-113-2104. 
Questionnaires will be administered before any other assessment, if applicable for that visit. If 
applicable, all other assessments will be completed after the questionnaires and before the 
infusion.  
All assessments will be completed before administering the IMP infusion. 
8.1.1. 
Use and Storage of Biological Samples 
Any samples remaining after the laboratory analyses as defined in the protocol have been 
completed can be stored for up to 15 years after the end of the study, in the laboratory or long 
term storage designated by the sponsor or research partners worldwide for future additional 
medical, academic, or scientific research to address any scientific questions related to 
efgartigimod, FcRn biology, or POTS, unless prohibited by local regulations or the participant. 
As stated in Section 7.2, participants withdrawing from the study are allowed to request the 
destruction of collected, untested samples. 
8.2. 
Efficacy Assessments 
Time points for all efficacy assessments are provided in the SoAs (Section 1.3). 
Questionnaires should be administered before any other study assessment and may be completed 
up to 1 day before the visit. 
Instructions on completing these assessments are provided in the Investigator Site File. 
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8.2.1. 
Questionnaires 
8.2.1.1. 
COMPASS 31 
COMPASS 31 is an easily scored questionnaire to evaluate the severity and distribution of 
autonomic symptoms in various autonomic nerve disorders, providing clinically relevant scores 
of autonomic symptom severity. The questionnaire is based on the well-established 169-item 
Autonomic Symptom Profile and the validated 84-question scoring instrument, the Composite 
Autonomic Symptom Score (COMPASS).16 The COMPASS 31 questionnaire has been 
previously used to assess patients with POTS.19,20 
The 31-item questionnaire requires approximately 10 minutes to administer and addresses 
6 domains: orthostatic intolerance, vasomotor, secretomotor, bladder, pupillomotor, and 
gastrointestinal-mixed upper and diarrhea. 
The modified version of COMPASS 31 (2-week recall) will be used throughout the study. 
Higher scores indicate a more severe degree of autonomic symptoms. 
8.2.1.2. 
MaPS 
The MaPS has been developed to assess the severity of the most common symptoms found in 
patients with POTS based on clinical experience and literature.23 The score consists of 
12 questions that assess symptoms burden related (tachycardia, palpitations, dizziness, 
presyncope) and unrelated to orthostatic intolerance (gastrointestinal symptoms, insomnia, 
concentration difficulties). 
Participants will grade their symptoms for the past 7 days using a numerical rating scale ranging 
from 0 (no symptoms) to 10 (very pronounced symptoms). The maximum score is 120 points, 
with higher scores indicating more severe symptoms. In general, patients with POTS score 
>40 points, whereas healthy controls have lower values. A score >90 points indicates 
debilitating/severe symptoms. 
8.2.1.3. 
PGI-S and PGI-C 
The PGI-S and PGI-C questionnaires are simple, participant-rated, single-item global measures 
of their perceived condition. 
• PGI-S: Severity of symptoms over the past week (1 week recall) and overall 
experience of symptoms over the past 2 weeks (2 week recall) are both rated on a 
4-point Likert scale, with scores ranging from 1 (none) to 4 (severe) 
• PGI-C: Overall change in symptoms from the start of IMP to time point is rated on a 
7-point Likert scale, with scores ranging from 1 (much better) to 7 (much worse) 
8.2.1.4. 
PROMIS 
PROMIS is a publicly available system of highly reliable, precise patient-reported health status 
measures of physical, mental, and social well-being. PROMIS instruments measure concepts 
including pain, fatigue, and physical function. 
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• PROMIS Fatigue Short Form 8a: assesses the impact and perceived fatigue during the 
last 7 days. This validated 8-question scale has 5 response options, with scores 
ranging from 1 to 5. Scores are converted to a T-score, and higher scores indicate 
higher fatigue levels. A decrease in score (negative change from baseline) indicates 
improvement in fatigue. 
• PROMIS Cognitive Function Short Form 6a: assesses the frequency of cognitive 
difficulties experienced in the past 7 days. The questionnaire comprises 6 questions 
on subjective cognitive difficulties regarding a patient’s concentration, memory, 
language, mental acuity, and perceived changes in cognitive functioning. The 
participant marks their response on a 5-point Likert scale, with lower scores 
indicating worse perceived cognitive functioning. 
8.2.2. 
 
 
 
 
 
. 
8.2.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
8.3. 
Safety Assessments 
Time points for all safety assessments are provided in the SoAs (Section 1.3). Safety measures 
will be assessed before IMP administration unless otherwise stated. 
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8.3.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
musculoskeletal, gastrointestinal, pulmonary, cardiovascular, respiratory, and 
neurological systems and general appearance, skin, and lymph nodes. Height and 
weight will also be measured without shoes, attired in light clothing, and recorded 
using validated instruments. 
• Brief physical examination will include assessments of gastrointestinal, pulmonary, 
cardiovascular, and respiratory systems and general appearance. 
8.3.2. 
Vital Signs 
• Oral temperature, pulse rate, respiratory rate, and blood pressure will be recorded 
before blood collection for laboratory tests. 
• Blood pressure and pulse will be assessed with the participant rested and seated.  
8.3.3. 
Electrocardiograms 
• Single 12-lead ECG(s) will be obtained using an ECG machine. On days when ECGs 
are performed, this will be the first assessment of the day. 
8.3.4. 
Protocol-Required Laboratory Tests 
• Blood and urine samples will be analyzed at a laboratory for serum chemistry and 
hematology, coagulation, urinalysis, serology (eg, viral marker testing), and specialty 
laboratory parameters. 
• See Appendix 2 (Table 5) for the list of protocol-required laboratory tests to be 
performed and the SoAs (Section 1.3) for the timing. 
• The investigator must review the laboratory results, document this review, and record 
any clinically significant changes occurring during the study as an AE. The laboratory 
results must be retained with source documents.  
• Abnormal laboratory findings associated with the underlying disease are not 
considered clinically significant unless judged by the investigator to be more severe 
than expected for the participant’s condition. 
8.3.5. 
Pregnancy Testing 
• WOCBP will be tested for pregnancy. Urine tests for pregnancy will occur at the time 
points specified in the SoAs (Section 1.3). On visits where both pregnancy testing and 
IMP administration will be performed, all pregnancy testing must be performed 
predose. Dosing should not begin until a negative pregnancy test result has been 
confirmed.   
• Pregnancy testing in WOCBP will be conducted at the end of relevant systemic 
exposure (ie, at the SFV). 
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• Additional pregnancy testing could be performed, as necessary by the investigator or 
required by local regulations, to establish the absence of pregnancy at any time during 
the study. 
• Any pregnancy reported during a clinical research study, including the safety 
follow-up period, is routinely monitored as standard practice. The pregnancy could 
have arisen from a female clinical study participant or a male participant's female 
partner. In either situation, consent will be requested to collect medical information 
about the pregnancy and the baby's health for up to 12 months after the baby’s birth. 
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting 
The definitions of AEs and SAEs are provided in Appendix 3 (Section 10.3). An AESI is an AE 
of scientific and medical concern specific to the sponsor’s product or program and described in 
Section 8.4.6. 
AEs (including SAEs, AESIs, and AEs of clinical interest) will be reported by the participant (or, 
if appropriate, by the caregiver or surrogate). 
The investigator and qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and monitoring all reported events, 
including those reported by the participant. 
The method of recording, evaluating, and assessing the causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3 
(Section 10.3). 
8.4.1. 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs will be collected from the signing of the ICF until the SFV, as specified in the SoAs 
(Section 1.3). 
All SAEs and AESIs will be recorded and reported to the sponsor or designee immediately, and 
under no circumstance will this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). The 
investigator will submit any updated SAE data to the sponsor within 24 hours of being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after the conclusion 
of the study participation. However, if the investigator learns of any SAE, including death, at any 
time after a participant has been discharged from the study, and they consider the event to be 
reasonably related to IMP or study participation, the investigator must promptly notify the 
sponsor. 
8.4.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and SAEs. Open-ended and 
nonleading verbal questioning of the participant is preferred to inquire about AE occurrences. 
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8.4.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator must proactively follow each participant at 
subsequent visits/contacts. All SAEs and AESIs defined in Section 8.4.6 will be followed until 
resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up 
(defined in Section 7.3). Further information on follow-up procedures is provided in 
Section 10.3. 
8.4.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that 
legal obligations and ethical responsibilities towards the safety of participants and the 
safety of IMP under clinical investigation are met.  
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of IMP under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/IECs, and investigators. 
• An investigator who receives a safety report describing an SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and 
file it with the IB and notify the IRB/IEC, if appropriate, according to local 
requirements. 
• The sponsor or designee will be responsible for reporting SUSARs to the relevant 
regulatory authorities and IEC/IRB, as per applicable regulatory requirements. The 
sponsor or designee will also be responsible for forwarding SUSAR reports to all 
study investigators, who will be required to report these SUSARs to their respective 
IECs/IRBs per local regulatory requirements.  
8.4.5. 
Pregnancy 
• If pregnancy is reported, the investigator will record the pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
pregnancy in the female participant or the female partner of the male participant. 
Contact details are provided in Serious Adverse Event Reporting  
• The participant and pregnant female partner, if consented (Section 10.1.3), will be 
followed to determine the outcome of the pregnancy. The investigator will collect 
follow-up information on the participant/pregnant female partner and the neonate and 
forward it to the sponsor. 
• While pregnancy itself is not considered an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE 
or SAE. Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs and will be 
reported accordingly. 
• Any poststudy pregnancy-related SAE considered reasonably related by the 
investigator to IMP will be reported to the sponsor as described in Section 8.4.4. 
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• Any female participant who becomes pregnant during the study will discontinue IMP. 
8.4.6. 
AESIs 
An AESI is an AE of scientific and medical concern specific to the sponsor’s product or 
program. An AESI can be serious or nonserious, related or unrelated to the IMP or study 
procedures. These events will be reported according to the same timeframe as that for SAEs 
specified in Section 8.4.1 and Section 10.3.4. 
Efgartigimod treatment leads to reduced IgG levels. As low IgG levels can be associated with 
increased infection risks, events under the MedDRA SOC Infections and infestations are 
considered AESIs in this study. These events will be reported according to the timeframe 
specified in Section 8.4.1 and Section 10.3.4, with the following information provided: 
• Causal pathogen 
• Location of infection 
• Relationship to an underlying medical condition, medical history, and concomitant 
medications 
• Reoccurrence of a previous infection 
• Any confirmatory procedure, culture, or urgent medical intervention, if applicable 
Participants for whom an AESI has been reported may be temporarily interrupted from IMP 
treatment, as specified in Section 7.1.2. 
8.4.7. 
AEs of Clinical Interest 
8.4.7.1. 
Infusion/Injection-Related Reactions 
All therapeutic proteins can elicit immune responses, potentially resulting in hypersensitivity or 
allergic reactions such as rash, urticaria, angioedema, serum sickness, and anaphylactoid or 
anaphylactic reactions. As with any SC or IV injection, injection- or infusion-related reactions 
can occur during or after administration. 
Overall, the frequency of injection-related reactions in clinical studies has been low.  
The efgartigimod IB provides more information on infusion/injection-related reactions. 
8.5. 
Pharmacokinetics 
Blood samples for PK analysis will be collected predose on IMP administration visits (at the 
same time as the blood sample for immunogenicity assessments) as described in the SoAs 
(Section 1.3). At visits where IMP is not administered, blood samples may be collected at any 
time during that visit. 
Efgartigimod serum concentrations will be determined using a validated method. 
8.6. 
Pharmacodynamics 
Blood samples for PD analysis will be collected predose on IMP administration visits (at the 
same time as the blood sample for immunogenicity assessments) as described in the SoAs 
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(Section 1.3). At visits where IMP is not administered, blood samples may be collected at any 
time during that visit. 
Total IgG concentrations will be quantified using validated methods at a central laboratory. 
Results will not be reported to investigative sites or other study personnel to maintain the parent 
study blind. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers 
Serum and whole blood will be collected predose at the time points specified in the SoAs 
(Section 1.3) to identify putative biomarkers and explore their relationship with clinical effects. 
At visits where IMP is not administered, blood samples may be collected at any time during that 
visit. These analyses are exploratory as no biomarker has been validated for PC-POTS.  
 
 
  
 
  
 
 
 
 
Procedures for collecting and shipping these samples are in the laboratory manual. 
8.8.1. 
 
 
 
 
 
 
 
8.8.2. 
 
 
 
 
 
 
  
8.8.3. 
 
 
 
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8.9. 
Immunogenicity Assessments 
Blood samples will be collected at the time points indicated in the SoAs (Section 1.3), predose 
on IMP administration visits (within ≤2 hours before infusion), to evaluate serum levels of 
ADAs to efgartigimod. At visits where IMP is not administered, blood samples may be collected 
at any time during that visit. 
Samples will be analyzed by the designated laboratory in a tiered approach using validated 
immunogenicity assays.27 Initially, samples will be screened for a positive assay response 
(tier 1). Screened positive samples will then be tested in a confirmation assay (tier 2). Finally, a 
titration of the ADA response will be performed on positive tier 2 samples to characterize the 
magnitude of the antibody response (tier 3). 
8.10. 
Health Economics or Medical Resource Utilization and Health 
Economics 
Health economics and/or medical resource utilizations are not evaluated in this study. 
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9. 
STATISTICAL CONSIDERATIONS 
The SAP will be finalized before the first interim analysis database lock and includes a more 
technical and detailed description of the statistical analyses described in this section. 
9.1. 
Statistical Hypothesis 
No formal hypothesis will be tested in this phase 2 OLE study. The primary objective of the 
study is to evaluate the long-term safety of efgartigimod in patients with PC-POTS. 
9.2. 
Analysis Sets 
The following analysis sets are defined: 
Analysis set 
Description 
Full analysis set (FAS) 
All enrolled participants 
Safety analysis set 
All participants exposed to study intervention. 
 
All listings, including those for safety data, will be based on the FAS. 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
The results of this study will not be used inferentially. No formal sample size calculation is 
presented. 
Summaries will include the number of observations (n), mean, SE, 95% CI, median, minimum, 
and maximum for continuous measures. Summaries will include sample size, frequencies, and 
percentages for categorical variables. For categorical variables, participants with missing data 
will be counted as a separate category; proportions will be calculated using as denominator all 
enrolled participants. 
All study visits will be recalculated based on actual dates. The rules for calculating the analysis 
visits and for imputing partial dates or missing dates will be documented in the SAP.  
Summaries will be provided both for the overall study population as well as grouped according 
to treatment received in Study ARGX-113-2104 (efgartigimod or placebo). 
9.3.1.1. 
Estimands 
No treatment effect will be estimated; the outcomes that will be summarized will be presented as 
descriptive and as pertaining to participants having efgartigimod as administered in the OLE, 
with in addition any treatments administered subsequent to efgartigimod, up to the end of 
scheduled follow-up. 
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9.3.2. 
Primary Endpoint Analysis 
The primary endpoint is the incidence and severity of AEs and AESIs, incidence of SAEs, 
changes in laboratory test results, vital signs, and ECG results. 
AEs will be coded using the latest version of the MedDRA classification system. 
All AEs starting on or after the first infusion will be categorized as TEAEs. 
TEAEs will be presented by SOC and PT, and will include the percentage of participants 
reporting at least one TEAE by SOC and PT and overall. 
Multiple occurrences of a single PT in a participant will be counted only once at the maximum 
severity/grade. 
The number and percentage of participants with most common AEs will be presented. 
AEs with missing severity or relationship to IMP will be classified as severe and 
treatment-related, respectively. All AEs will be summarized by relatedness to IMP. 
Any AEs leading to death or discontinuation of IMP will also be summarized. 
All AE data will be listed. 
The other safety endpoints will be summarized using descriptive statistics. 
9.3.3. 
Secondary Endpoint Analysis 
9.3.3.1. 
Efficacy 
For analyses of change from baseline, the baseline is defined as the latest measurement prior to 
enrollment in the OLE study. 
Summary statistics will be presented for the efficacy endpoints in Table 3 at baseline and at each 
scheduled visit for Study ARGX-113-2105. 
In addition to change from the primary OLE baseline, summaries of absolute values at each visit 
will be similarly presented. 
Plots of mean changes from the primary OLE baseline by visit will be presented, together with 
their 90% CI. Plots by visit of median change from the primary OLE baseline and its 
interquartile range will also be presented, represented by a boxplot at each visit.  
For the two endpoints measuring reduction in severity of PC-POTS symptoms (COMPASS 31 
and MaPS), summary statistics and plots for change from the parent study baseline will also be 
presented. 
9.3.3.2. 
Pharmacodynamics 
Absolute values, changes from baseline, and percent reduction from baseline in total IgG levels 
will be summarized using descriptive statistics. Two analyses will be presented, one using the 
baseline of the parent study (ARGX-113-2104); and the other using the baseline of the present 
OLE study (ARGX-113-2104 week 24 visit/ARGX-113-2105 baseline/day 1. 
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9.3.3.3. 
Pharmacokinetics 
Efgartigimod serum concentrations will be summarized using descriptive statistics. 
Efgartigimod serum trough concentrations will be calculated, in line with the secondary endpoint 
assessing exposure to efgartigimod. Details will be provided in SAP. 
9.3.3.4. 
Population Pharmacokinetic/Pharmacodynamic Analysis 
A population PK/PD analysis may be performed and may be reported separately from the final 
CSR. 
9.3.3.5. 
Immunogenicity 
Incidence and prevalence of ADAs will be summarized using descriptive statistics. 
9.3.3.6. 
Change of Dosing Regimen and Analysis 
Counts by visit will be presented of numbers and proportions on Q2W and QW dosing.  
The temporal relationship between dosing regimen and both efficacy and safety will be explored 
and displayed visually. 
COMPASS 31 efficacy score will be presented by visit for 2 subgroups, where the subgroups are 
defined as changing back at any time from Q2W to QW dosing regimen (Y/N). 
Further exploratory analysis by dosing regimen may be performed. 
Time from first infusion to switch back to QW dosing will be analyzed and a Kaplan-Meier plot 
of probability of staying on Q2W will be presented. 
9.3.4. 
Exploratory Endpoint Analysis 
 
 
 
 
9.4. 
Interim Analysis 
Interim analyses in support of regulatory interactions may be performed for this study. 
9.5. 
Sample Size Determination 
The results of this study will not be used inferentially, and no formal sample size calculation was 
performed. Approximately 38 participants are expected to roll over to this OLE study and 
receive efgartigimod IV 10 mg/kg, assuming approximately 90% of participants in the parent 
study (ARGX-113-2104) will be eligible to enroll in the OLE study. 
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted according to the protocol and the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences international ethical guidelines 
− Applicable ICH GCP guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementing 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.  
• Protocols and any substantial amendments to the protocol will require health 
authority approval before initiation except for changes necessary to eliminate an 
immediate hazard to study participants. 
• The investigator is responsible for providing the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently according to the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies, and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit a complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the study and for 1 year 
after completion of the study. 
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The following information will be collected: any significant payments from the sponsor such as a 
grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing 
consultation or honoraria, proprietary interest in IMP, significant equity interest in the sponsor as 
defined in 21 CFR 54 2(b) (1998). 
10.1.3. 
Informed Consent Process 
• The investigator or representative will explain the nature of the study, including risks 
and benefits to the potential participant and answer all questions before the participant 
completes the informed consent process by signing the informed consent form. 
• Potential participants must be informed that their participation is voluntary. A 
statement of informed consent must be signed that meets the requirements of the 
IRB/IEC or study center, ICH guidelines, 21 CFR 50, local regulations, and, where 
applicable, privacy and data protection requirements. 
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must be reconsented to the most current version of the ICF(s) during their 
participation in the study if the changes to the ICF impact participant participation 
• A copy of the ICF(s) must be provided to the participant (or their legally authorized 
representative). 
• A copy of the ICF(s) must be provided to the participant. 
• Participants who are rescreened are required to sign a new ICF (Section 5.4). 
10.1.4. 
Recruitment Strategy 
Not applicable. 
10.1.5. 
Data Protection 
• The sponsor will assign participants a unique identifier. Any participant records or 
datasets transferred to the sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be 
transferred. 
• The participant must be informed that the sponsor, sponsor representatives, competent 
authorities, etc., can review source data containing identifiers and will use their 
personal study-related data per local data protection law. The level of disclosure must 
also be explained to the participant who will be required to give consent for their data 
to be used as described in the informed consent. 
• The contract between sponsor and study sites specifies responsibilities of the parties 
related data protection, including handling of data security breaches and respective 
communication and cooperation of the parties. 
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• Information technology systems used to collect, process, and store study-related data 
are secured by technical and organizational security measures designed to protect 
such data against accidental or unlawful loss, alteration, or unauthorized disclosure or 
access. 
10.1.6. 
Committees Structure 
Not applicable. 
10.1.7. 
Dissemination of Clinical Study Data 
The sponsor will register and disclose the results of clinical studies as required by law. 
10.1.8. 
Data Quality Assurance 
• The sponsor or designee is responsible for the data management of this study, 
including quality checking of the data. 
• All participant data relating to the study will be recorded on eCRFs unless transmitted 
to the sponsor (or its designee) electronically (eg, laboratory data) or paper SAE 
forms. The investigator is responsible for verifying data entries are complete, 
accurate, and verifiable by electronically signing the eCRF. 
• Guidance on completing eCRFs is provided in the eCRF completion document. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and direct access to source data documents. 
• Study processes, study sites (including but not limited to site visits, central 
laboratories, vendors), the study database, and study documentation can be subject to 
quality assurance audit during the study by the sponsor or sponsor’s designee on 
behalf of the sponsor. In addition, inspections could be conducted by foreign or 
domestic regulatory bodies at their discretion. Such audits/inspections can occur 
during or after the completion of the study. 
• Records and documents, including signed ICFs, on the conduct of this study must be 
retained by the investigator for 25 years after study completion unless local 
regulations or institutional policies require a more extended retention period. Without 
the sponsor's written approval, no records will be destroyed during the retention 
period. No records are allowed to be transferred to another location or party without 
the sponsor’s written notification. 
• Monitoring details describing strategy and activities are described in a monitoring 
plan  
− Study monitors will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted following the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
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10.1.9. 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data, and its origin can be found in the 
monitoring plan. 
• The investigator must maintain accurate documentation (source data) that supports 
the information entered in the eCRF. 
• The sponsor or designee will perform monitoring to confirm that data entered into the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.10. 
Study and Site Start and Closure 
First Act of Recruitment 
The study start date is the date on which the first participant completes ARGX-113-2104 and 
rolls over to ARGX-113-2105. 
Study/Site Termination 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator could initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator could include but are 
not limited to: 
• For study termination: 
− Discontinuation of further compound development 
• For site termination: 
− Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor’s procedures, or GCP guidelines 
− Inadequate or lack of recruitment (evaluated after a reasonable amount of time) of 
participants by the investigator 
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− Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator will promptly inform the participant and ensure 
appropriate therapy and/or follow-up for the participant, as necessary. 
10.1.11. 
Publication Policy 
• The results of this study can be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally 
support publication of multicenter studies only in their entirety and not as individual 
site data. In this case, a coordinating investigator will be designated by mutual 
agreement. 
• Authorship will be determined by mutual agreement and consistent with International 
Committee of Medical Journal Editors authorship requirements. 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests listed in Table 5 will be performed as described in the Laboratory Manual. 
• Additional tests can be performed during the study as determined necessary by the 
investigator or required by local regulations. 
• Investigators must document their review of each laboratory test result. 
Table 5: 
Protocol-Required Laboratory Tests 
Laboratory Test 
Parameters 
Hematology 
RBC count 
platelet count 
hemoglobin 
hematocrit 
RBC indices: 
MCV 
MCH 
%reticulocytes 
 
WBC count with differential: 
neutrophils 
eosinophils 
lymphocytes 
basophils 
monocytes 
Serum chemistry 
ALT 
AST 
albumina 
BUN 
creatinine 
glucose 
potassium 
chloride 
bicarbonate 
sodium 
total proteina 
calcium 
bilirubin (total and direct) 
 
Routine urinalysis 
Specific gravity 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy testing 
Urine test (as needed for WOCBP potential, defined in Section 10.4.1)  
Specialty laboratory tests 
CRP, ESR, TSH 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; CRP=C-reactive 
protein; ESR=erythrocyte sedimentation rate; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular 
volume; RBC=red blood cell; TSH=thyroid stimulating hormone; WBC=white blood cell; WOCBP=women of 
childbearing potential 
a Results will be blinded up to and including the week 4 (day 29) visit. 
 
 
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• 
An alert email for the SAE and AESI reports on the eCRF will automatically be sent by 
email to the sponsor or designee's safety mailbox via the EDC system.  
• 
The paper SAE report form will be faxed or emailed to the sponsor’s designee (see the 
Serious Adverse Event Reporting details on page 2 of this protocol). 
 
 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Women of Childbearing Potential Definition 
A female is considered a WOCBP unless she is either:  
a. Postmenopausal: A postmenopausal state is defined by continuous amenorrhea for at 
least 1 year without an alternative medical cause with an FSH measurement of 
>40 IU/L. If a postmenopausal woman is using hormonal therapy, such as hormone 
replacement therapy or hormonal contraceptives, FSH levels might be suppressed and 
therefore an FSH test to confirm a postmenopausal state is not considered valid. In 
this case the postmenopausal state will need to be assessed by the investigator. 
b. Surgically sterilized: Women who have had a documented permanent sterilization 
procedure (eg, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) 
10.4.2. 
Contraception Guidance 
10.4.2.1. Female Contraception for Women of Childbearing Potential 
WOCBP must use one of the following contraception methods from signing the ICF until the last 
dose of IMP: 
The following Clinical Trials Facilitation and Coordination Group28 acceptable methods are 
permitted for efgartigimod studies: 
• Progestogen-only oral hormonal contraception in which inhibition of ovulation is not 
the primary mode of action 
• Male or female condom with or without spermicide 
• Cap, diaphragm, or sponge with spermicide 
10.4.2.2. Male Contraception 
No male contraception is required.  
 
 
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10.5. 
Appendix 5: Operational Considerations for COVID-19 Risk 
Mitigation 
Participants will be tested for SARS-CoV-2 if they are symptomatic or if applicable law requires 
testing; if applicable, a negative polymerase chain reaction test (central or local laboratory) is 
required within 72 hours before enrollment regardless of a participant’s vaccination status. 
During the study, the sites will implement all recommendations issued by the local government 
regarding the spread of COVID-19, including specific guidelines related to clinical research 
performed in clinical research centers. 
This appendix is intended for use only if unforeseen changes in the COVID-19 pandemic result 
in new restrictions at the site or new risks for participants or site staff from attending visits at the 
site. 
Additional testing for COVID-19 beyond what is listed in the SoAs (Section 1.3) is not required 
during the study unless required by local authorities. However, it is recommended that 
participants who develop COVID-19 symptoms while receiving IMP be tested, with results 
reported for the study. 
Critical Parameters to Be Collected During the Study 
All assessments will be performed as indicated in the SoAs (Section 1.3). If assessments cannot 
be performed due to the COVID-19 pandemic, the following information must be collected from 
the first visit through end of study: all AE and concomitant medication reporting, IMP 
administration, questionnaires, and protocol-required laboratory assessments. 
 
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10.6. 
Appendix 6: Home Study Visits 
A home nurse can travel to the participant’s home to conduct visits or meet the participant at a 
convenient alternate location).  For each home visit, the investigator or designee will confer with 
the participant via an audio or video interview to elicit AEs and concomitant medications and the 
participant's general well-being. The investigator or designee will also ensure the participant has 
completed all required efficacy assessments that can be done at home (eg, questionnaires). Any 
scheduled assessments will be conducted before the home nurse administers IMP.  
 
 
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11. 
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Heart Assoc. 2014;3(1):e000755. 
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16. Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W. COMPASS 31: a refined and 
abbreviated Composite Autonomic Symptom Score. Mayo Clin Proc. 
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