Double-blind, Randomized, Placebo-controlled Phase 3 Study Evaluating Efficacy and Safety of IgPro20 (Subcutaneous Immunoglobulin, HIZENTRA®) in Post-COVID-19 Postural Orthostatic Tachycardia Syndrome (POTS)
Phase: PHASE3
Conditions: Post-COVID Postural Orthostatic Tachycardia Syndrome
Sponsor: CSL Behring

 
 
 
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Template: RnD-FORM-000203241, v5.0 
 
Template Effective Date: 19 May 2023 
CLINICAL STUDY PROTOCOL 
Study Title: 
Double-blind, Randomized, Placebo-controlled Phase 3 study 
Evaluating Efficacy and Safety of IgPro20 (subcutaneous 
immunoglobulin, HIZENTRA®) in post-COVID-19 Postural 
Orthostatic Tachycardia Syndrome (POTS)  
Study Number: 
IgPro20_3010 
Version: 
Original 
Study Product: 
IgPro20 (subcutaneous immunoglobulin, HIZENTRA®) 
Brief Title: 
Double-blind, Randomized, Placebo-controlled Study 
Evaluating Efficacy and Safety of IgPro20 in post-COVID-19 
POTS 
Study Phase: 
Phase 3 
Sponsor Name and Legal 
Registered Address: 
CSL Behring LLC 
1020 First Avenue 
King of Prussia, Pennsylvania 19406 
United States of America 
Regulatory Agency Identifier Number(s): 
Pending 
EudraCT and / or EU 
Clinical Trial number: 
2023-508744-22-00 
IND: 
29874 
WHO: 
NA 
ClinicalTrials.gov: 
NA 
Protocol Version Date: 
11 April 2024 

CSL Behring 
SPONSOR SIGNATORY 
 
CSP Version: Original 
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Date 
(DD Month YYYY) 
lgPro20 
IgPro20 3010 
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PPD
PPD

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LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR 
CONDUCT OF THE STUDY 
A list of the personnel and organizations responsible for the conduct of the study will be supplied 
to study sites as part of the Investigator’s Study File. This list will be updated by the Sponsor and 
provided to the study sites as needed. 

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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase  
BP 
Blood pressure 
CIDP 
Chronic inflammatory demyelinating polyneuropathy 
COMPASS-31 
Composite Autonomic Symptom Score 31 
COVID-19 
Coronavirus disease 2019 
CSP 
Clinical Study Protocol 
eCOA 
Electronic clinical outcomes assessment 
eCRF 
Electronic case report form 
ECG 
Electrocardiogram 
EOS 
End of Study 
EQ-5D-5L 
EuroQol-5 dimension-5 levels 
GCP 
Good Clinical Practice 
GCSP 
Global Clinical Safety and Pharmacovigilance 
GI 
Gastrointestinal 
HR 
Heart rate 
HRT 
Hormone replacement therapy 
HRQoL 
Health-related Quality of Life 
ICE 
Intercurrent event 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
ISR 
Infusion site reaction 
ITT 
Intention-to-treat 
IVIG 
Intravenous immunoglobulin 

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Abbreviation 
Term 
MI 
Multiple imputation 
OHQ 
Orthostatic Hypotension Questionnaire 
OI 
Orthostatic intolerance 
PCR 
Polymerase chain reaction 
PGI-C 
Patient Global Impression of Change 
PGI-S 
Patient Global Impression of Severity 
PID 
Primary immunodeficiency 
PK 
Pharmacokinetics 
POTS 
Postural Orthostatic Tachycardia Syndrome 
PP 
Per-protocol 
PRO 
Patient-reported outcomes 
PROMIS 
Patient-reported Outcomes Measurement Information System 
QoL 
Quality of Life 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 
SCIG 
Subcutaneous immunoglobulin 
SD 
Standard deviation 
SF-12 
Short Form – 12 Item 
TEAE 
Treatment-emergent adverse event 
TS 
total score 
ULN 
Upper limit of normal 
US 
United States 
WPAI:SHP 
Work Productivity & Activity Impairment: Specific Health Problems 

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TABLE OF CONTENTS 
SPONSOR SIGNATORY ...............................................................................................................2 
LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR CONDUCT 
OF THE STUDY ..........................................................................................................3 
LIST OF ABBREVIATIONS ..........................................................................................................4 
TABLE OF CONTENTS .................................................................................................................6 
LIST OF TABLES .........................................................................................................................11 
LIST OF FIGURES .......................................................................................................................11 
1. 
PROTOCOL SUMMARY ..........................................................................................12 
1.1. 
Synopsis ......................................................................................................................12 
1.2. 
Study Schema .............................................................................................................18 
1.3. 
Schedule of Activities .................................................................................................19 
1.3.1. 
Schedule of Activities for Screening ..........................................................................19 
1.3.2. 
Schedule of Activities for the Double-blind and Open-label Treatment 
Periods ........................................................................................................................20 
1.3.3. 
Schedule of Activities: Pharmacokinetic Sampling in a Subset of Subjects at 
Week 41 ......................................................................................................................24 
2. 
INTRODUCTION ......................................................................................................25 
2.1. 
Background .................................................................................................................25 
2.2. 
Study Rationale ...........................................................................................................26 
2.3. 
Benefit / Risk Assessment ..........................................................................................27 
2.3.1. 
Benefit Assessment .....................................................................................................27 
2.3.2. 
Risk Assessment .........................................................................................................28 
2.3.3. 
Benefit / Risk Conclusion ...........................................................................................29 
3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS ..................................................30 
4. 
STUDY DESIGN .......................................................................................................34 
4.1. 
Overall Design ............................................................................................................34 
4.2. 
Scientific Rationale for Study Design ........................................................................34 
4.3. 
Dose Rationale ............................................................................................................36 
4.4. 
Start of Study Definition .............................................................................................36 
4.5. 
End of Study Definition ..............................................................................................36 
5. 
STUDY POPULATION .............................................................................................38 
5.1. 
Inclusion Criteria ........................................................................................................38 

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5.2. 
Exclusion Criteria .......................................................................................................40 
5.3. 
Lifestyle Considerations .............................................................................................42 
5.4. 
Screen Failure .............................................................................................................43 
6. 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY...........................44 
6.1. 
Investigational ProductS .............................................................................................44 
6.2. 
Other Study Interventions ...........................................................................................45 
6.3. 
Management of Investigational Product(s) .................................................................45 
6.4. 
Assignment of Subjects to Treatment Groups and Blinding ......................................45 
6.4.1. 
Randomization ............................................................................................................45 
6.4.2. 
Blinding ......................................................................................................................46 
6.5. 
Selection of Doses in the Study ..................................................................................47 
6.6. 
Selection and Timing of Dose for Each Subject .........................................................47 
6.7. 
IMP Infusion Training ................................................................................................47 
6.8. 
Dose Modification ......................................................................................................48 
6.9. 
Investigational Product Compliance ...........................................................................48 
6.10. 
Access to Investigational Product After the End of the Study ...................................48 
6.11. 
Overdose .....................................................................................................................48 
6.12. 
Prior and Concomitant Therapy ..................................................................................49 
7. 
SUBJECT WITHDRAWAL AND DISCONTINUATION OF 
INVESTIGATIONAL PRODUCT ............................................................................50 
7.1. 
Discontinuation of Investigational Product ................................................................50 
7.1.1. 
Temporary Interruption ..............................................................................................50 
7.1.2. 
Stopping Criteria for Investigational Product .............................................................50 
7.2. 
Subject Withdrawal from the Study ...........................................................................51 
7.3. 
Lost to Follow-up .......................................................................................................52 
7.4. 
Replacement Policy ....................................................................................................52 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................53 
8.1. 
Screening Assessments ...............................................................................................53 
8.2. 
Efficacy Assessments .................................................................................................54 
8.2.1. 
Standardized Standing Test ........................................................................................54 
8.2.2. 
Patient-reported Outcomes .........................................................................................54 
8.3. 
Safety Assessments .....................................................................................................57 

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8.3.1. 
Clinical Safety Laboratory Assessments ....................................................................58 
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Events ..........................58 
8.5. 
Pharmacokinetics ........................................................................................................59 
8.6. 
Biomarkers ..................................................................................................................59 
8.6.1. 
Autoantibodies and Disease Biomarkers in Blood .....................................................59 
8.6.2. 
Optional Blood Transcriptomics Analysis..................................................................59 
8.6.3. 
Optional Future Research ...........................................................................................60 
8.7. 
Genomics ....................................................................................................................60 
8.8. 
Immunogenicity Assessments ....................................................................................60 
8.9. 
Medical Resource Utilization and Health Economics ................................................60 
9. 
STATISTICAL CONSIDERATIONS .......................................................................61 
9.1. 
Statistical Hypotheses .................................................................................................61 
9.2. 
Sample Size Determination ........................................................................................61 
9.3. 
Analysis Sets ...............................................................................................................62 
9.3.1. 
Screened Analysis Set .................................................................................................62 
9.3.2. 
Intention-to-Treat Analysis Set ...................................................................................62 
9.3.3. 
Per-Protocol Analysis Set ...........................................................................................62 
9.3.4. 
Safety Analysis Set .....................................................................................................62 
9.3.5. 
Pharmacokinetic Analysis Set ....................................................................................62 
9.4. 
Statistical Analyses and Methods ...............................................................................63 
9.4.1. 
General Considerations ...............................................................................................63 
9.4.2. 
Efficacy Analyses .......................................................................................................63 
9.4.3. 
Multiplicity .................................................................................................................68 
9.4.4. 
Multiple Imputation ....................................................................................................68 
9.4.5. 
Tipping Point Analysis ...............................................................................................69 
9.4.6. 
Exploratory Analysis ..................................................................................................69 
9.4.7. 
Safety Analyses ..........................................................................................................69 
9.4.8. 
Pharmacokinetics Analyses ........................................................................................70 
9.4.9. 
Pharmacodynamic and Biomarker Analyses ..............................................................70 
9.4.10. 
Pharmacokinetic / Pharmacodynamic Analyses .........................................................70 
9.4.11. 
Other Analyses ............................................................................................................70 
9.4.12. 
Interim Analysis ..........................................................................................................71 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................72 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................72 
10.1.1. 
Clinical Trial Research Agreement ............................................................................72 
10.1.2. 
Regulatory and Ethics Considerations ........................................................................72 
10.1.3. 
Informed Consent Process ..........................................................................................73 
10.1.4. 
Data Protection ...........................................................................................................73 
10.1.5. 
Dissemination of Clinical Study Information and Data .............................................74 
10.1.6. 
Data Quality Assurance ..............................................................................................74 
10.1.7. 
Patient Recruitment ....................................................................................................75 
10.1.8. 
Committees Structure .................................................................................................75 
10.1.9. 
Source Documents ......................................................................................................75 
10.1.10. 
Premature Site Closure and Study Termination .........................................................76 
10.1.11. 
Publication Policy .......................................................................................................76 
10.2. 
Adverse Events and Serious Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .....................................................77 
10.2.1. 
Definitions ..................................................................................................................77 
10.2.2. 
Assessment of Severity ...............................................................................................79 
10.2.3. 
Assessment of Causality .............................................................................................79 
10.2.4. 
Observation Period for Adverse Events .....................................................................79 
10.2.5. 
Follow-up of Adverse Events .....................................................................................80 
10.2.6. 
Adverse Event Reporting ............................................................................................80 
10.2.7. 
IRB / IEC Reporting Requirements ............................................................................82 
10.3. 
Contraceptive Guidance ..............................................................................................82 
10.3.1. 
Definitions ..................................................................................................................82 
10.3.2. 
Contraception Guidance .............................................................................................83 
10.4. 
Study Assessment and Procedure Considerations ......................................................85 
10.4.1. 
Optional, On-demand Alternative Visit Modalities ....................................................85 
10.4.2. 
Use of Electronic Clinical Outcomes Assessment Solution .......................................85 
10.4.3. 
Genomics: Use and Analysis of DNA ........................................................................86 
10.5. 
Country-specific Requirements ..................................................................................86 
11. 
REFERENCES ...........................................................................................................87 

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APPENDIX 1. CLINICAL STUDY PROTOCOL AMENDMENT HISTORY ........................92 
APPENDIX 2. PRINCIPAL INVESTIGATOR SIGNATURE .................................................93 
 

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LIST OF TABLES 
Table 1: 
Summary of Safety Concerns Pertaining to IgPro20a ................................................28 
Table 2: 
Objectives, Endpoints, and Estimands........................................................................30 
Table 3: 
Pharmaceutical Properties and Formulation ...............................................................44 
Table 4: 
Safety Assessments .....................................................................................................57 
Table 5: 
Attributes of Primary and Key Secondary Estimand ..................................................64 
Table 6: 
Definitions of Adverse Event Severity .......................................................................79 
Table 7: 
Contraceptives Allowed During the Study .................................................................83 
Table 8: 
Optional, On-demand Alternative Visit Modalities ....................................................85 
LIST OF FIGURES 
Figure 1: 
Overall Study Schema ................................................................................................18 
Figure 2: 
Acceptable Methods for Confirming a SARS-CoV-2 Infection .................................40 
 

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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Study Title 
Double-blind, Randomized, Placebo-controlled Phase 3 Study Evaluating Efficacy and Safety of 
IgPro20 (subcutaneous immunoglobulin, HIZENTRA®) in post-COVID-19 Postural Orthostatic 
Tachycardia Syndrome (POTS) 
Development Phase: 3 
 
Objective(s) 
The primary objective of this study is to evaluate the efficacy of IgPro20 in comparison with placebo in 
adult subjects with post-COVID POTS. 
Overall Design 
This is a prospective, phase 3, multicenter, double-blind, randomized placebo-controlled study to 
investigate the efficacy, safety, and pharmacokinetics (PK) of repeat doses of IgPro20 in subjects with 
post SARS-CoV-2 infection 2019 postural orthostatic tachycardia syndrome (post-Coronavirus Disease 
2019 [COVID-19] POTS, hereafter referred to as post-COVID POTS). 
Eligible subjects will be randomized in a 2:1 ratio to receive subcutaneous (SC) infusions of IgPro20 at 
doses of 
g/kg/week or placebo for 24 weeks followed by an Open-label Treatment Period of 
28 weeks as depicted in Section 1.2. 
Study Course for Individual Subject 
The study will consist of a Screening Period of up to 4 weeks, a Double-blind Treatment Period 
(placebo-controlled) of 24 weeks, an Open-label Treatment Period of 28 weeks, and a 4-week Safety 
Follow-up Period after the last investigational medicinal product (IMP) administration. 
During the Double-blind Treatment Period, at least the first infusion for Week 1 and Week 2 are 
mandatory on site; training and supervised IMP SC infusions will be conducted at these site visits on 
Week 1 and Week 2. Optional visits can occur at Weeks 3 and 4 for infusion training only. The next 
mandatory visit is Week 5. 
Following the Double-blind Treatment Period, subjects will receive open-label treatment for 28 weeks 
and enter a 4-week Safety Follow-up Period after the last IMP administration. The first infusion of 
Week 25 should also occur on site under supervision as some subjects will be switched from placebo to 
active treatment. 
Study Duration for Individual Subject 
The estimated overall study duration for an individual subject will be approximately 60 weeks 
(15 months), based on the durations of the following study periods: 
• 
Screening Period: 4 weeks 
• 
Double-blind Treatment Period: 24 weeks 
• 
Open-label Treatment Period: 28 weeks 
• 
Safety Follow-up Period: 4 weeks 
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Number of Subjects 
Approximately 177 adult subjects with a confirmed diagnosis of post-COVID POTS will be enrolled 
into the study.  
Note: Subjects are considered “enrolled” in the study when they, or their legally acceptable 
representative, have agreed to participate in a clinical study after completing the informed consent 
process and screening. Potential subjects who are screened to determine their eligibility but fail 
screening or do not meet all eligibility criteria, are not considered enrolled. 
Diagnosis and Main Enrollment Criteria 
Inclusion Criteria 
1. Provide written informed consent and be willing and, in the opinion of the investigator, able to 
adhere to all protocol requirements 
2. Males and females aged ≥18 at the time of providing written informed consent 
3. Diagnosis of post-COVID POTS, defined by both:  
• 
Preceding COVID-19 infection, based on confirmed historical documentation of the 
following:  
- Documented history of SARS-CoV-2 infection (documented by antigen or polymerase 
chain reaction [PCR] test) 
OR  
- Documented clinical diagnosis of SARS-CoV-2 infection, based on the following 
criteria: 
1. One of the following documented physician-reported criteria: 
• 
COVID-19 specific treatment (eg, Nirmatrelvir + Ritonavir / Paxlovid, 
Remdesivir / Veklury, Molnupiravir / Lagevrio) 
OR 
• 
Documentation of one of the following ICD-10 codes: U07.1 (COVID-19, 
virus identified), U07.2** (COVID-19, virus not identified), U09.9** (post-
COVID-19 condition, unspecified) 
AND  
2. Documented patient-reported signs or symptoms*  
AND  
3. Documented patient-reported positive self-administered SARS-CoV-2 antigen 
test 
*Acceptable signs or symptoms: 
• 
Acute onset of fever AND cough (influenza-like illness) 
OR  

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• 
Any 3 or more of the following signs or symptoms: Fever, cough, general weakness 
/ fatigue, headache, myalgia, sore throat, coryza, dyspnoea, nausea, diarrhea, 
anorexia 
**Subjects with documentation of the ICD-10 codes U07.2 and U09.9 need to be discussed 
with the Sponsor’s Internal Medical Monitor to confirm eligibility based on entirety of 
documented evidence for preceding SARS-CoV-2 infection 
AND 
• 
Onset of POTS symptoms developing within 4 months after COVID-19 infection, as 
defined per consensus criteria [Vernino et al, 2021]  
– A sustained HR increase of ≥ 30 bpm [≥ 40 bpm for subjects aged 18 to 19 years] 
within 10 minutes of head-up tilt or standing test, in the absence of orthostatic 
hypotension (ie, sustained 20 mmHg decrease in SBP)  
AND 
– The presence of post-COVID POTS with persisting symptoms (eg, brain fog, fatigue, 
palpitations) for at least 3 months  
4. Composite Autonomic Symptom Score 31 (COMPASS-31) score of at least 40 at the 
Screening visit 
5. Positive confirmatory standardized standing test (ie, HR increase of ≥ 30 bpm [≥ 40 bpm for 
subjects aged 18 to 19 years] within 10 minutes in the absence of orthostatic hypotension) at 
the Screening visit  
Exclusion Criteria 
1. Treatment with IgG or plasmapheresis within 12 weeks before Screening 
2. Symptoms and / or diagnosis of or receiving treatment for POTS before COVID-19 infection 
3. Prior diagnosis of or receiving current treatment at Screening for the following conditions 
(unless onset was related to the inciting POTS-associated COVID-19 infection):  
• 
Neurologic conditions such as peripheral neuropathy, myalgic encephalomyelitis 
encephalitis / chronic fatigue syndrome, stroke, spinal cord injury or any known lesions in 
the central nervous system by imaging or neurological exam  
• 
Autoimmune conditions such as Sjögren’s syndrome, autoimmune autonomic neuropathy, 
multiple sclerosis, Crohn’s disease, celiac disease, lupus erythematosus, rheumatoid 
arthritis, myasthenia gravis  
• 
Pre-existing psychiatric disorders such as generalized anxiety disorder (formally 
diagnosed), anorexia nervosa, disorders causing hyperventilation  
• 
Endocrine disorders such as hyperthyroidism, pheochromocytoma   
• 
Cardiac disorders causing sinus tachycardia such as inappropriate sinus tachycardia, or 
arrythmias 

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• 
Other disorders / conditions causing sinus tachycardia such as Ehlers Danlos syndrome, 
mast cell activation syndrome, fever, pain, infection, moderate to severe anemia, 
hypovolemia or severe deconditioning caused by prolonged bed rest 
4. Presence of active infections such as: 
• 
Human immunodeficiency virus infection (or history of) 
• 
Hepatitis B: subjects who are hepatitis B core antibody-positive and who are hepatitis B 
surface antibody-negative will need to have a negative hepatitis B virus PCR result before 
enrollment. Hepatitis B surface antigen-positive or hepatitis B virus PCR-positive subjects 
will be excluded 
• 
Hepatitis C: subjects who are hepatitis C virus antibody-positive will need to have a 
negative hepatitis C virus PCR result before enrollment. Hepatitis C PCR-positive subjects 
will be excluded 
• 
Any uncontrolled systemic infection 
• 
Active SARS-CoV-2 infection 
Investigational Product(s), Dosage, and Mode of Administration 
IgPro20 is a 20% ready-to-use liquid formulation of polyvalent human IgG for SC administration 
produced by CSL Behring. The IgG portion represents all IgG subclasses present in human plasma. 
IgG function (fragment crystallizable region and antigen binding fragment mediated activity) is 
retained. The sterile 20% IgG solution is stabilized with 250 mmol/L L-proline at pH 4.8. IgPro20 also 
contains 8 to 30 mg/L polysorbate 80 (P80). It has a low sodium content (< 10 mmol/L), with an 
osmolality of approximately 380 mOsmol/kg, and does not contain any preservatives. 
In this study, IgPro20 will be administered at 
g/kg/week at a flow rate of up to 50 mL/h/site. 
The placebo comparator contains 2% human albumin solution in 250 mmol/L L-proline and 20 mg/L 
polysorbate 80. Placebo will be volume-matched for weekly administration. 
Criteria for Evaluation 
Primary Endpoint 
• 
Proportion of subjects no longer meeting diagnostic criteria of post-COVID POTS as measured 
by standardized standing test (ie, no longer experiencing HR increase of ≥ 30 bpm), in the 
absence of 20 mmHg decrease of SBP [orthostatic hypotension]) at the end of the Double-blind 
Treatment Period. 
Key Secondary Endpoints 
• 
Change from baseline in orthostatic intolerance (OI) score of COMPASS-31 at the end of 
Double-blind Treatment Period. 
• 
Change from baseline in COMPASS-31 total score at the end of the Double-blind Treatment 
Period. 
• 
Change from baseline in HR increase within 10 minutes of standing test at the end of the 
Double-blind Treatment Period. 
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PK Assessments 
Blood samples for IgG level determination will be collected pre-dose at baseline and all applicable 
study visits. Additional blood samples for IgG levels will be collected in a subset of subjects 
(N = approximately 25) during the Open-label Treatment Period for serial PK sampling starting at 
Week 41.  
Efficacy Assessments 
Heart rate as measured by a standardized standing test, OI score of COMPASS-31, and total 
COMPASS-31 score. 
Safety Assessments 
Adverse events (AEs), physical examinations, vital signs, and clinical safety laboratory tests. 
Quality of Life Assessments 
COMPASS-31, Malmö Symptom Score, Work Productivity & Activity Impairment: Specific Health 
Problems (WPAI:SHP), Short Form – 12 item (SF-12), EuroQol-5 dimension-5 levels (EQ-5D-5L), 
Patient-reported Outcomes Measurement Information System (PROMIS) Short Formv2.0 – Cognitive 
Function 6a, Orthostatic Hypotension Questionnaire (OHQ). 
Data Monitoring / Other Committees 
An unblinded Independent Data Monitoring Committee (IDMC) will monitor the safe conduct of the 
study. An IDMC charter outlines the roles and responsibilities of the committee and guides its 
operations. 
Statistical Methods 
The study is designed to test the null (H01) versus the alternative (H11) hypothesis of the primary 
endpoint for the proportion of subjects no longer meeting diagnostic criteria of post-COVID POTS as 
measured by standardized standing test (ie, no longer experiencing HR increase of ≥ 30 bpm, in the 
absence of orthostatic hypotension [ie, sustained 20 mmHg decrease of SBP]) at the end of the Double-
blind Treatment Period. 
All statistical tests will be 2-sided and will be performed at the 5% level of significance, unless 
otherwise stated. 
In general, continuous variables will be summarized using descriptive statistics (number of 
observations [n], mean, standard deviation [SD], median, minimum, and maximum). Categorical 
variables will be summarized using frequencies and percentages. For repeated observations of 
continuous variables, change from baseline will also be summarized. Summary statistics will be 
described separately for each treatment group. 
Baseline refers to the last measurement or the last calculated value before the first administration of 
IgPro20. For COMPASS-31, the assessment at the Screening visit will be used as baseline value (for 
total as well for all domains). 
Missing dates / times in AE and concomitant therapies data will be handled as described in the 
Statistical Analysis Plan (SAP). There will be no imputation schemes applied to missing data unless 
otherwise specified in the SAP. Values that are below the limit of quantification in the PK data will be 
handled as described in the SAP.  

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Sample size assumptions are based on the 30% and 60% response for the placebo and IgPro20 group, 
respectively; under these assumptions, at least 126 subjects will be required to provide 90% power (2:1 
randomization) to detect a 30% difference in proportion of responders using a Farrington-Manning test. 
An additional 18 subjects will be included to account for a futility analysis at 54 patients, and an 
additional 33 subjects will be randomized to ensure > 100 subjects treated with IgPro20 for >1 year 
will be achieved considering approximately 20% early drop out. Therefore, the final number of patients 
to be randomized is 177 (118:59). 

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1.2. 
Study Schema 
Figure 1: 
Overall Study Schema 
 
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1.3. 
Schedule of Activities 
1.3.1. 
Schedule of Activities for Screening 
 
Day -28 to Day -1 
Assessments 
Informed consent / IRT registration 
X 
Medical / surgical history and demographics  
X 
Inclusion / exclusion criteria 
X 
Record COVID-19 vaccination status 
X 
General physical examination, including height 
X 
12-lead ECG 
X 
Body weight 
X 
Vital signs 
X 
SARS-CoV-2 test a 
X 
Serum hCG pregnancy test 
X 
Hematology and biochemistry, including TSHb and morning  
cortisol levelsb 
X 
Virology blood sample (safety) 
X 
Urine sodium b 
X 
Adverse events 
X 
Concomitant therapies 
X 
Standing test c 
X 
COMPASS-31 d 
X 
PGI-S d 
X 
COMPASS-31 = Composite Autonomic Symptom Score 31; ECG = electrocardiogram; eCOA = electronic clinical 
outcomes assessment; IRT = interactive response technology; PGI-S = patient global impression of severity; PRO = 
patient-reported outcomes; PROMIS = Patient-reported Outcomes Measurement Information System; RT-PCR = 
reverse transcription polymerase chain reaction; SARS-COV-2 = Severe acute respiratory syndrome coronavirus 2; 
TSH = thyroid stimulating hormone.  
a Test to be performed at the study site as per local regulations. Negative for SARS-CoV-2 infection as determined 
using a molecular diagnostic test (RT-PCR or equivalent, rapid antigen test; antibody testing is not allowed) that 
has been approved by regulatory authorities or allowed under an emergency use authorization before Screening.  
b For subjects where these tests have not already been completed and assessed as normal after symptom onset. 
c The standing test should be the last assessment performed.  
d The PRO questionnaires are completed under supervision at the study site using the eCOA solution and may be 
administered after the following Screening assessments: informed consent / IRT registration, medical / surgical 
history and demographics, inclusion / exclusion criteria, COVID-19 vaccination status, general physical 
examination including height, body weight, vital signs, and SARS-CoV-2 test. The PRO questionnaires should be 
completed before any other study assessments, including the standing test and any blood collections.  

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1.3.2. 
Schedule of Activities for the Double-blind and Open-label Treatment Periods 
Period 
24-week Double-blind Treatment 
Transition 
visit 
28-week Open-label Treatment b 
Follow-
up 
UNS b 
EOS 
Visit 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
EOT 
17 
 
Day / Week  
D1 
W1a 
D8 
W2a 
D29 
W5a 
D57 
W9 
D85 
W13 
D113 
W17 
D141 
W21 
D169 
W25a 
D197 
W29 
D225 
W33 
D253
W37 
D281 
W41 
D309 
W45 
D337 
W49 
D365 
W53 
D393 
W57 
 
Window 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
 
Inclusion / exclusion 
criteria review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
X 
Body Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SARS-CoV-2 test c 
X d 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test 
X d 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Hematology  
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
Biochemistry  
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
PK trough e 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
Serial PK f 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Autoantibodies e 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Disease biomarkers e 
X 
X 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Future research 
(optional) e 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
RNA transcriptomics 
(optional) e 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 

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Period 
24-week Double-blind Treatment 
Transition 
visit 
28-week Open-label Treatment b 
Follow-
up 
UNS b 
EOS 
Visit 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
EOT 
17 
 
Day / Week  
D1 
W1a 
D8 
W2a 
D29 
W5a 
D57 
W9 
D85 
W13 
D113 
W17 
D141 
W21 
D169 
W25a 
D197 
W29 
D225 
W33 
D253
W37 
D281 
W41 
D309 
W45 
D337 
W49 
D365 
W53 
D393 
W57 
 
Window 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
 
Virology blood retention 
sample g 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
IMP assignment by IRT  
X 
X 
X 
X 
X 
X 
X  
X i 
X 
X 
X 
X 
X 
X 
 
 
X 
IMP weekly dose 
administration a 
X 
X 
X 
X 
X 
X 
X 
X i 
X 
X 
X 
X 
X 
X 
 
 
X 
Infusion 
training/supervised 
infusion  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
eDiary Training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review eDiary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
COMPASS-31 h 
X d 
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
X 
 
Malmö Symptom Score h 
X d 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
WPAI:SHP h 
X d 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
PGI-S and PGI-C for 
Orthostatic intolerance, 
general symptoms h 
X d 
 
X 
X 
X  
X 
X 
X 
 
 
 
 
 
 
X 
 
 
EQ-5D-5L h 
X d 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
SF-12 h 
X d 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
OHQ h 
X d 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
PROMIS Cognitive 
Function Short Form 6a h 
X d 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
Standing test j 
  
 
X 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
X 
 
 
Safety follow-up k 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 

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Period 
24-week Double-blind Treatment 
Transition 
visit 
28-week Open-label Treatment b 
Follow-
up 
UNS b 
EOS 
Visit 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
EOT 
17 
 
Day / Week  
D1 
W1a 
D8 
W2a 
D29 
W5a 
D57 
W9 
D85 
W13 
D113 
W17 
D141 
W21 
D169 
W25a 
D197 
W29 
D225 
W33 
D253
W37 
D281 
W41 
D309 
W45 
D337 
W49 
D365 
W53 
D393 
W57 
 
Window 
 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
±3d 
 
Adverse events 
Concomitant therapies 
COMPASS-31 = Composite Autonomic Symptom Score 31; D = day; ECG = electrocardiogram; eDiary = electronic diary; eCOA = Electronic clinical outcomes 
assessment; EOS = end of study; EOT = end of treatment; EQ-5D-5L= EuroQoL 5-Dimension Questionnaire; IMP = investigational medicinal product; IRT = 
interactive response technology; OHQ = Orthostatic Hypotension Questionnaire; PGI-C = patient global impression of change; PGI-S = patient global impression 
of severity; PK = pharmacokinetic; PRO = patient-reported outcomes; PROMIS = Patient-reported Outcomes Measurement Information System; RNA = 
ribonucleic acid; RT-PCR = reverse transcription polymerase chain reaction; SC = subcutaneous; SF-12 = short form – 12 item; UNS = unscheduled visit; W = 
week; WPAI:SHP = Work Productivity & Activity Impairment: Specific Health Problems. 
a Week 1 and Week 2 are mandatory on site; training and supervised IMP SC infusions will be conducted at the site for at least the first infusion on Week 1 and 
Week 2. Optional visits can occur at Weeks 3 and 4 for infusion training only. The next mandatory visit is Week 5. From Week 5, the subject will change to 
home treatment (with the exception of the first infusion of Week 25 to monitor infusions as some subjects will switch from placebo to active treatment). 
Subjects will self-administer IgPro20 on 
 infusion day(s) (see Section 6.6). All SC infusions for the previous week must be performed before the following 
study visit. All SC infusions planned in the same week as a study visit should not be started until after the study visit occurs (with the exception of Weeks 1 and 
2 for training purposes and the first infusion of Week 25, which should also occur on site under supervision as some subjects will be switched from placebo to 
active treatment). 
b Some visits may be performed remotely or by home health nurse at the subject’s home when available and allowed by local regulations after confirmation by 
the Sponsor. Further details on which visits can be performed remotely and details on remote processes can be found in the applicable study-specific manuals. 
c Test to be performed at the study site as per local regulations. Negative for SARS-CoV-2 infection as determined using a molecular diagnostic test (RT-PCR or 
equivalent, rapid antigen test; antibody testing is not allowed) that has been approved by regulatory authorities or allowed under an emergency use 
authorization. 
d Assessment must be performed before first dose administration. Assessment can be completed either at the Day 1 visit or one day before as preferred by the site 
and the subject. 
e Blood samples for IgG level determination, disease biomarkers, autoantibodies, future research, and RNA transcriptomics are to be collected pre-dose at 
baseline and all applicable study visits. 
f Blood samples for serial PK will be collected in a subset of subjects (N = approximately 25) (see Section 1.3.3).  
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g Virology blood sample for possible future assessment in case of evidence for a possible treatment-emergent virus. Infection assessment to occur only if required 
and after additional consent is obtained from the subject. To be collected before first dose of IMP on Day 1, first dose of Week 25 are administered, and after 
all study infusions have been completed at the EOT visit. 
h The PRO questionnaires are completed under supervision at the study site using the eCOA solution and administered before any other study procedures. 
COMPASS-31 recall period will be for the past week. 
i Assignment of IgPro20 only after all assessments are completed. The Week 25 visit is the only other site visit after the initial weeks where at least one infusion 
is to be performed on site. 
j The standing test should be the last assessment performed at any visit, as applicable. 
k In all early termination subjects a safety follow-up will be conducted 4 weeks after the last IMP dose via a telephone call. It will not be performed for subjects 
discontinuing IMP but remaining in the study for at least 1 subsequent visit 4 weeks after IMP discontinuation. For subjects completing all study visits per 
protocol, safety follow-up will be completed at the Week 57 Visit on-site. Please refer to Sections 7.1 and 7.2 for further details. 
.

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1.3.3. 
Schedule of Activities: Pharmacokinetic Sampling in a Subset of Subjects at 
Week 41 
Timepoint 
Timepoint Window 
Day 2: 24 hours after the start of Day 1 infusion 
± 3 hours 
Day 3: 48 hours after the start of Day 1 infusion 
± 3 hours 
Day 4: 72 hours after the start of Day 1 infusion 
± 3 hours 
Day 6: 120 hours after the start of Day 1 infusion 
± 3 hours 

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2. 
INTRODUCTION 
2.1. 
Background 
Long coronavirus disease (COVID) (also referred to as “post-acute sequelae of coronavirus 
disease 2019 [COVID-19]”) is a multisystemic condition often comprising severe symptoms 
including fatigue, cognitive dysfunction, post-exertional malaise, and palpitations, following 
an infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 
[Davis et al, 2021; Davis et al, 2023; Huang et al, 2021]. The underlying etiology is likely 
multifactorial, however autonomic dysfunction may play a significant role especially when 
manifested as Postural Orthostatic Tachycardia Syndrome (POTS), which has been 
documented following infection with SARS-CoV-2, independent of the severity of the 
preceding COVID-19 infection [Larsen et al, 2022]. Long COVID symptoms following acute 
COVID-19 infection in previously healthy and active individuals are debilitating and have 
many features of POTS including fatigue, palpitations, brain fog, dizziness, gastrointestinal 
issues, and exercise intolerance [Blitshteyn and Whitelaw, 2021; Davis et al, 2021; 
Goldstein, 2021; Parker et al, 2021; Thieben et al, 2007]. The diagnosis of POTS in adults 
requires presence of excessive orthostatic tachycardia of at least 30 bpm within 10 minutes of 
standing in the absence of orthostatic hypotension, accompanied by symptoms of chronic 
orthostatic intolerance (OI) (eg, brain fog, dizziness, palpitations) for a duration of at least 
3 months [Bryarly et al, 2019; Raj et al, 2020]. Bearing hallmarks of a serious condition, 
POTS can significantly impair functional status, mental health, and quality of life (QoL) 
causing many patients to become bedridden subsequently leading to economic and 
employment challenges [Anderson et al, 2014; Ormiston et al, 2022; Taub et al, 2021; 
Zadourian et al, 2018]. Similarly, post-COVID POTS has been described as an urgent public 
health concern in adults, with high morbidity and significant impact on QoL, as well as 
economic and employment challenges, with up to 60% of patients with residual autonomic 
symptoms post-COVID being unable to return to work 6 to 8 months after an acute 
COVID-19 infection [Blitshteyn and Whitelaw, 2021; Bourne et al, 2021; Raj et al, 2021a]. 
While the prevalence of POTS before the outbreak of the recent COVID-19 pandemic ranged 
between 0.2 and 1% in developed countries [Fedorowski, 2019; Zadourian et al, 2018] and 
between 0.1% and 1% in the United States (US) population specifically [Arnold et al, 2017; 
Zadourian et al, 2018], there has been a sharp rise in the incidence of POTS cases since the 
beginning of the pandemic due to the long-term effects of COVID-19 [Ormiston et al, 2022; 
Tafler et al, 2023]. Although clinical studies of COVID-19–related dysautonomia are limited 
to small case series and anecdotal reports, post-COVID POTS-like symptoms were reported 
in 34% of respondents in an international web-based survey of nearly 4000 COVID-19 
survivors [Blitshteyn and Whitelaw, 2021; Davis et al, 2021; Eshak et al, 2020; 
Goodman et al, 2021; Johansson et al, 2021; Novak, 2020], and recent reports indicate that 
approximately 2% to 14% of COVID-19 survivors develop post-COVID POTS 
[Davis et al, 2021; Ormiston et al, 2022]. The mean age of individuals with post-COVID 
POTS is 36 years with women being more predominantly affected than men [Amekran et al, 
2022; Blitshteyn and Whitelaw, 2021; Gall et al, 2022; Parker et al, 2021]. The natural 
history of post-COVID POTS is not fully understood with medium-term to long-term 
prognosis of affected individuals undefined [Kwan et al, 2022; Orminston et al, 2022], and a 

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similar absence of information on the course of disease for patients left completely untreated 
[Eshak et al, 2020; Goodman et al, 2021; Johansson et al, 2021; Novak, 2020]. 
The pathophysiology of autonomic dysfunction in long COVID remains unknown but has 
been suggested to be immune-mediated in nature based on the presence of non-specific 
immune markers reported in symptomatic patients [Blitshteyn and Whitelaw, 2021; 
Goodman et al, 2021]. Persistent complement activation has been seen in long COVID and 
may be driven by antigen–antibody complexes, involving autoantibodies and antibodies 
against herpesviruses, as well as cross-talk with a dysregulated coagulation system 
[Cervia-Hasler et al, 2024]. As post-COVID POTS has been described to be a syndrome 
associated with an inflammatory autoimmune dysregulation [Chadda et al, 2022] and 
elevated levels of functional autoantibodies to several G-protein coupled receptors have been 
seen in affected individuals [Jamal et al, 2023], treatment with high dose immunoglobulin G 
(IgG) is expected to exert immunomodulatory effects [Galeotti et al, 2017] which are thought 
to translate into improvement of clinical symptoms and vital signs in individuals with post-
COVID POTS.  
There are no approved treatments for individuals with post-COVID POTS to date, and the 
current management of post-COVID POTS is targeted towards symptom relief, rather than 
addressing the underlying pathophysiology [Mallick et al, 2023]. Improvement of symptoms 
under pharmacological treatment has been described, however, even under pharmacological 
treatment, symptoms persist in many patients [Abbate et al, 2023].  
Hence, there is an immediate unmet medical need for the development of novel treatment 
options that adequately address this serious condition in the described patient population. 
Based on limited but encouraging data from the literature on the use of IgG in POTS 
[Kesterson et al, 2023; Parker et al, 2021; Pitarokoili et al, 2021; Rodriguez et al, 2021; 
Schofield and Chemali, 2019; Weinstock et al, 2018], as well as the presumed mechanism of 
action of IgG and observed immunomodulatory effect in other closely related autoimmune 
conditions such as chronic inflammatory demyelinating polyneuropathy (CIDP), IgPro20 
represents a promising treatment option in post-COVID POTS. 
A detailed description of the chemistry, pharmacology, efficacy, and safety of IgPro20 is 
provided in the Investigator’s Brochure. 
2.2. 
Study Rationale 
Inflammation and autoimmunity are presumed underlying mechanisms of post-COVID 
POTS, supported by the presence of elevated autoantibodies and incidence of autoimmune 
conditions [Chadda et al, 2022; Jamal et al, 2023]. Even though the exact immunomodulatory 
mechanisms underlying IgG activity remain complex, high dose intravenous immunoglobulin 
(IVIG) and subcutaneous immunoglobulin (SCIG) may exert its beneficial effects in 
inflammatory and autoimmune diseases associated with autoantibodies by several potential 
mechanisms including neutralization of autoimmune antibodies, decreases in the deposition 
of complement, immunomodulation through activation of inhibitory FcγIIb receptor 
signaling, and acceleration of pathologic antibody clearance through neonatal Fc receptor 
saturation [Galeotti et al, 2017]. The proposed mode of action of high dose IgG may 

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therefore have beneficial impact on autonomic dysfunction in individuals with post-COVID 
POTS as a causative treatment.  
Investigators have seen improvement in POTS symptoms using high dose, off-label IVIG (up 
to 2 g/kg monthly) or SCIG (up to 1.9 g/kg monthly) in uncontrolled single cases or case 
series [Kesterson et al, 2023; Rodriguez et al, 2021; Schofield and Chemali, 2019; 
Weinstock et al, 2018], including individuals with post-COVID POTS [Parker et al, 2021]. 
Furthermore, weekly dosing of up to 
 g/kg of IgPro20 has demonstrated a positive benefit-
risk ratio as immunomodulatory therapy in CIDP an approved indication for HIZENTRA, 
and is the same dose proposed for post-COVID POTS. 
For both immune replacement (eg, primary immunodeficiency [PID]) as well as 
immunomodulation (eg, CIDP), a comparable short and long-term efficacy of SCIG and 
IVIG is assumed [Chapel et al, 2000; Chen et al, 2019]. Safety profiles of both IVIG and 
SCIG in immune replacement and immunomodulation have been well characterized. In 
contrast to IVIG, which can be associated with systemic side effects, the safety profile of 
SCIG is mainly characterized by local infusion site reactions [Ballow et al, 2018; 
Cherin et al, 2016; Gardulf and Nicolay, 2006; Nicolay et al, 2006; Perez et al, 2017]. 
Additionally, SCIG can be administered at home and has been shown to improve QoL, 
treatment satisfaction and therapy convenience [Gardulf and Nicolay, 2006; Nicolay et al, 
2006]. In the context of post-COVID POTS, which primarily affects a younger, previously 
active and healthy adult patient population [Blitshteyn and Whitelaw, 2021; Larsen et al, 
2022; Parker et al, 2021], home administration of SCIG might represent a patient-centric 
treatment option.  
The current lack of treatment for post-COVID-related POTS outside of symptomatic 
management warrants the initiation of a randomized double-blind study targeting the 
underlying autoimmune pathophysiology in post-COVID POTS by means of SCIG 
treatment. Therefore, a placebo-controlled study evaluating the effects of IgPro20 in 
177 subjects with POTS following acute COVID-19 infection is proposed. Randomization 
will be continued if the dropout rate is over 10%. 
2.3. 
Benefit / Risk Assessment 
IgPro20 is a marketed product that has been demonstrated to be a generally safe and well 
tolerated product in PID and CIDP. Weekly dosing of up to 
 g/kg of IgPro20 has 
demonstrated a positive benefit-risk ratio as immunomodulatory therapy in CIDP, which is 
the same dose proposed for post-COVID POTS.  
2.3.1. 
Benefit Assessment 
As post-COVID POTS is a disease with an autoimmune phenotype, affected individuals may 
experience benefits from the anti-inflammatory and immunomodulatory effects that high 
doses of IgPro20 exert. These include, but may not be limited to, reduction in symptoms of 
OI and improvement of inadequate heart rate (HR) increase after changing into a supine 
position, positively impacting QoL. 
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2.3.2. 
Risk Assessment 
2.3.2.1. 
Identified and Potential Risks Pertaining to IgPro20 
Although the safety profile of IgPro20 has not been evaluated in subjects with post-COVID 
POTS, IgPro20 has a well-established safety profile, with the important safety concerns from 
the risk management plan listed in Table 1. No additional risks are expected in this study. 
As noted, IgPro20 has been demonstrated to be safe based on safety data obtained from 
previous CSL-sponsored clinical studies in various indications with dosing up to 
 g/kg, 
and post-marketing experience collected over the past 13 years. The majority of adverse 
events (AEs) observed with IgPro20 administration in currently approved indications are 
nonserious infusion site reactions (ISRs). Adverse reactions such as local reactions, 
headache, fatigue, nausea, pain, pruritus, rash, vomiting, and pyrexia were observed during 
the clinical development program. In addition, in the post-marketing setting, reactions such 
as hypersensitivity, tremor, and burning sensation were reported, as well as rare events such 
as anaphylaxis, aseptic meningitis syndrome, and thrombotic events.  
The risk that products manufactured from plasma could transmit an infectious agent has been 
reduced by screening plasma donors for prior exposure to pathogens and by testing the 
donations for the presence of certain markers of infections. In addition, different 
complementary virus elimination processes used during the manufacture of IgPro20 
(incubation at pH 4, virus filtration, fractionation, and depth filtration) effectively reduce the 
potential for viral transmission. The manufacturing process was also investigated for its 
capacity to eliminate hamster-adapted scrapie agent 263K, a model for Creutzfeldt-Jakob 
disease and variant Creutzfeldt-Jakob disease. The results demonstrated substantial removal 
of the infectious agent by the manufacturing process in all model systems. To date, no viral 
infection related to the infusion of IgPro20 has been reported. However, the possibility of 
transmitting infective agents cannot be totally excluded. 
Table 1: 
Summary of Safety Concerns Pertaining to IgPro20a 
Important identified 
risks 
• Local reactions including ulceration-like ISRs. 
• Anaphylactic reactions.  
• Aseptic meningitis syndrome.  
• Thromboembolic events.  
Important potential 
risks 
• Increased or unknown risks in the home-based SC (self-) 
administration. 
• Exacerbation of existing hyperprolinemia. 
• Hemolysis. 
• Transmission of infectious agents. 
ISR = infusion site reaction; SC = subcutaneous. 
a as described in Hizentra Risk Management Plan 4.6 
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Further details on identified and potential risks for IgPro20 are available in the Investigator’s 
Brochure. 
With regard to the use in POTS (including post-COVID POTS), continuous post-marketing 
safety surveillance did not identify additional safety signals that are relevant to the use of 
SCIG in patients with this condition. The limited available literature data reports good 
tolerability of SCIG in POTS patients [Kesterson et al, 2023; Parker et al, 2021; Pitarokoili 
et al, 2021], while the use of IVIG is described as effective, but associated with systemic side 
effects, eg, aseptic meningitis [Rodriguez et al, 2021; Schofield and Chemali, 2019; 
Weinstock et al, 2018]. Subjects will be closely monitored during the study for adverse drug 
reactions that are potentially serious and other events. In addition, the study will be 
monitored by an independent data monitoring committee (IDMC). 
2.3.2.2. 
Potential Risks Pertaining to Placebo 
In this study, a 2% human albumin solution is used as placebo. The formulation will be 
developed by diluting the commercially available liquid albumin preparation manufactured 
under Good Manufacturing Practice conditions. The tolerability of SC application of human 
albumin was tested in a clinical trial with CIDP and was found to be similar to the experience 
with other plasma proteins (eg, IgG), as described above. No additional harm is expected 
from the use of albumin as placebo in the study subjects. The currently established safety 
profile of the investigational medicinal product (IMP) covers fully the safety profile of the 
commercial albumin solution that is used for developing the placebo. 
There is a high permeability for albumin between the SC compartment and the vascular 
system. In view of the SC data available, the absence of immunogenicity after intramuscular 
administration, and the high abundance of albumin in the body (> 25 mg/mL in interstitial 
fluid) [Poulsen, 1974], local reactions and immunogenicity are considered highly improbable 
at the doses administered in this study. 
2.3.2.3. 
Risks Pertaining to Crono S-PID-100 Infusion Pump 
The IMP will be administered using the Crono S-PID-100 Infusion Pump. There are no 
specific risks associated with Crono S-PID-100 Infusion Pump use. Technical malfunctioning 
or leakage from connections between syringe, tubing and / or needle, or the infusion site 
itself (eg, due to inadequate placement of the butterfly needle) may occur.  
2.3.2.4. 
Potential Risks of Failure of IgPro20 
The efficacy of IgPro20 in post-COVID POTS is currently unknown.  
2.3.3. 
Benefit / Risk Conclusion 
Considering IgPro20’s established safety profile and the measures taken to minimize risk to 
subjects participating in this study, the potential risks identified in association with IgPro20 
are justified by the anticipated benefits that may be afforded to subjects with post-COVID 
POTS. Thus, the associated benefit-risk of the study is acceptable for subjects enrolled in the 
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3. 
OBJECTIVES, ENDPOINTS, AND ESTIMANDS 
Table 2: 
Objectives, Endpoints, and Estimands 
Objectives 
Endpoints and Estimands 
Primary 
The primary objective of this study is to evaluate the 
efficacy of IgPro20 in comparison with placebo in 
adults with post-COVID POTS 
Endpoint: Proportion of subjects no longer meeting 
diagnostic criteria of post-COVID POTS as 
measured by standardized standing test (ie, no longer 
experiencing HR increase of ≥ 30 bpm, in the 
absence of 20 mmHg decrease of SBP [orthostatic 
hypotension]) at the end of the Double-blind 
Treatment Period. 
Estimand: The primary comparison of interest is to 
quantify the treatment effect of IgPro20 versus 
placebo. The treatment effect of interest is the 
difference in the proportion of subjects no longer 
meeting diagnostic criteria of post-COVID POTS as 
measured by standardized standing test (no longer 
experiencing HR increase of ≥ 30 bpm in the absence 
of 20 mmHg decrease of SBP [orthostatic 
hypotension]) 
Intercurrent events: see Section 9.4.2.1.1 
Population: Intent-To-Treat 
Treatment: IgPro20 vs. Placebo 
Population Summary: Point estimate and 95% CI 
for the difference in proportions. 

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Objectives 
Endpoints and Estimands 
Key Secondary 
To further evaluate the efficacy of IgPro20 in 
comparison with placebo in adults with post-COVID 
POTS 
1. Endpoint: Change from baseline in orthostatic 
intolerance score of COMPASS-31 at the end of 
Double-blind Treatment Period. 
Estimand: The comparison of interest is to quantify 
the treatment effect of IgPro20 versus placebo. The 
treatment effect of interest is differences from 
baseline in orthostatic intolerance score of 
COMPASS-31 at the end of the Double-blind 
Treatment Period. 
Intercurrent events: see Section 9.4.2.1.1 
2. Endpoint: Change from baseline in COMPASS-
31 total score at the end of the Double-blind 
Treatment Period. 
Estimand: The comparison of interest is to quantify 
the treatment effect of IgPro20 versus placebo. The 
treatment effect of interest is differences from 
baseline in COMPASS-31 total score at the end of 
the Double-blind Treatment Period. 
Intercurrent events: see Section 9.4.2.1.1 
3. Endpoint: Change from baseline in HR increase 
within 10 minutes of standing test at the end of the 
Double-blind Treatment Period.  
Estimand: The comparison of interest is to quantify 
the treatment effect of IgPro20 versus placebo. The 
treatment effect of interest is differences from 
baseline in HR increase within 10 minutes of 
standing test at the end of the Double-blind 
Treatment Period. 
Intercurrent events: see Section 9.4.2.1.1 
Secondary 
To evaluate the safety of IgPro20 in comparison with 
placebo in subjects with post-COVID POTS 
• 
Frequency counts and percentage of subjects 
with TEAEs, related TEAEs, serious TEAEs, 
and related serious TEAEs  
• 
Frequency counts and percentage of subjects 
with abnormal electrocardiograms at Screening, 
Week 25, and Week 53, as well as change from 
baseline at Week 25 and Week 53. 

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Objectives 
Endpoints and Estimands 
Exploratory 
To evaluate the pharmacokinetics of IgPro20 in 
subjects with post-COVID POTS 
• 
Concentration of serum total IgG: Ctrough at 
multiple time points during the study. 
• 
In serial PK subjects only; serial IgG PK 
collection Period: 
• 
Steady-state PK (at Week 41) 
o 
Cmax 
o 
Tmax 
o 
Cmin 
o 
AUC0-7d 
o 
AUC0-last 
To further evaluate the efficacy of IgPro20 in 
comparison with placebo in adults with post-COVID 
POTS 
• 
Proportion of subjects experiencing orthostatic 
hypotension at the end of the Double-blind 
Treatment Period. 
• 
Change from baseline in Malmö Symptom score 
at the end of the Double-blind Treatment Period. 
 
• 
Change from baseline in Mental Component 
Score, and Physical Component Score at the end 
of the Double-blind Treatment Period. 
• 
Change from baseline in remaining domains of 
COMPASS-31 at the end of the Double-blind 
Treatment Period. 
• 
Proportion of subjects whose orthostatic 
intolerance score and total COMPASS-31 score 
improved beyond the clinical meaningful 
difference thresholds (MSDs to be determined) 
at the end of the Double-blind Treatment Period. 
• 
Change from baseline in mean T-score on the 
PROMIS Cognitive function short form 6a at the 
end of the Double-blind Treatment Period. 
• 
Change from baseline in health utility index and 
global health status (VAS) as measured by EQ-
5D-5L at the end of the Double-blind Treatment 
Period. 
• 
Change from baseline in each of the component 
scores for WPAI:SH. 
• 
Change from baseline in the 2 domains of the 
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AUC0-l = Area under the concentration-time curve from time point 0 to the last quantifiable time point; AUC07d 
= Area under the concentration-time curve from time point 0 to day 7; AUC0-last = Area under the concentration-
time curve from time point 0 to the time of the last measurable concentration; CI = confidence interval; Cmax = 
maximum concentration; Cmin = minimum concentration; COMPASS-31 = Composite Autonomic Symptom 
Score 31; EQ5D-5L = EuroQol-5 dimension; HR = heart rate; PK = pharmacokinetic; OHQ = Orthostatic 
Hypotension Questionnaire; POTS = Postural Orthostatic Tachycardia Syndrome; SBP = systolic blood 
pressure; SF-12 = Short Form – 12item; TEAE = treatment-emergent adverse event; Tmax = time to reach 
maximum concentration; VAS = visual analog scale; WPAI:SH = Work Productivity & Activity Impairment: 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is a prospective, phase 3, multicenter, double-blind, randomized placebo-controlled 
study to investigate the efficacy, safety, and pharmacokinetics (PK) of repeat doses of 
IgPro20 in adult subjects with post-COVID POTS.  
Approximately 177 adult subjects with a confirmed diagnosis of post-COVID POTS as 
defined in Section 5.1 will be randomized into the study.  
An interim futility analysis will be conducted when 54 subjects have completed 24 weeks of 
treatment. Enrollment will be temporarily paused after the 54th subject has completed 24 
weeks of treatment until IDMC recommendation after futility analysis review has been 
received and reviewed by the Sponsor. The futility analysis is further described in the IDMC 
Statistical analysis Plan (SAP) and IDMC charter. 
Eligible subjects will be randomized in a 2:1 ratio to receive SC infusions of IgPro20 at doses 
of 
g/kg/week or matching placebo for 24 weeks followed by an Open-label Treatment 
Period of 28 weeks as depicted in Figure 1. The study duration for an individual subject will 
be up to 60 weeks.  
4.2. 
Scientific Rationale for Study Design 
The study will enroll adult subjects with post-COVID POTS whose QoL is severely impacted 
as measured by Composite Autonomic Symptom Score 31(COMPASS-31) (ie, with 
COMPASS-31 score ≥40 [Kedor et al, 2021]). The COMPASS-31 is a self-reported 
questionnaire measuring autonomic symptoms and is being commonly used in recent POTS 
trials. Patients with a history of POTS before confirmed COVID-19 diagnosis, as well as 
concomitant conditions, unless related to COVID-19, such as polyneuropathy, Ehlers Danlos, 
myalgic encephalitis / chronic fatigue syndrome, etc, will be excluded to avoid confounders. 
Subjects with use of any IgG product or plasmapheresis within 12 weeks before Screening 
will be excluded to avoid any carry-over effects from previous immunomodulatory treatment. 
The study population was chosen because patients with post-COVID POTS can be severely 
impacted by their condition in their daily life, and there is no approved treatment available. 
IgG has been shown to provide clinical benefits in the treatment of patients with POTS 
[Kesterson et al, 2023; Pitarokoili et al, 2021; Rodriguez et al, 2021; Schofield and 
Chemali, 2019; Weinstock et al, 2018], including individuals with post-COVID POTS 
[Parker et al, 2021]. Hence, IgG represents a promising treatment option for post-COVID 
POTS patients. 
As outlined in Section 2.3.2.1, even though IVIG has been described as effective in POTS 
treatment, it is associated with systemic side effects. In contrast, SCIG administration is 
mainly characterized by local ISRs [Ballow et al, 2018; Cherin et al, 2016; Gardulf and 
Nicolay, 2006; Nicolay et al, 2006; Perez et al, 2017]. For both immune replacement as well 
as immunomodulation, a comparable long-term efficacy of SCIG and IVIG is assumed 
[Chapel et al, 2000; Chen et al, 2019]. Additionally, SCIG can be administered at home and 
has been shown to improve QoL, treatment satisfaction, and therapy convenience 
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[Gardulf and Nicolay, 2006; Nicolay et al, 2006]. In the context of post-COVID POTS which 
primarily affects a younger, previously active and healthy patient population [Blitshteyn and 
Whitelaw, 2021; Larsen et al, 2022], home administration of SCIG might represent a 
patient-centric treatment option. Assuming comparable efficacy and considering the overall 
lower rate of systemic AEs, flexibility in dosing administration and improved QoL compared 
to IVIG, SCIG was chosen as the study drug. Additionally, IVIG may lead to a volume 
expansion due to the lower concentration, ie, greater volume, and direct administration to the 
blood stream. Given that volume expansion is one of the non-pharmacologic treatment 
options in post-COVID POTS, this may confound the results. SCIG has a higher 
concentration and is absorbed slowly through the lymph over multiple days [Rojavin et al, 
2020; von Achenbach et al, 2022]. Therefore, only a limited extent of volume expansion is 
expected, allowing a more reliable characterization of the immunomodulatory effects. 
Additional rationale on the selection of the dose is described in Section 4.3. 
A double-blind design is being used to avoid potential bias during data collection and 
evaluation of clinical endpoints. A placebo-controlled design is being used to optimize 
treatment sensitivity, reduce bias, and maintain the rigor of the study to support this 
indication. To collect additional longer-term safety data, the Double-blind Treatment Period 
will be followed by an Open-label Treatment Period. 
The primary endpoint is the proportion of subjects no longer meeting diagnostic criteria of 
post-COVID POTS as measured by standing test (ie, no longer experiencing HR increase of 
≥30 bpm, in the absence of 20 mmHg decrease in systolic blood pressure (SBP) [orthostatic 
hypotension]) evaluated after 24 weeks of double-blind treatment. It has been chosen as an 
HR increase of at least 30 bpm when standing is embedded in diagnostic criteria for POTS, 
based on consensus definition defined by major international Societies [Vernino et al, 2021]. 
Efficacy will be further characterized by 3 key secondary endpoints: change from baseline in 
both the OI subscale and total score (TS) of COMPASS-31 and change from baseline in HR 
measured by a standing test on a continuous scale. The OI subscale was chosen as a separate 
key secondary endpoint as OI symptoms were found to be most prominent to differentiate 
between POTS and other dysautonomias [Cortez et al, 2021], covering the most burdensome 
and frequent symptoms reported by POTS patients [Dipaola et al, 2020]. Consequently, this 
design allows for a thorough evaluation of the objective HR change tied back to the POTS 
diagnostic criteria first proposed in 1993 [Schondorf and Low, 1993], as well as the 
subjective assessment of how patients feel and function. The total COMPASS-31 score was 
chosen to evaluate the impact of treatment on multiple symptoms associated with POTS. 
Data regarding the expected effect size and placebo effect in post-COVID POTS are limited, 
as it represents a newly identified condition first described in 2020 [Miglis et al, 2020]. The 
natural history of post-COVID POTS is not fully understood with medium-term to long-term 
prognosis of affected individuals undefined [Kwan et al, 2022; Ormiston et al, 2022], and a 
similar absence of information on the course of disease for patients left completely untreated 
[Eshak et al, 2020; Goodman et al, 2021; Johansson et al, 2021; Novak, 2020]. Based on a 
natural history study following 45 POTS patients, approximately 30% of patients no longer 
experienced HR increase meeting POTS consensus criteria after at least 1 year of observation 
[Kang et al, 2019]. The present study is assuming a 30% placebo rate. In the absence of an 

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established minimally clinically important difference for the primary endpoint and in 
correspondence with experts, 30% treatment effect size are assumed. Additionally, these 
assumptions are taking into account that findings from POTS are being applied to post-
COVID POTS, as data in post-COVID POTS are sparse, and further research needs to be 
performed to shed light on potential differences and similarities. 
4.3. 
Dose Rationale 
To date, there are very few studies in the literature that examine SCIG or IVIG in POTS, and 
only one of these has been conducted in post-COVID POTS specifically (where 3 subjects 
were administered IVIG but the dose was not disclosed) [Parker et al, 2021]. In the available 
literature, SCIG and IVIG have been dosed up to 1.9 g/kg/month (approximately 0.48 
g/kg/week) and 2.0 g/kg/month (ie, 0.5 g/kg/week), respectively, in the POTS population. To 
date, no studies have evaluated safety and tolerability of doses greater than 2 g/kg/month of 
IVIG or SCIG for this or other autoimmune conditions. 
IgPro20 is approved for the immunomodulatory treatment of CIDP at the proposed dose level 
of up to 
 g/kg/week. There is significant clinical experience and safety data, both from 
clinical studies as well as post-marketing, for IgPro20 at 
 g/kg/week, demonstrating a 
good tolerability of the 
 g/kg/week dosing regimen. As described in the HIZENTRA® US 
Prescribing Information, the most commonly reported AEs for IgPro20 include Local 
Infusion Site Reactions, Headache, and Diarrhea. 
Weekly dosing of 
 g/kg has been used to treat CIDP subjects in the pivotal IgPro20 study 
with a safety profile that was comparable to a low dose, with the most frequent AEs being 
local ISRs. All local reactions (with either dose) were mild or moderate in intensity and the 
frequency decreased over time. The population considered for the post-COVID POTS study 
is relatively young with a mean age of 36 years [Amekran et al, 2022; Blitshteyn and 
Whitelaw, 2021; Gall et al, 2022; Parker et al, 2021]. The population is also expected to have 
few comorbidities. Therefore, the expectation is that this regimen will be well tolerated in 
this population. 
Considering the unmet medical need in this condition with no approved treatments, the 
established safety profile, and published data indicating clinical benefit with the proposed 
high dose of 
 g/kg/week, the proposed study assesses the relative efficacy of 
 g/kg/week versus placebo to maximize the chance for response. 
4.4. 
Start of Study Definition 
The study start date is the date on which the clinical study will be open for recruitment of 
subjects. The first act of recruitment is the time point when the first site is activated and will 
be considered the study start date.  
4.5. 
End of Study Definition  
The end of the study is defined as the date of the last visit of the last subject in the study / last 
scheduled procedure shown in the Schedule of Activities (Section 1.3) for the last subject in 
the study. 
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A subject is considered to have completed the study if they completed all study periods 
including the last visit. 
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 closeout visit has 
been performed. 

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5. 
STUDY POPULATION 
Subjects must meet all inclusion criteria and none of the exclusion criteria to be eligible for 
enrollment into this study. Prospective approval of protocol deviations from eligibility 
criteria, also known as protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
To be enrolled into the study, subjects must meet all of the following inclusion criteria: 
1. Provide written informed consent and be willing and, in the opinion of the 
investigator, able to adhere to all protocol requirements. 
2. Males and females aged ≥18 at the time of providing written informed consent. 
3. Diagnosis of post-COVID POTS, defined by both:  
• Preceding COVID-19 infection, based on confirmed historical documentation of 
the following (Figure 2): 
- Documented history of SARS-CoV-2 infection (documented by antigen or 
polymerase chain reaction [PCR] test)  
OR  
- Documented clinical diagnosis of SARS-CoV-2 infection, based on the 
following criteria: 
1. One of the following documented physician-reported criteria: 
• COVID-19 specific treatment (eg, Nirmatrelvir + Ritonavir / 
Paxlovid, Remdesivir / Veklury, Molnupiravir / Lagevrio 
OR 
• Documentation of one of the following ICD-10 codes: U07.1 
(COVID-19, virus identified), U07.2** (COVID-19, virus not 
identified), U09.9** (post-COVID-19 condition, unspecified) 
AND  
2. Documented patient-reported signs or symptoms*  
AND  
3. Documented patient-reported positive self-administered SARS-CoV-2 
antigen test 
*Acceptable signs or symptoms:  
• Acute onset of fever AND cough (influenza-like illness)  
OR  

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• Any 3 or more of the following signs or symptoms: Fever, cough, 
general weakness / fatigue, headache, myalgia, sore throat, coryza, 
dyspnoea, nausea, diarrhea, anorexia 
**Subjects with documentation of the ICD-10 codes U07.2 and 
U09.9 need to be discussed with the Sponsor’s Internal Medical 
Monitor to confirm eligibility based on entirety of documented 
evidence for preceding SARS-CoV-2 infection 
Figure 2 provides a decision tree for assessing a SARS-CoV-1 infection. 
AND 
• Onset of POTS symptoms developing within 4 months after COVID-19 infection, 
as defined per consensus criteria [Vernino et al, 2021]  
– A sustained HR increase of ≥ 30 bpm [≥ 40 bpm for subjects aged 18 to 19 
years] within 10 minutes of head-up tilt or standing test, in the absence of 
orthostatic hypotension (ie, sustained 20 mmHg decrease in SBP)  
AND 
– The presence of post-COVID POTS with persisting symptoms (eg, brain fog, 
fatigue, palpitations) for at least 3 months 
4. COMPASS-31 score of at least 40 at the Screening visit 
5. Positive confirmatory standardized standing test (ie, HR increase of ≥ 30 bpm 
[≥ 40 bpm for subjects aged 18 to 19 years] within 10 minutes in the absence of 
orthostatic hypotension) at the Screening visit 
6. According to the investigator’s judgment, the subject (or the subject’s legally 
acceptable representative[s]) understands the nature, scope, and possible 
consequences of the study 
7. Subject is capable of reading, understanding, and completing questions / assessments 
in an electronic clinical outcomes assessment (eCOA) solution  
8. Subject is willing to complete 52 weeks of SC infusions 

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Figure 2: 
Acceptable Methods for Confirming a SARS-CoV-2 Infection  
 
 
a Documented patient-reported signs or symptoms include either (1) acute onset of fever AND cough (influenza-
like illness) or (2) any 3 or more of the following signs or symptoms: Fever, cough, general weakness / 
fatigue, headache, myalgia, sore throat, coryza, dyspnoea, nausea, diarrhea, anorexia. All reported signs and 
symptoms must be documented in the patient medical history.  
b Examples of acceptable treatments include Nirmatrelvir + Ritonavir / Paxlovid, Remdesivir / Veklury, 
Molnupiravir / Lagevrio.  
c Permissable ICD-10 codes are as follows: U07.1 (COVID-19, virus identified), U07.2* (COVID-19, virus not 
identified), U09.9* (post-COVID-19 condition, unspecified).   
*If ICD-10 codes U07.2 and U09.9 are utilized, COVID-19 documentation to be reviewed by the Sponsor’s 
Internal Medical Monitor before subject is enrolled in the study.  
5.2. 
Exclusion Criteria 
Subjects must not be enrolled into the study if they meet any of the following exclusion 
criteria: 
1. Treatment with IgG or plasmapheresis within 12 weeks before Screening 
2. Symptoms and / or diagnosis of or receiving treatment for POTS before COVID-19 
infection 
3. Prior diagnosis of or receiving current treatment at Screening for the following 
conditions (unless onset was related to the inciting POTS-associated COVID-19 
infection):  
• Neurologic conditions such as peripheral neuropathy, myalgic encephalomyelitis 
encephalitis / chronic fatigue syndrome, stroke, spinal cord injury or any known 
lesions in the central nervous system by imaging or neurological exam;  

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• Autoimmune conditions such as Sjögren’s syndrome, autoimmune autonomic 
neuropathy, multiple sclerosis, Crohn’s disease, celiac disease, lupus 
erythematosus, rheumatoid arthritis, myasthenia gravis;  
• Pre-existing psychiatric disorders such as generalized anxiety disorder (formally 
diagnosed), anorexia nervosa, disorders causing hyperventilation;  
• Endocrine disorders such as hyperthyroidism, pheochromocytoma;   
• Cardiac disorders causing sinus tachycardia such as inappropriate sinus 
tachycardia, or arrythmias;  
• Other disorders / conditions causing sinus tachycardia such as Ehlers Danlos 
syndrome, mast cell activation syndrome, fever, pain, infection, moderate to 
severe anemia, hypovolemia or severe deconditioning caused by prolonged bed 
rest. 
4. Presence of active infections such as: 
• Human immunodeficiency virus infection (or history of). 
• Hepatitis B: subjects who are hepatitis B core antibody-positive and who are 
hepatitis B surface antibody-negative will need to have a negative hepatitis B 
virus PCR result before enrollment. Hepatitis B surface antigen-positive or 
hepatitis B virus PCR-positive subjects will be excluded. 
• Hepatitis C: subjects who are hepatitis C virus antibody-positive will need to have 
a negative hepatitis C virus PCR result before enrollment. Hepatitis C PCR-
positive subjects will be excluded. 
• Any uncontrolled systemic infection. 
• Active SARS-CoV-2 infection. 
5. Subjects with an implantable electronic defibrillator or pacemaker. 
6. History of documented thromboembolic event within 26 weeks before Baseline. 
7. Subjects receiving any prohibited treatments as described in Section 6.12, including 
new or changing exercise program. 
8. History of known or acquired congenital coagulopathies or laboratory evidence of 
current hypercoagulable state at Screening. 
9. Any ongoing malignancy unless in remission for > 1 year and clinically stable (except 
for basal cell carcinoma, carcinoma in situ, or localized cell carcinomas with surgical 
cure). 
10. Known hyperprolinemia. 
11. Protein-losing enteropathies or significant proteinuria, eg, nephrotic syndrome. 
12. Known or suspected hypersensitivity or other severe reactions to the IMP, to any 
excipients of the IMP, or to other immunoglobulins, or severe reactions to blood 
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13. Concurrent participation in another clinical study. 
14. Any condition that requires immediate initiation of IgG replacement or 
administration. 
15. Has current signs or symptoms of severe, progressive, or uncontrolled active 
inflammatory, renal (estimated glomerular filtration rate < 60 mL/min/1.73 m2), 
hepatic (aspartate aminotransferase [AST]/alanine aminotransferase [ALT] > 3 × 
upper limit of normal [ULN]), dermatologic, hematologic, gastrointestinal, endocrine, 
pulmonary, cardiac, psychiatric, or neurologic disease other than post-COVID POTS 
as judged by the investigator. 
16. Any issue that would render the subject unsuitable for participation in the study or 
unable to comply with study procedures, eg, inability to self-administer IMP or by aid 
through a caregiver. 
17. Pregnancy or breastfeeding, or intention to become pregnant or to father a child 
during the study. 
18. Fertile male subject or female subject of childbearing potential either not using or not 
willing to use a medically reliable method of contraception (see Section 10.3.2), not 
sexually abstinent during the study or for 28 days after receipt of the last infusion of 
IgPro20, or not surgically sterile before study enrollment.  
• All female subjects are assumed to be of childbearing potential except: 
- Subjects aged > 60 years. 
- Subjects aged 45 to 60 years (inclusive) with amenorrhea for ≥ 1 year with 
documented evidence of follicle-stimulating hormone level > 30 IU/L. If the 
follicle-stimulating hormone value is not available before randomization, a 
urine pregnancy test is required. 
- Subjects who are surgically sterile for ≥ 3 months before providing informed 
consent. 
• All male subjects are assumed fertile except subjects who are surgically sterile for 
≥ 3 months before providing informed consent. 
19. Alcohol, drug, or medication abuse within 1 year of providing informed consent. 
20. Any issue that, in the opinion of the investigator, would constitute a contraindication 
to perform standing test. 
21. Involved in the planning and / or conduct of the study (applies to the Sponsor’s staff, 
staff at the study site, and third-party vendors). 
5.3. 
Lifestyle Considerations  
Use of recreational drugs, either for recreational or potentially medical purposes, is not 
permitted. There are no other study-specific dietary or lifestyle restrictions for subjects who 
participate in the study.  

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Female subjects of childbearing potential must use a medically reliable form of contraception 
for the study duration. Acceptable methods of contraception are: 
• Abstinence, where abstinence is the preferred and usual lifestyle of the subject, 
including refraining from heterosexual intercourse during the entire period of risk 
associated with the IMP. Periodic abstinence (calendar, symptothermal, postovulation 
methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method are not acceptable definitions of abstinence. 
• Hormonal methods associated with inhibition of ovulation. Acceptable hormonal 
methods include: oral contraceptives, contraceptive medication patch, contraceptive 
medication injection, estrogen / progestin vaginal ring, or contraceptive medication 
implant. 
• At least 2 barrier methods. For example, female or male condoms with spermicidal 
foam or spermicidal jelly, or diaphragm with spermicidal foam or spermicidal jelly. 
The female condom and male condom should not be used together. 
• Use of intrauterine device (placed > 12 weeks before providing informed consent). 
• Bilateral tubal occlusion of female subjects (12 weeks before providing informed 
consent). 
• Vasectomy of male partner of female subjects (12 weeks before providing informed 
consent). 
5.4. 
Screen Failure 
A screen failure is defined as a subject who consents to participate in the clinical study but 
does not meet eligibility criteria. If a subject is not eligible for the study (ie, screen failure), 
minimal information should be recorded in the electronic case report form (eCRF) (ie, 
demography, disease-specific medical history, screen failure details, eligibility criteria, and 
any serious adverse events [SAEs]) to meet the Consolidated Standards of Reporting Trials 
publishing requirements and to respond to queries from regulatory authorities. Subjects may 
be rescreened once after discussion with the Sponsor’s Internal Medical Monitor.  

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6. 
STUDY INTERVENTIONS AND CONCOMITANT THERAPY 
6.1. 
Investigational ProductS 
In this protocol, IMP refers to both IgPro20 and placebo, unless specified otherwise. 
Table 3: 
Pharmaceutical Properties and Formulation 
Intervention Name 
IgPro20 
Placebo 
Type 
 
Biological / Vaccine 
Biological / Vaccine 
Use 
 
Experimental 
 
Placebo-Active Comparator 
 
Dose Formulation 
 
Solution for infusion 
 
Solution for infusion 
 
Unit Dose Strength 
 
200 mg/mL IgG in 250 mmol/L 
L-proline and 8 -30 mg/L 
polysorbate 80 
2% human albumin in 
250 mmol/L L-proline and 
20 mg/L polysorbate 80 
Dose and Regimen 
(Refer to Section 6.6)  
g/kg/week 
Volume-matched weekly 
administration 
Route of 
Administration 
 
Subcutaneous 
 
Subcutaneous 
 
Maximal infusion 
parameters 
Flow rate: 50 mL/h/site 
Volume: 50 mL/site 
Anatomical 
Location 
 
Abdomen, thigh, upper arm, or 
side of upper leg / hip 
Abdomen, thigh, upper arm, or 
side of upper leg / hip 
Sourcing 
 
Provided centrally by the Sponsor 
or Sponsor’s delegate 
Provided centrally by the Sponsor 
or Sponsor’s delegate 
Storage 
 
To be stored at the labeled 
conditions 
To be stored at the labeled 
conditions 
Packaging and 
Labeling 
IgPro20 will be provided in 50mL 
vials. Each vial will be packaged 
and labeled according to current 
ICH GMP and GCP guidelines 
and national legal requirements 
Placebo will be provided in 50mL 
vials. Each vial will be packaged 
and labeled according to current 
ICH GMP and GCP guidelines 
and national legal requirements 
GCP = Good Clinical Practice; GMP = Good Manufacturing Practice; ICH = International Council for 
Harmonisation 
Investigational medicinal product may be shipped from the study site to the subject’s home in 
accordance with country-specific requirements. 
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To ensure proper subject data confidentiality, a suitable courier service will be selected by 
CSL or the study site with CSL approval. 
6.2. 
Other Study Interventions 
Not applicable. 
6.3. 
Management of Investigational Product(s) 
• The IMP will be packaged and labeled according to current ICH Good 
Manufacturing Practice and Good Clinical Practice (GCP) guidelines, and 
applicable legal requirements. Specific details regarding packaging of the 
investigational product(s) are provided in the Site IMP Manual. 
• The IMP will be shipped by the Sponsor or delegate according to ICH GxP 
requirements.  
• The investigator or delegate will confirm receipt of all shipments of IMP in the 
Interactive Response Technology (IRT) system. 
• Records for the delivery of IMP to the study site, the inventory at the study site, 
assignment to each subject, and the destruction or return of IMP to the Sponsor 
(or delegate) must be maintained by the investigator (or delegate) using the IRT 
system. 
• All supplies of IMP must be accounted for throughout the study. 
• The investigator (or delegate) must provide reasons for any discrepancies in drug 
accountability in the IRT system. 
Further details regarding management of the IMP are provided in the Site IMP Manual. 
6.4. 
Assignment of Subjects to Treatment Groups and Blinding 
After providing written informed consent, the subject will be issued with a study-level unique 
subject identification number via the IRT system. The subject identification number will be 
used to identify the subject for the duration of the study. Subject identification numbers are 
not to be reassigned or reused for another subject in the study. 
6.4.1. 
Randomization 
Subjects will be randomized in a ratio of 2:1 to IgPro20 or matching placebo by means of the 
IRT. A centralized randomization schedule will be used.  
The IRT external service provider will prepare the study randomization code according to 
approved specifications. The IRT external service provider will keep the randomization code 
on file. 

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6.4.2. 
Blinding 
6.4.2.1. 
Blinding Method 
Site staff, including the investigator(s), will be blinded to treatment allocation. Subjects and 
Sponsor staff (except for IRT and Clinical Trial Supplies personnel) or delegates 
participating in the conduct of the study will also be blinded to treatment allocation (double-
blind). 
The IMP will be packaged and labeled to ensure blinding is maintained. The study site 
personnel will ensure the contents remain blinded to the subject and the study site personnel 
who will be conducting assessments. 
All samples analyzed by the central laboratory will remain blinded until database lock.  
Study unblinding will take place after the study database has been locked except in the 
situations as outlined in Section 6.4.2.2, Section 6.4.2.3, and Section 6.4.2.4. 
Adequate procedures are in place to ensure the integrity of the blinded data at the Sponsor. 
Study data will be provided to the IDMC as unblinded data, as requested. Details will be 
provided separately in the IDMC charter. 
The bioanalyst and pharmacokineticist responsible for the sample analysis and PK evaluation 
will be unblinded. However, they will agree not to disclose the randomization schedule. The 
preliminary PK data available during the study will refer to mean data with descriptive 
statistics and individual data without revealing any individual randomization numbers, 
subject numbers, or other sensitive information with the potential to lead to unblinding (eg, 
dates or times). 
6.4.2.2. 
Breaking the Blind for an Emergency 
The randomization code for individual subjects may be unblinded to a site during the study in 
emergency situations related to subject safety, if knowing the subject’s treatment assignment 
will change the investigator’s management of the subject’s condition. In case of an 
emergency for the reason of subject safety, the investigator should use the IRT to identify the 
treatment allocation for a subject. Whenever possible, the investigator should consult with the 
Sponsor before unblinding the randomization code. The reason for unblinding the 
randomization code must be fully recorded in the subject’s source documents and the 
investigator must follow the defined procedures provided in the study reference manuals. The 
subject’s treatment allocation should not be recorded in the subject’s source document. 
Subjects for whom treatment allocation is unblinded will be terminated from the study. 
6.4.2.3. 
Planned Unblinding Procedures 
Periodic unblinded safety reviews, as well as an interim analysis for futility after 54 subjects 
complete 24 weeks of treatment, are planned for this study for the purposes of safety 
monitoring activities review by the IDMC (see Section 10.1.8). With authorization from the 
Sponsor, randomization codes (only for subjects who are enrolled) will be provided to the 
external service provider performing analyses for the IDMC or the unblinded statistician, via 
the Clinical Data Warehouse. 

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At the end of the study, the Sponsor will authorize that the study be unblinded after database 
lock. The randomization codes will be accessed via the Sponsor’s Clinical Data Warehouse. 
6.4.2.4. 
Ad hoc Safety Unblinding 
The Sponsor’s Global Clinical Safety and Pharmacovigilance (GCSP) personnel may unblind 
the randomization code directly in the IRT ad hoc at any time during the study because of a 
safety concern. The purpose of the unblinded data review is to determine if there is a risk to 
subject safety that would require further action either for the management of an individual 
study subject or for the ongoing conduct of the study. The need to unblind on an ad hoc basis 
will be determined by the Sponsor’s GCSP senior leadership. 
6.5. 
Selection of Doses in the Study 
Considering the unmet medical need in post-COVID POTS, the established safety profile, 
and published data indicating clinical benefit with the proposed high dose of IgPro20 
 g/kg/week, the study assesses the relative efficacy of 
g/kg/week versus placebo to 
maximize the chance for response. 
6.6. 
Selection and Timing of Dose for Each Subject 
All IMP in the study will be administered by SC infusions as weekly doses of 
 g/kg. Based 
on subject preference and tolerability, the total weekly infusion volume can be infused over 
 infusion days per week. Details on how to divide the total weekly infusion volume are 
provided in the IMP manual. The SC infusions should be performed in a similar way 
throughout the study, ie, the same number of infusions and the same number of days each 
week after Week 2; however, the number of SC infusions per week or number of infusion 
sites per infusion can be adjusted during the study in case of intolerability to the dosing 
volume. All SC infusions for the previous week must be performed before the following 
study visit. All SC infusions planned in the same week as a study visit should not be started 
until after the study visit occurs (with the exception of Weeks 1 and 2 for training purposes 
and the first infusion of Week 25, which should also occur on site under supervision as some 
subjects will be switched from placebo to active treatment). The total dose / volume of IMP 
will be calculated on the basis of the body weight and managed by the IRT system. For 
subjects with weight >
 kg, the maximum dose will be 
 g / 
 mL IgPro20. 
6.7. 
IMP Infusion Training 
At least the first SC infusion for Week 1 and Week 2 must be administered during the study 
site visit to allow for training and confirmation of appropriate SC infusion technique. After 
Week 1 and Week 2, all weekly SC infusions will be self-administered by the subject or 
caregiver at home. Additional training at the site can be done at Weeks 3 and 4 if additional 
training is requested by the subject or, in the investigator’s opinion, the subject needs 
additional training. Further details on training of the appropriate SC infusion technique are 
provided in the Site IMP Manual.  
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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6.8. 
Dose Modification 
Dosing modifications in either g/kg dose or dosing frequency are not permitted during the 
study. With regards to dosing volume, minimal impact on trough IgG levels is expected 
based on PK simulations with up to ± 5 kg body weight change for the same dose. To 
account for potential dose changes due to body weight changes, body weight will be 
measured regularly and changes in body weight > ± 5 kg will require a dose volume 
adjustment. 
6.9. 
Investigational Product Compliance 
At least the first SC infusion for Week 1 and Week 2 will be administered under medical 
supervision. The date and time of each dose administered at the site will be recorded in the 
source documents. The dose of IMP and the subject’s identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
IMP.  
After Week 1 and Week 2, all weekly SC infusions will be self-administered at home after 
completing training (except for the Week 25 visit). Subjects will record details of their 
infusion in the electronic diary (eDiary) including whether the caregiver assisted in the SC 
infusion. In addition, subjects will bring all of their used / partially used vials of IMP to the 
study site at every study visit. Treatment compliance will be monitored based on review of 
the eDiary data and the number of returned vials, the results of which will be documented.  
A record of the quantity of IMP dispensed to and administered by each subject must be 
maintained and reconciled with study intervention and compliance records. Intervention start 
and stop dates, including dates for IMP delays and / or dose reductions, will also be recorded. 
6.10. 
Access to Investigational Product After the End of the Study 
Subjects will not be provided with IgPro20 by the Sponsor after completion of or withdrawal 
from the study. 
6.11. 
Overdose 
• Overdose is defined as the accidental or intentional infusion or ingestion of any 
dose of a product that is considered excessive. The effects of any potential 
overdose with IgPro20 have not been studied. 
• In the event of an overdose, the investigator should: 
• Contact the Sponsor’s Medical Monitor immediately. 
• Evaluate the subject to determine, in consultation with the Sponsor’s Medical 
Monitor, whether the IMP should be interrupted or discontinued, or whether the 
dose should be reduced, if applicable. 
• Closely monitor the subject for any AE, SAE, or clinical laboratory abnormalities.  
• Document the quantity of the excess dose of IMP and the duration of the 
overdose. 
See Section 10.2.6.1 for reporting AEs associated with overdose. 

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6.12. 
Prior and Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and / or herbal supplements) or other specific categories of interest that the subject is 
receiving at the time of enrollment or receives during the subject’s study participation must 
be recorded along with the following: 
• Indication. 
• Dates of administration including start and end dates, if applicable. 
• Dosage information including dose and frequency. 
The Sponsor’s Medical Monitor should be contacted if there are any questions regarding 
prior or concomitant therapy. 
The following may be used concomitantly during the study: 
• Nonpharmacological treatment if performed on stable regimen for at least 4 weeks 
before Screening and during the entire course of the study. 
• Fludrocortisone, midodrine, beta blockers, calcium channel blockers, ivabradine, 
pyridostigmine, droxidopa, low dose naltrexone; on stable doses for at least 
8 weeks before Screening and during entire course of the study. 
The following are prohibited: 
• Initiation of or changes to nonpharmaceutical treatment within 4 weeks before 
Screening and for the full course of study participation 
- IV fluids / albumin and parenteral nutrition within 4 weeks before study entry 
and during full course of study duration. 
• New or changing exercise therapy within 4 weeks before study entry and during 
full course of study duration. 
• Initiation of or changes to treatment with fludrocortisone, midodrine, beta 
blockers, calcium channel blockers, ivabradine, pyridostigmine, droxidopa, low 
dose naltrexone within 8 weeks before Screening and for the full course of study 
participation. 
• Polyclonal IVIG or SCIG products, plasmapheresis within 12 weeks before 
Screening and during study. 
• Average doses of prednisone equivalent ≥ 10 mg/day for ≥ 1 month before 
Baseline or during the full course of study participation. 
• Pre-medication with corticosteroids prior to SCIG infusions. 
• Systemic immunosuppressants within 12 weeks or 5 times the half-life before 
Screening, whichever is longer. 
• Rituximab within 24 weeks before Screening. 
• Live attenuated vaccines within 4 weeks of study entry and during full course of 
study duration. 

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7. 
SUBJECT WITHDRAWAL AND DISCONTINUATION OF 
INVESTIGATIONAL PRODUCT 
7.1. 
Discontinuation of Investigational Product 
Subjects may discontinue IMP at any time at their own request, or at the discretion of the 
investigator or the Sponsor for safety, behavioral, or administrative reasons. 
Subjects who discontinue IMP will remain in the study to complete follow-up activities or 
allow data collection as detailed in the Schedule of Activities (Section 1.3).  
If subjects discontinue IMP during the Double-blind Treatment Period, they are asked to 
complete the W25 treatment assessments at the study visit where IMP treatment is 
discontinued instead of the assessments scheduled for that particular visit. If subjects 
discontinue IMP during the Open-label Treatment Period, they are asked to complete the End 
of Treatment (EOT) assessments at the study visit where IMP treatment is discontinued 
instead of the assessments scheduled for that particular visit.  
Subjects discontinuing IMP who decline further study procedures / visit participation will be 
withdrawn from the study (see Section 7.2). 
7.1.1. 
Temporary Interruption 
A temporary interruption in treatment is not permitted unless first discussed with the 
Sponsor’s Medical Monitor. 
7.1.2. 
Stopping Criteria for Investigational Product 
The study may be stopped at any time per Sponsor’s decision. 
In addition, based on continuous safety monitoring or IDMC recommendation, the study can 
be either temporarily halted, modified via a protocol amendment, or stopped per Sponsor’s 
decision, including as a result of the futility interim analysis (see Section 9.4.12). 
If any of the following criteria are met, then all further administration of IMP and further 
enrollment of new subjects will be halted (ie, temporarily paused) until an assessment of the 
overall safety of continuing the study is completed: 
• 1 subject develops an SAE that results in death and is considered by the 
investigator, IDMC and / or the Sponsor to be related to the administration of 
IgPro20; 
OR 
• 1 subject develops any event that is deemed to pose an unacceptable risk to other 
subjects in the study, and these events are considered by the investigator, IDMC 
and / or CSL to be related to the administration of IgPro20. 
If any study halting criteria are met and/or the study is halted per IDMC recommendation, the 
Sponsor’s Global Safety Committees will conduct a safety assessment to establish if the 
study should be resumed or if the temporary halt should continue. The study can be resumed 

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on the recommendation of the Sponsor’s Global Safety Committees, in agreement with the 
IDMC, if the safety assessment concludes that no further study modifications, protocol 
amendments, or risk mitigation measures are necessary, and it is safe to resume the study. 
Regulators (on a conditional basis) and the Independent Ethics Committee (IEC) / 
Institutional Review Board (IRB) will be notified of the temporary halt and subsequent 
resumption of the study. A substantial protocol amendment will be submitted to the 
Regulators and the IEC / IRB for approval if the safety assessment concludes that 
modifications to the protocol (including addition of new risk mitigation measures) are 
required to resume the study. Ad-hoc unblinding procedures may be initiated as per the 
Sponsor’s standard operating procedures for further safety assessment, if needed. If the risk 
assessment concluded that continued dosing poses an unacceptable risk to subjects and no 
further risk mitigation steps can be applied, the Sponsor’s Global Safety Committees will be 
involved in the recommendation to halt the study. Regulators and the IEC / IRB will be 
notified of a study stop. 
7.2. 
Subject Withdrawal from the Study 
Subjects may withdraw from the study at any time at their own request or at the discretion of 
the investigator or CSL. The investigator should record in the eCRF and in the subject’s 
medical records the reason for study withdrawal, if provided by the subject in the case of 
withdrawn consent, and date of subject withdrawal. Subjects will be asked to complete the 
End of Study (EOS) visit assessments. 
In the case that subject IMP discontinuation and withdrawal from the study occur 
concurrently during the Double-blind Treatment Period, they are asked to complete the W25 
treatment assessments as well as the EOS assessments at the study visit where IMP treatment 
is discontinued instead of the assessments scheduled for that particular visit. Assessments 
included in both W25 and EOS visits should not be performed twice.  
If subject IMP discontinuation and withdrawal from the study occur concurrently during the 
Open-label Treatment Period, they are asked to complete the EOT assessments as well as the 
EOS assessments at the study visit where IMP treatment is discontinued instead of the 
assessments scheduled for that particular visit. Assessments included in both EOT and EOS 
visits should not be performed twice.  
In either case, a safety follow-up telephone call 28 days after the last IMP dose will be 
conducted by the study site to document AE and concomitant therapies. 
In accordance with the International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use (ICH) principles of GCP, the investigator always has the 
option to advise a subject to withdraw from treatment or the study if the subject’s safety or 
well-being is compromised by his or her further participation in the study. Concern for the 
interests of the subject must always prevail over the interests of the study. 
If a subject withdraws from the study, the Sponsor may retain and continue to use any data 
collected before the subject’s withdrawal of consent. 

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7.3. 
Lost to Follow-up 
If a subject repeatedly fails to attend scheduled study visits (ie, site, telephone, or home), the 
site must make 3 attempts to contact the subject, counsel the subject on the importance of 
maintaining the assigned study visit schedule and ascertain whether the subject wishes to 
(and determine whether they should) continue in the study. All attempts to contact the subject 
should be documented in the subject’s medical record. 
A subject will be considered lost to follow-up if he or she repeatedly fails to attend scheduled 
visits and cannot be contacted by the study site after 3 attempts. When a subject is lost to 
follow-up, he or she will be considered to have withdrawn from the study. 
7.4. 
Replacement Policy 
Subjects withdrawn from the study will not be replaced. 

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8. 
STUDY ASSESSMENTS AND PROCEDURES 
Study assessments and procedures and their timing are summarized in the Schedule of 
Activities (Section 1.3). Protocol waivers or exemptions are not allowed. 
The investigator should discuss any immediate safety concerns with the Sponsor’s Medical 
Monitor immediately upon occurrence or when the investigator becomes aware of the safety 
concern to determine if the subject should continue or discontinue IMP. 
Adherence to the study design requirements, including those specified in the Schedule of 
Activities (Section 1.3), is essential and required for study conduct. 
All Screening evaluations must be completed and reviewed to confirm that potential subjects 
meet all eligibility criteria. The investigator will maintain a Screening log to record details of 
all subjects screened and to confirm eligibility or record reasons for Screening failure, as 
applicable. 
Procedures conducted as part of the subject’s routine standard of care (eg, blood count) and 
obtained before signing of the informed consent form may be used for Screening or Baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the Schedule of Activities (Section 1.3). Safety, laboratory, 
or analyte results that could unblind the study will not be reported to study sites or other 
blinded personnel until the study has been unblinded. 
The maximum amount of blood collected from each subject over the duration of the study, 
including any extra assessments that may be required, will not exceed approximately 
200 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples. 
Study visits and assessments may be performed in a remote / off-site setting utilizing the 
following methods (if approved by the Sponsor and allowed according to local regulations): 
• Telemedicine visit, a virtual visit performed via videoconference or telephone by 
a delegated trained and qualified site personnel or a delegated mobile health 
provider who is trained and qualified to perform specific assessments or 
procedures.  
• Dedicated mobile health provider. 
An eDiary will be used in this study to collect home infusion compliance. 
8.1. 
Screening Assessments 
Screening / baseline assessments required to assess eligibility consist of obtaining informed 
consent, medical / surgical history, demographics, physical examination, including height, 
12-lead electrocardiogram (ECG), body weight, vital signs, SARS-CoV-2 test (antigen / PCR 
test to rule out active COVID-19 infection [reverse transcription polymerase chain reaction 
[RT-PCR] or equivalent, rapid antigen test that has been approved by regulatory authorities 
or allowed under an emergency use authorization before Screening per site’s local 

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regulations), clinical laboratory tests (including serum and urine hCG, hematology and 
biochemistry, urine sodium, and a virology blood sample), AEs, concomitant therapies, 
COMPASS-31, and a confirmatory standardized standing test.  
The following assessments will also be performed at Screening but are not required to 
determine eligibility: COVID-19 vaccination status, patient global impression of severity 
(PGI-S), patient global impression of change (PGI-C), Malmö Symptom Score, Work 
Productivity & Activity Impairment: Specific Health Problems (WPAI:SHP), EuroQoL 5 
Dimension Questionnaire (EQ-5D-5L), Short Form – 12 item (SF-12), Orthostatic 
Hypotension Questionnaire (OHQ), and Patient-reported Outcomes Measurement 
Information System (PROMIS) Cognitive Function Short Form 6a. 
8.2. 
Efficacy Assessments 
8.2.1. 
Standardized Standing Test 
Efficacy will be assessed using a standardized standing test. The standardized standing test 
mimics daily activities of POTS in a standardized manner [Finucane et al, 2019], and is 
therefore considered to be an objective, interpretable, and meaningful measurement to both 
patients and health care professionals. 
In general, subjects are asked to lie supine for 10 minutes to achieve stable baseline blood 
pressure (BP) values. At the end of the 10 minutes, baseline HR and BP will be assessed. 
After rest, subjects are asked to stand up as quickly as possible during inspiration (where 
possible) to minimize straining and arm movement. Heart rate and BP will be assessed at 1, 
3, 5, 7 and 10 minutes after standing. Subjects are then asked to sit or lie down until they 
have recovered. A separate standardized standing test protocol will be provided to sites with 
more detail on how to perform this assessment. 
The standardized standing test will be performed as the last assessment at the time points 
specified in the Schedule of Activities (Section 1.3).  
8.2.2. 
Patient-reported Outcomes 
All patient-reported outcome (PRO) assessments will be conducted electronically before any 
other study procedures. 
8.2.2.1. 
COMPASS-31 Score 
As key secondary endpoints, efficacy will be assessed by the change from baseline in both 
the OI score and total score of COMPASS-31 at the end of the Double-blind Treatment 
Period.  
The COMPASS-31 is a self-reported questionnaire that measures autonomic symptoms 
related to 6 domains: OI, vasomotor, secretomotor, gastrointestinal (GI), bladder and 
pupillomotor. This questionnaire generates a weighted score from 0 to 100, with higher 
scores representing higher symptom burden. A COMPASS-31 score of ≥ 40 indicates that 
patients have severe autonomic dysfunction [Kedor, 2021]. For the purpose of this study, the 
recall period of 1 week will be used. 

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The OI subscale was chosen as key secondary endpoint as OI symptoms were found to be 
most prominent to differentiate between POTS and other dysautonomias [Cortez et al, 2021], 
covering the most burdensome and frequent symptoms reported by POTS patients 
[Dipaola et al, 2020]. 
COMPASS-31 will be performed at the time points specified in the Schedule of Activities 
(Section 1.3). 
8.2.2.2. 
Malmö Symptom Score 
As an exploratory measure, efficacy will be assessed by the change in Malmö Symptom 
score at the end of the Double-blind Treatment Period. 
The Malmö Symptom score is a self-assessment of symptom burden using a visual analog 
scale graded from 0 (no symptoms) to 10 (very pronounced symptoms) based on 12 
commonly reported symptoms: 5 cardiac symptoms (palpitations, dizziness, presyncope, 
dyspnea, chest pain) and 7 non-cardiac symptoms (GI, insomnia, concentration difficulties, 
headache, myalgia, nausea, fatigue) [Spahic, 2023]. 
The Malmö Symptom score assessment will be performed at the time points specified in the 
Schedule of Activities (Section 1.3). 
8.2.2.3. 
Short Form – 12 Item (SF-12)  
SF-12 is a 12-item survey that assesses self-reported health-related QoL. It measures the 
functional health and well-being based on the subject’s assessment under 8 domains: physical 
activity, social activities, role activities, bodily pain, mental health, vitality, and general 
health perceptions [Ware, 1996].  
The SF-12 will be performed at the time points specified in the Schedule of Activities 
(Section 1.3). 
8.2.2.4. 
Orthostatic Hypotension Questionnaire (OHQ) 
The OHQ [Kaufman, 2012] is a 10-item instrument developed to measure the presence and 
severity of symptoms and the impact of orthostatic symptoms on daily activities. It contains 
2 domains: Orthostatic Hypotension Symptom Assessment (OHSA) (6 items) and Orthostatic 
Hypotension Daily Activity Scale (OHDAS) (4 items). Higher score indicates more severe 
symptoms. The instructions to the OHQ will be modified to exclude the note: "You should 
rate only the symptoms that are due to your low blood pressure problem" to make them more 
relevant to the study population.  
8.2.2.5. 
EuroQoL 5-Dimension Questionnaire (EQ-5D-5L) 
The EQ-5D-5L is a standardized measure of health status that provides a simple, generic 
measure of health for clinical and economic appraisal. The questionnaire, which is designed 
for self-completion by respondents, is applicable to a wide range of health conditions and 
treatments [EuroQol Group 1990]. 

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The EQ-5D-5L consists of 2 parts: 
• A descriptive profile comprising the following 5 dimensions: mobility, selfcare, 
usual activities, pain / discomfort, and anxiety / depression. Respondents rate each 
dimension based on 5 levels of severity (ie, no problems, slight problems, 
moderate problems, severe problems, and extreme problems). 
• A vertical visual analog scale, on which the respondent rates their overall health 
from ‘Best imaginable health state’ to “Worst imaginable health state.” 
The EQ-5D-5L will be performed at the time points specified in the Schedule of Activities 
(Section 1.3). 
8.2.2.6. 
Work Productivity and Activity Impairment Questionnaire: Specific Health 
Problem (WPAI:SHP) 
The efficacy of IgPro20 will be further evaluated by the change from baseline in the domain 
scores for WPAI:SHP Version 2.0. The subject will answer questions about the effect of his / 
her health on the ability to work or perform regular activities. The WPAI:SHP yields 4 types 
of scores: Absenteeism (work time missed); presenteesism (impairment at work / reduced on-
the-job effectiveness); work productivity loss (overall work impairment / absenteeism plus 
presenteeism) and activity impairment. The with higher scores indicating greater impairment 
and less productivity. 
The WPAI:SHP will be performed at the time points specified in the Schedule of Activities 
(Section 1.3). 
8.2.2.7. 
Patient Global Impression of Severity (PGI-S) and Patient Global Impression 
of Change (PGI-C) 
The PGI-S assesses the severity of OI and general symptoms, and the PGI-C assesses the 
change in severity of OI symptoms and overall disease impact. 
8.2.2.8. 
PROMIS Cognitive Functioning Short Form 6a 
POTS is known to impact patients' cognitive functioning. Patients often report difficulties 
with concentration, memory problems, and slowed information processing [Nadeem, 2023]. 
The level of cognitive impairment will be evaluated using the PROMIS Short Form v2.0 
Cognitive Function – 6a instrument that consists of 6 items about concentration, memory, 
processing speed, and overall sharpness of mind. 

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8.3. 
Safety Assessments 
Safety assessments will be performed at the time points specified in the Schedule of 
Activities (Section 1.3). 
Table 4: 
Safety Assessments 
Physical 
Examination, 
including Height 
and Weight 
As per the site’s standard procedure.  
 
Vital Signs 
• 
Blood Pressure (Systolic and 
Diastolic) 
• 
Body Temperature 
• 
Respiratory Rate 
• 
Pulse rate 
12-lead ECG 
Interpretation (investigator’s overall interpretation) 
Pregnancy 
Testing 
• 
Serum or urine test for β-hCG, as indicated, for women of childbearing 
potential. 
• 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required. In such cases, the subject must be excluded 
from participation if the serum pregnancy result is positive. 
Hematology  
• 
Platelets 
• 
Hematocrit 
• 
Hemoglobin 
• 
Erythrocytes (Red Blood Cell Count) 
• 
Leukocytes (White blood cell Count) 
• 
Reticulocytes 
• 
Red blood cell indices: Mean Corpuscular Hemoglobin Concentration, Mean 
Corpuscular Hemoglobin, Mean Corpuscular Volume, Erythrocyte 
Distribution Width 
• 
Differential: Neutrophils, Neutrophil Band Forms, Lymphocytes, 
Monocytes, Eosinophils, Basophils 
• D-dimera 
• 
Fibrinogena 
• 
Prothrombin timea 
Biochemistry 
• 
Phosphate 
• 
Calcium 
• 
Haptoglobin 
• 
Chloride 
• 
Cystatin C 
• 
Creatinine 
• 
C-reactive protein 
• 
Albumin 
• 
Direct bilirubin  
• 
Protein 
• 
Creatine kinase 
• 
Bilirubin 
• 
Creatinine clearance 
• 
Glucose 
• 
Total bilirubin 
• 
Alanine aminotransferase 
• 
Alkaline phosphatase 
• 
Aspartate aminotransferase 
• 
Blood urea nitrogen or Urea 
• 
Gamma glutamyl transferase 
• 
Thyroid stimulating hormoneb 
• 
Lactate dehydrogenase 
• 
Morning cortisol levelb 
Other Screening 
Tests 
Viral Serology: Blood samples are to be tested for the absence of HBV, HCV 
and HIV. 
Follicle-stimulating hormone: As needed in women of nonchildbearing 
potential only. 
Urine Sodiumb 

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Retention Sample Day 1 and Week 25 before first dose of IMP and after all study infusions have 
been completed at the EOT visit: retention sample for possible future 
assessment of unspecified viral agents 
aPTT = activated partial thromboplastin time; β-hCG = beta-human chorionic gonadotropin; ECG = 
electrocardiogram; EOT = end of treatment; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; IMP = investigational medicinal product; SARS-CoV-2 = Severe acute respiratory 
syndrome coronavirus 2. 
a Collected for all subjects at Screening only. 
b For subjects where these tests have not already been completed and assessed as normal after symptom onset. 
8.3.1. 
Clinical Safety Laboratory Assessments 
• The investigator must review the laboratory report, document this review, and 
record any clinically significant changes occurring during the study as an AE. The 
laboratory reports must be filed with the 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 subject’s condition. 
• All laboratory tests with values considered clinically significantly abnormal 
during participation in the study or after the last dose of IMP should be repeated 
until the values return to normal or baseline or are no longer considered clinically 
significant by the investigator or Sponsor’s Medical Monitor. 
- If clinically significant values do not return to normal / baseline within a time 
judged reasonable by the investigator, the etiology should be identified, and 
the Sponsor notified. 
- All protocol-required laboratory tests must be conducted in accordance with 
the laboratory manual and the Schedule of Activities (Section 1.3). 
- If laboratory values from nonprotocol-specified laboratory tests performed at 
the institution’s local laboratory require a change in subject management or 
are considered clinically significant by the investigator (eg, SAE or AE or 
dose modification), then the results must be recorded in the subject’s source 
documents. 
8.4. 
Adverse Events, Serious Adverse Events, and Other Safety Events 
AEs and SAEs are defined in Section 10.2.1. 
No AEs of special interest are defined for this study. 
The investigator and any qualified delegates are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for 
following up. 
The methods of reporting, recording, evaluating, and assessing causality of AEs, SAEs, and 
other significant AEs and the procedures for completing and transmitting SAE reports are 
provided in Section 10.2. 

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8.5. 
Pharmacokinetics 
Blood samples for IgG level determination will be collected pre-dose at baseline and study 
visits indicated in the Schedule of Activities (Section 1.3).  
Additional blood samples for IgG levels will be collected in a subset of subjects 
(N = approximately 25) during the Open-label Treatment Period for serial PK sampling 
starting at Week 41. The additional samples will be collected at the following time points:   
• Week 41, Day 2 (24 h ± 3 h after the start of Day 1 infusion) 
• Week 41, Day 3 (48 h ± 3 h after the start of Day 1 infusion) 
• Week 41, Day 4 (72 h ± 3 h after the start of Day 1 infusion) 
• Week 41, Day 6 (120 h ± 3 h after the start of Day 1 infusion) 
The samples for total serum IgG concentrations will be analyzed by a centralized 
bioanalytical laboratory. IgG concentrations during the Double-blind Treatment Period will 
not be disclosed prior to unblinding.  
8.6. 
Biomarkers 
8.6.1. 
Autoantibodies and Disease Biomarkers in Blood  
Blood samples (serum /plasma) will be collected for the measurement of autoantibodies and 
disease biomarkers (eg, cytokines) that may be related to post-COVID POTS and will be 
assessed to determine baseline cytokine levels as well as proportion of autoantibody-positive 
subjects. Additional samples will be collected post-treatment as indicated in the Schedule of 
Activities (Section 1.3) to determine change from baseline, and to assess the relationship 
between change from baseline and efficacy.  
The assessments of disease biomarkers may include, but are not limited to, the following: 
alpha 1 adrenergic receptor antibody, muscarinic receptor antibody, and anti-nuclear 
antibodies. Autoantibodies and disease biomarkers, including additional markers of 
proinflammatory response (eg, IL-6, IL-8 and other cytokines previously described as 
elevated in POTS) may be measured as exploratory research analysis, and will be included in 
an exploratory biomarker report, but will not be included in the clinical study report. 
Blood samples for autoantibody and cytokine assessment are collected at the time points 
specified in the Schedule of Activities (Section 1.3). 
Samples may be retained for up to 15 years and then destroyed. 
8.6.2. 
Optional Blood Transcriptomics Analysis 
In subjects who consent, whole blood samples will be collected and stored for RNA 
sequencing and transcriptomic analysis of changes in inflammatory pathways in peripheral 
blood and potential biomarkers of treatment response, disease activity, comorbid conditions 
and safety. The results of RNA transcriptomics analysis will be part of an exploratory 
research analysis and will be included in an exploratory biomarker report, which will not be 
included in the clinical study report.  

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8.6.3. 
Optional Future Research 
Subjects may optionally consent for future research samples (blood) and residual samples 
(including PK) to be used for future research. Such research is directed at better 
understanding disease and the activity and interaction of IgPro20 with related molecular 
pathways, drug pharmacology, insight into the mechanisms of AEs, and the discovery of new 
therapeutic targets. Samples may also be used to facilitate biomarker innovation, developing 
new testing methodology and statistical analysis. Samples may be retained for up to 15 years 
and then destroyed. 
8.7. 
Genomics 
Genomics will not be evaluated in this study.  
8.8. 
Immunogenicity Assessments 
Immunogenicity will not be evaluated in this study. 
8.9. 
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics will not be evaluated in this study. 

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9. 
STATISTICAL CONSIDERATIONS 
9.1. 
Statistical Hypotheses 
The study is designed to test the null (H01) versus the alternative (H11) hypothesis of the 
primary endpoint for the proportion of subjects no longer meeting diagnostic criteria of post-
COVID POTS as measured by standardized standing test (ie, no longer experiencing HR 
increase of ≥ 30 bpm, in the absence of orthostatic hypotension [ie, sustained 20 mmHg 
decrease of SBP]) at the end of the Double-blind Treatment Period. 
H01: PIgPro20 ≤ PPlacebo    versus 
H11: PIgPro20 > PPlacebo 
Where PIgPro20 and PPlacebo indicate the proportion of subjects no longer meeting diagnostic 
criteria of post-COVID POTS as measured by standardized standing test in the IgPro20 and 
placebo group, respectively. The test for superiority will be performed at a 1-sided alpha 
level of 2.5% using a Farrington-Manning test. 
Hypothesis for the key secondary endpoints are: 
H02: µIgPro20 ≥ µPlacebo    versus 
H12: µIgPro20 < µPlacebo 
Where, µIgPro20 and µPlacebo correspond to the treatment group means of interindividual 
changes in OI score of COMPASS-31 for IgPro20 and placebo, respectively. The test for 
superiority will be performed using a t-test. 
H03: µIgPro20 ≥ µPlacebo    versus 
H13: µIgPro20 < µPlacebo 
Where µIgPro20 and µPlacebo correspond to the treatment group means of interindividual 
changes in COMPASS-31total score for IgPro20 and placebo, respectively. The test for 
superiority will be performed using a t-test. 
H04: µIgPro20 ≥ µPlacebo    versus 
H14: µIgPro20 < µPlacebo 
Where µIgPro20 and µPlacebo correspond to the treatment group means of interindividual 
changes in HR for IgPro20 and placebo, respectively. The test for superiority will be 
performed using a t-test. 
Testing will be performed accounting for multiplicity as outlined in Section 9.4.3 to preserve 
the alpha level of 2.5%. 
9.2. 
Sample Size Determination 
Based on the rationale presented in Section 4.3, assuming the proportion of subjects no 
longer meeting diagnostic criteria of post-COVID POTS as measured by standardized 
standing test at the end of the Double-blind Treatment Period. Sample size assumptions are 
based on the 30% and 60% response for the placebo and IgPro20 group, respectively; under 

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these assumptions, at least 126 subjects will be required to provide 90% power (2:1 
randomization) to detect a 30% difference in proportion of responders using a 
Farrington-Manning test for a 1-sided alpha of 2.5%. An additional 18 subjects will be 
randomized to account for a futility analysis at 54 subjects, and an additional 33 subjects will 
be randomized to ensure > 100 subjects treated with IgPro20 for >1 year will be achieved 
considering approximately 20% early drop out. Therefore, the final number of patients to be 
randomized is 177 (118:59).  
For hypothesis testing, an alpha of 2.5% (1-sided) will be used. Randomization will be 
continued if the dropout rate is over 10%.  
9.3. 
Analysis Sets 
All decisions regarding definition of analyses sets will be made prior to unblinding. 
9.3.1. 
Screened Analysis Set 
The Screened Analysis Set consists of all subjects who provided written informed consent. 
9.3.2. 
Intention-to-Treat Analysis Set 
The Intention-to-Treat (ITT) analysis set consists of all subjects in the Screened Analysis Set 
who were randomized into the study. This analysis set will be analyzed using the treatment to 
which the subject was randomized regardless of the treatment actually received.  
9.3.3. 
Per-Protocol Analysis Set 
The Per-protocol (PP) set will consist of all subjects who satisfy the ITT criteria and have no 
major protocol deviations that impact the primary efficacy endpoint (as defined in the SAP). 
Subjects in the PP set will be analyzed using the ITT principle (ie, according to randomized 
treatment assignment). 
9.3.4. 
Safety Analysis Set 
The Safety Analysis Set consists of all subjects in the ITT Analysis Set who received any 
IMP. The Safety Analysis Set will be analyzed using the treatment that the subject actually 
received. 
9.3.5. 
Pharmacokinetic Analysis Set 
The PK Analysis Set consists of all subjects in the Safety Analysis Set with at least 
1 quantifiable PK concentration of IgG after administration. 
The PK Substudy Analysis Set includes all subjects in the Safety Analysis Set who enrolled 
into the PK Substudy and have intensive concentration data to provide interpretable results 
for the specific parameters of interest for IgG. 

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9.4. 
Statistical Analyses and Methods 
The SAP will include a more technical and detailed description of the statistical analyses 
described in this section. This section is a summary of the planned statistical analyses of the 
most important endpoints. 
9.4.1. 
General Considerations 
All statistical tests will be 2-sided and will be performed at the 5% level of significance, 
unless otherwise stated. 
In general, continuous variables will be summarized using descriptive statistics (number of 
observations [n], mean, standard deviation [SD], median, minimum, and maximum). 
Categorical variables will be summarized using frequencies and percentages. For repeated 
observations of continuous variables, change from baseline will also be summarized. 
Summary statistics will be described separately for each treatment group. 
Baseline refers to the last measurement or the last calculated value before the first 
administration of IgPro20. For COMPASS-31, the assessment at the Screening visit will be 
used as baseline value (for total as well for all domains). 
Missing dates / times in AE and concomitant therapies data will be handled as described in 
the SAP. There will be no imputation schemes applied to missing data unless otherwise 
specified in the SAP. Values that are below the limit of quantification in the PK data will be 
handled as described in the SAP. 
9.4.2. 
Efficacy Analyses 
All efficacy analyses will be conducted using the ITT Analysis Set except otherwise. The 
details of all analyses, as well as by visit analysis, will be defined in the SAP. 
9.4.2.1. 
Primary Estimand and Analysis of Primary Efficacy Endpoint 
The subject’s response status of no longer meeting diagnostic criteria of post-COVID POTS 
as measured by standardized standing test (ie, no longer experiencing HR increase of 
≥ 30 bpm, in the absence of 20 mmHg decrease of HR [orthostatic hypotension]) will be 
assessed as the primary endpoint.  
A subject is considered a responder if  
HRw25,10min – HRw25,0min < 30 bpm   and 
BPw25,as – BP W25,bs > -20 mmHg 
Where, HRW25,10min indicates the average of the 2 highest HR measures (bpm) within 
10 minutes after start of the standing test at W25, HRW25,0min indicates the HR measure (bpm) 
at start of the standing test at W25, BPW25,as indicates the systolic blood pressure measure 
(mmHg) at any time point within 10 minutes after start of the standing test at W25, and 
BPW25,bs indicates the systolic blood pressure measure at the start of the standing test at W25. 
Consequently, a subject is considered a non-responder, if  
HRw25,10min – HRw25,0min ≥ 30 bpm   or 
BPw25,as – BP W25,bs ≤ -20 mmHg 

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Response rates [%] will be determined for placebo and IgPro20. 
For each treatment group point estimates and 95% Wilson Score confidence intervals will be 
provided, for the difference between treatment groups (IgPro20 – placebo) the point estimate, 
95% Farrington-Manning confidence interval and 1-sided p-value will be provided.  
To show the magnitude of the HR increase at baseline (HR10min, baseline – HR0min, baseline) and at 
W25 (HR10min, W25 – HR0min, W25), the proportion of subjects within the following categories 
will be analyzed. This analysis will show the proportion of the subjects with normal HR 
increase after the standing test at the end of the treatment period. 
- HR increase < 10 bpm 
- 10 bpm ≥ HR increase < 15 bpm 
- 15 bpm ≥ HR increase < 20 bpm 
- 20 bpm ≥ HR increase < 25 bpm 
- 25 bpm ≥ HR increase < 30 bpm 
- 30 bpm ≥ HR increase < 35 bpm 
- 35 bpm ≥ HR increase < 40 bpm 
- 40 bpm ≥ HR increase < 45 bpm 
- 45 bpm ≥ HR increase < 50 bpm 
- HR increase ≥ 50 bpm 
9.4.2.1.1. Detail of Primary Estimand 
The primary comparison of interest is to quantify the treatment effect of IgPro20 versus 
placebo. The treatment effect of interest is the difference in the proportion of subjects no 
longer meeting diagnostic criteria of post-COVID POTS as measured by standardized 
standing test (no longer experiencing HR increase of ≥ 30 bpm in the absence of 20 mmHg 
decrease of SBP [orthostatic hypotension]). 
The attributes of the primary estimand, as defined in the ICH E9(R1) guidance, are provided 
in Table 5. 
Table 5: 
Attributes of Primary and Key Secondary Estimand 
Estimand 
Attribute 
Subjects no longer meeting diagnostic criteria of post-COVID POTS as measured by 
standardized standing test. 
Population 
Adults (≥ 18 years of age) with post-COVID-19 Postural Orthostatic Tachycardia 
Syndrome (POTS) 
Treatment 
Randomized IMP (blinded IgPro20 or blinded placebo) 

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Endpoint 
Primary: Proportion of subjects no longer meeting diagnostic criteria of post-COVID 
POTS as measured by standardized standing test. 
Key secondary:  
• 
Change from baseline in orthostatic intolerance score (OI) of COMPASS-31 at the 
end of the Double-blind Treatment Period. Change from baseline in COMPASS-31 
total score (TS) at the end of the Double-blind Treatment Period. 
• 
Change from baseline in HR increase within 10 minutes of standing test at the end of 
the Double-blind Treatment Period. 
Intercurrent 
Event 
Strategy 
Description 
Imputation details 
Treatment 
(IMP) 
discontinuation 
due to LoE, 
related adverse 
event or lack 
of compliance 
Composite / 
Hypothetical  
Discontinuation due to lack of 
efficacy will be treated as a failure. 
Only data collected prior to treatment 
(IMP) discontinuation will be 
analyzed 
Primary endpoint: non-responder  
Key secondary endpoints: MI 
based on placebo group after ICE 
Treatment 
discontinuation 
(not due to 
LoE, related 
AE nor lack of 
compliance) 
Hypothetical  
Depending on the subject’s status 
until the last known visit and specific 
intercurrent event that contributed to 
the lost to follow-up, the relevant 
above intercurrent events will be 
considered for analyses. 
Primary endpoint: MI based on 
randomized treatment  
Key secondary endpoints: MI 
based on randomized treatment 
Stop of IMP 
but continues 
the study up to 
end of the 
Double-blind 
Treatment 
Period 
Treatment-
policy 
The occurrence of missing IMP will 
be ignored, and data analyzed as 
planned to determine response status. 
No action needed 
Prohibited 
therapies 
Composite / 
Hypothetical  
Data after the intake of prohibited 
medication with a potential effect on 
the primary or key secondary 
endpoints will be disregarded.   
Primary endpoint: non-responder  
Key secondary endpoints: MI 
based on placebo group after ICE 
Concomitant 
therapies 
Treatment 
policy  
Data will be collected and analyzed 
regardless of whether an allowed 
concomitant therapy is given. 
No action needed 
Death not 
related to IMP 
or disease 
Composite 
Depending on the subject’s status 
until the last known visit and specific 
intercurrent event that contributed to 
the lost to follow-up, the relevant 
above intercurrent events will be 
considered for analyses. 
No data beyond the date of death will 
be imputed. 
Primary endpoint: MI based on 
placebo group 
Key secondary endpoints: MI 
based on placebo group 

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Intercurrent 
Event 
Strategy 
Description 
Imputation details 
Death related 
to IMP or 
disease 
Composite  
Death will be considered as treatment 
failure.  
No data beyond the date of death will 
be imputed. 
Primary endpoint: non-responder 
Key secondary endpoints: 
imputing worst score / highest 
HR observed 
Lost to follow-
up 
Hypothetical 
Depending on the subject’s status 
until the last known visit and specific 
intercurrent event that contributed to 
the lost to follow-up, the relevant 
above intercurrent events will be 
considered for analyses. 
Primary endpoint: MI based on 
randomized treatment  
Key secondary endpoints: MI 
based on randomized treatment 
Population-
level 
Summary 
Primary: Point estimate and 95% CI for the difference in proportions. 
Key secondary: Point estimate and 95% CI for difference in means. 
CI = confidence interval; ICE = intercurrent event; IMP = investigational medicinal product; LoE = lack of 
efficacy; MI = multiple imputation; POTS = Postural Orthostatic Tachycardia Syndrome 
9.4.2.1.2. Sensitivity Analysis 
The following sensitivity analyses are planned for the primary efficacy endpoint:  
• Using the PP analysis set. 
• Using a tipping point analysis: for subjects with an ICE (see Section 9.4.2.1.1 for 
further details), the HR after the ICE will be imputed using a multiple imputations 
approach (see Section 9.4.4 for further details). 
9.4.2.2. 
Analysis of Key Secondary Endpoints 
To further evaluate the efficacy of IgPro20 in adult subjects with post-COVID POTS, the 
following key secondary endpoints will be conducted: 
1. Change from baseline in OI score of COMPASS-31 at the end of Double-blind 
Treatment Period 
For each subject OIchange = OIW25 – OIbaseline will be calculated, where OIW25 
corresponds to the OI score of COMPASS-31 at Week 25 and baseline, respectively. 
Descriptive statistics of the individual changes will be calculated by treatment group, 
including means and 95% CIs. Treatment group means will be tested for superiority 
by using a t-test. Hypothesis testing as outlined in Section 9.1 will be done.  
2. Change from baseline in TS of COMPASS-31 at the end of the Double-blind 
Treatment Period 
For each subject TSchange = TSW25 – TSbaseline will be calculated, where TSW25 
corresponds to the TS of COMPASS-31 at Week 25 and baseline, respectively. 
Descriptive statistics of the individual changes will be calculated by treatment group, 
including means and 95% CIs. Treatment group means will be tested for superiority 
by using a t-test. Hypothesis testing as outlined in Section 9.1 will be done. 

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3. Change from baseline in HR increase within 10◦minutes of standing test at the end of 
the Double-blind Treatment Period: 
For each subject HRchange = (HR W25,10min – HR W25,0min) – (HR baseline,10min – HR 
baseline,0min) will be calculated, where HR W25,10min indicates the average of the two 
highest HR measures (bpm) within 10 minutes after start of the standing test at W25, 
HR W25,0min indicates the HR measure (bpm) at start of the standing test at Week 25, 
and likewise for baseline. Descriptive statistics of the individual changes will be 
calculated by treatment group, including means and 95% CIs. Treatment group means 
will be tested for superiority by using a t-test. Hypothesis testing as outlined in 
Section 9.1 will be done. 
Additional analyses 
To show the magnitude of the improvement of OI score of COMPASS-31, OI scores at 
baseline (OIbaseline) and at W25 (OIW25), the proportion of subjects within the following 
categories will be analyzed. This analysis will show the proportion of the subjects with OI 
symptom score improvement at the end of the treatment period. 
• OI Score ≥ 36 
• 33 ≥ OI Score < 36 
• 30 ≥ OI Score < 33 
• 27 ≥ OI Score < 30 
• 24 ≥ OI Score < 27 
• 21 ≥ OI Score < 24 
• 18 ≥ OI Score < 21 
• 15 ≥ OI Score < 18 
• 12 ≥ OI Score < 15  
• OI Score < 12 
To show the magnitude of the improvement of TS score of COMPASS-31, TS scores at 
baseline (TSbaseline) and at W25 (TSW25), the proportion of subjects within the following 
categories will be analyzed. This analysis will show the proportion of the subjects with TS 
symptom score improvement at the end of the treatment period. 
• Total Score ≥ 91  
• 86 ≥ Total Score < 91 
• 81 ≥ Total Score < 86 
• 76 ≥ Total Score < 81 
• 71 ≥ Total Score < 76 
• 66 ≥ Total Score < 71 

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• 61 ≥ Total Score < 66  
• 56 ≥ Total Score < 61  
• 50 ≥ Total Score < 56  
• Total Score < 50 
To show the proportion of subjects with normal HR after 24 weeks of treatment also had 
improvement in their OI and TS of COMPASS-31, the correlation between HR and OI as 
well as TS will be done using the Spearman correlation. Sensitivity Analysis of Key 
Secondary Endpoints 
The following sensitivity analyses are planned for the key secondary efficacy endpoints:  
• using the PP analysis set 
• using a tipping point analysis: for subjects with an ICE the HR and COMPASS-31 
after the ICE (see Section 9.4.2.1.1 for further details) will be imputed using a 
multiple imputation (see Section 9.4.4). 
9.4.3. 
Multiplicity 
Issues related to multiplicity arising from testing the primary endpoint and key secondary 
endpoints will be addressed using pre-defined hierarchical testing procedure of the primary 
and key secondary endpoints with following order at an alpha level of 2.5%:  
1. Hypothesis tested: primary endpoint 
2. Hypothesis tested: 1stkey secondary endpoint; change from baseline in OI domain of 
the COMPASS-31 
3. Hypothesis tested: 1st key secondary endpoint; change from baseline in COMPASS-
31 total score 
4. Hypothesis tested: 2nd key secondary endpoint; change from baseline in HR increase 
9.4.4. 
Multiple Imputation 
For subjects with an ICE (see Section 9.4.2.1.1) that considers multiple imputation data after 
the ICE will be disregarded (if applicable) and be imputed using a multiple imputations 
approach. 
Intermittent missing replacement step: If intermittent values are missing for any of the 
data included in the multiple imputation analysis, the intermittent values will be imputed first 
using a Markov Chain Monte Carlo method 50 times to create 50 data sets with only 
monotone missing. The corresponding data sets will be used as input data sets for 
replacement of the post-ICE missing values using monotone regression; as the preceding step 
led already to 50 data sets, the number of imputations in this step is to be set to 1.  
Imputation step: Replacement of missing values for HR,W5,0min, HRW5,10min, HRW9,0min, 
HRW9,10min, HRW13,0min, HRW13,10min, HRW17,0min, HRW17,10min, HRW21,0min, HRW21,10min, 
HRW25,0min, and HRW25,10min, OIW5, OIW9, and OIW25 as well as TSW5, TSW9, and TSW25 (if 

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applicable), will be done using multiple imputations based on monotone regression with the 
covariates treatment, country, HR at baseline, COMPASS-31TS and OI at baseline and HR 
and COMPASS-31 TS and OI values from previous weeks by SAS® PROC MI for 
50 imputations with a seed of 7562032. The HR value at the end of the standing test will be 
considered as the average of the two highest values within 10 minutes after start of the 
standing test. 
Analysis step: For each of the 50 analyses of the primary and key secondary endpoints will 
be performed as outlined in Section 9.4.2.1 and Section 9.4.2.2.  
For the primary endpoint, each subject’s response status will be derived as in Section 9.4.2.1. 
For the first key secondary endpoint, the imputed HR will be used. 
For the second and third key secondary endpoints, the imputed COMPASS-31 values will be 
used. 
Combination step: The corresponding results across the data sets are combined for overall 
inference using SAS® PROC MIANALYZE according to Rubin’s rule to give the 1-sided 
p-values for hypothesis testing, and the corresponding measures (responder rate, mean, 95% 
CIs, as applicable). 
9.4.5. 
Tipping Point Analysis 
A tipping point analysis will be done to assess the robustness of the assumptions for the 
multiple imputation and will be done only if primary analysis has a p-value < 0.025 (1-sided).  
For each of the primary and key secondary endpoints, the treatment differences (D) are 
obtained from the main analysis as HRIgPro20,W25,0min  - HRplacebo,W25,0min and HRIgPro20,W25,10min  
- HRplacebo,W25,10min (for primary and  third key secondary endpoint) and OI IgPro20,W25 – 
OIpplacebo,W25 as well as TSIgPro20,W25 – TSplacebo,W25 (for the first and second key secondary 
endpoints) from the primary analyses. The HR value at the end of the standing test will be 
considered as the average of the two highest values within 10 minutes after start of the 
standing test.  
For each λ =0.05 to1 (by 0.05) steps, subtract λ×∆ from the imputed values of the IgPro20 
treatment group in each of the 50 imputed datasets from the primary analysis. Continue with 
the analysis and combination step as described above for each λ. 
9.4.6. 
Exploratory Analysis 
The proportion of subjects with orthostatic hypotension, the change in Malmö Symptom 
score, EQ-5D-5L utility scores and visual analog scale, WPAI total and domain scores, SF-12 
domain score, the remaining domains of COMPASS-31 and the proportion of patients who 
achieved the clinically meaningful improvement in OI and total domains of COMPASS-31 at 
the end of the Double-blind Treatment Period for IgPro20 vs placebo will be summarized. 
9.4.7. 
Safety Analyses 
All safety analyses will be performed by treatment group using the Safety Analysis Set. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. 

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Treatment-emergent AEs (TEAEs) are defined as AEs reported at or after the start of IMP 
administration. The number and percentage of subjects with TEAEs will be reported. 
Frequency counts and percentages will also be presented for subjects with 
treatment-emergent SAEs, TEAEs leading to withdrawal or discontinuation of investigational 
product, TEAEs by severity, and TEAEs by relationship to investigational product. All AEs 
will be listed. 
Analyses of other safety assessments such as ECGs, vital signs, and clinical laboratory safety 
markers will be described in the SAP. 
9.4.8. 
Pharmacokinetics Analyses 
IgG concentrations will be listed for individual subjects and summarized by nominal 
(planned) visit and timepoints, as well as by treatment group (IgPro20 vs placebo). Individual 
concentration-time profiles and mean (± SD) profiles will be plotted using actual time points 
for individual plots and nominal (planned) time points for mean profiles on both log-linear 
and linear scales.  
Ctroughs will be measured for all subjects. Other parameters, including AUC0-tau (tau=Day 7), 
Cmax and Tmax, will be derived for the subjects with serial sampling on Week 41 using 
noncompartmental methods. The PK parameters will be listed individually and summarized. 
Additional information on the analyses of PK parameters will be provided in the SAP. The 
PK Analysis Set or PK Substudy Analysis Set will be used. 
The IgG concentration data may be used, possibly in combination with IgPro20 data from 
previous studies, to further develop the population PK model. 
9.4.9. 
Pharmacodynamic and Biomarker Analyses 
If applicable, additional exploratory biomarker analyses will be described in a separate 
biomarker SAP and may be reported outside of the SAP and clinical study report. 
9.4.10. 
Pharmacokinetic / Pharmacodynamic Analyses 
Relationships between trough concentrations and other PD/biomarker endpoints may be 
explored through graphical and statistical regression analyses as appropriate. Details will be 
provided in the SAP. 
9.4.11. 
Other Analyses 
Subgroup Analyses of Primary Endpoint  
Internal consistency of observed treatment effect across major subgroups on the primary 
endpoint will be investigated. Subgroup factors are shown in the list below:  
• Subjects received a COVID-19 vaccine  
- Yes  
- No  

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• Age 
- ≥18 – <20 Years  
- ≥20 – <26 Years  
- ≥26 – <46 Years  
- ≥46 – <65 Years  
- ≥ 65 Years  
• Sex: 
- Female  
- Male  
• Baseline total COMPASS-31 score:  
- ≥40 – <46 
- ≥46 – <51 
- ≥51 – <56 
- ≥ 56 
Subgroup analysis will use the same analytical approach as in the primary endpoint analysis. 
9.4.12. 
Interim Analysis 
Simulation within EAST software was used to determine time point and operating 
characteristics of an interim analysis for futility using a gamma family alpha spending 
function. There is neither a plan for sample size re-estimation during the trial nor for early 
stopping for efficacy. For a futility boundary of 10% (ie, if response rate with IgPro20 
IgPro20 – response rate with placebo is < 10%) there is a probability to stop under H0 (no 
treatment effect) of 75.8% and to stop the study under H1 (assumed treatment effect of 30%) 
of 7.4% at the time the futility analysis is performed (when 54 subjects have completed the 
first 24 weeks of treatment). Please see below for further scenarios (total N of 177). This 
boundary and timepoint for the interim analysis was considered suitable considering 
recruitment.  
The detailed of boundaries and timepoint for the interim analysis will be described in IDMC 
SAP and IDMC charter. 

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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1. 
Regulatory, Ethical, and Study Oversight Considerations 
10.1.1. 
Clinical Trial Research Agreement 
This study will be conducted under a Clinical Trial Research Agreement between the 
Sponsor and the institution(s) representing the investigational study site(s). Financial support 
to the investigational site(s) will be detailed in the Clinical Trial Research Agreement. The 
Clinical Trial Research Agreement must be signed before the commencement of the study 
and will clearly delineate the responsibilities and obligations of investigator and Sponsor and 
will form the contractual basis under which the clinical study will be conducted. Clinical 
Trial Research Agreements may be executed by electronic signature in compliance with 
21 CFR Part 11 and simple or advanced electronic signature according to EU Regulation 
No 910/2014 - eIDAS. 
10.1.2. 
Regulatory and Ethics Considerations 
This study will be conducted in accordance with the Clinical Study Protocol (CSP) and with 
the following: 
Consensus ethical principles derived from international guidelines including the Declaration 
of Helsinki. 
• Applicable ICH GCP Guidelines. 
• Applicable laws and regulations. 
• The CSP, CSP amendments, Informed Consent Form (ICF), Investigator’s 
Brochure, and other relevant documents (eg, advertisements) must be submitted to 
an Institutional Review Board (IRB) / Independent Ethics Committee (IEC) by the 
investigator and reviewed and approved by the IRB / IEC before the study is 
initiated. 
• Any CSP amendments will require IRB / IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study subjects. 
• CSP and CSP amendments will require health authority approval prior to 
initiation except for changes necessary to eliminate an immediate hazard to study 
subjects. 
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 in accordance with 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. 

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• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB / IEC, European Clinical Trials 
Regulation 536/2014 for clinical studies (if applicable), European Medical Device 
Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations. 
10.1.3. 
Informed Consent Process 
Informed consent will be obtained from all subjects or legally authorized representatives, if 
appropriate, before any study-related procedures are performed. 
The investigator or delegate will explain the nature of the study to the subject or their legally 
authorized representative and answer all questions regarding the study. 
Subjects or their legally authorized representative must be informed that their participation is 
voluntary. Subjects or their legally authorized representative will be required to sign a 
statement of informed consent, either via paper or electronic means, that meets the applicable 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act requirements, and the IRB / IEC or study site. 
The medical record must include a statement that written informed consent was obtained 
before the subject was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
Subjects or their legally authorized representative 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 subject or their legally authorized 
representative. 
OR 
The ICF will contain a separate section or addendum that addresses the use of samples for 
optional exploratory research. The investigator or authorized delegate will explain to each 
subject the objectives of the exploratory research. Subjects will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during 
the storage period. 
10.1.4. 
Data Protection 
Measures used to protect individual subject data include the following: 
Subjects will be assigned a unique identifier by the Sponsor. Any subject records or datasets 
that are transferred to the Sponsor will contain the identifier only; subject names or any 
information which would make the subject identifiable will not be transferred. 
The subject must be informed that their personal study-related data will be used by the 
Sponsor in accordance with all applicable data protection laws. The level of disclosure must 
also be explained to the subject who will be required to give consent for their data to be used 
as described in the ICF. 

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The subject must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB / IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Dissemination of Clinical Study Information and Data 
The Sponsor will provide the relevant CSP information in public database(s) before or at 
commencement of the study. The Sponsor may also provide study information for inclusion 
in national registries according to local regulatory requirements. 
Results of this study will be disclosed according to the relevant regulatory requirements. All 
publications in peer-reviewed medical journals resulting from this study will be listed in the 
original CSP registration record. 
This CSP will be made public following study completion with results posting in any 
applicable public registry (eg, ClinicalTrials.gov). Company confidential information within 
the CSP and personal protected data may be redacted as defined by regulatory authorities. 
10.1.6. 
Data Quality Assurance 
All subject data relating to the study will be recorded either through the IRT system or on 
printed or eCRFs unless transmitted to the Sponsor or delegate electronically (eg, laboratory 
data). The investigator is responsible for verifying that data entries are accurate and correct 
by physically or electronically signing the eCRF. 
Guidance on completion of eCRFs will be provided in the eCRF. 
The investigator must permit study-related monitoring, audits, IRB / IEC review, and 
regulatory agency inspections, and provide direct access to source data documents. 
The Sponsor or delegate is responsible for the data management of this study including 
quality checks of the data. 
The Sponsor assumes accountability for actions delegated to other individuals (eg, contract 
research organizations). 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for the timeline outlined in the Clinical Trial Research 
Agreement. 
Quality tolerance limits, where appropriate, will be predefined in the Quality Risk 
Management Plan to identify systematic issues that can impact participant safety and / or 
reliability of study results. These predefined parameters will be monitored during the study 
and important deviations from the quality tolerance limits and remedial actions taken may be 
summarized in the clinical study report. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk-Based Quality Management), methods, responsibilities, and requirements, 
including handling of noncompliance issues and monitoring techniques (central, remote, or 
on-site monitoring), are provided in the Monitoring Plan and Quality Risk Management Plan. 

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10.1.7. 
Patient Recruitment 
As part of this clinical trial, patients will be recruited using digital ads on social media 
platforms. Images and text used in the ads require IRB or EC approval prior to use. 
Once a potential participant clicks on the digital ad, they will be directed to a landing page 
where they will review and accept a Privacy Policy and Terms of Use detailing the purpose 
of data collection, what data will be collected, how it will be used, and their rights under 
applicable data privacy laws. Should they choose to proceed, the potential participant is then 
directed to a pre-screening questionnaire to answer a few questions about their condition and 
their contact information. 
Once the pre-screening questionnaire is completed, these responses are reviewed by the 
patient referral vendor. Potential participants confirm their potential eligibility, their interest 
in potential participation, and consent to sharing their information with the clinical research 
site. Once the patient referral vendor shares the information with the clinical research site, the 
investigator will directly confirm initial eligibility and interest with the potential participant. 
10.1.8. 
Committees Structure 
10.1.8.1. Independent Data Monitoring Committee 
An unblinded IDMC will monitor the safe conduct of the study. An IDMC charter outlines 
the roles and responsibilities of the committee and guides its operations. The IDMC consists 
of qualified POTS clinical experts and scientists who are not investigators in the study and 
not otherwise associated with the Sponsor. The IDMC responsibilities include the following: 
• Review the safety data at planned intervals and identify if significant safety 
concerns arise during the study. 
• Provide recommendations to the Sponsor regarding study conduct matters that 
affect safety. 
• Request an interim safety review whenever one is warranted. 
• Recommend modifications to study conduct or early study termination, if 
warranted due to safety concerns. 
• Review efficacy and safety data and make recommendations regarding study 
progression or termination due to futility (see Section 10.1.10). 
10.1.9. 
Source Documents 
Source documents (including eCOA / eDiary) provide evidence for the existence of the 
subject and substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
The definition of what constitutes source data can be found in the Clinical Trial Research 
Agreement. 
Data reported through the IRT system or entered into the eCRF that are transcribed from 
source documents must be consistent with the source documents. If there are data 

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discrepancies, the discrepancies must be explained. The investigator may need to request 
previous medical records or transfer records, depending on the study. Current medical 
records must also be available. 
The investigator must maintain accurate documentation (source data) to support the 
information entered into the CRF. 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of subjects are being protected; and that the study is 
being conducted in accordance with the currently approved CSP and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.10. 
Premature Site Closure and Study Termination 
The Sponsor or delegate reserves the right to close the study site prematurely or terminate the 
study at any time for any reason at the sole discretion of the Sponsor. Reasons for premature 
site closure include, but are not limited to: 
• Failure of the investigator to comply with the CSP, the requirements of the 
IRB / IEC or local health authorities, the Sponsor’s procedures, or GCP 
guidelines. 
• Inadequate recruitment (evaluated after a reasonable amount of time) of subjects 
by the investigator. 
• Enrollment target achieved earlier than expected. 
• The reason for study termination may include, but is not limited to, 
discontinuation of IMP development for any reason. If the study is terminated or 
suspended, the Sponsor will promptly notify the investigators, the IRBs / IECs, 
the regulatory authorities, and any contract research organization(s) used in the 
study and provide the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The investigator will promptly inform the 
subject and should ensure that they are properly transitioned out of the study. 
10.1.11. 
Publication Policy 
The rights and obligations of investigators and the Sponsor concerning any formal 
presentation or publication of data collected as a direct or indirect result of this study will be 
addressed specifically in the Clinical Trial Research Agreement for the study. 

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10.2. 
Adverse Events and Serious Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting 
10.2.1. 
Definitions 
10.2.1.1. Adverse Event 
An AE is any untoward medical occurrence in a clinical study subject administered an 
investigational product and that does not necessarily have a causal relationship with this 
treatment. An AE can, therefore, be any unfavorable and unintended sign (including an 
abnormal, clinically significant laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not considered 
related to the medicinal (investigational) product. 
The observation period for AEs is defined in Section 10.2.4. 
Adverse events may include: 
• Exacerbation (ie, an increase in the frequency or severity) of a preexisting 
condition. Preexisting conditions should be recorded on the Medical History 
eCRF and only reported as an AE if there is an increase in the frequency or 
severity of the condition during the study. 
• A clinical event occurring after consent and before IMP administration. 
• Intercurrent illnesses with an onset after administration of IMP. 
Adverse events do not include: 
• Events identified at Screening that meet exclusion criteria. 
• Medical or surgical procedures (the condition that leads to the procedure is the 
AE). 
• Situations where an untoward medical occurrence has not taken place. For 
example: 
- Planned hospitalizations related to preexisting conditions that have not 
worsened. 
- Hospitalizations that occur for procedures not due to an AE (eg, cosmetic 
surgery). 
- Hospitalizations for a diagnostic procedure where the hospital stay is less than 
24 hours in duration or for normal management procedures (eg, 
chemotherapy). 
• Overdose of IMP or any concomitant therapy that does not result in any adverse 
signs or symptoms. 
For laboratory and other safety parameters (eg, vital signs), any instances of absolute values 
or changes at any visit after study start that are considered by the investigator as clinically 
significant must be recorded on the AE eCRF. In addition, at the investigator’s discretion, 

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any changes or trends over time in laboratory parameters may be recorded on the AE eCRF if 
such changes or trends are considered to be clinically relevant, even if the absolute values are 
within the reference range. 
Laboratory findings do not need to be reported as AEs in the following cases: 
• Laboratory parameters already beyond the reference range at screening, unless a 
further increase / decrease can be considered an exacerbation of a preexisting 
condition. 
• Abnormal laboratory parameters caused by mechanical or physical influences on 
the blood sample (eg, in vitro hemolysis) and flagged as such by the laboratory in 
the laboratory report. 
• Abnormal parameters that are obviously biologically implausible (eg, values that 
are incompatible with life or outside the measuring range). 
• An abnormal laboratory value that cannot be confirmed after repeat analysis, 
preferably in the same laboratory (ie, the previous result could be marked as not 
valid and should not necessarily be reported as an AE). 
10.2.1.2. Serious Adverse Event 
An SAE is defined as any untoward medical occurrence that at any dose: 
• Results in death – The event must be the cause of death for the SAE to meet this 
serious criterion. 
• Is life-threatening – The term “life-threatening” refers to an event in which the 
subject was at risk of death at the time of the event; it does not refer to an event 
that hypothetically might have caused death if it had been more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
– Hospital admissions for planned surgery or for normal disease management 
procedures (eg, chemotherapy) are not considered as defining criteria for SAEs. 
• Results in persistent or significant disability or incapacity. 
• Is a congenital anomaly or birth defect. 
• Is medically significant – A medically significant event is defined as an event 
that does not necessarily meet any of the SAE criteria, but which is considered by 
the investigator to potentially jeopardize the subject or to require medical or 
surgical intervention to prevent one of the above outcomes listed as an SAE 
criterion. 
Adverse events that do not fall into the above categories are defined as nonserious AEs. 

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10.2.2. 
Assessment of Severity 
The severity of each AE (ie, nonserious and serious) is to be assessed by the investigator as 
follows: 
Table 6: 
Definitions of Adverse Event Severity 
Severity 
Definition 
Mild 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities 
of daily living. 
Moderate 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the subject. 
Severe 
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
AE = adverse event. 
Source: CDISC SDTM Severity Intensity Scale for Adverse Event Terminology. 
10.2.3. 
Assessment of Causality 
The causal relationship of an AE to IMP, the medical device (constituent), or the combination 
of device and investigational product must always be assessed by the investigator. All AEs 
will be classified as either related or not related to IMP, the medical device (constituent), or 
the combination of device and IMP. If a causality assessment is not provided for an AE 
(including an SAE), that AE will be considered related to IMP, the medical device 
(constituent), or the combination of device and IMP until clarified with the site. 
The degree of certainty with which an AE is attributed to IMP, the medical device 
(constituent), or the combination of device and IMP or an alternative cause (eg, natural 
history of the underlying disease, concomitant therapy) will be determined by how well the 
event can be understood in terms of: 
• Known pharmacology of IgPro20. 
• Clinically and / or pathophysiologically plausible context. 
• Reaction of a similar nature previously observed with similar products or reported 
in the literature for similar products as being product-related (eg, headache, facial 
flushing, pallor). 
• Plausibility supported by the temporal relationship (eg, the event being related by 
time to administration or termination of treatment with IMP, drug withdrawal, or 
reproduced on rechallenge). 
10.2.4. 
Observation Period for Adverse Events 
The observation period for the reporting of AEs (and SAEs) for an individual subject will 
start at the time of giving written informed consent for participation in the current study and 
finish 4 weeks after the last dose or until resolution of an ongoing AE. 

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If the investigator becomes aware of an SAE that has started after the observation period has 
ended, and there is at least a possible causal relationship with IMP, the event must be 
reported to the Sponsor (Section 10.2.6.2). 
10.2.5. 
Follow-up of Adverse Events 
Every effort should be made to follow AEs until resolution or stabilization. Ongoing, 
nonserious AEs that have not resolved or stabilized will be followed until the subject 
completes the study. Serious adverse events will be followed until the AE resolves, stabilizes, 
or the subject is lost to follow-up. 
10.2.6. 
Adverse Event Reporting 
10.2.6.1. Adverse Events 
At each study visit, the investigator (or delegate) will inquire and determine whether any AEs 
have occurred. All AEs are to be recorded directly on the eCRF and must be consistent with 
the source documents, if available. If known, the medical diagnosis of an AE should be 
recorded in preference to the listing of individual signs, laboratory findings, and / or 
symptoms.  
If, during the study, a subject presents with a preexisting condition that was not noted at the 
time of study entry, the condition should be retrospectively recorded on the Medical History 
eCRF. 
10.2.6.2. Serious Adverse Events 
This study will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH Guideline E2A (Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting). 
For SAEs occurring during the study, the investigator or delegate will enter all relevant 
information directly in the eCRF and must be consistent with the source documents, if 
available. 
All SAEs that occur during the study, whether or not causally related to IMP, must be 
entered into the eCRF immediately and must be sent to the Sponsor within 24 hours of 
the investigator becoming aware of the event.  
Adverse events occurring between the subject’s written informed consent and the first 
exposure to IMP, and that meet at least 1 of the criteria for seriousness, must be entered into 
the eCRF in the same manner as other SAEs and will be included in the clinical study 
database. 
Any SAE that occurs after the EOS Visit that is considered to be causally related to IMP 
must be reported immediately (ie, within 24 hours of the investigator becoming aware of 
the event) to the Sponsor. Such events are not entered into the CRF. 

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The minimum requirements for the reporting of SAEs are: 
• Subject identification number. 
• Suspected medicinal product and / or procedure. 
• Event term. 
• Identity of reporting source (ie, subject, caregiver, treating physician, 
investigator). 
If the minimum requirements for reporting are fulfilled, the investigator should not wait to 
receive additional information to fully document the event. 
In addition, the investigator must: 
• Report all SAEs to the relevant IRB / IEC within the time frame specified by the 
IRB / IEC. 
• If the subject is an active subject in the study: 
- Enter follow-up information in the CRF until the SAE has resolved or, in the 
case of permanent impairment, until stabilized. 
- Ensure that the causality assessment for all SAEs is entered into the CRF. 
• If the subject is no longer participating in the study, report the follow-up 
information to the Sponsor. 
In cases of death, the investigator should supply the Sponsor and the IRB / IEC (as 
applicable) with any additional information as it becomes available (eg, autopsy reports and 
detailed medical reports). 
10.2.6.3. Adverse Events of Special Interest 
No adverse events of special interest are defined for this study. 
10.2.6.4. Other Significant Events 
10.2.6.5. Overdose 
Any overdose that occurs in association with an adverse sign or symptom must be entered 
into the eCRF as an AE; if the AE meets any seriousness criteria, the event must be reported 
as an SAE (see Section 10.2.6.2). 
The details (ie, volume, location of infusions, infusion rate) of an overdose of the IMP 
(defined in Section 6.11) must be recorded into the appropriate CRF. Details of an overdose 
of any concomitant therapy must be recorded on the concomitant therapies CRF. 
10.2.6.6. Pregnancy and Breastfeeding 
A female subject or female partner of a male subject who becomes pregnant while 
participating in the study, or up to and including 5 times the half-life of IMP after the last 
dose of IgPro20, must notify the investigator within 24 hours of a positive pregnancy result. 

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If a female subject becomes pregnant, she must discontinue treatment with IgPro20, but may 
continue other study procedures at the discretion of the investigator. If the female subject is 
in the active treatment period of the study (ie, receiving study drug), her participation will be 
discontinued and the procedure for discontinuation of a subject will be followed, as described 
in Section 7). 
The investigator must notify the Sponsor within 5 days of becoming aware of the pregnancy. 
Whenever possible, a pregnancy in a subject or in a female partner of a male subject exposed 
to IgPro20 should be followed to term to assess any potential occurrence of congenital 
anomalies or birth defects. Any follow-up information, including premature termination or 
the status of the mother and child after delivery, should be reported by the investigator to the 
Sponsor using a Pregnancy Reporting / Outcome Form. 
All abnormal pregnancies and neonatal outcomes (eg, spontaneous abortion, stillbirth, 
neonatal death, or congenital anomaly) will meet the criteria for SAE classification. 
The investigator should follow the procedure for reporting these events as SAEs 
(see Section 10.2.6.2). 
10.2.7. 
IRB / IEC Reporting Requirements 
The time frame within which an IRB / IEC must be notified of deaths and IMP-related 
unexpected SAEs is stipulated by each IRB / IEC. It is the investigator’s responsibility to 
comply with the requirements for IRB / IEC notification. The Sponsor will provide 
investigators with all details of all SAEs reported to health authorities. 
10.3. 
Contraceptive Guidance 
10.3.1. 
Definitions 
Woman of Childbearing Potential 
Women are considered women of childbearing potential (ie, fertile) from the time of 
menarche until becoming postmenopausal unless permanently sterile. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of IMP, additional evaluation should be considered. 
Woman of Nonchildbearing Potential 
Women are considered women of nonchildbearing potential if they are postmenopausal or 
premenopausal and permanently sterile. 
Postmenopausal 
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
• A high follicle-stimulating hormone level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 

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of 12 months of amenorrhea, confirmation with more than 1 follicle-stimulating 
hormone measurement is required. 
• Women on HRT and whose menopausal status is in doubt  
- will be required to use 1 of the nonestrogen hormonal highly effective 
contraception methods if they wish to continue their HRT during the study.  
- must discontinue HRT to allow confirmation of postmenopausal status before 
study enrollment. 
Permanently Sterile 
Permanent sterilization methods (for the purpose of this study) include: 
• Documented hysterectomy. 
• Documented bilateral salpingectomy. 
• Documented bilateral oophorectomy. 
For individuals with permanent infertility due to a medical cause other than those listed 
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), investigator 
discretion should be exercised when determining the subject’s eligibility for enrollment in the 
study. 
Note: Documentation can come from the site personnel’s review of the subject’s medical 
records, physical examination, or medical history interview. 
10.3.2. 
Contraception Guidance 
Contraceptive use by males or females should be consistent with local regulations regarding 
the use of contraceptive methods in clinical studies. 
Table 7: 
Contraceptives Allowed During the Study 
Method 
Failure 
Rate 
Type 
Highly Effective a 
Low User 
Dependency 
< 1% 
• 
Implantable progestogen-only hormone contraception 
associated with inhibition of ovulation a 
• 
Intrauterine device  
• 
Intrauterine hormone-releasing system a 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical 
cause) 
Azoospermia is a highly effective contraceptive method 
provided that the partner is the sole sexual partner of the 
woman of childbearing potential and the absence of sperm has 

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Method 
Failure 
Rate 
Type 
been confirmed. If not, an additional highly effective method of 
contraception should be used. Spermatogenesis cycle is 
approximately 90 days 
Note: documentation of azoospermia for a male subject can come 
from the site personnel’s review of the subject’s medical records, 
medical examination, or medical history interview 
Highly 
Effective User 
Dependent a 
< 1% 
• 
Combined (estrogen- and progestogen-containing) hormonal 
contraception associated with inhibition of ovulation b 
o oral 
o intravaginal 
o transdermal 
o injectable 
• 
Progestogen-only hormone contraception associated with 
inhibition of ovulation   
o oral 
o injectable 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only 
if defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the investigational 
product. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the subject. 
Effective 
Methods c Not 
Considered 
Highly Effective 
≥ 1% 
• 
Progestogen-only oral hormonal contraception where 
inhibition of ovulation is not the primary mode of action 
• 
Male or female condom with or without spermicide 
• 
Cervical cap, diaphragm, or sponge with spermicide 
• 
A combination of male condom with either cervical cap, 
diaphragm, or sponge with spermicide (double-barrier 
methods) d 
a Failure rate of < 1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
b If hormonal contraception efficacy is potentially decreased due to interaction with investigational product, add: 
Male condoms must be used in addition to hormonal contraception. If locally required, in accordance with 

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Clinical Trial Facilitation Group guidelines, acceptable contraceptive methods are limited to those which 
inhibit ovulation as the primary mode of action. 
c Considered effective, but not highly effective – failure rate of ≥ 1% per year. Periodic abstinence (calendar, 
symptothermal, and postovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhea method are not acceptable methods of contraception. 
d Male condom and female condom should not be used together (due to risk of failure from friction). 
10.4. 
Study Assessment and Procedure Considerations 
10.4.1. 
Optional, On-demand Alternative Visit Modalities 
The following alternative visit modalities may be implemented with Sponsor approval as per 
the Schedule of Activities (Section 1.3): phone or video conference calls at home for safety 
follow-up, including assessment of AEs and concomitant therapies, and hematology, 
biochemistry, and pregnancy blood sampling at a local laboratory, where possible. 
Telemedicine or virtual study visits may be performed by qualified, designated study site 
personnel if approved by the Sponsor. 
Home health visits may be performed by a qualified medical provider approved by the 
Sponsor. 
A local laboratory may be used to collect and analyze protocol-required assessments. 
Electronic clinical outcomes assessment (eCOA) solutions may also be offered directly to the 
subject to ensure that subjects can enter data remotely. In case alternative visit modalities are 
used in the study, data will continue to be protected and stored securely without disruption. 
Table 8: 
Optional, On-demand Alternative Visit Modalities 
Activity 
Visit Day / Number 
Permitted Visit Modality 
Weight and BP  
 
Home Health  
PK Collection  
 
Home Health  
IMP Dispensing  
 
Direct to Patient Shipment  
BP = blood pressure; IMP = investigational medicinal product; PK = pharmacokinetic 
10.4.2. 
Use of Electronic Clinical Outcomes Assessment Solution 
An eCOA solution will be used by the subjects and / or sites. 
The eCOA solution captures electronic source data in a controlled and consistent way and 
provides access for investigators to these source data. The system also allows the subject’s 
health status to be remotely monitored during the study. The data residing in the eCOA 
system provider’s database are considered the source and are always under the control of the 
investigator. 
The investigator (or delegate) will have access to all eCOA data entered at site and / or all 
data reported within the subject eDiary via a secure, role-based web portal provided by an 
external eCOA system provider. The eCOA system provider will transfer a copy of the 

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source data across to the Sponsor’s Clinical Data Warehouse at a predefined frequency via a 
secure data channel for systematic review by the Sponsor’s clinical team. 
The eCOA provider engaged for this study is responsible for providing a solution that 
conforms to all pertinent regulations. The solution is never intended to be a substitute for 
normal medical care of the subject. The vendor hosts the eCOA data on behalf of the 
investigators, until each investigator receives a certified archive copy of all diary data relating 
to subjects at that site and has confirmed that it is readable. 
10.4.3. 
Genomics: Use and Analysis of DNA 
Not applicable 
10.5. 
Country-specific Requirements 
Not applicable 

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11. 
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APPENDIX 1. CLINICAL STUDY PROTOCOL AMENDMENT 
HISTORY 
 
Not applicable 
 

 
 
 
 
 
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APPENDIX 2. PRINCIPAL INVESTIGATOR SIGNATURE 
SIGNATURE OF PRINCIPAL INVESTIGATOR 
Study Title: 
Double-blind, Randomized, Placebo-controlled Phase 3 Study 
Evaluating Efficacy and Safety of IgPro20 (subcutaneous 
immunoglobulin, HIZENTRA®) in post-COVID-19 Postural 
Orthostatic Tachycardia Syndrome (POTS) 
Study Number: 
IgPro20_3010 
Site Number:  
I have read the Clinical Study Protocol (CSP) version 1.0  titled “Double-blind, Randomized, 
Placebo-controlled Phase 3 Study Evaluating Efficacy and Safety of IgPro20 (subcutaneous 
immunoglobulin, HIZENTRA®) in post-COVID-19 Postural Orthostatic Tachycardia 
Syndrome (POTS)”. 
By signing this CSP, I agree to conduct the clinical study, after approval by an Institutional 
Review Board or Independent Ethics Committee (as appropriate), in accordance with the 
CSP, the standards of Good Clinical Practice (as defined by the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use), ethical 
principles that have their origin in the Declaration of Helsinki, and applicable regulatory 
requirements. 
Changes to the CSP will only be implemented after written approval is received from the 
Sponsor and the Institutional Review Board or Independent Ethics Committee (as 
appropriate) with the exception of medical emergencies. 
I will ensure that study staff fully understand and follow the CSP. 
 
 
 
(Signature) 
 
 
Date (DD Month YYYY) 
(Printed name) 
 
 
 
(Title) 
 
 
 

Version: 6.0
Signature Page 1 of 1
--- Do Not Detach This Signature Page ---
glbdctmp
Print Date: 09-Dec-2025 11:55:39 GMT-05:00
Signature Page
IgPro20_3010 - Protocol - 11Apr2024
Signed By
Date (GMT)
Approved-
24-Apr-2024 14:47:37
Approved-
24-Apr-2024 14:48:20
Approved-
24-Apr-2024 14:53:26
PPD
PPD
PPD
PPD
PPD
PPD