Clinical trial NCT05633407
Conditions: Postural Orthostatic Tachycardia Syndrome
Keywords: POTS Long COVID Postural Orthostatic Tachycardia Syndrome efgartigimod
Sponsor: argenx
Start date: 2022-09-23; Completion date: 2024-04-18
Enrollment: 53 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study aims to investigate the safety, tolerability, efficacy, pharmacodynamics (PD), pharmacokinetics (PK), and immunogenicity of efgartigimod compared to placebo in participants with post-COVID-19 postural orthostatic tachycardia syndrome (POTS) (post-COVID-19 POTS).

Detailed description:
The study aims to investigate the safety, tolerability, efficacy, pharmacodynamics (PD), pharmacokinetics (PK), and immunogenicity of efgartigimod compared to placebo in participants with post-COVID-19 postural orthostatic tachycardia syndrome (POTS) (post-COVID-19 POTS). Efgartigimod may be a viable treatment option for individuals diagnosed with post-COVID-19 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.

Arms: arm 1: Receive efgartigimod IV 10mg/kg during weekly infusions during a treatment period of 24 weeks arm 2: Receive a matching placebo during weekly infusions during a treatment period of 24 weeks
Interventions: intervention 1: Efgartigimod intervention 2: Placebo
Intervention descriptions: intervention 1: Efgartigimod IV 10 mg/kg infusion qw for 24 weeks. Participants will be randomized to receive efgartigimod IV 10 mg/kg or matching placebo in a 2:1 ratio, respectively intervention 2: Receive a matching placebo during weekly infusions during a treatment period of 24 weeks.

Participants will be randomized to receive efgartigimod IV 10 mg/kg or matching placebo in a 2:1 ratio, respectively

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol ARGX-113-2104 v3.0 
 
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CLINICAL STUDY PROTOCOL 
Protocol Title: 
A phase 2 randomized, double-blinded, placebo-controlled study to 
evaluate the efficacy and safety of efgartigimod IV in adult patients 
with post–COVID-19 postural orthostatic tachycardia syndrome 
(POTS) 
Protocol Number: 
ARGX-113-2104 
Version Number: 
3.0 (Amendment 2) 
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): 
 
Approval Date: 
25 Jul 2023 
 
 
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Sponsor’s Medical 
Contact: 
  
Global Clinical Trial Physician 
argenx BV  
33 Arch St  
Boston, MA  
United States 
Email:
 
Sponsor’s Designee: 
IQVIA  
 
24-Hour Urgent 
Medical Helpline:  
IQVIA’s Medical Emergency Contact Center can be accessed 24/7 by 
calling the relevant telephone number(s) 
Americas: +1 (973) 659-6677 (main) or +1 (512) 652-0191 (backup) 
Serious Adverse 
Event Reporting: 
Email Address: safety@argenx.com 
Fax: +1 833 874 7325  
The information contained in this medium is the property of argenx BV and/or its 
subsidiaries (jointly “argenx”) and is confidential and proprietary. Without prior 
authorization from argenx, information contained herein may not be used, reproduced, 
divulged, published, or otherwise disclosed to anyone. 
 
 
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SIGNATURE OF SPONSOR 
 
Protocol Title: 
A phase 2 randomized, double-blinded, placebo-controlled study to 
evaluate the efficacy and safety of efgartigimod IV in adult patients 
with post–COVID-19 postural orthostatic tachycardia syndrome 
(POTS)  
Protocol Number: 
ARGX-113-2104 
Sponsor Signatory: 
 
 
See appended signature page 
 
 
, MD, PhD 
Chief Medical Officer, argenx BV 
 
 
Date  
 
 
 
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SIGNATURE OF THE INVESTIGATOR 
Investigator’s Acknowledgment 
I have read the protocol for study ARGX-113-2104. 
Title: A phase 2 randomized, double-blinded, placebo-controlled study to evaluate the efficacy 
and safety of efgartigimod IV in adult patients with post–COVID-19 postural orthostatic 
tachycardia syndrome (POTS) 
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 should not be disclosed, 
other than 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 may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may 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, 
should 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 print or type) 
 
 
 
 
Signature 
 
 
 
Date 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES 
DOCUMENT HISTORY 
 
Document 
Date 
Amendment 2 
25 Jul 2023 
Amendment 1 
11 Dec 2022 
Original Protocol v1.0 
25 Mar 2022 
Amendment 2 (25 Jul 2023) 
This amendment is considered to be 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 update Section 3, Inclusion Criterion 3a to allow for 
diagnosis of post-COVID-19 POTS based on a history of COVID-19, per previous positive test 
result from either laboratory-confirmed COVID-19 test (eg, a PCR test) or 
non-laboratory-confirmed COVID-19 test (eg, rapid antigen test); this positive result may be 
either documented or patient-reported.  
 
Section # and Name 
Description of Change 
Brief Rationale 
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 
Section 4.1, Overall design 
Corrected follow-up period from 7 weeks 
(56 days ± 3 days) to 8 weeks (56 days ± 
3 days). 
Minor error in original protocol 
wording required update. 
Section 2.3.1, Risk 
Assessment 
Infusion-related reactions mitigation 
strategy changed from: 
“Monitor participants for 1 hour at the site 
after IMP administration. IMP will be 
administered by a healthcare professional.”  
to  
“Monitor participants during 
administration and for 30 minutes 
thereafter for clinical signs and symptoms 
of infusion/injection-related reactions. 
Infusion/injection-related reactions are 
considered AEs of clinical interest 
(Section 8.4.7).” 
Monitoring requirements updated 
and reference to AEs of clinical 
interest section added for 
consistency across the 
efgartigimod program. 
New row added for Infusion /injection-site 
reactions, including summary of data and 
mitigation strategy. 
Updated per current safety 
requirements for efgartigimod. 
Section 5.1, Inclusion criteria 
Update of inclusion criterion 3a to allow 
documented or patient-reported 
confirmation of a previous positive 
To allow patients who are unable 
to provide documentation of a 
prior PCR test to be included in 
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Section # and Name 
Description of Change 
Brief Rationale 
laboratory or non-laboratory test for 
COVID-19. 
the study. 
Section 5.4, Screen Failures 
Section 6.4, Blinding 
Section 7, IMP 
Discontinuation and 
Participant 
Discontinuation/Withdrawal 
Updated wording throughout for 
consistency with current template 
language. 
Updated per current CSP template 
for consistency across the 
efgartigimod program. 
Section 7.1.1, Permanent 
Discontinuation 
Removal of sentence:  
“Blood samples for participants remaining 
in the study following IMP discontinuation 
will be collected for PK analyses as per the 
SoA (Section 1.3) for up to 3 weeks post 
IMP discontinuation." 
Not required in this section; PK 
sampling requirements are 
captured in Section 8.5, 
Pharmacokinetics. 
Added allowance for participants who 
have discontinued IMP but remained in the 
study to attend previously scheduled visits 
via telephone or web teleconferencing. 
To encourage participants who 
have discontinued IMP to 
continue with previously 
scheduled visits. 
Clarified that if the participant cannot 
attend the previously scheduled visits for 
any reason, the study site will minimally 
perform an EDV and the SFV on-site. 
Wording updated to clarify the 
intended process. 
Updated requirement for EDV from within 
the 7 days after the participant’s final IMP 
administration to within 7 days after of last 
contact with the participant. 
Updated per current CSP template 
for consistency across the 
efgartigimod program. 
Added the following to the list of 
circumstances which will result in 
permanent discontinuation of IMP: 
“Participant develops a new or recurrent 
malignancy except for basal cell 
carcinoma of the skin, regardless of 
relationship”. 
Updated per current safety 
requirements for efgartigimod. 
Section 7.2, Participant 
Discontinuation/Withdrawal 
from the Study 
Updated to clarify that if a participant 
withdraws consent to participate in future 
research, data collected up to that point 
may be retained and used for the results of 
the study. 
Wording updated to clarify the 
intended process. 
Change of process from “participants 
withdrawing from the study can request 
the destruction of collected untested 
samples” to “samples collected from 
participants who have withdrawn from the 
study will be used for the study results but 
not for future research”. 
Updated for clarity around what 
use of samples are permitted or 
disallowed following patient 
withdrawal from the study. 
 
Removal of the following line:  
“Before withdrawing from the study, the 
participant will attend the EDV within 7 
Removed as visit attendance is 
not mandated following 
participant discontinuation or 
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Section # and Name 
Description of Change 
Brief Rationale 
days after their final IMP dose. The data 
collected at the EDV are specified in the 
Schedule of Activities (SoA) (Section 1.3). 
The SFV will occur within 56 days (± 3 
days) of the participant’s final IMP dose.” 
study withdrawal; EDV 
attendance following IMP 
discontinuation is captured in 
Section 7.1. 
Section 7.3, Lost to Follow-up 
Clarified that lost to follow-up items must 
be completed if a participant fails to 
complete a required study visit, rather than 
if a participant fails to attend a required 
study visit. 
Updated per current CSP template 
for consistency across the 
efgartigimod program. 
Added statement that participants who 
continue to be unreachable after attempts 
to regain contact will be recorded as lost to 
follow-up. 
Wording updated to clarify the 
intended process. 
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 8.3, Safety 
Assessments 
Clarified that new abnormal or worsened 
pre-existing conditions that the 
investigator considers clinically significant 
will be reported as an AE where observed 
after signing the informed consent form, 
rather than where observed after screening. 
Updated per current CSP template 
for consistency across the 
efgartigimod program. 
Section 8.4, Adverse Events, 
Serious Adverse Events, and 
Other Safety Reporting 
Text updated with the following changes: 
• Added “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.” 
• Removed “or the participant’s legally 
authorized representative” from the list 
of individuals who may report an AE 
on behalf of the patient. 
• Clarified that the investigator and 
qualified designees are responsible for 
monitoring all reported events, 
including those reported by the 
participant. 
Updated per current CSP template 
for consistency across the 
efgartigimod program. 
Section 8.4.5, Pregnancy 
Clarified that the pregnant female partner 
of a participant will be followed to 
determine the outcome of the pregnancy 
only where the pregnant female partner has 
consented to this.  
Wording updated to clarify the 
intended process. 
Section 8.4.6, Adverse Events 
of Special Interest 
Specified that AESIs will be reported 
according to the same timeframe as that 
for SAEs specified in Section 8.4.1 and 
Section 10.3.4. 
Wording added to clarify the 
intended process. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.4.7, AEs of Clinical 
Interest 
Addition of new section detailing AEs of 
clinical interest (infusion/injection-related 
reactions and injection site reaction). 
Updated per current CSP template 
for consistency across the 
efgartigimod program. 
Section 1.3, Schedule of 
activities 
Section 
 
Section 8.8.1.2, 
 
 
 
 
References to "plasma" samples are 
removed throughout the protocol. 
Corrected as no plasma samples 
will be taken. 
Section 10.4.2.2, Male 
Contraception 
Updated to remove male contraception 
requirements. 
Updated per current safety 
requirements for efgartigimod. 
Section 10.7, Appendix 7: 
Protocol Amendment History 
Addition of appendix to capture fprotocol 
amendment history prior to the current 
amendment. 
Added per CSP template 
requirements. 
 
No other changes were made during this protocol amendment. 
 
 
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TABLE OF CONTENTS 
SIGNATURE OF THE INVESTIGATOR ......................................................................................4 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................................................5 
LIST OF ABBREVIATIONS ........................................................................................................14 
1. 
PROTOCOL SUMMARY ..........................................................................................15 
1.1. 
Synopsis ......................................................................................................................15 
1.2. 
Schema ........................................................................................................................17 
1.3. 
Schedule of Activities .................................................................................................18 
2. 
INTRODUCTION ......................................................................................................22 
2.1. 
Study Rationale ...........................................................................................................22 
2.2. 
Background .................................................................................................................22 
2.3. 
Benefit/Risk Assessment ............................................................................................23 
2.3.1. 
Risk Assessment .........................................................................................................23 
2.3.2. 
Benefit Assessment .....................................................................................................24 
2.3.3. 
Overall Benefit-Risk Conclusion ................................................................................24 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ..................................................25 
4. 
STUDY DESIGN .......................................................................................................27 
4.1. 
Overall Design ............................................................................................................27 
4.2. 
Scientific Rationale for Study Design ........................................................................27 
4.3. 
Justification for Dose ..................................................................................................28 
4.4. 
End-of-Study Definition .............................................................................................28 
5. 
STUDY POPULATION .............................................................................................30 
5.1. 
Inclusion Criteria ........................................................................................................30 
5.2. 
Exclusion Criteria .......................................................................................................31 
5.3. 
Lifestyle Considerations .............................................................................................32 
5.3.1. 
Meals and Dietary Restrictions ...................................................................................32 
5.3.2. 
Caffeine, Alcohol, and Tobacco .................................................................................32 
5.3.3. 
Activity .......................................................................................................................32 
5.4. 
Screen Failures ............................................................................................................32 
5.5. 
Criteria for Temporarily Delaying Enrollment ...........................................................33 
6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ........................34 
6.1. 
Study Intervention(s) Administered ...........................................................................34 
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6.2. 
Preparation, Handling, Storage, and Accountability ..................................................34 
6.3. 
Assignment to Study Intervention ..............................................................................35 
6.4. 
Blinding ......................................................................................................................35 
6.5. 
Study Compliance .......................................................................................................35 
6.6. 
Dose Modification ......................................................................................................36 
6.7. 
Continued Access to IMP After the End of the Study ................................................36 
6.8. 
Treatment of Overdose ...............................................................................................36 
6.9. 
Prior and Concomitant Therapy ..................................................................................36 
6.9.1. 
Prohibited Medication ................................................................................................36 
7. 
IMP DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................38 
7.1. 
IMP Discontinuation ...................................................................................................38 
7.1.1. 
Permanent Discontinuation .........................................................................................38 
7.1.2. 
Temporary Discontinuation ........................................................................................38 
7.2. 
Participant Discontinuation/Withdrawal from the Study ...........................................39 
7.3. 
Lost to Follow-up .......................................................................................................39 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................40 
8.1. 
Administrative and General/Baseline Procedures ......................................................40 
8.1.1. 
Screening ....................................................................................................................40 
8.1.2. 
Use and Storage of Blood Samples ............................................................................41 
8.2. 
Efficacy Assessments .................................................................................................41 
8.2.1. 
Questionnaires ............................................................................................................41 
8.2.1.1. 
COMPASS 31 .............................................................................................................41 
8.2.1.2. 
MaPS...........................................................................................................................41 
8.2.1.3. 
PGI-S and PGI-C ........................................................................................................42 
8.2.1.4. 
PROMIS .....................................................................................................................42 
8.2.1.5. 
Exit Interview .............................................................................................................42 
8.2.2. 
42 
8.2.3. 
 .................................................................................43 
8.2.4. 
 ....................................................................................43 
8.3. 
Safety Assessments .....................................................................................................43 
8.3.1. 
Physical Examinations ................................................................................................44 
8.3.2. 
Vital Signs ..................................................................................................................44 
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8.3.3. 
Electrocardiograms .....................................................................................................44 
8.3.4. 
Clinical Safety 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 
8.4.3. 
Follow-up of AEs and SAEs .......................................................................................45 
8.4.4. 
Regulatory Reporting Requirements for SAEs ...........................................................45 
8.4.5. 
Pregnancy ...................................................................................................................46 
8.4.6. 
Adverse Events of Special Interest .............................................................................46 
8.4.7. 
AEs of Clinical Interest ..............................................................................................47 
8.4.7.1. 
Infusion/Injection-Related Reactions .........................................................................47 
8.4.7.2. 
Injection Site Reaction ................................................................................................47 
8.5. 
Pharmacokinetics ........................................................................................................47 
8.6. 
Pharmacodynamics .....................................................................................................48 
8.7. 
Genetics ......................................................................................................................48 
8.8. 
Biomarkers ..................................................................................................................48 
8.8.1. 
 .............................................................................................48 
8.8.1.1. 
 ................................................48 
8.8.1.2. 
 ............48 
8.8.1.3. 
 .....................................................................................49 
8.9. 
Immunogenicity Assessments ....................................................................................49 
8.10. 
Health Economics or Medical Resource Utilization and Health Economics .............49 
8.10.1. 
49 
8.10.2. 
50 
9. 
STATISTICAL CONSIDERATIONS .......................................................................51 
9.1. 
Statistical Hypothesis ..................................................................................................51 
9.2. 
Analysis Sets ...............................................................................................................51 
9.3. 
Statistical Analyses .....................................................................................................51 
9.3.1. 
General Considerations ...............................................................................................51 
9.4. 
Interim Analysis ..........................................................................................................52 
9.5. 
Sample Size Determination ........................................................................................52 
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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. 
Data Protection ...........................................................................................................54 
10.1.5. 
Data Safety Monitoring Board ....................................................................................54 
10.1.6. 
Dissemination of Clinical Study Data ........................................................................55 
10.1.7. 
Data Quality Assurance ..............................................................................................55 
10.1.7.1. 
Data Handling and Record-Keeping ...........................................................................55 
10.1.7.2. 
Quality Assurance Audit .............................................................................................56 
10.1.7.3. 
Quality Control ...........................................................................................................56 
10.1.8. 
Source Documents ......................................................................................................57 
10.1.9. 
Monitoring ..................................................................................................................57 
10.1.10. 
Data Management .......................................................................................................58 
10.1.11. 
Study and Site Start and Closure ................................................................................59 
10.1.12. 
Investigator Obligations ..............................................................................................60 
10.1.13. 
Protocol Signatures .....................................................................................................60 
10.1.14. 
Publication Policy .......................................................................................................60 
10.2. 
Appendix 2: Clinical Laboratory Tests .......................................................................62 
10.2.1. 
Other Screening Tests .................................................................................................62 
10.2.1.1. 
SARS-CoV-2 ..............................................................................................................62 
10.2.1.2. 
Hepatitis B Virus ........................................................................................................63 
10.2.1.3. 
Hepatitis C Virus ........................................................................................................63 
10.2.1.4. 
Human Immunodeficiency Virus ...............................................................................63 
10.3. 
Appendix 3: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow up, and Reporting ........................................................................64 
10.3.1. 
Definition of AE .........................................................................................................64 
10.3.2. 
Definition of SAE .......................................................................................................65 
10.3.3. 
Recording and Follow Up of AE and/or SAE ............................................................65 
10.3.4. 
Reporting of SAEs and AESIs ....................................................................................67 
10.4. 
Appendix 4: Contraceptive and Barrier Guidance ......................................................68 
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10.4.1. 
Women of Childbearing Potential Definition .............................................................68 
10.4.2. 
Contraception Guidance .............................................................................................68 
10.4.2.1. 
Female Contraception for Women of Childbearing Potential ....................................68 
10.4.2.2. 
Male Contraception ....................................................................................................69 
10.5. 
Appendix 5: Operational Considerations for COVID-19 Risk Mitigation .................70 
10.5.1. 
Testing for COVID-19 ................................................................................................70 
10.5.2. 
Critical Parameters to Be Collected During the Study ...............................................70 
10.5.3. 
Mandatory Site Visits .................................................................................................70 
10.6. 
Appendix 6 Home Study Visits ..................................................................................71 
10.7. 
Appendix 7: Protocol Amendment History ................................................................72 
11. 
REFERENCES ...........................................................................................................79 
 
LIST OF TABLES 
Table 1: 
Study Intervention(s) Administered ...........................................................................34 
Table 2: 
Protocol-Required Laboratory Tests...........................................................................62 
Table 3: 
Interpretation of Hepatitis B Serological Test Results ...............................................63 
Table 4: 
Interpretation of the Hepatitis C Antibody Test .........................................................63 
 
LIST OF FIGURES 
Figure 1: 
ARGX-113-2104 Study Overview .............................................................................17 
 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Expansion 
 
 
ADA 
antidrug antibody(ies) 
AE 
adverse events 
COMPASS 31 
Composite Autonomic Symptom Score 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
EDC 
electronic data capture 
EDV 
early discontinuation visit 
FcRn 
neonatal Fc receptor 
IgG 
immunoglobulin G 
NCI 
National Cancer Institute 
MaPS 
Malmö POTS symptom score 
OLE 
open-label extension 
PD 
pharmacodynamic(s) 
PGI-C 
Patient Global Impression – Change 
PGI-S 
Patient Global Impression – Severity 
PK 
pharmacokinetic(s) 
PLEX 
plasma exchange 
POTS 
postural orthostatic tachycardia syndrome 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
 
 
SC 
subcutaneous 
SFV 
safety follow-up visit 
SoA 
schedule of activities 
WOCBP 
women of childbearing potential 
 
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• Assess the pharmacodynamic (PD) 
effect of efgartigimod  
• Absolute values, changes from baseline, and 
percent reduction from baseline in total IgG 
levels 
• Assess the pharmacokinetic (PK) profile 
of efgartigimod 
• Efgartigimod serum concentration-time profile 
• Assess the immunogenicity of 
efgartigimod 
• Incidence and prevalence of antidrug antibodies 
(ADA) against efgartigimod 
Overall Design Synopsis: 
This phase 2 study is a randomized, double-blinded, placebo-controlled, parallel-group study in 
participants with post–COVID-19 POTS. 
The sponsor/designee, investigator, and participant are blinded to investigational medicinal 
product (IMP) treatment assignment. 
Brief Summary: 
This study aims to evaluate the efficacy and safety of weekly infusions of efgartigimod IV 
10 mg/kg compared to matched-placebo IV in adult participants with post–COVID-19 POTS. 
After an up to 28-day screening period, eligible participants will be randomized to efgartigimod 
IV 10 mg/kg or placebo in a 2:1 ratio, respectively, at baseline. IMP will be administered weekly 
during the 24-week randomized treatment period. At the end of the randomized treatment period, 
eligible participants may roll over into an open-label extension (OLE) study ARGX-113-2105 or 
remain in this study through the end of the 56-day follow-up period.  
Number of Participants: 
Approximately 42 participants will be randomized to IMP (efgartigimod IV 10 mg/kg or 
placebo). 
Note: Enrolled means the participant agrees to participate in the clinical study after completing 
the informed consent process.  
Study Arms and Duration: 
Each participant will participate in the following study periods: 
• Screening period of approximately 4 weeks 
• Treatment period of 24 weeks  
• Follow-up period of approximately 8 weeks (56 days ± 3 days) for participants who 
do not roll over to the OLE study ARGX-113-2105 
Participants will receive IMP weekly during the 24-week treatment period, with the final weekly 
dose administered at week 23. 
Data Monitoring/Other Committee: No 
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1.2. 
Schema 
Figure 1: 
ARGX-113-2104 Study Overview 
42 participants 
randomized in a 2:1 
ratio to efgartigimod IV 
or placebo, respectively
Efgartigimod IV 10 mg/kg
Placebo
24-week treatment period
weekly infusions 
up to 4 weeks
Screening 
and baseline
56 ±3-day
follow-up or
roll over to
OLE study
ARGX-113-2105
 
IV=intravenous; OLE=open-label extension
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1.3. 
Schedule of Activities 
 
SCN 
Study week 
SFV 
Applicable 
protocol 
section(s) 
BL 
1 
2 
3 
4 
5-7 
8 
9-11 
12 
13-
17 
18 
19-
23 
24 
IDVa 
EDVb 
Study day (±2) 
-28  
to -1 
1c 
8 
15 
22 
29 
36-
50 
57 
64-
78 
85 
92-
120 
127 
134-
162 
169 
 
 
218d 
All activities (safety and efficacy assessments, predose blood sampling) will be completed before administering the IMP infusion. 
Visits that must be attended on-site are SCN, BL, W1, W2, W4, W12, W24, IDV, EDV, and SFV 
Eligibility/BL only 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 10.1.3  
SARS-CoV-2 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.2 
HIV/HBV/HCV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.2  
FSH test f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 10.4.1  
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Active stand test (HR 
on 10-minute stand) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.1.1 
Eligibility check 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.1 
Section 5.2  
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 6.3 
Questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
COMPASS 31 
(original) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.2.1 
COMPASS 31 
(modified) 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
Section 8.2.1 
MaPS 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
 
Section 8.2.1.2 
PGI-S, PGI-C 
 
Xg 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
 
Section 8.2.1.3 
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SCN 
Study week 
SFV 
Applicable 
protocol 
section(s) 
BL 
1 
2 
3 
4 
5-7 
8 
9-11 
12 
13-
17 
18 
19-
23 
24 
IDVa 
EDVb 
Study day (±2) 
-28  
to -1 
1c 
8 
15 
22 
29 
36-
50 
57 
64-
78 
85 
92-
120 
127 
134-
162 
169 
 
 
218d 
All activities (safety and efficacy assessments, predose blood sampling) will be completed before administering the IMP infusion. 
Visits that must be attended on-site are SCN, BL, W1, W2, W4, W12, W24, IDV, EDV, and SFV 
PROMIS Fatigue 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
Section 8.2.1.4  
 
PROMIS Cognition 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
Section 8.2.1.4  
 
Exit interview 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xh 
 
 
 
Section 8.2.1.5  
Efficacy testsi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety except 
reviews 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationk 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Section 8.3.1  
Weight/heightl 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Section 6.1  
Section 8.3.1  
Vital sign 
measurements m 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Section 8.3.2  
ECGn 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Section 8.3.3  
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SCN 
Study week 
SFV 
Applicable 
protocol 
section(s) 
BL 
1 
2 
3 
4 
5-7 
8 
9-11 
12 
13-
17 
18 
19-
23 
24 
IDVa 
EDVb 
Study day (±2) 
-28  
to -1 
1c 
8 
15 
22 
29 
36-
50 
57 
64-
78 
85 
92-
120 
127 
134-
162 
169 
 
 
218d 
All activities (safety and efficacy assessments, predose blood sampling) will be completed before administering the IMP infusion. 
Visits that must be attended on-site are SCN, BL, W1, W2, W4, W12, W24, IDV, EDV, and SFV 
TSH/CRP/ESR 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Table 2 
Serum chemistry and 
hematology 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
Section 8.3.4 
Table 2 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
 
Table 2  
Pregnancy testo 
X 
X 
 
 
 
X 
 
X 
 
X 
W1
6 
 
W2
0 
X 
X 
X 
X 
Section 8.3.5 
Section 8.4.5 
Blood sampling 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.1.2 
PK profilep 
 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
 
Section 8.5 
PD profileq 
X 
X 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Section 8.6  
 
 
 
 
AE review 
Continuous monitoring 
Section 8.4 
Conmed review 
Continuous monitoring 
Section 6.9 
IMP infusion 
 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Section 6 
ADA=antidrug antibodies; AE=adverse event; BL=baseline; COMPASS=composite autonomic symptom score; 
Conmed=concomitant medications; CRP=C-reactive protein; ECG=electrocardiogram; EDV=early discontinuation visit; ESR=erythrocyte sedimentation rate; 
FSH=follicle-stimulating hormone; 
; HBV=hepatitis B virus; HCV=hepatitis C virus; HR=heart rate; IDV=IMP discontinuation visit; 
IMP=investigational medicinal product; PCR=polymerase chain reaction; PD=pharmacodynamics; PGI-C=Patient Global Impression–Change; PGI-S=Patient 
Global Impression–Severity; PK=pharmacokinetics; POTS=postural orthostatic tachycardia syndrome; PROMIS=Patient-Reported Outcomes Measurement 
Information System; SCN=screening; SFV=safety follow-up visit; TSH=thyroid stimulating hormone; WOCBP=women of childbearing potential 
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a The IDV will be performed at the next scheduled visit after permanent IMP discontinuation and applies for participants who discontinue IMP but remain in the 
study. Participants who permanently discontinue IMP will perform the IDV and then be asked to proceed with their regularly scheduled visits (Section 7.1). 
b Within 7 days after last dose of IMP. The EDV applies for participants who discontinue the study. 
c The first infusion of IMP will occur only once all BL assessments have been completed. 
d Participants will attend an SFV unless rolling over into the OLE study ARGX-113-2105. For participants who discontinue IMP but remain in the study 
attending on-site visits, safety assessments will occur on the previously scheduled visit closer to 56 days (±3 days) from the last IMP dose. 
e A positive PCR test for SARS-CoV-2 during screening is exclusionary for study participation (Section 5.2, exclusion criterion 6). 
f FSH will be measured in postmenopausal women during screening to confirm their postmenopausal state. The investigator will assess the postmenopausal state 
in postmenopausal women receiving hormonal therapy. Tests may be analyzed at a local or a central laboratory. 
g The participant will complete only the PGI-S and not the PGI-C at BL. 
h The participant’s perspective on the questionnaires administered during the study will be captured in an optional exit interview. The interview can be conducted 
after EDV for participants who prematurely discontinue the study. 
i These assessments may be performed on the day before the scheduled time point. 
j Eligibility is based on a change in orthostatic HR with either active stand testing or head-up tilt testing, consistent with consensus criteria (Section 5.1, 
inclusion criterion 3.a). Participants who do not meet this criterion with active stand testing may be reevaluated using the head-up tilt test to confirm eligibility 
during the screening period. 
k The physical examination will comprise a full assessment of systems at screening and a brief assessment at all other time points. See Section 8.3.1 for specific 
parameters. 
l Height will be measured only at screening. 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. 
m Vital signs will be measured before collecting any blood sample or administering IMP infusions. Vital sign parameters are listed in Section 8.3.2. 
n On days when ECGs are performed, this will be the first assessment of the day. 
o WOCBP will be tested for pregnancy by serum at screening and urine on day 1 (BL) and during the study, including the follow-up period. 
p At IMP administration visits, blood for PK analyses will be collected predose (within 2 hours before the infusion) and postdose (within 30 minutes after the end 
of the infusion). At other visits, blood samples may be collected at any time during that visit. Blood samples for participants remaining in the study following 
IMP discontinuation will be collected for up to 3 weeks post IMP discontinuation for PK analysis. 
q At IMP administration visits, blood for PD, immunogenicity, and biomarker analyses will be collected predose (within the 2 hours before IMP infusion). At 
other visits, blood samples may be collected at any time during that visit. 
 
 
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2. 
INTRODUCTION 
The study aims to investigate the safety, tolerability, efficacy, pharmacodynamics (PD), 
pharmacokinetics (PK), and immunogenicity of efgartigimod compared to placebo in 
participants with post–COVID-19 postural orthostatic tachycardia syndrome (POTS)  
(post–COVID-19 POTS). 
2.1. 
Study Rationale 
Efgartigimod is a first-in-class antibody fragment that binds to the neonatal Fc receptor (FcRn). 
This binding prevents FcRn from recycling immunoglobulin G (IgG) and leads to a reduction in 
circulating disease-causing autoantibodies. Approved by the Food and Drug Administration 
(FDA) in the US for use in adult patients with acetylcholine receptor (AChR) antibody-positive 
generalized myasthenia gravis (gMG) efgartigimod is being clinically developed in other 
autoimmune diseases mediated by pathogenic IgG autoantibodies.  
Efgartigimod may be a viable treatment option for individuals diagnosed with post–COVID-19 
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. 
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 heart rate [HR] increment of not 
less than 30 beats/minute [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, with rapid improvement upon return to a supine position; 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 post–COVID-19 POTS. 
Currently, the underlying pathophysiology and effective treatments are unknown for post–
COVID-19 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 have a higher prevalence of autoantibodies, including ganglionic AChR antibody 
G-protein coupled receptor (GPCR) antibodies, which could increase sympathetic tone by 
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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 post–COVID-19 POTS could be caused by IgG 
autoantibodies that induce autonomic dysfunction. The aim of this phase 2 study is to evaluate if 
efgartigimod is safe and efficacious in treating the autonomic symptoms and clinical 
manifestations of autonomic dysfunction in patients diagnosed with POTS after COVID-19.  
A detailed description of the chemistry, pharmacology, efficacy, and safety of efgartigimod is 
provided in the Investigator’s Brochure (IB).  
2.3. 
Benefit/Risk Assessment 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of efgartigimod may be found 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 infection risk. 
Exclude participants with 
clinically significant uncontrolled 
infections, malignancies, or 
certain viral infections 
(Section 5.2). 
Monitor for infections, considered 
an AE of special interest (AESI) 
(Section 8.4.6), and temporarily 
interrupt IMP dosing as specified 
in Section 7.1.2. 
Infusion-related 
reactions (IRR) 
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/injection-
related reactions. 
Infusion/injection-related 
reactions are considered AEs of 
clinical interest (Section 8.4.7). 
Infusion/injection-
site reactions 
Most AEs have been mild, transient 
injection site reactions, including 
erythema, pain, bruising, pruritus, 
burning, tenderness, edema, induration, 
Continuously monitor participants 
for injection site reactions. 
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Potential clinically 
significant risk  
Summary of data/rationale for risk 
Mitigation strategy 
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. 
Infusion/injection-site reactions 
are considered AEs of clinical 
interest (Section 8.4.7). 
2.3.2. 
Benefit Assessment 
Efgartigimod has been investigated in nonclinical studies, phase 1 clinical pharmacology studies 
in healthy subjects, and phase 2-3 clinical studies in patients with IgG-driven autoimmune 
diseases, including gMG, primary immune thrombocytopenia (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 post–COVID-19 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 post–COVID-19 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 post–COVID-19 
POTS. 
Detailed information is provided in the efgartigimod IB on the known and expected benefits and 
risks and reasonably expected AEs from efgartigimod clinical studies.
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a randomized, double-blinded, placebo-controlled, parallel-group, phase 2 study. 
The total study duration is approximately 36 weeks comprising: 
• Screening period of approximately 4 weeks 
• Treatment period of 24 weeks  
• Follow-up period of approximately 8 weeks (56 days ± 3 days) for participants who 
do not roll over to the open-label extension (OLE) study ARGX-113-2105 
The study population is adult patients with new-onset POTS post–COVID-19. 
Participants will be randomized to receive efgartigimod IV 10 mg/kg or matching placebo in a 
2:1 ratio, respectively. 
IMP (efgartigimod or matching placebo) will be administered during the treatment period in an 
approximately 1-hour IV infusion once weekly by site staff or a home nurse. The final dose will 
be administered at week 23. 
At week 24, eligible participants may roll over into a single-arm OLE ARGX-113-2105.  
4.2. 
Scientific Rationale for Study Design 
This study aims to evaluate the efficacy and safety of weekly infusions of efgartigimod IV 
10 mg/kg compared to matched-placebo IV in adult participants with post–COVID-19 POTS. 
The study design is randomized, double-blinded, and placebo-controlled to evaluate the effect of 
efgartigimod administered as an IV infusion compared to placebo. The study consists of a 
treatment period when all participants will receive weekly IV infusions for 24 weeks. As there 
are no standardized approved therapies for post–COVID-19 POTS, the comparison to placebo is 
justified. 
The primary endpoints are the safety and tolerability of efgartigimod in participants with 
post-COVID-19 POTS and efficacy as assessed by change from baseline to week 24 in 
COMPASS 31 (2-week recall version) and the MaPS. Safety and tolerability are included as a 
primary endpoint as efgartigimod has not been previously administered in this patient 
population.  
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).  
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). 
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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 (A. Fedorowski, unpublished data, 2022). 
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 secondary 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  
4.3. 
Justification for Dose 
Weekly doses of efgartigimod IV 10 mg/kg will be administered to achieve a maximal total IgG 
reduction (PD effect), thereby ensuring maximal clinical response on the efficacy outcomes. 
As the hypothesis for treating post–COVID-19 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). Considering the chronic nature of post–COVID-19 
POTS, the dosing regimen of weekly IV administration 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 weekly (q7d) through IV 
infusion achieved approximately 70% IgG reduction, including pathogenic autoantibodies. 
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 weekly IV dose regimen 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 treatment period (or follow-up period, if 
applicable) has been completed.  
Participants rolling over to the OLE study ARGX-113-2105 will have completed this study at 
week 24. 
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Participants not rolling over to the OLE study ARGX-113-2105 will have completed this study 
after the safety follow-up visit (SFV) or early discontinuation visit (EDV). If a participant 
continues in the study after discontinuing IMP, this will be week 23 or at the SFV (if permanent 
IMP discontinuation is <56 days from week 23). 
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5. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Reached the age of consent when signing the informed consent form 
2. Capable of providing signed informed consent, as described in Section 10.1.3, and 
complying with protocol requirements 
3. Diagnosed with new-onset POTS post–COVID-19 established by the following:  
a. History of COVID-19 based on a previous positive test result from either 
laboratory-confirmed COVID-19 test (eg, a PCR test) or non-laboratory-confirmed 
COVID-19  test (eg, rapid antigen test); this positive result may be either documented 
or patient-reported 
b. Tilt table or orthostatic vital sign measurements during screening consistent with 
consensus criteria: sustained HR increase of ≥30 bpm within 10 min of standing or 
head-up tilt (≥40 bpm for individuals aged 18 to 19 years) and/or HR reaching 
>120 bpm within 10 min; absence of sustained 20 mmHg decrease in systolic blood 
pressure (SBP) 
c. Ongoing symptoms of POTS confirmed by the investigator with at least 3 symptoms 
in each of the following areas lasting longer than 12 weeks after either diagnosis of 
COVID-19 or after hospital discharge for COVID-19: 
i. 
Vasomotor symptoms: fatigue, orthostatic intolerance, brain fog, exertional 
dyspnea, difficulty with concentration, venous pooling, and exercise 
intolerance 
ii. 
Sympathetic over-compensation symptoms: palpitation, heat intolerance, 
nausea with or without vomiting, insomnia, anxiety, lack of appetite, chest 
pain, and diaphoresis 
4. COMPASS 31 ≥35 at screening 
5. Agree to use contraceptives consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies and the following: 
Male participants: see Section 10.4.2.2 
Female participants of childbearing potential (defined in Section 10.4.1) must have a 
negative serum pregnancy test at screening and a negative urine pregnancy test at 
baseline before receiving IMP. Contraceptive requirements are provided in 
Section 10.4.2.1. 
6. Body mass index (BMI) <35 kg/m2 
 
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5.2. 
Exclusion Criteria  
Participants will be excluded from the study if any of the following criteria apply: 
1. Diagnosis of or receiving treatment for the following conditions before COVID-19: 
peripheral neuropathy, POTS, myalgic encephalomyelitis encephalitis/chronic fatigue 
syndrome, Ehlers Danlos syndrome confirmed by genetic testing, autonomic neuropathy, 
multiple sclerosis, stroke, spinal cord injury, or any known lesions in the central nervous 
system by imaging or neurological exam 
2. History of or currently being treated for clinically significant ongoing cardiac arrythmia, 
heart failure, myocarditis, pulmonary embolism requiring anticoagulation, pulmonary 
fibrosis, or critical illness-related polyneuropathy or myopathy 
3. Known autoimmune disease that, in the investigator’s judgment, would interfere with an 
accurate assessment of clinical symptoms of post–COVID-19 POTS or puts the 
participant at undue risk 
4. Known HIV disease or common variable immunodeficiency 
5. History of malignancy unless considered cured by adequate treatment with no evidence 
of recurrence for ≥3 years before the first administration of IMP. Adequately-treated 
participants with the following cancers may be included at any time: 
a. Basal cell or squamous cell skin cancer 
b. Carcinoma in situ of the cervix 
c. Carcinoma in situ of the breast 
d. Incidental histological finding of prostate cancer (TNM stage T1a or T1b) 
6. Clinically significant uncontrolled active or chronic bacterial, viral, or fungal infection or 
positive SARS-CoV-2 PCR test at screening 
7. Positive serum test at screening for an active infection with any of the following: 
a. Hepatitis B virus (HBV) that is indicative of an acute or chronic infection, unless 
associated with a negative HB surface antigen (HBsAg) or negative HBV DNA test 
b. Hepatitis C virus (HCV) based on HCV antibody assay unless a negative RNA test is 
available 
c. HIV 
8. A medical condition that could confound the results of the study or put the participant at 
undue risk in the investigator’s judgment 
9. Clinically significant disease, recent major surgery (within 3 months of screening), or 
intends to have surgery during the study; or any other condition that in the opinion of the 
investigator could confound the results of the study or put the participant at undue risk 
10. Total IgG <4 g/L at screening 
11. Received within 12 weeks or 5 half-lives (whichever is longer) before screening an 
investigational product  
12. Received within 12 weeks before screening either intravenous immunoglobulin (Ig) IV or 
SC or plasma exchange (PLEX)  
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13. Received a live or live-attenuated vaccine less than 4 weeks before screening 
14. Known hypersensitivity to IMP or 1 of its excipients 
15. Previously participated in an efgartigimod clinical study and received at least 1 dose of 
IMP 
16. Currently participating in another interventional clinical study 
17. History (within 12 months of screening) of or current alcohol, drug, or medication abuse 
18. Pregnant or lactating or intends to become pregnant during the study 
19. Unwilling to remain on a stable regimen of medications during the study 
20. Unwilling to avoid initiation of new physical rehabilitation or other physician-prescribed 
exercise programs during the 24-week treatment period 
5.3. 
Lifestyle Considerations 
5.3.1. 
Meals and Dietary Restrictions 
No restrictions apply. 
5.3.2. 
Caffeine, Alcohol, and Tobacco 
No restrictions apply except for those described in the exclusion criteria (Section 5.2, exclusion 
criterion 17). 
5.3.3. 
Activity 
Participants will not initiate a new physical rehabilitation or other physician-prescribed exercise 
programs during the 24-week treatment period (See Section 5.2, exclusion criterion 20). 
5.4. 
Screen Failures 
A screen failure occurs when a participant who has signed the ICF is not assigned to IMP. A 
minimal set of screen failure information (demography, screen failure details, eligibility criteria, 
SAE reports) is required to ensure transparent reporting of screen failure participants and address 
regulatory authority queries.  
• Retesting: Participants with exclusionary clinical laboratory results, ECGs, vital sign 
measurements, etc that are inconsistent with their medical history or clinical 
evaluation, can be retested once within the remaining screening period to confirm the 
test value(s).  
• Rescreening: Participants who do not initially meet this study’s eligibility criteria can 
be rescreened once. For example, a participant who does not meet eligibility criteria 
because of an acute illness ongoing during screening (considering the illness itself 
does not violate inclusion/exclusion criteria), they can be rescreened once the illness 
is resolved or the medical issue stabilized. Rescreened participants will be 
reconsented and assigned a new participant number for each rescreening event. 
 
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5.5. 
Criteria for Temporarily Delaying Enrollment 
Not applicable. 
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6. 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY 
IMP includes efgartigimod and placebo. All IMPs are manufactured according to Good 
Manufacturing Practice regulations. 
6.1. 
Study Intervention(s) Administered 
Table 1: 
Study Intervention(s) Administered 
Intervention label 
Efgartigimod IV 
Placebo 
Intervention name 
Efgartigimod IV 
Placebo 
Intervention description 
Sterile, colorless, clear concentrate 
solution for intravenous infusion 
efgartigimod 20 mg/mL, 
administered IV 
Sterile, colorless, clear concentrate 
solution for infusion, with the 
same excipients as efgartigimod 
IV, but without the active 
ingredient (efgartigimod) 
Type  
Biologic 
Placebo 
Dose formulation 
Infusion 
Infusion 
Unit dose strength(s) 
20 mg/mL 
Not applicable 
Dosage level(s) 
10 mg/kg qw ×24 weeks 
Not applicable 
Route of administration 
IV infusion 
IV infusion 
Use 
Experimental 
Placebo-comparator 
IMP and NIMP/AxMP 
IMP 
IMP 
Sourcing 
Centrally by the sponsor/designee 
Centrally by the sponsor/designee 
Packaging and labeling 
IMP will be provided in glass 
vials. Each vial will be labeled as 
required per country requirements. 
IMP will be provided in glass 
vials. Each vial will be labeled as 
required per country requirements. 
Former name 
ARGX-113 
Not applicable 
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. 
6.2. 
Preparation, Handling, Storage, and Accountability 
The IMP will be supplied to the investigational site by the sponsor/designees’ designated IMP 
supply vendor.  
Appropriate dilutions in a 0.9% saline solution in an infusion bag will be prepared before 
administration with an IV pump. 
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) 
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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. 
Only participants enrolled in the study may receive IMP, and only authorized site staff or 
designee may supply or administer IMP.  
At a minimum, the first 3 doses of IMP must be administered on-site. These doses are scheduled 
to be administered at the baseline visit and the week 1 and 2 visits, but 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. 
Participants will be observed for at least 30 minutes after the end of the 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 
Participants whose eligibility has been confirmed will be randomized using interactive response 
technology (IRT) in a 2:1 ratio to efgartigimod or placebo, respectively. The preplanned 
randomization list will be produced using permuted blocks. 
6.4. 
Blinding 
This is a double-blinded study. The IRT will be programmed with blind-breaking instructions. In 
case of an emergency, the investigator is solely responsible for determining if unblinding of the 
IMP assignment is necessary. Participant safety must always be the first consideration in making 
such a determination.  
If the investigator decides that unblinding is warranted, the investigator can contact the sponsor 
before unblinding a participant’s IMP unless this could delay emergency treatment for the 
participant. If a participant’s IMP assignment has been unblinded, the sponsor must be notified 
within 24 hours of this occurrence. The date and reason for the unblinding must be recorded in 
the source documents. 
6.5. 
Study Compliance 
Under medical supervision, participants will receive IMP directly from the site staff or delegate. 
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.  
Any participant who misses a scheduled dose (±2 days) will wait to receive the next scheduled 
dose (see Section 1.3). 
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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. 
6.7. 
Continued Access to IMP After the End of the Study 
At the end of the study, eligible participants may enroll in the OLE study ARGX-113-2105 and 
receive open-label efgartigimod. 
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/designee does not recommend specific treatment for an overdose.  
In the event of an overdose, the investigator will: 
• Contact the medical monitor (MM) immediately 
• Evaluate the participant to determine if IMP should be interrupted in consultation 
with the MM 
• Closely monitor the participant for any AE/SAE and laboratory abnormalities 
Document the quantity of the excess dose and the overdose duration and report any AE/SAE that 
occurred in association with the overdose.  
6.9. 
Prior and Concomitant Therapy 
Participants should 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 screening 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: 
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• Subcutaneous or intravenous immunoglobulin 
• PLEX 
• 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. 
IMP DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
Discontinuation of specific sites or the entire study is described in Appendix 1 (Section 10.1). 
7.1. 
IMP Discontinuation 
7.1.1. 
Permanent Discontinuation 
Permanent discontinuation of IMP occurs when the participant stops receiving IMP before the 
end of the study and does not resume receiving IMP. The participant also must not have 
withdrawn informed consent. 
The investigator will document the primary reason for early discontinuation of IMP. 
Participants who permanently discontinue IMP will be encouraged to remain in the study and 
attend any previously scheduled visits, even if only by telephone. Participants unwilling to 
participate in on-site visits for AE and concomitant medication monitoring will be offered the 
option to attend these visits by web teleconferencing or telephone. If the participant cannot 
attend the previously scheduled visits for any reason, the study site will minimally perform the 
EDV and the SFV on-site. 
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: 
• Participant becomes pregnant or intends to become pregnant (refer to Section 8.3.5) 
• Investigator decides that discontinuing IMP is in the participant’s best interest (the 
sponsor will be informed)  
• Participant develops an SAE or AE that contraindicates further administration of IMP 
in the investigator’s opinion or an AE of National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) grade 4 that is considered 
related to IMP by the sponsor 
• Participant develops a new or recurrent malignancy except for basal cell carcinoma of 
the skin, regardless of relationship 
• The participant receives a prohibited medication or substance (Section 6.9.1) 
Participants permanently discontinuing IMP will be ineligible to roll over into the OLE study. 
7.1.2. 
Temporary Discontinuation 
Temporary discontinuation of IMP occurs when the participant discontinues receiving IMP 
before the end of the study and resumes once the cause for the discontinuation has been resolved. 
Reasons for temporary discontinuation may include an AE that meets the following criteria : 
• Any SAE considered related to IMP by the sponsor 
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• Clinically significant active infection considered related to the IMP by the sponsor 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
Study withdrawal is defined as the permanent cessation of further participation in any study 
assessment before its planned completion. 
The primary reason for permanent study withdrawal will be recorded. 
The following circumstances will result in permanent discontinuation and withdrawal from the 
study: 
• Participant withdrawal of consent 
• Sponsor request 
If the participant also withdraws consent to participate in future research, the sponsor can retain 
and continue to use any data collected before such consent was withdrawn.  
• Samples collected from participants who have withdrawn from the study will be used 
for the study results but not for future research. 
Participants withdrawn from the study will be ineligible to roll over into the OLE 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, and will be recorded as lost to follow-up.  
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers or 
exemptions are not allowed. 
Adherence to the study design requirements, including those specified in the SoA (Section 1.3), 
is essential and required for study conduct. 
Visits that must be attended on-site are SCN, BL, W1, W2, W4, W12, W24, IMP discontinuation 
visit, EDV, and SFV. All other visits may occur at the participant’s home (Appendix 6, 
Section 10.6)  
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria before randomization. The investigator will maintain a screening log 
to record details of all participants screened and confirm eligibility or record reasons for 
screening failure, as applicable. 
Operational considerations due to the COVID-19 pandemic are provided in Section 10.5. Per 
local health authority/ethics requirements, the sponsor/designee or the investigator may 
implement alternate strategies for participant visits, assessments, medication distribution, and 
monitoring. 
8.1. 
Administrative and General/Baseline Procedures 
All significant findings, surgeries, and pre-existing conditions (including allergies) present at 
screening will be reported. Complete information will be collected on medical and surgical 
history and concomitant medical conditions and specifying those ongoing at screening. 
Details collected as a part of the medical history must include but are not limited to all previous 
treatment/therapy for COVID-19 and post–COVID-19 POTS. 
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 except the postdose PK blood sample. 
All assessments will be completed before administering the IMP infusion. 
8.1.1. 
Screening 
Eligibility is based on a change in orthostatic HR with either active stand testing or head-up tilt 
testing, consistent with consensus criteria (Section 5.1, criterion 3.a) (Shelton).15,23 Participants 
who do not meet this criterion with active stand testing may be evaluated using the head-up tilt 
test to confirm eligibility during the screening period. In this case, investigators may direct the 
participant to withhold medications based on clinical judgment that could confound the head-up 
tilt test interpretation. The screening head-up tilt testing may occur on the same day as other 
screening assessments or another day during the screening period.  
Blood samples collected at the screening visit may be used to validate methods to measure 
efgartigimod, antibodies, and biomarkers. Participants must consent to their samples being used 
before such procedures are performed. 
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8.1.2. 
Use and Storage of Blood Samples 
Any samples remaining after the laboratory analyses as defined in the protocol have been 
completed may be stored for up to 15 years after the end of the study, in the laboratory or long 
term storage worldwide designated by the sponsor/designee or research partners for future 
additional medical, academic, or scientific research to address any scientific questions related to 
efgartigimod, FcRn biology, or POTS, unless this would not be allowed according to local 
regulations or the participant would not have agreed. 
8.2. 
Efficacy Assessments 
Time points for all efficacy assessments are provided in the SoA (Section 1.3). 
Questionnaires should be administered before any other study assessment and may be completed 
up to 1 day before the visit. 
Please see the Investigator Site File for instructions on administering these assessments. 
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 (ASP) 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 original version of COMPASS 31 (longer recall) will be administered at screening and the 
modified version (2-week recall) will be administered at baseline and all other time points. 
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 (A. Fedorowski, unpublished 
data, 2022). The score consists of 12 questions that assess symptom burden related (tachycardia, 
palpitations, dizziness, presyncope) and unrelated to orthostatic intolerance (GI symptoms, 
insomnia, concentration difficulties). 
Participants will grade their symptoms for the past 7 days using a visual analog scale (VAS) 
ranging from 0 (no symptoms) to 10 (worst possible). 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. 
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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 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. 
• 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. 
• 
 
 
 
 
 
 
8.2.1.5. 
Exit Interview 
Trained independent moderators will interview approximately 15 to 20 participants over the 
telephone within 14 days after the week 24 visit. Participants will respond to open-ended 
questions on their experience with post–COVID-19 POTS and provide their perspectives on the 
relevance, completeness, and comprehensibility of questionnaires implemented during the study. 
For participants who prematurely discontinue the study, the interview can be conducted after 
their EDV. 
Participation in the interview is optional. 
Further details will be provided in a separate interview manual. 
8.2.2. 
 
 
 
 
 
 
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8.2.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2.4. 
 
 
 
 
 
 
 
 
8.3. 
Safety Assessments 
Time points for all safety assessments are provided in the SoA (Section 1.3). Safety measures 
will be assessed before IMP infusion unless otherwise stated. 
At screening, clinically significant abnormalities in any safety assessment will be reported as 
medical history. New abnormal or worsened pre-existing conditions observed after signing the 
informed consent form that the investigator considers clinically significant will be reported as an 
AE. 
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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 calibrated 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. 
Clinical Safety 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 2) for the list of clinical laboratory tests to be performed and the SoA 
(Section 1.3) for the timing and frequency. 
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 by serum at screening. Urine tests for pregnancy will occur 
at the time points specified in the SoA (Section 1.3). 
Pregnancy testing in WOCBP will be conducted at the end of relevant systemic exposure (ie, at 
the SFV). 
Additional pregnancy testing may be performed as necessary by the investigator or required by 
local regulations to establish the absence of pregnancy at any time during the study. 
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8.4. 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting 
The definitions of AE and SAE 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 SoA 
(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 it 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. 
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 toward the safety of participants and the 
safety of a IMP under clinical investigation are met. 
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• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a 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 an investigator 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 suspected unexpected 
serious adverse reactions (SUSARs) to the relevant regulatory authorities and 
IEC/IRB, 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, if consented, the pregnant female partner of a participant), 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. 
• Any female participant who becomes pregnant during the study will discontinue IMP. 
8.4.6. 
Adverse Events of Special Interest 
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: 
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• 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 temporary 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. 
8.4.7.2. 
Injection Site Reaction 
An injection site reaction is any AE developing at the site of the injection. Localized injection 
site reactions were frequently observed in studies in which efgartigimod and PH20 were 
administered SC. The most frequently reported injection site reaction AEs were Injection site 
erythema, Injection site pain, and Injection site swelling.   
Any injection site reaction will be reported as an AE (Section 8.4). Certain types of local 
reactions may be photographed and shared with the sponsor for review and assessment.  
As a routine precaution, participants will be trained or observed closely by a trained health care 
professional for any potential injection-site reaction.  
Refer to the current IB for more information on injection site reactions. 
8.5. 
Pharmacokinetics 
Blood samples for PK analysis will be collected at the time points specified in the SoA 
(Section 1.3). At IMP administration visits, PK blood samples will be collected predose (within 
the 2 hours before IMP infusion) and postdose (within the 30 minutes after the end of the 
infusion). Samples collected after the end of infusion should be collected in the opposite arm 
from the arm used for IMP infusion. On other visits, a single blood sample will be collected as 
described in the SoA. Blood samples for participants remaining in the study following IMP 
discontinuation will be collected as per the SoA for up to 3 weeks post IMP discontinuation. 
Efgartigimod serum concentrations will be determined using a validated method. 
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8.6. 
Pharmacodynamics 
Blood samples for PD analysis will be collected at the time points specified in the SoA 
(Section 1.3). At IMP administration visits, PD blood samples will be collected predose (within 
the 2 hours before IMP infusion). At other visits, 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 study 
blind. 
8.7. 
Genetics 
Genetics will not be evaluated in this study. 
8.8. 
Biomarkers 
Serum and whole blood will be collected at the time points specified in the SoA (Section 1.3) to 
identify 
 At IMP 
administration visits, samples will be collected predose (within the 2 hours before IMP infusion). 
At other visits, blood samples may be collected at any time during that visit. 
 
  
8.8.1. 
 
The impact of efgartigimod treatment on
 will confirm the 
 
 
  
Specific analyses may include:  
• 
 
 
 
 
 
Procedures for collecting and shipping these samples are in the laboratory manual. 
8.8.1.1. 
 
 will be performed to determine changes in 
 
These 
 may include, but are not limited to, 
 
 Such 
 provide a 
 appropriate 
for 
. The serum 
 may be reported in the final CSR or separately. 
8.8.1.2. 
s 
 who 
have 
27 
 
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includes but may not be limited to 
 
These analyses may be reported in the final CSR or separately. 
8.8.1.3. 
 
 cells will be collected and isolated from whole blood, and a 
decision will be made at the end of the study as to whether these samples will be analyzed with 
. This will be done only if both 
 
 (Section 2.1). If so, results 
of 
 will be reported (separately from the final CSR). If they are not 
analyzed for this purpose, the samples will be retained for potential future research, per 
Section 8.1.2. 
 will be used to assess changes in 
 
 
 
. These analyses will help characterize the cellular pathological mechanism by 
investigating 
 
 
Further, such markers may eventually aid in designing innovative patient-centric, molecular 
pathology-driven clinical studies. 
8.9. 
Immunogenicity Assessments 
Blood samples to evaluate serum levels of ADAs to efgartigimod will be collected at the time 
points specified in the SoA (Section 1.3). At IMP administration visits, blood samples will be 
collected predose (within the 2 hours before IMP infusion). At other visits, 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. 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 
8.10.1. 
 
 
 
 
 
 
 
 
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8.10.2. 
 
 
 
 
 
 
 
 
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9. 
STATISTICAL CONSIDERATIONS 
The statistical analysis plan (SAP) will be completed before 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 study. Primary endpoints COMPASS 31 and 
Malmö POTS will be analyzed using longitudinal mixed model repeated measures using the 
change from baseline as the response value. Prognostic variables are baseline and visit by 
treatment interaction using an unstructured variance covariance matrix. The treatment effect and 
95% CIs will be estimated at week 24 using an appropriate contrast. Inference will be based on 
the precision of the estimation rather than hypothesis testing. 
9.2. 
Analysis Sets 
The following analysis sets are defined: 
Participant Analysis Set 
Description 
Full analysis set 
All randomized participants 
Safety analysis set 
All participants exposed to IMP 
The full analysis set will be used to analyze endpoints related to the efficacy objectives, and the 
safety analysis set will be used to analyze the endpoints and assessments related to safety. 
Participants will be included in the efficacy analyses according to the intended IMP assignment 
and included in the safety analyses according to the IMP actually received. 
9.3. 
Statistical Analyses 
9.3.1. 
General Considerations 
• Data collected will be listed with derived variables. Descriptive statistical methods 
will be used to analyze safety and efficacy data. 
• Summaries will be provided by treatment assignment and overall. 
• 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. 
• The baseline value will be the last assessment before the first administration of IMP. 
• All study visits will be recalculated based on actual dates. The rules for calculating 
the analysis visits will be documented in the SAP. 
• Rules for imputing partial dates or missing dates will be provided in the SAP. 
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• Exposure to IMP will be summarized by treatment group. 
• TEAEs, AESIs, SAEs, and other safety parameters will be summarized by treatment 
group. 
• AEs will be classified using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA) classification system.  
• AEs, AESIs, and SAEs will be listed corresponding to MedDRA system organ class 
(SOC) and preferred term (PT). 
• Multiple occurrences of a single PT in a participant will be counted only once at the 
maximum severity/grade.  
• 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. 
• Population PK/PD analysis may be performed based on the PK and PD data and 
reported separately. 
• Laboratory parameters, physical examinations, vital sign measurements, ECG data, 
and PK, PD, immunogenicity, and biomarker results will be analyzed descriptively. 
9.4. 
Interim Analysis 
An unblinded interim analysis may be conducted mid-course at the sponsor/designee’s 
discretion. Results will be available to senior sponsor/designee staff only while maintaining the 
clinical study team members’ blind to IMP assignment.  
9.5. 
Sample Size Determination 
The anticipated width of the 95% CI of the treatment difference on changes from baseline in 
COMPASS 31 is estimated as follows: 
The SD of COMPASS 31 at a single time point in subjects living with POTS is assumed to 
be approximately 15, with mean score of 50.20 As the COMPASS 31 scale has favorable test-
retest reliability, the Pearson correlation between 2 measurements is assumed to be a 
minimum of 0.8.18 
From this, it is estimated that the within-subject SD on COMPASS 31 is approximately , 
from which the SD on the change from baseline is derived to be approximately 
 
Therefore, the anticipated width (half-width) of the 95% CI is approximately 
 assuming 
complete data, which could increase to 
 when applying a conservative dropout rate of 
%. With an anticipated 95% CI half-width 
, COMPASS 31 data from approximately 
42 participants will provide sufficient precision to estimate the treatment effect at week 24. 
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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 (CIOMS) international ethical guidelines 
• Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(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 will be responsible for 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/designee with sufficient, accurate 
financial information as requested to allow the sponsor/designee to submit a complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing changes in financial interests during the study through 
1 year after the study completes. 
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10.1.3. 
Informed Consent Process 
Before signing the ICF, participants will be instructed not to participate in any other clinical 
study that involves an intervention or collection of data until the completion of the current study. 
The investigator or their representative will explain the following to the participant and answer 
all questions regarding the study: the nature of the study, its purpose, the procedures involved, 
the expected duration, any potential discomfort, potential alternative procedure(s) or course(s) of 
treatment available, and the extent of maintaining the confidentiality of the participant’s records. 
The investigator or their representative will explain the nature of the study—including the risks 
and benefits—to the participant and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, privacy and data protection requirements, where applicable, and the 
IRB/IEC or site. 
The medical record must include a statement that written informed consent was obtained before 
any study related activity was performed 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. 
A copy of the ICF(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICF. 
10.1.4. 
Data Protection 
The sponsor/designee will assign participants a unique identifier. Any participant records or 
datasets transferred to the sponsor/designee 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/designee will use their personal study-related 
data following local data protection laws. The extent 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 participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor/designee, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation. 
10.1.5. 
Data Safety Monitoring Board 
Not applicable. 
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10.1.6. 
Dissemination of Clinical Study Data 
The sponsor/designee and auditor may access participant records to monitor this study, auditing 
and managing progress details. The investigator must be fully aware that the sponsor/designee 
and auditor can inspect documents to verify the accuracy and completeness of a participant’s 
chart and eCRF records. Such information must be kept confidential in locked facilities that 
allow for this. The investigator will prepare and maintain adequate and accurate source 
documents to record all observations, and other pertinent data for each participant enrolled in the 
study. 
The investigator is responsible for maintaining source documents. These will be made available 
for verification by the sponsor/designee’s monitor at each monitoring visit. The investigator must 
submit an eCRF for each participant, regardless of the duration of participation or administration 
of IMP (ie, an eCRF has to be submitted for screen failures). All supportive documentation 
submitted with the eCRF, such as laboratory or hospital records, should be clearly identified with 
the study and participant number. Any personal information, including participant name, should 
be removed or rendered illegible to preserve data privacy. 
10.1.7. 
Data Quality Assurance 
All participant data relating to the study will be recorded on eCRFs unless electronically 
transmitted to the sponsor/designee (eg, laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by electronically signing the eCRF. 
The eCRF Completion Guidelines document will provide instructions for completing eCRFs. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and direct access to source data documents. 
Monitoring details describing strategy, including definition of study critical data items 
and processes (eg, risk-based initiatives in operations and quality such as risk management 
and mitigation strategies and analytical risk-based monitoring), methods, responsibilities, 
and requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the monitoring plan. 
The sponsor/designee is responsible for the data management of this study, including quality 
checking of the data. 
The sponsor/designee assumes accountability for actions delegated to other individuals (eg, 
contract research organizations). 
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 in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.7.1. Data Handling and Record-Keeping 
It is the investigator’s responsibility to maintain essential study documents (records and 
documents pertaining to the conduct of this study and the distribution of IMP, including 
regulatory documents, eCRFs, signed participant ICFs, laboratory test results, IMP inventory 
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records, source documents, relevant correspondence, AE reports, and all other supporting 
documentation) as required by the applicable national regulatory requirements. The study site 
will retain these documents for 25 years minimally after study completion. The study site should 
retain such documents until at least 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in an ICH 
region, or at least 2 years after the formal discontinuation of clinical development of the IMP. 
The sponsor/designee will notify the principal investigator of these events. 
These documents should be retained for a longer period if required by the applicable regulatory 
requirements or the hospital, institution, or private practice in which the study is being 
conducted. Participant identification codes (ie, participant names and corresponding study 
numbers) will be retained for this same period of time. These documents may be transferred to 
another responsible party, acceptable to the sponsor/designee, who agrees to abide by the 
retention policies. The investigator is required to notify the sponsor/designee (or an authorized 
representative) in writing before changing the location or status of any essential clinical study 
documents. The investigator must contact the sponsor/designee before disposing of any study 
records. 
No records should be disposed of without the written approval of the sponsor/designee. 
For studies conducted outside the US under a US investigational new drug (IND), the principal 
investigator must comply with US FDA IND regulations and with those of the relevant national 
and local health authorities. 
10.1.7.2. Quality Assurance Audit 
Study processes, study sites (including, but not limited to site visits, central laboratories, 
vendors), the study database, and study documentation may be subject to quality assurance audit 
during the study by the sponsor/designee. In addition, inspections may be conducted by 
regulatory bodies at their discretion. Such audits/inspections can occur at any time during or after 
completion of the study. 
10.1.7.3. Quality Control 
Quality control will be applied to each stage of study-related activities. 
The following steps will be taken to ensure the accuracy, consistency, completeness, 
and reliability of the data: 
• Investigator meetings 
• Central laboratories for clinical laboratory parameters 
• Site initiation visit 
• Routine site monitoring 
• Ongoing site communication and training 
• Ongoing oversight by sponsor/designee of safety parameters and adherence to selection 
criteria 
• Eligibility review by sponsor/designee and medical monitors 
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• Data management quality control checks 
• Continuous data acquisition and cleaning 
• Quality control check of the CSR 
• To avoid interobserver variability, every effort should be made to ensure that the same 
individual who made the initial baseline determinations completes all efficacy and safety 
evaluations. 
In addition, periodic audits can be performed as specified in Section 10.1.7.2. 
When audits or inspections are conducted, access must be authorized for all study-related 
documents, including medical history and concomitant medication documentation 
to the authorized sponsor/designee’s representatives and regulatory authorities. 
10.1.8. 
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 on the eCRF 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. 
The investigator must maintain accurate documentation (source data) that supports 
the information entered on the eCRF. 
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 in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9. 
Monitoring 
The sponsor/designee has engaged the services of a designee to perform all clinical study 
monitoring functions within this clinical study. The sponsor/designee’s designee monitors will 
work following its SOPs. 
Monitoring visits must be conducted according to the applicable ICH GCP guidelines to verify 
that, among others, the: 
• Data are authentic, accurate, and complete 
• Safety and rights of participants are being protected 
• The study is conducted following the currently approved protocol, other study 
agreements, and all applicable regulatory requirements. 
The investigator and the head of the medical institution (where applicable) agree to allow 
the sponsor/designee’s monitor direct access to all relevant documents. 
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The investigator must ensure reasonable time, space, and qualified personnel for monitoring 
visits. 
The sponsor/designee will perform an eCRF review, source document verification (wherever 
allowed per local regulations), and source document review. 
The source documentation agreement form describes the source data for the different data 
on the eCRF. This document should be completed and signed by the sponsor/designee 
and the investigator and filed in the investigator’s study file. Any data item for which the eCRF 
will serve as the source must be identified, agreed upon, and documented in the source 
documentation agreement form. 
Upon completion or premature discontinuation from the study, the sponsor/designee will conduct 
site closure activities with the investigator and site staff as appropriate, following applicable 
regulations, ICH GCP guidelines, and sponsor/designee procedures. 
10.1.10. 
Data Management 
Data generated within this clinical study will be processed according to the SOPs of the 
sponsor/designee’s data management and biostatistics departments. 
Case report forms are provided for each participant in electronic format (ie, eCRF). Data will 
be transcribed by the study site staff from the source documents onto the eCRF, per local 
regulations. Data must be entered in English. The sponsor/designee will provide guidelines for 
eCRF completion, including collecting the investigator’s e-signature, which will be provided by 
the sponsor/designee. Appropriate training and security measures will be completed by the 
investigator and all designated site staff before the study is initiated. Any data will be entered 
into the system for any study participant at the site. 
The eCRF is essentially considered a data entry form and should not constitute the original 
(or source) medical records unless otherwise specified. Source documents are those used by the 
investigator or hospital and relate to the participant’s medical history, verify the existence of the 
participant, the inclusion and exclusion criteria, and all records covering the participant’s 
participation in the study. Source documents can include laboratory notes, ECG results, 
memoranda, pharmacy dispensing records, participant files, etc. The eCRFs will be completed by 
the investigator or the site’s qualified designee once the data are available. 
As a matter of regulation, the investigator is responsible for the accuracy and authenticity of all 
clinical data entered onto eCRFs. Before database lock, each completed eCRF must be reviewed 
for accuracy by the investigator, corrected as necessary, and then approved. The investigator’s 
e-signature confirms that the information contained on the eCRFs has been reviewed 
by the investigator and is true and accurate. The investigator will be required to sign off the 
eCRF electronically. 
The data will be verified for completeness, missing data, inconsistencies, and necessary medical 
clarifications. Queries arising from these checks will be flagged to the study site, and the study 
site staff will correct data, confirm, or clarify data as appropriate. The sponsor/designee will 
describe the review process in a data management plan and a monitoring plan. Any change, 
including the issuing of queries, will be fully audit-trailed by the electronic data capture (EDC) 
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system, meaning the name of the person, time and date stamp, and the reason for change are 
captured. 
Data will also be provided by third-party vendors, such as the results generated by the central 
laboratories, ECG reader, etc. These data will need to be reconciled with the data recorded 
on the eCRF before it can be merged with the eCRF data into the clinical database. The 
sponsor/designee will provide a data management plan describing this reconciliation. 
AEs, concomitant diseases, and medical history terms will be assigned to a lowest level term 
and a PT, and will be classified by high level term, high level group term, and primary SOC 
according to the MedDRA thesaurus. 
Prior and concomitant medications will be classified according to active drug substance using the 
World Health Organization (WHO) drug dictionary (WHODD). The generic name, the preferred 
name, and the WHO name will be assigned using the WHODD thesaurus. 
The anatomical therapeutic chemical classes will be assigned to prior and concomitant 
medications. Prior and concomitant procedures will be coded according to the MedDRA 
thesaurus. 
10.1.11. 
Study and Site Start and Closure 
The study start date is the date when the clinical study will be open for recruitment 
of participants upon the availability of mandatory approvals. 
The sponsor/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/designee. 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 may initiate study site closure at any time, provided there is reasonable cause 
and enough advanced notice provided of the intended termination. 
Reasons for the early closure of a study site by the sponsor/designee may include but are not 
limited to: 
• Inability to achieve the recruitment target within a reasonable time 
• Determination that no further benefits are expected from the study (in the 
sponsor/designee’s judgment) 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor/designee’s procedures, or GCP guidelines 
• Discontinuation of further study medication development 
If the study is prematurely terminated or suspended, the sponsor/designee will promptly inform 
the investigators, the IECs/IRBs, the regulatory authorities, designee, and any vendors used 
in the study of the reason for termination or suspension as specified by the applicable regulatory 
requirements. The investigator shall promptly inform the participant and assure appropriate 
participant therapy and/or follow up. 
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The study can also be terminated by the regulatory authority for any reason or at a site level 
by the IRB/IEC. The sponsor/designee may close individual study sites prematurely for reasons 
such as poor protocol compliance or unsatisfactory recruitment of participants. 
10.1.12. 
Investigator Obligations 
Qualified investigators will conduct this study under the sponsorship of argenx BV and IQVIA 
(the sponsor’s designee). 
The name and telephone/fax numbers of the sponsor/designee’s contact personnel are listed in 
the investigator study file provided to each site. 
The investigator is responsible for ensuring that all study site personnel, including 
subinvestigators, adhere to all applicable regulations and guidelines, including local laws 
and regulations, regarding the study, both during and after study completion. The investigator 
is responsible for informing the IRB/IEC of the study’s progress and obtaining annual IRB/IEC 
renewal. The investigator is responsible for informing the IRB/IEC of the study’s completion and 
providing the IRB/IEC with a summary of the study results. 
The investigator will comply with the protocol that has been approved/given favorable opinion 
by the IRB/IEC, according to ICH GCP and applicable regulatory requirements. The investigator 
is ultimately responsible for conducting all aspects of the study at the study site and verifying the 
integrity of all data transmitted to the sponsor/designee by signature. The term “investigator,” 
used in this protocol and other study documents, refers to the investigator or site staff that 
the investigator has designated to perform specific duties. Subinvestigators or other designated 
site staff can sign for the investigator, except where the investigator’s signature is specifically 
required. 
10.1.13. 
Protocol Signatures 
After reading the protocol, each site’s principal investigator will sign the protocol signature page 
and send a copy of the signed page to the sponsor/designee). By signing the protocol, 
the principal investigator confirms in writing that they have read, understand, and will strictly 
adhere to the study protocol and will conduct the study following ICH tripartite guidelines 
for GCP and applicable regulatory requirements. The study will not be initiated at any site where 
its principal investigator has not signed the protocol. 
10.1.14. 
Publication Policy 
All information regarding efgartigimod supplied by the sponsor/designee to the investigator and 
all data generated as a result of this study, are considered confidential and remain the sole 
property of the sponsor/designee. The results of the study will be reported in a CSR. 
The CSR will be ICH E3 compliant and submitted following local regulations. 
The results of this study may be published or presented at scientific meetings. Any manuscript, 
abstract or other publication, presentation of results, or information associated with the study 
must be prepared with the sponsor/designee after the study results have been analyzed 
and reported and submitted to the sponsor/designee for review and comment before submission 
for publication or presentation. Study participant identifiers will not be used in the publication 
of results. 
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The sponsor/designee will comply with the requirements for the publication of study results. 
Following standard editorial and ethical practice, the sponsor/designee will generally support the 
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. 
Based on scientific input and recruitment efforts, the authorship will be determined by mutual 
agreement and consistent with the International Committee of Medical Journal Editors criteria. 
The sponsor/designee will register and disclose the results of clinical studies as required by law. 
 
 
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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests listed in Table 2 will be performed as described in the Laboratory Manual. 
• Protocol-specific requirements for the inclusion and exclusion of participants are detailed 
in Section 5.1 and Section 5.2, respectively. 
• Additional tests may be performed during the study as determined necessary by the 
investigator or required by local regulations. 
• Investigators must document their review of each laboratory safety report. 
Table 2: 
Protocol-Required Laboratory Tests 
Laboratory Test 
Parameters 
Hematology 
RBC count 
platelet count 
hemoglobin 
hematocrit 
RBC indices: 
MCV 
MCH 
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 
Highly sensitive serum hCG pregnancy serum test at screening and urine test at other 
time points (as needed for WOCBP potential, defined in Appendix 4 Section 10.4.1)  
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (See Appendix 4 Section 10.4.1) 
Specialty laboratory tests 
C-reactive protein 
ESR 
TSH 
Other screening tests 
SARS-CoV-2 nasopharyngeal swab test 
Serology for HBV, HCV, HIV (see exclusion criterion 7 and Sections 10.2.1.2, 
10.2.1.3, and Section 10.2.1.4, respectively) 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; ESR=erythrocyte 
sedimentation rate; FSH=follicle-stimulating hormone; hCG=human chorionic gonadotropin; HBV=hepatitis B 
virus; HCV=hepatitis C virus; 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. 
10.2.1. 
Other Screening Tests 
10.2.1.1. SARS-CoV-2 
A SARS-CoV-2 nasopharyngeal swab test will be performed on all participants at screening; 
individuals with positive test results are excluded from participating in the study (Section 5.2, 
exclusion criterion 6). 
Additional COVID-19 testing recommendations/guidelines are presented in Section 10.5. 
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10.2.1.2. Hepatitis B Virus 
Participants with an active acute or chronic hepatitis B viral infection at screening will be 
excluded from randomization in the study. 
The following combinations of serologic markers will be used to identify an active HBV 
infection (https://www.cdc.gov/hepatitis/HBV/PDFs/SerologicChartv8.pdf): 
Table 3: 
Interpretation of Hepatitis B Serological Test Results 
Test result 
Interpretation 
HBsAg 
Anti-HBc 
Anti-HBs 
Positive 
Positive 
Negative 
The patient cannot be randomized in the study because the test 
results indicate an active HBV infection.  
Negative 
Positive 
Negative 
The patient cannot be randomized in the study because the test 
results indicate a low-level chronic HBV infection with 
impaired liver function.a 
anti-HBc=total hepatitis B core antibody; anti-HBs=hepatitis B surface antibody 
a This decision will be made by a medical physician with enough experience in hepatology or infectious disease. 
Additional tests (eg, HBV viral load) could be required to determine the patient’s status. 
10.2.1.3. Hepatitis C Virus 
Participants with an active acute or chronic hepatitis C viral infection at screening cannot be 
randomized in the study. The hepatitis C virus antibody serologic test will identify an active 
hepatitis C viral infection as indicated in Table 4.  
Table 4: 
Interpretation of the Hepatitis C Antibody Test 
HCV antibody 
test result 
Interpretation 
Positive 
The patient cannot be randomized in the study because the test results indicate an 
active acute or chronic HCV infection unless associated with a negative HCV RNA test 
HCV=hepatitis C virus 
10.2.1.4. Human Immunodeficiency Virus 
Individuals who are HIV positive are not eligible for this study. 
 
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10.4. 
Appendix 4: Contraceptive and Barrier Guidance 
10.4.1. 
Women of Childbearing Potential Definition 
A woman is considered to be of childbearing potential (WOCBP) unless she is either:  
• Postmenopausal:  
− continuous amenorrhea for ≥1 year without an alternative medical cause 
− FSH >40 IU/L 
If a postmenopausal woman is using hormonal therapy, such as hormone replacement 
therapy or hormonal contraceptives, FSH levels could be suppressed and therefore an FSH 
test to confirm a postmenopausal state is not considered valid. In this case the 
postmenopausal state will be assessed by the investigator. 
• Surgically sterilized: 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. 
• Combined (estrogen- and progestogen containing) hormonal contraception associated 
with inhibition of ovulation: 
− Oral 
− Intravaginal 
− Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
− Oral 
− Injectable 
− Implantable 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
• Vasectomized partner 
• Sexual abstinence: a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the IMP. The 
reliability of sexual abstinence needs to be evaluated concerning the duration of the 
study and the preferred and usual lifestyle of the participant 
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• Progestogen-only hormonal contraception in which inhibition of ovulation is not the 
primary mode of action 
− Oral 
− Injectable 
− Implantable 
• 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 
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 to be used 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. The sponsor/designee and the clinical site must agree to the duration of these changes. 
10.5.1. 
Testing for COVID-19 
Additional testing for COVID-19 beyond what is listed in the SoA (Section 1.3) is not required 
during the study. However, it is recommended that participants who develop COVID-19 
symptoms be tested, and results reported for the study. 
10.5.2. 
Critical Parameters to Be Collected During the Study 
All assessments should be performed as indicated in the SoA (Section 1.3). If assessments cannot 
be performed because of the COVID-19 pandemic, the following critical parameters must be 
collected: all AE reporting, administration site reactions, IMP administration, questionnaires, and 
safety laboratory assessments from the first visit through the end of study. 
Analyses may be performed at a local laboratory if the central laboratory is unavailable because 
of the pandemic. 
10.5.3. 
Mandatory Site Visits 
All visits designated as mandatory on-site visits must occur at the site. If adaptations are required 
because of the COVID-19 pandemic, the following visits must still be attended at the site: 
• Screening visits 
• Baseline/day 1  
− Participants cannot be randomly assigned to IMP unless this visit occurs on-site. 
• W1, W2, W4, W12, W24, IMP discontinuation visit, EDV, and SFV
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10.6. 
Appendix 6 Home Study Visits 
During the study, a home nurse may travel to the participant’s home to conduct visits (or the 
participant may go to 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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10.7. 
Appendix 7: Protocol Amendment History 
Amendment 1 (11 Dec 2022) 
This amendment is considered to be 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 primary rationale for this amendment is to correct the time point at which the final dose of 
IMP will be administered. Other clarifications and corrections have been made and are 
summarized below. 
The major changes from protocol version 1.0 to protocol version 2.0 are summarized in the 
following table. Minor editorial changes, including the correction of typographical errors and 
formatting inconsistencies, are not summarized in the table. Refer to the List of Abbreviations  
for any undefined abbreviations. 
Section # and Name 
Description of Change 
Brief Rationale 
SIGNATURE OF 
SPONSOR 
, MD, PhD is 
now the sponsor signatory 
for this protocol. 
Effective 01 Apr 2022, Dr. 
 
became the sponsor’s 
chief medical officer. 
Title Page 
argenx telephone numbers 
for 24-hour urgent medical 
helpline have been 
replaced with IQVIA 
telephone numbers. 
IQVIA is responsible for the 
24-hour urgent medical helpline. 
1.3. Schedule of Activities 
An IMP discontinuation 
visit has been added to the 
study. 
The protocol has been updated in 
several places to make consistent 
with current argenx 
standards/guidance. 
1.3. Schedule of Activities 
8. STUDY ASSESSMENTS 
AND PROCEDURES 
10.5.3. Mandatory Site 
Visits 
Week 1, week 2, and the 
IMP discontinuation visit 
were added to the list of 
visits that must be on-site. 
The first 3 doses should be 
administered on-site for 
participant safety reasons. The 
language has been updated to 
designate week 1 and week 2 as 
on-site visits. 
1.1 Synopsis 
1.2. Schema 
1.3. Schedule of Activities 
4.1. Overall Design 
7.2. Participant 
Discontinuation/Withdrawal 
from the Study 
The time between last IMP 
dose and the follow-up 
visit has been amended 
from 60 days to 56 days 
(±3 days) dose. 
The protocol has been updated in 
several places to make consistent 
with current argenx 
standards/guidance. 
1.3. Schedule of Activities 
A footnote has been added 
The protocol has been updated in 
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Section # and Name 
Description of Change 
Brief Rationale 
to clarify that the EDV will 
be within 7 days of the last 
dose of IMP, and that the 
visit applies for 
participants who 
discontinue the study. 
several places to make consistent 
with current argenx 
standards/guidance. 
4.4. End-of-Study Definition A clarification has been 
added to note that if a 
participant continues in the 
study after discontinuing 
IMP, this will be week 23 
or at the SFV (if permanent 
IMP discontinuation is 
<56 days from week 23) 
The protocol has been updated in 
several places to make consistent 
with current argenx 
standards/guidance. 
7.1. Discontinuation of IMP 
The text regarding 
discontinuation of IMP has 
been substantially updated. 
The protocol has been updated in 
several places to make consistent 
with current argenx 
standards/guidance. 
7.2. Participant 
Discontinuation/Withdrawal 
from the Study 
The text regarding 
discontinuation of IMP has 
been substantially updated. 
The protocol has been updated in 
several places to make consistent 
with current argenx 
standards/guidance. 
7.3. Lost to Follow-up 
A minor change has been 
made to the wording in this 
section. 
The protocol has been updated in 
several places to make consistent 
with current argenx 
standards/guidance. 
1.3. Schedule of Activities 
6.1. Study Intervention(s) 
Administered 
Wording modified to 
clarify that dose level will 
be recalculated for if a 
participant’s weight has 
changed (increased or 
decreased) by more than 
10% from baseline. 
This text has been updated to 
more accurately describe the 
criteria for redosing. 
6.6. Dose Modification 
Wording added about 
recalculation of 
weight-based dose. 
This text has been updated in line 
with the sponsor’s current 
standards. 
6.2. Preparation, Handling, 
Storage, and Accountability 
Language was added to 
note that, at a minimum, 
the first 3 doses of IMP 
must be administered 
on-site. 
This text was updated to align 
with changes to Sections 1.3, 8, 
and 10.5.3. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
1.3. Schedule of Activities 
4.1. Overall Design 
The week 24 dose has been 
removed. 
This was a correction; there will 
be no dosing at this time point. 
1.3. Schedule of Activities 
8.3.3. Electrocardiograms 
Language was added to 
note that ECGs will be the 
first assessment of the day 
on days when they are 
performed. 
ECGs should be performed first 
because heart rate may increase 
after certain other assessments 
are performed. 
8.2.3. 
 
 
Language was added that 
the tilt test will be the first 
of these tests to be 
performed. 
POTS symptoms are more likely 
to be reproduced by testing in the 
morning. 
1.3. Schedule of Activities 
3. Objectives, Endpoints, 
and Estimands 
8.2.3. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The original frequency of testing 
was considered burdensome on 
the participant, and was 
unnecessary because the active 
stand test and tilt test both 
measure increase in heart rate on 
standing.  
1.3. Schedule of Activities 
8.2.2. 
 
8.2.3. 
 
 
8.2.4. 
 
 
Language was added to 
note that efficacy 
assessments may be 
performed on the day 
before the scheduled time 
point. 
This update was made to relieve 
the burden of testing for the 
participant. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.5. Pharmacokinetics 
Language was added that 
pharmacokinetic samples 
collected after the end of 
infusion should be 
collected in the opposite 
arm from the arm used for 
IMP infusion. 
This instruction was added in to 
clarify best practice for collection 
of pharmacokinetic samples. 
1.3. Schedule of Activities 
The study day for SFV was 
changed from 230 to 218. 
SFV was recalculated to occur 
56 days after the dose at 
week 23. 
1.3. Schedule of Activities 
In footnote b, the detail 
that the SFV would be 
60 days after final IMP 
dose was removed. 
Corrected because for 
participants who remain on study 
despite discontinuing IMP, the 
SFV will not be 60 days (now 
amended to 56 days) after final 
IMP dose. 
1.3. Schedule of Activities 
The study days for visits 
during weeks 19-23 were 
updated from 134-161 to 
134-162, and the study day 
for week 24 was updated 
from 170 to 169. 
These were corrections due to 
miscalculations in the original 
Schedule of Activities. 
1.3. Schedule of Activities 
8.5. Pharmacokinetics 
8.6. Pharmacodynamics 
8.8. Biomarkers 
8.9. Immunogenicity 
Assessments 
Text added to note that 
blood samples on days 
other than IMP 
administration visits can be 
taken at any point during 
that visit. 
This clarification was added as 
previously the protocol had 
suggested sampling predose for 
all visits, which was not 
appropriate for visits where no 
dosing will be performed. 
1.3. Schedule of Activities 
8.5. Pharmacokinetics 
Blood samples for 
participants remaining in 
the study following IMP 
discontinuation will be 
collected as per the SoA 
for up to 3 weeks post IMP 
discontinuation for PK 
analysis. 
These samples have been added 
because IMP is expected to still 
be detectable in blood for this 
period of time following 
permanent discontinuation. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3. Schedule of Activities 
8.2.1.5. Exit Interview 
Language was added to 
note that for participants 
who prematurely 
discontinue the study, the 
exit interview can be 
conducted after their EDV. 
This was a clarification because 
the original protocol only 
described this interview relative 
to the week 24 visit. 
2.3.1 Risk Assessment 
The potential risk to 
teratogenicity/fetotoxicity 
has been removed, the risk 
‘immune modulation 
leading to increased 
infection’ has been 
reworded to ‘serious 
infection,’ and the 
mitigation strategy for 
IRRs has been updated. 
The language was updated to 
reflect the sponsor’s current risks 
and mitigation strategy for 
efgartigimod IV. 
1.1 Synopsis 
3. Objectives, Endpoints, 
and Estimands 
The reference to change 
from baseline for PGI-C 
removed from the 
secondary endpoint. 
Baseline assessment is not 
applicable for this assessment. 
8.8.1.1. Serum 
Autoantibodies and SARS-
CoV-2 Antibodies 
The description of the 
analyses has been updated. 
The language was updated to be 
more specific. 
8.8.1.3. 
 
 
Language was added to 
note that a decision will be 
made at the end of the 
study as to whether the 
samples will be analyzed; 
if not, the samples will be 
retained for potential future 
research. 
 
 
 
 
10.3.3. Recording and 
Follow Up of AE and/or 
SAE 
The bullet “New or 
updated information will 
be recorded in the 
originally submitted 
documents” was deleted. 
The language was removed 
because per the current process 
this is not done. 
10.2. Appendix 2: Clinical 
Laboratory Tests 
Language was added to 
note that results for 
albumin and total protein 
will be blinded. 
This clarification was added 
because results for these serum 
chemistry parameters may give 
an indication of treatment 
received. 
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Section # and Name 
Description of Change 
Brief Rationale 
8.8.1.2. 
 
 
 
 
Language was added to 
note that the analyses may 
be reported in the final 
CSR or separately, and that 
the analyses will be 
performed using 
 
 
The language was updated for 
clarity. 
8.10.1. 
 
The description of the 
scoring was updated to 
include the 
. 
This language was updated for 
completeness/clarity. 
6.9.1. Prohibited Medication 
Noted that the prohibition 
of live or live-attenuated 
vaccines also applies for up 
to 28 days after the final 
dose of IMP. 
This text has been updated in line 
with the sponsor’s current 
standards. 
10.1.10 Data Management 
The sentence “No data 
collection or source data 
verification will be 
performed on race and 
ethnicity unless requested 
by local regulations” was 
deleted. 
These data will be captured in the 
eCRF 
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11. 
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4. Dani M, Dirksen A, Taraborrelli P, et al. Autonomic dysfunction in ‘long COVID’: 
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7. Vernino S, Bourne KM, Stiles LE, et al. Postural orthostatic tachycardia syndrome 
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tachycardia syndrome after COVID-19. Clin Auton Res. 2020;30(5):449-451. 
11. Bisaccia G, Ricci F, Recce V, et al. Post-acute Sequelae of COVID-19 and 
cardiovascular autonomic dysfunction: what do we know? J Cardiovasc Dev Dis. 
2021;8(11):156. 
12. Wallukat G, Hohberger B, Wenzel K, et al. Functional autoantibodies against G-protein 
coupled receptors in patients with persistent long-COVID-19 symptoms. J Transl 
Autoimmun. 2021;4:100100. 
13. Li H, Yu X, Liles C, et al. Autoimmune basis for postural tachycardia syndrome. J Am 
Heart Assoc. 2014;3(1):e000755. 
14. Kharraziha I, Axelsson J, Ricci F, et al. Serum activity against G protein-coupled 
receptors and severity of orthostatic symptoms in postural orthostatic tachycardia 
syndrome. J Am Heart Assoc. 2020;9(15):e015989. 
15. Vernino S, Stiles LE. Autoimmunity in postural orthostatic tachycardia syndrome: 
current understanding. Auton Neurosci. 2018;215:78-82. 
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16.1.9. 
Documentation of Statistical Methods 
Document 
Date 
Statistical analysis plan – v3.0 
02 May 2024 
Clinical Study Report ARGX-113-2104 
Efgartigimod IV—post–COVID-19 POTS
                          12 Mar 2025
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 STATISTICAL ANALYSIS PLAN 
 
Protocol No. ARGX-113-2104 
A phase 2 randomized, double-blinded, placebo-controlled study to 
evaluate the efficacy and safety of efgartigimod IV in adult patients 
with post COVID-19 postural orthostatic tachycardia syndrome 
(POTS) 
- 
AUTHORS: 
 
VERSION NUMBER AND DATE: V3.0 02 May 2024 
 
 
 
  
 
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TABLE OF CONTENTS 
1. INTRODUCTION............................................................................................................. 12 
2. STUDY OBJECTIVES AND ENDPOINTS ................................................................... 12 
3. STUDY DESIGN ............................................................................................................... 15 
3.1. 
General Description ....................................................................................................................................... 15 
3.2. 
Sample Size ..................................................................................................................................................... 16 
3.3. 
Schedule of Activities ..................................................................................................................................... 17 
3.4. 
Changes to Analysis from Protocol .............................................................................................................. 17 
4. PLANNED ANALYSES ................................................................................................... 17 
4.1. 
Data Monitoring Committee ......................................................................................................................... 17 
4.2. 
Interim Analysis ............................................................................................................................................. 17 
4.3. 
Final Analysis ................................................................................................................................................. 18 
5. ANALYSIS SETS.............................................................................................................. 18 
5.1. 
Enrolled Analysis Set [ENR] ......................................................................................................................... 18 
5.2. 
Full Analysis Set [FAS] ................................................................................................................................. 18 
5.3. 
Safety Analysis Set [SAF] .............................................................................................................................. 18 
5.4. 
PK Analysis Set [PKAS] ................................................................................................................................ 19 
6. GENERAL CONSIDERATIONS ................................................................................... 19 
6.1. 
Reference Start Date and Study Day ........................................................................................................... 19 
6.2. 
Baseline ........................................................................................................................................................... 20 
6.3. 
Windowing Conventions ............................................................................................................................... 20 
6.4. 
Worst-case ...................................................................................................................................................... 26 
  
 
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6.5. 
Treatment-emergent Abnormality/Toxicity ................................................................................................ 26 
6.6. 
Statistical Tests .............................................................................................................................................. 26 
6.7. 
Values below or Above the Quantification Limit ........................................................................................ 26 
6.8. 
Common Calculations ................................................................................................................................... 27 
6.9. 
Software Version ............................................................................................................................................ 27 
7. STATISTICAL CONSIDERATIONS ............................................................................ 27 
7.1. 
Missing Data ................................................................................................................................................... 27 
7.2. 
Output Presentation ...................................................................................................................................... 27 
7.3. 
Multiple Comparisons/ Multiplicity ............................................................................................................. 28 
8. DISPOSITION AND WITHDRAWALS ........................................................................ 29 
8.1. 
Disposition ...................................................................................................................................................... 29 
8.2. 
Protocol Deviations ........................................................................................................................................ 29 
9. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 30 
9.1. 
Derivations ..................................................................................................................................................... 30 
10. MEDICAL HISTORY .................................................................................................... 31 
11. THERAPIES ................................................................................................................... 31 
12. STUDY MEDICATION EXPOSURE .......................................................................... 32 
12.1. Derivations ..................................................................................................................................................... 32 
13. STUDY MEDICATION COMPLIANCE .................................................................... 32 
13.1. Derivations ..................................................................................................................................................... 32 
14. EFFICACY OUTCOMES.............................................................................................. 33 
14.1. Primary Efficacy ............................................................................................................................................ 33 
  
 
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14.1.1. 
Primary Efficacy Variables & Derivations .............................................................................................. 33 
14.1.1.1. 
Change from baseline to week 24 in the Composite Autonomic Symptom Score 31 (COMPASS 
31) (2-week recall version) 
33 
14.1.1.2. 
Change from baseline to week 24 in the Malmö POTS Symptom Score (MaPS) 
35 
14.1.1.3. 
Supplementary Analysis of Primary Efficacy Variables 
35 
14.2. Secondary Efficacy ........................................................................................................................................ 39 
14.2.1. 
Secondary Efficacy Variables & Derivations .......................................................................................... 39 
14.2.1.1. 
Change from baseline (CFB) to week 24 in the Patient Global Impression of Severity (PGI-S) 
39 
14.2.1.2. 
Patient Global Impression of Change (PGI-C) at week 24 
40 
14.2.1.3. 
Change from baseline to week 24 in the Patient-Reported Outcomes Measurement Information 
System (PROMIS) Fatigue Short Form 8a 
40 
14.2.1.4. 
Change from baseline to week 24 in the PROMIS Cognitive Function Short Form 6a 
41 
14.3. Exploratory Efficacy ..................................................................................................................................... 41 
. 
 
 
 
 
 
 
 
 
 
 
 
15. PHARMACODYNAMIC ANALYSIS.......................................................................... 43 
16. IMMUNOGENICITY ANALYSIS ............................................................................... 44 
17. BIOMARKER ANALYSIS ............................................................................................ 48 
18. SAFETY OUTCOMES .................................................................................................. 49 
18.1. Adverse Events ............................................................................................................................................... 49 
18.1.1. 
All TEAEs ............................................................................................................................................... 52 
18.2. Laboratory Evaluations ................................................................................................................................ 53 
18.2.1. 
Laboratory Specific Derivations .............................................................................................................. 54 
18.3. ECG Evaluations ........................................................................................................................................... 55 
18.3.1. 
ECG Abnormal Criteria ........................................................................................................................... 56 
18.4. Vital Signs ....................................................................................................................................................... 56 
18.4.1. 
Vital Signs Abnormal Criteria ................................................................................................................. 57 
18.5. Physical Examination .................................................................................................................................... 57 
  
 
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19. PHARMACOKINETIC ANALYSIS ............................................................................ 58 
20. REFERENCES ................................................................................................................ 59 
APPENDIX 1.  PROGRAMMING CONVENTIONS FOR OUTPUTS ......................... 60 
IQVIA Output Conventions...................................................................................................................................... 60 
Dates & Times ............................................................................................................................................................ 60 
Presentation of Treatment Groups .......................................................................................................................... 60 
Listings ....................................................................................................................................................................... 60 
APPENDIX 2.TOXICITY GRADES .................................................................................. 61 
APPENDIX 3. .. ALGORITHM FOR PRIOR /CONCOMITANT MEDICATIONS AND 
ADVERSE EVENTS: ........................................................................................................... 63 
 
 
  
 
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FPA 
Final Planned Analysis 
HR 
heart rate 
IAWK12 
Interim Analysis Week 12 
IAWK24 
Interim Analysis Week 24 
ICF 
informed consent form 
IgG  
immunoglobulin G 
IMP 
investigational medicinal product 
IRR 
infusion related reactions 
LLN 
lower limit of normal 
MaPS  
Malmö POTS symptom score 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
Msec 
millisecond 
NCI 
National Cancer Institute 
ND 
not determined 
OLE  
open-label extension 
PD  
pharmacodynamic(s) 
PGI-C  
Patient Global Impression  Change 
PGI-S  
Patient Global Impression  Severity 
PK  
pharmacokinetic(s) 
PKAS 
pharmacokinetic analysis set 
 
 
 
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WOCBP  
women of childbearing potential 
 
 
 
 
 
 
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o 
 
 
Table B: 
Estimands 
Objectives 
Estimands 
Primary 
 
 
The estimand is the difference 
between treatment arms in change 
from baseline to week 24 in 
COMPASS-31 and MaPS 
irrespective of whether stopping 
IMP or using prohibited 
medication. 
 
Treatment conditions 
Efgartigimod or placebo irrespective of study treatment 
discontinuation and/or prohibited medication. 
Population 
Randomized participants with post COVID-19 postural orthostatic 
tachycardia syndrome as defined in FAS 
Variable (endpoint) 
Change from baseline to week 24 in COMPASS-31/MaPS 
 
Intercurrent events  
Early discontinuation of study treatment 
Use of any prohibited medications 
 
 
Summary measure 
Difference in LS means, corresponding 95% CI and p-value 
 
.  
For the Main estimand:  
The available data occurring on or after ICEs will be analyzed as observed (Treatment policy). The reasoning of 
treatment policy is to estimate the COMPASS-31 and MaPS response based on the available data and data will 
be analyzed as it is (regardless of the intercurrent event occurring). 
 
For Supportive analysis of estimands 
 
 
 
 
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Composite Variable strategy: Assessment on or after ICEs will be treated missing and imputed assuming 
MNAR delta adjustment imputation. The rationale behind composite strategy is, discontinue of study treatment 
or use of prohibited medications will affect the COMPASS-31 and MaPS response.     
 
3. STUDY DESIGN 
3.1. General Description 
This study aims to evaluate the efficacy and safety of weekly infusions of efgartigimod IV 10 mg/kg compared 
to matched-placebo IV in adult participants with post COVID-19 POTS. This is a randomized, double-blinded, 
placebo-controlled, parallel-group, phase 2 study. The total study duration is approximately 36 weeks 
comprising:  
 
Screening period of approximately 4 weeks 
 
Treatment period of 24 weeks 
 
Follow-up period of approximately 8 weeks (56 days ± 3 days) for participants who do not roll over 
to the open-label extension (OLE) study ARGX-113-2105 
42 participants are planned to be randomized to estimate the treatment effect at week 24. 
 
 of treatment period or follow-up period 
or early discontinuation visit (EDV), as applicable. 
 
Treatment and Dosing: 
The study population is adult patients with new-onset POTS post COVID-19. Participant eligibility for trial 
participation is evaluated based on inclusion/exclusion criteria during screen period. Eligible participants will 
receive weekly infusions of efgartigimod IV 10 mg/kg or matching placebo in a 2:1 ratio according to 
randomization. The 10 mg/kg efgartigimod dose is based on body weight, and the maximum total dose per 
 recalculated if a 
 from baseline. 
Investigational medicinal product (efgartigimod or matching placebo) will be administered during the treatment 
period in an approximately 1-hour IV infusion once weekly by site staff or a home nurse.  IMP administration at 
home will not commence until after 3 doses have been administered on-site. Any participant who misses a 
scheduled dose (±2 days) will wait to receive the next scheduled dose.  
 
 
 
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The final dose is to be administered at week 23. At week 24, eligible participants may roll over into a single-
arm OLE ARGX-113-2105. Participants permanently discontinuing IMP will be ineligible to roll over into the 
OLE study. 
 
 
Blinding: 
This study is double-blinded, and the sponsor/designee, participants, and investigators are blinded to IMP 
treatment assignment. Investigator can determine whether unblinding of the IMP assignment is necessary in 
emergencies. The date and reason for the unblinding should be recorded. 
 
Table C: 
Study Overview 
3.2. Sample Size 
The anticipated width of the 95% CI of the treatment difference on changes from baseline in COMPASS 31 is 
estimated as follows: 
The SD of COMPASS 31 at a single time point in subjects living with POTS is assumed to be approximately 
with mean score of
 As the COMPASS 31 scale has favourable test-retest reliability, the Pearson 
correlation between 2 measurements is assumed to be a minimum of 
 
From this, it is estimated that the within-subject SD on COMPASS 31 is approximately , from which the SD 
on the change from baseline is derived to be approximately 
 
Therefore, the anticipated width (half-width) of the 95% CI is approximately 
 assuming complete data, 
which could increase to 
 when applying a conservative dropout rate of 
%. With an anticipated 95% CI 
half-width 
 COMPASS 31 data from approximately 42 participants will provide sufficient precision to 
estimate the treatment effect at week 24. 
 
 
 
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3.3. Schedule of Activities 
Schedule of activities can be found in Section 1.3 of the protocol. 
3.4. Changes to Analysis from Protocol 
The protocol mentions mixed model repeated measures as the method of analyzing the Primary endpoints, 
however the protocol does not mention estimands or Intercurrent events. The SAP considers estimands and 
intercurrent events. As a result, the main analysis method will be using the mixed model repeated measures and 
ANCOVA after applying MNAR to missing data from the intercurrent events will be used as supplementary 
analysis.  
The baseline for Questionnaire responses will be the final assessment before the initial administration of IMP up 
until 3 days post IMP, recorded under baseline visit. The information obtained through this method will be used 
to inform the development of Phase 3 trials. 
4. PLANNED ANALYSES 
The following analyses will be performed for this study: 
 
Interim Analysis at the end of treatment phase 
 
Final Analysis 
4.1. Data Monitoring Committee 
There will be no Data monitoring Committee for this study. 
4.2. Interim Analysis  
One interim analysis will take place for this study once all the participants have either completed the week 12 
assessments or discontinued the study prior to week 24. A further interim will be carried out at week 24.  
Interim analyses identified in this SAP will be performed by IQVIA Biostatistics following authorization of this 
SAP, database lock and analysis sets. The results of interim analysis week 12 will be based on the unblinded 
treatment groups by a separate unblinded team who is otherwise not involved within the trial. Section 9.4 of the 
protocol can be referred to for reference of interim analysis. 
 
 
 
 
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Derivations and definitions for the interim analysis will be based on those required for the final analysis 
contained in this SAP, unless deviations are stated within the text. The list of outputs provided with the full set 
of output templates (planned for the final analysis) will highlight which of these outputs will also be provided 
for the interim analysis. 
Access to data will be controlled by access rights to folders where data is stored and manipulated within IQVIA 
and access to the sFTP used for data transfer. 
4.3. Final Analysis  
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics following 
authorization of this SAP, database lock, analysis sets and unblinding of treatment. 
Pharmacokinetic analysis is being performed by the IQVIA Clinical Pharmacology Department in conjunction 
with BIOS group, PK concentration listings and summary statistics will be described in this SAP. A separate 
modeling and simulation analysis plan will be prepared to describe planned population PK/PD analysis. 
5. ANALYSIS SETS 
Agreement and authorization of participants included/excluded from each analysis set will be conducted prior to 
the unblinding of the study. 
5.1. Enrolled Analysis Set [ENR] 
The enrolled analysis set (ENR) will contain all participants who provided informed consent. 
5.2. Full Analysis Set [FAS] 
The full analysis set (FAS) will contain all randomized participants who received at least one dose of IMP and 
classified as Planned Treatment. 
5.3. Safety Analysis Set [SAF] 
The safety analysis set (SAF) will contain all randomized participants who received at least one dose of IMP. 
Data from these participants will be classified according to actual treatment received. The actual treatment arm 
will be the same as the planned treatment arm unless the participant received IMP other than the planned one 
 
 
 
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for the whole study. 
 
5.4. PK Analysis Set [PKAS]  
The PK analysis set (PKAS) used for the descriptive summaries of efgartigimod serum concentrations will 
consist of all randomized participants who receive at least one dose of efgartigimod and have at least 1 
measured concentration of efgartigimod at a scheduled PK time point after start of dosing without protocol 
violations or events with potential to affect the PK concentration. Participants in this population will be used for 
all PK summaries. 
 
When using the FAS, participants will be classified according to their planned treatment arm. For analyses 
performed on the SAF or PKAS, the actual treatment arm will be considered. The actual treatment arm will be 
the same as the planned treatment arm unless the participant received IMP other than the planned one for the 
whole study. 
6. GENERAL CONSIDERATIONS 
6.1. Reference Start Date and Study Day 
Study Day will be calculated from the reference start date and will be used to show start/stop day of 
assessments and events. It will appear in every listing where an assessment date or event date appears. 
 
Reference start date is defined as the day of the first dose of IMP. 
 
If the date of the event is on or after the reference date, then:  
o 
Study Day = (date of event  reference date) + 1.  
 
If the date of the event is prior to the reference date, then:  
o 
Study Day = (date of event  reference date). 
In the situation where the event date is partial or missing, the date will appear partial or missing in the listings, 
and Study Day. Date implies a complete date having day, month and year available.  Unless otherwise 
specified, the study day will remain missing when it cannot be calculated due to absence or incompleteness of 
the concerned and/or reference dates.  
 
 
 
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In case the participant never received IMP, the date/time of randomization will be used instead of first IMP 
administration date/time. 
End of study (EOS) is defined as 
date of treatment period completion 
and/or safety follow-up or early discontinuation visit. 
End of treatment (EOT) is defined as date of treatment completion or date of permanent discontinuation of IMP. 
6.2. Baseline 
Unless otherwise specified, baseline is defined as the last available non-missing measurement taken prior to 
reference start date/time. 
Assessments performed on the same day as the first IMP administration but without time information collected 
or with time information exactly equal to the time of first IMP administration and which are planned predose 
will be considered as predose.  
For parameters related to questionnaires, baseline assessment is the last evaluable assessment before the initial 
administration of IMP up until within 3 days after IMP, collected gathered during the baseline visit for 
questionnaires. It includes COMPASS 31, MaPS, PGIC, PGIS, PROMIS (Cognitive Function Short Form 6a, 
Fatigue Short Form 8a, Global Health Scale score) and EQ-5D-5L. 
In case the participant never received IMP, the date/time of randomization will be used instead of first IMP 
administration date/time. 
Adverse Events (AEs) and medications commencing on the reference start date will be considered post-baseline 
unless otherwise indicated based on available start date/time combination or collected electronic case report 
form (eCRF) information that identifies the individual event/medication as starting prior to first IMP 
administration. 
6.3. Windowing Conventions  
All assessments, including unscheduled assessments, will be allocated to analysis visit window. Tables and 
listings will be based on analysis window defined below. Allocations of assessments will be performed using 
their relative day. 
 
 
 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
6.4. Worst-case  
A worst-case analysis visit will be created for parameters for which abnormalities and/or toxicity grades (e.g., 
labs, vital signs, ECGs) are defined to summarize values considered as the worst-case. For abnormalities worst-
case is derived per parameter and in case both the lowest and the highest values are considered abnormal, a 
participant can have two worst-case analysis visits for a same parameter. For toxicity grades the worst-case is 
the value associated to the highest toxicity grade and is derived per parameter and toxicity direction (hypo / 
hyper). 
All non-missing post-baseline values, including unscheduled assessments will be considered when deriving the 
worst-case analysis visit. 
6.5. Treatment-emergent Abnormality/Toxicity 
A treatment-emergent abnormality/toxicity (for laboratory assessments, vital signs, or ECGs) is defined as any 
postbaseline abnormality/toxicity that was not present at baseline (eg, hemoglobin normal at baseline and grade 
1 postbaseline; glucose low at baseline and high postbaseline; QTcF [450; 480] ms at baseline and >500 ms 
postbaseline). 
6.6. Statistical Tests 
The default significant level will be 5%; confidence intervals (CIs) will be 95% and all tests will be two-sided, 
unless otherwise specified in the description of the analyses. 
6.7. Values below or Above the Quantification Limit 
 
  
 
Safety and PD values expressed as below (or above) the quantification limit will be imputed by 
the value of the quantification limit itself. For participants with a baseline PD value below/above 
the quantification limit, the PD parameter will be excluded from the statistical analyses involving 
change and percent change from baseline. Listings will always show the non-imputed values. 
 
Pharmacokinetic concentrations below the lower quantification limit will be reported in the 
listings as BLQ. For descriptive statistical analysis, all BLQ values will be set to zero. Listings 
will always present BLQ. 
 
 
 
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Author: 
 
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Version Date:  
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Effective Date: 01Nov2021 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
6.8. Common Calculations 
For quantitative measurements, change from baseline will be calculated as: 
o 
Change from baseline at Visit X = Value at Visit X  baseline value. 
A percent change from baseline can be calculated as. 
o 
Percent change from baseline at Visit X = (actual value at Visit X -baseline value) *100/baseline value. 
6.9. Software Version 
All analyses will be conducted using SAS version 9.4 or higher. 
7. STATISTICAL CONSIDERATIONS 
7.1. Missing Data 
For imputation of missing values related to efficacy and safety, see appropriate section of the applicable 
endpoints. 
Missing efgartigimod concentrations will not be imputed. 
7.2. Output Presentation 
For continuous variables, full descriptive statistics will only be presented if there are at least 2 non-missing 
observations. Alternatively, only the number of non-missing data points and mean are shown. In tables by 
analysis visit, only analysis visits with at least 10 participants (overall) will be shown. 
 
Descriptive statistics for safety and efficacy will include the number of non-missing data points, the arithmetic 
mean, the standard deviation (SD), the median, minimum, Q1, Q3, maximum, and for efficacy the standard 
error (SE) and 95% CI may be provided in addition (refer to output templates for details). 
 
Mean, Q1, Q3 95% Confidence interval and median will be presented with one more decimal place than the 
measured values. SE and SD will be presented with two more decimal places than the measured values. 
Minimum and maximum will be presented with the same number of decimal places as the measured values. 
 
 
 
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Document: 
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Author: 
 
Version Number: 
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Version Date:  
02 May 2024
Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019, 2021 IQVIA. All rights reserved. The contents of this document are confidential 
and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
 
Descriptive statistics for PD parameters will include the number of non-missing data points, the arithmetic 
mean, the SD, the SE, the 95% CI, the median, minimum, Q1, Q3, and maximum. Descriptive statistics of total 
IgG levels 
. 
 
Descriptive statistics for PK serum concentrations will include the number of observed values, arithmetic mean, 
SD, median, minimum and maximum, CV%, the GM, and geometric CV%. Serum concentrations will be 
reported as received by the bioanalytical laboratory.  
 
ut the decimals and rounded to the 
nearest integer. If at least one BLQ value is reported at a specific time point, the GM and geometric CV% for 
that time point will not be calculated. In addition, if more than half of the values per time point are BLQ, the 
arithmetic mean will be reported as BLQ and SD, CV%, GM, and geometric CV% will not be calculated. 
 
Descriptive statistics for immunogenicity titer values will include the number of observed values, arithmetic 
mean, SE, 95% CI, median, Q1, Q3, minimum, maximum, the GM, and geometric CV%. 
 
For event-type safety data, the number and percentage of participants with an event will be shown. The 
denominator will be all participants in the analysis set per treatment. 
 
For frequency tabulations and cross-tabulations, the denominator will be the number of participants per 
treatment arm. For tables where results are shown by analysis visit, the denominator will be the number of 
participants per treatment arm and analysis visit. Missing values will not be included in the denominator count 
when computing percentages. For cross-tabulation of post-
category will be shown for baseline results, if applicable. Percentages will be presented with 1 decimal place. 
 
Appendix 1 shows conventions for presentation of data in outputs. 
7.3. Multiple Comparisons/ Multiplicity 
No multiple comparison adjustment or alpha sharing to be considered.  
 
 
 
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Effective Date: 01Nov2021 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
8. DISPOSITION AND WITHDRAWALS 
All participants who provide informed consent will be accounted for in this study.  
8.1. Disposition 
The number of participants will be summarized for ENR for the Final Planned Analysis (FPA). The number of 
participants per country and site will also be provided using the SAF for the FPA. The number of participants 
who completed or discontinued the treatment using the SAF, for IAWK12, IAWK24 and FPA and/or the study 
along with the reason for discontinuation will be summarized using the FAS for both the IAWK12, IAWK24 
and FPA. 
 
Participant disposition and withdrawals will be presented for the FAS set. 
Data will be tabulated at least for; 
 
participants each analysis sets for the FPA. 
 
number and percentage of participants randomized, completed, or discontinued the study for the 
IAWK12, IAWK24 and FPA. 
 
number and percentage of participants for each study discontinuation reason or the IAWK12, 
IAWK24 and FPA. 
 
number and percentage of participants discontinuing treatment but continuing study assessments for 
the IAWK12, IAWK24 and FPA. 
 
number and percentage of participants who roll over to OLE study ARGX-113-2105 for the FAS, 
IAWK12, IAWK24 and FPA. 
A listing of participant disposition will be prepared to present information about treatment allocation, treatment 
discontinuation and study discontinuation.  
8.2. Protocol Deviations 
 
Frequency counts and percentages of participants with protocol deviations will be summarized, by 
class of deviations and overall using the FAS for the FPA. 
 
A listing will be prepared containing types of deviations and class along with additional information 
concerning all protocol deviations as available.   
 
 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
9. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic and other baseline characteristics will be summarized using descriptive statistics for the FAS for 
IAWK12, IAWK24 and FPA. 
The following demographic and other baseline characteristics will be reported for this study: 
 
Age (years) - calculated relative to date of consent - overall. 
 
18-<65 years 
 
65-<75 years 
 
>=75 years 
 
Sex 
 
Childbearing potential for female subjects only 
 
Race  
 
Ethnicity 
 
Base line weight (kg) 
 
Height (cm) 
 
Baseline BMI (kg/m2) 
 
Time since diagnosis (years) - calculated relative to date of consent. 
 
SARS-CoV-2 
 
Active stand test (HR on 10-minute stand) 
 
Head-up tilt test 
Summary statistics including n, mean, median, SD, Q1, Q3, minimum and maximum will be presented for 
continuous variables such as age, height, weight, BMI, time since diagnosis, active stand test (HR on 10-minute 
stand) and head-up tilt test. Frequency counts and percentages will be presented for categorical variables such 
as sex, race, ethnicity, and SARS-CoV-2. 
 
All demographic data and baseline characteristics will be listed. 
9.1. Derivations 
 
BMI (kg/ m2) = weight (kg)/ height (m)2 
 
Time since diagnosis is defined as (date of ICF  date of diagnosis) / 365.25. Partially missing date 
of diagnosis will be imputed as follows: 
 
Missing day of diagnosis will be imputed with 1 
 
 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
 
Percent reduction = (baseline-actual)*100/baseline 
10. MEDICAL HISTORY  
Surgical and Medical History & Concomitant illnesses information will be presented for the SAF. 
Medical History and Concomitant illnesses will be coded using the latest version of MedDRA (medical 
dictionary for regulatory activities). 
 
Medical History conditions are defined as those conditions which stop prior to or at screening.  Hence, any 
medical history abnormalities/conditions and any event including medical history for COVID and POTS 
before or at screening will be presented as Medical History.  
 
Concomitant illnesses which started prior to or at screening date and are ongoing during the study will be 
reported. These are also recorded in Medical History page of the eCRF. 
 
Medical history and concomitant illnesses will be presented by SOC and PT.  
Details collected as a part of the medical history must include but are not limited to all previous 
treatment/therapy for COVID-19 and post COVID-19 POTS. 
 
Frequency and percentage of participants with findings by SOC and PT will be presented for FPA only. 
11. THERAPIES 
All therapies will be coded using WHO-DRUG and presented for the SAF. Anatomical Therapeutic Chemical 
(ATC) selection is performed. ATC coding up to level 4 is available in the clinical database. 
 
See Appendix 3 for handling of partial and missing dates for medications  
 
Based on their start dates, therapies will be allocated to 1 or both of the following categories: 
 
 
Prior therapy: the therapy strictly started before the first dose date.  
 
Concomitant therapy: the therapy was taken on or after the first dose date.  
If the start and/or stop date is incomplete or missing, the therapy will be allocated to both categories unless the 
available parts of the start and/or stop date provide evidence that the therapy was not administered during the 
specific period. 
 
 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
 
Prior and concomitant therapies will be tabulated by ATC class (level 1 and 3) and generic term. All 
prior and concomitant therapies will be listed. 
12. STUDY MEDICATION EXPOSURE 
Exposure to IMP in days will be summarized for the SAF for IAWK12, IAWK24 and FPA. 
 
The infusion start date/time and infusion end date/time of each dose administered along with total dose 
administered at each visit will be recorded. The date of first study infusion will be taken from the eCRF 
Exposure - Infusion
infusion 
form. Interruptions, compliance, and dose changes are not taken into account for duration of exposure.  
 
As per protocol, a variation of more than 10% of the amount of 10 mg/kg will be considered an 
overdose
Exposure  Infusion
 
The total treatment administration duration will be summarized using descriptive statistics. All IMP 
administration data will be listed. Participants with an overdose of IMP will be listed. 
12.1. 
Derivations 
 
Total treatment administration duration (days) = date of last IMP administration  date of first IMP 
administration + 1.  
 
Number of administrations = Number and percentage of participants receiving 1,2,3 etc. 
administrations overall 
13. STUDY MEDICATION COMPLIANCE  
The infusion is given once a week by site staff or delegate. At least, the first 3 doses of IMP (at baseline, week 1 
and 2 or subsequent if previous doses are missed) must be administered on-site.   
The compliance will be summarized descriptively. Compliance will be further categorized as <80, 80-100, 
>100.  
13.1. 
Derivations 
Compliance is defined as: 100* (number of doses received/number of doses expected). Number of doses 
 
 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
expected will be based on participants expecting study drug infusion/administration 
Exposure  
Infusion  irrespective of dosing received. Only visits up to treatment discontinuation are considered in the 
compliance calculation. 
14. EFFICACY OUTCOMES 
14.1. 
Primary Efficacy 
14.1.1. Primary Efficacy Variables & Derivations 
The primary efficacy variables are: 
 
Change from baseline to week 24 in the Composite Autonomic Symptom Score 31 (COMPASS 31)  
 
Change from baseline to week 24 in the Malmö POTS Symptom Score (MaPS)  
Efficacy endpoints will be analyzed using the FAS for IAWK12 and IAWK24 (Note data will be used for all 
subjects up to the cut of date for IAWK12, the data will not be truncated to week 12 therefore the change from 
baseline to week 24 ANCOVA will contain a subset of the subjects available at week 12 cut off,, whereas the 
MMRM will contain all subjects within the cutoff regardless of where they are within the trial up to week 24 .) 
 
Estimand for primary analysis is as defined in Table B. The estimand is the difference between treatment arms 
in change from baseline to week 24 in COMPASS-31 and MaPS irrespective of stopping IMP or using 
prohibited medication. Missing data due to withdrawal of consent/loss to follow-up will be imputed based on 
subjects remaining in the study, irrespective of whether those subjects discontinued study treatment or used 
prohibited medications later than the imputation. 
 
Intercurrent Events (ICE) are early discontinuation of study treatment and use of any prohibited medications.  
14.1.1.1. Change from baseline to week 24 in the Composite Autonomic Symptom Score 31 
(COMPASS 31) (2-week recall version) 
 
The primary objective of the study is to evaluate the efficacy of efgartigimod in reducing the severity of post-
COVID-19 POTS symptoms.  
 For change from baseline to week 24 in COMPASS 31 (2-week recall version) and MaPs, between treatment 
group difference will be analyzed using longitudinal mixed model repeated measures (MMRM). Without 
 
 
 
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Author: 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
imputation of intercurrent events. 
The model will be implemented in SAS using the MIXED procedure and will include the change from baseline 
in COMPASS31 as the dependent variable and baseline value of COMPASS31, interaction of baseline value 
with visit as covariates. Fixed effects in the model will be treatment, visit and treatment by visit interactions. 
The visits included in the model will be weeks 2, 4, 12 and 24. All data will be included for subject in the 
IAWK12 even if it is for visits after week 12.  
Within-subject correlation will be modeled by assuming an unstructured variance covariance matrix, and the 
Kenward-Roger degrees of freedom method will be used.  
 
If the default Newton Raphson algorithm used by SAS PROC MIXED fails to converge, the following steps 
will be taken to avoid lack of convergence while maintaining an unstructured variance: 
The Fisher scoring algorithm (via the SCORING=5 option of the PROC MIXED statement) will be used to 
obtain the initial values of covariance parameters. 
If the above fails, the no-diagonal factor analytic structure will be used, which effectively performs the 
Cholesky decomposition via the TYPE=FA0(V) option of the REPEATED statement, where V is the total 
number of distinct visits in the response vector (counting only rows where all model components are non-
missing). 
If all of the above fail, the variance-and-correlations parameterization will be attempted using TYPE=UNR. 
 
In case if model does not converge after all of the above steps, following covariance structures will be tested for 
convergence (in order) ANTE(1), TOEPH, ARH(1), CSH, TOEP, AR(1), and CS.  
 
To estimate the difference between the efgartigimod and placebo in mean change from baseline to Week 24, a 
treatment-by-visit interaction contrast will be constructed (i.e., the treatment group contrast at Week 24).  On 
the basis of this analysis, LS means, SE with 95% CI for placebo and efgartigimod will be reported, along with 
difference in LS means of efgartigimod vs placebo (with SE), 95% 2-sided CI. 2-sided p-value for testing 
differences between treatment groups will also be presented. Inference will be based on the precision of the 
estimation rather than hypothesis testing. 
analysis stage): 
 
proc mixed data=COMPASS31 method=REML; 
 
 
class BCOMPASS31 ARMCD VISIT USUBJID; 
model change = BCOMPASS31 ARMCD VISIT BCOMPASS* VISIT 
ARMCD*VISIT/ddfm=kenwardroger; 
 
 
repeated VISIT / type=un subject = USUBJID; 
 
 
lsmeans ARMCD*VISIT / pdiff cl; 
 
 
ods output lsmeans = lsm;  * contains the adjusted means; 
 
 
ods output diffs = dif;  * contains treatment differences; 
 
 
 
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run; 
 
For change from baseline to week 24 in MaPS, between treatment group difference will be analyzed using 
MMRM, except with change from baseline in MaPS as the dependent variable and baseline value of MaPS as 
covariate.  
 
The visits included in the model will be weeks 2, 4, 8, 12, 18 and 24. 
 
14.1.1.2. Change from baseline to week 24 in the Malmö POTS Symptom Score (MaPS) 
 
The MaPS score consists of 12 questions that will assess symptom burden related (tachycardia, palpitations, 
dizziness, presyncope) and unrelated to orthostatic intolerance (GI symptoms, insomnia, concentration 
difficulties). Participants will grade their symptoms for the past 7 days using a 11-point scale ranging from 0 
(no symptoms) to 10 (worst possible). The items will be summed to yield a total score with a maximum value of 
120 points, with higher scores indicating more severe symptoms. This total score will be derived 
programmatically.  
 
For change from baseline to week 24 in MaPS score, analysis will be presented similar to analysis proposed for 
COMPASS 31. Summary statistics will be provided in terms of absolute value and changes from baseline for 
each visit using FAS for IAWK12 and IAWK24. All data will be included for subject in the IA even if it is for 
visits after week 12. 
 
For change from baseline to week 24 in MaPS, between treatment group difference will be analyzed using 
ANCOVA as presented in section 14.1.1.1, except with change from baseline in MaPS as the dependent 
variable and baseline value of MaPS as covariate.  
14.1.1.3. Supplementary Analysis of Primary Efficacy Variables 
 
COMPASS 31 questionnaire is to evaluate the severity and distribution of autonomic symptoms in various 
autonomic nerve disorders. The 31-item questionnaire addresses 6 domains: orthostatic intolerance, vasomotor, 
secretomotor, bladder, pupillomotor, and gastrointestinal-mixed upper and diarrhea. The original version of 
COMPASS 31 (longer recall) will be administered at screening and the modified version (2-week recall) will be 
administered at baseline and all other time points. The modified COMPASS 31 version used in the ARGX-113-
2104 study modified the recall period to 2 weeks in contrast with the original COMPASS 31. 
 
 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
Participants are asked to respond to each of the item question using different, response options depending on 
each item, based on their perceived symptoms experience over the last 2 weeks. The response options are 
different depending on item content and vary from dichotomous to 7-point scale options. The modified 
COMPASS 31 has 6 domains that sum up to a total score of 0 to 100. Higher scores indicate a more severe 
degree of autonomic symptoms.  
 
The modified COMPASS 31, scoring algorithm for each domain and total scores will be provided by external 
vendor. This total score will be considered for change from baseline analysis. 
 
The supplementary primary efficacy analysis will be performed for the FAS for IAWK12 and IAWK24. 
Summary statistics will also be provided in terms of absolute value and changes from baseline for each visit 
where no imputation performed on missing data. 
 
The estimand uses the composite approach, and is the difference between treatment arms in change from 
baseline to week 24 in COMPASS-31 and MaPS with outcomes after stopping IMP and /or using prohibited 
medication imputed as gaining no further benefit over and above that of the control arm. 
 
Treatment Condition: Efgartigimod or placebo assuming less efficacious outcome post ICE 
Population: Randomized participants with post COVID-19 postural orthostatic tachycardia syndrome as 
defined in FAS. 
Variable/Endpoint(s): Change from baseline to week 24 in the Composite Autonomic Symptom Score 
31/change from baseline to week 24 in the Malmö POTS Symptom Score (MaPS) 
Intercurrent Events (ICE): Composite Approach, with Imputation using MNAR model delta adjustment 
imputation. 
 Delta adjustment will be applied to only treatment arm and ICE occurred; no delta adjustment will be 
performed for placebo arm. Any missing data other than ICE in treatment arm will be imputed using MAR 
assumption. Missing data under placebo arm will be imputed assuming MAR , irrespective of ICEs. The result 
will be created assuming delta=3, 4, 5. Further sensitivity analysis can be performed with different deltas. 
a. 
Early discontinuation of study treatment 
b. Use of any prohibited medications  
Population-level summary: 
Change from baseline mean difference between placebo and efgartigimod in 
COMPASS-31 and MaPS presenting Difference in LS means, corresponding 95% CI and p-value using the 
FAS. 
 
 
 
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Document: 
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Author: 
 
Version Number: 
3.0
 
Version Date:  
02 May 2024
Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
 
Explicit details regarding the imputation of missing values are provided via sample SAS code that is intended to 
demonstrate the application of these strategies. Minor alterations to SAP code may be performed. Example code 
for generating the missing imputed data is as follows: 
 
Identify ICE 1 and ICE 2, 
Seperate patient and ICE , this data will be mergred before applying MNAR 
  
perform MI using MCMC, to impute only the non-monotone missing values (IMPUTE=MONOTONE) 
 
PROC MI DATA=DIA NIMPUTE=500 SEED=9453 OUT=DIA_mono; 
   VAR trt BASVAL change_1-change_4 ; 
   MCMC CHAIN=SINGLE NBITER=200 NITER=100 IMPUTE=MONOTONE; 
RUN; 
 
Merge ICEs patient wise 
Apply MAR for Placebo treated patient with or without ICE it will be  
 
PROC MI DATA=DIA_mono_(where=(trt=0)) NIMPUTE=1 SEED=4648 OUT=DIA_imputed_MAR; 
 
 by _imputation_; 
   VAR trt BASVAL change_1-change_4; 
   CLASS trt; 
   MONOTONE REGRESSION; 
RUN; 
 
 
ICE 
Approach for dealing with the ICE 
Discontinuation  of study 
treatment 
Composite approach:  scores after treatment discontinuation in participants who 
discontinue treatment and refused to stay in the study will in the case of both the 
experimental arm and the control arm be imputed being modelled as gaining no 
further benefit over and above that of the control arm. 
Use of any prohibited 
medication 
Composite approach: assessments after visit x, if the ICE has taken place at visit x 
will in the case of both the experimental arm and the control arm be imputed 
being modelled as gaining no further benefit over and above that of the control 
arm. 
 
 
 
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Author: 
 
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Version Date:  
02 May 2024
Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
Apply MNAR only for those ICE under treatment arm who have intercurrent event other than study treatment 
discontinuation  
 
PROC MI DATA=DIA_mono_(where=(trt=1)) NIMPUTE=1 SEED=4648 OUT=DIA_imputed_MNAR; 
 
  by _imputation_; 
   VAR BASVAL  change_1-change_4; 
   CLASS  ICE;  
   MONOTONE REGRESSION; 
   mnar adjust(change_2 / delta=3 adjustobs=(ICE='2'));  /*ICE=2 means other than  study treatment 
discontinuation  */ 
   mnar adjust(change_3 / delta=3 adjustobs=(ICE='2')); 
   mnar adjust(change_4 / delta=3 adjustobs=(ICE='2')); 
RUN; 
 
If  the above methodology is unable to be undertaken due to the small sample sizes expected at week 12 
analysis or subsequently at week 24, the ANCOVA analysis will be undertaken on observed data only,  
For the change from baseline to 24 weeks for both the COMPASS 31 analysis an ANCOVA will also be 
calculated using the FAS by the Proc Mixed procedure, example code is: 
 
Ods output estimates =est; 
      proc mixed data=COMPASS31 method=REML; 
 
 
class BCOMPASS31 ARMCD ; 
model change = BCOMPASS31 ARMCD /solution; 
 
 
LSMEANS trt / diff=control('0') cl; 
 
ODS OUTPUT Diffs=lsdiffs LSMeans=lsm solutionF=Parms; 
 
BY visit _imputation_; 
 
run; 
(i.e using week 24 data only.) 
 
Combine the imputations using proc MIanalysis 
 
proc mianalyze parms(classvar=full)=lsdiffs; 
     
BY visit; 
      class trt ; 
      modeleffects trt; 
ods output ParameterEstimates=MIAN_lsdiffs; 
run; 
 
 
 
 
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Document: 
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Author: 
 
Version Number: 
3.0
 
Version Date:  
02 May 2024
Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019, 2021 IQVIA. All rights reserved. The contents of this document are confidential 
and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
 
 
14.2. 
Secondary Efficacy 
The secondary efficacy analyses will be performed for the FAS. 
14.2.1. Secondary Efficacy Variables & Derivations 
14.2.1.1. Change from baseline (CFB) to week 24 in the Patient Global Impression of Severity (PGI-S) 
Patient Global Impression of Severity (PGI-S): 
 
Severity of symptoms over the past week (1-week recall) 
 
overall experience of symptoms over the past 2 weeks (2-week recall)  
are both rated on a 4-point type Likert scale, with scores ranging from 1 (none), 2(mild), 3(moderate) and 4 
(severe). 
 
Positive PGIS change (1, 2, 3) indicates worsening
improvement while considering change from baseline to week 24 for both 1 week recall and 2 week recall 
results separately using the FAS for the IAWK12 and  IAWK24. 
Table I: 
PGIS Change 
Improved 3 categories 
CFB = -3 
Improved 2 categories 
CFB =-2 
Improved 1 categories 
CFB =-1 
No Change 
CFB =0 
Worsened 1 category 
CFB =+1 
Worsened 2 categories 
CFB =+2 
Worsened 3 categories 
CFB = +3 
 
The number and percentage of participants with each PGI-S score will be summarized by treatment and time 
point, for the FAS. Number and percentages will also be presented for CFB categories for both 1 week recall 
and 2 week recall responses separately using the FAS for the IAWK12 and IAWK24.. 
 
These PGI-S score will further define as Improvement (with CFB as -3, -2 or -1), No Change (with CFB as 0) 
and Worsening (with CFB as +1, +2, +3).  
 
 
 
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Document: 
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Author: 
 
Version Number: 
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Version Date:  
02 May 2024
Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
 
The proportion of efgartigimod and placebo participants with improvement at week 24 will be compared using, 
 for both the 1 week recall and 2 week recall results using the FAS 
for the IAWK12 and IAWK24. 
14.2.1.2. Patient Global Impression of Change (PGI-C) at week 24 
The Patient Global Impression of Change (PGI-
of change in their overall symptom severity. Overall change in symptoms from the start of IMP to time point is 
rated on a 7-point Likert scale, with scores ranging from Much Better (1), Somewhat Better (2), A Little Better 
(3), No change (4), A Little Worse (5), Somewhat Worse (6), and Much Worse (7). 
 
The number and percentage of participants with each PGI-C score will be summarized by treatment and time 
point, for the FAS for IAWK12and IAWK24. 
 
These PGI-C score will further define as Improvement 
No Change 
Worsening 
 
.  
 
The proportion of efgartigimod and placebo participants with improvement at week 24 will be compared using a 
 for IAWK12 and IAWK24 using the FAS.  
14.2.1.3. Change from baseline to week 24 in the Patient-Reported Outcomes Measurement Information 
System (PROMIS) Fatigue Short Form 8a 
PROMIS Fatigue Short Form 8a assesses the impact and perceived fatigue during the last 7 days, through 8-
question scale with scores ranging from 1 to 5. Scores are converted to a T-score and received within the eCOA 
transfers. 
 
The number and percentage of participants with each PROMIS score will be summarized by treatment and time 
point, for the FAS. T-scores will be descriptively summarized to present absolute value and changes from 
baseline for each visit for IAWK12 and IAWK24 using the FAS. 
 
For change from baseline to week 24 in PROMIS Fatigue Short Form 8a, between treatment group difference 
will be analysed using longitudinal mixed model repeated measures (MMRM) as presented in section 14.1.1.1, 
using FAS except with change from baseline in PROMIS Fatigue as the dependent variable and baseline value 
 
 
 
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Document: 
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Author: 
 
Version Number: 
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Version Date:  
02 May 2024
Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
of PROMIS Fatigue as covariate.  The visits included in the model will be baseline, weeks 2, 4, 12 and 24. 
14.2.1.4. Change from baseline to week 24 in the PROMIS Cognitive Function Short Form 6a 
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 
participant  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. Scores are converted to a T-score and received within the eCOA data transfers. 
 
The number and percentage of participants with each individual PROMIS score will be summarized by 
treatment and time point, for the FAS for the IAWK12 and IAWK24. T-score will be descriptively summarized 
to present absolute value and changes from baseline for each visit. 
 
For change from baseline to week 24 in PROMIS Cognitive, between treatment group difference will be 
analysed using longitudinal mixed model repeated measures (MMRM) as presented in section 14.1.1.1, except 
with change from baseline to week 24 in PROMIS Fatigue as the dependent variable and baseline value of 
PROMIS Cognitive as covariate using FAS for the IAWK12 and IAWK24. The visits included in the model 
will be baseline, weeks 4, 12 and 24. 
14.3. 
Exploratory Efficacy  
The exploratory efficacy analyses and QoL will be performed for the FAS. 
 
Summary statistics will be provided in terms of absolute value and changes from baseline for each visit. 
 
14.3.1. 
  
 
 
 
 
 
 
 
 
 
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Author: 
 
Version Number: 
3.0
 
Version Date:  
02 May 2024
Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
14.3.5. 
 
 
 
 
   
 
 
 
 
 
 
 
 
14.3.6. 
 
 
 
 
 
 
 
 
 
 
 
 
 
15. PHARMACODYNAMIC ANALYSIS  
Pharmacodynamic (PD) effect of efgartigimod will be assessed via, Total IgG. PD analyses will be performed 
 
 
 
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Document: 
BIOSdata\argenx\Efgartigimod\HAB40220\Biostatistics\Documentation\SAP 
Author: 
 
Version Number: 
3.0
 
Version Date:  
02 May 2024
Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019, 2021 IQVIA. All rights reserved. The contents of this document are confidential 
and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
in the SAF for the IAWK12, IAWK24 and FPA.  
 
Total IgG will be summarized using descriptive statistics at each analysis visit. Absolute values, changes from 
baseline, and percent reduction from baseline will be presented. In addition to the planned time points, the 
following time points will also be shown: 
 
Maximum drop from baseline 
 
Minimum postbaseline value 
Additionally, lines chart showing change in Total IgG over time will be prepared.  
 
 
Charts of IgG % change from Baseline by time for each Subject will be generated for the IAWK12 and 
IAWK24.   
 
The mean values to week 12 will be charted by line plot with SE (error bars) by week and by treatment 
for the IAWK12. 
All PD data will be listed. 
16. IMMUNOGENICITY ANALYSIS  
Incidence and prevalence of antidrug antibodies (ADA) against efgartigimod will be assessed in the SAF for the 
FPA. ADAs to efgartigimod is measured at the time points specified in the schedule of activities of protocol, 
primarily at baseline, week 1, 4, 12, 24, and SFV. 
 
Immunogenicity samples are analyzed in a 3-tiered approach: 
 
All samples are evaluated in the ADA screening assay and are scored ADA screening positive (tier 1) or 
negative. 
 
If a sample is scored positive in the ADA screening assay, it is further evaluated in the confirmatory assay 
(tier 2) and is scored confirmed positive (positive immuno-depletion) or confirmed negative (negative 
immuno-depletion). 
 
If a sample is scored as confirmed positive, the samples are further characterized in the ADA titration assay 
(to determine titer).  
If available, a titer result will be reported for the ADA confirmed positive samples. However, a titer result is not 
always available: 
 
If the ADA confirmed positive sample could not be run in the titration assay (e.g., due to insufficient 
immuno-
. 
 
 
 
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Author: 
 
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Version Date:  
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Effective Date: 01Nov2021 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
 
considered ADA positive because it was confirmed positive in the second tier.  
 
he ADA sample status is ADA 
unevaluable. 
An overview of this 3-tiered approach and all possible ADA sample results that will be reported by the 
laboratory is given below. From these reported ADA sample results, a final ADA sample status must be derived 
dur
 
 
 
 
 
 
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Document: 
BIOSdata\argenx\Efgartigimod\HAB40220\Biostatistics\Documentation\SAP 
Author: 
 
Version Number: 
3.0
 
Version Date:  
02 May 2024
Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019, 2021 IQVIA. All rights reserved. The contents of this document are confidential 
and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
the dilution factor).  
 
Frequency tabulations (number and percentages) will be provided with ADA negative/positive/unevaluable 
samples per visit. 
 
Frequency tabulations (number and percentages) will be provided in 1 table for: 
 
ADA unevaluable Participants 
 
ADA baseline positive/negative/unevaluable samples 
 
Participants per ADA participant classification 
 
Prevalence and incidence of ADA 
 
Correlation tables by ADA against efgartigimod participant classification will be provided for the following 
parameters: 
 
Mean drug concentration over time  
 
Mean percent change from baseline in [total IgG] 
 
COMPASS-31 and MaPS  
 
TEAEs by MedDRA SOC and PT 
 
Serious TEAEs by MedDRA SOC and PT 
 
Injection/infusion-related reactions 
 
 
 
ADA against efgartigimod titer values will be summarized using descriptive statistics by ADA 
participant  
 
classification at each analysis visit. 
 
All available data for ADA against efgartigimod will be listed, while also showing the ADA sample 
status and participant classification. 
17. BIOMARKER ANALYSIS  
Frequency tabulations (number and percentages) for categorical variables and summary statistics for continuous 
variables will be provided in terms of absolute value and changes from baseline for each visit for below except 
 
 
 
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Document: 
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Author: 
 
Version Number: 
3.0
 
Version Date:  
02 May 2024
Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019, 2021 IQVIA. All rights reserved. The contents of this document are confidential 
and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
Treatment-emergent adverse events (TEAEs) are defined as AEs with onset on or after the first 
administration of IMP up to and including 60 days after the last IMP administration before the event (refer to 
schematic). 
 
D1: IMP start  D40: Start IMP interruption  
D120: IMP 
restart  
D160: Start IMP disc  
D240: 
Study 
disc  
IMP  
 
IMP  
 
 
TE: D1-D40 
TE: 
D40+60 
days  
Non-TE: 
D101-119  
TE:D120-
D160  
TE: 
D160+60 
days  
Non-
TE: 
>D220  
 
 
AEs will be considered treatment-emergent based on their start date/time. If the AE start date/time is incomplete 
or missing, the AE will be considered treatment-emergent unless the available part of the AE start or stop 
date/time provide evidence that the event did not occur within 60 days from last IMP administration before the 
event. 
 
AE onset and duration will be calculated as follows when start and stop dates are fully known: 
AE onset day (vs. first administration) 
o 
administration: AE start date  date of first administration + 1 day 
o 
AE start date < date of first administration: AE start date  date of first administration  
o 
AE duration (days) = 
o 
AE end date  AE start date + 1 day 
o 
Study discontinuation date =  
o 
AE start date + 1 day (when the AE start date is fully known but the AE is not resolved at the end 
of the study). 
 
 
 
Severity is classed as mild/ moderate/ severe/ life-threatening/ death.  If a participant reports a TEAE more than 
once within that SOC/ PT, the AE with the worst-case severity will be used in the corresponding severity 
summaries. 
 
Relationship
 
 
 
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Author: 
 
Version Number: 
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Version Date:  
02 May 2024
Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019, 2021 IQVIA. All rights reserved. The contents of this document are confidential 
and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
same AE more than once within that SOC/ PT, the AE with the worst-case relationship to IMP will be used in 
the corresponding relationship summaries. 
 
AEs leading to discontinuation of IMP 
 
Adverse event of special interest (AESI) can be serious or nonserious, related, or unrelated to the IMP or 
study procedures. Infections are considered AESIs and are defined as events with a PT that falls under the 
MedDRA SOC 
 
 
Infusion related reactions (IRRs) are defined as all AEs with a MedDRA PT that is listed in either: 
 
MedDRA Hypersensitivity SMQ broad selection 
 
MedDRA Anaphylactic reaction SMQ broad selection 
 
 
 
MedDRA Extravasation events (injections, infusions and implants) SMQ broad selection, excluding 
implantsand occurs within 48 hours of an infusion/injection, or within 2 days if the AE start time is 
not available. In case of partially missing AE start date, the AE will be considered an IRR, unless the 
available parts of the AE start date provide evidence it did not occur within 48 hours of an 
infusion/injection. 
 
table presenting overall TEAEs and a 
data listing along with primary cause of death. 
 
Summary tables will only include TEAEs. However, all AEs reported during the study will be listed. Summary 
tables by SOC and PT will be sorted alphabetically. 
An overview table of AEs will be presented by treatment  to show number and percentage of participants with 
at least one event, and the number of events and the event rate per 100 PYFU, for the SAF at the IAWK12, 
IAWK24 and FPA for the following;; 
 
 
 
TEAEs (IAWK12, IAWK24 and FPA) 
 
Serious TEAEs (IAWK12, IAWK24 and FPA) 
 
 (IAWK12, IAWK24 and FPA) 
 
Fatal TEAEs 
 
 
 
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Version Number: 
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Version Date:  
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
 
Treatment-related TEAEs according to the Principle Investigator (IAWK12, IAWK24 and FPA) 
 
Procedures-related TEAEs (FPA Only) 
 
Serious treatment-related TEAEs (IAWK12, IAWK24 and FPA) 
 
TEAEs leading to IMP discontinuation (IAWK12, IAWK24 and FPA) 
 
TEAEs leading to IMP interruption  
 
TEAEs of special interest (IAWK12, IAWK24 and FPA) 
 
IRRs (IAWK12, IAWK24 and FPA) 
The overview table will also include a 95% Agresti-Min CI (in case <30 participants in each group) or a 95% 
Newcombe CI (in case of >30 participants in each group) CI for the difference in AE rate between efgartigimod 
and placebo.  
 
The event rate per 100 PYFU is defined as 100 * the number of events divided by the sum of the follow-up time 
during which an event is considered treatment-emergent of all participants per treatment arm expressed in years 
(i.e. divided by 365.25). 
 
All AEs, including pretreatment events will be listed. 
18.1.1. All TEAEs 
Summary tables will only include TEAEs and will be presented by System Organ Class (SOC) and Preferred 
Term (PT) for each treatment group. Table will contain number and percentage of participants with at least one 
event and the number of events (except for TEAEs by worst toxicity) for TEAE. These outputs will be provided 
for: 
 
TEAEs 
 
Serious TEAEs 
 
Nonserious TEAEs 
 
 
TEAEs by worst toxicity (FPA Only) 
 
Treatment-related TEAEs 
 
Procedure-related TEAEs 
 
Serious treatment-related TEAEs 
 
TEAEs leading to IMP discontinuation 
 
 
 
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Author: 
 
Version Number: 
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Effective Date: 01Nov2021 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
 
TEAEs of special interest by worst outcome 
 
IRRs 
 
Serious IRR (IAWK12, IAWK24 and FPA) 
 
 
18.2. 
Laboratory Evaluations 
Results from the central laboratory will be included in the reporting of this study for serum chemistry and 
hematology, coagulation, urinalysis, serology (eg, viral marker testing), and specialty laboratory parameters. A 
list of laboratory assessments to be included in the outputs is included in Appendix 2 (Table 2) of the protocol.  
These are mainly as follows. 
Table K: 
Laboratory Assessments 
Hematology 
RBC count, platelet count, hemoglobin, 
hematocrit, MCV, MCH, %reticulocytes, WBC 
count with differential: neutrophils, eosinophils, 
lymphocytes, basophils, monocytes 
Serum chemistry 
ALT, AST, albumin, blood urea nitrogen, 
creatinine, glucose, potassium, chloride 
bicarbonate, sodium, total protein, 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 of the protocol) 
Specialty laboratory tests: 
 
 
CRP, ESR, TSH 
 
Normal ranges are available as provided by the central laboratory and results will be presented in standardized 
units unless specified otherwise. Clinically significant changes occurring during the study are recorded as an 
 
 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
AE. 
 
 
quantification (ULQ), will be converted to X for the purpose of descriptive summaries, but will be presented as 
e listings. For Toxicity grades the <X and >X will be represented within 
the scores.  
Continuous laboratory parameters will be summarized using descriptive statistics of actual values and changes 
from baseline at each analysis visit. Categorical parameters will only be listed.  
The following summaries will be provided for laboratory data: 
 
Continuous laboratory parameters to be summarized using descriptive statistics of actual values and changes 
from baseline at each analysis visit for SAF at the IAWK12, IAWK24 and FPA. 
Laboratory toxicity grades to be presented as cross-tabulations of the toxicity at each postbaseline analysis visit 
and at the worst-case analysis visit versus the baseline toxicity for SAF at the IAWK12, IAWK24 and FPA. 
Laboratory abnormalities as cross-tabulations of the abnormality at each postbaseline analysis visit and at the 
worst-case analysis visit versus the baseline abnormality for SAF at the IAWK12, IAWK24 and FPA.  
The number of participants with treatment-emergent abnormalities will also be shown. The denominator for the 
percentage is the total number of participants per treatment arm and per analysis visit in the SAF. 
Listing of participants with any post-
 
18.2.1. Laboratory Specific Derivations 
All datapoints obtained after informed consent up to 60 days after IMP discontinuation or database cutoff will 
be considered.  
The following abnormality categories will be defined: 
 
Low: value < lower limit of normal range 
 
Normal: lower limit of normal rang
 
 
High: value > upper limit of normal range 
 
Notes: 
 
Classification will be done in standardized units, using non imputed values and limits. 
 
For the worst-case analysis visits, as defined in section 6.4, an additional category low + high is 
defined in case there are both low and high post-baseline values. 
Toxicity grades will be computed according to the National Cancer Institute (NCI) common toxicity criteria for 
 
 
 
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Author: 
 
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Version Date:  
02 May 2024
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Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
adverse events (CTCAE) toxicity grading list (version 5.0). The implementation of these toxicity grades for 
analysis is presented in appendix 2. Only the parameters described in appendix 2 will be computed, according to 
the declared limits for each grade. 
 
Only lab parameters specified within the protocol will be analyzed and, only those both in the protocol and in 
appendix 2 will be considered for toxicity, all others that are in the protocol and not in appendix 2  but have 
High/Low/Normal will be presented in the abnormality table. 
18.3. 
ECG Evaluations 
Results from the central ECG (Electrocardiogram) Reading Centre will be included in the reporting of this 
study. Single 12-lead ECG(s) will be obtained using an ECG machine. The following ECG parameters will be 
reported for this study: 
 
HR (bpm) 
 
PR Interval (msec) 
 
QRS Interval (msec) 
 
RR Interval (msec) 
 
QT Interval (msec) 
 
QTcF Interval (msec)  
 
QTcB Interval (msec) 
All datapoints obtained after informed consent up to 60 days after IMP discontinuation or database cutoff will 
be considered. 
The following summaries will be provided for ECG data: 
ECG parameters will be summarized using descriptive statistics at each analysis visit for the SAF for FPA only. 
Abnormalities of the actual values will be presented as cross-tabulations of the abnormality at each postbaseline 
analysis visit and at the worst-case analysis visit versus the baseline abnormality. Numbers and cumulative 
numbers (QTc only) of participants with treatment-emergent abnormalities will also be shown. The 
denominator for the percentage is the total number of participants per treatment arm and per analysis visit in the 
SAF for FPA only.  
Abnormalities of the QTc changes will be presented as tabulations of the change abnormality at each 
postbaseline analysis visit and at the worst-case analysis visit. Cumulative numbers of participants with change 
abnormalities will also be shown. The denominator for the percentage is the total number of participants per 
treatment arm and per analysis visit in the SAF. Produced for the FPA only. 
All ECG data will be listed, but only for participants with any postbaseline abnormality. 
 
 
 
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Author: 
 
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Version Date:  
02 May 2024
Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
18.3.1. ECG Abnormal Criteria 
Abnormal quantitative ECG measurements will be identified in accordance with the following predefined 
abnormal criteria for HR, QRS and PR interval: 
 
 
HR (bpm) 
PR (ms) 
QRS (ms) 
Low 
<40 
<120 
- 
Normal 
40-100 
120-220 
0-120 
High 
>100 
>220 
>120 
Note: For the worst-case analysis visit, as defined in Section 6.4, an additional category "low + high" is defined 
if there are both low and high postbaseline values. 
Absolute values for QT interval, QTcB interval and QTcF will be classified as: 
Actual values: 
o 
 
o 
]450; 480] 
o 
]480; 500] 
o 
> 500 
Changes from baseline: 
o 
 
o 
]30; 60] 
o 
> 60 
Note: The worst-case, as defined in Section 6.4, is the highest postbaseline value and associated change. 
18.4. 
Vital Signs 
The following Vital Signs measurements will be reported for this study for SAF at the IA and FPA.: 
 
Systolic Blood Pressure (mmHg) 
 
Diastolic Blood Pressure (mmHg) 
 
Pulse Rate (bpm) 
 
Respiratory Rate (breaths/min) 
 
Oral 
 
  
Vital signs parameters will be summarized using descriptive statistics at each analysis visit. Abnormalities will 
 
 
 
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Version Date:  
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Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
19. PHARMACOKINETIC ANALYSIS  
PK analyses will be performed in the PKAS. 
At IMP administration visits, PK blood samples will be collected pre-dose (within the 2 hours before IMP 
infusion) and post-dose (within the 30 minutes after the end of the infusion). 
A listing of PK blood sample collection times, derived sampling time deviations, and concentrations will be 
provided for the PKAS for FPA only.  
Serum concentrations will be summarized using descriptive statistics for efgartigimod. Concentrations that are 
BLQ will be treated as zero for the computation of descriptive statistics. If at least one BLQ value is reported at 
a specific time point, the GM and geometric CV% for that time point will not be calculated. The 
pharmacokineticist will determine a strategy for dealing with data affected by protocol deviations or events 
which may impact the quality of PK concentration data on a case-by-case basis with input from the study 
physician, as needed. Examples of protocol deviations or events include, but may not be limited to the 
following: 
 
When a predose sample is taken after IMP administration. 
 
When the most recent IMP administration before the scheduled pre-dose PK sample is missed (not 
applicable for Day 1). 
 
When post-dose samples are collected following the occurrence of incomplete or incorrect dosing.  
 
Any event related to sample collection, handling and storage that affects the integrity of the samples 
and/or the bioanalytical results. 
 
When pre-dose PK samples are taken outside the visit windows. 
 
The study visit windows are ±2 days.  
In the case of a protocol deviation or event which may impact the quality of PK, the PK data collected may be 
excluded from the summaries and a reason for the exclusion of the data point will be added in the appropriate 
listing. 
The strategy for the population PK analysis and any related exposure-response modeling utilizing the 
efgartigamod concentration and IgG data collected from this study will be outlined separately in the modeling 
data analysis plan. 
 
 
 
 
 
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Author: 
 
Version Number: 
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Version Date:  
02 May 2024
Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019, 2021 IQVIA. All rights reserved. The contents of this document are confidential 
and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
20. REFERENCES  
1. Dobson, A. J. (2002). An introduction to generalized linear models, 2nd ed. Chapman & Hall/CRC. 
2. ICH-E3 Structure and Content of Clinical Study Reports  Step 4: 30 Nov 1995. 
3. ICH Topic E6 (R2) Guideline for Good Clinical Practice  Step 4: 9 Nov 2016. 
4. ICH Topic E9 Statistical Principles for Clinical Trials  Step 4: September 1998. 
5. ICH Topic E9 (R1) Statistical Principles for Clinical Trials, Addendum on Estimands and Sensitivity 
Analysis is Clinical Trials  Step 4: November 2019. 
6. ICH guideline E14: the clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for 
non-antiarrhythmic drugs (R3)  questions and answers: January 2016. 
7. Guideline on Missing Data in Confirmatory Clinical Trials - CHMP, 2 July 2010  
 
 
 
 
 
 
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Document: 
BIOSdata\argenx\Efgartigimod\HAB40220\Biostatistics\Documentation\SAP 
Author: 
 
Version Number: 
3.0
 
Version Date:  
02 May 2024
Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019, 2021 IQVIA. All rights reserved. The contents of this document are confidential 
and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
IQVIA Output Conventions 
Outputs will be presented according IQVIA Standard conventions. Kindly refer to output templates for 
additional information. 
Dates & Times 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
Presentation of Treatment Groups 
For outputs, treatment groups will be represented as follows and in the given order: 
Treatment Group for Tables, Listings and Figures 
Efgartigimod 
Placebo 
In the general characteristics analysis, an overall total will be added to summarize all participants over 
treatments. Overall totals will be shown last. 
Listings 
All listings will be ordered by the following (unless otherwise indicated in the template): 
 
Randomized 
ascending dose group] and then control/ placebo  
 
Center-participant ID,  
 
Date (where applicable), 
For listings where non-randomized participants are included, these will appear in a category after the 
 
 
 
 
 
 
 
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Version Date:  
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Template No.:  CS_TP_BS016 Revision 7 
Reference:  CS_WI_BS005 
Effective Date: 01Nov2021 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
APPENDIX 2. TOXICITY GRADES 
The table below shows how the CTCAE, v5.0: 27 Nov 2017 will be implemented in the analysis. 
Paramater 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Alanine amino 
transferase 
 
>1-3 *ULN 
>3-5 *ULN 
>5-20 *ULN 
>20 *ULN 
Albumin 
g/L 
<LLN-30 
<30-20 
<20 
- 
g/dL 
<LLN-3 
<3-2 
<2 
- 
Alkaline phosphatase 
 
>1.0-2.5 
*ULN 
>2.5-5.0 
*ULN 
>5.0-20.0 
*ULN 
>20.0 *ULN 
Aspartate amino 
transferase 
 
>1-3 *ULN 
>3-5 *ULN 
>5-20 *ULN 
>20 *ULN 
Bilirubin (total) 
 
>1.0-1.5 
*ULN 
>1.5-3.0 
*ULN 
>3.0-10.0 
*ULN 
>10.0 *ULN 
Calcium (ionized) low 
mmol/L 
<LLN-1.0 
<1.0-0.9 
<0.9-0.8 
<0.8 
mg/dL 
<LLN-4.0 
<4.0-3.6 
<3.6-3.2 
<3.2 
Calcium (ionized) high 
mmol/L 
>ULN-1.5 
>1.5-1.6 
>1.6-1.8 
>1.8 
mg/dL 
>ULN-6.0 
>6.0-6.4 
>6.4-7.2 
>7.2 
Calcium (corrected) 
low 
mmol/L 
<LLN-2.00 
<2.00-1.75 
<1.75-1.50 
<1.50 
mg/dL 
<LLN-8 
<8-7 
<7-6 
<6 
Calcium (corrected) 
high 
mmol/L 
>ULN-2.9 
>2.9-3.1 
>3.1-3.4 
>3.4 
mg/dL 
>ULN-11.5 
>11.5-12.5 
>12.5-13.5 
>13.5 
Creatinine 
 
>1.0-1.5 
*ULN 
>1.5-3.0 
*ULN 
>3.0-6.0 
*ULN 
>6.0 *ULN 
Glucose (fasting) low 
mmol/L 
<LLN-3.0 
<3.0-2.2 
<2.2-1.7 
<1.7 
Potassium low 
mmol/L 
- 
<LLN-3.0 
<3.0-2.5 
<2.5 
mEq/L 
- 
<LLN-3.0 
<3.0-2.5 
<2.5 
Potassium high 
mmol/L 
>ULN-5.5 
>5.5-6.0 
>6.0-7.0 
>7.0 
mEq/L 
>ULN-5.5 
>5.5-6.0 
>6.0-7.0 
>7.0 
Sodium low 
mmol/L 
<LLN-130 
- 
<130-120 
<120 
mEq/L 
<LLN-130 
- 
<130-120 
<120 
 
 
 
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and proprietary to IQVIA Holdings Inc. and ts subsidiaries. Unauthorized use  disclosure or reproduction is strictly prohibited. 
Paramater 
Unit 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Sodium high 
mmol/L 
>ULN-150 
>150-155 
>155-160 
>160 
mEq/L 
>ULN-150 
>150-155 
>155-160 
>160 
Lymphocytes (absolute 
count) low 
giga/L 
<LLN-0.80 
<0.80-0.50 
<0.50-0.20 
<0.20 
counts/mm3 
<LLN-800 
<800-500 
<500-200 
<200 
Lymphocytes (absolute 
count) high 
giga/L 
- 
>4-20 
>20 
- 
counts/mm3 
- 
>4000-20000
>20000 
- 
Neutrophils (absolute 
count) low 
giga/L 
<LLN-1.5 
<1.5-1.0 
<1.0-0.5 
<0.5 
counts/mm3 
<LLN-1500 
<1500-1000 
<1000-500 
<500 
Platelets 
giga/L 
<LLN-75 
<75-50 
<50-25 
<25 
White blood cells 
giga/L 
<LLN-3 
<3-2 
<2-1 
<1 
counts/mm3 
<LLN-3000 
<3000-2000 
<2000-1000 
<1000 
CTCAE= Common Terminology Criteria for Adverse Events; LLN=lower limit of normal; ULN=upper limit of 
normal , values within normal ranges will be presented as Grade 0 for toxicity outputs. 
Note: In case ULN/LLN is higher/lower than the upper/lower limit of grade 1 (or even higher grades), ULN/LLN 
will be ignored and only the fixed values of CTCAE will be considered. 
 
 
 
 
 
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