Post-Marketing Study to Evaluate the Efficacy and Safety of PANZYGA in Pediatric Patients With Chronic Immune Thrombocytopenia (ITP)
Phase: PHASE4
Conditions: Chronic Immune Thrombocytopenia
Sponsor: Octapharma

Property of Octapharma. Do not copy or distribute without written permission.
 
 
 
 
 
 
 
Clinical Study Report 
NGAM-10 
 
 
16.1.1 
Study Protocol and Study Protocol Amendments 
16.1.1.1 
Protocol Version 01 (30 Jan 2019) 
16.1.1.2 
Protocol Amendment #1 (21 May 2019) 
16.1.1.3 
Protocol Version 02 (21 May 2019) 
16.1.1.4 
Protocol Amendment #2 (05 Aug 2019) 
16.1.1.5 
Protocol Version 03 (05 Aug 2019) 
16.1.1.6 
Protocol Amendment #3 (27 Apr 2020) 
16.1.1.7 
Protocol Version 04 (27 Apr 2020) 
 
Page 1 of 260 
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16.1.1 Study Protocol and Study Protocol Amendments 
16.1.1.1 
Protocol Version 01 (30 Jan 2019) .................................................................. 3 
16.1.1.2 
Protocol Amendment #1 (21 May 2019) ........................................................ 61 
16.1.1.3 
Protocol Version 02 (21 May 2019) ............................................................... 68 
16.1.1.4 
Protocol Amendment #2 (05 Aug 2019) ....................................................... 127 
16.1.1.5 
Protocol Version 03 (05 Aug 2019) .............................................................. 136 
16.1.1.6 
Protocol Amendment #3 (27 Apr 2020) ....................................................... 196 
16.1.1.7 
Protocol Version 04 (27 Apr 2020) ............................................................... 201 
 
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This document contains confidential and proprietary information of Octapharma AG. 
Do not copy or distribute without written permission. 
090-CSP-NGAM-10-V01/DOC ID 2880 
 
CLINICAL STUDY PROTOCOL 
NGAM-10 
Post-Marketing Study to Evaluate the Efficacy 
and Safety of PANZYGA in Pediatric Patients with 
Chronic Immune Thrombocytopenia (ITP) 
Investigational Product: 
PANZYGA 
Indication: 
Chronic Immune Thrombocytopenia (ITP) 
Study Design: 
Prospective, open-label, single-arm, multi-
center study  
Sponsor: 
Octapharma USA 
121 River Street, 12th Floor 
Hoboken, NJ 07030 
Study Number: 
NGAM-10 
IND Number / BLA Number: 
IND 14121 / BLA 125587 
Development Phase: 
Phase 4 
Planned Clinical Start: 
Q2/Q3 2019 
Planned Clinical End: 
Q1 2022 
Date of Protocol: 
30-Jan-2019 
Version: 
01 
 
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Study Protocol No. NGAM-10, Version 01 CONFIDENTIAL 
30-Jan-2019 
 
Page 2 of 58 
STUDY OUTLINE  
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
30-Jan-2019 
 
Title of Study: 
Post-Marketing Study to Evaluate the Efficacy and Safety of PANZYGA in 
Pediatric Patients with Chronic Immune Thrombocytopenia (ITP) 
Indication: 
Chronic Immune Thrombocytopenia (ITP) 
Number of Study Centre(s): 
Up to 8 sites in the USA 
Objectives: 
Primary Objective: 
The primary objective is to evaluate the efficacy of PANZYGA in increasing the 
platelet count in pediatric patients with chronic ITP. 
Secondary Objectives: 
The secondary objectives of this study are to: 
• Assess safety of up to 2 g/kg PANZYGA (1 g/kg PANZYGA on Day 1 
and an optional dose of 1 g/kg PANZYGA on Day 3) infused in the 
pediatric population within the scope of the clinical study 
• Determine the time to reach a platelet count of 50x109/L 
• Determine duration of time during which the platelet count is maintained 
at the level ≥50х109/L 
• Determine the maximum platelet count during the study 
Study Design: 
This is a prospective, open-label, single-arm, multicenter, Phase 4 study 
evaluating the efficacy and safety of PANZYGA in pediatric patients with chronic 
ITP. 
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Study Protocol No. NGAM-10, Version 01 CONFIDENTIAL 
30-Jan-2019 
 
Page 3 of 58 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
30-Jan-2019 
 
Number of Patients: 
At least 20 patients 
Patient Selection Criteria: 
Inclusion Criteria: 
1. Females and males aged from ≥1 year to <18 years old 
2. Confirmed diagnosis of Chronic Immune Thrombocytopenia (ITP) 
according to American Society of Hematology (ASH) 2011 guidelines 
3. Platelets count <30x109/L at the Baseline Visit 
4. Voluntarily given written informed consent (provided by patient’s parent 
or legal guardian) and assent (provided by patient [if age-appropriate per 
IRB requirements]) 
5. Females of childbearing potential have been using at least 1 acceptable 
form of birth control for a minimum of 30 days (or a minimum of 3 months 
for hormonal contraceptives) prior to the Screening visit, and must agree 
to use at least 1 acceptable method of contraception for 30 days after 
the last dose of PANZYGA. Acceptable methods of birth control for this 
study include: intrauterine device (IUD), hormonal contraception, male 
or female condom, spermicide gel, diaphragm, sponge, or cervical cap. 
Abstinence is not considered an acceptable method of birth control.  
6. Parent or legal guardian must agree and be willing to assist the 
participant attend study visits, and to follow all protocol requirements and 
instructions of the study doctor 
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30-Jan-2019 
 
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Exclusion Criteria: 
1. Thrombocytopenia secondary to other diseases (such as Acquired 
Immunodeficiency Syndrome [AIDS] or systemic lupus erythematosus 
[SLE]), drug-related thrombocytopenia, or congenital thrombocytopenia 
2. Administration of intravenous immunoglobulin (IGIV) or anti-D 
immunoglobulin within 3 weeks before enrollment 
3. Administration of thrombopoietin receptor agonists when the dose has 
NOT been stable within 3 weeks before enrollment and a dosage change 
is planned before Day 32 
4. Administration of oral immunosuppressants when the dose has NOT 
been stable during the preceding 2 months (2 weeks for long-term 
corticosteroid therapy) and a dosage change is planned before Day 32 
(Note: topical agents and inhaled corticosteroid therapy use is permitted) 
5. Administration of long-term anti-prolific agents or attenuated androgen 
therapy when the dose has NOT been stable during the preceding 
2 months and no dosage change is planned until Day 32 
6. Nonresponsive to previous treatment with IGIV or anti-D immunoglobulin 
7. Evidence of an active major bleeding episode at Screening 
8. Splenectomy in the previous 4 weeks or planned splenectomy 
throughout the study period 
9. Evans syndrome (experiencing active disease with 2 out of 3 of the 
following: autoimmune thrombocytopenia, autoimmune hemolytic 
anemia, and/or autoimmune neutropenia) 
10. Known 
or 
suspected 
human immunodeficiency virus 
(HIV), 
hepatitis B virus (HBV), and/or hepatitis C virus (HCV) infections 
11. Emergency surgery in the previous 4 weeks 
12. Severe liver and/or kidney disease (alanine aminotransferase [ALT] 
>3x upper limit of normal (ULN), aspartate aminotransferase [AST] 
>3x upper limit of normal (ULN), and/or creatinine >120 µmol/L) 
13. History of severe hypersensitivity to blood or plasma derived products, 
or any component of the PANZYGA 
14. Known immunoglobulin A (IgA) deficiency and antibodies against IgA 
15. History of, or suspected alcohol or drug abuse in the previous year 
16. Females who are pregnant or nursing  
17. Unable or unwilling to comply with the study protocol 
18. Receipt of any other investigational medicinal product within 3 months 
before study entry 
19. Risk factors* for thromboembolic events in whom the risks outweigh the 
potential benefit of PANZYGA treatment. 
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Study Protocol No. NGAM-10, Version 01 CONFIDENTIAL 
30-Jan-2019 
 
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Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
30-Jan-2019 
 
20. Any other condition(s), that in the Investigator’s opinion, make it 
undesirable for the patient to participate in the study or may interfere with 
protocol compliance.  
* Risk factors include, but are not limited to: obesity, advanced age, 
hypertension, diabetes, a history of atherosclerosis/vascular disease or 
thrombotic events, hyperlipidemia, multiple cardiovascular risk factors, acquired 
or inherited thrombophilic disorders, prolonged periods of immobilization, 
severe hypovolemia, central venous catheterization, active malignancy and/or 
known or suspected hyperviscosity. 
Test Product, Dose, and Mode of Administration: 
PANZYGA (Immune Globulin, intravenous, human-ifas). PANZYGA must be 
stored and transported light-protected at +2°C (36°F) to +8°C (46°F) and must 
be brought to room temperature before use. 
Patients will receive a dose of 1 g/kg body weight PANZYGA given on Day 1 
and optionally another dose of 1 g/kg PANZYGA given on Day 3; body-weight 
dependent doses will be based on each patient’s weight collected at Baseline. 
Total PANZYGA doses will be 1 g/kg for patients receiving only 1 dose on Day 1 
and 2 g/kg for those receiving the optional Day 3 dose. Prior to the Day 3 
infusion, each patient’s preinfusion platelet count will be reviewed by the 
Investigator. If the Day 3 platelet count shows evidence of response as 
indicated by the platelet count at least doubling from Baseline count AND is 
>50x109/L, the Day 3 infusion will not be administered. If the Baseline platelet 
count has doubled but is ≤50x109/L, the Day 3 infusion will be administered. 
PANZYGA will be delivered by intravenous infusion according to the 
recommended flow rates: 
• Initial infusion rate of 0.01 mL/kg/min (60 mg/kg/hr) for the first 
30 minutes 
• If tolerated, increase to 0.02 mL/kg/min (120 mg/kg/hr) for the second 
30 minutes 
• If tolerated, increase to 0.04 mL/kg/min (240 mg/kg/hr) for the third 
30 minutes 
• If tolerated, increase to 0.08 mL/kg/min (480 mg/kg/hr) for the remainder 
of the infusion.  
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Study Protocol No. NGAM-10, Version 01 CONFIDENTIAL 
30-Jan-2019 
 
Page 6 of 58 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
30-Jan-2019 
 
Infusion rates should not exceed 0.08 mL/kg/min and should not exceed 
8.0 mL/min. The infusion rate may be gradually increased as tolerated by the 
patient. 
If an adverse event (AE) occurs during infusion, the infusion rate should be 
reduced to half the rate at which the event occurred, or the infusion should be 
interrupted until symptoms subside. The infusion may then be resumed at a rate 
tolerated by the patient. 
The batch number(s) used will be recorded in the study documentation and 
electronic data capture (EDC) system. 
Duration of Treatment: 
Screening Period: 1 week 
Treatment Period: up to 3 days 
Follow-up Period: 29 days 
Reference Therapy, Dose, and Mode of Administration: 
Not Applicable 
Study Outcome Parameters (Primary and Secondary Endpoints): 
Primary Endpoint: 
The primary efficacy parameter is defined as an increase in platelet count at 
least once to ≥50x109/L within 7 days after the first infusion, ie, by Day 8 
(increase must occur at least once on any day up to and including Day 8). This 
definition of clinical response will serve as the basis for the primary endpoint, 
the response rate (ie, the proportion of patients with an elevation of platelet 
count at least once to 50x109/L within 7 days [ie, by Day 8] after the first 
infusion). 
Secondary Endpoints: 
• Time to reach a platelet count of 50x109/L 
• Duration of platelet response defined as the number of days the platelet 
count remains above 50x109/L 
• Maximum platelet count during the study 
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Study Protocol No. NGAM-10, Version 01 CONFIDENTIAL 
30-Jan-2019 
 
Page 7 of 58 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
30-Jan-2019 
 
Safety Parameters: 
• AEs 
• Vital signs (blood pressure, heart rate, temperature, respiratory rate) 
• Physical examination 
• Laboratory parameters: hematology (including reticulocytes), hemolysis, 
platelet count, serum chemistry (including lactase dehydrogenase 
[LDH]). 
Study Procedures: 
The study will be conducted in accordance with ICH-GCP and US FDA 
regulations.  
The Flow Chart of Assessments specifies the procedures that will be performed 
at each study visit. 
Baseline Visit 
After appropriate information about the study and PANZYGA has been provided 
and written informed consent/assent has been obtained, patients will be 
evaluated for study eligibility according to the inclusion/exclusion criteria. These 
evaluations will include demographics, medical/surgical history, current 
medications, physical examinations, blood and urine samples, along with other 
safety and baseline evaluations as specified in the Flow Chart of Assessments. 
Infusion Visits (Day 1 and Day 3) 
The first PANZYGA infusion must begin no more than 2 days after Baseline 
evaluations have been completed and eligibility criteria have been confirmed. If 
Baseline and Day 1 Visits occur on the same day, Day 1 investigations do not 
need to be repeated. If Baseline evaluations are completed more than 2 days 
before Day 1, then the platelet count must be repeated and evaluated by the 
Investigator prior to the first infusion.  
Patients who have met all of the inclusion criteria and none of the exclusion 
criteria will return to the study site for their first PANZYGA infusion. Required 
assessments will be performed as specified in the Flow Chart of Assessments, 
including safety evaluations before and after each infusion. Patients will remain 
at the study site during the infusion and for about 30 minutes after the end of 
each infusion to complete vital sign measurements. 
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Study Protocol No. NGAM-10, Version 01 CONFIDENTIAL 
30-Jan-2019 
 
Page 8 of 58 
Name of Sponsor/Company: 
Octapharma USA 
 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
Marketing Study to Evaluate the Efficacy 
 
Patients will receive a dose of 1 g/kg body weight PANZYGA on Day 1 and 
optionally another dose of 1 g/kg PANZYGA on Day 3; body-weight dependent 
doses will be based on each patient’s weight collected at Baseline. Total 
PANZYGA doses will be 1 g/kg for patients receiving only 1 dose on Day 1 and 
2 g/kg for those receiving the optional Day 3 dose. 
Safety  of  PAN ZYGA in Pediatric Patients with 
Chronic
Patients will return to the study site as indicated in the Flow Chart of 
Assessments for continued efficacy and safety evaluations. 
Day 32 (End of Study/Early Termination Visit) 
Patients will return to the study site on Day 32 for final safety assessments/End 
of Study (EOS) visit. Patients withdrawn early from the study will be encouraged 
to return to the study site and complete the EOS assessments. 
Statistical Analysis: 
The primary endpoint for this study is the proportion of patients with an increase 
in platelet count to ≥50x109/L at least once within 7 days after the first infusion. 
This proportion will be assessed and presented together with its associated 
95% confidence interval to facilitate comparison with results from other studies 
and published data. Because of the limited number of patients, no formal 
hypothesis test will be performed; any p-value or confidence interval presented 
is to be understood in the exploratory sense. 
All data collected will be presented descriptively. The time to reach the desired 
increase in platelet count as well as the duration of response will be presented 
in listings and summarized in statistical tables. Individual profiles of platelet 
count over time will be presented as Trellis plots. 
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30-Jan-2019 
 
Page 9 of 58 
Name of Sponsor/Company: 
 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
30-Jan-2019 
 
All safety data, including tolerability assessments, abnormal laboratory values, 
and AEs will also be listed and summarized statistically. 
Statistical presentations will be fit to the nature of individual data items and 
include sample characteristics, frequency counts and rates. Product-limit 
survival function estimates (Kaplan-Meier Plots), confidence intervals and 
graphs will be included as appropriate. 
The following populations will be considered for the statistical analysis: 
• Safety Analysis Set (SAF): All patients who received at least part of one 
infusion of PANZYGA. 
• Full Analysis Set (FAS): All patients in the SAF who satisfy all major 
eligibility criteria and for whom any post-baseline data is available. This 
is the set of eligible patients with treatment effects measured, according 
to the intention-to-treat (ITT) principle. 
• Per-Protocol Set I (PP1): All patients in the FAS, excluding those with 
significant protocol deviations before the primary efficacy assessment on 
day 8 is completed, and which may have an impact on the evaluation of 
the primary endpoint. 
• Per-Protocol Set II (PP2): All patients in the FAS, excluding those with 
significant protocol violations potentially affecting the (secondary) 
efficacy evaluations.  
Only protocol deviations with the potential to significantly affect the study results 
or to invalidate the interpretation of the data obtained will lead to exclusion of 
patients from the PP sets. The inclusion of each patient in the respective 
analysis populations will be determined before database lock in a data review 
meeting by a panel consisting of a medical expert from the Sponsor, the clinical 
study manager, the data manager, and the study statistician. 
A detailed Statistical Analysis Plan (SAP) will be compiled as a separate 
document. 
 
 
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Study Protocol No. NGAM-10, Version 01 CONFIDENTIAL 
30-Jan-2019 
 
Page 10 of 58 
FLOW CHART OF ASSESSMENTS 
Table 1: 
Flow Chart of Assessments 
ASSESSMENTS 
Scr / BL1 
Day 
1 
Day 
3 
Day 
5 
Day 
8 
Day 
15 
Day 
22 
Day 
3212 
 
Visit Window (Days) 
-7 / -2 
0 
0 
±1 
±1 
±3 
±3 
±5 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion / Exclusion Criteria Review 
X 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Medical and Surgical History2 
X 
 
 
 
 
 
 
 
Body Weight 
X 
 
 
 
 
 
 
 
Physical Examination  
X3 
X3 
X4 
X4 
X4 
X3 
X4 
X3 
Urine or Blood Pregnancy Test (females of 
child-bearing potential) 
X 
 
 
 
 
 
 
X 
Hematology: CBC with white blood cell 
(WBC) differential, hematocrit, hemoglobin, 
platelet counts, reticulocytes  
X 
X5,6 
X5,6,7 
X 
X 
X 
X 
X 
Hemolysis: total, direct, and indirect bilirubin 
X 
X 
X 
X 
X 
 
X 
X 
Serum Chemistry: ALT, AST, creatinine, Na, 
Ca, K, BUN, LDH 
X 
X 
X 
 
 
 
X 
X 
Viral markers (HIV, HCV, HBV nucleic acid 
test [NAT]) 
X7 
 
 
 
 
 
 
 
PANZYGA INFUSIONS 
 
X 
X8 
 
 
 
 
 
Vital Signs: heart rate, blood pressure, 
temperature, respiratory rate 
X 
X9 
X9 
 
 
 
X 
X 
AE Monitoring10 
 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Therapy (drug and 
non-drug)11 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BL = Baseline, Scr = Screening 
1) Screening Period is 7 days. Day 1 (first PANZYGA infusion) must occur no more than 2 days after Baseline 
evaluations have been completed. If the Baseline visit occurs more than 2 days after Baseline evaluations have 
been completed, the platelet count must be repeated and evaluated by the Investigator before initiation of the Day 1 
infusion. If Baseline and Day 1 Visits occur on the same day, the Day 1 investigations need not be repeated.  
2) Medical History will be collected for the previous year and will include the onset date of ITP. Surgical history will 
include the date of splenectomy (if applicable), and any other surgical procedures in the previous year.  
3) Brief Physical Examination: general appearance, skin, heart, lungs, abdomen, extremities 
4) Limited Physical Examination with targeted body systems per Investigator discretion  
5) Pre-infusion 
6) Platelet count, hematocrit, and hemoglobin results must be available and reviewed by the Investigator prior to start 
of the infusion 
7) HIV/HCV/HBV NAT Test: Infusions may begin before the results are back if the Investigator is not aware of, and the 
patient isn’t exhibiting clinical signs of, any viral infection. 
8) If the Day 3 preinfusion platelet count shows evidence of response as indicated by the platelet count at least 
doubling from Baseline count AND >50x109/L, the Day 3 infusion will not be administered. If the Baseline platelet 
count has doubled but is ≤50x109/L, the Day 3 infusion will be administered.  
9) Vital Signs: at the start of the infusion, approximately 15 minutes (±15 minutes) after each infusion rate change, and 
approximately 30 minutes after the end of the infusion 
10) The start date and start time will be collected for any adverse events starting at Day 1 through Day 32/EOS visit  
11) Prior medications will be collected for the 3 months. The start date and start time will be collected for any 
concomitant medications taken on Day 1 through Day 32/EOS visit 
12) Day 32 visit will correspond to the Early Termination visit for patients who are withdrawn early from the study 
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Study Protocol No. NGAM-10, Version 01 CONFIDENTIAL 
30-Jan-2019 
PROTOCOL SIGNATURES 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and applicable regulatory requirements. 
 
e 
Octapharma Pharmazeutika Produktionsgesellschaft mbH 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
Tel: 
 
 
Octapharma USA, Inc. 
121 River Street, Suite 1201 
Hoboken, NJ, USA 
Tel: 
 
Signature 
 
 
Signature 
Date 
Octapharma Pharmazeutika Produktionsgesellschaft mbH 
Obertaaerstr. 235, A-1100 Vienna, Austria 
Tel: 
 
 
Signature 
Octapharma Pharmazeutika Produktionsgesellschaft mbH 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
Tel: 
 
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Date 
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Study Protocol No. NGAM-10, Version 01 CONFIDENTIAL 
30-Jan-2019
Page 12 of 58 
TABLE OF CONTENTS 
STUDY OUTLINE ............................................................................................................. 2
FLOW CHART OF ASSESSMENTS ............................................................................. 10
PROTOCOL SIGNATURES .......................................................................................... 11
TABLE OF CONTENTS ................................................................................................. 12
TABLE OF TABLES ...................................................................................................... 15
LIST OF ABBREVIATIONS ........................................................................................... 16
1
INTRODUCTION.................................................................................................... 18
1.1
RATIONALE FOR CONDUCTING THE STUDY ..................................................... 19
1.2
DOSE RATIONALE.......................................................................................... 19
1.3
BENEFIT-RISK STATEMENT............................................................................ 19
2
STUDY OBJECTIVES............................................................................................ 21
2.1
PRIMARY OBJECTIVES ................................................................................... 21
2.2
SECONDARY OBJECTIVES.............................................................................. 21
3
INVESTIGATIONAL PLAN.................................................................................... 22
3.1
PRIMARY AND SECONDARY ENDPOINTS......................................................... 22
3.1.1 Primary Endpoint ............................................................................. 22
3.1.2 Secondary Endpoints....................................................................... 22
3.2
OVERALL STUDY DESIGN AND PLAN .............................................................. 22
3.3
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP(S)........... 23
3.3.1 Study Design.................................................................................... 23
3.3.2 Control Group(s) .............................................................................. 24
3.3.3 Study Parameters ............................................................................ 24
4
STUDY POPULATION........................................................................................... 25
4.1
POPULATION BASE ........................................................................................ 25
4.1.1 Inclusion Criteria .............................................................................. 25
4.1.2 Exclusion Criteria............................................................................. 25
4.2
PRIOR AND CONCOMITANT THERAPY ............................................................. 26
4.3
WITHDRAWAL AND REPLACEMENT OF PATIENTS ............................................ 27
4.3.1 Premature Patient Withdrawal ......................................................... 27 
4.3.2
Patient Replacement Policy ............................................................. 28 
4.4
ASSIGNMENT OF PATIENTS TO TREATMENT GROUPS ..................................... 28
4.5
RELEVANT PROTOCOL DEVIATIONS ............................................................... 28
4.6
SUBSEQUENT THERAPY ................................................................................. 28
5 
INVESTIGATIONAL MEDICINAL PRODUCT ...................................................... 29
5.1
CHARACTERIZATION OF INVESTIGATIONAL PRODUCT ..................................... 29
5.2
PACKAGING AND LABELLING .......................................................................... 29
5.3
CONDITIONS FOR STORAGE AND USE ............................................................ 30
5.4
DOSE AND DOSING SCHEDULE ...................................................................... 30
5.5
PREPARATION AND METHOD OF ADMINISTRATION .......................................... 31
5.6
BLINDING, EMERGENCY ENVELOPES, AND BREAKING THE STUDY BLIND ........ 31
5.7
TREATMENT COMPLIANCE ............................................................................. 31
5.7.1 Drug Dispensing and Accountability................................................ 31 
5.7.2 Assessment of Treatment Compliance ........................................... 32 
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6 
STUDY CONDUCT ................................................................................................ 33
6.1 
OBSERVATIONS BY VISIT ............................................................................... 33
6.1.1 Baseline Visit/Screening Period ...................................................... 33 
6.1.2 Day 1 ................................................................................................ 33 
6.1.3 Day 3 ................................................................................................ 34 
6.1.4 Day 5 and Day 8 (± 1 day) ............................................................... 34 
6.1.5 Day 15 and Day 22 (± 3 days) ......................................................... 34 
6.1.6 Day 32 (End of Study Visit) (± 5 days) ............................................ 35 
6.1.7 Visit Windows Used in this Study, including Tolerances ................ 35 
6.2 
DURATION OF STUDY ..................................................................................... 35
6.2.1 Planned Duration for an Individual Patient ...................................... 35 
6.2.2 Planned Duration for the Study as a Whole .................................... 35
6.2.3 Premature Termination of the Study ............................................... 36 
7
ASSESSMENTS AND METHODS ........................................................................ 37
7.1
DEMOGRAPHIC AND BASELINE INFORMATION ................................................. 37
7.1.1 Demographic and Baseline characteristics ..................................... 37
7.1.2 Medical and Surgical history............................................................ 37
7.1.3 Viral Marker Tests............................................................................ 37
7.1.4 Prior and Concomitant Medication Use........................................... 37
7.2
EFFICACY ASSESSMENTS .............................................................................. 37
7.3
SAFETY ASSESSMENTS ................................................................................. 38
7.3.1 Assessments for Safety Evaluations ............................................... 38
7.3.2 Adverse Events................................................................................ 38
7.3.3 Serious Adverse Events .................................................................. 41
7.3.4 SAE Reporting Timelines ................................................................ 41
7.3.5 Laboratory Tests.............................................................................. 42
7.3.6 Vital Signs ........................................................................................ 43
7.3.7 Physical Examination including Height and Body Weight............... 43
7.3.8 Other Relevant Safety Information .................................................. 43
7.4
OTHER ASSESSMENTS .................................................................................. 44
7.5
APPROPRIATENESS OF MEASUREMENTS........................................................ 44
8
DATA HANDLING AND RECORD KEEPING ...................................................... 45
8.1
DOCUMENTATION OF DATA............................................................................ 45
8.1.1 Source Data and Records ............................................................... 45 
8.1.2
Electronic Case Report Forms ........................................................ 45
8.1.3 Changes to Electronic Case Report Form Data .............................. 45 
8.2
INFORMATION TO INVESTIGATORS .................................................................. 46
8.3
RESPONSIBILITIES ......................................................................................... 46
8.4
INVESTIGATOR’S SITE FILE ............................................................................ 46
8.5
PROVISION OF ADDITIONAL INFORMATION ...................................................... 47
8.6
INDEPENDENT DATA MONITORING COMMITTEE .............................................. 47
9 
STATISTICAL METHODS AND SAMPLE SIZE ................................................... 48
9.1
DETERMINATION OF SAMPLE SIZE.................................................................. 48
9.2
STATISTICAL ANALYSIS .................................................................................. 48
9.2.1 Populations for Analysis .................................................................. 49 
9.2.2 Efficacy Analysis Plan ...................................................................... 49 
9.2.3 Safety Analysis Plan ........................................................................ 50 
9.2.4 Handling of Missing Data ................................................................. 51 
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9.3 
RANDOMIZATION, STRATIFICATION, AND CODE RELEASE ............................... 51
9.4 
INTERIM ANALYSIS ......................................................................................... 51
10 
ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ............ 52
10.1 ETHICAL/REGULATORY FRAMEWORK ............................................................. 52
10.2 APPROVAL OF STUDY DOCUMENTS................................................................ 52
10.3 PATIENT INFORMATION AND INFORMED CONSENT .......................................... 52
10.4 PROTOCOL AMENDMENTS ............................................................................. 53
10.5 CONFIDENTIALITY OF PATIENT DATA .............................................................. 53
11
QUALITY CONTROL AND QUALITY ASSURANCE ........................................... 54
11.1 PERIODIC MONITORING ................................................................................. 54
11.2 AUDIT AND INSPECTION ................................................................................. 54
12
REPORTING AND PUBLICATION ....................................................................... 55
12.1 CLINICAL STUDY REPORT.............................................................................. 55
12.2 PUBLICATION POLICY..................................................................................... 55
13
LIABILITIES AND INSURANCE ........................................................................... 56
14
REFERENCES ....................................................................................................... 57
15
APPENDICES ........................................................................................................ 58
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TABLE OF TABLES 
Table 1:
Flow Chart of Assessments ............................................................... 10
Table 2:
Prohibited Medications....................................................................... 27
Table 3:
Qualitative and Quantitative Composition of PANZYGA .................. 29
Table 4:
Visit Windows Used in this Study ...................................................... 35
Table 5:
Laboratory Tests and Time Points..................................................... 42
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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine Aminotransferase 
ASH 
American Society of Hematology 
AST 
Aspartate Aminotransferase 
CIDP 
Chronic Inflammatory Demyelinating Poly(radiculo)neuropathy 
CRO 
Contract Research Organisation 
DEHP 
Diethylhexylphthalate 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOS 
End of Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus
IB 
Investigator’s Brochure
ICH 
International Conference on Harmonisation
IDMC 
Independent Data Monitoring Committee
IEC 
Independent Ethics Committee
ifas 
4-letter meaningless suffix assigned by FDA at the end of newly
approved biologics
IgA 
immunoglobulin A
IMP 
Investigational Medicinal Product 
IRB
Institutional Review Board 
ITP 
Immune Thrombocytopenia 
ITT
Intention-to-Treat 
IUD 
Intrauterine device 
IGIV
Intravenous Immunoglobulin 
LDH 
lactase dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMN 
Multifocal Motor Neuropathy 
NAT 
Nucleic Acid Test 
PMR 
Post-Marketing Requirement 
PREA 
Pediatric Research Equity Act 
PP 
Per-Protocol 
PP1 
Per-Protocol Set 1 
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Abbreviation 
Description 
PP2 
Per-Protocol Set II 
PVC 
Polyvinyl Chloride 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
SLE 
systemic lupus erythematosus 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent Adverse Event 
TNBP 
tri-n-butyl phosphate 
TPO-RA 
Thrombopoietin Receptor Agonists 
ULN 
Upper Limit of Normal 
USC 
United States Code 
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1 
INTRODUCTION 
Since more than five decades immunoglobulins have been used to provide 
antibodies for the prevention of viral and bacterial diseases (replacement 
therapy) in immunocompromised patients. Within the last 25 years intravenous 
immunoglobulin (IGIV) has been proven to be useful in a wide variety of clinical 
conditions other than replacement therapy of immunocompromised patients, in 
which IGIV exhibits an immunomodulatory effect. These include Idiopathic 
Thrombocytopenic (ITP) in children and adults at high risk of bleeding or prior to 
surgery to correct the platelet count, Kawasaki disease, and Guillain-Barré 
syndrome (GBS). More recently, single IGIV brands have also been licensed for 
Multifocal Motor Neuropathy (MMN) and Chronic Inflammatory Demyelinating 
Poly(radiculo)neuropathy (CIDP). Experimental off-label use of IGIV mostly in 
other neurological and dermatological indications is widespread. 
ITP is an immune-mediated (disorder characterized by increased platelet 
destruction. The reason for platelet destruction is the development of 
autoantibodies to platelet-membrane antigens. These antibodies are particularly 
produced in the spleen which is also the major site of platelet destruction [1]. In 
patients suffering from ITP, several studies have shown IGIV effective in 
increasing platelet counts to prevent or control bleeding [2-4] The mechanism of 
action in ITP is not fully elucidated but includes immunomodulatory effects, 
particularly the modulation of cytokines, soluble cytokine receptors and cytokine 
receptor antagonists with anti-inflammatory effects as well as complement 
modulation. 
Broadly, 2 categories of agents are available for the treatment of ITP: 1) those 
that rapidly and transiently interfere with the process of platelet destruction for 
management of acute bleeding or bleeding risk (front-line therapies), and 
2) those with potential to provide a more durable improvement in the platelet 
count (second-line therapies). Corticosteroids, IGIV, and anti-D immune globulin 
remain the mainstay of front-line treatment of acute bleeding symptoms in both 
adults and children [5]. Although corticosteroids remain the most commonly used 
ITP therapy, controversy still exists surrounding selection of agent, dosing, and 
duration of therapy. For treatment with prednisone, it is generally accepted that 
shorter courses are preferable to chronic therapy. The 2010 International 
Consensus Report on the investigation and management of primary ITP 
developed by an international working group address three classes of second-
line therapies: splenectomy, rituximab, and the thrombopoietin receptor agonists 
(TPO-RA). Due to a relative lack of data, their use was recommended only in 
patients who were refractory to splenectomy and other therapies. Further study 
results in 2016 demonstrated that TPO-RA agents are being used in children with 
ITP of varying duration and severity. The response was similar to clinical trials, 
but the sustainability of response varied. Future studies need to focus on the ideal 
timing and rationale for these medications in pediatric patients [6]. 
PANZYGA is a human immunoglobulin solution with 10% protein content for 
intravenous administration. PANZYGA is made from a pool of at least 
1000 donations of human fresh-frozen plasma per batch.  
PANZYGA was granted a US approval by the US Food and Drug Administration 
(FDA) in August 2018. The license in 2 indications (primary humoral 
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immunodeficiency diseases and chronic immune thrombocytopenia) was granted 
based on 2 completed studies. The first study in Primary Immune Deficiency 
included 51 children and adults from ages 2 years to 65 years who were dosed 
at 200 mg/kg to 800 mg/kg body weight every 3 to 4 weeks for 360 days. The 
second study in Immune Thrombocytopenia included 40 adults with chronic ITP 
receiving 2 gm/kg body weight over 2 consecutive days. Of the 36 subjects in the 
full analysis set, 29 patients (81%: 95% CI: 64% to 92%) responded to PANZYGA 
with a rise in platelet count to at least 50x109/L within 7 days after the first 
infusion. 
Further information can be found in the Investigator’s Brochure (IB). 
1.1 Rationale for Conducting the Study 
Under the Pediatric Research Equity Act (PREA) (21 United States Code [USC]
355c) all applications for new active ingredients, new indications, new dosage
forms, new dosing regimens or new routes of administration are required to
contain an assessment of the safety and effectiveness of the product for the
claimed indication in pediatric patients unless this required is waived, deferred or
inapplicable.
This post-marketing requirement (PMR) study was requested by the US FDA 
after PANZYGA received marketing approval in the United States. The rationale
for conducting this PMR study is to investigate the efficacy and safety of
PANZYGA in children suffering from primary ITP.
The study will be conducted in compliance with the protocol, International
Conference on Harmonisation-Good Clinical Practice (ICH-GCP), US FDA Code
of Federal Regulations, and other local regulatory requirements.
1.2 Dose Rationale 
According to recent guidelines, IGIV is recommended for patients with platelet
counts <30x109/L in case of severe bleeding and/or mucous membrane bleeding.
Standard doses should be studied (0.8 g/kg to1 g/kg on Day 1, which may be
repeated once within 3 days, or 0.4 g/kg/day for 2 to 5 days). If other dosage
regimens are to be applied for, they should be supported by clinical data. [7,8].
The dose option for this study is within the recommended guidelines.
1.3
Benefit-Risk Statement
The safety profile of IGIV is well characterized and, in general, the same type of
adverse reactions may be expected for PANZYGA. No new or unknown safety
problems are expected to emerge which are not already described in the
Investigator's Brochure.
Data obtained from the clinical trials conducted with PANZYGA in the adult ITP 
population clearly met the recommended clinical response criteria for efficacy as 
set out in the relevant FDA and EU guidelines. These data are comparable with 
available literature data on other commercial IVIGs and formed the basis for 
marketing authorization in Europe and the US. The safety profile of PANZYGA is 
satisfactory and the number of infusional AEs are below the levels as 
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recommended by the FDA for products of this class. Efficacy and safety data with 
PANZYGA in 3 clinical studies in 51 patients (also including pediatric patients) 
with primary immunodeficiency (PID) and in 40 patients with immune 
thrombocytopenia (ITP) are available. Available data are sufficient to expect 
favorable benefit-risk profile of PANZYGA in the pediatric ITP population. 
Expected clinical benefit of using PANZYGA in this study is an increase in 
platelets level to control or prevent bleeding. The main known risks are listed 
below: 
• Thrombosis may occur with immune globulin intravenous (IGIV) products, 
including PANZYGA. Risk factors may include: advanced age, prolonged 
immobilization, hypercoagulable conditions, history of venous or arterial 
thrombosis, 
use 
of 
estrogens, 
indwelling 
vascular 
catheters, 
hyperviscosity, and cardiovascular risk factors. 
• Renal dysfunction, acute renal failure, osmotic nephropathy, and death 
may occur with the administration of IGIV products in predisposed 
patients. Renal dysfunction and acute renal failure occur more commonly 
in patients receiving IGIV products containing sucrose. PANZYGA does 
not contain sucrose. 
• For patients at risk of thrombosis, renal dysfunction, or renal failure, 
administer PANZYGA at the minimum infusion rate practicable. Ensure 
adequate hydration in patients before administration. Monitor for signs and 
symptoms of thrombosis and assess blood viscosity in patients at risk for 
hyperviscosity. 
• Standard measures are taken to prevent infections resulting from the use 
of medicinal products prepared from human blood or plasma. Despite this, 
when medicinal products prepared from human blood or plasma are 
administered, the possibility of transmitting infective agents cannot be 
totally excluded. During the manufacturing process of PANZYGA, 
significant viral reduction is obtained. 
Inclusion and exclusion criteria, recommendations on the rate of infusion, 
dosage, and monitoring procedures provided in this protocol sufficiently mitigate 
above mentioned risks and must be adhered to.  
No new or unknown safety problems are expected to emerge in pediatric ITP 
population, which are not listed above or described in the Investigator's Brochure. 
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2 
STUDY OBJECTIVES 
2.1 Primary Objectives 
The primary objective is to evaluate the efficacy of PANZYGA in increasing the 
platelet count in pediatric patients with chronic ITP. 
2.2 Secondary Objectives 
The secondary objectives of this study are to: 
•
Assess safety of up to 2 g/kg PANZYGA (1 g/kg PANZYGA on Day 1 and
an optional dose of 1 g/kg PANZYGA on Day 3) infused in the pediatric 
population within the scope of the clinical study
•
Determine the time to reach a platelet count of 50x109/L
•
Determine duration of time during which the platelet count is maintained
at the level ≥50х109/L
•
Determine the maximum platelet count during the study
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3 
INVESTIGATIONAL PLAN 
3.1 Primary and Secondary Endpoints 
3.1.1 Primary Endpoint 
The primary efficacy parameter is defined as an increase in platelet count at least 
once to ≥50x109/L within 7 days after the first infusion, ie, by Day 8 (increase 
must occur at least once on any day up to and including Day 8). This definition of 
clinical response will serve as the basis for the primary endpoint, the response 
rate (ie, the proportion of patients with an elevation of platelet count at least once 
to 50x109/L within 7 days [ie, Day 8] after the first infusion). 
3.1.2 Secondary Endpoints 
Secondary endpoints are defined to further evaluate the efficacy and safety of
the PANZYGA infused in the pediatric population.
The following parameters will be used to for efficacy assessments:
•
Time to reach a platelet count of 50x109/L
•
Duration of platelet response defined as the number of days the platelet
count remains above 50x109/L
•
Maximum platelet count during the study
The following parameters will be used for safety assessments:
•
AEs
•
Vital signs (blood pressure, heart rate, temperature, respiratory rate)
•
Physical examination
•
Laboratory parameters: hematology (including reticulocytes), hemolysis,
platelet count, serum chemistry (including lactase dehydrogenase [LDH]).
3.2
Overall Study Design and Plan
This is a prospective, open-label, single-arm, multicenter, Phase 4 study 
evaluating the efficacy and safety of the investigational product, PANZYGA, in
pediatric patients with chronic ITP.
The study will enroll at least 20 patients 1 year to <18 years old and will not be
stratified by age group. A patient is considered enrolled into the study after 
successfully completing all baseline assessments and receiving at least a partial
dose of PANZYGA.
Patients with a confirmed diagnosis of chronic ITP, without evidence of active 
major bleeding, may be enrolled in the study. Study procedures will only begin 
after written informed consent (from parent or guardian) and assent (from the 
patient, as age appropriate per Institutional Review Board [IRB] requirements) 
have been obtained. Patients who meet all of the inclusion and none of the 
exclusion criteria may receive the first infusion of PANZYGA within 2 days after 
Baseline investigations have been completed. 
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Each patient will be administered PANZYGA by intravenous infusion at a dose of 
1 g/kg body weight PANZYGA on Day 1 and optionally another dose of 1 g/kg 
PANZYGA on Day 3; body-weight dependent doses will be based on each 
patient’s weight collected at Baseline. Total PANZYGA doses will be 1 g/kg for 
patients receiving only 1 dose on Day 1 and 2g/kg for those receiving the optional 
Day 3 dose. Prior to the Day 3 infusion, Investigators will assess each patient’s 
preinfusion platelet count, hematocrit, and hemoglobin. Patients whose platelet 
count shows evidence of response as indicated by the platelet count at least 
doubling from Baseline count AND is >50x109/L, the Day 3 infusion will not be 
administered. If the Baseline platelet count has doubled but is ≤50x109/L, the 
Day 3 infusion will be administered. If any parameters indicate a clinically relevant 
change such that, in the Investigator’s opinion, it is not safe to administer the 
second infusion, the patient should be withdrawn from study treatment; however, 
the patient will be followed for safety through Day 32.  
Study interventions and procedures will be performed at predefined timepoints 
(see Section 6.1 and the Flow Chart of Assessments [Table 1]) including (but are 
not limited to): blood draws for safety evaluations, vital signs, body weight, 
physical examinations, AE monitoring, and changes in concomitant medication 
use. Patients will have clinic visits on Days 1, 3, 5, 8, 15, and 22. They will return 
to the clinic for a final safety follow-up evaluation at Day 32/End of Study (EOS) 
Visit.  
PANZYGA infusions may be stopped or interrupted at any time if, in the 
Investigator’s opinion, it is not safe to continue or is not in the patient’s best 
interest. Patients who have received a partial dose of PANZYGA should be 
followed for safety evaluations through Day 32/EOS.  
The study is planned to begin screening procedures Q2/Q3 2019 at up to 8 sites 
in the USA, with recruitment lasting approximately 30 months, and is anticipated 
to complete in Q1 2022. The study duration for a single patient will be 
approximately 39 days, including up to a 1-week Screening period.  
3.3 Discussion of Study Design and Choice of Control Group(s) 
3.3.1 Study Design 
This study was designed to meet the US FDA’s requirements under the PREA 
(21 USC 355c) for a post-approval study of PANZYGA in the pediatric population. 
US FDA is requiring a pediatric study for the treatment of ITP to evaluate 
PANZYGA for the treatment of ITP in patients ages ≥1 year to <18 years. All of 
the US FDA’s recommendations have been incorporated into the protocol.  
This study design is also in line with study protocols evaluating NGAM in adults, 
with the frequency of blood draws and number of visits reduced to accommodate 
a pediatric population. Because of the limited number of patients that will be 
enrolled in this study, along with the increased blood volume and additional site 
visits that would be required to meet the full recommendations in the European 
Medicines Agency (EMA) Guideline for confirmatory visits and blood draws, the 
secondary efficacy endpoints were selected to allow efficacy evaluations in this 
patient population. 
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3.3.2 Control Group(s) 
A placebo control group will not be included in this post-approval study. An active 
control group is not considered relevant, as the objective of this study is to 
evaluate the efficacy and safety of PANZYGA in the pediatric population, not to 
compare the efficacy and safety of PANZYGA versus another IGIV treatment. 
3.3.3 Study Parameters 
The primary therapeutic target for ITP treatment is an increase in the platelet
count. Therefore, the primary endpoint chosen for the study, namely the response
rate (ie, the proportion of patients with an increase in platelets at least once to
≥50x109/L within 7 days after the first infusion), is appropriate to adequately
describe the efficacy of treatment of PANZYGA in the pediatric population.
To assess the efficacy of PANZYGA in correcting the platelet count, this response
rate has been chosen as the primary endpoint. There are several definitions of
response published in guidelines and commonly used for the evaluation of ITP
treatment; however, an increase in platelets to ≥50x109/L is the most established
definition of response [7] and as such has been chosen for this post-marketing
approval study.
The secondary efficacy endpoints chosen are in accordance with the primary
endpoint, in order to further characterize the effect on the increase in platelet
count.
The safety assessments, including AE, vital signs, laboratory results, and
physical examination are appropriate and commonly used parameters to monitor
the of IGIV treatment during a clinical study.
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4 
STUDY POPULATION 
4.1 Population Base 
At least 20 female or male patients 1 year to <18 years old with chronic ITP will 
be eligible for this study.  
4.1.1 Inclusion Criteria 
Patients who meet all of the following criteria are eligible for the study: 
1. Females and males aged from 1 year to <18 years old
2. Confirmed diagnosis of Chronic Immune Thrombocytopenia (ITP) 
according to American Society of Hematology (ASH 2011) guidelines
3. Platelets count <30x109/L at the Baseline Visit
4. Voluntarily given written informed consent (provided by patient’s 
parent or legal guardian) and assent (provided by patient)
5. Females of childbearing potential have been using at least
1 acceptable form of birth control for a minimum of 30 days (or a
minimum of 3 months for hormonal contraceptives) prior to the
Screening visit, and must agree to use at least 1 acceptable method
of contraception for 30 days after the last dose of PANZYGA.
Acceptable methods include: intrauterine device (IUD), hormonal
contraception, male or female condom, spermicide gel, diaphragm,
sponge, or cervical cap. Abstinence is not considered an acceptable
method of birth control.
6. Parent or legal guardian must agree and be willing to assist the
participant attend study visits, and to follow all protocol requirements 
and instructions of the study doctor
4.1.2 Exclusion Criteria
Patients who meet any of the following criteria are not eligible for the study:
1. Thrombocytopenia secondary to other diseases (such as Acquired
Immunodeficiency Syndrome [AIDS] or systemic lupus 
erythematosus [SLE]), drug-related thrombocytopenia, or congenital
thrombocytopenia
2. Administration of intravenous immunoglobulin (IGIV) or anti-D
immunoglobulin within 3 weeks before enrollment
3. Administration of thrombopoietin receptor agonists when the dose
has NOT been stable within 3 weeks before enrollment and a dosage
change is planned before Day 32
4. Administration of oral immunosuppressants when the dose has NOT
been stable during the preceding 2 months (2 weeks for long-term
corticosteroid therapy) and a dosage change is planned before
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Day 32 (Note: topical agents and inhaled corticosteroid therapy use is 
permitted) 
5. Administration of long-term anti-prolific agents or attenuated
androgen therapy when the dose has NOT been stable during the
preceding 2 months and no dosage change is planned until Day 32
6. Nonresponsive to previous treatment with IGIV or anti-D
immunoglobulin
7. Evidence of an active major bleeding episode at Screening
8. Splenectomy in the previous 4 weeks or planned splenectomy
throughout the study period
9. Evans syndrome (experiencing active disease with 2 out of 3 of the
following: autoimmune thrombocytopenia, autoimmune hemolytic 
anemia, and/or autoimmune neutropenia)
10.Known or suspected human immunodeficiency virus (HIV),
hepatitis B virus (HBV), and/or hepatitis C virus (HCV) infections
11. Emergency surgery in the previous 4 weeks
12.Severe liver and/or kidney disease (alanine aminotransferase [ALT]
>3x upper limit of normal (ULN), aspartate aminotransferase [AST]
>3x upper limit of normal (ULN), and/or creatinine >120 µmol/L)
13.History of severe hypersensitivity to blood or plasma derived
products, or any component of the PANZYGA
14.Known immunoglobulin A (IgA) deficiency and antibodies against IgA
15.History of, or suspected, alcohol or drug abuse in the previous year
16.Females who are pregnant or nursing
17.Unable or unwilling to comply with the study protocol
18.Receipt of any other investigational medicinal product within
3 months before study entry
19.Risk factors* for thromboembolic events in whom the risks outweigh
the potential benefit of PANZYGA treatment.
20.Any other condition(s), that in the Investigator’s opinion, make it
undesirable for the patient to participate in the study or may interfere
with protocol compliance.
* Risk factors include, but are not limited to: obesity, advanced age, hypertension,
diabetes, a history of atherosclerosis/vascular disease or thrombotic events,
hyperlipidemia, multiple cardiovascular risk factors, acquired or inherited
thrombophilic
disorders,
prolonged
periods 
of
immobilization,
severe
hypovolemia, central venous catheterization, active malignancy and/or known or 
suspected hyperviscosity.
4.2 Prior and Concomitant Therapy 
Details on medications taken within the previous 3 months prior to the Baseline 
Visit and any concomitant medications taken during the study must be recorded 
in the electronic case report form (eCRF). 
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Use of the following medications are forbidden during the study as specified 
below (Table 2): 
Table 2: 
Prohibited Medications 
Medication 
Time Window 
IGIV 
prohibited for 3 weeks prior to Baseline Visit 
through Day 32 
anti-D immunoglobulin 
prohibited for 3 weeks prior to Baseline Visit 
through Day 32 
oral immunosuppressants 
prohibited during Screening Period through
Day 32 unless patients have been receiving
a stable dose for 2 months (2 weeks for long-
term corticosteroid therapies) prior to
Screening Visit
thrombopoietin receptor agonists 
prohibited during Screening Period through
Day 32 unless patients have been receiving
stable dose for 3 months prior to Screening
Visit
long-term anti-prolific agents or 
attenuated androgen therapy 
prohibited during Screening Period through
Day 32 unless patients have been on a
stable dose for 2 months prior to Screening
Visit
any other blood or plasma-derived 
product* 
prohibited during Screening Period through
Day 32
receipt of any other investigational 
product 
prohibited within 3 months prior to Baseline
Visit through Day 32
* Patients who are non-responders or requiring emergent ITP treatment (other than PANZYGA specified in this protocol)
will be followed for safety and complete all assessments through Day 32.
Trade names of drugs corresponding to the categories provided in Table 2 will
be provided in a Study Manual.
4.3
Withdrawal and Replacement of Patients
4.3.1 Premature Patient Withdrawal
Patients have the right to withdraw from the study at any time for any reason,
without the need to justify their decision; parents or legal guardians also have the
right to withdraw a patient on the patient’s behalf. The Investigator also has the
right to withdraw patients in case of AEs, poor compliance, or other reasons.
Because an excessive rate of withdrawals can render the study noninterpretable,
any unnecessary withdrawal of patients should be avoided.
For any withdrawals after study entry, the Investigator will obtain all the required
details and document the reason(s) for discontinuation. If the reason for 
withdrawal of a patient is an AE, the main specific event or laboratory test will be
recorded, and the Investigator will make thorough efforts to clearly document the
outcome. Patients should return to the study site and have all safety evaluations,
including safety laboratory tests, completed as specified at the Day 32 visit
(See Section 6.1.6).
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4.3.2 Patient Replacement Policy 
Patients withdrawn from the study will not be replaced. Under no circumstances 
will patients who enroll in the study be permitted to re-enroll after study 
completion. Patients who fail during the Screening Period (also referred to as 
Screen Failures) may be re-screened upon written approval from the Sponsor. 
4.4 Assignment of Patients to Treatment Groups 
This is an open-label non-randomized study. All patients will receive PANZYGA. 
4.5 Relevant Protocol Deviations 
In case of any major protocol deviation, the Investigator and Octapharma will
decide on the further participation of the patient in this study after having
discussed all relevant aspects.
A list of all included patients with all deviations from the intended study 
procedures and other criteria that may affect the patient's data validity for 
statistical analysis will be prepared upon clinical completion of the study. This will
also be discussed by a panel consisting of the clinical study manager, a medical
expert of the Sponsor, the data manager and the study statistician. This panel 
will decide upon the membership of the patient in the Full Analysis Set (FAS), Per 
Protocol (PP) Set 1 (PP2), PP Set 2 (PP2), and Safety Analysis Set for statistical
analysis.
4.6 Subsequent Therapy 
If a patient withdraws from the study or is withdrawn by the Investigator by their
parent/legal guardian, he/she will receive treatment by the Investigator or 
personal physician according to institutional standard of care.
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5 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1 Characterization of Investigational Product 
Name of Medicinal Product: 
 
PANZYGA 
Active ingredient of PANZYGA: Immune globulin human-ifas 
Table 3: 
Qualitative and Quantitative Composition of PANZYGA 
Name of Ingredient 
Amount 
Total protein  
9.0 – 11.0 g/100 mL 
Protein composition 
≥95% Ig (≥96% Ig)* 
IgG content  
86 – 110 mg/mL 
Glycine 
15.0 – 19.5 mg/mL (17.3 mg/mL)*  
Water for Injection 
ad 1mL  
*Depending on regulatory requirements 
PANZYGA is a solvent/detergent (S/D)-treated, sterile preparation of highly 
purified immunoglobulin G (IgG) derived from large pools of human plasma. 
PANZYGA is a solution for infusion to be administered intravenously.  
This preparation contains approximately 100 mg of protein per mL (10%), of 
which not less than 96% is normal human immunoglobulin G. PANZYGA contains 
not more than 3% aggregates, not less than 90% monomers and dimers, and not 
more than 3% fragments. On average, the product contains 100 μg/mL of IgA, 
and lower amounts of IgM.  
PANZYGA contains only trace amounts of sodium, and the pH is between 4.5 
and 5.0. The osmolality is in the range of 240 to 310 mosmol/kg.  
The manufacturing process for PANZYGA isolates IgG without additional 
chemical or enzymatic modification, and the Fc portion is maintained intact. 
PANZYGA contains the IgG antibody activities present in the donor population. 
IgG subclasses are fully represented with the following approximate percentages 
of total IgG: IgG1 is 65%, IgG2 is 28%, IgG3 is 3% and IgG4 is 4%.  
PANZYGA contains a broad spectrum of IgG antibodies against bacterial and 
viral agents that are capable of opsonization and neutralization of microbes and 
toxins. PANZYGA contains glycine (15.0 to 19.5 mg/mL), but no preservatives or 
sucrose.  
All units of human plasma used in the manufacture of PANZYGA are provided by 
FDA-approved blood and plasma establishments, and are tested by FDA-
licensed serological tests for HBsAg, antibodies to HCV and HIV and Nucleic Acid 
Test (NAT) for HCV and HIV-1 and found to be non-reactive (negative).  
5.2 Packaging and Labelling 
PANZYGA for investigational use only will be labeled according to US FDA 
regulations. Details of the labeling will be included in the Pharmacy Manual. 
The batch number(s) used will be recorded in the study documentation and EDC. 
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5.3 Conditions for Storage and Use 
PANZYGA must be stored and transported light-protected at +2°C (36°F) to +8°C 
(46°F) and must be brought to room temperature before use.  
Storage temperature must be maintained at +2°C (36°F) to +8°C (46°F) and will 
be monitored for the duration of the study by reviewing the temperature logs. 
PANZYGA must not be frozen prior to use. 
PANZYGA must not be used after its expiry date.  
PANZYGA must not be mixed with other medicinal products. 
Each PANZYGA bottle is for single use only. 
Authorized personnel at the individual study sites will ensure that PANZYGA is 
stored in appropriate conditions in a secure refrigerator with restricted access and 
in compliance with national regulations. 
5.4 Dose and Dosing Schedule 
PANZYGA will be administered by intravenous infusion. Patients should be 
adequately hydrated prior to infusion. 
Patients will receive a dose of 1 g/kg body weight PANZYGA given on Day 1 and 
optionally another dose of 1 g/kg PANZYGA given on Day 3; body-weight 
dependent doses will be based on each patient’s weight collected at Baseline. 
Total PANZYGA doses will be 1 g/kg for patients receiving only 1 dose on Day 1 
and 2 g/kg for those receiving the optional Day 3 dose. If the Day 3 platelet count 
shows evidence of response as indicated by the platelet count at least doubling 
from Baseline count AND is >50x109/L, the Day 3 infusion will not be 
administered. If the Baseline platelet count has doubled but is ≤50x109/L, the 
Day 3 infusion will be administered.  
PANZYGA will be delivered by intravenous infusion according to the 
recommended flow rates: 
• Initial infusion rate of 0.01 mL/kg/min (60 mg/kg/hr) for the first 30 minutes 
• If tolerated, increase to 0.02 mL/kg/min (120 mg/kg/hr) for the second 
30 minutes 
• If tolerated, increase to 0.04 mL/kg/min (240 mg/kg/hr) for the third 
30 minutes 
• If tolerated, increase to 0.08 mL/kg/min (480 mg/kg/hr) for the remainder 
of the infusion.  
Infusion rates should not exceed 0.08 mL/kg/min and should not exceed 
8.0 mL/min.  
If an adverse event (AE) occurs during infusion, the infusion rate should be 
reduced to half the rate at which the event occurred, or the infusion should be 
interrupted until symptoms subside. The infusion may then be resumed at an 
infusion rate tolerated by the patient. The infusion rate may be gradually 
increased as tolerated by the patient.  
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5.5 Preparation and Method of Administration 
All patients will be infused at the study site under the surveillance of authorized 
study site staff.  
After calculating the volume required for the dose using the patient’s Baseline 
body weight (see Section 5.4), the appropriate number of vials will be removed 
from the refrigerator. Vials of different sizes may be combined to reach the 
required amount of IgG. The exact dose will be administered, and the empty and 
partially used vials will be retained by the site for drug accountability and dose 
verification.  
PANZYGA vials must be allowed to warm to room or body temperature before
infusion. After PANZYGA vials have been brought to room or body temperature,
they should be inspected visually for particulate matter and discoloration prior to
administration. The solution should be clear or slightly opalescent. DO NOT USE
IF
TURBID,
DISCOLORATION
IS 
OBSERVED,
AND/OR
FLOATING
PARTICLES ARE PRESENT. Solutions that are cloudy or vials that have a
deposit must not be used and must be discarded according to local policy.
Aseptic technique must be used throughout the entire procedure.
The contents of bottles must be pooled under aseptic conditions into sterile
infusion bags and administered immediately after pooling. Only polyvinyl chloride
(PVC)-free, diethylhexylphthalate (DEHP)-free and latex–free, infusion bags can
be used. Once pooled, a label will be applied on the infusion bag. Detailed
instructions of this process and an example label will be included in the Pharmacy 
Manual.
PANZYGA will be infused into a vein using standard infusion supplies provided
by the individual site. Standard procedures should be followed to prime the
infusion line with a priming solution (eg, normal saline). At the end of each
infusion, the infusion line will be flushed with normal saline solution.
Additional information regarding PANZYGA preparation and infusion procedures
will be provided in a pharmacy manual.
Please refer to special warnings and precautions for use provided in the
PANZYGA Investigator Brochure.
5.6
Blinding, Emergency Envelopes, and Breaking the Study Blind
Not applicable.
5.7 Treatment Compliance 
5.7.1 Drug Dispensing and Accountability 
The Sponsor or designee will provide and deliver all PANZYGA to participating 
Investigators. A Drug Inventory and Dispensing Log will be kept current by the 
Investigator, detailing the dates and quantities of PANZYGA received, dispensed 
to each patient, and the quantity remaining at the study site.  
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The Drug Inventory and Dispensing Log will be available to the monitor to verify 
drug accountability during the study. The study monitor will inventory all empty 
and partially used vials of PANZYGA and will cross-check this inventory versus 
the patient source documentation (records), eCRF, and the Drug Inventory and 
Dispensing Log. 
Unused and partially used vials may be destroyed at the study site or returned to 
the Sponsor for destruction according to institutional practice. Vials may be 
destroyed only after drug accountability has been verified and fully reconciled by 
the monitor and after the Sponsor has granted written approval of destruction. 
Additional information regarding PANZYGA drug accountability procedures will
be provided in a pharmacy manual.
5.7.2 Assessment of Treatment Compliance 
All patients will be infused at the study site under the surveillance of authorized
study personnel. Infusion details will be documented together with the batch
number(s) in the source data and eCRF.
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6 
STUDY CONDUCT  
Procedures performed at each study visit are presented in the Flow Chart of 
Assessments (see Table 1). Time windows and tolerances are provided in Table 
4. 
6.1 Observations by Visit 
6.1.1 Baseline Visit/Screening Period 
The following assessments will be performed during the Screening Period. The 
Screening Period can last up to 1 week (to accommodate patient schedules and 
the informed consent/assent process); however, all Baseline evaluations should 
be completed within 2 days before the first administration of PANZYGA. 
• Obtaining voluntarily given, written (signed and dated) informed consent 
and assent (as age appropriate) 
• Inclusion and exclusion criteria 
• Demographic and baseline characteristics 
• Medical and surgical history (previous 1 year) 
• Splenectomy history 
• Physical examination 
• Vital signs 
• Body weight 
• Blood samples for serum chemistry, hematology, and hemolysis analytes 
• Blood or urine pregnancy test (females of childbearing potential, only) 
• Blood samples for viral markers 
• Documentation of prior medications (previous 3 months) 
6.1.2 Day 1 
Day 1 should take place within 2 days after Baseline evaluations have been 
completed. If the Baseline and Day 1 Visits occur on the same day, the Baseline 
investigations do not need to be repeated. If the Baseline evaluations are 
completed more than 2 days before Day 1, the platelet count must be repeated 
and evaluated by the Investigator prior to initiating the first infusion. 
Before the administration/infusion of PANZYGA, patient eligibility will be re-
evaluated. The following assessments will be performed before PANZYGA 
infusion: 
• Confirmation of inclusion and exclusion criteria 
• Physical examination 
• Vital signs 
• Blood samples for serum chemistry, hematology, and hemolysis analytes 
The following activities will be performed during or after PANZYGA infusion: 
• PANZYGA infusion 
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• Vital signs (at the start of the infusion, 15 minutes (±15 minutes) after each 
infusion rate change, and approximately 30 minutes after the end of the 
infusion) 
• Monitoring for AEs 
• Documentation of concomitant medication use 
6.1.3 Day 3 
The following assessments will be performed before PANZYGA infusion: 
• Physical examination 
• Vital signs 
• Blood samples for serum chemistry, hematology, and hemolysis analytes 
NOTE: platelet, hemoglobin and hematocrit results must be available and 
reviewed by the Investigator prior to initiating the Day 3 infusion 
The Investigator will assess each patient’s Day 3 preinfusion platelet count, 
hematocrit, and hemoglobin. If the Day 3 platelet count shows evidence of clinical 
response, as indicated by the platelet count at least doubling from Baseline count 
AND is >50x109/L, the Day 3 infusion will not be administered. If the Baseline 
platelet count has doubled but is ≤50x109/L, the Day 3 infusion will be 
administered. In the event that the Day 3 infusion is not administered, all other 
Day 3 assessments will still be completed. If any of these hematology parameters 
indicate a clinically relevant change such that, in the Investigator’s opinion, it is 
not safe to administer the second infusion the patient should be withdrawn from 
study treatment but will be followed for safety through Day 32. 
The following activities will be performed during or after PANZYGA infusion: 
• PANZYGA infusion 
• Vital signs (at the start of the infusion, 15 minutes (±15 minutes) after each 
infusion rate change, and approximately 30 minutes after the end of the 
infusion) 
• Monitoring for AEs 
• Documentation of concomitant medication use 
6.1.4 Day 5 and Day 8 (± 1 day) 
The following assessments will be performed at Day 5 and Day 8: 
• Physical examination  
• Blood samples for serum chemistry, hematology, and hemolysis analytes 
• Monitoring for AEs 
• Documentation of concomitant medication use 
6.1.5 Day 15 and Day 22 (± 3 days) 
The following assessments will be performed at Day 15 and Day 22: 
• Physical examination 
• Blood samples for hematology analytes 
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•
Monitoring for AEs
•
Documentation of concomitant medication use
6.1.6 Day 32 (End of Study Visit) (± 5 days) 
Patients will return to the study site on Day 32 for final safety assessments/EOS 
Visit. Patients who were withdrawn early from the study should return to the study 
site for a final safety assessment. The following assessments will be performed:  
•
Physical examination
•
Vital signs
•
Blood samples for serum chemistry, hematology, and hemolysis analytes
•
Documentation of concomitant medication use
After Day 32, the clinical study is considered completed for the patient. No further 
study-related
assessments will
be
performed,
unless safety
concerns
(eg, ongoing AEs) require follow-up.
6.1.7 Visit Windows Used in this Study, including Tolerances
In this study, the following time windows and tolerances apply (Table 4):
Table 4: 
Visit Windows Used in this Study 
Time point 
Tolerance 
Screening Period 
7 days prior to Day 1
Final Baseline Evaluations 
-2 days before Day 1
Day 1 
none
Day 3 
none
Day 5 
±1 day 
Day 8 
±1 days 
Day 15 and Day 22 
±3 days 
Day 32 
± 5 days 
6.2
Duration of Study
6.2.1 Planned Duration for an Individual Patient
The duration of the entire study for each patient will be approximately 39 days, 
including a 7-day Screening Period.
6.2.2 Planned Duration for the Study as a Whole 
The study will be considered completed when all patients have completed the 
Day 32 EOS Visit. 
The estimated start of the study (enrollment of first patient) is Q2/Q3 2019, and 
the estimated end of the study (last visit of last patient) is Q1 2022. 
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6.2.3 Premature Termination of the Study 
Both the responsible Investigators and the Sponsor reserve the right to terminate 
the study at any time. Should this be necessary, study close-out procedures will 
be arranged on an individual site basis after review and consultation by both 
parties. In terminating the study, the Sponsor and the Investigator will ensure that 
adequate consideration is given to the protection of the patients' interests. 
Furthermore, the Investigator should promptly inform the IRB and provide a 
detailed written explanation. Pertinent regulatory authorities and IRBs will be 
informed in accordance with applicable regulatory requirements. 
6.2.3.1 Early Termination of the Entire Clinical Study 
At any time, the study as a whole will be terminated prematurely if: 
•
New toxicological or pharmacological findings or safety reports invalidate
the earlier positive benefit-risk-assessment for the pediatric population
•
Any other reason rendering the continuation of the study impossible for 
the Sponsor
6.2.3.2 Early Termination at an Individual Study Site
At any time, the study can be terminated at an individual study site if:
•
The site cannot comply with the requirements of the protocol
•
The site cannot comply with GCP or other regulatory standards
•
The site does not meet the required recruitment rate
Should the study be prematurely terminated, all study materials, including
PANZYGA, must be returned to the Sponsor.
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7 
ASSESSMENTS AND METHODS 
7.1 Demographic and Baseline Information 
Demographic and baseline information will be recorded during the Screening 
Period: 
7.1.1 Demographic and Baseline characteristics 
The demographic and baseline characteristics are sex, age, race and ethnic 
origin, height, and weight. 
7.1.2 Medical and Surgical history 
The medical history will be collected for the previous year and will be obtained by 
interviewing the patient. Records of past diseases and treatments (eg, hospital 
discharge letters) will be obtained for the study files, if available. The onset date 
of ITP will be recorded. 
Surgical history will include the date of splenectomy (if applicable) and any other 
surgical procedures in the previous year.  
7.1.3 Viral Marker Tests 
At the Screening Visit, blood samples for viral markers (HIV, HCV, HBV NAT) will 
be collected and tested at the local laboratory according to the site’s standard 
procedures, to rule out secondary infections that may cause ITP. Infusions may 
begin before the results are back if the Investigator is not aware of, and the patient 
isn’t exhibiting clinical signs of, any viral infection. 
7.1.4 Prior and Concomitant Medication Use 
Prior medication use will be obtained by interview and review of patient charts 
(if available). 
Concomitant medication use, defined as medications with a start date and time 
after the start of the Day 1 infusion, will be collected throughout the study. The 
start date and time of medication use will be collected on Day 1 and throughout 
the study.  
7.2 Efficacy Assessments 
All efficacy assessments will be based on platelet counts performed throughout 
the study.  
Platelet counts will be performed at Baseline (within 2 days prior to the first 
PANZYGA infusion), at Day 1 and Day 3 prior to planned PANZYGA infusions, 
and then at all remaining study visits (Days 5, 8, 15, 22, and 32). 
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7.3 Safety Assessments 
7.3.1 Assessments for Safety Evaluations 
The following assessments will be performed to evaluate the safety of PANZYGA 
in the pediatric population: 
•
AEs and Serious Adverse Events (SAEs)
•
Clinical laboratory tests
•
Vital signs
•
Physical examinations
•
Pregnancies
7.3.2 Adverse Events 
7.3.2.1 Definitions 
•
Adverse event (AE): An AE is any untoward medical occurrence in a
study /patient receiving an investigational medicinal product (IMP) and
which does not necessarily have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including
an
abnormal
laboratory
finding),
symptom,
or disease
temporally
associated with the use of an IMP, whether or not related to the IMP.
•
Adverse drug reaction (ADR): An ADR is any noxious and unintended
response to an IMP related to any dose. The phrase ‘response to an IMP’
means that a causal relationship between the IMP and an AE carries at
least a reasonable possibility (ie, the relationship cannot be ruled out).
•
Other significant AEs: Any marked laboratory abnormalities or any AEs
that lead to an intervention, including withdrawal of drug treatment, dose
reduction, or significant additional concomitant therapy.
•
Treatment-emergent AE
(TEAE):
Any
AE
that
newly
appeared,
increased in frequency, or worsened in severity following the time of the
first IMP infusion until the end of the safety follow-up period.
•
Infusional AE: Any AE that occurs from the time of infusion and within the
72 hour period after end of infusion.
•
Withdrawal due to AE/ADR: AE/ADR leading to discontinuation of
treatment with IMP. Any such events will be followed up by the Investigator 
until the event is resolved or until the medical condition of the patient is
stable. All follow-up information collected will be made available to the
Sponsor.
7.3.2.2 Collection of AEs 
The condition of the patient will be monitored throughout the study. At each visit, 
whether scheduled or unscheduled, AEs will be elicited using a standard 
nonleading question such as “How have you been since the last visit/during the 
previous study period?” In addition, the Investigator will check the patient diaries 
(if applicable) for any documented event. 
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Any AE or ADR which occurs during the study will be noted in detail on the 
appropriate pages of the eCRF. If the patient reports several signs or symptoms 
representing a single syndrome or diagnosis, the diagnosis should be recorded 
in the eCRF. The Investigator will grade the severity of all AEs or ADRs (mild, 
moderate, or severe), the seriousness (non-serious or serious), and the causality 
as defined in Section 7.3.2.3, Section 7.3.3, and Section 7.3.2.4, respectively. 
The Sponsor is responsible for assessing the expectedness of each ADR 
(expected or unexpected) as defined in Section 7.3.2.5. 
In the event of clinically significant abnormal laboratory findings, the tests will be
confirmed and the patient followed up until the laboratory values have returned
to normal and/or an adequate explanation for the abnormality has become
available.
Diseases, signs and symptoms, and/or laboratory abnormalities already present
before the first administration of IMP will not be considered AEs unless an
exacerbation in intensity or frequency (worsening) occurs.
The Investigator will provide detailed information about any abnormalities and
about the nature of and reasons for any action taken as well as any other 
observations or comments that may be useful for the interpretation and
understanding of an AE or ADR.
7.3.2.3 Severity of AEs
The intensity/severity of AEs will be graded as follows:
•
Mild: an AE, usually transient, which causes discomfort but does not
interfere with the patient’s routine activities
•
Moderate: an AE which is sufficiently discomforting to interfere with the
patient’s routine activities
•
Severe: an AE which is incapacitating and prevents the pursuit of the
patient’s routine activities
The grading of an AE is up to the medical judgement of the Investigator and will
be decided on a case-by-case basis.
7.3.2.4 Causality of AEs
The relationship of AEs to the administered IMP will be assessed by the
Investigator:
•
Probable: reports including good reasons and sufficient documentation to
assume a causal relationship, in the sense of plausible, conceivable, likely,
but not necessarily highly probable. A reaction that follows a reasonable
temporal sequence from administration of the IMP; or that follows a known
or expected response pattern to the suspected medicine; or that is
confirmed by stopping or reducing the dosage of the medicine and that
could not reasonably be explained by known characteristics of the
patient’s clinical state.
•
Possible: reports containing sufficient information to accept the possibility
of a causal relationship, in the sense of not impossible and not unlikely,
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although the connection is uncertain or doubtful, for example because of 
missing data or insufficient evidence. A reaction that follows a reasonable 
temporal sequence from administration of the IMP; that follows a known 
or expected response pattern to the suspected medicine; but that could 
readily have been produced by a number of other factors. 
•
Unlikely: reports not following a reasonable temporal sequence from IMP
administration. An event which may have been produced by the patient’s
clinical state or by environmental factors or other therapies administered.
•
Not related (unrelated): events for which sufficient information exists to
conclude that the etiology is unrelated to the IMP.
•
Unclassified: reports which for one reason or another are not assessable.
7.3.2.5 Classification of ADRs by Expectedness
ADRs will be classified by the Sponsor as either expected or unexpected:
•
Expected: an ADR that is listed in the current edition of the Investigator’s
Brochure or other reference safety information.
•
Unexpected: an ADR that is not listed in the current edition of the
Investigator’s Brochure or other reference safety information, or that differs 
because of greater severity or greater specificity.
7.3.2.6 Outcome of AEs
The outcome of all reported AEs will be documented as follows:
1. Recovered, resolved
2. Recovering, resolving
3. Not recovered, not resolved
4. Recovered, resolved with sequelae
5. Fatal
6. Unknown
NOTE: A patient’s death per se is not an event, but an outcome. The event which
resulted in the patient’s death must be fully documented and reported, even in
case the death occurs within 4 weeks after IMP treatment end and regardless of
whether or not it is considered treatment-related.
7.3.2.7 Action(s) taken
AEs requiring action or therapy must be treated with recognized standards of 
medical care to protect the health and well-being of the patient. Appropriate 
resuscitation equipment and medicines must be available to ensure the best 
possible treatment in an emergency situation. 
The action taken by the Investigator must be documented: 
a) General actions taken in the event of an AE
–
None
–
Medication (other than IMP) or other (eg, physical) therapy started
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–
Test performed
–
Other (to be specified)
b) IMP-related actions taken in the event of an AE
–
None
–
Product withdrawn
–
Dose reduced
–
Dose increased
The Investigator will follow up on each AE until it has resolved or until the medical
condition of the patient has stabilized. Any relevant follow-up information will be
reported to the Sponsor.
7.3.3 Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
•
results in death
•
is life-threatening (see below)
•
requires hospitalization or prolongation of existing hospitalization
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect
•
is another important medical event
NOTE: The term ‘life-threatening’ refers to an event in which the patient was, in
the view of the reporting Investigator, at immediate risk of death at the time of the
event; it does not refer to an event which may hypothetically have caused death
had it been more severe.
In deciding whether an AE/ADR is serious, medical judgment should be
exercised. Thus, important AEs/ADRs that are not immediately life-threatening or 
do not result in death or hospitalization but may jeopardize the patient or may
require intervention to prevent one of the other outcomes listed in the definitions 
above should also be considered serious.
In addition, although not classified under the seriousness criteria, all suspected
transmissions of an infectious agent should be reported as SAE. A suspected
virus transmission means that virus antigen has been detected in the patient. A 
passive transmission of antibodies alone does not constitute a suspected virus 
transmission.
7.3.4 SAE Reporting Timelines 
All SAEs, whether or not they are suspected to be related to study treatment, are 
to be reported immediately by telephone, fax, or email to the Clinical Project 
Manager or designee with the contact detailed provided to each site in the 
Investigator Site Binder. The contact details will also be communicated at the 
study initiation visit. 
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In addition, within 24 hours after recognition of the event, an Octapharma Serious 
Adverse Event Report must be completed and submitted to: 
Octapharma’s Corporate Drug Safety Unit 
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
Fax: 
 
E-mail: 
 
24 hours emergency telephone numbers: 
 or  
 
Waivers the from SAE Reporting Requirement 
Waivers from the SAE reporting requirement include surgeries that are elective 
or were planned before study entry or prolongations of existing hospitalizations 
for economic or social, but not medical, reasons. Such surgeries or prolongations 
of hospitalizations should not be considered SAEs. 
7.3.5 Laboratory Tests 
Clinical laboratory parameters will be investigated during the study at the time 
points specified in the Flow Chart of Assessments (Table 1).  
All of the study-specific laboratory tests will be performed at the local laboratories 
for each study site. The laboratory test and sample collection timing are specified 
below (Table 5). 
Table 5: 
Laboratory Tests and Time Points 
Test 
Timing 
Hematology (complete blood count, WBC 
differential, hematocrit, hemoglobin, platelet 
counts, reticulocytes) 
During Screening (Baseline evaluation), at 
Days 1, 3, 5, 8, 15, 22, and at Day 32/EOS 
Hemolysis (total, direct, and indirect 
bilirubin)  
During Screening (Baseline evaluation), at 
Days 1, 3, 5, 8, 22, and at Day 32/EOS 
Serum chemistry (ALT, AST, creatinine, Na, 
Ca, K, BUN, LDH) 
During Screening (Baseline evaluation), 
Days 1, 3, 22, and at Day 32/EOS 
Blood or Urine pregnancy test (females of 
childbearing potential) 
During Screening (Baseline evaluation) and 
Day 32/EOS 
Virology: HIV, HCV, HBV NAT 
During Screening (Baseline evaluation, see 
Section 7.1.3)  
Investigational sites will follow all site and local laboratory standard operating 
procedures for sample collection and handling and will provide the sponsor with 
normal reference ranges and laboratory certification certificates.  
The methods of determination and normal ranges for each parameter from each 
local laboratory will be provided in the clinical study report.  
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7.3.6 Vital Signs 
Vital signs will be collected at the time points specified in the Flow Chart of 
Assessments (Table 1) are blood pressure, body temperature, pulse rate, and 
respiratory rate. 
On Day 1 and Day 3, vital sign measurements will be recorded before the start 
of the infusion, 15 minutes (±15 minutes) after every infusion rate change, and 
approximately 30 minutes after the end of the infusion. 
7.3.7 Physical Examination including Height and Body Weight. 
Physical examinations will be performed at the visits specified in the Flow Chart
of Assessments (Table 1).
Both height and weight will be measured at Baseline. 
7.3.8 Other Relevant Safety Information 
a) Post-study related safety reports
Any SAE which occurs during the study (ie, within 4 weeks after the last
PANZYGA administration, which for most patients will be up to and including
Day 32) will be reported by the Investigator to the Sponsor. Proactive monitoring
for post-study SAEs is not required.
In case a post-study SAE is identified, the Investigator should complete an SAE
form and also state the relation to the clinical study in the report.
Deaths occurring during the study (ie, within 4 weeks after the last PANZYGA 
administration, which for most patients will be up to and including Day 32) should
also be reported, regardless of whether or not they are considered treatment-
related.
b) Pregnancies
Every effort will be made to avoid a pregnancy during the use of an IMP.
Pregnancies occurring during the study (fetal exposure to PANZYGA) need to be
reported.
In case of pregnancy during the study, the Investigator should complete the
Pregnancy Notification Form and send or fax it to the Clinical Project Manager or 
designee (Section 7.3.4).
Follow-up information on the outcome of both mother and fetus will be requested
by a Sponsor representative.
c) Overdose, interaction, medication error and lack of efficacy
The following safety relevant information should be reported as an AE or, if the 
reaction fulfills one of the criteria for seriousness, as SAE. 
d) Drug overdose
An overdose is a deliberate or inadvertent administration of a treatment at a dose 
higher than specified in the protocol and higher than the known therapeutic dose 
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that is of clinical relevance. The reaction must be clearly identified as an 
overdose. 
e) Drug interaction
A drug interaction is a situation in which a substance or medicinal product affects 
the activity of an IMP, ie, increases or decreases its effects, or produces an effect 
that none of the products would exhibit on its own. The reaction must be clearly 
identified as a drug interaction. 
f)
Medication error
A medication error involves the inadvertent administration or unintended use of a
medicinal product which may be caused by the naming, presentation of
pharmaceutical form/packaging, or instructions for use/labelling. The reaction
must be clearly identified as a medication error.
g) Lack of efficacy
Lack of efficacy is suspected when the therapeutic result is not as expected. One
example of lack of efficacy could be platelets not increasing following the correct
administration of IVIG.
7.4 Other Assessments 
7.5
Appropriateness of Measurements
For efficacy evaluations, platelet counts provide a direct measure of the response
to IGIV treatment in ITP patients and has been widely used for this purpose in
many clinical trials of similar nature. The test is performed routinely at each
hospital and is considered to be a reliable and robust parameter.
The definition of response used for the primary endpoint is the most established
procedure to obtain a dichotomy of success/failure that can be used to calculate
the response rate. It is also acceptable to US FDA and was used as the primary 
efficacy endpoint in their approval of PANZYGA in the treatment of chronic ITP
in adults and is thus expected to best facilitate their review of the efficacy of
PANZYGA in this pediatric population.
Monitoring AEs, vital signs, laboratory safety tests, and physical examinations 
are standard procedures used to evaluate the safety of investigational products
in clinical studies.
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8 
DATA HANDLING AND RECORD KEEPING 
8.1 Documentation of Data 
8.1.1 Source Data and Records 
Source data are defined as all information related to clinical findings, 
observations, or other activities in the study; written down in original records or 
certified copies of original records; or electronic medical records; allowing 
reconstruction and evaluation of the clinical study. 
The Investigator will maintain adequate source records (eg, case histories or
patient files for each patient enrolled). Source records should be preserved for
the maximum period of time required by local regulations.
For each patient enrolled, the Investigator will indicate in the source record(s) that
the patient is participating in this study.
All data entered in the eCRF must be supported by source data in the patient
records.
The Investigator will permit study-related monitoring, audit(s), IEC/IRB review(s),
and
regulatory
inspection(s),
by providing
direct
access to
the
source
data/records.
The Investigator may authorize site staff (eg, sub-Investigators, research nurses)
to enter study data into the eCRF. This must be documented in the Delegation of
Authority Log signed by the Investigator.
8.1.2 Electronic Case Report Forms
For each patient enrolled, an eCRF will be completed within the Electronic Data
Capture (EDC) system and approved by the Investigator or an authorized sub-
Investigator.
Study site staff (eg, research nurse, study coordinator, Investigator) will be
responsible for entering patient data into the validated EDC system. All study site
personnel will be trained on the EDC system and study-specific eCRFs prior to
receiving access to the live database for data entry.
The study site will be provided with the approved eCRF Completion Guidelines 
to assist in data entry and data issues/questions. The study site will be notified
once the eCRF is active to begin data entry. Additional site training may be
provided as refreshers throughout the study, if needed. All persons allowed to
enter or change eCRF data must be listed in the Delegation of Authority Log.
8.1.3 Changes to Electronic Case Report Form Data 
Monitors will perform source data verification (SDV) as defined for the study. 
If any errors or discrepancies in the eCRFs are found during data entry or review, 
discrepancies will be generated programmatically within the EDC system, and 
‘manual’ queries will be generated by either a monitor or Data Management.  
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Discrepancies and queries can only be corrected by the Investigator(s) or other 
authorized site personnel. An audit trail documents all changes to the data over 
the entire study period. If the reason for a change is not obvious, a comment must 
be supplied in the query’s response, stating the reason for the change, prior to 
closing. The study monitor should provide guidance to Investigator(s) and the 
Investigator(s)’ designated representatives on making such corrections.  
Once queries have been resolved by the site staff, the resolutions are assessed 
by Data Management. If the query response provided confirms the data as 
correct, the discrepancy will be closed. If the response does not adequately 
address the question raised, a new query will be issued for further clarification. 
Manual checks will be performed, and electronic data check programs run,
throughout the study until the data is clean and the database is ready for lock. All
discrepancies will be resolved prior to database lock. There will be a final run of
the programmed checks to ensure all discrepancies are closed out, SDV will be
confirmed as complete by the monitor, and all eCRFs will be approved by the
Investigator prior to database lock.
8.2 Information to Investigators 
An IB will be handed out to the Investigator before the start of the study. The IB
contains all information in the Sponsor’s possession necessary for the
Investigator to be fully and accurately informed about the safety of the IMP under 
evaluation and the respective benefit-risk ratio.
The IB will be updated by the Sponsor at regular intervals and whenever relevant
new information concerning PANZYGA becomes available.
All participating investigators will be informed about relevant study procedures,
about the methods for rating relevant study outcomes, and how to enter data into
the eCRF in order to reduce discrepancies. At the study initiation visit, the eCRF
will be explained to all study site staff entitled to document data in the eCRF.
The Investigator will be kept informed of important data that relate to the safe use
of PANZYGA as the study proceeds.
8.3
Responsibilities
The Principal Investigator is accountable for the conduct of the clinical study.
Responsibilities may be delegated to appropriately qualified persons.
A Delegation of Authority Log will be filled in and signed by the Principal
Investigator. In accordance with this authority log, study site staff (eg, sub-
Investigators, research nurses) are authorized to perform tasks relating to the
study.
8.4 Investigator’s Site File 
At each study site, the Investigator is responsible for maintaining all records to 
enable the conduct of the study to be fully documented. Essential documents as 
required by GCP guidelines and regulations (eg, copies of the protocol, study 
approval letters, all original informed consent and assent forms, site electronic 
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versions of all eCRFs, drug dispensing and accountability logs, correspondence 
pertaining to the study) should be filed accurately and kept by the Investigator for 
the maximum period of time required by local regulations. 
The Investigator is responsible for maintaining a confidential patient identification 
code list, which provides the unique link between named source records and 
eCRF data for the Sponsor. The Investigator must arrange for the retention of 
this confidential list for the maximum period of time required by local regulations. 
No study document should be destroyed without prior written agreement between
the Investigator and the Sponsor. Should the Investigator elect to assign the
study documents to another party, or move them to another location, the Sponsor
must be notified in writing.
8.5 Provision of Additional Information 
On request, the Investigator will supply the Sponsor with additional data relating
to the study, or copies of relevant source records, ensuring that the patient’s 
confidentiality is
maintained.
This
is particularly important
when source
documents are illegible or when errors in data transcription are encountered.
In the event of particular issues or governmental queries, it is also necessary to
have access to the complete study records, provided that the patient’s 
confidentiality is protected in accordance with applicable regulations.
8.6
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be established by the
Sponsor. The IDMC will be composed of recognized experts in the fields of
hematology and/or critical care who are not actively recruiting patients.
The IDMC will review relevant data periodically during the study and will give
advice on the continuation, modification, or termination of the study. A written
study-specific procedure will define in detail the composition, responsibilities, and
procedures of the IDMC.
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9 
STATISTICAL METHODS AND SAMPLE SIZE 
Statistical analysis will be delegated under an agreement of transfer of 
responsibilities to an external contract research organization (CRO). All 
Octapharma procedures and policies must be met by this CRO. Discrepancies or 
exceptions will be approved by the Sponsor's Manager of Biometrics. 
9.1 Determination of Sample Size 
At least 20 patients who meet all eligibility criteria will be enrolled in the study. 
The purpose of this study is to evaluate the efficacy and safety of PANZYGA in
pediatric patients with chronic ITP; the chosen number of 20 patients to be
enrolled is not derived from statistical considerations of power but driven by
feasibility constraints with respect to finding pediatric ITP patient eligible and
willing to participate in this study.
We expect the true proportion of responders to be comparable to results from 
similar studies in adult patients, as there is no published data or expert statement
that
would
indicate
otherwise.
Looking
at
possible
outcome
scenarios,
20 evaluable patients give the following picture from a statistical point of view:
Power Considerations for 20 Evaluable Patients:
Even though the chosen number of 20 pediatric patients is thus not sufficient ‘to
power’ the study, it will still allow the Sponsor to gather enough clinical evidence
to obtain a sound and meaningful medical assessment of the efficacy and safety 
of PANZYGA in pediatric patients with chronic ITP.
9.2
Statistical Analysis
A formal statistical analysis plan describing all details of the analyses to be
performed will be prepared by the study statistician and approved by the Sponsor
prior to the start of the statistical analysis.
No confirmatory statistical analysis will be performed; the results of this study will 
be presented at the descriptive level only. 
In general, and if not detailed otherwise in the Statistical Analysis Plan (SAP), all 
statistical presentations will be fit to the nature and type of the individual data 
items: 
•
Binary data (whether or not an event has occurred): counts and
proportions
•
Count data (the frequency of an event in a set time period): rate (count per
unit time)
Exact 95% 
Hypothetical power to show that the true response 
-
o=o.s -
o=o.6 
Responders 
Confidence Limits 
r.ate is above 6 (l~sided, a •0.025), given that it is in 
fact equal to the observed proportion 
100.. 
Number 
Proportion 
Lower 
Upper 
6=0.5 
6=0.6 
"°" 
11 
55% 
31,5% 
76,9% 
5,5% 
'°" 
12 
60% 
36,1% 
80,9% 
12,6% 
2,1% 
'°" 
'""' 
13 
65% 
40,8% 
84,6% 
24,5% 
4,4% 
j '°" 
14 
70% 
45,7% 
88,1% 
41,6% 
10,7% 
g '°" 
15 
75% 
50,9% 
91,3% 
61,7% 
22,5% 
'°" 
16 
80% 
56,3% 
94,3% 
80,4% 
41,1% 
2°" 
17 
85% 
62,1% 
96,8% 
93,3% 
64,8% 
10,0 
°" 
18 
90% 
68,3% 
98,8% 
98,9% 
86,7% 
'°" -
""' 
'°" 
9("' 
100.. 
19 
95% 
75,1% 
99,9% 
100,0% 
98,4% 
True Pfoportion 
20 
100% 
83,2% 
100,0% 
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•
Continuous data (measurements on a continuous scale, including quasi-
continuous variables): arithmetic mean, standard deviation, median, lower
and upper quartile, minimum, maximum
•
Scales data (Ordinal and Non-ordinal): absolute and relative frequencies
•
Time-to-event data (how long it takes to observe the outcome of interest,
e.g. the initial treatment response): time to event or last evaluation
(censored data in case subjects are lost to follow-up) and event rate. Such
parameters may also be presented as Kaplan-Meier plots of the product-
limit survival function estimates.
9.2.1 Populations for Analysis 
The following populations will be considered for the statistical analysis: 
•
Safety Analysis Set (SAF): All patients who received at least part of
1 infusion of PANZYGA.
•
Full Analysis Set (FAS): All patients in the SAF who satisfy all major
eligibility criteria and for whom any post-baseline data is available. This is 
the set of eligible patients with treatment effects measured, according to
the intention-to-treat (ITT) principle.
•
Per-Protocol Set I (PP1): All patients in the FAS, excluding those with
significant protocol deviations before the primary efficacy assessment on
Day 8 is completed, and which may have an impact on the evaluation of
the primary endpoint.
•
Per-Protocol Set II (PP2): All patients in the FAS, excluding those with
significant protocol violations potentially affecting the (secondary) efficacy 
evaluations.
Only protocol deviations with the potential to significantly affect the study results
or to invalidate the interpretation of the data obtained will lead to exclusion of
patients from the PP sets. The inclusion of each patient in the respective analysis 
populations will be determined before database lock in a data review meeting by 
a panel consisting of a medical expert from the Sponsor, the clinical study 
manager, the data manager, and the study statistician.
The analysis of safety will be based on the SAF.
The evaluation of the primary objective will be performed for the FAS 
(ITT analysis) and for the PP1 set (PP analysis) to assess the robustness of the
results. The primary analysis will be the ITT analysis.
For secondary objectives ITT and PP2 analyses will be carried out; again the
ITT analysis is considered the primary analysis and will be presented first in the
report.
9.2.2 Efficacy Analysis Plan 
The primary and secondary efficacy parameters will be determined on the basis 
of the patient's platelet concentration, listed individually, and presented 
descriptively. 
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The primary endpoint parameter ‘response’ is defined as an increase in platelet 
count at least once to ≥50x109/L within 7 days after the first infusion, ie, by Day 8 
(increase must occur at least once on any day up to and including Day 8). 
The number and proportion of responders will be presented, together with the 
associated exact 95% confidence intervals. 
The time to reach the desired increase in platelet count as well as the duration of 
response and the maximum platelet levels will be presented in listings and 
summarized in statistical tables. 
Individual profiles of platelet count over time will be presented as Trellis plots. 
9.2.3 Safety Analysis Plan 
The safety analysis will comprise descriptive statistics, tabulations, and listings of
all TEAEs, safety laboratory results, vital signs, and physical examination
findings. All reported AEs will be coded according to the Medical Dictionary for 
Regulatory Activities) MedDRA.
An AE is defined as treatment-emergent if first onset or worsening is after start
of the first infusion of PANZYGA. Only TEAEs are accounted for in the analysis.
AEs will be record at the start of the fist infusion of PANZYGA. AEs that occur 
between informed consent/assent and the start of the first PANZYGA infusion will
be recorded under Medical History.
Incidences of treatment-emergent AEs will be given as the number and
percentage of patients who experienced any or a particular AE, including serious
and drug-related AEs.
The summary tables for AEs will be given by system organ class and preferred
term. Additionally, AEs will be summarized by severity and relationship to study 
treatment. In addition to the tables presenting incidences including all AEs,
incidences will be determined for the subset of SAEs and drug-related AEs.
Incidences of infusional AEs will be given as the number and percentage of
patients who experienced any or a particular infusional AE, including serious and
drug-related AEs.
The summary tables for infusional AEs will be given by system organ class and
preferred term. Additionally, infusional AEs will be summarized by severity and
relationship to study treatment. In addition to the tables presenting incidences
including all infusional AEs, incidences will be determined for the subset of SAEs
and drug-related AEs.
Narratives will be prepared describing each death, other SAEs, and other 
significant AEs that are judged to be of special interest because of clinical 
importance. 
For each routine laboratory parameter at each visit the actual result, the change 
from baseline, the out-of-range flag and the assessment of clinical relevance will 
be summarized descriptively. 
Vital signs include systolic and diastolic blood pressure, pulse rate, body 
temperature and the respiratory rate; descriptive tables on the sampling statistics 
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of these parameters at each time point will be provided for the values as well as 
for their changes to baseline. 
9.2.4 Handling of Missing Data 
No replacement of missing data values is planned, but only observed results (and 
platelet counts) will be included in the analyses. 
9.3 Randomization, Stratification, and Code Release 
This is an open-label non-randomized study; therefore, no randomization code
list or procedure for code release are required. Patients will not be stratified by
age group.
9.4 Interim Analysis  
No interim analysis is planned. 
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10 ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE 
ASPECTS 
10.1 Ethical/Regulatory Framework 
This study will be conducted in accordance with the ethical principles laid down 
in the Declaration of Helsinki. The study protocol and any subsequent 
amendment(s) will be submitted to an IEC/ IRB and to the Regulatory Authority. 
The study will be conducted in compliance with the protocol, GCP guidelines, and 
applicable regulatory requirements. 
The regulatory application or submission for regulatory approval will be made by
the Sponsor or designated third party (eg, CRO) as required by national law.
10.2 Approval of Study Documents 
The study protocol, a sample of the patient information and informed consent
form, assent form, any other materials provided to the patient and their
parent/legal guardian, and further requested information will be submitted by the
Sponsor or the Investigator to the appropriate IEC/IRB and the Regulatory
Authority. The study must be approved by the IEC/IRB and the Regulatory 
Authority before any IMP may be shipped to the study sites and any patient is
exposed to a study-related procedure.
The Sponsor, the Investigator, and any third party (eg, CRO) involved in obtaining
approval must inform each other in writing that all ethical and legal requirements
have been met before the first patient is enrolled in the study.
10.3 Patient Information and Informed Consent
The Investigator will obtain freely given written consent from each the patient after 
an appropriate explanation of the aims, methods, anticipated benefits, potential
hazards, and any other aspect of the study which is relevant to the patient’s
decision to participate. The informed consent form must be signed, with name
and date and time noted by the patient, before the patient is exposed to any
study-related procedure, including screening tests for eligibility.
For patients not qualified to give legal consent, written consent must be obtained
from the legal parent/guardian. If children are old enough to understand the risks 
and benefits of the study, they should also be informed and provide their written
consent using an assent form.
The Investigator will explain that the patients are completely free to refuse to enter 
the study or to withdraw from it at any time, without any consequences for their 
further care and without the need to justify. The Investigator will complete the 
informed consent section of the CRF for each patient enrolled. 
Each patient (and parent/legal guardian, as appropriate) will be informed that 
his/her medical (source) records may be reviewed by the study monitor, a quality 
assurance auditor, or a health authority inspector, in accordance with applicable 
regulations, and that these persons are bound by confidentiality obligations. 
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10.4 Protocol Amendments 
Any prospective change to the protocol will be agreed between the Investigator 
(Co-ordinating Investigator in multi-center studies) and the Sponsor prior to its 
implementation. Any such amendments will be submitted to the any competent 
IEC/IRB and/or competent authority responsible as required by applicable 
regulations. 
IEC/IRB approval will, at a minimum, be requested for any change to this protocol
which could affect the safety of the patients, the objective/design of the study,
any increase in dosage or duration of exposure to the IMP, an increase in the
number of patients treated, the addition of a new test or procedure, or the
dropping of a test intended to monitor safety.
10.5 Confidentiality of Patient Data 
The Investigator will ensure that the patient’s confidentiality is preserved. On
eCRFs or any other documents submitted to the Sponsor, the patients will not be
identified by their names, but by a unique patient identifier. Documents not
intended for submission to the Sponsor, ie, the confidential patient identification
code list, original consent and assent forms, and source records, will be
maintained by the Investigator in strict confidence.
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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Periodic Monitoring 
The monitor will contact and visit the Investigator periodically to review all study-
related source data/records, verify the adherence to the protocol and the 
completeness, correctness and accuracy of all CRF entries compared to source 
data. The Investigator will cooperate with the monitor to ensure that any 
discrepancies identified are resolved. 
For this study, the first monitoring visit shall take place shortly after the inclusion
of the first patient. Thereafter, monitoring frequency will depend on study
progress and in accordance with the study clinical monitoring plan.
The monitor must be given direct access to source documents (original
documents, data, and records). Direct access includes permission to examine,
analyze, verify, and reproduce any records and reports that are important to the
evaluation of the clinical study. Source data will be available for all data in the
eCRFs, including all laboratory results.
11.2 Audit and Inspection 
The Investigator will make all study-related source data and records available to
a qualified quality assurance auditor mandated by the Sponsor, or to
IEC/IRB/regulatory inspectors, after reasonable notice. The main purposes of an
audit or inspection are to confirm that the rights and welfare of the patients have
been adequately protected, and that all data relevant for the assessment of safety
and efficacy of PANZYGA have been reported to the Sponsor.
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12 REPORTING AND PUBLICATION 
12.1 Clinical Study Report 
A clinical study report (in accordance with relevant guidelines and the Sponsor’s 
Standard Operating Procedures [SOPs]) will be prepared by the Sponsor after 
completion of the study. The Co-ordinating Investigator will approve the final 
study report after review. 
12.2 Publication Policy
The results of this study may be published or presented at scientific meetings.
If the Investigator wants to publish or present study results, the Investigator
agrees to inform the Sponsor and to submit all manuscripts or abstracts to the
Sponsor before submission to an editorial board or scientific review committee.
This will allow the Sponsor to protect proprietary information and to provide
comments based on information that may not yet be available to the Investigator.
In accordance with standard editorial and ethical practice, the Sponsor will
support publication of multi-center studies only in their entirety and not as
individual center data. Authorship will be determined by mutual agreement.
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13 LIABILITIES AND INSURANCE 
In order to cover any potential damage or injury occurring to a patient in 
association with PANZYGA or participation in the study, the Sponsor will contract 
insurance in accordance with local regulations. 
The Investigator is responsible for dispensing PANZYGA according to this 
protocol and for its secure storage and safe handling throughout the study. 
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14 REFERENCES 
1. Diagnosis and treatment of idiopathic thrombocytopenic purpura:
recommendations of the American Society of Hematology. The American
Society of Hematology ITP Practice Guideline Panel. Ann.Intern.Med.
1997;126:319-326.
2. Brenner B: Clinical experience with Octagam, a solvent detergent (SD)
virus inactivated intravenous gammaglobulin. Clin.Exp.Rheumatol.
1996;14:S115-S119.
3. Imbach P: 
Immune thrombocytopenic purpura and intravenous
immunoglobulin. Cancer. 1991;68:1422-1425.
4. Newland AC, Burton I, Cavenagh JD, et al: Vigam-S, a solvent/detergent-
treated intravenous immunoglobulin, in idiopathic thrombocytopenic
purpura. Transfus.Med. 2001;11:37-44.
5. Despotovic JM:
Emerging
therapies in
immune
thrombocytopenia.
American Society of Hematology. The Hematologist, ASH News and
Reports. 2018:15:4;1-7.
6. Neunert C, Despotovic J, Haley K, et. al. Thrombopoietin receptor agonist
use in children: data from the pediatric ITP consortium of North America
ICON2
study.
Pediatric
Blood
& Cancer.
2016:63(8),
1407-1413.
doi:10.1002/pbc.26003
7. European Medicines Agency, Guideline on the clinical investigation of
human normal immunoglobulin for intravenous administration (IVIg).
EMA/CHMP/BPWP/94033/2007
rev.
3.
Retrieved
from:
https://www.ema.europa.eu/documents/scientific-guideline/guideline-
clinical-investigation-human-normal-immunoglobulin-intravenous-
administration-ivig-rev-3_en.pdf
8. American Society of Hematology 2011 Clinical Practice Guideline on the
Evaluation and Management of Immune Thrombocytopenia (ITP), Quick
Reference Guide.
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15 APPENDICES 
Not applicable. 
Page 60 of 260 

Protocol Amendment #1 NGAM-10 
CONFIDENTIAL 
Page 1 of 7 
21-May-2019
PROTOCOL AMENDMENT #1 
STUDY NUMBER: 
NGAM-10 
STUDY TITLE: 
Post-Marketing Study to Evaluate the Efficacy and 
Safety of PANZYGA in Pediatric Patients with 
Chronic Immune Thrombocytopenia (ITP) 
SPONSOR: 
Octapharma USA 
121 River Street, 12th Floor 
Hoboken, NJ 07030 
TEST PRODUCT: 
PANZYGA 
IND / BLA NUMBERS: 
IND 14121 / BLA 125587 
APPROVED BY: 
Octapharma Pharmazeutika ProduktionsgmbH 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
PROTOCOL: 
DATE: 
Final Version 01 
30 Jan 2019 
Protocol Amendment #1 
21 May 2019 
Final Version 02 
21 May 2019 
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Protocol Amendment #1 NGAM-10 
CONFIDENTIAL 
Page 2 of 7 
21-May-2019
Rationale for the Amendment: 
FDA reviewed Study Protocol No. NGAM-10 Version 01 and provided 7 comments 
to the Sponsor in a communication dated 16-May-2019. The rationale for 
Amendment 01 of Protocol NGAM-10 is to address these 7 comments.  
In addition, an error was identified in the Flow Chart of Assessments regarding the 
requirement for hematology / hemolysis and serum chemistry assessments at Day 
5, 8, 15 and Day 22 with Sections 6.1.4 and 6.1.5 of the protocol; Amendment 1 
reconciles this inconstancy. 
The following changes made throughout the protocol were considered significant
and are documented in the red-line version of the protocol:
MODIFICATION 1: Expedited Safety Reporting Requirements 
The protocol includes the expedited safety reporting of SAEs of the Investigator to
the Sponsor in Section 7.3.4. FDA requested that the protocol also include the plan
for Sponsor expedited safety reporting to FDA.
Previous requirement:
Protocol was silent on Sponsor expedited safety 
reporting requirements to FDA.
Amended Requirement: A plan for Sponsor expedited safety reporting to FDA 
was added, along with additional Investigator SAE reporting requirements, as 
specified in 21 CFR 312.32. The following text was added to Protocol
Section 7.3.4:
The Investigator must update the Octapharma Serious Adverse Event Report as
soon as any additional information becomes available. The Investigator must also
report SAEs to the IRB/IEC as required by local and national laws. The Investigator 
must maintain documentation of all communications to and from the IRB/IEC.
In accordance with 21 CFR 312.32 and local authorities, the
Sponsor will submit to the FDA unexpected adverse reactions within
15 calendar days. Unexpected fatal or life-threatening adverse reactions will be
submitted within 7 calendar days.
MODIFICATION 2: Infusion-Related Adverse Events
Instructions for handling infusion-related adverse events were modified such that in
the event of Grade 2 or higher infusion-related reactions the PANZYGA infusion
would be stopped; the infusions may be resumed at a lower rate after the
symptoms subside. This change will align the management of infusion related
reactions with the PANZYGA label (See Protocol Section 5.4) and Study Outline. 
Previous requirement: 
If an adverse event (AE) occurs during infusion, the infusion rate should be 
reduced to half the rate at which the event occurred, or the infusion should be 
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Protocol Amendment #1 NGAM-10 
CONFIDENTIAL 
Page 3 of 7 
21-May-2019
interrupted until symptoms subside. The infusion may then be resumed at an 
infusion rate tolerated by the patient. The infusion rate may be gradually increased 
as tolerated by the patient. 
Amended Requirement: 
If a Grade 2 (moderate) or higher infusion-related adverse event (AE) occurs 
during infusion, the Panzyga infusion will be stopped. After infusion-related 
symptoms subside, the infusion may be resumed at a lower rate. The infusion rate 
may be gradually increased as tolerated by the patient. 
If a Grade 1 (mild) infusion-related AE occurs during infusion, the infusion rate
should be reduced to half the rate at which the event occurred, or the infusion
should be interrupted until symptoms subside. The infusion may then be resumed
at an infusion rate tolerated by the patient. The infusion rate may be gradually 
increased as tolerated by the patient.
MODIFICATION 3: Managing Hypersensitivity Reactions 
FDA requested that, to enhance the safety of participating patients, the protocol be
amended to provide instructions that study sites have access to epinephrine in the
event of severe hypersensitivity reaction, as specified in the PANZYGA label) and 
to include details regarding management of hypersensitivity reactions to Panzyga
(See Protocol Section 7.3.2.8).
Previous requirement: Protocol was silent on epinephrine access and handling
hypersensitivity reactions.
Amended Requirement: A new section - Section 7.3.2.8: Managing
Hypersensitivity Reactions – was added to the protocol.
Section 7.3.2.8
Managing Hypersensitivity Reactions
Severe hypersensitivity reactions may occur during PANZYGA infusions. In the
case of any subject exhibiting clinical signs of severe acute hypersensitivity
reactions to PANZYGA, the PANZYGA infusion must be immediately stopped.
Each site must have Epinephrine readily available and follow their institution’s
standard procedure for Epinephrine administration and monitoring. After the
hypersensitivity reaction subsides, the infusion may be resumed at a lower rate if
allowed per the site Epinephrine administration and monitoring procedures, and
per Investigator discretion.
MODIFICATION 4: Pre-medication Use Prior to PANZYGA Infusions 
The protocol did not specify whether or not pre-medication use was allowed prior to 
PANZYGA infusions. FDA requested that the protocol be amended to specifically 
state that patients with a history of hypersensitivity to IGIV may receive pre-
medication with H-1 blockers or antipyretics. This change was incorporated 
throughout the body of the protocol.   
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Previous requirement: Protocol was silent on pre-medication use prior to 
PANZYGA infusions.  
Amended requirement: A section was added to the protocol (Section 4.2.1:
Allowed Pre-medications) to state that patients with a history of hypersensitivity to
IGIV may receive premedication with H-1 blockers or antipyretics. In addition, the
protocol was amended to include site instructions at each study visit to document
any pre-medications that were administered with previous IGIV treatment
(Section 6.1.1: Baseline Visit/Screening Period), and to instruct sites to administer 
pre-medications, as appropriate (Section 6.1.2: Day 1 and Section 6.1.3: Day 3),
and to provide site instructions to collect any pre-medication use as a prior 
medication (Section 7.1.4: Prior and Concomitant Medication Use)
Section 4.2.1 
Allowed Pre-medications 
Use of H-1 blockers or antipyretics are allowed for patients who have history of
hypersensitivity to IGIV treatment; this may minimize the severity of possible
infusion-related reactions in patients already predisposed to hypersensitivity 
reactions. All pre-medications administered prior to PANZYGA administration must
be recorded in the eCRF.
Section 6.1.1 
Baseline Visit/Screening Period
•
Documentation of prior medications (previous 3 months), including
administration of pre-medication(s) as appropriate (see Section 4.2.1)
Section 6.1.2 
Day 1 
•
Administration of pre-medication(s) as appropriate (see Section 4.2.1)
Section 6.1.3 
Day 3 
•
Administration of pre-medication(s) as appropriate (see Section 4.2.1)
Section 7.1.4 
Prior and Concomitant Medication Use
Prior medication use will be obtained by interview and review of patient charts 
(if available). Patients will be queried specifically for use of H-1 blockers or 
antipyretics as pre-medications prior to previous IGIV treatments
MODIFICATION 5: Vital Sign Assessment Times After PANZYGA Infusions
FDA requested additional vital sign assessments after the start of the PANZYGA
infusion, specifically to add vital signs assessments prior to any infusion rate
change and to assess them every hour. This change was incorporated throughout
the body of the protocol.
Previous requirement: The following vital assessments were specified in the 
protocol: Vital signs (at the start of the infusion, 15 minutes (±15 minutes) after 
each infusion rate change, and approximately 30 minutes after the end of the 
infusion. 
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Protocol Amendment #1 NGAM-10 
CONFIDENTIAL 
 
 
 
 
 
Page 5 of 7 
21-May-2019 
Amended requirement: The following changes were made each of these sections 
of the protocol: 
Study Outline 
Flow Chart of Assessments footnote #9 
Section 6.1.2 Day 1 
Section 6.1.3 Day 3 
Vital signs (at the start of the infusion and every 60 minutes (±15 minutes) 
thereafter until the end of the infusion. In addition, vital sign measurements will be 
recorded just prior to every infusion rate change (-10 minutes), 15 minutes 
(+15 minutes) after each infusion rate change, and approximately 30 minutes after 
the end of the infusion) 
MODIFICATION 6: Thrombopoietin Receptor Agonist - Stable Dose 
Thrombopoietin receptor agonist use is prohibited during Screening through 
Day 32 unless patients have been on a stable dose for 3 weeks. An error was 
identified in Table 2 which stated 3 months (rather than 3 weeks).  
Previous requirement:  
Table 2: 
Prohibited Medications 
Medication 
Time Window  
thrombopoietin receptor agonists 
prohibited during Screening Period 
through Day 32 unless patients have 
been receiving stable dose for 3 months 
prior to Screening Visit 
Amended requirement: 
Table 2: 
Prohibited Medications 
Medication 
Time Window  
thrombopoietin receptor agonists 
prohibited during Screening Period 
through Day 32 unless patients have 
been receiving stable dose for 3 weeks 
months prior to Screening Visit 
MODIFICATION 7: Long-term Anti-prolific Agents or Attenuated Androgen 
Therapy – Stable Dose 
Long-term anti-prolific agents or attenuated androgen therapy is prohibited during 
Screening through Day 32 unless patients have been on a stable dose for 
2 months and a dosage change was planned before Day 32. Exclusion Criterion #5 
stated that patients would be excluded if no dosage was planned before Day 32 
(indicating a dosage change was required or a patient was excluded). The 
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Protocol Amendment #1 NGAM-10 
CONFIDENTIAL 
Page 6 of 7 
21-May-2019
language for this exclusion criterion was modified to clarify that no dose change 
was permitted during the study.  
Previous Requirement: 
Study Outline Exclusion Criterion #5 
Section 4.1.2 Exclusion Criterion #5 
Administration of long-term anti-prolific agents or attenuated androgen therapy 
when the dose has NOT been stable during the preceding 2 months and no 
dosage change is planned until Day 32 
Amended Requirement: 
Study Outline Exclusion Criterion #5 
Section 4.1.2 Exclusion Criterion #5 
Administration of long-term anti-prolific agents or attenuated androgen therapy 
when the dose has NOT been stable during the preceding 2 months and a dosage
change is planned before Day 32
MODIFICATION 8: Place holder for hematology / hemolysis analytes and
serum chemistry assessments 
Previous Requirement:
Table 1
Hemolysis is required on Screening/Baseline/Day 1,3,5,8,22 and 32
Serum Chemistry is required on Screening/Baseline/Day 1,3 and 32
Amended Requirement:
Table 1
Hemolysis is required on Screening/Baseline/Day 1,3,5,8,15, 22 and 32
Serum Chemistry is required on Screening/Baseline/Day 1,3,5,8 and 32
This is now consistent with Sections 6.1.4 and 6.1.5 in the body of the protocol.
Please see the attached redline version for documentation of these substantive
changes.
Page 66 of 260 

Protocol Amendment #1 NGAM-10 
CONFIDENTIAL 
AGREEMENT: These signatures constitute approval of this protocol 
amendment and provide the necessary assurance that the study will be 
conducted according to all stipulations of protocol and amendments. 
Authorised person for signing the Study Protocol and Protocol Amendments 
on behalf of the Sponsor and Sponsor's Medical Expert: 
Date: 
 
Octapharma Pharmazeutika Produktionsgesellschaft m.b.H. 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
Tel; 
 Fax: 
 
 of the Amendment: 
_ _ Date: 
 
Octapharma USA, Inc. 
121 River Street. Suite 1201 
Tel: 
, Fax 
 
 
 
Octapharma Pharmazeutika Produktionsgesellschaft m.b.H. 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
Tel: 
, Fax: 
 
Page 7 of 7 
21-May-2019 
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This document contains confidential and proprietary information of Octapharma AG. 
Do not copy or distribute without written permission. 
090-CSP-NGAM-10-V01/DOC ID 2880
CLINICAL STUDY PROTOCOL 
NGAM-10 
Post-Marketing  Stud y to Evalua te the Efficacy 
and Safety  o f PANZY GA in Pediat ric Patients 
with 
Chronic Immune Thrombocytopenia (ITP)
Investigational Product: 
PANZYGA 
Indication: 
Chronic Immune Thrombocytopenia (ITP)
Study Design: 
Prospective, open-label, single-arm, multi-
center study
Sponsor: 
Octapharma USA
121 River Street, 12th Floor
Hoboken, NJ 07030
Study Number: 
NGAM-10
IND Number / BLA Number: 
IND 14121 / BLA 125587
Development Phase: 
Phase 4
Planned Clinical Start:
Q2/Q3 2019 
Planned Clinical End:
Q1 2022 
Date of Protocol:
21-May-2019
Version:
02 
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Study Protocol No. NGAM-10, Version 02 CONFIDENTIAL 
21-May-2019
Page 2 of 59 
STUDY OUTLINE 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
21-May-2019
Title of Study: 
Post-Marketing Study to Evaluate the Efficacy and Safety of PANZYGA in
Pediatric Patients with Chronic Immune Thrombocytopenia (ITP)
Indication: 
Chronic Immune Thrombocytopenia (ITP) 
Number of Study Centre(s): 
Up to 8 sites in the USA 
Objectives: 
Primary Objective: 
The primary objective is to evaluate the efficacy of PANZYGA in increasing the
platelet count in pediatric patients with chronic ITP.
Secondary Objectives:
The secondary objectives of this study are to:
•
Assess safety of up to 2 g/kg PANZYGA (1 g/kg PANZYGA on Day 1 
and an optional dose of 1 g/kg PANZYGA on Day 3) infused in the
pediatric population within the scope of the clinical study
•
Determine the time to reach a platelet count of 50x109/L
•
Determine duration of time during which the platelet count is maintained
at the level ≥50х109/L
•
Determine the maximum platelet count during the study
Study Design: 
This is a prospective, open-label, single-arm, multicenter, Phase 4 study 
evaluating the efficacy and safety of PANZYGA in pediatric patients with chronic 
ITP. 
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Page 3 of 59 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
21-May-2019
Number of Patients: 
At least 20 patients 
Patient Selection Criteria: 
Inclusion Criteria: 
1. Females and males aged from ≥1 year to <18 years old
2. Confirmed diagnosis of Chronic Immune Thrombocytopenia (ITP) 
according to American Society of Hematology (ASH) 2011 guidelines
3. Platelets count <30x109/L at the Baseline Visit
4. Voluntarily given written informed consent (provided by patient’s parent
or legal guardian) and assent (provided by patient [if age-appropriate per
IRB requirements])
5. Females of childbearing potential have been using at least 1 acceptable
form of birth control for a minimum of 30 days (or a minimum of 3 months 
for hormonal contraceptives) prior to the Screening visit, and must agree
to use at least 1 acceptable method of contraception for 30 days after 
the last dose of PANZYGA. Acceptable methods of birth control for this
study include: intrauterine device (IUD), hormonal contraception, male
or female condom, spermicide gel, diaphragm, sponge, or cervical cap. 
Abstinence is not considered an acceptable method of birth control.
6. Parent or legal guardian must agree and be willing to assist the
participant attend study visits, and to follow all protocol requirements and
instructions of the study doctor
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Study Protocol No. NGAM-10, Version 02 CONFIDENTIAL 
21-May-2019
Page 4 of 59 
Exclusion Criteria: 
1. Thrombocytopenia secondary to other diseases (such as Acquired
Immunodeficiency Syndrome [AIDS] or systemic lupus erythematosus
[SLE]), drug-related thrombocytopenia, or congenital thrombocytopenia
2. Administration of intravenous immunoglobulin (IGIV) or anti-D
immunoglobulin within 3 weeks before enrollment
3. Administration of thrombopoietin receptor agonists when the dose has
NOT been stable within 3 weeks before enrollment and a dosage change
is planned before Day 32
4. Administration of oral immunosuppressants when the dose has NOT
been stable during the preceding 2 months (2 weeks for long-term
corticosteroid therapy) and a dosage change is planned before Day 32
(Note: topical agents and inhaled corticosteroid therapy use is permitted)
5. Administration of long-term anti-prolific agents or attenuated androgen
therapy when the dose has NOT been stable during the preceding
2 months and a dosage change is planned before Day 32
6. Nonresponsive to previous treatment with IGIV or anti-D immunoglobulin
7. Evidence of an active major bleeding episode at Screening
8. Splenectomy
in
the
previous 4 weeks or planned
splenectomy 
throughout the study period
9. Evans syndrome (experiencing active disease with 2 out of 3 of the
following:
autoimmune
thrombocytopenia,
autoimmune
hemolytic 
anemia, and/or autoimmune neutropenia)
10.Known
or 
suspected
human immunodeficiency virus 
(HIV),
hepatitis B virus (HBV), and/or hepatitis C virus (HCV) infections
11.Emergency surgery in the previous 4 weeks
12.Severe liver and/or kidney disease (alanine aminotransferase [ALT]
>3x upper limit of normal (ULN), aspartate aminotransferase [AST]
>3x upper limit of normal (ULN), and/or creatinine >120 µmol/L)
13. History of severe hypersensitivity to blood or plasma derived products,
or any component of the PANZYGA
14. Known immunoglobulin A (IgA) deficiency and antibodies against IgA
15. History of, or suspected alcohol or drug abuse in the previous year
16. Females who are pregnant or nursing
17. Unable or unwilling to comply with the study protocol
18. Receipt of any other investigational medicinal product within 3 months
before study entry
19. Risk factors* for thromboembolic events in whom the risks outweigh the
potential benefit of PANZYGA treatment.
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Page 5 of 59 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
21-May-2019
20.Any other condition(s), that in the Investigator’s opinion, make it
undesirable for the patient to participate in the study or may interfere with
protocol compliance.
* Risk factors include, but are not limited to: obesity, advanced age,
hypertension, diabetes, a history of atherosclerosis/vascular disease or
thrombotic events, hyperlipidemia, multiple cardiovascular risk factors, acquired
or inherited thrombophilic disorders, prolonged periods of immobilization,
severe hypovolemia, central venous catheterization, active malignancy and/or 
known or suspected hyperviscosity.
Test Product, Dose, and Mode of Administration:
PANZYGA (Immune Globulin, intravenous, human-ifas). PANZYGA must be
stored and transported light-protected at +2°C (36°F) to +8°C (46°F) and must
be brought to room temperature before use.
Patients will receive a dose of 1 g/kg body weight PANZYGA given on Day 1
and optionally another dose of 1 g/kg PANZYGA given on Day 3; body-weight
dependent doses will be based on each patient’s weight collected at Baseline. 
Total PANZYGA doses will be 1 g/kg for patients receiving only 1 dose on Day 1 
and 2 g/kg for those receiving the optional Day 3 dose. Prior to the Day 3 
infusion, each patient’s preinfusion platelet count will be reviewed by the
Investigator. If the Day 3 platelet count shows evidence of response as
indicated by the platelet count at least doubling from Baseline count AND is 
>50x109/L, the Day 3 infusion will not be administered. If the Baseline platelet
count has doubled but is ≤50x109/L, the Day 3 infusion will be administered.
PANZYGA
will be delivered by intravenous infusion according to the
recommended flow rates:
•
Initial infusion rate of 0.01 mL/kg/min (60 mg/kg/hr) for the first
30 minutes
•
If tolerated, increase to 0.02 mL/kg/min (120 mg/kg/hr) for the second
30 minutes
•
If tolerated, increase to 0.04 mL/kg/min (240 mg/kg/hr) for the third
30 minutes
•
If tolerated, increase to 0.08 mL/kg/min (480 mg/kg/hr) for the remainder
of the infusion.
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Page 6 of 59 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
21-May-2019 
 
Infusion rates should not exceed 0.08 mL/kg/min and should not exceed 
8.0 mL/min. The infusion rate may be gradually increased as tolerated by the 
patient. 
If a Grade 2 or higher (moderate) infusion-related adverse event (AE) occurs 
during infusion, the Panzyga infusion will be stopped. After infusion-related 
symptoms subside, the infusion may be resumed at a lower rate. The infusion 
rate may be gradually increased as tolerated by the patient. 
If a Grade 1 (mild) infusion-related AE occurs during infusion, the infusion rate 
should be reduced to half the rate at which the event occurred, or the infusion 
should be interrupted until symptoms subside. The infusion may then be 
resumed at a rate tolerated by the patient.The batch number(s) used will be 
recorded in the study documentation and electronic data capture (EDC) system. 
Duration of Treatment: 
Screening Period: 1 week 
Treatment Period: up to 3 days 
Follow-up Period: 29 days 
Reference Therapy, Dose, and Mode of Administration: 
Not Applicable 
Study Outcome Parameters (Primary and Secondary Endpoints): 
Primary Endpoint: 
The primary efficacy parameter is defined as an increase in platelet count at 
least once to ≥50x109/L within 7 days after the first infusion, ie, by Day 8 
(increase must occur at least once on any day up to and including Day 8). This 
definition of clinical response will serve as the basis for the primary endpoint, 
the response rate (ie, the proportion of patients with an elevation of platelet 
count at least once to 50x109/L within 7 days [ie, by Day 8] after the first 
infusion). 
Secondary Endpoints: 
• Time to reach a platelet count of 50x109/L 
• Duration of platelet response defined as the number of days the platelet 
count remains above 50x109/L 
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Page 7 of 59 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
21-May-2019
•
Maximum platelet count during the study
Safety Parameters: 
•
AEs
•
Vital signs (blood pressure, heart rate, temperature, respiratory rate)
•
Physical examination
•
Laboratory parameters: hematology (including reticulocytes), hemolysis,
platelet count, serum chemistry (including lactase dehydrogenase
[LDH]).
Study Procedures: 
The study will be conducted in accordance with ICH-GCP and US FDA
regulations.
The Flow Chart of Assessments specifies the procedures that will be performed
at each study visit.
Baseline Visit 
After appropriate information about the study and PANZYGA has been provided
and written informed consent/assent has been obtained, patients will be
evaluated for study eligibility according to the inclusion/exclusion criteria. These
evaluations will
include
demographics,
medical/surgical
history,
current
medications, physical examinations, blood and urine samples, along with other 
safety and baseline evaluations as specified in the Flow Chart of Assessments.
Infusion Visits (Day 1 and Day 3)
The first PANZYGA infusion must begin no more than 2 days after Baseline
evaluations have been completed and eligibility criteria have been confirmed. If
Baseline and Day 1 Visits occur on the same day, Day 1 investigations do not
need to be repeated. If Baseline evaluations are completed more than 2 days
before Day 1, then the platelet count must be repeated and evaluated by the
Investigator prior to the first infusion.
Patients who have met all of the inclusion criteria and none of the exclusion 
criteria will return to the study site for their first PANZYGA infusion. Required 
assessments will be performed as specified in the Flow Chart of Assessments, 
including safety evaluations before and after each infusion. Patients will remain 
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Page 8 of 59 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
21-May-2019
at the study site during the infusion and for about 30 minutes after the end of
each infusion to complete vital sign measurements.
Patients will receive a dose of 1 g/kg body weight PANZYGA on Day 1 and 
optionally another dose of 1 g/kg PANZYGA on Day 3; body-weight dependent
doses will be based on each patient’s weight collected at Baseline. Total
PANZYGA doses will be 1 g/kg for patients receiving only 1 dose on Day 1 and
2 g/kg for those receiving the optional Day 3 dose.
Prior to the Day 3 infusion, the Investigator will assess each patient’s
preinfusion platelet count, hematocrit, and hemoglobin. If the Day 3 platelet
count shows evidence of response, as indicated by the platelet count at least
doubling from Baseline count AND >50x109/L, the Day 3 infusion will not be
administered. If the Baseline platelet count has doubled but is ≤50x109/L, the
Day 3 infusion will be administered. If any of these parameters indicate a
clinically relevant change such that, in the Investigator’s opinion, it is not safe
to administer the second infusion the patient should be withdrawn from study
treatment but will be followed for safety through Day 32.
Assessment Day 5 though Day 22
Patients will return to the study site as indicated in the Flow Chart of
Assessments for continued efficacy and safety evaluations.
Day 32 (End of Study/Early Termination Visit)
Patients will return to the study site on Day 32 for final safety assessments/End
of Study (EOS) visit. Patients withdrawn early from the study will be encouraged
to return to the study site and complete the EOS assessments.
Statistical Analysis:
The primary endpoint for this study is the proportion of patients with an increase 
in platelet count to ≥50x109/L at least once within 7 days after the first infusion. 
This proportion will be assessed and presented together with its associated 
95% confidence interval to facilitate comparison with results from other studies 
and published data. Because of the limited number of patients, no formal 
hypothesis test will be performed; any p-value or confidence interval presented 
is to be understood in the exploratory sense. 
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Page 9 of 59 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
21-May-2019
All data collected will be presented descriptively. The time to reach the desired
increase in platelet count as well as the duration of response will be presented
in listings and summarized in statistical tables. Individual profiles of platelet
count over time will be presented as Trellis plots.
All safety data, including tolerability assessments, abnormal laboratory values,
and AEs will also be listed and summarized statistically.
Statistical presentations will be fit to the nature of individual data items and
include sample characteristics, frequency counts and rates. Product-limit
survival function estimates (Kaplan-Meier Plots), confidence intervals and
graphs will be included as appropriate.
The following populations will be considered for the statistical analysis:
•
Safety Analysis Set (SAF): All patients who received at least part of one
infusion of PANZYGA.
•
Full Analysis Set (FAS): All patients in the SAF who satisfy all major 
eligibility criteria and for whom any post-baseline data is available. This
is the set of eligible patients with treatment effects measured, according
to the intention-to-treat (ITT) principle.
•
Per-Protocol Set I (PP1): All patients in the FAS, excluding those with
significant protocol deviations before the primary efficacy assessment on
day 8 is completed, and which may have an impact on the evaluation of
the primary endpoint.
•
Per-Protocol Set II (PP2): All patients in the FAS, excluding those with
significant protocol violations potentially affecting the (secondary) 
efficacy evaluations. 
Only protocol deviations with the potential to significantly affect the study results
or to invalidate the interpretation of the data obtained will lead to exclusion of
patients from the PP sets. The inclusion of each patient in the respective
analysis populations will be determined before database lock in a data review
meeting by a panel consisting of a medical expert from the Sponsor, the clinical
study manager, the data manager, and the study statistician.
A detailed Statistical Analysis Plan (SAP) will be compiled as a separate 
document. 
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FLOW CHART OF ASSESSMENTS 
Table 1: 
Flow Chart of Assessments 
ASSESSMENTS 
Scr / BL1 
Day 
1 
Day 
3 
Day 
5 
Day 
8 
Day 
15 
Day 
22 
Day 
3212
Visit Window (Days) 
-7 / -2
0 
0 
±1 
±1 
±3 
±3 
±5 
Informed Consent 
X 
Inclusion / Exclusion Criteria Review 
X 
X 
Demographics 
X 
Medical and Surgical History2 
X 
Body Weight 
X 
Physical Examination 
X3 
X3 
X4 
X4 
X4 
X3 
X4 
X3 
Urine or Blood Pregnancy Test (females of 
child-bearing potential) 
X 
X 
Hematology: CBC with white blood cell 
(WBC) differential, hematocrit, hemoglobin, 
platelet counts, reticulocytes  
X 
X5,6 
X5,6,7 
X 
X 
X 
X 
X 
Hemolysis: total, direct, and indirect bilirubin 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry: ALT, AST, creatinine, Na, 
Ca, K, BUN, LDH 
X 
X 
X 
X 
X 
X 
Viral markers (HIV, HCV, HBV nucleic acid 
test [NAT]) 
X7 
PANZYGA INFUSIONS 
X 
X8 
Vital Signs: heart rate, blood pressure, 
temperature, respiratory rate 
X 
X9 
X9 
X 
X 
AE Monitoring10 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Therapy (drug and 
non-drug)11
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BL = Baseline, Scr = Screening 
1) Screening Period is 7 days. Day 1 (first PANZYGA infusion) must occur no more than 2 days after Baseline 
evaluations have been completed. If the Baseline visit occurs more than 2 days after Baseline evaluations have 
been completed, the platelet count must be repeated and evaluated by the Investigator before initiation of the Day 1
infusion. If Baseline and Day 1 Visits occur on the same day, the Day 1 investigations need not be repeated.
2) Medical History will be collected for the previous year and will include the onset date of ITP. Surgical history will 
include the date of splenectomy (if applicable), and any other surgical procedures in the previous year.
3) Brief Physical Examination: general appearance, skin, heart, lungs, abdomen, extremities
4) Limited Physical Examination with targeted body systems per Investigator discretion
5) Pre-infusion
6) Platelet count, hematocrit, and hemoglobin results must be available and reviewed by the Investigator prior to start
of the infusion 
7) HIV/HCV/HBV NAT Test: Infusions may begin before the results are back if the Investigator is not aware of, and the 
patient isn’t exhibiting clinical signs of, any viral infection.
8) If the Day 3 preinfusion platelet count shows evidence of response as indicated by the platelet count at least
doubling from Baseline count AND >50x109/L, the Day 3 infusion will not be administered. If the Baseline platelet
count has doubled but is ≤50x109/L, the Day 3 infusion will be administered.
9) Vital Signs: at the start of the infusion and every 60 minutes (±15 minutes) thereafter until the end of the infusion. In
addition, vital sign measurements will be recorded just prior to every infusion rate change (-10 minutes), 15 minutes
(+15 minutes) after each infusion rate change, and approximately 30 minutes after the end of the infusion
10) The start date and start time will be collected for any adverse events starting at Day 1 through Day 32/EOS visit
11) Prior medications will be collected for the 3 months. The start date and start time will be collected for any 
concomitant medications taken on Day 1 through Day 32/EOS visit
12) Day 32 visit will correspond to the Early Termination visit for patients who are withdrawn early from the study
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Study Protocol No. NGAM-10, Version 02 CONFIDENTIAL 
PROTOCOL SIGNATURES 
 
 
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Tel: 
 
 
Octapharma USA. Inc. 
121 River Street, Suite 1201 
Hoboken, NJ, USA 
Tel: 
 
Signature 
 
 
Signature 
Date 
Octapharma Pharmazeutika Produktionsgesellschaft mbH 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
Tel: 
 
 
 
 
Signature 
Octapharma Pharmazeutika Produktionsgesellschaft mbH 
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21-May-2019 
2 9 MAY 2019 
Date 
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TABLE OF CONTENTS 
STUDY OUTLINE ............................................................................................................. 2
FLOW CHART OF ASSESSMENTS ............................................................................. 10
PROTOCOL SIGNATURES .......................................................................................... 11
TABLE OF CONTENTS ................................................................................................. 12
TABLE OF TABLES ...................................................................................................... 15
LIST OF ABBREVIATIONS ........................................................................................... 16
1
INTRODUCTION.................................................................................................... 18
1.1
RATIONALE FOR CONDUCTING THE STUDY ..................................................... 19
1.2
DOSE RATIONALE.......................................................................................... 19
1.3
BENEFIT-RISK STATEMENT............................................................................ 19
2
STUDY OBJECTIVES............................................................................................ 21
2.1
PRIMARY OBJECTIVES ................................................................................... 21
2.2
SECONDARY OBJECTIVES.............................................................................. 21
3
INVESTIGATIONAL PLAN.................................................................................... 22
3.1
PRIMARY AND SECONDARY ENDPOINTS......................................................... 22
3.1.1 Primary Endpoint ............................................................................. 22
3.1.2 Secondary Endpoints....................................................................... 22
3.2
OVERALL STUDY DESIGN AND PLAN .............................................................. 22
3.3
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP(S)........... 23
3.3.1 Study Design.................................................................................... 23
3.3.2 Control Group(s) .............................................................................. 24
3.3.3 Study Parameters ............................................................................ 24
4
STUDY POPULATION........................................................................................... 25
4.1
POPULATION BASE ........................................................................................ 25
4.1.1 Inclusion Criteria .............................................................................. 25
4.1.2 Exclusion Criteria............................................................................. 25
4.2
PRIOR AND CONCOMITANT THERAPY ............................................................. 26
4.2.1
Allowed Pre-medications ................................................................. 27 
4.2.2
Prohibited Medications .................................................................... 27 
4.3
WITHDRAWAL AND REPLACEMENT OF PATIENTS ............................................ 27
4.3.1 Premature Patient Withdrawal ......................................................... 27 
4.3.2 Patient Replacement Policy ............................................................. 28 
4.4
ASSIGNMENT OF PATIENTS TO TREATMENT GROUPS ..................................... 28
4.5
RELEVANT PROTOCOL DEVIATIONS ............................................................... 28
4.6
SUBSEQUENT THERAPY ................................................................................. 28
5 
INVESTIGATIONAL MEDICINAL PRODUCT ...................................................... 29
5.1
CHARACTERIZATION OF INVESTIGATIONAL PRODUCT ..................................... 29
5.2
PACKAGING AND LABELLING .......................................................................... 29
5.3
CONDITIONS FOR STORAGE AND USE ............................................................ 30
5.4
DOSE AND DOSING SCHEDULE ...................................................................... 30
5.5
PREPARATION AND METHOD OF ADMINISTRATION .......................................... 31
5.6
BLINDING, EMERGENCY ENVELOPES, AND BREAKING THE STUDY BLIND ........ 31
5.7
TREATMENT COMPLIANCE ............................................................................. 31
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5.7.1 Drug Dispensing and Accountability................................................ 31 
5.7.2 Assessment of Treatment Compliance ........................................... 32 
6 
STUDY CONDUCT ................................................................................................ 33
6.1 
OBSERVATIONS BY VISIT ............................................................................... 33
6.1.1 Baseline Visit/Screening Period ...................................................... 33 
6.1.2 Day 1 ................................................................................................ 33 
6.1.3 Day 3 ................................................................................................ 34 
6.1.4 Day 5 and Day 8 (± 1 day) ............................................................... 34 
6.1.5 Day 15 and Day 22 (± 3 days) ......................................................... 35 
6.1.6 Day 32 (End of Study Visit) (± 5 days) ............................................ 35 
6.1.7 Visit Windows Used in this Study, including Tolerances ................ 35
6.2 
DURATION OF STUDY ..................................................................................... 35
6.2.1 Planned Duration for an Individual Patient...................................... 35
6.2.2 Planned Duration for the Study as a Whole .................................... 36
6.2.3 Premature Termination of the Study ............................................... 36
7
ASSESSMENTS AND METHODS ........................................................................ 37
7.1
DEMOGRAPHIC AND BASELINE INFORMATION ................................................. 37
7.1.1 Demographic and Baseline characteristics ..................................... 37
7.1.2 Medical and Surgical history............................................................ 37
7.1.3 Viral Marker Tests............................................................................ 37
7.1.4 Prior and Concomitant Medication Use........................................... 37
7.2
EFFICACY ASSESSMENTS .............................................................................. 37
7.3
SAFETY ASSESSMENTS ................................................................................. 38
7.3.1 Assessments for Safety Evaluations ............................................... 38
7.3.2 Adverse Events................................................................................ 38
7.3.3 Serious Adverse Events .................................................................. 41
7.3.4 SAE Reporting Timelines ................................................................ 42
7.3.5 Laboratory Tests.............................................................................. 42
7.3.6 Vital Signs ........................................................................................ 43
7.3.7 Physical Examination including Height and Body Weight............... 43
7.3.8 Other Relevant Safety Information .................................................. 43
7.4
OTHER ASSESSMENTS .................................................................................. 44
7.5
APPROPRIATENESS OF MEASUREMENTS........................................................ 44
8
DATA HANDLING AND RECORD KEEPING ...................................................... 46
8.1
DOCUMENTATION OF DATA............................................................................ 46
8.1.1 Source Data and Records ............................................................... 46 
8.1.2 Electronic Case Report Forms ........................................................ 46 
8.1.3 Changes to Electronic Case Report Form Data .............................. 46 
8.2
INFORMATION TO INVESTIGATORS .................................................................. 47
8.3
RESPONSIBILITIES ......................................................................................... 47
8.4
INVESTIGATOR’S SITE FILE ............................................................................ 47
8.5
PROVISION OF ADDITIONAL INFORMATION ...................................................... 48
8.6
INDEPENDENT DATA MONITORING COMMITTEE .............................................. 48
9 
STATISTICAL METHODS AND SAMPLE SIZE ................................................... 49
9.1
DETERMINATION OF SAMPLE SIZE.................................................................. 49
9.2
STATISTICAL ANALYSIS .................................................................................. 49
9.2.1 Populations for Analysis .................................................................. 50 
9.2.2 Efficacy Analysis Plan ...................................................................... 50 
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9.2.3 Safety Analysis Plan ........................................................................ 51 
9.2.4 Handling of Missing Data ................................................................. 52 
9.3 
RANDOMIZATION, STRATIFICATION, AND CODE RELEASE ............................... 52
9.4 
INTERIM ANALYSIS ......................................................................................... 52
10 
ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ............ 53
10.1 ETHICAL/REGULATORY FRAMEWORK ............................................................. 53
10.2 APPROVAL OF STUDY DOCUMENTS................................................................ 53
10.3 PATIENT INFORMATION AND INFORMED CONSENT .......................................... 53
10.4 PROTOCOL AMENDMENTS ............................................................................. 54
10.5 CONFIDENTIALITY OF PATIENT DATA .............................................................. 54
11
QUALITY CONTROL AND QUALITY ASSURANCE........................................... 55
11.1 PERIODIC MONITORING ................................................................................. 55
11.2 AUDIT AND INSPECTION ................................................................................. 55
12
REPORTING AND PUBLICATION ....................................................................... 56
12.1 CLINICAL STUDY REPORT.............................................................................. 56
12.2 PUBLICATION POLICY..................................................................................... 56
13
LIABILITIES AND INSURANCE ........................................................................... 57
14
REFERENCES ....................................................................................................... 58
15
APPENDICES ........................................................................................................ 59
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TABLE OF TABLES 
Table 1:
Flow Chart of Assessments ............................................................... 10
Table 2:
Prohibited Medications....................................................................... 27
Table 3:
Qualitative and Quantitative Composition of PANZYGA .................. 29
Table 4:
Visit Windows Used in this Study ...................................................... 35
Table 5:
Laboratory Tests and Time Points..................................................... 42
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Page 16 of 59 
LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine Aminotransferase 
ASH 
American Society of Hematology 
AST 
Aspartate Aminotransferase 
CIDP 
Chronic Inflammatory Demyelinating Poly(radiculo)neuropathy 
CRO 
Contract Research Organisation 
DEHP 
Diethylhexylphthalate  
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOS 
End of Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
ifas 
4-letter meaningless suffix assigned by FDA at the end of newly 
approved biologics 
IgA 
immunoglobulin A 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITP 
Immune Thrombocytopenia 
ITT 
Intention-to-Treat 
IUD 
Intrauterine device 
IGIV 
Intravenous Immunoglobulin 
LDH 
lactase dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMN 
Multifocal Motor Neuropathy 
NAT 
Nucleic Acid Test 
PMR 
Post-Marketing Requirement 
PREA 
Pediatric Research Equity Act 
PP 
Per-Protocol 
PP1 
Per-Protocol Set 1 
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Abbreviation 
Description 
PP2 
Per-Protocol Set II 
PVC 
Polyvinyl Chloride 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
SLE 
systemic lupus erythematosus 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent Adverse Event 
TNBP 
tri-n-butyl phosphate 
TPO-RA 
Thrombopoietin Receptor Agonists 
ULN 
Upper Limit of Normal 
USC 
United States Code 
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1 
INTRODUCTION 
Since more than five decades immunoglobulins have been used to provide
antibodies for the prevention of viral and bacterial diseases (replacement
therapy) in immunocompromised patients. Within the last 25 years intravenous
immunoglobulin (IGIV) has been proven to be useful in a wide variety of clinical
conditions other than replacement therapy of immunocompromised patients, in
which IGIV exhibits an immunomodulatory effect. These include Idiopathic
Thrombocytopenic (ITP) in children and adults at high risk of bleeding or prior to
surgery to correct the platelet count, Kawasaki disease, and Guillain-Barré
syndrome (GBS). More recently, single IGIV brands have also been licensed for 
Multifocal Motor Neuropathy (MMN) and Chronic Inflammatory Demyelinating
Poly(radiculo)neuropathy (CIDP). Experimental off-label use of IGIV mostly in
other neurological and dermatological indications is widespread.
ITP is an immune-mediated (disorder characterized by increased platelet
destruction.
The
reason
for platelet
destruction
is the
development
of
autoantibodies to platelet-membrane antigens. These antibodies are particularly 
produced in the spleen which is also the major site of platelet destruction [1]. In
patients suffering from ITP, several studies have shown IGIV effective in
increasing platelet counts to prevent or control bleeding [2-4] The mechanism of
action in ITP is not fully elucidated but includes immunomodulatory effects,
particularly the modulation of cytokines, soluble cytokine receptors and cytokine
receptor antagonists with anti-inflammatory effects as well as complement
modulation.
Broadly, 2 categories of agents are available for the treatment of ITP: 1) those
that rapidly and transiently interfere with the process of platelet destruction for
management of acute bleeding or bleeding risk (front-line therapies), and
2) those with potential to provide a more durable improvement in the platelet
count (second-line therapies). Corticosteroids, IGIV, and anti-D immune globulin
remain the mainstay of front-line treatment of acute bleeding symptoms in both
adults and children [5]. Although corticosteroids remain the most commonly used
ITP therapy, controversy still exists surrounding selection of agent, dosing, and
duration of therapy. For treatment with prednisone, it is generally accepted that
shorter courses are preferable to chronic therapy. The 2010 International
Consensus Report on the investigation and management of primary ITP
developed by an international working group address three classes of second-
line therapies: splenectomy, rituximab, and the thrombopoietin receptor agonists 
(TPO-RA). Due to a relative lack of data, their use was recommended only in
patients who were refractory to splenectomy and other therapies. Further study 
results in 2016 demonstrated that TPO-RA agents are being used in children with
ITP of varying duration and severity. The response was similar to clinical trials,
but the sustainability of response varied. Future studies need to focus on the ideal
timing and rationale for these medications in pediatric patients [6].
PANZYGA is a human immunoglobulin solution with 10% protein content for 
intravenous administration. PANZYGA is made from a pool of at least 
1000 donations of human fresh-frozen plasma per batch.  
PANZYGA was granted a US approval by the US Food and Drug Administration 
(FDA) in August 2018. The license in 2 indications (primary humoral 
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Page 19 of 59 
immunodeficiency diseases and chronic immune thrombocytopenia) was granted 
based on 2 completed studies. The first study in Primary Immune Deficiency 
included 51 children and adults from ages 2 years to 65 years who were dosed 
at 200 mg/kg to 800 mg/kg body weight every 3 to 4 weeks for 360 days. The 
second study in Immune Thrombocytopenia included 40 adults with chronic ITP 
receiving 2 gm/kg body weight over 2 consecutive days. Of the 36 subjects in the 
full analysis set, 29 patients (81%: 95% CI: 64% to 92%) responded to PANZYGA 
with a rise in platelet count to at least 50x109/L within 7 days after the first 
infusion. 
Further information can be found in the Investigator’s Brochure (IB). 
1.1 Rationale for Conducting the Study 
Under the Pediatric Research Equity Act (PREA) (21 United States Code [USC]
355c) all applications for new active ingredients, new indications, new dosage
forms, new dosing regimens or new routes of administration are required to
contain an assessment of the safety and effectiveness of the product for the
claimed indication in pediatric patients unless this required is waived, deferred or
inapplicable.
This post-marketing requirement (PMR) study was requested by the US FDA 
after PANZYGA received marketing approval in the United States. The rationale
for conducting this PMR study is to investigate the efficacy and safety of
PANZYGA in children suffering from primary ITP.
The study will be conducted in compliance with the protocol, International
Conference on Harmonisation-Good Clinical Practice (ICH-GCP), US FDA Code
of Federal Regulations, and other local regulatory requirements.
1.2 Dose Rationale 
According to recent guidelines, IGIV is recommended for patients with platelet
counts <30x109/L in case of severe bleeding and/or mucous membrane bleeding.
Standard doses should be studied (0.8 g/kg to1 g/kg on Day 1, which may be
repeated once within 3 days, or 0.4 g/kg/day for 2 to 5 days). If other dosage
regimens are to be applied for, they should be supported by clinical data. [7,8].
The dose option for this study is within the recommended guidelines.
1.3
Benefit-Risk Statement
The safety profile of IGIV is well characterized and, in general, the same type of
adverse reactions may be expected for PANZYGA. No new or unknown safety
problems are expected to emerge which are not already described in the
Investigator's Brochure.
Data obtained from the clinical trials conducted with PANZYGA in the adult ITP 
population clearly met the recommended clinical response criteria for efficacy as 
set out in the relevant FDA and EU guidelines. These data are comparable with 
available literature data on other commercial IVIGs and formed the basis for 
marketing authorization in Europe and the US. The safety profile of PANZYGA is 
satisfactory and the number of infusional AEs are below the levels as 
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recommended by the FDA for products of this class. Efficacy and safety data with 
PANZYGA in 3 clinical studies in 51 patients (also including pediatric patients) 
with primary immunodeficiency (PID) and in 40 patients with immune 
thrombocytopenia (ITP) are available. Available data are sufficient to expect 
favorable benefit-risk profile of PANZYGA in the pediatric ITP population. 
Expected clinical benefit of using PANZYGA in this study is an increase in 
platelets level to control or prevent bleeding. The main known risks are listed 
below: 
•
Thrombosis may occur with immune globulin intravenous (IGIV) products,
including PANZYGA. Risk factors may include: advanced age, prolonged
immobilization, hypercoagulable conditions, history of venous or arterial
thrombosis,
use
of
estrogens,
indwelling
vascular 
catheters,
hyperviscosity, and cardiovascular risk factors.
•
Renal dysfunction, acute renal failure, osmotic nephropathy, and death
may occur with the administration of IGIV products in predisposed
patients. Renal dysfunction and acute renal failure occur more commonly
in patients receiving IGIV products containing sucrose. PANZYGA does 
not contain sucrose.
•
For patients at risk of thrombosis, renal dysfunction, or renal failure,
administer PANZYGA at the minimum infusion rate practicable. Ensure
adequate hydration in patients before administration. Monitor for signs and
symptoms of thrombosis and assess blood viscosity in patients at risk for 
hyperviscosity.
•
Standard measures are taken to prevent infections resulting from the use
of medicinal products prepared from human blood or plasma. Despite this,
when medicinal products prepared from human blood or plasma are
administered, the possibility of transmitting infective agents cannot be
totally excluded. During the manufacturing process of PANZYGA,
significant viral reduction is obtained.
Inclusion and exclusion criteria, recommendations on the rate of infusion,
dosage, and monitoring procedures provided in this protocol sufficiently mitigate
above mentioned risks and must be adhered to.
No new or unknown safety problems are expected to emerge in pediatric ITP
population, which are not listed above or described in the Investigator's Brochure.
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2 
STUDY OBJECTIVES 
2.1 Primary Objectives 
The primary objective is to evaluate the efficacy of PANZYGA in increasing the 
platelet count in pediatric patients with chronic ITP. 
2.2 Secondary Objectives 
The secondary objectives of this study are to: 
•
Assess safety of up to 2 g/kg PANZYGA (1 g/kg PANZYGA on Day 1 and
an optional dose of 1 g/kg PANZYGA on Day 3) infused in the pediatric 
population within the scope of the clinical study
•
Determine the time to reach a platelet count of 50x109/L
•
Determine duration of time during which the platelet count is maintained
at the level ≥50х109/L
•
Determine the maximum platelet count during the study
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3 
INVESTIGATIONAL PLAN 
3.1 Primary and Secondary Endpoints 
3.1.1 Primary Endpoint 
The primary efficacy parameter is defined as an increase in platelet count at least 
once to ≥50x109/L within 7 days after the first infusion, ie, by Day 8 (increase 
must occur at least once on any day up to and including Day 8). This definition of 
clinical response will serve as the basis for the primary endpoint, the response 
rate (ie, the proportion of patients with an elevation of platelet count at least once 
to 50x109/L within 7 days [ie, Day 8] after the first infusion). 
3.1.2 Secondary Endpoints 
Secondary endpoints are defined to further evaluate the efficacy and safety of
the PANZYGA infused in the pediatric population.
The following parameters will be used to for efficacy assessments:
•
Time to reach a platelet count of 50x109/L
•
Duration of platelet response defined as the number of days the platelet
count remains above 50x109/L
•
Maximum platelet count during the study
The following parameters will be used for safety assessments:
•
AEs
•
Vital signs (blood pressure, heart rate, temperature, respiratory rate)
•
Physical examination
•
Laboratory parameters: hematology (including reticulocytes), hemolysis,
platelet count, serum chemistry (including lactase dehydrogenase [LDH]).
3.2
Overall Study Design and Plan
This is a prospective, open-label, single-arm, multicenter, Phase 4 study 
evaluating the efficacy and safety of the investigational product, PANZYGA, in
pediatric patients with chronic ITP.
The study will enroll at least 20 patients 1 year to <18 years old and will not be
stratified by age group. A patient is considered enrolled into the study after 
successfully completing all baseline assessments and receiving at least a partial
dose of PANZYGA.
Patients with a confirmed diagnosis of chronic ITP, without evidence of active 
major bleeding, may be enrolled in the study. Study procedures will only begin 
after written informed consent (from parent or guardian) and assent (from the 
patient, as age appropriate per Institutional Review Board [IRB] requirements) 
have been obtained. Patients who meet all of the inclusion and none of the 
exclusion criteria may receive the first infusion of PANZYGA within 2 days after 
Baseline investigations have been completed. 
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Each patient will be administered PANZYGA by intravenous infusion at a dose of
1 g/kg body weight PANZYGA on Day 1 and optionally another dose of 1 g/kg
PANZYGA on Day 3; body-weight dependent doses will be based on each
patient’s weight collected at Baseline. Total PANZYGA doses will be 1 g/kg for
patients receiving only 1 dose on Day 1 and 2g/kg for those receiving the optional
Day 3 dose. Prior to the Day 3 infusion, Investigators will assess each patient’s 
preinfusion platelet count, hematocrit, and hemoglobin. Patients whose platelet
count shows evidence of response as indicated by the platelet count at least
doubling from Baseline count AND is >50x109/L, the Day 3 infusion will not be
administered. If the Baseline platelet count has doubled but is ≤50x109/L, the
Day 3 infusion will be administered. If any parameters indicate a clinically relevant
change such that, in the Investigator’s opinion, it is not safe to administer the
second infusion, the patient should be withdrawn from study treatment; however,
the patient will be followed for safety through Day 32.
Study interventions and procedures will be performed at predefined timepoints
(see Section 6.1 and the Flow Chart of Assessments [Table 1]) including (but are
not limited to): blood draws for safety evaluations, vital signs, body weight,
physical examinations, AE monitoring, and changes in concomitant medication
use. Patients will have clinic visits on Days 1, 3, 5, 8, 15, and 22. They will return
to the clinic for a final safety follow-up evaluation at Day 32/End of Study (EOS)
Visit.
PANZYGA infusions may be stopped or interrupted at any time if, in the
Investigator’s opinion, it is not safe to continue or is not in the patient’s best
interest. Patients who have received a partial dose of PANZYGA should be
followed for safety evaluations through Day 32/EOS.
The study is planned to begin screening procedures Q2/Q3 2019 at up to 8 sites 
in the USA, with recruitment lasting approximately 30 months, and is anticipated
to complete in Q1 2022. The study duration for a single patient will be
approximately 39 days, including up to a 1-week Screening period.
3.3
Discussion of Study Design and Choice of Control Group(s)
3.3.1 Study Design
This study was designed to meet the US FDA’s requirements under the PREA
(21 USC 355c) for a post-approval study of PANZYGA in the pediatric population.
US FDA is requiring a pediatric study for the treatment of ITP to evaluate
PANZYGA for the treatment of ITP in patients ages ≥1 year to <18 years. All of
the US FDA’s recommendations have been incorporated into the protocol.
This study design is also in line with study protocols evaluating NGAM in adults, 
with the frequency of blood draws and number of visits reduced to accommodate 
a pediatric population. Because of the limited number of patients that will be 
enrolled in this study, along with the increased blood volume and additional site 
visits that would be required to meet the full recommendations in the European 
Medicines Agency (EMA) Guideline for confirmatory visits and blood draws, the 
secondary efficacy endpoints were selected to allow efficacy evaluations in this 
patient population. 
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3.3.2 Control Group(s) 
A placebo control group will not be included in this post-approval study. An active 
control group is not considered relevant, as the objective of this study is to 
evaluate the efficacy and safety of PANZYGA in the pediatric population, not to 
compare the efficacy and safety of PANZYGA versus another IGIV treatment. 
3.3.3 Study Parameters 
The primary therapeutic target for ITP treatment is an increase in the platelet
count. Therefore, the primary endpoint chosen for the study, namely the response
rate (ie, the proportion of patients with an increase in platelets at least once to
≥50x109/L within 7 days after the first infusion), is appropriate to adequately
describe the efficacy of treatment of PANZYGA in the pediatric population.
To assess the efficacy of PANZYGA in correcting the platelet count, this response
rate has been chosen as the primary endpoint. There are several definitions of
response published in guidelines and commonly used for the evaluation of ITP
treatment; however, an increase in platelets to ≥50x109/L is the most established
definition of response [7] and as such has been chosen for this post-marketing
approval study.
The secondary efficacy endpoints chosen are in accordance with the primary
endpoint, in order to further characterize the effect on the increase in platelet
count.
The safety assessments, including AE, vital signs, laboratory results, and
physical examination are appropriate and commonly used parameters to monitor
the of IGIV treatment during a clinical study.
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4 
STUDY POPULATION 
4.1 Population Base 
At least 20 female or male patients 1 year to <18 years old with chronic ITP will 
be eligible for this study.  
4.1.1 Inclusion Criteria 
Patients who meet all of the following criteria are eligible for the study: 
1. Females and males aged from 1 year to <18 years old
2. Confirmed diagnosis of Chronic Immune Thrombocytopenia (ITP) 
according to American Society of Hematology (ASH 2011) guidelines
3. Platelets count <30x109/L at the Baseline Visit
4. Voluntarily given written informed consent (provided by patient’s 
parent or legal guardian) and assent (provided by patient)
5. Females of childbearing potential have been using at least
1 acceptable form of birth control for a minimum of 30 days (or a
minimum of 3 months for hormonal contraceptives) prior to the
Screening visit, and must agree to use at least 1 acceptable method
of contraception for 30 days after the last dose of PANZYGA.
Acceptable methods include: intrauterine device (IUD), hormonal
contraception, male or female condom, spermicide gel, diaphragm,
sponge, or cervical cap. Abstinence is not considered an acceptable
method of birth control.
6. Parent or legal guardian must agree and be willing to assist the
participant attend study visits, and to follow all protocol requirements 
and instructions of the study doctor
4.1.2 Exclusion Criteria
Patients who meet any of the following criteria are not eligible for the study:
1. Thrombocytopenia secondary to other diseases (such as Acquired
Immunodeficiency Syndrome [AIDS] or systemic lupus 
erythematosus [SLE]), drug-related thrombocytopenia, or congenital
thrombocytopenia
2. Administration of intravenous immunoglobulin (IGIV) or anti-D
immunoglobulin within 3 weeks before enrollment
3. Administration of thrombopoietin receptor agonists when the dose
has NOT been stable within 3 weeks before enrollment and a dosage
change is planned before Day 32
4. Administration of oral immunosuppressants when the dose has NOT
been stable during the preceding 2 months (2 weeks for long-term
corticosteroid therapy) and a dosage change is planned before
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Day 32 (Note: topical agents and inhaled corticosteroid therapy use is 
permitted) 
5. Administration of long-term anti-prolific agents or attenuated
androgen therapy when the dose has NOT been stable during the
preceding 2 months and a dosage change is planned before Day 32
6. Nonresponsive to previous treatment with IGIV or anti-D
immunoglobulin
7. Evidence of an active major bleeding episode at Screening
8. Splenectomy in the previous 4 weeks or planned splenectomy
throughout the study period
9. Evans syndrome (experiencing active disease with 2 out of 3 of the
following: autoimmune thrombocytopenia, autoimmune hemolytic 
anemia, and/or autoimmune neutropenia)
10.Known or suspected human immunodeficiency virus (HIV),
hepatitis B virus (HBV), and/or hepatitis C virus (HCV) infections
11. Emergency surgery in the previous 4 weeks
12.Severe liver and/or kidney disease (alanine aminotransferase [ALT]
>3x upper limit of normal (ULN), aspartate aminotransferase [AST]
>3x upper limit of normal (ULN), and/or creatinine >120 µmol/L)
13.History of severe hypersensitivity to blood or plasma derived
products, or any component of the PANZYGA
14.Known immunoglobulin A (IgA) deficiency and antibodies against IgA
15.History of, or suspected, alcohol or drug abuse in the previous year
16.Females who are pregnant or nursing
17.Unable or unwilling to comply with the study protocol
18.Receipt of any other investigational medicinal product within
3 months before study entry
19.Risk factors* for thromboembolic events in whom the risks outweigh
the potential benefit of PANZYGA treatment.
20.Any other condition(s), that in the Investigator’s opinion, make it
undesirable for the patient to participate in the study or may interfere
with protocol compliance.
* Risk factors include, but are not limited to: obesity, advanced age, hypertension,
diabetes, a history of atherosclerosis/vascular disease or thrombotic events,
hyperlipidemia, multiple cardiovascular risk factors, acquired or inherited
thrombophilic
disorders,
prolonged
periods 
of
immobilization,
severe
hypovolemia, central venous catheterization, active malignancy and/or known or 
suspected hyperviscosity.
4.2 Prior and Concomitant Therapy 
Details on medications taken within the previous 3 months prior to the Baseline 
Visit and any concomitant medications taken during the study must be recorded 
in the electronic case report form (eCRF). 
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4.2.1 Allowed Pre-medications 
Use of H-1 blockers or antipyretics are allowed for patients who have history of 
hypersensitivity to IGIV treatment; this may minimize the severity of possible 
infusion-related reactions in patients already predisposed to hypersensitivity 
reactions. All pre-medications administered prior to PANZYGA administration 
must be recorded in the eCRF.  
4.2.2 Prohibited Medications 
Use of the following medications are forbidden during the study as specified 
below (Table 2): 
Table 2: 
Prohibited Medications 
Medication 
Time Window  
IGIV 
prohibited for 3 weeks prior to Baseline Visit 
through Day 32 
anti-D immunoglobulin 
prohibited for 3 weeks prior to Baseline Visit 
through Day 32 
oral immunosuppressants  
prohibited during Screening Period through 
Day 32 unless patients have been receiving 
a stable dose for 2 months (2 weeks for long-
term corticosteroid therapies) prior to 
Screening Visit 
thrombopoietin receptor agonists 
prohibited during Screening Period through 
Day 32 unless patients have been receiving 
stable dose for 3 weeks prior to Screening 
Visit 
long-term anti-prolific agents or 
attenuated androgen therapy 
prohibited during Screening Period through 
Day 32 unless patients have been on a 
stable dose for 2 months prior to Screening 
Visit 
any other blood or plasma-derived 
product* 
prohibited during Screening Period through 
Day 32  
receipt of any other investigational 
product 
prohibited within 3 months prior to Baseline 
Visit through Day 32 
* Patients who are non-responders or requiring emergent ITP treatment (other than PANZYGA specified in this protocol) 
will be followed for safety and complete all assessments through Day 32.  
Trade names of drugs corresponding to the categories provided in Table 2 will 
be provided in a Study Manual.  
4.3 Withdrawal and Replacement of Patients 
4.3.1 Premature Patient Withdrawal 
Patients have the right to withdraw from the study at any time for any reason, 
without the need to justify their decision; parents or legal guardians also have the 
right to withdraw a patient on the patient’s behalf. The Investigator also has the 
right to withdraw patients in case of AEs, poor compliance, or other reasons. 
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Because an excessive rate of withdrawals can render the study noninterpretable, 
any unnecessary withdrawal of patients should be avoided. 
For any withdrawals after study entry, the Investigator will obtain all the required 
details and document the reason(s) for discontinuation. If the reason for 
withdrawal of a patient is an AE, the main specific event or laboratory test will be 
recorded, and the Investigator will make thorough efforts to clearly document the 
outcome. Patients should return to the study site and have all safety evaluations, 
including safety laboratory tests, completed as specified at the Day 32 visit 
(See Section 6.1.6).  
4.3.2 Patient Replacement Policy 
Patients withdrawn from the study will not be replaced. Under no circumstances
will patients who enroll in the study be permitted to re-enroll after study
completion. Patients who fail during the Screening Period (also referred to as 
Screen Failures) may be re-screened upon written approval from the Sponsor.
4.4
Assignment of Patients to Treatment Groups
This is an open-label non-randomized study. All patients will receive PANZYGA.
4.5 Relevant Protocol Deviations 
In case of any major protocol deviation, the Investigator and Octapharma will
decide on the further participation of the patient in this study after having
discussed all relevant aspects.
A list of all included patients with all deviations from the intended study 
procedures and other criteria that may affect the patient's data validity for 
statistical analysis will be prepared upon clinical completion of the study. This will
also be discussed by a panel consisting of the clinical study manager, a medical
expert of the Sponsor, the data manager and the study statistician. This panel
will decide upon the membership of the patient in the Full Analysis Set (FAS), Per 
Protocol (PP) Set 1 (PP2), PP Set 2 (PP2), and Safety Analysis Set for statistical
analysis.
4.6
Subsequent Therapy
If a patient withdraws from the study or is withdrawn by the Investigator by their
parent/legal guardian, he/she will receive treatment by the Investigator or 
personal physician according to institutional standard of care.
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5 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1 Characterization of Investigational Product 
Name of Medicinal Product: 
 
PANZYGA 
Active ingredient of PANZYGA: Immune globulin human-ifas 
Table 3: 
Qualitative and Quantitative Composition of PANZYGA 
Name of Ingredient 
Amount 
Total protein 
9.0 – 11.0 g/100 mL 
Protein composition 
≥95% Ig (≥96% Ig)* 
IgG content 
86 – 110 mg/mL 
Glycine 
15.0 – 19.5 mg/mL (17.3 mg/mL)* 
Water for Injection 
ad 1mL 
*Depending on regulatory requirements
PANZYGA is a solvent/detergent (S/D)-treated, sterile preparation of highly 
purified immunoglobulin G (IgG) derived from large pools of human plasma.
PANZYGA is a solution for infusion to be administered intravenously.
This preparation contains approximately 100 mg of protein per mL (10%), of
which not less than 96% is normal human immunoglobulin G. PANZYGA contains 
not more than 3% aggregates, not less than 90% monomers and dimers, and not
more than 3% fragments. On average, the product contains 100 μg/mL of IgA,
and lower amounts of IgM.
PANZYGA contains only trace amounts of sodium, and the pH is between 4.5
and 5.0. The osmolality is in the range of 240 to 310 mosmol/kg.
The manufacturing process for PANZYGA isolates IgG without additional
chemical or enzymatic modification, and the Fc portion is maintained intact.
PANZYGA contains the IgG antibody activities present in the donor population.
IgG subclasses are fully represented with the following approximate percentages
of total IgG: IgG1 is 65%, IgG2 is 28%, IgG3 is 3% and IgG4 is 4%.
PANZYGA contains a broad spectrum of IgG antibodies against bacterial and
viral agents that are capable of opsonization and neutralization of microbes and
toxins. PANZYGA contains glycine (15.0 to 19.5 mg/mL), but no preservatives or
sucrose.
All units of human plasma used in the manufacture of PANZYGA are provided by
FDA-approved blood and plasma establishments, and are tested by FDA-
licensed serological tests for HBsAg, antibodies to HCV and HIV and Nucleic Acid
Test (NAT) for HCV and HIV-1 and found to be non-reactive (negative).
5.2 Packaging and Labelling 
PANZYGA for investigational use only will be labeled according to US FDA 
regulations. Details of the labeling will be included in the Pharmacy Manual. 
The batch number(s) used will be recorded in the study documentation and EDC. 
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5.3 Conditions for Storage and Use 
PANZYGA must be stored and transported light-protected at +2°C (36°F) to +8°C 
(46°F) and must be brought to room temperature before use.  
Storage temperature must be maintained at +2°C (36°F) to +8°C (46°F) and will 
be monitored for the duration of the study by reviewing the temperature logs. 
PANZYGA must not be frozen prior to use. 
PANZYGA must not be used after its expiry date.  
PANZYGA must not be mixed with other medicinal products. 
Each PANZYGA bottle is for single use only. 
Authorized personnel at the individual study sites will ensure that PANZYGA is 
stored in appropriate conditions in a secure refrigerator with restricted access and
in compliance with national regulations.
5.4 Dose and Dosing Schedule 
PANZYGA will be administered by intravenous infusion. Patients should be
adequately hydrated prior to infusion.
Patients will receive a dose of 1 g/kg body weight PANZYGA given on Day 1 and
optionally another dose of 1 g/kg PANZYGA given on Day 3; body-weight
dependent doses will be based on each patient’s weight collected at Baseline. 
Total PANZYGA doses will be 1 g/kg for patients receiving only 1 dose on Day 1 
and 2 g/kg for those receiving the optional Day 3 dose. If the Day 3 platelet count
shows evidence of response as indicated by the platelet count at least doubling
from Baseline count AND is >50x109/L, the Day 3 infusion will not be
administered. If the Baseline platelet count has doubled but is ≤50x109/L, the
Day 3 infusion will be administered. 
PANZYGA
will
be
delivered
by intravenous infusion
according
to
the
recommended flow rates:
•
Initial infusion rate of 0.01 mL/kg/min (60 mg/kg/hr) for the first 30 minutes
•
If tolerated, increase to 0.02 mL/kg/min (120 mg/kg/hr) for the second
30 minutes
•
If tolerated, increase to 0.04 mL/kg/min (240 mg/kg/hr) for the third
30 minutes
•
If tolerated, increase to 0.08 mL/kg/min (480 mg/kg/hr) for the remainder
of the infusion.
Infusion rates should not exceed 0.08 mL/kg/min and should not exceed 
8.0 mL/min.  
If a Grade 2 (moderate) or higher infusion-related adverse event (AE) occurs 
during infusion, the Panzyga infusion will be stopped. After infusion-related 
symptoms subside, the infusion may be resumed at a lower rate. The infusion 
rate may be gradually increased as tolerated by the patient. 
If a Grade 1 (mild) infusion-related AE occurs during infusion, the infusion rate 
should be reduced to half the rate at which the event occurred, or the infusion 
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should be interrupted until symptoms subside. The infusion may then be resumed 
at an infusion rate tolerated by the patient. The infusion rate may be gradually 
increased as tolerated by the patient.  
5.5 Preparation and Method of Administration 
All patients will be infused at the study site under the surveillance of authorized 
study site staff.  
After calculating the volume required for the dose using the patient’s Baseline
body weight (see Section 5.4), the appropriate number of vials will be removed
from the refrigerator. Vials of different sizes may be combined to reach the
required amount of IgG. The exact dose will be administered, and the empty and
partially used vials will be retained by the site for drug accountability and dose
verification.
PANZYGA vials must be allowed to warm to room or body temperature before
infusion. After PANZYGA vials have been brought to room or body temperature,
they should be inspected visually for particulate matter and discoloration prior to
administration. The solution should be clear or slightly opalescent. DO NOT USE
IF
TURBID,
DISCOLORATION
IS 
OBSERVED,
AND/OR
FLOATING
PARTICLES ARE PRESENT. Solutions that are cloudy or vials that have a
deposit must not be used and must be discarded according to local policy.
Aseptic technique must be used throughout the entire procedure.
The contents of bottles must be pooled under aseptic conditions into sterile
infusion bags and administered immediately after pooling. Only polyvinyl chloride
(PVC)-free, diethylhexylphthalate (DEHP)-free and latex–free, infusion bags can
be used. Once pooled, a label will be applied on the infusion bag. Detailed
instructions of this process and an example label will be included in the Pharmacy 
Manual.
PANZYGA will be infused into a vein using standard infusion supplies provided
by the individual site. Standard procedures should be followed to prime the
infusion line with a priming solution (eg, normal saline). At the end of each
infusion, the infusion line will be flushed with normal saline solution.
Additional information regarding PANZYGA preparation and infusion procedures
will be provided in a pharmacy manual.
Please refer to special warnings and precautions for use provided in the
PANZYGA Investigator Brochure.
5.6 Blinding, Emergency Envelopes, and Breaking the Study Blind 
Not applicable. 
5.7 Treatment Compliance 
5.7.1 Drug Dispensing and Accountability 
The Sponsor or designee will provide and deliver all PANZYGA to participating 
Investigators. A Drug Inventory and Dispensing Log will be kept current by the 
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Investigator, detailing the dates and quantities of PANZYGA received, dispensed 
to each patient, and the quantity remaining at the study site.  
The Drug Inventory and Dispensing Log will be available to the monitor to verify 
drug accountability during the study. The study monitor will inventory all empty 
and partially used vials of PANZYGA and will cross-check this inventory versus 
the patient source documentation (records), eCRF, and the Drug Inventory and 
Dispensing Log. 
Unused and partially used vials may be destroyed at the study site or returned to
the Sponsor for destruction according to institutional practice. Vials may be
destroyed only after drug accountability has been verified and fully reconciled by
the monitor and after the Sponsor has granted written approval of destruction.
Additional information regarding PANZYGA drug accountability procedures will
be provided in a pharmacy manual.
5.7.2 Assessment of Treatment Compliance 
All patients will be infused at the study site under the surveillance of authorized
study personnel. Infusion details will be documented together with the batch
number(s) in the source data and eCRF.
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6 
STUDY CONDUCT 
Procedures performed at each study visit are presented in the Flow Chart of 
Assessments (see Table 1). Time windows and tolerances are provided in Table 
4. 
6.1 Observations by Visit 
6.1.1 Baseline Visit/Screening Period 
The following assessments will be performed during the Screening Period. The
Screening Period can last up to 1 week (to accommodate patient schedules and
the informed consent/assent process); however, all Baseline evaluations should
be completed within 2 days before the first administration of PANZYGA.
•
Obtaining voluntarily given, written (signed and dated) informed consent
and assent (as age appropriate)
•
Inclusion and exclusion criteria
•
Demographic and baseline characteristics
•
Medical and surgical history (previous 1 year)
•
Splenectomy history
•
Physical examination
•
Vital signs
•
Body weight
•
Blood samples for serum chemistry, hematology, and hemolysis analytes
•
Blood or urine pregnancy test (females of childbearing potential, only)
•
Blood samples for viral markers
•
Documentation of prior medications (previous 3 months), including
administration of pre-medication(s) as appropriate (see Section 4.2.1)
6.1.2 Day 1 
Day 1 should take place within 2 days after Baseline evaluations have been
completed. If the Baseline and Day 1 Visits occur on the same day, the Baseline
investigations do not need to be repeated. If the Baseline evaluations are
completed more than 2 days before Day 1, the platelet count must be repeated
and evaluated by the Investigator prior to initiating the first infusion.
Before the administration/infusion of PANZYGA, patient eligibility will be re-
evaluated. The following assessments/activities will be performed before
PANZYGA infusion:
•
Confirmation of inclusion and exclusion criteria
•
Physical examination
•
Vital signs
•
Blood samples for serum chemistry, hematology, and hemolysis analytes
•
Administration of pre-medication(s) as appropriate (see Section 4.2.1)
The following activities will be performed during or after PANZYGA infusion: 
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•
PANZYGA infusion
•
Vital signs (at the start of the infusion and every 60 minutes (±15 minutes)
thereafter until the end of the infusion. In addition, vital sign measurements
will be recorded just prior to every infusion rate change (-10 minutes),
15 minutes (+15 minutes) after each infusion rate change, and
approximately 30 minutes after the end of the infusion)
•
Monitoring for AEs
•
Documentation of concomitant medication use
6.1.3 Day 3 
The following assessments/activities will be performed before PANZYGA 
infusion:
•
Physical examination
•
Vital signs
•
Blood samples for serum chemistry, hematology, and hemolysis analytes
•
NOTE: platelet, hemoglobin and hematocrit results must be available and
reviewed by the Investigator prior to initiating the Day 3 infusion
•
Administration of pre-medication(s) as appropriate (see Section 4.2.1)
The Investigator will assess each patient’s Day 3 preinfusion platelet count,
hematocrit, and hemoglobin. If the Day 3 platelet count shows evidence of clinical
response, as indicated by the platelet count at least doubling from Baseline count
AND is >50x109/L, the Day 3 infusion will not be administered. If the Baseline
platelet count has doubled but is ≤50x109/L, the Day 3 infusion will be
administered. In the event that the Day 3 infusion is not administered, all other
Day 3 assessments will still be completed. If any of these hematology parameters
indicate a clinically relevant change such that, in the Investigator’s opinion, it is
not safe to administer the second infusion the patient should be withdrawn from 
study treatment but will be followed for safety through Day 32.
The following activities will be performed during or after PANZYGA infusion:
•
PANZYGA infusion
•
Vital signs (at the start of the infusion and every 60 minutes (±15 minutes) 
thereafter until the end of the infusion. In addition, vital sign measurements
will be recorded just prior to every infusion rate change (-10 minutes),
15 minutes (+15 minutes) after
each
infusion
rate
change,
and
approximately 30 minutes after the end of the infusion)
•
Monitoring for AEs
•
Documentation of concomitant medication use
6.1.4 Day 5 and Day 8 (± 1 day) 
The following assessments will be performed at Day 5 and Day 8: 
•
Physical examination
•
Blood samples for serum chemistry, hematology, and hemolysis analytes
•
Monitoring for AEs
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•
Documentation of concomitant medication use
6.1.5 Day 15 and Day 22 (± 3 days) 
The following assessments will be performed at Day 15 and Day 22: 
•
Physical examination
•
Blood samples for hematology and hemolysis analytes
•
Monitoring for AEs
•
Documentation of concomitant medication use
6.1.6 Day 32 (End of Study Visit) (± 5 days) 
Patients will return to the study site on Day 32 for final safety assessments/EOS
Visit. Patients who were withdrawn early from the study should return to the study
site for a final safety assessment. The following assessments will be performed:
•
Physical examination
•
Vital signs
•
Blood samples for serum chemistry, hematology, and hemolysis analytes
•
Documentation of concomitant medication use
After Day 32, the clinical study is considered completed for the patient. No further 
study-related
assessments will
be
performed,
unless safety
concerns
(eg, ongoing AEs) require follow-up.
6.1.7 Visit Windows Used in this Study, including Tolerances
In this study, the following time windows and tolerances apply (Table 4):
Table 4: 
Visit Windows Used in this Study
Time point 
Tolerance 
Screening Period 
7 days prior to Day 1 
Final Baseline Evaluations
-2 days before Day 1
Day 1 
none 
Day 3 
none 
Day 5
±1 day 
Day 8
±1 days 
Day 15 and Day 22 
±3 days 
Day 32
± 5 days 
6.2 Duration of Study 
6.2.1 Planned Duration for an Individual Patient 
The duration of the entire study for each patient will be approximately 39 days, 
including a 7-day Screening Period. 
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6.2.2 Planned Duration for the Study as a Whole 
The study will be considered completed when all patients have completed the 
Day 32 EOS Visit. 
The estimated start of the study (enrollment of first patient) is Q2/Q3 2019, and 
the estimated end of the study (last visit of last patient) is Q1 2022. 
6.2.3 Premature Termination of the Study 
Both the responsible Investigators and the Sponsor reserve the right to terminate
the study at any time. Should this be necessary, study close-out procedures will
be arranged on an individual site basis after review and consultation by both
parties. In terminating the study, the Sponsor and the Investigator will ensure that
adequate consideration is given to the protection of the patients' interests.
Furthermore, the Investigator should promptly inform the IRB and provide a
detailed written explanation. Pertinent regulatory authorities and IRBs will be
informed in accordance with applicable regulatory requirements.
6.2.3.1 Early Termination of the Entire Clinical Study
At any time, the study as a whole will be terminated prematurely if:
•
New toxicological or pharmacological findings or safety reports invalidate
the earlier positive benefit-risk-assessment for the pediatric population
•
Any other reason rendering the continuation of the study impossible for 
the Sponsor
6.2.3.2 Early Termination at an Individual Study Site
At any time, the study can be terminated at an individual study site if:
•
The site cannot comply with the requirements of the protocol
•
The site cannot comply with GCP or other regulatory standards
•
The site does not meet the required recruitment rate
Should the study be prematurely terminated, all study materials, including
PANZYGA, must be returned to the Sponsor.
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7 
ASSESSMENTS AND METHODS 
7.1 Demographic and Baseline Information 
Demographic and baseline information will be recorded during the Screening 
Period: 
7.1.1 Demographic and Baseline characteristics 
The demographic and baseline characteristics are sex, age, race and ethnic 
origin, height, and weight. 
7.1.2 Medical and Surgical history 
The medical history will be collected for the previous year and will be obtained by
interviewing the patient. Records of past diseases and treatments (eg, hospital
discharge letters) will be obtained for the study files, if available. The onset date
of ITP will be recorded.
Surgical history will include the date of splenectomy (if applicable) and any other 
surgical procedures in the previous year.
7.1.3 Viral Marker Tests 
At the Screening Visit, blood samples for viral markers (HIV, HCV, HBV NAT) will
be collected and tested at the local laboratory according to the site’s standard
procedures, to rule out secondary infections that may cause ITP. Infusions may 
begin before the results are back if the Investigator is not aware of, and the patient
isn’t exhibiting clinical signs of, any viral infection.
7.1.4 Prior and Concomitant Medication Use
Prior medication use will be obtained by interview and review of patient charts 
(if available). Patients will queried specifically for use of H-1 blockers or 
antipyretics as pre-medications prior to previous IGIV treatments. 
Concomitant medication use, defined as medications with a start date and time
after the start of the Day 1 infusion, will be collected throughout the study. The
start date and time of medication use will be collected on Day 1 and throughout
the study.
7.2
Efficacy Assessments
All efficacy assessments will be based on platelet counts performed throughout 
the study.  
Platelet counts will be performed at Baseline (within 2 days prior to the first 
PANZYGA infusion), at Day 1 and Day 3 prior to planned PANZYGA infusions, 
and then at all remaining study visits (Days 5, 8, 15, 22, and 32). 
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7.3 Safety Assessments 
7.3.1 Assessments for Safety Evaluations 
The following assessments will be performed to evaluate the safety of PANZYGA 
in the pediatric population: 
•
AEs and Serious Adverse Events (SAEs)
•
Clinical laboratory tests
•
Vital signs
•
Physical examinations
•
Pregnancies
7.3.2 Adverse Events 
7.3.2.1 Definitions 
•
Adverse event (AE): An AE is any untoward medical occurrence in a
study /patient receiving an investigational medicinal product (IMP) and
which does not necessarily have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including
an
abnormal
laboratory
finding),
symptom,
or disease
temporally
associated with the use of an IMP, whether or not related to the IMP.
•
Adverse drug reaction (ADR): An ADR is any noxious and unintended
response to an IMP related to any dose. The phrase ‘response to an IMP’
means that a causal relationship between the IMP and an AE carries at
least a reasonable possibility (ie, the relationship cannot be ruled out).
•
Other significant AEs: Any marked laboratory abnormalities or any AEs
that lead to an intervention, including withdrawal of drug treatment, dose
reduction, or significant additional concomitant therapy.
•
Treatment-emergent AE
(TEAE):
Any
AE
that
newly
appeared,
increased in frequency, or worsened in severity following the time of the
first IMP infusion until the end of the safety follow-up period.
•
Infusional AE: Any AE that occurs from the time of infusion and within the
72 hour period after end of infusion.
•
Withdrawal due to AE/ADR: AE/ADR leading to discontinuation of
treatment with IMP. Any such events will be followed up by the Investigator 
until the event is resolved or until the medical condition of the patient is
stable. All follow-up information collected will be made available to the
Sponsor.
7.3.2.2 Collection of AEs 
The condition of the patient will be monitored throughout the study. At each visit, 
whether scheduled or unscheduled, AEs will be elicited using a standard 
nonleading question such as “How have you been since the last visit/during the 
previous study period?” In addition, the Investigator will check the patient diaries 
(if applicable) for any documented event. 
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Any AE or ADR which occurs during the study will be noted in detail on the 
appropriate pages of the eCRF. If the patient reports several signs or symptoms 
representing a single syndrome or diagnosis, the diagnosis should be recorded 
in the eCRF. The Investigator will grade the severity of all AEs or ADRs (mild, 
moderate, or severe), the seriousness (non-serious or serious), and the causality 
as defined in Section 7.3.2.3, Section 7.3.3, and Section 7.3.2.4, respectively. 
The Sponsor is responsible for assessing the expectedness of each ADR 
(expected or unexpected) as defined in Section 7.3.2.5. 
In the event of clinically significant abnormal laboratory findings, the tests will be
confirmed and the patient followed up until the laboratory values have returned
to normal and/or an adequate explanation for the abnormality has become
available.
Diseases, signs and symptoms, and/or laboratory abnormalities already present
before the first administration of IMP will not be considered AEs unless an
exacerbation in intensity or frequency (worsening) occurs.
The Investigator will provide detailed information about any abnormalities and
about the nature of and reasons for any action taken as well as any other 
observations or comments that may be useful for the interpretation and
understanding of an AE or ADR.
7.3.2.3 Severity of AEs
The intensity/severity of AEs will be graded as follows:
•
Mild: an AE, usually transient, which causes discomfort but does not
interfere with the patient’s routine activities
•
Moderate: an AE which is sufficiently discomforting to interfere with the
patient’s routine activities
•
Severe: an AE which is incapacitating and prevents the pursuit of the
patient’s routine activities
The grading of an AE is up to the medical judgement of the Investigator and will
be decided on a case-by-case basis.
7.3.2.4 Causality of AEs
The relationship of AEs to the administered IMP will be assessed by the
Investigator:
•
Probable: reports including good reasons and sufficient documentation to
assume a causal relationship, in the sense of plausible, conceivable, likely,
but not necessarily highly probable. A reaction that follows a reasonable
temporal sequence from administration of the IMP; or that follows a known
or expected response pattern to the suspected medicine; or that is
confirmed by stopping or reducing the dosage of the medicine and that
could not reasonably be explained by known characteristics of the
patient’s clinical state.
•
Possible: reports containing sufficient information to accept the possibility
of a causal relationship, in the sense of not impossible and not unlikely,
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although the connection is uncertain or doubtful, for example because of 
missing data or insufficient evidence. A reaction that follows a reasonable 
temporal sequence from administration of the IMP; that follows a known 
or expected response pattern to the suspected medicine; but that could 
readily have been produced by a number of other factors. 
• Unlikely: reports not following a reasonable temporal sequence from IMP 
administration. An event which may have been produced by the patient’s 
clinical state or by environmental factors or other therapies administered. 
• Not related (unrelated): events for which sufficient information exists to 
conclude that the etiology is unrelated to the IMP. 
• Unclassified: reports which for one reason or another are not assessable. 
7.3.2.5 Classification of ADRs by Expectedness 
ADRs will be classified by the Sponsor as either expected or unexpected: 
• Expected: an ADR that is listed in the current edition of the Investigator’s 
Brochure or other reference safety information. 
• Unexpected: an ADR that is not listed in the current edition of the 
Investigator’s Brochure or other reference safety information, or that differs 
because of greater severity or greater specificity. 
7.3.2.6 Outcome of AEs 
The outcome of all reported AEs will be documented as follows: 
1. Recovered, resolved 
2. Recovering, resolving 
3. Not recovered, not resolved 
4. Recovered, resolved with sequelae 
5. Fatal 
6. Unknown 
NOTE: A patient’s death per se is not an event, but an outcome. The event which 
resulted in the patient’s death must be fully documented and reported, even in 
case the death occurs within 4 weeks after IMP treatment end and regardless of 
whether or not it is considered treatment-related. 
7.3.2.7 Action(s) taken 
AEs requiring action or therapy must be treated with recognized standards of 
medical care to protect the health and well-being of the patient. Appropriate 
resuscitation equipment and medicines must be available to ensure the best 
possible treatment in an emergency situation. 
The action taken by the Investigator must be documented: 
a) General actions taken in the event of an AE 
– None 
– Medication (other than IMP) or other (eg, physical) therapy started 
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–
Test performed
–
Other (to be specified)
b) IMP-related actions taken in the event of an AE
–
None
–
Product withdrawn
–
Dose reduced
–
Dose increased
The Investigator will follow up on each AE until it has resolved or until the medical
condition of the patient has stabilized. Any relevant follow-up information will be
reported to the Sponsor.
7.3.2.8 Managing Hypersensitivity Reactions 
Severe hypersensitivity reactions may occur during PANZYGA infusions [9]. In
the case of any subject exhibiting clinical signs of severe acute hypersensitivity 
reactions to PANZYGA, the PANZYGA infusion must be immediately stopped. 
Each site must have Epinephrine readily available and follow their institution’s
standard procedure for Epinephrine administration and monitoring. After the
hypersensitivity reaction subsides, the infusion may be resumed at a lower rate
if allowed per the site Epinephrine administration and monitoring procedures, and
per Investigator discretion.
7.3.3 Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
•
results in death
•
is life-threatening (see below)
•
requires hospitalization or prolongation of existing hospitalization
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect
•
is another important medical event
NOTE: The term ‘life-threatening’ refers to an event in which the patient was, in
the view of the reporting Investigator, at immediate risk of death at the time of the
event; it does not refer to an event which may hypothetically have caused death
had it been more severe.
In deciding whether an AE/ADR is serious, medical judgment should be 
exercised. Thus, important AEs/ADRs that are not immediately life-threatening or 
do not result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definitions 
above should also be considered serious.  
In addition, although not classified under the seriousness criteria, all suspected 
transmissions of an infectious agent should be reported as SAE. A suspected 
virus transmission means that virus antigen has been detected in the patient. A 
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passive transmission of antibodies alone does not constitute a suspected virus 
transmission. 
7.3.4 SAE Reporting Timelines 
All SAEs, whether or not they are suspected to be related to study treatment, are 
to be reported immediately by telephone, fax, or email to the Clinical Project 
Manager or designee with the contact detailed provided to each site in the 
Investigator Site Binder. The contact details will also be communicated at the 
study initiation visit. 
In addition, within 24 hours after recognition of the event, an Octapharma Serious
Adverse Event Report must be completed and submitted to:
Octapharma’s Corporate Drug Safety Unit 
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
Fax: 
E-mail:
24 hours emergency telephone numbers:
or 
The Investigator must update the Octapharma Serious Adverse Event Report as
soon as any additional information becomes available. The Investigator must also
report SAEs to the IRB/IEC as required by local and national laws. The
Investigator must maintain documentation of all communications to and from the
IRB/IEC.
In accordance with 21 CFR 312.32 and local authorities, the
Sponsor will submit to the FDA unexpected adverse reactions within
15 calendar days. Unexpected fatal or life-threatening adverse reactions will be
submitted within 7 calendar days.
Waivers the from SAE Reporting Requirement
Waivers from the SAE reporting requirement include surgeries that are elective
or were planned before study entry or prolongations of existing hospitalizations 
for economic or social, but not medical, reasons. Such surgeries or prolongations
of hospitalizations should not be considered SAEs.
7.3.5 Laboratory Tests 
Clinical laboratory parameters will be investigated during the study at the time 
points specified in the Flow Chart of Assessments (Table 1).  
All of the study-specific laboratory tests will be performed at the local laboratories 
for each study site. The laboratory test and sample collection timing are specified 
below (Table 5). 
Table 5: 
Laboratory Tests and Time Points 
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Test 
Timing 
Hematology (complete blood count, WBC 
differential, hematocrit, hemoglobin, platelet 
counts, reticulocytes) 
During Screening (Baseline evaluation), at 
Days 1, 3, 5, 8, 15, 22, and at Day 32/EOS 
Hemolysis (total, direct, and indirect 
bilirubin)  
During Screening (Baseline evaluation), at 
Days 1, 3, 5, 8, 22, and at Day 32/EOS 
Serum chemistry (ALT, AST, creatinine, Na, 
Ca, K, BUN, LDH) 
During Screening (Baseline evaluation), 
Days 1, 3, 22, and at Day 32/EOS 
Blood or Urine pregnancy test (females of 
childbearing potential) 
During Screening (Baseline evaluation) and 
Day 32/EOS 
Virology: HIV, HCV, HBV NAT 
During Screening (Baseline evaluation, see 
Section 7.1.3)  
Investigational sites will follow all site and local laboratory standard operating
procedures for sample collection and handling and will provide the sponsor with
normal reference ranges and laboratory certification certificates.
The methods of determination and normal ranges for each parameter from each
local laboratory will be provided in the clinical study report.
7.3.6 Vital Signs 
Vital signs will be collected at the time points specified in the Flow Chart of
Assessments (Table 1) are blood pressure, body temperature, pulse rate, and
respiratory rate.
On Day 1 and Day 3, vital sign measurements will be recorded before the start
of the infusion and every 60 minutes (±15 minutes) thereafter until the end of the
infusion. In addition, vital sign measurements will be recorded just prior to every
infusion rate change (-10 minutes), 15 minutes (+15 minutes) after every infusion
rate change, and approximately 30 minutes after the end of the infusion.
7.3.7 Physical Examination including Height and Body Weight.
Physical examinations will be performed at the visits specified in the Flow Chart
of Assessments (Table 1).
Both height and weight will be measured at Baseline.
7.3.8 Other Relevant Safety Information
a) Post-study related safety reports
Any SAE which occurs during the study (ie, within 4 weeks after the last 
PANZYGA administration, which for most patients will be up to and including 
Day 32) will be reported by the Investigator to the Sponsor. Proactive monitoring 
for post-study SAEs is not required. 
In case a post-study SAE is identified, the Investigator should complete an SAE 
form and also state the relation to the clinical study in the report. 
Deaths occurring during the study (ie, within 4 weeks after the last PANZYGA 
administration, which for most patients will be up to and including Day 32) should 
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also be reported, regardless of whether or not they are considered treatment-
related. 
b) Pregnancies
Every effort will be made to avoid a pregnancy during the use of an IMP. 
Pregnancies occurring during the study (fetal exposure to PANZYGA) need to be 
reported.  
In case of pregnancy during the study, the Investigator should complete the 
Pregnancy Notification Form and send or fax it to the Clinical Project Manager or 
designee (Section 7.3.4). 
Follow-up information on the outcome of both mother and fetus will be requested
by a Sponsor representative.
c) Overdose, interaction, medication error and lack of efficacy
The following safety relevant information should be reported as an AE or, if the
reaction fulfills one of the criteria for seriousness, as SAE.
d) Drug overdose
An overdose is a deliberate or inadvertent administration of a treatment at a dose
higher than specified in the protocol and higher than the known therapeutic dose
that is of clinical relevance. The reaction must be clearly identified as an
overdose.
e) Drug interaction
A drug interaction is a situation in which a substance or medicinal product affects 
the activity of an IMP, ie, increases or decreases its effects, or produces an effect
that none of the products would exhibit on its own. The reaction must be clearly 
identified as a drug interaction.
f)
Medication error
A medication error involves the inadvertent administration or unintended use of a
medicinal product which may be caused by the naming, presentation of
pharmaceutical form/packaging, or instructions for use/labelling. The reaction
must be clearly identified as a medication error.
g) Lack of efficacy
Lack of efficacy is suspected when the therapeutic result is not as expected. One
example of lack of efficacy could be platelets not increasing following the correct
administration of IVIG.
7.4 Other Assessments 
7.5 Appropriateness of Measurements 
For efficacy evaluations, platelet counts provide a direct measure of the response 
to IGIV treatment in ITP patients and has been widely used for this purpose in 
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many clinical trials of similar nature. The test is performed routinely at each 
hospital and is considered to be a reliable and robust parameter. 
The definition of response used for the primary endpoint is the most established 
procedure to obtain a dichotomy of success/failure that can be used to calculate 
the response rate. It is also acceptable to US FDA and was used as the primary 
efficacy endpoint in their approval of PANZYGA in the treatment of chronic ITP 
in adults and is thus expected to best facilitate their review of the efficacy of 
PANZYGA in this pediatric population. 
Monitoring AEs, vital signs, laboratory safety tests, and physical examinations 
are standard procedures used to evaluate the safety of investigational products
in clinical studies.
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8 
DATA HANDLING AND RECORD KEEPING 
8.1 Documentation of Data 
8.1.1 Source Data and Records 
Source data are defined as all information related to clinical findings, 
observations, or other activities in the study; written down in original records or 
certified copies of original records; or electronic medical records; allowing 
reconstruction and evaluation of the clinical study. 
The Investigator will maintain adequate source records (eg, case histories or
patient files for each patient enrolled). Source records should be preserved for
the maximum period of time required by local regulations.
For each patient enrolled, the Investigator will indicate in the source record(s) that
the patient is participating in this study.
All data entered in the eCRF must be supported by source data in the patient
records.
The Investigator will permit study-related monitoring, audit(s), IEC/IRB review(s),
and
regulatory
inspection(s),
by providing
direct
access to
the
source
data/records.
The Investigator may authorize site staff (eg, sub-Investigators, research nurses)
to enter study data into the eCRF. This must be documented in the Delegation of
Authority Log signed by the Investigator.
8.1.2 Electronic Case Report Forms
For each patient enrolled, an eCRF will be completed within the Electronic Data
Capture (EDC) system and approved by the Investigator or an authorized sub-
Investigator.
Study site staff (eg, research nurse, study coordinator, Investigator) will be
responsible for entering patient data into the validated EDC system. All study site
personnel will be trained on the EDC system and study-specific eCRFs prior to
receiving access to the live database for data entry.
The study site will be provided with the approved eCRF Completion Guidelines 
to assist in data entry and data issues/questions. The study site will be notified
once the eCRF is active to begin data entry. Additional site training may be
provided as refreshers throughout the study, if needed. All persons allowed to
enter or change eCRF data must be listed in the Delegation of Authority Log.
8.1.3 Changes to Electronic Case Report Form Data 
Monitors will perform source data verification (SDV) as defined for the study. 
If any errors or discrepancies in the eCRFs are found during data entry or review, 
discrepancies will be generated programmatically within the EDC system, and 
‘manual’ queries will be generated by either a monitor or Data Management.  
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Discrepancies and queries can only be corrected by the Investigator(s) or other 
authorized site personnel. An audit trail documents all changes to the data over 
the entire study period. If the reason for a change is not obvious, a comment must 
be supplied in the query’s response, stating the reason for the change, prior to 
closing. The study monitor should provide guidance to Investigator(s) and the 
Investigator(s)’ designated representatives on making such corrections.  
Once queries have been resolved by the site staff, the resolutions are assessed 
by Data Management. If the query response provided confirms the data as 
correct, the discrepancy will be closed. If the response does not adequately 
address the question raised, a new query will be issued for further clarification. 
Manual checks will be performed, and electronic data check programs run,
throughout the study until the data is clean and the database is ready for lock. All
discrepancies will be resolved prior to database lock. There will be a final run of
the programmed checks to ensure all discrepancies are closed out, SDV will be
confirmed as complete by the monitor, and all eCRFs will be approved by the
Investigator prior to database lock.
8.2 Information to Investigators 
An IB will be handed out to the Investigator before the start of the study. The IB
contains all information in the Sponsor’s possession necessary for the
Investigator to be fully and accurately informed about the safety of the IMP under 
evaluation and the respective benefit-risk ratio.
The IB will be updated by the Sponsor at regular intervals and whenever relevant
new information concerning PANZYGA becomes available.
All participating investigators will be informed about relevant study procedures,
about the methods for rating relevant study outcomes, and how to enter data into
the eCRF in order to reduce discrepancies. At the study initiation visit, the eCRF
will be explained to all study site staff entitled to document data in the eCRF.
The Investigator will be kept informed of important data that relate to the safe use
of PANZYGA as the study proceeds.
8.3
Responsibilities
The Principal Investigator is accountable for the conduct of the clinical study.
Responsibilities may be delegated to appropriately qualified persons.
A Delegation of Authority Log will be filled in and signed by the Principal
Investigator. In accordance with this authority log, study site staff (eg, sub-
Investigators, research nurses) are authorized to perform tasks relating to the
study.
8.4 Investigator’s Site File 
At each study site, the Investigator is responsible for maintaining all records to 
enable the conduct of the study to be fully documented. Essential documents as 
required by GCP guidelines and regulations (eg, copies of the protocol, study 
approval letters, all original informed consent and assent forms, site electronic 
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versions of all eCRFs, drug dispensing and accountability logs, correspondence 
pertaining to the study) should be filed accurately and kept by the Investigator for 
the maximum period of time required by local regulations. 
The Investigator is responsible for maintaining a confidential patient identification 
code list, which provides the unique link between named source records and 
eCRF data for the Sponsor. The Investigator must arrange for the retention of 
this confidential list for the maximum period of time required by local regulations. 
No study document should be destroyed without prior written agreement between
the Investigator and the Sponsor. Should the Investigator elect to assign the
study documents to another party, or move them to another location, the Sponsor
must be notified in writing.
8.5 Provision of Additional Information 
On request, the Investigator will supply the Sponsor with additional data relating
to the study, or copies of relevant source records, ensuring that the patient’s 
confidentiality is
maintained.
This
is particularly important
when source 
documents are illegible or when errors in data transcription are encountered.
In the event of particular issues or governmental queries, it is also necessary to
have access to the complete study records, provided that the patient’s 
confidentiality is protected in accordance with applicable regulations.
8.6
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be established by the
Sponsor. The IDMC will be composed of recognized experts in the fields of
hematology and/or critical care who are not actively recruiting patients.
The IDMC will review relevant data periodically during the study and will give
advice on the continuation, modification, or termination of the study. A written
study-specific procedure will define in detail the composition, responsibilities, and
procedures of the IDMC.
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9 
STATISTICAL METHODS AND SAMPLE SIZE 
Statistical analysis will be delegated under an agreement of transfer of 
responsibilities to an external contract research organization (CRO). All 
Octapharma procedures and policies must be met by this CRO. Discrepancies or 
exceptions will be approved by the Sponsor's Manager of Biometrics. 
9.1 Determination of Sample Size 
At least 20 patients who meet all eligibility criteria will be enrolled in the study. 
The purpose of this study is to evaluate the efficacy and safety of PANZYGA in 
pediatric patients with chronic ITP; the chosen number of 20 patients to be 
enrolled is not derived from statistical considerations of power but driven by 
feasibility constraints with respect to finding pediatric ITP patient eligible and 
willing to participate in this study. 
We expect the true proportion of responders to be comparable to results from 
similar studies in adult patients, as there is no published data or expert statement 
that would indicate otherwise. Looking at possible outcome scenarios, 
20 evaluable patients give the following picture from a statistical point of view: 
Power Considerations for 20 Evaluable Patients: 
Even though the chosen number of 20 pediatric patients is thus not sufficient ‘to 
power’ the study, it will still allow the Sponsor to gather enough clinical evidence 
to obtain a sound and meaningful medical assessment of the efficacy and safety 
of PANZYGA in pediatric patients with chronic ITP. 
9.2 Statistical Analysis 
A formal statistical analysis plan describing all details of the analyses to be 
performed will be prepared by the study statistician and approved by the Sponsor 
prior to the start of the statistical analysis. 
No confirmatory statistical analysis will be performed; the results of this study will 
be presented at the descriptive level only. 
In general, and if not detailed otherwise in the Statistical Analysis Plan (SAP), all 
statistical presentations will be fit to the nature and type of the individual data 
items: 
•
Binary data (whether or not an event has occurred): counts and
proportions
•
Count data (the frequency of an event in a set time period): rate (count per
unit time)
Exact 95% 
Hypothetical power to show that the true response 
-
o=o.s -
o=o.6 
Responders 
Confidence Limits 
r.ate is above 6 (l~sided, a •0.025), given that it is in 
fact equal to the observed proportion 
100.. 
Number 
Proportion 
Lower 
Upper 
6=0.5 
6=0.6 
"°" 
11 
55% 
31,5% 
76,9% 
5,5% 
'°" 
12 
60% 
36,1% 
80,9% 
12,6% 
2,1% 
'°" 
'""' 
13 
65% 
40,8% 
84,6% 
24,5% 
4,4% 
j '°" 
14 
70% 
45,7% 
88,1% 
41,6% 
10,7% 
g '°" 
15 
75% 
50,9% 
91,3% 
61,7% 
22,5% 
'°" 
16 
80% 
56,3% 
94,3% 
80,4% 
41,1% 
2°" 
17 
85% 
62,1% 
96,8% 
93,3% 
64,8% 
10,0 
°" 
18 
90% 
68,3% 
98,8% 
98,9% 
86,7% 
'°" -
""' 
'°" 
9("' 
100.. 
19 
95% 
75,1% 
99,9% 
100,0% 
98,4% 
True Pfoportion 
20 
100% 
83,2% 
100,0% 
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•
Continuous data (measurements on a continuous scale, including quasi-
continuous variables): arithmetic mean, standard deviation, median, lower
and upper quartile, minimum, maximum
•
Scales data (Ordinal and Non-ordinal): absolute and relative frequencies
•
Time-to-event data (how long it takes to observe the outcome of interest,
e.g. the initial treatment response): time to event or last evaluation
(censored data in case subjects are lost to follow-up) and event rate. Such
parameters may also be presented as Kaplan-Meier plots of the product-
limit survival function estimates.
9.2.1 Populations for Analysis 
The following populations will be considered for the statistical analysis: 
•
Safety Analysis Set (SAF): All patients who received at least part of
1 infusion of PANZYGA.
•
Full Analysis Set (FAS): All patients in the SAF who satisfy all major
eligibility criteria and for whom any post-baseline data is available. This is 
the set of eligible patients with treatment effects measured, according to
the intention-to-treat (ITT) principle.
•
Per-Protocol Set I (PP1): All patients in the FAS, excluding those with
significant protocol deviations before the primary efficacy assessment on
Day 8 is completed, and which may have an impact on the evaluation of
the primary endpoint.
•
Per-Protocol Set II (PP2): All patients in the FAS, excluding those with
significant protocol violations potentially affecting the (secondary) efficacy 
evaluations.
Only protocol deviations with the potential to significantly affect the study results
or to invalidate the interpretation of the data obtained will lead to exclusion of
patients from the PP sets. The inclusion of each patient in the respective analysis 
populations will be determined before database lock in a data review meeting by 
a panel consisting of a medical expert from the Sponsor, the clinical study 
manager, the data manager, and the study statistician.
The analysis of safety will be based on the SAF.
The evaluation of the primary objective will be performed for the FAS 
(ITT analysis) and for the PP1 set (PP analysis) to assess the robustness of the
results. The primary analysis will be the ITT analysis.
For secondary objectives ITT and PP2 analyses will be carried out; again the
ITT analysis is considered the primary analysis and will be presented first in the
report.
9.2.2 Efficacy Analysis Plan 
The primary and secondary efficacy parameters will be determined on the basis 
of the patient's platelet concentration, listed individually, and presented 
descriptively. 
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The primary endpoint parameter ‘response’ is defined as an increase in platelet 
count at least once to ≥50x109/L within 7 days after the first infusion, ie, by Day 8 
(increase must occur at least once on any day up to and including Day 8). 
The number and proportion of responders will be presented, together with the 
associated exact 95% confidence intervals. 
The time to reach the desired increase in platelet count as well as the duration of 
response and the maximum platelet levels will be presented in listings and 
summarized in statistical tables. 
Individual profiles of platelet count over time will be presented as Trellis plots. 
9.2.3 Safety Analysis Plan 
The safety analysis will comprise descriptive statistics, tabulations, and listings of
all TEAEs, safety laboratory results, vital signs, and physical examination
findings. All reported AEs will be coded according to the Medical Dictionary for 
Regulatory Activities) MedDRA.
An AE is defined as treatment-emergent if first onset or worsening is after start
of the first infusion of PANZYGA. Only TEAEs are accounted for in the analysis.
AEs will be record at the start of the fist infusion of PANZYGA. AEs that occur 
between informed consent/assent and the start of the first PANZYGA infusion will
be recorded under Medical History.
Incidences of treatment-emergent AEs will be given as the number and
percentage of patients who experienced any or a particular AE, including serious
and drug-related AEs.
The summary tables for AEs will be given by system organ class and preferred
term. Additionally, AEs will be summarized by severity and relationship to study 
treatment. In addition to the tables presenting incidences including all AEs,
incidences will be determined for the subset of SAEs and drug-related AEs.
Incidences of infusional AEs will be given as the number and percentage of
patients who experienced any or a particular infusional AE, including serious and
drug-related AEs.
The summary tables for infusional AEs will be given by system organ class and
preferred term. Additionally, infusional AEs will be summarized by severity and
relationship to study treatment. In addition to the tables presenting incidences
including all infusional AEs, incidences will be determined for the subset of SAEs
and drug-related AEs.
Narratives will be prepared describing each death, other SAEs, and other 
significant AEs that are judged to be of special interest because of clinical 
importance. 
For each routine laboratory parameter at each visit the actual result, the change 
from baseline, the out-of-range flag and the assessment of clinical relevance will 
be summarized descriptively. 
Vital signs include systolic and diastolic blood pressure, pulse rate, body 
temperature and the respiratory rate; descriptive tables on the sampling statistics 
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of these parameters at each time point will be provided for the values as well as 
for their changes to baseline. 
9.2.4 Handling of Missing Data 
No replacement of missing data values is planned, but only observed results (and 
platelet counts) will be included in the analyses. 
9.3 Randomization, Stratification, and Code Release 
This is an open-label non-randomized study; therefore, no randomization code 
list or procedure for code release are required. Patients will not be stratified by 
age group.  
9.4 Interim Analysis  
No interim analysis is planned.  
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10 ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE 
ASPECTS 
10.1 Ethical/Regulatory Framework 
This study will be conducted in accordance with the ethical principles laid down 
in the Declaration of Helsinki. The study protocol and any subsequent 
amendment(s) will be submitted to an IEC/ IRB and to the Regulatory Authority. 
The study will be conducted in compliance with the protocol, GCP guidelines, and 
applicable regulatory requirements. 
The regulatory application or submission for regulatory approval will be made by
the Sponsor or designated third party (eg, CRO) as required by national law.
10.2 Approval of Study Documents 
The study protocol, a sample of the patient information and informed consent
form, assent form, any other materials provided to the patient and their
parent/legal guardian, and further requested information will be submitted by the
Sponsor or the Investigator to the appropriate IEC/IRB and the Regulatory
Authority. The study must be approved by the IEC/IRB and the Regulatory 
Authority before any IMP may be shipped to the study sites and any patient is
exposed to a study-related procedure.
The Sponsor, the Investigator, and any third party (eg, CRO) involved in obtaining
approval must inform each other in writing that all ethical and legal requirements
have been met before the first patient is enrolled in the study.
10.3 Patient Information and Informed Consent
The Investigator will obtain freely given written consent from each the patient after 
an appropriate explanation of the aims, methods, anticipated benefits, potential
hazards, and any other aspect of the study which is relevant to the patient’s
decision to participate. The informed consent form must be signed, with name
and date and time noted by the patient, before the patient is exposed to any
study-related procedure, including screening tests for eligibility.
For patients not qualified to give legal consent, written consent must be obtained
from the legal parent/guardian. If children are old enough to understand the risks 
and benefits of the study, they should also be informed and provide their written
consent using an assent form.
The Investigator will explain that the patients are completely free to refuse to enter 
the study or to withdraw from it at any time, without any consequences for their 
further care and without the need to justify. The Investigator will complete the 
informed consent section of the CRF for each patient enrolled. 
Each patient (and parent/legal guardian, as appropriate) will be informed that 
his/her medical (source) records may be reviewed by the study monitor, a quality 
assurance auditor, or a health authority inspector, in accordance with applicable 
regulations, and that these persons are bound by confidentiality obligations. 
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10.4 Protocol Amendments 
Any prospective change to the protocol will be agreed between the Investigator 
(Co-ordinating Investigator in multi-center studies) and the Sponsor prior to its 
implementation. Any such amendments will be submitted to the any competent 
IEC/IRB and/or competent authority responsible as required by applicable 
regulations. 
IEC/IRB approval will, at a minimum, be requested for any change to this protocol
which could affect the safety of the patients, the objective/design of the study,
any increase in dosage or duration of exposure to the IMP, an increase in the
number of patients treated, the addition of a new test or procedure, or the
dropping of a test intended to monitor safety.
10.5 Confidentiality of Patient Data 
The Investigator will ensure that the patient’s confidentiality is preserved. On
eCRFs or any other documents submitted to the Sponsor, the patients will not be
identified by their names, but by a unique patient identifier. Documents not
intended for submission to the Sponsor, ie, the confidential patient identification
code list, original consent and assent forms, and source records, will be
maintained by the Investigator in strict confidence.
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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Periodic Monitoring 
The monitor will contact and visit the Investigator periodically to review all study-
related source data/records, verify the adherence to the protocol and the 
completeness, correctness and accuracy of all CRF entries compared to source 
data. The Investigator will cooperate with the monitor to ensure that any 
discrepancies identified are resolved. 
For this study, the first monitoring visit shall take place shortly after the inclusion
of the first patient. Thereafter, monitoring frequency will depend on study
progress and in accordance with the study clinical monitoring plan.
The monitor must be given direct access to source documents (original
documents, data, and records). Direct access includes permission to examine,
analyze, verify, and reproduce any records and reports that are important to the
evaluation of the clinical study. Source data will be available for all data in the
eCRFs, including all laboratory results.
11.2 Audit and Inspection 
The Investigator will make all study-related source data and records available to
a qualified quality assurance auditor mandated by the Sponsor, or to
IEC/IRB/regulatory inspectors, after reasonable notice. The main purposes of an
audit or inspection are to confirm that the rights and welfare of the patients have
been adequately protected, and that all data relevant for the assessment of safety
and efficacy of PANZYGA have been reported to the Sponsor.
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12 REPORTING AND PUBLICATION 
12.1 Clinical Study Report 
A clinical study report (in accordance with relevant guidelines and the Sponsor’s 
Standard Operating Procedures [SOPs]) will be prepared by the Sponsor after 
completion of the study. The Co-ordinating Investigator will approve the final 
study report after review. 
12.2 Publication Policy
The results of this study may be published or presented at scientific meetings.
If the Investigator wants to publish or present study results, the Investigator
agrees to inform the Sponsor and to submit all manuscripts or abstracts to the
Sponsor before submission to an editorial board or scientific review committee.
This will allow the Sponsor to protect proprietary information and to provide
comments based on information that may not yet be available to the Investigator.
In accordance with standard editorial and ethical practice, the Sponsor will
support publication of multi-center studies only in their entirety and not as
individual center data. Authorship will be determined by mutual agreement.
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13 LIABILITIES AND INSURANCE 
In order to cover any potential damage or injury occurring to a patient in 
association with PANZYGA or participation in the study, the Sponsor will contract 
insurance in accordance with local regulations. 
The Investigator is responsible for dispensing PANZYGA according to this 
protocol and for its secure storage and safe handling throughout the study. 
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14 REFERENCES 
1. Diagnosis and treatment of idiopathic thrombocytopenic purpura:
recommendations of the American Society of Hematology. The American
Society of Hematology ITP Practice Guideline Panel. Ann.Intern.Med.
1997;126:319-326.
2. Brenner B: Clinical experience with Octagam, a solvent detergent (SD)
virus inactivated intravenous gammaglobulin. Clin.Exp.Rheumatol.
1996;14:S115-S119.
3. Imbach P: 
Immune thrombocytopenic purpura and intravenous
immunoglobulin. Cancer. 1991;68:1422-1425.
4. Newland AC, Burton I, Cavenagh JD, et al: Vigam-S, a solvent/detergent-
treated intravenous immunoglobulin, in idiopathic thrombocytopenic
purpura. Transfus.Med. 2001;11:37-44.
5. Despotovic JM:
Emerging
therapies in
immune
thrombocytopenia.
American Society of Hematology. The Hematologist, ASH News and
Reports. 2018:15:4;1-7.
6. Neunert C, Despotovic J, Haley K, et. al. Thrombopoietin receptor agonist
use in children: data from the pediatric ITP consortium of North America
ICON2
study.
Pediatric
Blood
& Cancer.
2016:63(8),
1407-1413.
doi:10.1002/pbc.26003
7. European Medicines Agency, Guideline on the clinical investigation of
human normal immunoglobulin for intravenous administration (IVIg).
EMA/CHMP/BPWP/94033/2007
rev.
3.
Retrieved
from:
https://www.ema.europa.eu/documents/scientific-guideline/guideline-
clinical-investigation-human-normal-immunoglobulin-intravenous-
administration-ivig-rev-3_en.pdf
8. American Society of Hematology 2011 Clinical Practice Guideline on the
Evaluation and Management of Immune Thrombocytopenia (ITP), Quick
Reference Guide.
9. PANZYGA [package insert]. Hoboken, NJ: Octapharma USA Inc; 2018.
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15 APPENDICES 
Not applicable. 
Page 126 of 260 

Protocol Amendment #2 NGAM-10 
CONFIDENTIAL 
Page 1 of 9 
05-Aug-2019
PROTOCOL AMENDMENT #2 
STUDY NUMBER: 
NGAM-10 
STUDY TITLE: 
Post-Marketing Study to Evaluate the Efficacy 
and Safety of PANZYGA in Pediatric Patients 
with Chronic Immune Thrombocytopenia (ITP) 
SPONSOR: 
Octapharma USA 
121 River Street, 12th Floor 
Hoboken, NJ 07030 
TEST PRODUCT: 
PANZYGA 
IND / BLA NUMBERS: 
IND 14121 / BLA 125587 
APPROVED BY: 
Octapharma Pharmazeutika ProduktionsgmbH 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
PROTOCOL: 
DATE: 
Final Version 01 
30 Jan 2019 
Protocol Amendment #1 
21 May 2019 
Final Version 02 
21 May 2019 
Protocol Amendment #2 
05 Aug 2019 
Final Version 03 
05 Aug 2019 
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Protocol Amendment #2 NGAM-10 
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Rationale for the Amendment: 
FDA reviewed Study Protocol No. NGAM-10 Version 02, including Amendment 
01 and provided one comment to the Sponsor in a communication dated 01-
Aug-2019. The rationale for Amendment 02 to be included in Version 3 of 
Protocol NGAM-10 is to address that FDA’s comment.  
In addition, the exclusionary time for a splenectomy has been increased from 
4 weeks to 3 months, in order to further enhance patient safety and assure that 
patients have an adequate recovery time prior to enrolling into this study.  
In order to accommodate the pediatric population and improve protocol
compliance, the protocol has been amended to allow study visits that do not
involve Panzyga infusions and only include safety assessments (including
clinical laboratory evaluations) to be conducted locally by the patient’s primary 
care physician or local laboratory services.
Other changes were incorporated throughout the protocol to provide additional
instruction to Investigators including allowable time windows for changing
infusion rates, vital sign assessments, collection of patient body weight and
height, and reconciliation of discrepancies identified between the Flow Chart of
Assessments and Section 6.1: Observations by Visit.
The following changes made throughout the protocol were considered
significant. All substantive and non-substantive changes (including
administrative changes and grammatical, punctuation, or formatting corrections) 
are documented in the red-line version of the protocol.
MODIFICATION 1: Managing Hypersensitivity Reactions
FDA requested that, to enhance the safety of participating patients, the protocol
be amended such that in the event of severe hypersensitivity reactions or 
anaphylaxis, any further Panzyga administration should be discontinued and
not resumed.
Previous requirement:
Section 7.3.2.8: Managing Hypersensitivity Reactions
Severe hypersensitivity reactions may occur during PANZYGA infusions [9]. In
the case of any subject exhibiting clinical signs of severe acute hypersensitivity
reactions to PANZYGA, the PANZYGA infusion must be immediately stopped. 
Each site must have Epinephrine readily available and follow their institution’s
standard procedure for Epinephrine administration and monitoring. After the
hypersensitivity reaction subsides, the infusion may be resumed at a lower rate
if allowed per the site Epinephrine administration and monitoring procedures, 
and per Investigator discretion.
Amended Requirement: 
Section 7.3.2.8: Managing Hypersensitivity Reactions 
Severe hypersensitivity reactions may occur during PANZYGA infusions [9]. In 
the case of any subject exhibiting clinical signs of severe acute hypersensitivity 
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reactions to PANZYGA, the PANZYGA infusion must be immediately stopped. 
Each site must have Epinephrine readily available and follow their institution’s 
standard procedure for Epinephrine administration and monitoring. If a subject 
developed severe hypersensitivity or anaphylactoid reactions, any further 
Panzyga administration should be discontinued and not resumed.  
MODIFICATION 2: Increasing Exclusionary Time Requirement after 
Splenectomy 
In order to enhance patient safety and assure that patients have an adequate 
recovery time prior to enrolling into this study, the exclusionary time for a 
splenectomy has been increased from 4 weeks to 3 months. 
Previous requirement: 
Study Outline: Exclusion Criterion #8 
Section 4.1.2: Exclusion Criterion #8 
8) Splenectomy in the previous 4 weeks or planned splenectomy throughout
the study period
Amended Requirement: 
Study Outline: Exclusion Criterion #8 
Section 4.1.2: Exclusion Criterion #8 
8) Splenectomy in the previous 4 weeks 3 months or planned splenectomy 
throughout the study period
MODIFICATION 3: Allowable Time Windows for Changing Infusion Rates
The protocol was silent on the allowable time windows for changing infusion
rates. Time windows of ±5 minutes have been added in order to provide
direction to the Investigators.
Previous requirement:
Study Outline
Section 5.4: Dose and Dosing Schedule
PANZYGA
will
be
delivered
by intravenous infusion
according
to
the
recommended flow rates:
•
Initial infusion rate of 0.01 mL/kg/min (60 mg/kg/hr) for the first
30 minutes
•
If tolerated, increase to 0.02 mL/kg/min (120 mg/kg/hr) for the second
30 minutes
•
If tolerated, increase to 0.04 mL/kg/min (240 mg/kg/hr) for the third
30 minutes
•
If tolerated, increase to 0.08 mL/kg/min (480 mg/kg/hr) for the remainder
of the infusion
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Amended Requirement:  
Study Outline 
Section 5.4: Dose and Dosing Schedule 
PANZYGA will be delivered by intravenous infusion according to the 
recommended flow rates: 
•
Initial infusion rate of 0.01 mL/kg/min (60 mg/kg/hr) for the first
30 minutes (±5 minutes)
•
If tolerated, increase to 0.02 mL/kg/min (120 mg/kg/hr) for the second
30 minutes (±5 minutes)
•
If tolerated, increase to 0.04 mL/kg/min (240 mg/kg/hr) for the third
30 minutes (±5 minutes)
•
If tolerated, increase to 0.08 mL/kg/min (480 mg/kg/hr) for the remainder 
of the infusion
MODIFICATION 4: Allowable Time Window for Vital Sign Assessments
Taken at the End of the Infusion
The protocol was silent on the time windows for vital signs taken after the end
of the Panzyga infusion. Time windows of +15 minutes have been added in
order to provide direction to the Investigators.
Previous requirement:
Table 1 Flow Chart of Assessments Footnote 9
Footnote 9) Vital Signs: at the start of the infusion and every 60 minutes 
(±15 minutes) thereafter until the end of the infusion. In addition, vital sign
measurements will be recorded just prior to every infusion rate change
(-10 minutes), 15 minutes (+15 minutes) after each infusion rate change, and
approximately 30 minutes after the end of the infusion.
Section 6.1.2: Day 1
Section 6.1.3: Day 3
•
Vital signs (at the start of the infusion and every 60 minutes 
(±15 minutes) thereafter until the end of the infusion. In addition, vital
sign measurements will be recorded just prior to every infusion rate
change (-10 minutes), 15 minutes (+15 minutes) after each infusion rate
change, and approximately 30 minutes after the end of the infusion)
Amended Requirement: 
Table 1 Flow Chart of Assessments Footnote 9
Footnote 9) Vital Signs: at the start of the infusion and every 60 minutes 
(±15 minutes) thereafter until the end of the infusion. In addition, vital sign
measurements will be recorded just prior to every infusion rate change
(-10 minutes), 15 minutes (+15 minutes) after each infusion rate change, and
approximately 30 minutes (+15 minutes) after the end of the infusion
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Section 6.1.2: Day 1 
Section 6.1.3: Day 3 
•
Vital signs (at the start of the infusion and every 60 minutes
(±15 minutes) thereafter until the end of the infusion. In addition, vital
sign measurements will be recorded just prior to every infusion rate
change (-10 minutes), 15 minutes (+15 minutes) after each infusion rate
change, and approximately 30 minutes (+15 minutes) after the end of the
infusion
MODIFICATION 5: Clarification of Body Weight and Height Assessments 
Section 7.3.7 (Physical Examination including Body Weight and Height) 
specifies that patient body weight and height are part of the physical
examination performed at Baseline. In order to clarify this requirement, specific 
instructions regarding the measurement of body weight and height have been
added elsewhere in the protocol. 
Previous requirement:
The Flow Chart of Assessments (Table 1) and the description of assessments
performed at the Baseline Visit (Section 6.1.1) specified a physical examination
but did not specifically address the collection of height at the Baseline visit. 
Amended Requirement:
Table 1: Flow Chart of Assessments and Footnote 3
“Height” was added after Physical Examination in the Flow Chart, and further 
clarification was added to Footnote 3 indicating that height would only be
collected at Baseline, only (see example below extracted from Table 1).
ASSESSMENTS 
Screening / Baseline
Physical Examination and Height
X3 
Footnote 3) Brief Physical Examination: general appearance, skin, heart, lungs,
abdomen, extremities. Height will only be collected at Baseline.
Section 6.1.1: Baseline Visit/Screening Period
•
Physical examination and height
MODIFICATION 6: Reconcile Vital Sign Assessments at Day 22
Vital sign assessments are not required at the Day 22 visit and are not included
in the assessments listed in Day 22 Visit procedures (Section 6.1.5). The Flow
Chart of Assessments (Table 1) included an “X” in the box under the Day 22 
assessments.
Amended Requirement:  
Table 1: Flow Chart of Assessments 
The “X” was removed in table under the Day 22 assessments (see below 
extracted from Table 1). 
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ASSESSMENTS 
Scr / BL1 
Day 
1 
Day 
3 
Day 
512
Day 
812 
Day 
1512 
Day 
2212 
Day 
3213
Vital Signs: heart rate, blood pressure, 
temperature, respiratory rate 
X 
X9 
X9 
X 
X 
MODIFICATION 7: Reconcile Adverse Event Collection and Pregnancy 
Tests 
Both adverse event collection and pregnancy tests are required at the Day 32 
visit; these requirements are indicated in the Flow Chart of Assessments 
(Table 1). However, they are not specified in Section 6.1.6: Day 32 (End of 
Study Visit) assessments.  
Adverse events will be collected from the start of the first infusion on Day 1, as 
specified in Footnote 10 in the Flow Chart of Assessments (Table 1). Further 
clarification will be provided to the Investigator in Section 6.1.6: Day 32 (End of
Study Visit) and Section 7.3.2.2: Collection of AEs.
Amended Requirement:  
Section 6.1.6: Day 32 (End of Study Visit) 
•
Physical examination
•
Vital signs
•
Blood samples for serum chemistry, hematology, and hemolysis analytes
•
Blood or urine pregnancy test (females of childbearing potential, only)
•
Monitoring for AEs
•
Documentation of concomitant medication use
Section 7.3.2.2 Collection of AEs
AEs will be collected from the start of the first infusion on Day 1. Any illnesses 
captured between signing the ICF and the first infusion will be captured under 
medical history. The condition of the patient will be monitored throughout the
study. At each visit, whether scheduled or unscheduled, AEs will be elicited
using a standard nonleading question such as “How have you been since the
last visit/during the previous study period?” In addition, the Investigator will
check the patient diaries (if applicable) for any documented event.
MODIFICATION 8: Reconsent of Patients Who Turn 18 Years Old during
Study Participation 
The patient population for this study includes infants and children from ≥1 year 
to <18 years old. It is possible that some patients may turn 18 years old during
their participation. Therefore, a note was added to the age-related inclusion
criterion that these patients must be re-consented after their 18th birthday.
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Amended Requirement: 
Study Outline: Inclusion Criterion #1 
Section 4.1.1: Inclusion Criterion #1 
1) Females and males aged from 1 year to <18 years old
Note: Patients who turn 18 years old during study participation must be re-
consented at their next study visit with an adult informed consent form.
MODIFICATION 9: Allowing Safety Assessment Visits to be Performed 
Locally by the Patient’s Primary Care Physician and/or 
Local Laboratory Services 
The patient population for this study includes infants and children from ≥1 year 
to <18 years old. As this is a rare disease being treated at specialty centers,
sometimes the patient population may be 2 to 3 hours away from the study
center. This could cause difficulty with compliance. In order to accommodate
the needs of this population and their parents or guardians and improve 
compliance with the protocol visit schedule, the clinical sites that will be
participating in this study have requested that the protocol allow study visits that
do not involve Panzyga infusions to be conducted locally by the patient’s 
primary care physician. Days 5, 8, 15, and 22 include limited physical
examinations, adverse event and concomitant medication use documentation,
and blood draws for clinical laboratory assessments. Required interactions and
communication channels between the local physician and the Principal
Investigator (eg, telemedicine or other means of electronic communication) will
be outlined in the Investigator Site File.
Previous requirement:
The protocol does not address study visits taking place at locations other than
those associated with the Principal Investigator’s clinical site.
Amended Requirement: 
Table 1: Flow Chart of Assessments
A footnote (new Footnote 12) was added to Day 5, Day 8, Day 15, and Day 22
Visit Days in the flow chart, and the original Footnote 12 was changed to
Footnote 13. In addition, it was clarified that limited physical examinations 
would be performed on Day 3 and Day 15 (see example below extracted from 
Table 1: Flow Chart of Assessments).
ASSESSMENTS 
Scr / BL1 
Day 
1 
Day 
3 
Day 
512
Day 
812 
Day 
1512 
Day 
2212 
Day 
3213 
12 
Physical Examination and Height 
X3 
X3 
X3X4 
X4 
X4 
X3X4 
X4 
X3 
Footnote 3) Brief Physical Examination: general appearance, skin, heart, lungs, 
abdomen, extremities. Height will only be collected at Baseline. 
Footnote 4) Limited Physical Examination with targeted body systems per 
Investigator discretion.  
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Footnote 12) Days 5, 8, 15, and 22 visits may be performed locally by patient’s 
primary care physician or a local laboratory service upon agreement with the 
site Principal Investigator, the IRB, and the Sponsor. 
Footnote 13 12) Day 32 visit will correspond to the Early Termination visit for 
patients who are withdrawn early from the study, 
Section 6.1.4: Day 5 and Day 8 
Day 5 and Day 8 visits and assessments may be performed locally (by patient’s 
primary care physician or local laboratory services) upon agreement with the 
site Principal Investigator, the IRB, and the Sponsor. Required interactions and 
communication channels between the primary care physician and the Principal 
Investigator (eg, telemedicine or other means of electronic communication) will 
be outlined in the Investigator Site Binder. 
Section 6.1.5: Day 15 and Day 22 
Day 15 and Day 22 visits and assessments may be performed locally (by 
patient’s primary care physician or local laboratory services) upon agreement 
with the site Principal Investigator, the IRB, and the Sponsor. Required 
interactions and communication channels between the primary care physician 
and the Principal Investigator (eg, telemedicine or other means of electronic 
communication) will be outlined in the Investigator Site Binder. 
Section 7.3.5: Laboratory Tests 
Investigational sites will follow all site and local laboratory standard operating 
procedures for sample collection and handling and will provide the sSponsor 
with normal reference ranges and laboratory certification certificates. Upon 
agreement with site Principal Investigator, the IRB, and the Sponsor, Days 5, 8, 
15, and 22 visits may be performed locally by the patient’s primary care 
physician. Laboratory samples may be collected by a patient’s primary care 
physician or by a local laboratory service (that draws, processes, and reports 
laboratory results) that is in the proximity of the patient’s home; these samples 
must be analyzed according to the chosen laboratory’s standard operating 
procedures. Normal reference ranges and laboratory certification certificates of 
any laboratories will also be provided to the Sponsor. 
 
Please see the attached redline version for documentation of these substantive 
changes, along with minor grammatical, formatting, punctuation, and other non-
substantive changes.  
Page 134 of 260 

Protocol Amendment #2 NGAM-1 0 
CONFIDENTIAL 
AGREEMENT: These signatures constitute approval of this protocol 
amendment and provide the necessary assurance that the study will be 
conducted according to all stipulations of protocol and amendments. 
Authorised person for signing the Study Protocol and Protocol 
Amendments on behalf of the Sponsor and Sponsor's Medical Expert: 
 
Octapharma Pharmazeutika Produktionsgesellschaft m.b H 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
Tel: 
, Fax: 
 
 of the Amendment: 
Date: 
----
 
Octapharma USA, Inc 
121 River Street, Suite 1201 
Tel: 
, Fax 
 
 
Date: 
__ _ 
 
Octapharma Pharmazeutika Produktionsgesellschaft m.b.H 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
Tel 
. Fax·
 
Page 9 of 9 
05-Aug-2019 
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Property of Octapharma. Do not copy or distribute without written permission.

Property of Octapharma. Do not copy or distribute without written permission.
This document contains confidential and proprietary information of Octapharma AG. 
Do not copy or distribute without written permission. 
090-CSP-NGAM-10-V01/DOC ID 3021
CLINICAL STUDY PROTOCOL 
NGAM-10 
Post-Marketing Study to Evaluate the Efficacy
and Safety of PANZYGA in Pediatric Patients with 
Chronic Immune Thrombocytopenia (ITP)
Investigational Product: 
PANZYGA 
Indication: 
Chronic Immune Thrombocytopenia (ITP) 
Study Design: 
Prospective, open-label, single-arm, multi-
center study 
Sponsor: 
Octapharma USA 
121 River Street, 12th Floor
Hoboken, NJ 07030
Study Number: 
NGAM-10
IND Number / BLA Number: 
IND 14121 / BLA 125587 
Development Phase: 
Phase 4 
Planned Clinical Start: 
Q3 2019 
Planned Clinical End: 
Q1 2022 
Date of Protocol: 
05-Aug-2019
Version: 
03 (Incorporating Amendment 2) 
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Study Protocol No. NGAM-10, Version 03 CONFIDENTIAL 
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Page 2 of 60 
STUDY OUTLINE 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
05-Aug-2019
Title of Study: 
Post-Marketing Study to Evaluate the Efficacy and Safety of PANZYGA in
Pediatric Patients with Chronic Immune Thrombocytopenia (ITP)
Indication: 
Chronic Immune Thrombocytopenia (ITP) 
Number of Study Centre(s): 
Up to 8 sites in the USA 
Objectives: 
Primary Objective: 
The primary objective is to evaluate the efficacy of PANZYGA in increasing the
platelet count in pediatric patients with chronic ITP.
Secondary Objectives:
The secondary objectives of this study are to:
•
Assess safety of up to 2 g/kg PANZYGA (1 g/kg PANZYGA on Day 1 
and an optional dose of 1 g/kg PANZYGA on Day 3) infused in the
pediatric population within the scope of the clinical study
•
Determine the time to reach a platelet count of 50x109/L
•
Determine duration of time during which the platelet count is maintained
at the level ≥50х109/L
•
Determine the maximum platelet count during the study
Study Design: 
This is a prospective, open-label, single-arm, multicenter, Phase 4 study 
evaluating the efficacy and safety of PANZYGA in pediatric patients with chronic 
ITP. 
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Page 3 of 60 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
05-Aug-2019
Number of Patients: 
At least 20 patients 
Patient Selection Criteria: 
Inclusion Criteria: 
1. Females and males aged from ≥1 year to <18 years old
Note: Patients who turn 18 years old during study participation must be
re-consented at their next study visit with an adult informed consent form.
2. Confirmed diagnosis of Chronic Immune Thrombocytopenia (ITP) 
according to American Society of Hematology (ASH) 2011 guidelines
3. Platelets count <30x109/L at the Baseline Visit
4. Voluntarily given written informed consent (provided by patient’s parent
or legal guardian) and assent (provided by patient [if age-appropriate per
IRB requirements])
5. Females of childbearing potential who have been using at least
1 acceptable form of birth control for a minimum of 30 days (or a
minimum of 3 months for hormonal contraceptives) prior to the
Screening visit, and must agree to use at least 1 acceptable method of
contraception for 30 days after the last dose of PANZYGA. Acceptable
methods of birth control for this study include: intrauterine device (IUD),
hormonal contraception, male or female condom, spermicide gel,
diaphragm, sponge, or cervical cap. Abstinence is not considered an
acceptable method of birth control.
6. Parent or legal guardian must agree and be willing to assist the
participant attend study visits, and to follow all protocol requirements and
instructions of the study doctor
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Page 4 of 60 
Exclusion Criteria: 
 
2. Administration of intravenous immunoglobulin (IGIV) or anti-D
immunoglobulin within 3 weeks before enrollment
3. Administration of thrombopoietin receptor agonists when the dose has
NOT been stable within 3 weeks before enrollment and a dosage change
is planned before Day 32
4. Administration of oral immunosuppressants when the dose has NOT
been stable during the preceding 2 months (2 weeks for long-term
corticosteroid therapy) and a dosage change is planned before Day 32
(Note: topical agents and inhaled corticosteroid therapy use is permitted)
5. Administration of long-term anti-prolific agents or attenuated androgen
therapy when the dose has NOT been stable during the preceding
2 months and a dosage change is planned before Day 32
6. Nonresponsive to previous treatment with IGIV or anti-D immunoglobulin
7. Evidence of an active major bleeding episode at Screening
8. Splenectomy in the previous 3 months or planned splenectomy
throughout the study period
9. Evans syndrome (experiencing active disease with 2 out of 3 of the
following:
autoimmune
thrombocytopenia,
autoimmune
hemolytic 
anemia, and/or autoimmune neutropenia)
10.Known
or 
suspected
human immunodeficiency virus 
(HIV),
hepatitis B virus (HBV), and/or hepatitis C virus (HCV) infections
11.Emergency surgery in the previous 4 weeks
12.Severe liver and/or kidney disease (alanine aminotransferase [ALT]
>3x upper limit of normal (ULN), aspartate aminotransferase [AST]
>3x upper limit of normal (ULN), and/or creatinine >120 µmol/L)
13. History of severe hypersensitivity to blood or plasma derived products,
or any component of the PANZYGA
14. Known immunoglobulin A (IgA) deficiency and antibodies against IgA
15. History of, or suspected alcohol or drug abuse in the previous year
16. Females who are pregnant or nursing
17. Unable or unwilling to comply with the study protocol
18. Receipt of any other investigational medicinal product within 3 months
before study entry
19. Risk factors* for thromboembolic events in whom the risks outweigh the
potential benefit of PANZYGA treatment.
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Page 5 of 60 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
05-Aug-2019
20.Any other condition(s), that in the Investigator’s opinion, make it
undesirable for the patient to participate in the study or may interfere with
protocol compliance.
* Risk factors include, but are not limited to: obesity, advanced age,
hypertension, diabetes, a history of atherosclerosis/vascular disease or
thrombotic events, hyperlipidemia, multiple cardiovascular risk factors, acquired
or inherited thrombophilic disorders, prolonged periods of immobilization,
severe hypovolemia, central venous catheterization, active malignancy and/or 
known or suspected hyperviscosity.
Test Product, Dose, and Mode of Administration:
PANZYGA (Immune Globulin, intravenous, human-ifas). PANZYGA must be
stored and transported light-protected at +2°C (36°F) to +8°C (46°F) and must
be brought to room temperature before use.
Patients will receive a dose of 1 g/kg body weight PANZYGA given on Day 1
and optionally another dose of 1 g/kg PANZYGA given on Day 3; body-weight
dependent doses will be based on each patient’s weight collected at Baseline. 
Total PANZYGA doses will be 1 g/kg for patients receiving only 1 dose on Day 1 
and 2 g/kg for those receiving the optional Day 3 dose. Prior to the Day 3 
infusion, each patient’s preinfusion platelet count will be reviewed by the
Investigator. If the Day 3 platelet count shows evidence of response as
indicated by the platelet count at least doubling from Baseline count AND is 
>50x109/L, the Day 3 infusion will not be administered. If the Baseline platelet
count has doubled but is ≤50x109/L, the Day 3 infusion will be administered.
PANZYGA
will be delivered by intravenous infusion according to the
recommended flow rates:
•
Initial infusion rate of 0.01 mL/kg/min (60 mg/kg/hr) for the first
30 minutes (±5 minutes)
•
If tolerated, increase to 0.02 mL/kg/min (120 mg/kg/hr) for the second
30 minutes (±5 minutes)
•
If tolerated, increase to 0.04 mL/kg/min (240 mg/kg/hr) for the third
30 minutes (±5 minutes)
•
If tolerated, increase to 0.08 mL/kg/min (480 mg/kg/hr) for the remainder
of the infusion.
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Page 6 of 60 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
05-Aug-2019
Infusion rates should not exceed 0.08 mL/kg/min and should not exceed
8.0 mL/min. The infusion rate may be gradually increased as tolerated by the
patient.
If a Grade 2 or higher (moderate) infusion-related adverse event (AE) occurs
during infusion, the Panzyga infusion will be stopped. After infusion-related
symptoms subside, the infusion may be resumed at a lower rate. The infusion
rate may be gradually increased as tolerated by the patient.
If a Grade 1 (mild) infusion-related AE occurs during infusion, the infusion rate
should be reduced to half the rate at which the event occurred, or the infusion
should be interrupted until symptoms subside. The infusion may then be
resumed at a rate tolerated by the patient. The batch number(s) used will be
recorded in the study documentation and electronic data capture (EDC) system.
Duration of Treatment:
Screening Period: 1 week
Treatment Period: up to 3 days
Follow-up Period: 29 days
Reference Therapy, Dose, and Mode of Administration:
Not Applicable
Study Outcome Parameters (Primary and Secondary Endpoints):
Primary Endpoint:
The primary efficacy parameter is defined as an increase in platelet count at
least once to ≥50x109/L within 7 days after the first infusion, ie, by Day 8 
(increase must occur at least once on any day up to and including Day 8). This 
definition of clinical response will serve as the basis for the primary endpoint,
the response rate (ie, the proportion of patients with an elevation of platelet
count at least once to 50x109/L within 7 days [ie, by Day 8] after the first
infusion).
Secondary Endpoints: 
•
Time to reach a platelet count of 50x109/L
•
Duration of platelet response defined as the number of days the platelet
count remains above 50x109/L
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Page 7 of 60 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
05-Aug-2019
•
Maximum platelet count during the study
Safety Parameters: 
•
AEs
•
Vital signs (blood pressure, heart rate, temperature, respiratory rate)
•
Physical examination
•
Laboratory parameters: hematology (including reticulocytes), hemolysis,
platelet count, serum chemistry (including lactase dehydrogenase
[LDH]).
Study Procedures: 
The study will be conducted in accordance with ICH-GCP and US FDA
regulations.
The Flow Chart of Assessments specifies the procedures that will be performed
at each study visit.
Baseline Visit 
After appropriate information about the study and PANZYGA has been provided
and written informed consent/assent has been obtained, patients will be
evaluated for study eligibility according to the inclusion/exclusion criteria. These
evaluations will
include
demographics,
medical/surgical
history,
current
medications, physical examinations, blood and urine samples, along with other 
safety and baseline evaluations as specified in the Flow Chart of Assessments.
Infusion Visits (Day 1 and Day 3)
The first PANZYGA infusion must begin no more than 2 days after Baseline
evaluations have been completed and eligibility criteria have been confirmed. If
Baseline and Day 1 Visits occur on the same day, Day 1 investigations do not
need to be repeated. If Baseline evaluations are completed more than 2 days
before Day 1, then the platelet count must be repeated and evaluated by the
Investigator prior to the first infusion.
Patients who have met all of the inclusion criteria and none of the exclusion 
criteria will return to the study site for their first PANZYGA infusion. Required 
assessments will be performed as specified in the Flow Chart of Assessments, 
including safety evaluations before and after each infusion. Patients will remain 
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Page 8 of 60 
Name of Sponsor/Company: 
Octapharma USA 
 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
Marketing Study to Evaluate the Efficacy 
at the study site during the infusion and for about 30 minutes after the end of
each infusion to complete vital sign measurements.
Safety of PAN ZYGA in  Pedi at r ic P atients wit h 
Chroni c
Assessment Day 5 though Day 22
Patients will return to the study site as indicated in the Flow Chart of
Assessments for continued efficacy and safety evaluations.
Day 32 (End of Study/Early Termination Visit)
Patients will return to the study site on Day 32 for final safety assessments/End
of Study (EOS) visit. Patients withdrawn early from the study will be encouraged
to return to the study site and complete the EOS assessments.
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Page 9 of 60 
Statistical Analysis: 
The primary endpoint for this study is the proportion of patients with an increase 
in platelet count to ≥50x109/L at least once within 7 days after the first infusion. 
This proportion will be assessed and presented together with its associated 
95% confidence interval to facilitate comparison with results from other studies 
and published data. Because of the limited number of patients, no formal 
hypothesis test will be performed; any p-value or confidence interval presented 
is to be understood in the exploratory sense. 
All data collected will be presented descriptively. The time to reach the desired
increase in platelet count as well as the duration of response will be presented
in listings and summarized in statistical tables. Individual profiles of platelet
count over time will be presented as Trellis plots.
All safety data, including tolerability assessments, abnormal laboratory values,
and AEs will also be listed and summarized statistically.
Statistical presentations will be fit to the nature of individual data items and
include sample characteristics, frequency counts and rates. Product-limit
survival function estimates (Kaplan-Meier Plots), confidence intervals and
graphs will be included as appropriate.
The following populations will be considered for the statistical analysis:
•
Safety Analysis Set (SAF): All patients who received at least part of one
infusion of PANZYGA.
•
Full Analysis Set (FAS): All patients in the SAF who satisfy all major 
eligibility criteria and for whom any post-baseline data is available. This
is the set of eligible patients with treatment effects measured, according
to the intention-to-treat (ITT) principle.
•
Per-Protocol Set I (PP1): All patients in the FAS, excluding those with
significant protocol deviations before the primary efficacy assessment on
day 8 is completed, and which may have an impact on the evaluation of
the primary endpoint.
•
Per-Protocol Set II (PP2): All patients in the FAS, excluding those with
significant protocol violations potentially affecting the (secondary) 
efficacy evaluations. 
Only protocol deviations with the potential to significantly affect the study results
or to invalidate the interpretation of the data obtained will lead to exclusion of
patients from the PP sets. The inclusion of each patient in the respective
analysis populations will be determined before database lock in a data review
meeting by a panel consisting of a medical expert from the Sponsor, the clinical
study manager, the data manager, and the study statistician.
A detailed Statistical Analysis Plan (SAP) will be compiled as a separate 
document. 
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Study Protocol No. NGAM-10, Version 03 CONFIDENTIAL 
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Page 10 of 60 
FLOW CHART OF ASSESSMENTS 
Table 1: 
Flow Chart of Assessments 
ASSESSMENTS 
Scr / BL1 
Day 
1 
Day 
3 
Day 
512
Day 
812 
Day 
1512 
Day 
2212 
Day 
3213
Visit Window (Days) 
-7 / -2
0 
0 
±1 
±1 
±3 
±3 
±5 
Informed Consent 
X 
Inclusion / Exclusion Criteria Review 
X 
X 
Demographics 
X 
Medical and Surgical History2 
X 
Body Weight 
X 
Physical Examination and Height 
X3 
X3 
X3 
X4 
X4 
X4 
X4 
X3 
Urine or Blood Pregnancy Test (females of 
child-bearing potential) 
X 
X 
Hematology: CBC with white blood cell 
(WBC) differential, hematocrit, hemoglobin, 
platelet counts, reticulocytes  
X 
X5,6 
X5,6,7 
X 
X 
X 
X 
X 
Hemolysis: total, direct, and indirect bilirubin 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry: ALT, AST, creatinine, Na, 
Ca, K, BUN, LDH 
X 
X 
X 
X 
X 
X 
Viral markers (HIV, HCV, HBV nucleic acid 
test [NAT]) 
X7 
PANZYGA INFUSIONS 
X 
X8 
Vital Signs: heart rate, blood pressure, 
temperature, respiratory rate 
X 
X9 
X9 
X 
AE Monitoring10 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Therapy (drug and 
non-drug)11
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BL = Baseline, Scr = Screening 
1) Screening Period is 7 days. Day 1 (first PANZYGA infusion) must occur no more than 2 days after Baseline 
evaluations have been completed. If the Baseline visit occurs more than 2 days after Baseline evaluations have 
been completed, the platelet count must be repeated and evaluated by the Investigator before initiation of the Day 1
infusion. If Baseline and Day 1 Visits occur on the same day, the Day 1 investigations need not be repeated.
2) Medical History will be collected for the previous year and will include the onset date of ITP. Surgical history will 
include the date of splenectomy (if applicable), and any other surgical procedures in the previous year.
3) Brief Physical Examination: general appearance, skin, heart, lungs, abdomen, extremities. Height will only be 
collected at Baseline.
4) Limited Physical Examination with targeted body systems per Investigator discretion.
5) Pre-infusion
6) Platelet count, hematocrit, and hemoglobin results must be available and reviewed by the Investigator prior to start
of the infusion. 
7) HIV/HCV/HBV NAT Test: Infusions may begin before the results are back if the Investigator is not aware of, and the 
patient isn’t exhibiting clinical signs of, any viral infection.
8) If the Day 3 preinfusion platelet count shows evidence of response as indicated by the platelet count at least
doubling from Baseline count AND >50x109/L, the Day 3 infusion will not be administered. If the Baseline platelet
count has doubled but is ≤50x109/L, the Day 3 infusion will be administered.
9) Vital Signs: at the start of the infusion and every 60 minutes (±15 minutes) thereafter until the end of the infusion. In
addition, vital sign measurements will be recorded just prior to every infusion rate change (-10 minutes), 15 minutes
(+15 minutes) after each infusion rate change, and approximately 30 minutes (+15 minutes) after the end of the 
infusion. 
10) The start date and start time will be collected for any adverse events starting at Day 1 through Day 32/EOS visit.
11) Prior medications will be collected for the 3 months. The start date and start time will be collected for any 
concomitant medications taken on Day 1 through Day 32/EOS visit.
12) Days 5, 8, 15, and 22 visits may be performed locally by patient’s primary care physician or a local laboratory 
service upon agreement with the site Principal Investigator, the IRB, and the Sponsor.
13) Day 32 visit will correspond to the Early Termination visit for patients who are withdrawn early from the study.
Page 145 of 260 
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Study Protocol No. NGAM-10, Version 03 CONFIDENTIAL 
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PROTOCOL SIGNATURES 
This study is intended to be conducted in compliance with the protocol. 
Good Clinical Practice and
 
 
Octc1pharma Phf1rmazeL1tika Produktionsgesellschaft mbH 
Oberlaaerstr. 235 A- 1100 Vienna. Austria 
Tel: 
 
 
Octapharma USA, Inc. 
121 River Street. Suite 1201 
Hoboken, NJ, USA 
Tel: 
 
 
Signature 
Octapharma Pharmazeutika Produktionsgesellschaft mbH 
Oberlaaerstr. 235. A-1100 Vienna, Austria 
Tel: 
 
 
Signature 
Octapharma Pharmazeutika Produktionsgesellschaft mbH 
Ooerlaaerstr. 235, A-1100 Vienna, Austria 
Tel: 
 
Page 11 of 60 
1 2 AUG ?019 
Date 
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Study Protocol No. NGAM-10, Version 03 CONFIDENTIAL 
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Page 12 of 60 
TABLE OF CONTENTS 
STUDY OUTLINE ............................................................................................................. 2
FLOW CHART OF ASSESSMENTS ............................................................................. 10
PROTOCOL SIGNATURES .......................................................................................... 11
TABLE OF CONTENTS ................................................................................................. 12
TABLE OF TABLES ...................................................................................................... 15
LIST OF ABBREVIATIONS ........................................................................................... 16
1
INTRODUCTION.................................................................................................... 18
1.1
RATIONALE FOR CONDUCTING THE STUDY ..................................................... 19
1.2
DOSE RATIONALE.......................................................................................... 19
1.3
BENEFIT-RISK STATEMENT............................................................................ 19
2
STUDY OBJECTIVES............................................................................................ 21
2.1
PRIMARY OBJECTIVES ................................................................................... 21
2.2
SECONDARY OBJECTIVES.............................................................................. 21
3
INVESTIGATIONAL PLAN.................................................................................... 22
3.1
PRIMARY AND SECONDARY ENDPOINTS......................................................... 22
3.1.1 Primary Endpoint ............................................................................. 22
3.1.2 Secondary Endpoints....................................................................... 22
3.2
OVERALL STUDY DESIGN AND PLAN .............................................................. 22
3.3
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP(S)........... 23
3.3.1 Study Design.................................................................................... 23
3.3.2 Control Group(s) .............................................................................. 24
3.3.3 Study Parameters ............................................................................ 24
4
STUDY POPULATION........................................................................................... 25
4.1
POPULATION BASE ........................................................................................ 25
4.1.1 Inclusion Criteria .............................................................................. 25
4.1.2 Exclusion Criteria............................................................................. 25
4.2
PRIOR AND CONCOMITANT THERAPY ............................................................. 27
4.2.1
Allowed Pre-medications ................................................................. 27 
4.2.2
Prohibited Medications .................................................................... 27 
4.3
WITHDRAWAL AND REPLACEMENT OF PATIENTS ............................................ 28
4.3.1 Premature Patient Withdrawal ......................................................... 28 
4.3.2 Patient Replacement Policy ............................................................. 28 
4.4
ASSIGNMENT OF PATIENTS TO TREATMENT GROUPS ..................................... 28
4.5
RELEVANT PROTOCOL DEVIATIONS ............................................................... 28
4.6
SUBSEQUENT THERAPY ................................................................................. 28
5 
INVESTIGATIONAL MEDICINAL PRODUCT ...................................................... 29
5.1
CHARACTERIZATION OF INVESTIGATIONAL PRODUCT ..................................... 29
5.2
PACKAGING AND LABELLING .......................................................................... 29
5.3
CONDITIONS FOR STORAGE AND USE ............................................................ 30
5.4
DOSE AND DOSING SCHEDULE ...................................................................... 30
5.5
PREPARATION AND METHOD OF ADMINISTRATION .......................................... 31
5.6
BLINDING, EMERGENCY ENVELOPES, AND BREAKING THE STUDY BLIND ........ 31
5.7
TREATMENT COMPLIANCE ............................................................................. 32
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5.7.1 Drug Dispensing and Accountability................................................ 32 
5.7.2 Assessment of Treatment Compliance ........................................... 32 
6 
STUDY CONDUCT ................................................................................................ 33
6.1 
OBSERVATIONS BY VISIT ............................................................................... 33
6.1.1 Baseline Visit/Screening Period ...................................................... 33 
6.1.2 Day 1 ................................................................................................ 33 
6.1.3 Day 3 ................................................................................................ 34 
6.1.4 Day 5 and Day 8 (± 1 day) ............................................................... 34 
6.1.5 Day 15 and Day 22 (± 3 days) ......................................................... 35 
6.1.6 Day 32 (End of Study Visit) (± 5 days) ............................................ 35 
6.1.7 Visit Windows Used in this Study, including Tolerances ................ 35
6.2 
DURATION OF STUDY ..................................................................................... 36
6.2.1 Planned Duration for an Individual Patient...................................... 36
6.2.2 Planned Duration for the Study as a Whole .................................... 36
6.2.3 Premature Termination of the Study ............................................... 36
7
ASSESSMENTS AND METHODS ........................................................................ 38
7.1
DEMOGRAPHIC AND BASELINE INFORMATION ................................................. 38
7.1.1 Demographic and Baseline characteristics ..................................... 38
7.1.2 Medical and Surgical history............................................................ 38
7.1.3 Viral Marker Tests............................................................................ 38
7.1.4 Prior and Concomitant Medication Use........................................... 38
7.2
EFFICACY ASSESSMENTS .............................................................................. 38
7.3
SAFETY ASSESSMENTS ................................................................................. 39
7.3.1 Assessments for Safety Evaluations ............................................... 39
7.3.2 Adverse Events................................................................................ 39
7.3.3 Serious Adverse Events .................................................................. 42
7.3.4 SAE Reporting Timelines ................................................................ 43
7.3.5 Laboratory Tests.............................................................................. 43
7.3.6 Vital Signs ........................................................................................ 44
7.3.7 Physical Examination including Height and Body Weight............... 44
7.3.8 Other Relevant Safety Information .................................................. 45
7.4
OTHER ASSESSMENTS .................................................................................. 46
7.5
APPROPRIATENESS OF MEASUREMENTS........................................................ 46
8
DATA HANDLING AND RECORD KEEPING ...................................................... 47
8.1
DOCUMENTATION OF DATA............................................................................ 47
8.1.1 Source Data and Records ............................................................... 47 
8.1.2 Electronic Case Report Forms ........................................................ 47 
8.1.3 Changes to Electronic Case Report Form Data .............................. 47 
8.2
INFORMATION TO INVESTIGATORS .................................................................. 48
8.3
RESPONSIBILITIES ......................................................................................... 48
8.4
INVESTIGATOR’S SITE FILE ............................................................................ 48
8.5
PROVISION OF ADDITIONAL INFORMATION ...................................................... 49
8.6
INDEPENDENT DATA MONITORING COMMITTEE .............................................. 49
9 
STATISTICAL METHODS AND SAMPLE SIZE ................................................... 50
9.1
DETERMINATION OF SAMPLE SIZE.................................................................. 50
9.2
STATISTICAL ANALYSIS .................................................................................. 50
9.2.1 Populations for Analysis .................................................................. 51 
9.2.2 Efficacy Analysis Plan ...................................................................... 51 
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9.2.3 Safety Analysis Plan ........................................................................ 52 
9.2.4 Handling of Missing Data ................................................................. 53 
9.3 
RANDOMIZATION, STRATIFICATION, AND CODE RELEASE ............................... 53
9.4 
INTERIM ANALYSIS ......................................................................................... 53
10 
ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ............ 54
10.1 ETHICAL/REGULATORY FRAMEWORK ............................................................. 54
10.2 APPROVAL OF STUDY DOCUMENTS................................................................ 54
10.3 PATIENT INFORMATION AND INFORMED CONSENT .......................................... 54
10.4 PROTOCOL AMENDMENTS ............................................................................. 55
10.5 CONFIDENTIALITY OF PATIENT DATA .............................................................. 55
11
QUALITY CONTROL AND QUALITY ASSURANCE........................................... 56
11.1 PERIODIC MONITORING ................................................................................. 56
11.2 AUDIT AND INSPECTION ................................................................................. 56
12
REPORTING AND PUBLICATION ....................................................................... 57
12.1 CLINICAL STUDY REPORT.............................................................................. 57
12.2 PUBLICATION POLICY..................................................................................... 57
13
LIABILITIES AND INSURANCE ........................................................................... 58
14
REFERENCES ....................................................................................................... 59
15
APPENDICES ........................................................................................................ 60
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TABLE OF TABLES 
Table 1:
Flow Chart of Assessments ............................................................... 10
Table 2:
Prohibited Medications....................................................................... 27
Table 3:
Qualitative and Quantitative Composition of PANZYGA .................. 29
Table 4:
Visit Windows Used in this Study ...................................................... 35
Table 5:
Laboratory Tests and Time Points..................................................... 44
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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine Aminotransferase 
ASH 
American Society of Hematology 
AST 
Aspartate Aminotransferase 
CIDP 
Chronic Inflammatory Demyelinating Poly(radiculo)neuropathy 
CRO 
Contract Research Organisation 
DEHP 
Diethylhexylphthalate 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOS 
End of Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus
IB 
Investigator’s Brochure
ICH 
International Conference on Harmonisation
IDMC 
Independent Data Monitoring Committee
IEC 
Independent Ethics Committee
ifas 
4-letter meaningless suffix assigned by FDA at the end of newly
approved biologics
IgA 
immunoglobulin A
IMP 
Investigational Medicinal Product 
IRB
Institutional Review Board 
ITP 
Immune Thrombocytopenia 
ITT
Intention-to-Treat 
IUD 
Intrauterine device 
IGIV
Intravenous Immunoglobulin 
LDH 
lactase dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMN 
Multifocal Motor Neuropathy 
NAT 
Nucleic Acid Test 
PMR 
Post-Marketing Requirement 
PREA 
Pediatric Research Equity Act 
PP 
Per-Protocol 
PP1 
Per-Protocol Set 1 
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Abbreviation 
Description 
PP2 
Per-Protocol Set II 
PVC 
Polyvinyl Chloride 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
SLE 
systemic lupus erythematosus 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent Adverse Event 
TNBP 
tri-n-butyl phosphate 
TPO-RA 
Thrombopoietin Receptor Agonists 
ULN 
Upper Limit of Normal 
USC 
United States Code 
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1 
INTRODUCTION 
Since more than five decades immunoglobulins have been used to provide 
antibodies for the prevention of viral and bacterial diseases (replacement 
therapy) in immunocompromised patients. Within the last 25 years intravenous 
immunoglobulin (IGIV) has been proven to be useful in a wide variety of clinical 
conditions other than replacement therapy of immunocompromised patients, in 
which IGIV exhibits an immunomodulatory effect. These include Idiopathic 
Thrombocytopenic (ITP) in children and adults at high risk of bleeding or prior to 
surgery to correct the platelet count, Kawasaki disease, and Guillain-Barré 
syndrome (GBS). More recently, single IGIV brands have also been licensed for 
Multifocal Motor Neuropathy (MMN) and Chronic Inflammatory Demyelinating 
Poly(radiculo)neuropathy (CIDP). Experimental off-label use of IGIV mostly in 
other neurological and dermatological indications is widespread. 
ITP is an immune-mediated (disorder characterized by increased platelet 
destruction. The reason for platelet destruction is the development of 
autoantibodies to platelet-membrane antigens. These antibodies are particularly 
produced in the spleen which is also the major site of platelet destruction [1]. In 
patients suffering from ITP, several studies have shown IGIV effective in 
increasing platelet counts to prevent or control bleeding [2-4] The mechanism of 
action in ITP is not fully elucidated but includes immunomodulatory effects, 
particularly the modulation of cytokines, soluble cytokine receptors and cytokine 
receptor antagonists with anti-inflammatory effects as well as complement 
modulation. 
Broadly, 2 categories of agents are available for the treatment of ITP: 1) those 
that rapidly and transiently interfere with the process of platelet destruction for 
management of acute bleeding or bleeding risk (front-line therapies), and 
2) those with potential to provide a more durable improvement in the platelet 
count (second-line therapies). Corticosteroids, IGIV, and anti-D immune globulin 
remain the mainstay of front-line treatment of acute bleeding symptoms in both 
adults and children [5]. Although corticosteroids remain the most commonly used 
ITP therapy, controversy still exists surrounding selection of agent, dosing, and 
duration of therapy. For treatment with prednisone, it is generally accepted that 
shorter courses are preferable to chronic therapy. The 2010 International 
Consensus Report on the investigation and management of primary ITP 
developed by an international working group address three classes of second-
line therapies: splenectomy, rituximab, and the thrombopoietin receptor agonists 
(TPO-RA). Due to a relative lack of data, their use was recommended only in 
patients who were refractory to splenectomy and other therapies. Further study 
results in 2016 demonstrated that TPO-RA agents are being used in children with 
ITP of varying duration and severity. The response was similar to clinical trials, 
but the sustainability of response varied. Future studies need to focus on the ideal 
timing and rationale for these medications in pediatric patients [6]. 
PANZYGA is a human immunoglobulin solution with 10% protein content for 
intravenous administration. PANZYGA is made from a pool of at least 
1000 donations of human fresh-frozen plasma per batch.  
PANZYGA was granted a US approval by the US Food and Drug Administration 
(FDA) in August 2018. The license in 2 indications (primary humoral 
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immunodeficiency diseases and chronic immune thrombocytopenia) was granted 
based on 2 completed studies. The first study in Primary Immune Deficiency 
included 51 children and adults from ages 2 years to 65 years who were dosed 
at 200 mg/kg to 800 mg/kg body weight every 3 to 4 weeks for 360 days. The 
second study in Immune Thrombocytopenia included 40 adults with chronic ITP 
receiving 2 gm/kg body weight over 2 consecutive days. Of the 36 subjects in the 
full analysis set, 29 patients (81%: 95% CI: 64% to 92%) responded to PANZYGA 
with a rise in platelet count to at least 50x109/L within 7 days after the first 
infusion. 
Further information can be found in the Investigator’s Brochure (IB). 
1.1 Rationale for Conducting the Study 
Under the Pediatric Research Equity Act (PREA) (21 United States Code [USC]
355c) all applications for new active ingredients, new indications, new dosage
forms, new dosing regimens or new routes of administration are required to
contain an assessment of the safety and effectiveness of the product for the
claimed indication in pediatric patients unless this required is waived, deferred or
inapplicable.
This post-marketing requirement (PMR) study was requested by the US FDA 
after PANZYGA received marketing approval in the United States. The rationale
for conducting this PMR study is to investigate the efficacy and safety of
PANZYGA in children suffering from primary ITP.
The study will be conducted in compliance with the protocol, International
Conference on Harmonisation-Good Clinical Practice (ICH-GCP), US FDA Code
of Federal Regulations, and other local regulatory requirements.
1.2 Dose Rationale 
According to recent guidelines, IGIV is recommended for patients with platelet
counts <30x109/L in case of severe bleeding and/or mucous membrane bleeding.
Standard doses should be studied (0.8 g/kg to1 g/kg on Day 1, which may be
repeated once within 3 days, or 0.4 g/kg/day for 2 to 5 days). If other dosage
regimens are to be applied for, they should be supported by clinical data. [7,8].
The dose option for this study is within the recommended guidelines.
1.3
Benefit-Risk Statement
The safety profile of IGIV is well characterized and, in general, the same type of
adverse reactions may be expected for PANZYGA. No new or unknown safety
problems are expected to emerge which are not already described in the
Investigator's Brochure.
Data obtained from the clinical trials conducted with PANZYGA in the adult ITP 
population clearly met the recommended clinical response criteria for efficacy as 
set out in the relevant FDA and EU guidelines. These data are comparable with 
available literature data on other commercial IVIGs and formed the basis for 
marketing authorization in Europe and the US. The safety profile of PANZYGA is 
satisfactory and the number of infusional AEs are below the levels as 
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recommended by the FDA for products of this class. Efficacy and safety data with 
PANZYGA in 3 clinical studies in 51 patients (also including pediatric patients) 
with primary immunodeficiency (PID) and in 40 patients with immune 
thrombocytopenia (ITP) are available. Available data are sufficient to expect 
favorable benefit-risk profile of PANZYGA in the pediatric ITP population. 
Expected clinical benefit of using PANZYGA in this study is an increase in 
platelets level to control or prevent bleeding. The main known risks are listed 
below: 
•
Thrombosis may occur with immune globulin intravenous (IGIV) products,
including PANZYGA. Risk factors may include: advanced age, prolonged
immobilization, hypercoagulable conditions, history of venous or arterial
thrombosis,
use
of
estrogens,
indwelling
vascular 
catheters,
hyperviscosity, and cardiovascular risk factors.
•
Renal dysfunction, acute renal failure, osmotic nephropathy, and death
may occur with the administration of IGIV products in predisposed
patients. Renal dysfunction and acute renal failure occur more commonly
in patients receiving IGIV products containing sucrose. PANZYGA does 
not contain sucrose.
•
For patients at risk of thrombosis, renal dysfunction, or renal failure,
administer PANZYGA at the minimum infusion rate practicable. Ensure
adequate hydration in patients before administration. Monitor for signs and
symptoms of thrombosis and assess blood viscosity in patients at risk for 
hyperviscosity.
•
Standard measures are taken to prevent infections resulting from the use
of medicinal products prepared from human blood or plasma. Despite this,
when medicinal products prepared from human blood or plasma are
administered, the possibility of transmitting infective agents cannot be
totally excluded. During the manufacturing process of PANZYGA,
significant viral reduction is obtained.
Inclusion and exclusion criteria, recommendations on the rate of infusion,
dosage, and monitoring procedures provided in this protocol sufficiently mitigate
above mentioned risks and must be adhered to.
No new or unknown safety problems are expected to emerge in pediatric ITP
population, which are not listed above or described in the Investigator's Brochure.
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2 
STUDY OBJECTIVES 
2.1 Primary Objectives 
The primary objective is to evaluate the efficacy of PANZYGA in increasing the 
platelet count in pediatric patients with chronic ITP. 
2.2 Secondary Objectives 
The secondary objectives of this study are to: 
•
Assess safety of up to 2 g/kg PANZYGA (1 g/kg PANZYGA on Day 1 and
an optional dose of 1 g/kg PANZYGA on Day 3) infused in the pediatric 
population within the scope of the clinical study
•
Determine the time to reach a platelet count of 50x109/L
•
Determine duration of time during which the platelet count is maintained
at the level ≥50х109/L
•
Determine the maximum platelet count during the study
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3 
INVESTIGATIONAL PLAN 
3.1 Primary and Secondary Endpoints 
3.1.1 Primary Endpoint 
The primary efficacy parameter is defined as an increase in platelet count at least 
once to ≥50x109/L within 7 days after the first infusion, ie, by Day 8 (increase 
must occur at least once on any day up to and including Day 8). This definition of 
clinical response will serve as the basis for the primary endpoint, the response 
rate (ie, the proportion of patients with an elevation of platelet count at least once 
to 50x109/L within 7 days [ie, Day 8] after the first infusion). 
3.1.2 Secondary Endpoints 
Secondary endpoints are defined to further evaluate the efficacy and safety of
the PANZYGA infused in the pediatric population.
The following parameters will be used to for efficacy assessments:
•
Time to reach a platelet count of 50x109/L
•
Duration of platelet response defined as the number of days the platelet
count remains above 50x109/L
•
Maximum platelet count during the study
The following parameters will be used for safety assessments:
•
AEs
•
Vital signs (blood pressure, heart rate, temperature, respiratory rate)
•
Physical examination
•
Laboratory parameters: hematology (including reticulocytes), hemolysis,
platelet count, serum chemistry (including lactase dehydrogenase [LDH])
3.2
Overall Study Design and Plan
This is a prospective, open-label, single-arm, multicenter, Phase 4 study 
evaluating the efficacy and safety of the investigational product, PANZYGA, in
pediatric patients with chronic ITP.
The study will enroll at least 20 patients 1 year to <18 years old and will not be
stratified by age group. A patient is considered enrolled into the study after 
successfully completing all baseline assessments and receiving at least a partial
dose of PANZYGA.
Patients with a confirmed diagnosis of chronic ITP, without evidence of active 
major bleeding, may be enrolled in the study. Study procedures will only begin 
after written informed consent (from parent or guardian) and assent (from the 
patient, as age appropriate per Institutional Review Board [IRB] requirements) 
have been obtained. Patients who meet all of the inclusion and none of the 
exclusion criteria may receive the first infusion of PANZYGA within 2 days after 
Baseline investigations have been completed. 
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Each patient will be administered PANZYGA by intravenous infusion at a dose of 
1 g/kg body weight PANZYGA on Day 1 and optionally another dose of 1 g/kg 
PANZYGA on Day 3; body-weight dependent doses will be based on each 
patient’s weight collected at Baseline. Total PANZYGA doses will be 1 g/kg for 
patients receiving only 1 dose on Day 1 and 2g/kg for those receiving the optional 
Day 3 dose. Prior to the Day 3 infusion, Investigators will assess each patient’s 
preinfusion platelet count, hematocrit, and hemoglobin. Patients whose platelet 
count shows evidence of response as indicated by the platelet count at least 
doubling from Baseline count AND is >50x109/L, the Day 3 infusion will not be 
administered. If the Baseline platelet count has doubled but is ≤50x109/L, the 
Day 3 infusion will be administered. If any parameters indicate a clinically relevant 
change such that, in the Investigator’s opinion, it is not safe to administer the 
second infusion, the patient should be withdrawn from study treatment; however, 
the patient will be followed for safety through Day 32.  
Study interventions and procedures will be performed at predefined timepoints 
(see Section 6.1 and the Flow Chart of Assessments [Table 1]) including (but are 
not limited to): blood draws for safety evaluations, vital signs, body weight, 
physical examinations, AE monitoring, and changes in concomitant medication 
use. Patients will have clinic visits on Days 1, 3, 5, 8, 15, and 22. They will return 
to the clinic for a final safety follow-up evaluation at Day 32/End of Study (EOS) 
Visit.  
PANZYGA infusions may be stopped or interrupted at any time if, in the 
Investigator’s opinion, it is not safe to continue or is not in the patient’s best 
interest. Patients who have received a partial dose of PANZYGA should be 
followed for safety evaluations through Day 32/EOS.  
The study is planned to begin screening procedures Q3 2019 at up to 8 sites in 
the USA, with recruitment lasting approximately 30 months, and is anticipated to 
complete in Q1 2022. The study duration for a single patient will be approximately 
39 days, including up to a 1-week Screening period.  
3.3 Discussion of Study Design and Choice of Control Group(s) 
3.3.1 Study Design 
This study was designed to meet the US FDA’s requirements under the PREA 
(21 USC 355c) for a post-approval study of PANZYGA in the pediatric population. 
US FDA is requiring a pediatric study for the treatment of ITP to evaluate 
PANZYGA for the treatment of ITP in patients ages ≥1 year to <18 years. All of 
the US FDA’s recommendations have been incorporated into the protocol.  
This study design is also in line with study protocols evaluating NGAM in adults, 
with the frequency of blood draws and number of visits reduced to accommodate 
a pediatric population. Because of the limited number of patients that will be 
enrolled in this study, along with the increased blood volume and additional site 
visits that would be required to meet the full recommendations in the European 
Medicines Agency (EMA) Guideline for confirmatory visits and blood draws, the 
secondary efficacy endpoints were selected to allow efficacy evaluations in this 
patient population. 
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3.3.2 Control Group(s) 
A placebo control group will not be included in this post-approval study. An active 
control group is not considered relevant, as the objective of this study is to 
evaluate the efficacy and safety of PANZYGA in the pediatric population, not to 
compare the efficacy and safety of PANZYGA versus another IGIV treatment. 
3.3.3 Study Parameters 
The primary therapeutic target for ITP treatment is an increase in the platelet
count. Therefore, the primary endpoint chosen for the study, namely the response
rate (ie, the proportion of patients with an increase in platelets at least once to
≥50x109/L within 7 days after the first infusion), is appropriate to adequately
describe the efficacy of treatment of PANZYGA in the pediatric population.
To assess the efficacy of PANZYGA in correcting the platelet count, this response
rate has been chosen as the primary endpoint. There are several definitions of
response published in guidelines and commonly used for the evaluation of ITP
treatment; however, an increase in platelets to ≥50x109/L is the most established
definition of response [7] and as such has been chosen for this post-marketing
approval study.
The secondary efficacy endpoints chosen are in accordance with the primary
endpoint, in order to further characterize the effect on the increase in platelet
count.
The safety assessments, including AE, vital signs, laboratory results, and
physical examination are appropriate and commonly used parameters to monitor
the of IGIV treatment during a clinical study.
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4 
STUDY POPULATION 
4.1 Population Base 
At least 20 female or male patients 1 year to <18 years old with chronic ITP will 
be eligible for this study.  
4.1.1 Inclusion Criteria 
Patients who meet all of the following criteria are eligible for the study: 
1. Females and males aged from 1 year to <18 years old
Note: Patients who turn 18 years old during study participation must
be re-consented at their next study visit with an adult informed consent
form.
2. Confirmed diagnosis of Chronic Immune Thrombocytopenia (ITP) 
according to American Society of Hematology (ASH 2011) guidelines
3. Platelets count <30x109/L at the Baseline Visit
4. Voluntarily given written informed consent (provided by patient’s 
parent or legal guardian) and assent (provided by patient)
5. Females of childbearing potential who have been using at least
1 acceptable form of birth control for a minimum of 30 days (or a
minimum of 3 months for hormonal contraceptives) prior to the
Screening visit, and must agree to use at least 1 acceptable method
of contraception for 30 days after the last dose of PANZYGA.
Acceptable methods include: intrauterine device (IUD), hormonal
contraception, male or female condom, spermicide gel, diaphragm,
sponge, or cervical cap. Abstinence is not considered an acceptable
method of birth control.
6. Parent or legal guardian must agree and be willing to assist the
participant attend study visits, and to follow all protocol requirements 
and instructions of the study doctor
4.1.2 Exclusion Criteria
Patients who meet any of the following criteria are not eligible for the study:
1. Thrombocytopenia secondary to other diseases (such as Acquired
Immunodeficiency Syndrome [AIDS] or systemic lupus
erythematosus [SLE]), drug-related thrombocytopenia, or congenital
thrombocytopenia
2. Administration of intravenous immunoglobulin (IGIV) or anti-D
immunoglobulin within 3 weeks before enrollment
3. Administration of thrombopoietin receptor agonists when the dose
has NOT been stable within 3 weeks before enrollment and a dosage
change is planned before Day 32
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4. Administration of oral immunosuppressants when the dose has NOT 
been stable during the preceding 2 months (2 weeks for long-term 
corticosteroid therapy) and a dosage change is planned before 
Day 32 (Note: topical agents and inhaled corticosteroid therapy use is 
permitted) 
5. Administration of long-term anti-prolific agents or attenuated 
androgen therapy when the dose has NOT been stable during the 
preceding 2 months and a dosage change is planned before Day 32 
6. Nonresponsive to previous treatment with IGIV or anti-D 
immunoglobulin 
7. Evidence of an active major bleeding episode at Screening 
8. Splenectomy in the previous 3 months or planned splenectomy 
throughout the study period 
9. Evans syndrome (experiencing active disease with 2 out of 3 of the 
following: autoimmune thrombocytopenia, autoimmune hemolytic 
anemia, and/or autoimmune neutropenia) 
10. Known or suspected human immunodeficiency virus (HIV), 
hepatitis B virus (HBV), and/or hepatitis C virus (HCV) infections 
11. Emergency surgery in the previous 4 weeks 
12. Severe liver and/or kidney disease (alanine aminotransferase [ALT] 
>3x upper limit of normal (ULN), aspartate aminotransferase [AST] 
>3x upper limit of normal (ULN), and/or creatinine >120 µmol/L) 
13. History of severe hypersensitivity to blood or plasma derived 
products, or any component of the PANZYGA 
14. Known immunoglobulin A (IgA) deficiency and antibodies against IgA 
15. History of, or suspected, alcohol or drug abuse in the previous year 
16. Females who are pregnant or nursing  
17. Unable or unwilling to comply with the study protocol 
18. Receipt of any other investigational medicinal product within 
3 months before study entry 
19. Risk factors* for thromboembolic events in whom the risks outweigh 
the potential benefit of PANZYGA treatment. 
20. Any other condition(s), that in the Investigator’s opinion, make it 
undesirable for the patient to participate in the study or may interfere 
with protocol compliance.  
* Risk factors include, but are not limited to: obesity, advanced age, hypertension, 
diabetes, a history of atherosclerosis/vascular disease or thrombotic events, 
hyperlipidemia, multiple cardiovascular risk factors, acquired or inherited 
thrombophilic 
disorders, 
prolonged 
periods 
of 
immobilization, 
severe 
hypovolemia, central venous catheterization, active malignancy and/or known or 
suspected hyperviscosity. 
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4.2 Prior and Concomitant Therapy 
Details on medications taken within the previous 3 months prior to the Baseline 
Visit and any concomitant medications taken during the study must be recorded 
in the electronic case report form (eCRF). 
4.2.1 Allowed Pre-medications 
Use of H-1 blockers or antipyretics are allowed for patients who have history of 
hypersensitivity to IGIV treatment; this may minimize the severity of possible 
infusion-related reactions in patients already predisposed to hypersensitivity 
reactions. All pre-medications administered prior to PANZYGA administration 
must be recorded in the eCRF.  
4.2.2 Prohibited Medications 
Use of the following medications are forbidden during the study as specified 
below (Table 2):
Table 2: 
Prohibited Medications 
Medication 
Time Window 
IGIV 
prohibited for 3 weeks prior to Baseline Visit
through Day 32
anti-D immunoglobulin 
prohibited for 3 weeks prior to Baseline Visit
through Day 32
oral immunosuppressants 
prohibited during Screening Period through
Day 32 unless patients have been receiving
a stable dose for 2 months (2 weeks for long-
term corticosteroid therapies) prior to
Screening Visit
thrombopoietin receptor agonists
prohibited during Screening Period through 
Day 32 unless patients have been receiving 
stable dose for 3 weeks prior to Screening 
Visit 
long-term anti-prolific agents or
attenuated androgen therapy
prohibited during Screening Period through 
Day 32 unless patients have been on a 
stable dose for 2 months prior to Screening 
Visit 
any other blood or plasma-derived
product*
prohibited during Screening Period through 
Day 32  
receipt of any other investigational
product
prohibited within 3 months prior to Baseline 
Visit through Day 32 
* Patients who are non-responders or requiring emergent ITP treatment (other than PANZYGA specified in this protocol)
will be followed for safety and complete all assessments through Day 32.
Trade names of drugs corresponding to the categories provided in Table 2 will
be provided in the Investigator Site Binder.
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4.3 Withdrawal and Replacement of Patients 
4.3.1 Premature Patient Withdrawal 
Patients have the right to withdraw from the study at any time for any reason, 
without the need to justify their decision; parents or legal guardians also have the 
right to withdraw a patient on the patient’s behalf. The Investigator also has the 
right to withdraw patients in case of AEs, poor compliance, or other reasons. 
Because an excessive rate of withdrawals can render the study noninterpretable, 
any unnecessary withdrawal of patients should be avoided. 
For any withdrawals after study entry, the Investigator will obtain all the required
details and document the reason(s) for discontinuation. If the reason for 
withdrawal of a patient is an AE, the main specific event or laboratory test will be
recorded, and the Investigator will make thorough efforts to clearly document the
outcome. Patients should return to the study site and have all safety evaluations,
including safety laboratory tests, completed as specified at the Day 32 visit
(See Section 6.1.6).
4.3.2 Patient Replacement Policy 
Patients withdrawn from the study will not be replaced. Under no circumstances
will patients who enroll in the study be permitted to re-enroll after study
completion. Patients who fail during the Screening Period (also referred to as 
Screen Failures) may be re-screened upon written approval from the Sponsor.
4.4
Assignment of Patients to Treatment Groups
This is an open-label non-randomized study. All patients will receive PANZYGA.
4.5
Relevant Protocol Deviations
In case of any major protocol deviation, the Investigator and Octapharma will
decide on the further participation of the patient in this study after having
discussed all relevant aspects.
A list of all included patients with all deviations from the intended study 
procedures and other criteria that may affect the patient's data validity for 
statistical analysis will be prepared upon clinical completion of the study. This will
also be discussed by a panel consisting of the clinical study manager, a medical
expert of the Sponsor, the data manager and the study statistician. This panel
will decide upon the membership of the patient in the Full Analysis Set (FAS), Per 
Protocol (PP) Set 1 (PP2), PP Set 2 (PP2), and Safety Analysis Set for statistical
analysis.
4.6 Subsequent Therapy 
If a patient withdraws from the study or is withdrawn by the Investigator by their 
parent/legal guardian, he/she will receive treatment by the Investigator or 
personal physician according to institutional standard of care.  
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5 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1 Characterization of Investigational Product 
Name of Medicinal Product: 
PANZYGA 
Active ingredient of PANZYGA: Immune globulin human-ifas 
Table 3: 
Qualitative and Quantitative Composition of PANZYGA 
Name of Ingredient 
Amount 
Total protein 
9.0 – 11.0 g/100 mL 
Protein composition 
≥95% Ig (≥96% Ig)* 
IgG content 
86 – 110 mg/mL 
Glycine 
15.0 – 19.5 mg/mL (17.3 mg/mL)* 
Water for Injection 
ad 1mL 
*Depending on regulatory requirements
PANZYGA is a solvent/detergent (S/D)-treated, sterile preparation of highly 
purified immunoglobulin G (IgG) derived from large pools of human plasma.
PANZYGA is a solution for infusion to be administered intravenously.
This preparation contains approximately 100 mg of protein per mL (10%), of
which not less than 96% is normal human immunoglobulin G. PANZYGA contains 
not more than 3% aggregates, not less than 90% monomers and dimers, and not
more than 3% fragments. On average, the product contains 100 μg/mL of IgA,
and lower amounts of IgM.
PANZYGA contains only trace amounts of sodium, and the pH is between 4.5
and 5.0. The osmolality is in the range of 240 to 310 mosmol/kg.
The manufacturing process for PANZYGA isolates IgG without additional
chemical or enzymatic modification, and the Fc portion is maintained intact.
PANZYGA contains the IgG antibody activities present in the donor population.
IgG subclasses are fully represented with the following approximate percentages
of total IgG: IgG1 is 65%, IgG2 is 28%, IgG3 is 3% and IgG4 is 4%.
PANZYGA contains a broad spectrum of IgG antibodies against bacterial and
viral agents that are capable of opsonization and neutralization of microbes and
toxins. PANZYGA contains glycine (15.0 to 19.5 mg/mL), but no preservatives or
sucrose.
All units of human plasma used in the manufacture of PANZYGA are provided by
FDA-approved blood and plasma establishments, and are tested by FDA-
licensed serological tests for HBsAg, antibodies to HCV and HIV and Nucleic Acid
Test (NAT) for HCV and HIV-1 and found to be non-reactive (negative).
5.2 Packaging and Labelling 
PANZYGA for investigational use only will be labeled according to US FDA 
regulations. Details of the labeling will be included in the Pharmacy Manual. 
The batch number(s) used will be recorded in the study documentation and EDC. 
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5.3 Conditions for Storage and Use 
PANZYGA must be stored and transported light-protected at +2°C (36°F) to +8°C 
(46°F) and must be brought to room temperature before use.  
Storage temperature must be maintained at +2°C (36°F) to +8°C (46°F) and will 
be monitored for the duration of the study by reviewing the temperature logs. 
PANZYGA must not be frozen prior to use. 
PANZYGA must not be used after its expiry date.  
PANZYGA must not be mixed with other medicinal products. 
Each PANZYGA bottle is for single use only. 
Authorized personnel at the individual study sites will ensure that PANZYGA is 
stored in appropriate conditions in a secure refrigerator with restricted access and 
in compliance with national regulations. 
5.4 Dose and Dosing Schedule 
PANZYGA will be administered by intravenous infusion. Patients should be 
adequately hydrated prior to infusion. 
Patients will receive a dose of 1 g/kg body weight PANZYGA given on Day 1 and 
optionally another dose of 1 g/kg PANZYGA given on Day 3; body-weight 
dependent doses will be based on each patient’s weight collected at Baseline. 
Total PANZYGA doses will be 1 g/kg for patients receiving only 1 dose on Day 1 
and 2 g/kg for those receiving the optional Day 3 dose. If the Day 3 platelet count 
shows evidence of response as indicated by the platelet count at least doubling 
from Baseline count AND is >50x109/L, the Day 3 infusion will not be 
administered. If the Baseline platelet count has doubled but is ≤50x109/L, the 
Day 3 infusion will be administered.  
PANZYGA will be delivered by intravenous infusion according to the 
recommended flow rates: 
• Initial infusion rate of 0.01 mL/kg/min (60 mg/kg/hr) for the first 30 minutes 
(±5 minutes) 
• If tolerated, increase to 0.02 mL/kg/min (120 mg/kg/hr) for the second 
30 minutes (±5 minutes) 
• If tolerated, increase to 0.04 mL/kg/min (240 mg/kg/hr) for the third 
30 minutes (±5 minutes) 
• If tolerated, increase to 0.08 mL/kg/min (480 mg/kg/hr) for the remainder 
of the infusion 
Infusion rates should not exceed 0.08 mL/kg/min and should not exceed 
8.0 mL/min.  
If a Grade 2 (moderate) or higher infusion-related adverse event (AE) occurs 
during infusion, the Panzyga infusion will be stopped. After infusion-related 
symptoms subside, the infusion may be resumed at a lower rate. The infusion 
rate may be gradually increased as tolerated by the patient. 
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If a Grade 1 (mild) infusion-related AE occurs during infusion, the infusion rate 
should be reduced to half the rate at which the event occurred, or the infusion 
should be interrupted until symptoms subside. The infusion may then be resumed 
at an infusion rate tolerated by the patient. The infusion rate may be gradually 
increased as tolerated by the patient.  
5.5 Preparation and Method of Administration 
All patients will be infused at the study site under the surveillance of authorized 
study site staff.  
After calculating the volume required for the dose using the patient’s Baseline
body weight (see Section 5.4), the appropriate number of vials will be removed
from the refrigerator. Vials of different sizes may be combined to reach the
required amount of IgG. The exact dose will be administered, and the empty and
partially used vials will be retained by the site for drug accountability and dose
verification.
PANZYGA vials must be allowed to warm to room or body temperature before
infusion. After PANZYGA vials have been brought to room or body temperature,
they should be inspected visually for particulate matter and discoloration prior to
administration. The solution should be clear or slightly opalescent. DO NOT USE
IF
TURBID,
DISCOLORATION
IS 
OBSERVED,
AND/OR
FLOATING
PARTICLES ARE PRESENT. Solutions that are cloudy or vials that have a
deposit must not be used and must be discarded according to local policy.
Aseptic technique must be used throughout the entire procedure.
The contents of bottles must be pooled under aseptic conditions into sterile
infusion bags and administered immediately after pooling. Only polyvinyl chloride
(PVC)-free, diethylhexylphthalate (DEHP)-free and latex–free, infusion bags can
be used. Once pooled, a label will be applied on the infusion bag. Detailed
instructions of this process and an example label will be included in the Pharmacy 
Manual.
PANZYGA will be infused into a vein using standard infusion supplies provided
by the individual site. Standard procedures should be followed to prime the
infusion line with a priming solution (eg, normal saline). At the end of each
infusion, the infusion line will be flushed with normal saline solution.
Additional information regarding PANZYGA preparation and infusion procedures
will be provided in a pharmacy manual.
Please refer to special warnings and precautions for use provided in the
PANZYGA Investigator Brochure.
5.6 Blinding, Emergency Envelopes, and Breaking the Study Blind 
Not applicable. 
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5.7 Treatment Compliance 
5.7.1 Drug Dispensing and Accountability 
The Sponsor or designee will provide and deliver all PANZYGA to participating 
Investigators. A Drug Inventory and Dispensing Log will be kept current by the 
Investigator, detailing the dates and quantities of PANZYGA received, dispensed 
to each patient, and the quantity remaining at the study site.  
The Drug Inventory and Dispensing Log will be available to the monitor to verify
drug accountability during the study. The study monitor will inventory all empty 
and partially used vials of PANZYGA and will cross-check this inventory versus
the patient source documentation (records), eCRF, and the Drug Inventory and
Dispensing Log.
Unused and partially used vials may be destroyed at the study site or returned to
the Sponsor for destruction according to institutional practice. Vials may be
destroyed only after drug accountability has been verified and fully reconciled by
the monitor and after the Sponsor has granted written approval of destruction.
Additional information regarding PANZYGA drug accountability procedures will
be provided in a pharmacy manual.
5.7.2 Assessment of Treatment Compliance 
All patients will be infused at the study site under the surveillance of authorized
study personnel. Infusion details will be documented together with the batch
number(s) in the source data and eCRF.
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6 
STUDY CONDUCT  
Procedures performed at each study visit are presented in the Flow Chart of 
Assessments (see Table 1). Time windows and tolerances are provided in Table 
4. 
6.1 Observations by Visit 
6.1.1 Baseline Visit/Screening Period 
The following assessments will be performed during the Screening Period. The 
Screening Period can last up to 1 week (to accommodate patient schedules and 
the informed consent/assent process); however, all Baseline evaluations should 
be completed within 2 days before the first administration of PANZYGA. 
• Obtaining voluntarily given, written (signed and dated) informed consent 
and assent (as age appropriate) 
• Inclusion and exclusion criteria 
• Demographic and baseline characteristics 
• Medical and surgical history (previous 1 year) 
• Splenectomy history 
• Physical examination and height 
• Vital signs 
• Body weight 
• Blood samples for serum chemistry, hematology, and hemolysis analytes 
• Blood or urine pregnancy test (females of childbearing potential, only) 
• Blood samples for viral markers 
• Documentation of prior medications (previous 3 months), including 
administration of pre-medication(s) as appropriate (see Section 4.2.1) 
6.1.2 Day 1 
Day 1 should take place within 2 days after Baseline evaluations have been 
completed. If the Baseline and Day 1 Visits occur on the same day, the Baseline 
investigations do not need to be repeated. If the Baseline evaluations are 
completed more than 2 days before Day 1, the platelet count must be repeated 
and evaluated by the Investigator prior to initiating the first infusion. 
Before the administration/infusion of PANZYGA, patient eligibility will be re-
evaluated. The following assessments/activities will be performed before 
PANZYGA infusion: 
• Confirmation of inclusion and exclusion criteria 
• Physical examination 
• Vital signs 
• Blood samples for serum chemistry, hematology, and hemolysis analytes 
• Administration of pre-medication(s) as appropriate (see Section 4.2.1) 
The following activities will be performed during or after PANZYGA infusion: 
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•
PANZYGA infusion
•
Vital signs (at the start of the infusion and every 60 minutes (±15 minutes)
thereafter until the end of the infusion. In addition, vital sign measurements
will be recorded just prior to every infusion rate change (-10 minutes),
15 minutes (+15 minutes) after each infusion rate change, and
approximately 30 minutes (+15 minutes) after the end of the infusion
•
Monitoring for AEs
•
Documentation of concomitant medication use
6.1.3 Day 3 
The following assessments/activities will be performed before PANZYGA 
infusion:
•
Physical examination
•
Vital signs
•
Blood samples for serum chemistry, hematology, and hemolysis analytes
•
NOTE: platelet, hemoglobin and hematocrit results must be available and
reviewed by the Investigator prior to initiating the Day 3 infusion
•
Administration of pre-medication(s) as appropriate (see Section 4.2.1)
The Investigator will assess each patient’s Day 3 preinfusion platelet count,
hematocrit, and hemoglobin. If the Day 3 platelet count shows evidence of clinical
response, as indicated by the platelet count at least doubling from Baseline count
AND is >50x109/L, the Day 3 infusion will not be administered. If the Baseline
platelet count has doubled but is ≤50x109/L, the Day 3 infusion will be
administered. In the event that the Day 3 infusion is not administered, all other
Day 3 assessments will still be completed. If any of these hematology parameters
indicate a clinically relevant change such that, in the Investigator’s opinion, it is
not safe to administer the second infusion the patient should be withdrawn from
study treatment but will be followed for safety through Day 32.
The following activities will be performed during or after PANZYGA infusion:
•
PANZYGA infusion
•
Vital signs (at the start of the infusion and every 60 minutes (±15 minutes) 
thereafter until the end of the infusion. In addition, vital sign measurements
will be recorded just prior to every infusion rate change (-10 minutes),
15 minutes (+15 minutes) after
each
infusion
rate
change,
and
approximately 30 minutes (+15 minutes) after the end of the infusion
•
Monitoring for AEs
•
Documentation of concomitant medication use
6.1.4 Day 5 and Day 8 (± 1 day) 
Day 5 and Day 8 visits and assessments may be performed locally (by patient’s 
primary care physician or local laboratory services) upon agreement with the site 
Principal Investigator, the IRB, and the Sponsor. Required interactions and 
communication channels between the primary care physician and the Principal 
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Investigator (eg, telemedicine or other means of electronic communication) will 
be outlined in the Investigator Site Binder. 
The following assessments will be performed at Day 5 and Day 8: 
•
Physical examination
•
Blood samples for serum chemistry, hematology, and hemolysis analytes
•
Monitoring for AEs
•
Documentation of concomitant medication use
6.1.5 Day 15 and Day 22 (± 3 days) 
Day 15 and Day 22 visits and assessments may be performed locally (by patient’s 
primary care physician or local laboratory services) upon agreement with the site
Principal Investigator, the IRB, and the Sponsor. Required interactions and
communication channels between the primary care physician and the Principal
Investigator (eg, telemedicine or other means of electronic communication) will
be outlined in the Investigator Site Binder.
The following assessments will be performed at Day 15 and Day 22:
•
Physical examination
•
Blood samples for hematology and hemolysis analytes
•
Monitoring for AEs
•
Documentation of concomitant medication use
6.1.6 Day 32 (End of Study Visit) (± 5 days)
Patients will return to the study site on Day 32 for final safety assessments/EOS
Visit. Patients who were withdrawn early from the study should return to the study
site for a final safety assessment. The following assessments will be performed:
•
Physical examination
•
Vital signs
•
Blood samples for serum chemistry, hematology, and hemolysis analytes
•
Blood or urine pregnancy test (females of childbearing potential, only)
•
Monitoring for AEs
•
Documentation of concomitant medication use
After Day 32, the clinical study is considered completed for the patient. No further 
study-related
assessments will
be
performed,
unless safety
concerns
(eg, ongoing AEs) require follow-up.
6.1.7 Visit Windows Used in this Study, including Tolerances 
In this study, the following time windows and tolerances apply (Table 4): 
Table 4: 
Visit Windows Used in this Study 
Time point 
Tolerance 
Screening Period 
7 days prior to Day 1 
Final Baseline Evaluations 
-2 days before Day 1
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Time point 
Tolerance 
Day 1 
none 
Day 3 
none 
Day 5 
±1 day 
Day 8  
±1 days 
Day 15 and Day 22 
±3 days 
Day 32 
± 5 days 
6.2 Duration of Study 
6.2.1 Planned Duration for an Individual Patient 
The duration of the entire study for each patient will be approximately 39 days, 
including a 7-day Screening Period. 
6.2.2 Planned Duration for the Study as a Whole 
The study will be considered completed when all patients have completed the 
Day 32 EOS Visit. 
The estimated start of the study (enrollment of first patient) is Q3 2019, and the 
estimated end of the study (last visit of last patient) is Q1 2022. 
6.2.3 Premature Termination of the Study 
Both the responsible Investigators and the Sponsor reserve the right to terminate 
the study at any time. Should this be necessary, study close-out procedures will 
be arranged on an individual site basis after review and consultation by both 
parties. In terminating the study, the Sponsor and the Investigator will ensure that 
adequate consideration is given to the protection of the patients' interests. 
Furthermore, the Investigator should promptly inform the IRB and provide a 
detailed written explanation. Pertinent regulatory authorities and IRBs will be 
informed in accordance with applicable regulatory requirements. 
6.2.3.1 Early Termination of the Entire Clinical Study 
At any time, the study as a whole will be terminated prematurely if: 
• New toxicological or pharmacological findings or safety reports invalidate 
the earlier positive benefit-risk-assessment for the pediatric population 
• Any other reason rendering the continuation of the study impossible for 
the Sponsor 
6.2.3.2 Early Termination at an Individual Study Site 
At any time, the study can be terminated at an individual study site if: 
• The site cannot comply with the requirements of the protocol 
• The site cannot comply with GCP or other regulatory standards 
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• The site does not meet the required recruitment rate 
Should the study be prematurely terminated, all study materials, including 
PANZYGA, must be returned to the Sponsor. 
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7 
ASSESSMENTS AND METHODS 
7.1 Demographic and Baseline Information 
Demographic and baseline information will be recorded during the Screening 
Period: 
7.1.1 Demographic and Baseline characteristics 
The demographic and baseline characteristics are sex, age, race and ethnic 
origin, height, and weight. 
7.1.2 Medical and Surgical history 
The medical history will be collected for the previous year and will be obtained by
interviewing the patient. Records of past diseases and treatments (eg, hospital
discharge letters) will be obtained for the study files, if available. The onset date
of ITP will be recorded.
Surgical history will include the date of splenectomy (if applicable) and any other 
surgical procedures in the previous year.
7.1.3 Viral Marker Tests 
At the Screening Visit, blood samples for viral markers (HIV, HCV, HBV NAT) will
be collected and tested at the local laboratory according to the site’s standard
procedures, to rule out secondary infections that may cause ITP. Infusions may 
begin before the results are back if the Investigator is not aware of, and the patient
isn’t exhibiting clinical signs of, any viral infection.
7.1.4 Prior and Concomitant Medication Use
Prior medication use will be obtained by interview and review of patient charts 
(if available). Patients will be queried specifically for use of H-1 blockers or 
antipyretics as pre-medications prior to previous IGIV treatments. 
Concomitant medication use, defined as medications with a start date and time
after the start of the Day 1 infusion, will be collected throughout the study. The
start date and time of medication use will be collected on Day 1 and throughout
the study.
7.2
Efficacy Assessments
All efficacy assessments will be based on platelet counts performed throughout 
the study.  
Platelet counts will be performed at Baseline (within 2 days prior to the first 
PANZYGA infusion), at Day 1 and Day 3 prior to planned PANZYGA infusions, 
and then at all remaining study visits (Days 5, 8, 15, 22, and 32). 
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7.3 Safety Assessments 
7.3.1 Assessments for Safety Evaluations 
The following assessments will be performed to evaluate the safety of PANZYGA 
in the pediatric population: 
•
AEs and Serious Adverse Events (SAEs)
•
Clinical laboratory tests
•
Vital signs
•
Physical examinations
•
Pregnancies
7.3.2 Adverse Events 
7.3.2.1 Definitions 
•
Adverse event (AE): An AE is any untoward medical occurrence in a
study /patient receiving an investigational medicinal product (IMP) and
which does not necessarily have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including
an
abnormal
laboratory
finding),
symptom,
or disease
temporally
associated with the use of an IMP, whether or not related to the IMP.
•
Adverse drug reaction (ADR): An ADR is any noxious and unintended
response to an IMP related to any dose. The phrase ‘response to an IMP’
means that a causal relationship between the IMP and an AE carries at
least a reasonable possibility (ie, the relationship cannot be ruled out).
•
Other significant AEs: Any marked laboratory abnormalities or any AEs
that lead to an intervention, including withdrawal of drug treatment, dose
reduction, or significant additional concomitant therapy.
•
Treatment-emergent AE
(TEAE):
Any
AE
that
newly
appeared,
increased in frequency, or worsened in severity following the time of the
first IMP infusion until the end of the safety follow-up period.
•
Infusional AE: Any AE that occurs from the time of infusion and within the
72 hour period after end of infusion.
•
Withdrawal due to AE/ADR: AE/ADR leading to discontinuation of
treatment with IMP. Any such events will be followed up by the Investigator 
until the event is resolved or until the medical condition of the patient is
stable. All follow-up information collected will be made available to the
Sponsor.
7.3.2.2 Collection of AEs 
AEs will be collected from the start of the first infusion on Day 1. Any illnesses 
captured between signing the ICF and the first infusion will be captured under 
medical history. The condition of the patient will be monitored throughout the 
study. At each visit, whether scheduled or unscheduled, AEs will be elicited using 
a standard nonleading question such as “How have you been since the last 
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visit/during the previous study period?” In addition, the Investigator will check the 
patient diaries (if applicable) for any documented event. 
Any AE or ADR which occurs during the study will be noted in detail on the 
appropriate pages of the eCRF. If the patient reports several signs or symptoms 
representing a single syndrome or diagnosis, the diagnosis should be recorded 
in the eCRF. The Investigator will grade the severity of all AEs or ADRs (mild, 
moderate, or severe), the seriousness (non-serious or serious), and the causality 
as defined in Section 7.3.2.3, Section 7.3.3, and Section 7.3.2.4, respectively. 
The Sponsor is responsible for assessing the expectedness of each ADR 
(expected or unexpected) as defined in Section 7.3.2.5. 
In the event of clinically significant abnormal laboratory findings, the tests will be
confirmed and the patient followed until the laboratory values have returned to
normal and/or an adequate explanation for the abnormality has become
available.
Diseases, signs and symptoms, and/or laboratory abnormalities already present
before the first administration of IMP will not be considered AEs unless an
exacerbation in intensity or frequency (worsening) occurs.
The Investigator will provide detailed information about any abnormalities and
about the nature of and reasons for any action taken as well as any other 
observations or comments that may be useful for the interpretation and
understanding of an AE or ADR.
7.3.2.3 Severity of AEs
The intensity/severity of AEs will be graded as follows:
•
Mild: an AE, usually transient, which causes discomfort but does not
interfere with the patient’s routine activities
•
Moderate: an AE which is sufficiently discomforting to interfere with the
patient’s routine activities
•
Severe: an AE which is incapacitating and prevents the pursuit of the
patient’s routine activities
The grading of an AE is up to the medical judgement of the Investigator and will
be decided on a case-by-case basis.
7.3.2.4 Causality of AEs
The relationship of AEs to the administered IMP will be assessed by the
Investigator:
•
Probable: reports including good reasons and sufficient documentation to
assume a causal relationship, in the sense of plausible, conceivable, likely,
but not necessarily highly probable. A reaction that follows a reasonable
temporal sequence from administration of the IMP; or that follows a known
or expected response pattern to the suspected medicine; or that is
confirmed by stopping or reducing the dosage of the medicine and that
could not reasonably be explained by known characteristics of the
patient’s clinical state.
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• Possible: reports containing sufficient information to accept the possibility 
of a causal relationship, in the sense of not impossible and not unlikely, 
although the connection is uncertain or doubtful, for example because of 
missing data or insufficient evidence. A reaction that follows a reasonable 
temporal sequence from administration of the IMP; that follows a known 
or expected response pattern to the suspected medicine; but that could 
readily have been produced by a number of other factors. 
• Unlikely: reports not following a reasonable temporal sequence from IMP 
administration. An event which may have been produced by the patient’s 
clinical state or by environmental factors or other therapies administered. 
• Not related (unrelated): events for which sufficient information exists to 
conclude that the etiology is unrelated to the IMP. 
• Unclassified: reports which for one reason or another are not assessable. 
7.3.2.5 Classification of ADRs by Expectedness 
ADRs will be classified by the Sponsor as either expected or unexpected: 
• Expected: an ADR that is listed in the current edition of the Investigator’s 
Brochure or other reference safety information. 
• Unexpected: an ADR that is not listed in the current edition of the 
Investigator’s Brochure or other reference safety information, or that differs 
because of greater severity or greater specificity. 
7.3.2.6 Outcome of AEs 
The outcome of all reported AEs will be documented as follows: 
1. Recovered, resolved 
2. Recovering, resolving 
3. Not recovered, not resolved 
4. Recovered, resolved with sequelae 
5. Fatal 
6. Unknown 
NOTE: A patient’s death per se is not an event, but an outcome. The event which 
resulted in the patient’s death must be fully documented and reported, even in 
case the death occurs within 4 weeks after IMP treatment end and regardless of 
whether or not it is considered treatment-related. 
7.3.2.7 Action(s) taken 
AEs requiring action or therapy must be treated with recognized standards of 
medical care to protect the health and well-being of the patient. Appropriate 
resuscitation equipment and medicines must be available to ensure the best 
possible treatment in an emergency situation. 
The action taken by the Investigator must be documented: 
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a) General actions taken in the event of an AE
–
None
–
Medication (other than IMP) or other (eg, physical) therapy started
–
Test performed
–
Other (to be specified)
b) IMP-related actions taken in the event of an AE
–
None
–
Product withdrawn
–
Dose reduced
–
Dose increased
The Investigator will follow up on each AE until it has resolved or until the medical
condition of the patient has stabilized. Any relevant follow-up information will be
reported to the Sponsor.
7.3.2.8 Managing Hypersensitivity Reactions 
Severe hypersensitivity reactions may occur during PANZYGA infusions [9]. In
the case of any subject exhibiting clinical signs of severe hypersensitivity 
reactions to PANZYGA, the PANZYGA infusion must be immediately stopped. 
Each site must have Epinephrine readily available and follow their institution’s
standard procedure for Epinephrine administration and monitoring. If a subject
develops severe hypersensitivity or anaphylactoid reactions, any further Panzyga
administration should be discontinued and not resumed.
7.3.3 Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
•
results in death
•
is life-threatening (see below)
•
requires hospitalization or prolongation of existing hospitalization
•
results in persistent or significant disability/incapacity
•
is a congenital anomaly/birth defect
•
is another important medical event
NOTE: The term ‘life-threatening’ refers to an event in which the patient was, in
the view of the reporting Investigator, at immediate risk of death at the time of the
event; it does not refer to an event which may hypothetically have caused death
had it been more severe.
In deciding whether an AE/ADR is serious, medical judgment should be 
exercised. Thus, important AEs/ADRs that are not immediately life-threatening or 
do not result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definitions 
above should also be considered serious.  
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In addition, although not classified under the seriousness criteria, all suspected 
transmissions of an infectious agent should be reported as SAE. A suspected 
virus transmission means that virus antigen has been detected in the patient. A 
passive transmission of antibodies alone does not constitute a suspected virus 
transmission. 
7.3.4 SAE Reporting Timelines 
All SAEs, whether or not they are suspected to be related to study treatment, are
to be reported immediately by telephone, fax, or email to the Clinical Project
Manager or designee with the contact detailed provided to each site in the
Investigator Site Binder. The contact details will also be communicated at the
study initiation visit.
In addition, within 24 hours after recognition of the event, an Octapharma Serious
Adverse Event Report must be completed and submitted to:
Octapharma’s Corporate Drug Safety Unit
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H.
Oberlaaer Strasse 235, 1100 Vienna, Austria
Fax:
E-mail:
24 hours emergency telephone numbers:
 or 
The Investigator must update the Octapharma Serious Adverse Event Report as
soon as any additional information becomes available. The Investigator must also
report SAEs to the IRB/IEC as required by local and national laws. The
Investigator must maintain documentation of all communications to and from the
IRB/IEC.
In accordance with 21 CFR 312.32 and local authorities, the Sponsor will submit
to the FDA unexpected adverse reactions within 15 calendar days. Unexpected
fatal or life-threatening adverse reactions will be submitted within 7 calendar
days.
Waivers the from SAE Reporting Requirement
Waivers from the SAE reporting requirement include surgeries that are elective
or were planned before study entry or prolongations of existing hospitalizations 
for economic or social, but not medical, reasons. Such surgeries or prolongations
of hospitalizations should not be considered SAEs.
7.3.5 Laboratory Tests 
Clinical laboratory parameters will be investigated during the study at the time 
points specified in the Flow Chart of Assessments (Table 1).  
All of the study-specific laboratory tests will be performed at the local laboratories 
for each study site. The laboratory test and sample collection timing are specified 
below (Table 5). 
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Table 5: 
Laboratory Tests and Time Points 
Test 
Timing 
Hematology (complete blood count, WBC 
differential, hematocrit, hemoglobin, platelet 
counts, reticulocytes) 
During Screening (Baseline evaluation), at 
Days 1, 3, 5, 8, 15, 22, and at Day 32/EOS 
Hemolysis (total, direct, and indirect 
bilirubin)  
During Screening (Baseline evaluation), at 
Days 1, 3, 5, 8, 22, and at Day 32/EOS 
Serum chemistry (ALT, AST, creatinine, Na, 
Ca, K, BUN, LDH) 
During Screening (Baseline evaluation), 
Days 1, 3, 22, and at Day 32/EOS 
Blood or Urine pregnancy test (females of 
childbearing potential) 
During Screening (Baseline evaluation) and 
Day 32/EOS 
Virology: HIV, HCV, HBV NAT 
During Screening (Baseline evaluation, see
Section 7.1.3) 
Investigational sites will follow all site and local laboratory standard operating
procedures for sample collection and handling and will provide the Sponsor with
normal
reference
ranges and
laboratory
certification
certificates.
Upon
agreement with site Principal Investigator, the IRB, and the Sponsor, Days 5, 8,
15, and 22 visits may be performed locally by the patient’s primary care physician. 
Laboratory samples may be collected by a patient’s primary care physician or by 
a local laboratory service (that draws, processes, and reports laboratory results) 
that is in the proximity of the patient’s home; these samples must be analyzed
according to the chosen laboratory’s standard operating procedures. Normal
reference ranges and laboratory certification certificates of any laboratories will
also be provided to the Sponsor.
The methods of determination and normal ranges for each parameter from each
local laboratory will be provided in the clinical study report.
7.3.6 Vital Signs 
Vital signs will be collected at the time points specified in the Flow Chart of
Assessments (Table 1) are blood pressure, body temperature, pulse rate, and
respiratory rate.
On Day 1 and Day 3, vital sign measurements will be recorded before the start
of the infusion and every 60 minutes (±15 minutes) thereafter until the end of the
infusion. In addition, vital sign measurements will be recorded just prior to every
infusion rate change (-10 minutes), 15 minutes (+15 minutes) after every infusion
rate change, and approximately 30 minutes (+15 minutes) after the end of the
infusion.
7.3.7 Physical Examination including Height and Body Weight. 
Physical examinations will be performed at the visits specified in the Flow Chart 
of Assessments (Table 1). 
Both height and weight will be measured at Baseline. 
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7.3.8 Other Relevant Safety Information 
a) Post-study related safety reports
Any SAE which occurs during the study (ie, within 4 weeks after the last 
PANZYGA administration, which for most patients will be up to and including 
Day 32) will be reported by the Investigator to the Sponsor. Proactive monitoring 
for post-study SAEs is not required. 
In case a post-study SAE is identified, the Investigator should complete an SAE 
form and also state the relation to the clinical study in the report. 
Deaths occurring during the study (ie, within 4 weeks after the last PANZYGA 
administration, which for most patients will be up to and including Day 32) should
also be reported, regardless of whether or not they are considered treatment-
related.
b) Pregnancies
Every effort will be made to avoid a pregnancy during the use of an IMP.
Pregnancies occurring during the study (fetal exposure to PANZYGA) need to be
reported.
In case of pregnancy during the study, the Investigator should complete the
Pregnancy Notification Form and send or fax it to the Clinical Project Manager or 
designee (Section 7.3.4).
Follow-up information on the outcome of both mother and fetus will be requested
by a Sponsor representative.
c) Overdose, interaction, medication error and lack of efficacy
The following safety relevant information should be reported as an AE or, if the
reaction fulfills one of the criteria for seriousness, as SAE.
d) Drug overdose
An overdose is a deliberate or inadvertent administration of a treatment at a dose
higher than specified in the protocol and higher than the known therapeutic dose
that is of clinical relevance. The reaction must be clearly identified as an
overdose.
e) Drug interaction
A drug interaction is a situation in which a substance or medicinal product affects 
the activity of an IMP, ie, increases or decreases its effects, or produces an effect
that none of the products would exhibit on its own. The reaction must be clearly 
identified as a drug interaction.
f)
Medication error
A medication error involves the inadvertent administration or unintended use of a 
medicinal product which may be caused by the naming, presentation of 
pharmaceutical form/packaging, or instructions for use/labelling. The reaction 
must be clearly identified as a medication error. 
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g) Lack of efficacy
Lack of efficacy is suspected when the therapeutic result is not as expected. One 
example of lack of efficacy could be platelets not increasing following the correct 
administration of IVIG. 
7.4 Other Assessments 
7.5 Appropriateness of Measurements 
For efficacy evaluations, platelet counts provide a direct measure of the response
to IGIV treatment in ITP patients and has been widely used for this purpose in
many clinical trials of similar nature. The test is performed routinely at each
hospital and is considered to be a reliable and robust parameter.
The definition of response used for the primary endpoint is the most established
procedure to obtain a dichotomy of success/failure that can be used to calculate
the response rate. It is also acceptable to US FDA and was used as the primary 
efficacy endpoint in their approval of PANZYGA in the treatment of chronic ITP
in adults and is thus expected to best facilitate their review of the efficacy of
PANZYGA in this pediatric population.
Monitoring AEs, vital signs, laboratory safety tests, and physical examinations 
are standard procedures used to evaluate the safety of investigational products
in clinical studies.
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8 
DATA HANDLING AND RECORD KEEPING 
8.1 Documentation of Data 
8.1.1 Source Data and Records 
Source data are defined as all information related to clinical findings, 
observations, or other activities in the study; written down in original records or 
certified copies of original records; or electronic medical records; allowing 
reconstruction and evaluation of the clinical study. 
The Investigator will maintain adequate source records (eg, case histories or
patient files for each patient enrolled). Source records should be preserved for
the maximum period of time required by local regulations.
For each patient enrolled, the Investigator will indicate in the source record(s) that
the patient is participating in this study.
All data entered in the eCRF must be supported by source data in the patient
records.
The Investigator will permit study-related monitoring, audit(s), IEC/IRB review(s),
and
regulatory
inspection(s),
by providing
direct
access to
the
source
data/records.
The Investigator may authorize site staff (eg, sub-Investigators, research nurses)
to enter study data into the eCRF. This must be documented in the Delegation of
Authority Log signed by the Investigator.
8.1.2 Electronic Case Report Forms
For each patient enrolled, an eCRF will be completed within the Electronic Data
Capture (EDC) system and approved by the Investigator or an authorized sub-
Investigator.
Study site staff (eg, research nurse, study coordinator, Investigator) will be
responsible for entering patient data into the validated EDC system. All study site
personnel will be trained on the EDC system and study-specific eCRFs prior to
receiving access to the live database for data entry.
The study site will be provided with the approved eCRF Completion Guidelines 
to assist in data entry and data issues/questions. The study site will be notified
once the eCRF is active to begin data entry. Additional site training may be
provided as refreshers throughout the study, if needed. All persons allowed to
enter or change eCRF data must be listed in the Delegation of Authority Log.
8.1.3 Changes to Electronic Case Report Form Data 
Monitors will perform source data verification (SDV) as defined for the study. 
If any errors or discrepancies in the eCRFs are found during data entry or review, 
discrepancies will be generated programmatically within the EDC system, and 
‘manual’ queries will be generated by either a monitor or Data Management.  
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Discrepancies and queries can only be corrected by the Investigator(s) or other 
authorized site personnel. An audit trail documents all changes to the data over 
the entire study period. If the reason for a change is not obvious, a comment must 
be supplied in the query’s response, stating the reason for the change, prior to 
closing. The study monitor should provide guidance to Investigator(s) and the 
Investigator(s)’ designated representatives on making such corrections.  
Once queries have been resolved by the site staff, the resolutions are assessed 
by Data Management. If the query response provided confirms the data as 
correct, the discrepancy will be closed. If the response does not adequately 
address the question raised, a new query will be issued for further clarification. 
Manual checks will be performed, and electronic data check programs run,
throughout the study until the data is clean and the database is ready for lock. All
discrepancies will be resolved prior to database lock. There will be a final run of
the programmed checks to ensure all discrepancies are closed out, SDV will be
confirmed as complete by the monitor, and all eCRFs will be approved by the
Investigator prior to database lock.
8.2 Information to Investigators 
An IB will be handed out to the Investigator before the start of the study. The IB
contains all information in the Sponsor’s possession necessary for the
Investigator to be fully and accurately informed about the safety of the IMP under 
evaluation and the respective benefit-risk ratio.
The IB will be updated by the Sponsor at regular intervals and whenever relevant
new information concerning PANZYGA becomes available.
All participating investigators will be informed about relevant study procedures,
about the methods for rating relevant study outcomes, and how to enter data into
the eCRF in order to reduce discrepancies. At the study initiation visit, the eCRF
will be explained to all study site staff entitled to document data in the eCRF.
The Investigator will be kept informed of important data that relate to the safe use
of PANZYGA as the study proceeds.
8.3
Responsibilities
The Principal Investigator is accountable for the conduct of the clinical study.
Responsibilities may be delegated to appropriately qualified persons.
A Delegation of Authority Log will be filled in and signed by the Principal
Investigator. In accordance with this authority log, study site staff (eg, sub-
Investigators, research nurses) are authorized to perform tasks relating to the
study.
8.4 Investigator’s Site File 
At each study site, the Investigator is responsible for maintaining all records to 
enable the conduct of the study to be fully documented. Essential documents as 
required by GCP guidelines and regulations (eg, copies of the protocol, study 
approval letters, all original informed consent and assent forms, site electronic 
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versions of all eCRFs, drug dispensing and accountability logs, correspondence 
pertaining to the study) should be filed accurately and kept by the Investigator for 
the maximum period of time required by local regulations. 
The Investigator is responsible for maintaining a confidential patient identification 
code list, which provides the unique link between named source records and 
eCRF data for the Sponsor. The Investigator must arrange for the retention of 
this confidential list for the maximum period of time required by local regulations. 
No study document should be destroyed without prior written agreement between
the Investigator and the Sponsor. Should the Investigator elect to assign the
study documents to another party, or move them to another location, the Sponsor
must be notified in writing.
8.5 Provision of Additional Information 
On request, the Investigator will supply the Sponsor with additional data relating
to the study, or copies of relevant source records, ensuring that the patient’s 
confidentiality is
maintained.
This
is particularly important
when source
documents are illegible or when errors in data transcription are encountered.
In the event of particular issues or governmental queries, it is also necessary to
have access to the complete study records, provided that the patient’s 
confidentiality is protected in accordance with applicable regulations.
8.6
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be established by the
Sponsor. The IDMC will be composed of recognized experts in the fields of
hematology and/or critical care who are not actively recruiting patients.
The IDMC will review relevant data periodically during the study and will give
advice on the continuation, modification, or termination of the study. A written
study-specific procedure will define in detail the composition, responsibilities, and
procedures of the IDMC.
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9 
STATISTICAL METHODS AND SAMPLE SIZE 
Statistical analysis will be delegated under an agreement of transfer of 
responsibilities to an external contract research organization (CRO). All 
Octapharma procedures and policies must be met by this CRO. Discrepancies or 
exceptions will be approved by the Sponsor's Manager of Biometrics. 
9.1 Determination of Sample Size 
At least 20 patients who meet all eligibility criteria will be enrolled in the study. 
The purpose of this study is to evaluate the efficacy and safety of PANZYGA in 
pediatric patients with chronic ITP; the chosen number of 20 patients to be 
enrolled is not derived from statistical considerations of power but driven by 
feasibility constraints with respect to finding pediatric ITP patient eligible and 
willing to participate in this study. 
We expect the true proportion of responders to be comparable to results from 
similar studies in adult patients, as there is no published data or expert statement 
that would indicate otherwise. Looking at possible outcome scenarios, 
20 evaluable patients give the following picture from a statistical point of view: 
Power Considerations for 20 Evaluable Patients: 
Even though the chosen number of 20 pediatric patients is thus not sufficient ‘to 
power’ the study, it will still allow the Sponsor to gather enough clinical evidence 
to obtain a sound and meaningful medical assessment of the efficacy and safety 
of PANZYGA in pediatric patients with chronic ITP. 
9.2 Statistical Analysis 
A formal statistical analysis plan describing all details of the analyses to be 
performed will be prepared by the study statistician and approved by the Sponsor 
prior to the start of the statistical analysis. 
No confirmatory statistical analysis will be performed; the results of this study will 
be presented at the descriptive level only. 
In general, and if not detailed otherwise in the Statistical Analysis Plan (SAP), all 
statistical presentations will be fit to the nature and type of the individual data 
items: 
•
Binary data (whether or not an event has occurred): counts and
proportions
•
Count data (the frequency of an event in a set time period): rate (count per
unit time)
Exact 95% 
Hypothetical power to show that the true response 
-
o=o.s -
o=o.6 
Responders 
Confidence Limits 
r.ate is above 6 (l~sided, a •0.025), given that it is in 
fact equal to the observed proportion 
100.. 
Number 
Proportion 
Lower 
Upper 
6=0.5 
6=0.6 
"°" 
11 
55% 
31,5% 
76,9% 
5,5% 
'°" 
12 
60% 
36,1% 
80,9% 
12,6% 
2,1% 
'°" 
'""' 
13 
65% 
40,8% 
84,6% 
24,5% 
4,4% 
j '°" 
14 
70% 
45,7% 
88,1% 
41,6% 
10,7% 
g '°" 
15 
75% 
50,9% 
91,3% 
61,7% 
22,5% 
'°" 
16 
80% 
56,3% 
94,3% 
80,4% 
41,1% 
2°" 
17 
85% 
62,1% 
96,8% 
93,3% 
64,8% 
10,0 
°" 
18 
90% 
68,3% 
98,8% 
98,9% 
86,7% 
'°" -
""' 
'°" 
9("' 
100.. 
19 
95% 
75,1% 
99,9% 
100,0% 
98,4% 
True Pfoportion 
20 
100% 
83,2% 
100,0% 
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•
Continuous data (measurements on a continuous scale, including quasi-
continuous variables): arithmetic mean, standard deviation, median, lower
and upper quartile, minimum, maximum
•
Scales data (Ordinal and Non-ordinal): absolute and relative frequencies
•
Time-to-event data (how long it takes to observe the outcome of interest,
e.g. the initial treatment response): time to event or last evaluation
(censored data in case subjects are lost to follow-up) and event rate. Such
parameters may also be presented as Kaplan-Meier plots of the product-
limit survival function estimates.
9.2.1 Populations for Analysis 
The following populations will be considered for the statistical analysis: 
•
Safety Analysis Set (SAF): All patients who received at least part of
1 infusion of PANZYGA.
•
Full Analysis Set (FAS): All patients in the SAF who satisfy all major
eligibility criteria and for whom any post-baseline data is available. This is 
the set of eligible patients with treatment effects measured, according to
the intention-to-treat (ITT) principle.
•
Per-Protocol Set I (PP1): All patients in the FAS, excluding those with
significant protocol deviations before the primary efficacy assessment on
Day 8 is completed, and which may have an impact on the evaluation of
the primary endpoint.
•
Per-Protocol Set II (PP2): All patients in the FAS, excluding those with
significant protocol violations potentially affecting the (secondary) efficacy 
evaluations.
Only protocol deviations with the potential to significantly affect the study results
or to invalidate the interpretation of the data obtained will lead to exclusion of
patients from the PP sets. The inclusion of each patient in the respective analysis 
populations will be determined before database lock in a data review meeting by 
a panel consisting of a medical expert from the Sponsor, the clinical study 
manager, the data manager, and the study statistician.
The analysis of safety will be based on the SAF.
The evaluation of the primary objective will be performed for the FAS 
(ITT analysis) and for the PP1 set (PP analysis) to assess the robustness of the
results. The primary analysis will be the ITT analysis.
For secondary objectives ITT and PP2 analyses will be carried out; again the
ITT analysis is considered the primary analysis and will be presented first in the
report.
9.2.2 Efficacy Analysis Plan 
The primary and secondary efficacy parameters will be determined on the basis 
of the patient's platelet concentration, listed individually, and presented 
descriptively. 
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The primary endpoint parameter ‘response’ is defined as an increase in platelet 
count at least once to ≥50x109/L within 7 days after the first infusion, ie, by Day 8 
(increase must occur at least once on any day up to and including Day 8). 
The number and proportion of responders will be presented, together with the 
associated exact 95% confidence intervals. 
The time to reach the desired increase in platelet count as well as the duration of 
response and the maximum platelet levels will be presented in listings and 
summarized in statistical tables. 
Individual profiles of platelet count over time will be presented as Trellis plots. 
9.2.3 Safety Analysis Plan 
The safety analysis will comprise descriptive statistics, tabulations, and listings of
all TEAEs, safety laboratory results, vital signs, and physical examination
findings. All reported AEs will be coded according to the Medical Dictionary for 
Regulatory Activities) MedDRA.
An AE is defined as treatment-emergent if first onset or worsening is after start
of the first infusion of PANZYGA. Only TEAEs are accounted for in the analysis.
AEs will be record at the start of the fist infusion of PANZYGA. AEs that occur 
between informed consent/assent and the start of the first PANZYGA infusion will
be recorded under Medical History.
Incidences of treatment-emergent AEs will be given as the number and
percentage of patients who experienced any or a particular AE, including serious
and drug-related AEs.
The summary tables for AEs will be given by system organ class and preferred
term. Additionally, AEs will be summarized by severity and relationship to study 
treatment. In addition to the tables presenting incidences including all AEs,
incidences will be determined for the subset of SAEs and drug-related AEs.
Incidences of infusional AEs will be given as the number and percentage of
patients who experienced any or a particular infusional AE, including serious and
drug-related AEs.
The summary tables for infusional AEs will be given by system organ class and
preferred term. Additionally, infusional AEs will be summarized by severity and
relationship to study treatment. In addition to the tables presenting incidences
including all infusional AEs, incidences will be determined for the subset of SAEs
and drug-related AEs.
Narratives will be prepared describing each death, other SAEs, and other 
significant AEs that are judged to be of special interest because of clinical 
importance. 
For each routine laboratory parameter at each visit the actual result, the change 
from baseline, the out-of-range flag and the assessment of clinical relevance will 
be summarized descriptively. 
Vital signs include systolic and diastolic blood pressure, pulse rate, body 
temperature and the respiratory rate; descriptive tables on the sampling statistics 
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of these parameters at each time point will be provided for the values as well as 
for their changes to baseline. 
9.2.4 Handling of Missing Data 
No replacement of missing data values is planned, but only observed results (and 
platelet counts) will be included in the analyses. 
9.3 Randomization, Stratification, and Code Release 
This is an open-label non-randomized study; therefore, no randomization code
list or procedure for code release are required. Patients will not be stratified by
age group.
9.4 Interim Analysis  
No interim analysis is planned. 
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10 ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE 
ASPECTS 
10.1 Ethical/Regulatory Framework 
This study will be conducted in accordance with the ethical principles laid down 
in the Declaration of Helsinki. The study protocol and any subsequent 
amendment(s) will be submitted to an IEC/ IRB and to the Regulatory Authority. 
The study will be conducted in compliance with the protocol, GCP guidelines, and 
applicable regulatory requirements. 
The regulatory application or submission for regulatory approval will be made by
the Sponsor or designated third party (eg, CRO) as required by national law.
10.2 Approval of Study Documents 
The study protocol, a sample of the patient information and informed consent
form, assent form, any other materials provided to the patient and their
parent/legal guardian, and further requested information will be submitted by the
Sponsor or the Investigator to the appropriate IEC/IRB and the Regulatory
Authority. The study must be approved by the IEC/IRB and the Regulatory 
Authority before any IMP may be shipped to the study sites and any patient is
exposed to a study-related procedure.
The Sponsor, the Investigator, and any third party (eg, CRO) involved in obtaining
approval must inform each other in writing that all ethical and legal requirements
have been met before the first patient is enrolled in the study.
10.3 Patient Information and Informed Consent
The Investigator will obtain freely given written consent from each the patient after 
an appropriate explanation of the aims, methods, anticipated benefits, potential
hazards, and any other aspect of the study which is relevant to the patient’s
decision to participate. The informed consent form must be signed, with name
and date and time noted by the patient, before the patient is exposed to any
study-related procedure, including screening tests for eligibility.
For patients not qualified to give legal consent, written consent must be obtained
from the legal parent/guardian. If children are old enough to understand the risks 
and benefits of the study, they should also be informed and provide their written
consent using an assent form.
The Investigator will explain that the patients are completely free to refuse to enter 
the study or to withdraw from it at any time, without any consequences for their 
further care and without the need to justify. The Investigator will complete the 
informed consent section of the CRF for each patient enrolled. 
Each patient (and parent/legal guardian, as appropriate) will be informed that 
his/her medical (source) records may be reviewed by the study monitor, a quality 
assurance auditor, or a health authority inspector, in accordance with applicable 
regulations, and that these persons are bound by confidentiality obligations. 
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10.4 Protocol Amendments 
Any prospective change to the protocol will be agreed between the Investigator 
(Co-ordinating Investigator in multi-center studies) and the Sponsor prior to its 
implementation. Any such amendments will be submitted to the any competent 
IEC/IRB and/or competent authority responsible as required by applicable 
regulations. 
IEC/IRB approval will, at a minimum, be requested for any change to this protocol 
which could affect the safety of the patients, the objective/design of the study, 
any increase in dosage or duration of exposure to the IMP, an increase in the 
number of patients treated, the addition of a new test or procedure, or the 
dropping of a test intended to monitor safety. 
10.5 Confidentiality of Patient Data 
The Investigator will ensure that the patient’s confidentiality is preserved. On 
eCRFs or any other documents submitted to the Sponsor, the patients will not be 
identified by their names, but by a unique patient identifier. Documents not 
intended for submission to the Sponsor, ie, the confidential patient identification 
code list, original consent and assent forms, and source records, will be 
maintained by the Investigator in strict confidence. 
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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Periodic Monitoring 
The monitor will contact and visit the Investigator periodically to review all study-
related source data/records, verify the adherence to the protocol and the 
completeness, correctness and accuracy of all CRF entries compared to source 
data. The Investigator will cooperate with the monitor to ensure that any 
discrepancies identified are resolved. 
For this study, the first monitoring visit shall take place shortly after the inclusion
of the first patient. Thereafter, monitoring frequency will depend on study
progress and in accordance with the study clinical monitoring plan.
The monitor must be given direct access to source documents (original
documents, data, and records). Direct access includes permission to examine,
analyze, verify, and reproduce any records and reports that are important to the
evaluation of the clinical study. Source data will be available for all data in the
eCRFs, including all laboratory results.
11.2 Audit and Inspection 
The Investigator will make all study-related source data and records available to
a qualified quality assurance auditor mandated by the Sponsor, or to
IEC/IRB/regulatory inspectors, after reasonable notice. The main purposes of an
audit or inspection are to confirm that the rights and welfare of the patients have
been adequately protected, and that all data relevant for the assessment of safety
and efficacy of PANZYGA have been reported to the Sponsor.
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Page 57 of 60 
12 REPORTING AND PUBLICATION 
12.1 Clinical Study Report 
A clinical study report (in accordance with relevant guidelines and the Sponsor’s 
Standard Operating Procedures [SOPs]) will be prepared by the Sponsor after 
completion of the study. The Co-ordinating Investigator will approve the final 
study report after review. 
12.2 Publication Policy 
The results of this study may be published or presented at scientific meetings. 
If the Investigator wants to publish or present study results, the Investigator 
agrees to inform the Sponsor and to submit all manuscripts or abstracts to the 
Sponsor before submission to an editorial board or scientific review committee. 
This will allow the Sponsor to protect proprietary information and to provide 
comments based on information that may not yet be available to the Investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will 
support publication of multi-center studies only in their entirety and not as 
individual center data. Authorship will be determined by mutual agreement. 
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Page 58 of 60 
13 LIABILITIES AND INSURANCE 
In order to cover any potential damage or injury occurring to a patient in 
association with PANZYGA or participation in the study, the Sponsor will contract 
insurance in accordance with local regulations. 
The Investigator is responsible for dispensing PANZYGA according to this 
protocol and for its secure storage and safe handling throughout the study. 
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Page 59 of 60 
14 REFERENCES 
1. Diagnosis and treatment of idiopathic thrombocytopenic purpura:
recommendations of the American Society of Hematology. The American
Society of Hematology ITP Practice Guideline Panel. Ann.Intern.Med.
1997;126:319-326.
2. Brenner B: Clinical experience with Octagam, a solvent detergent (SD)
virus inactivated intravenous gammaglobulin. Clin.Exp.Rheumatol.
1996;14:S115-S119.
3. Imbach P: 
Immune thrombocytopenic purpura and intravenous
immunoglobulin. Cancer. 1991;68:1422-1425.
4. Newland AC, Burton I, Cavenagh JD, et al: Vigam-S, a solvent/detergent-
treated intravenous immunoglobulin, in idiopathic thrombocytopenic
purpura. Transfus.Med. 2001;11:37-44.
5. Despotovic JM:
Emerging
therapies in
immune
thrombocytopenia.
American Society of Hematology. The Hematologist, ASH News and
Reports. 2018:15:4;1-7.
6. Neunert C, Despotovic J, Haley K, et. al. Thrombopoietin receptor agonist
use in children: data from the pediatric ITP consortium of North America
ICON2
study.
Pediatric
Blood
& Cancer.
2016:63(8),
1407-1413.
doi:10.1002/pbc.26003
7. European Medicines Agency, Guideline on the clinical investigation of
human normal immunoglobulin for intravenous administration (IVIg).
EMA/CHMP/BPWP/94033/2007
rev.
3.
Retrieved
from:
https://www.ema.europa.eu/documents/scientific-guideline/guideline-
clinical-investigation-human-normal-immunoglobulin-intravenous-
administration-ivig-rev-3_en.pdf
8. American Society of Hematology 2011 Clinical Practice Guideline on the
Evaluation and Management of Immune Thrombocytopenia (ITP), Quick
Reference Guide.
9. PANZYGA [package insert]. Hoboken, NJ: Octapharma USA Inc; 2018.
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Page 60 of 60 
15 APPENDICES 
Not applicable. 
Page 195 of 260 

Protocol Amendment #3 NGAM-10 
CONFIDENTIAL 
Page 1 of 5 
27-Apr-2020
PROTOCOL AMENDMENT #3 
STUDY NUMBER: 
NGAM-10 
STUDY TITLE: 
Post-Marketing Study to Evaluate the Efficacy 
and Safety of PANZYGA in Pediatric Patients 
with Chronic Immune Thrombocytopenia (ITP) 
SPONSOR: 
Octapharma USA, Inc. 
117 West Century Road 
Paramus, NJ  07652 
TEST PRODUCT: 
PANZYGA 
IND / BLA NUMBERS: 
IND 14121 / BLA 125587 
APPROVED BY: 
Octapharma Pharmazeutika ProduktionsgmbH 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
PROTOCOL: 
DATE: 
Final Version 01 
30 Jan 2019 
Protocol Amendment #1 
21 May 2019 
Final Version 02 
21 May 2019 
Protocol Amendment #2 
05 Aug 2019 
Final Version 03 
05 Aug 2019 
Protocol Amendment #3 
27 Apr 2020 
Final Version 04 
27 Apr 2020 
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Protocol Amendment #3 NGAM-10 
CONFIDENTIAL 
Page 2 of 5 
27-Apr-2020
Rationale for the Amendment: 
In March 2020, revised in April 2020, FDA issued a COVID-19 guidance
document to “…provide general considerations to assist sponsors in assuring the
safety of trial participants, maintaining compliance with good clinical practice 
(GCP), and minimizing risks to trial integrity during the COVID-19 pandemic.”
(Guidance for Industry – FDA Guidance on the Conduct of Clinical Trials of
Medical Products during COVID-19 Pandemic. March 2020, rev. April 2020). The
protocol has been amended to address considerations specified in the guidance
document. The primary change has been to require that sites receive written
approval from the Sponsor prior to enrolling patients, thereby confirming that the
site has: a COVID-19 policy in place that allows patient enrollment, adequate staff
available to treat and follow patients during the pandemic, the ability for the
monitor to conduct remote monitoring visits, and evaluated safety risks to the
patient of enrolling versus not enrolling in the study. The protocol has also been
amended to specify that in the event of any circumstances that may occur, 
including but not limited to the COVID-19 pandemic, remote monitoring visits 
would be allowed.
In addition to addressing FDA COVID-19 guidance document recommendations, 
the following changes made throughout the protocol were considered significant:
•
Patients may not be enrolled into the study without first receiving written
approval by the Sponsor. Investigators must complete a study-specific
form indicating that they have evaluated the risks versus benefits of patient
participation during the COVID-19 pandemic and verifying that the facility
has procedures in place to ensure patient safety (Section 6.1.2). 
•
In the event of any circumstances that may occur that prohibit on-site
monitoring visits (including but not limited to the COVID-19 pandemic),
remote monitoring visits would be allowed (Section 11.1).
In addition to these changes enforced to comply with the FDA COVID-19 
guidance document, some other minor changes to clarify sections of the protocol
as described:
•
The planned study start date was amended from Q3 2019 to Q1 2020 as
first patient was enrolled during Q1 2020. The study end date was not
changed; therefore, recruitment time period was changed from will now be
approximately 30 months to approximately 24 months.
•
Inclusion Criterion #2 was modified to reflect the updated ASH Guidelines
for Chronic ITP
•
Inclusion Criterion #5 was modified to clarify that acceptable forms of
contraception must be used throughout the study and that abstinence
would be considered an acceptable form of birth control for non-sexually
active females.
•
Exclusion Criterion #2 was modified to include a time window surrounding
the exclusionary administration of intravenous immunoglobulin or anti-D
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Protocol Amendment #3 NGAM-10 
CONFIDENTIAL 
Page 3 of 5 
27-Apr-2020
immunoglobulin prior to the first infusion; it is now within 3 weeks (±3 days) 
before enrollment. 
•
Exclusion Criterion #6 was modified to clarify that only patients who have
never responded to previous IGIV or anti-D immunoglobulin would be
excluded. Patient who have responded, but may have on occasion not
responded, can be enrolled.
•
Clarified that the Screening/Baseline Visit may take place on the same day
as Day 1. If the visits take place on the same day, Day 1 procedures do
not need to be repeated prior to PANZYGA infusion.
•
The protocol had specified that PANZYGA would not be administered on
Day 3 if both of the following occurred: the platelet count doubled from
Day 1 AND was >50x109/L. Per Investigator input, and in order to simplify
the instructions and avoid protocol deviations, the protocol was amended
such that only platelet counts would be used as the determining factor of
whether or not Panzyga would be administered on Day 3. Whether or not
the platelet count doubled from Screening/Baseline would not be taken
into consideration.
•
Additional instructions were provided to the Investigator regarding the
expected body systems evaluated as part of brief versus targeted physical
examinations. Brief physical examinations will include examinations of the
patient’s general
appearance,
skin,
heart,
lungs,
abdomen,
and
extremities. Targeted physical examinations will be limited to targeted
body systems per Investigator discretion.
•
Section 4.2.2 (Prohibited Medication) added that in the event the platelet
count has not reached >50x109/L by Day 8 prohibited medications would
be allowed for patient safety.
•
Section 5.5 was amended to delete the word “exact” in front of dosing:
“The exact dose will be administered, and the empty and partially used
vials will be retained by the site for drug accountability and dose
verification.” Clinics in the US recommend rounding IVIG doses to the
nearest 5 grams in adults and 1 gram in children (which is within 10% of
the prescribed dose). Removing “exact” will prevent the generation of
protocol deviations for these small dose changes that do not affect subject
safety.
•
Clarified that sites may use non-PVC-free infusion bags, if PVC-free bags
are not available.
•
Clarified that sites may use a solution other than normal saline to flush the
infusion line, per their routine procedures.
•
Clarified that the study site pharmacy may follow their own drug dispensing
and accountability procedures, if they are required to do so. Adherence
site-specific pharmacy requirements will not be considered a protocol
deviation.
•
Section 9.2.2 (Efficacy Analysis Plan) was updated to reflect the most
current draft Statistical Analysis Plan.
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Protocol Amendment #3 NGAM-10 
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Page 4 of 5 
27-Apr-2020
•
Inconsistencies identified between protocol sections, along with
grammatical, punctuation, and formatting corrections were addressed.
•
Updated Sponsor address
Please see the attached redline version for documentation of these substantive 
changes, along with minor grammatical, formatting, punctuation, and other non-
substantive changes.  
Page 199 of 260 

emtucolArneru:JmenUi3 .. ..NGAM-1 o 
-----C -O.NEIDE.NIIAL 
AGREEMENT: These signatures constitute approval of this protocol 
amendment and provide the necessary assurance that the study will be 
conducted according to all stipulations of protocol and amendments. 
Authorised 
person for signing the Study Protocol and Protocol 
Amendments on behalf of the Sponsor and Sponsor's Medical Expert: 
 
Octapharma Pharmazeutika Prod. Ges m.b.H 
Oberlaaerstr. 235, A-1100 Vienna , Austria 
Tel: 
, Fax: 
 
 
Octapharma USA, Inc. 
117 West Century Road 
Paramus , NJ 07652 
Tel:
, Fax
 
Page 5 of 5 
27-Apr-2020 
Page 200 of 260 
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Property of Octapharma. Do not copy or distribute without written permission.
This document contains confidential and proprietary information of Octapharma AG. 
Do not copy or distribute without written permission. 
090-CSP-NGAM-10-V01/DOC ID 3021
CLINICAL STUDY PROTOCOL
NGAM-10
Post-Marketing Study to Evaluate the Efficacy 
and Safety of PANZYGA in Pediatric Patients with 
Chronic Immune Thrombocytopenia (ITP)
Investigational Product: 
PANZYGA 
Indication: 
Chronic Immune Thrombocytopenia (ITP)
Study Design: 
Prospective, open-label, single-arm, multi-
center study 
Sponsor: 
Octapharma USA, Inc.
117 West Century Road
Paramus, NJ 07652
Study Number: 
NGAM-10 
IND Number / BLA Number: 
IND 14121 / BLA 125587
Development Phase: 
Phase 4
Planned Clinical Start: 
Q1 2020
Planned Clinical End: 
Q1 2022
Date of Protocol: 
27 Apr 2020 
Version: 
04 (Incorporating Amendment 3) 
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Study Protocol No. NGAM-10, Version 04 CONFIDENTIAL 
27Apr2020 
Page 2 of 60 
STUDY OUTLINE 
Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
27Apr2020 
Title of Study: 
Post-Marketing Study to Evaluate the Efficacy and Safety of PANZYGA in
Pediatric Patients with Chronic Immune Thrombocytopenia (ITP)
Indication: 
Chronic Immune Thrombocytopenia (ITP) 
Number of Study Centre(s): 
Up to 8 sites in the USA 
Objectives: 
Primary Objective: 
The primary objective is to evaluate the efficacy of PANZYGA in increasing the
platelet count in pediatric patients with chronic ITP.
Secondary Objectives:
The secondary objectives of this study are to:
•
Assess safety of up to 2 g/kg PANZYGA (1 g/kg PANZYGA on Day 1 
and an optional dose of 1 g/kg PANZYGA on Day 3) infused in the
pediatric population within the scope of the clinical study
•
Determine the time to reach a platelet count of 50x109/L
•
Determine duration of time during which the platelet count is maintained
at the level ≥50х109/L
•
Determine the maximum platelet count during the study
Study Design: 
This is a prospective, open-label, single-arm, multicenter, Phase 4 study 
evaluating the efficacy and safety of PANZYGA in pediatric patients with chronic 
ITP. 
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Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
27Apr2020 
Number of Patients: 
At least 20 patients 
Patient Selection Criteria: 
Inclusion Criteria: 
1. Females and males aged from ≥1 year to <18 years old
Note: Patients who turn 18 years old during study participation must be
re-consented at their next study visit with an adult informed consent form.
2. Confirmed diagnosis of Chronic Immune Thrombocytopenia (ITP) 
according to American Society of Hematology (ASH) 2019 guidelines
3. Platelets count <30x109/L at the Baseline Visit
4. Voluntarily given written informed consent (provided by patient’s parent
or legal guardian) and assent (provided by patient [if age-appropriate per
IRB requirements])
5. Sexually active females who have been using at least 1 acceptable form
of birth control for a minimum of 30 days (or a minimum of 3 months for
hormonal contraceptives) prior to the Screening visit, and must agree to
use at least 1 acceptable method of contraception throughout the study 
and for 30 days after the last dose of PANZYGA. Acceptable methods of
birth control for this study include: intrauterine device (IUD), hormonal
contraception, male or female condom, spermicide gel, diaphragm,
sponge, or cervical cap. For non-sexually active females who have
begun menstruating, abstinence is considered an acceptable method of
birth control.
6. Parent or legal guardian must agree and be willing to assist the
participant attend study visits, and to follow all protocol requirements and
instructions of the study doctor
Exclusion Criteria: 
1. Thrombocytopenia secondary to other diseases (such as Acquired
Immunodeficiency Syndrome [AIDS] or systemic lupus erythematosus
[SLE]), drug-related thrombocytopenia, or congenital thrombocytopenia
2. Administration of intravenous immunoglobulin (IGIV) or anti-D
immunoglobulin within 3 weeks (±3 days) before enrollment
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Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
27Apr2020 
3. Administration of thrombopoietin receptor agonists when the dose has 
NOT been stable within 3 weeks before enrollment and a dosage change
is planned before Day 32
4. Administration of oral immunosuppressants when the dose has NOT
been stable during the preceding 2 months (2 weeks for long-term
corticosteroid therapy) and a dosage change is planned before Day 32
(Note: topical agents and inhaled corticosteroid therapy use is permitted)
5. Administration of long-term anti-prolific agents or attenuated androgen
therapy when the dose has NOT been stable during the preceding
2 months and a dosage change is planned before Day 32
6. Consistently nonresponsive to previous treatment with IGIV or anti-D 
immunoglobulin
7. Evidence of an active major bleeding episode at Screening
8. Splenectomy in
the
previous 3 months
or planned
splenectomy
throughout the study period
9. Evans syndrome (experiencing active disease with 2 out of 3 of the
following:
autoimmune
thrombocytopenia,
autoimmune
hemolytic
anemia, and/or autoimmune neutropenia)
10.Known
or 
suspected
human immunodeficiency virus 
(HIV),
hepatitis B virus (HBV), and/or hepatitis C virus (HCV) infections
11.Emergency surgery in the previous 4 weeks
12.Severe liver and/or kidney disease (alanine aminotransferase [ALT]
>3x upper limit of normal (ULN), aspartate aminotransferase [AST]
>3x upper limit of normal (ULN), and/or creatinine >120 µmol/L)
13. History of severe hypersensitivity to blood or plasma derived products,
or any component of the PANZYGA
14. Known immunoglobulin A (IgA) deficiency and antibodies against IgA
15. History of, or suspected alcohol or drug abuse in the previous year
16. Females who are pregnant or nursing
17. Unable or unwilling to comply with the study protocol
18. Receipt of any other investigational medicinal product within 3 months
before study entry
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Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
27Apr2020 
19.Risk factors* for thromboembolic events in whom the risks outweigh the
potential benefit of PANZYGA treatment.
20.Any other condition(s), that in the Investigator’s opinion, make it
undesirable for the patient to participate in the study or may interfere with
protocol compliance.
* Risk factors include, but are not limited to: obesity, advanced age,
hypertension, diabetes, a history of atherosclerosis/vascular disease or
thrombotic events, hyperlipidemia, multiple cardiovascular risk factors, acquired
or inherited thrombophilic disorders, prolonged periods of immobilization,
severe hypovolemia, central venous catheterization, active malignancy and/or
known or suspected hyperviscosity.
Test Product, Dose, and Mode of Administration:
PANZYGA (Immune Globulin, intravenous, human-ifas). PANZYGA must be
stored and transported light-protected at +2°C (36°F) to +8°C (46°F) and must
be brought to room temperature before use.
Patients will receive a dose of 1 g/kg body weight PANZYGA given on Day 1
and optionally another dose of 1 g/kg PANZYGA given on Day 3; body-weight
dependent doses will be based on each patient’s weight collected at Baseline. 
Total PANZYGA doses will be 1 g/kg for patients receiving only 1 dose on Day 1 
and 2 g/kg for those receiving the optional Day 3 dose. Prior to the Day 3 
infusion, each patient’s preinfusion platelet count will be reviewed by the
Investigator. If the Day 3 platelet count is >50x109/L, the Day 3 infusion will not
be administered. If the Baseline platelet count is still ≤50x109/L, the Day 3 
infusion will be administered.
PANZYGA will be delivered by intravenous infusion according to the
recommended flow rates:
•
Initial infusion rate of 0.01 mL/kg/min (60 mg/kg/hr) for the first
30 minutes (±5 minutes)
•
If tolerated, increase to 0.02 mL/kg/min (120 mg/kg/hr) for the second
30 minutes (±5 minutes)
•
If tolerated, increase to 0.04 mL/kg/min (240 mg/kg/hr) for the third
30 minutes (±5 minutes)
•
If tolerated, increase to 0.08 mL/kg/min (480 mg/kg/hr) for the remainder
of the infusion.
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Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
27Apr2020 
Infusion rates should not exceed 0.08 mL/kg/min and should not exceed
8.0 mL/min. The infusion rate may be gradually increased as tolerated by the
patient.
If a Grade 2 or higher (moderate) infusion-related adverse event (AE) occurs
during infusion, the PANZYGA infusion will be stopped. After infusion-related
symptoms subside, the infusion may be resumed at a lower rate. The infusion
rate may be gradually increased as tolerated by the patient.
If a Grade 1 (mild) infusion-related AE occurs during infusion, the infusion rate
should be reduced to half the rate at which the event occurred, or the infusion
should be interrupted until symptoms subside. The infusion may then be
resumed at a rate tolerated by the patient. The batch number(s) used will be
recorded in the study documentation and electronic data capture (EDC) system.
Duration of Treatment:
Screening Period: 1 week
Treatment Period: up to 3 days
Follow-up Period: 29 days
Reference Therapy, Dose, and Mode of Administration:
Not Applicable
Study Outcome Parameters (Primary and Secondary Endpoints):
Primary Endpoint:
The primary efficacy parameter is defined as an increase in platelet count at
least once to ≥50x109/L within 7 days after the first infusion, ie, by Day 8 
(increase must occur at least once on any day up to and including Day 8). This
definition of clinical response will serve as the basis for the primary endpoint,
the response rate (ie, the proportion of patients with an elevation of platelet
count at least once to 50x109/L within 7 days [ie, by Day 8] after the first
infusion).
Secondary Endpoints: 
•
Time to reach a platelet count of 50x109/L
•
Duration of platelet response defined as the number of days the platelet
count remains above 50x109/L
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Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
27Apr2020 
•
Maximum platelet count during the study
Safety Parameters: 
•
AEs
•
Vital signs (blood pressure, heart rate, temperature, respiratory rate)
•
Physical examination
•
Laboratory parameters: hematology (including reticulocytes), hemolysis,
platelet count, serum chemistry (including lactase dehydrogenase
[LDH]).
Study Procedures: 
The study will be conducted in accordance with ICH-GCP and US FDA
regulations.
The Flow Chart of Assessments specifies the procedures that will be performed
at each study visit.
Baseline Visit / Screening Period
After appropriate information about the study and PANZYGA has been provided
and written informed consent/assent has been obtained, patients will be
evaluated for study eligibility according to the inclusion/exclusion criteria. These
evaluations will
include
demographics,
medical/surgical
history,
current
medications, physical examinations, blood and urine samples, along with other
safety and baseline evaluations as specified in the Flow Chart of Assessments.
Infusion Visits (Day 1 and Day 3)
The first PANZYGA infusion must begin no more than 2 days after Baseline
evaluations have been completed and eligibility criteria have been confirmed. If
Baseline and Day 1 Visits occur on the same day, Day 1 investigations do not
need to be repeated. If Baseline evaluations are completed more than 2 days
before Day 1, then the platelet count must be repeated and evaluated by the
Investigator prior to the first infusion.
Patients who have met all of the inclusion criteria and none of the exclusion 
criteria will return to the study site for their first PANZYGA infusion. Required 
assessments will be performed as specified in the Flow Chart of Assessments, 
including safety evaluations before and after each infusion. Patients will remain 
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Name of Sponsor/Company: 
Octapharma USA 
Name of Investigational Product: 
PANZYGA 
Protocol Identification Code: 
NGAM-10 
Name of Active Ingredient: 
Immune globulin human-ifas 
Date of Final Protocol: 
27Apr2020 
at the study site during the infusion and for about 30 minutes after the end of
each infusion to complete vital sign measurements.
Patients will receive a dose of 1 g/kg body weight PANZYGA on Day 1 and 
optionally another dose of 1 g/kg PANZYGA on Day 3; body-weight dependent
doses will be based on each patient’s weight collected at Baseline. Total
PANZYGA doses will be 1 g/kg for patients receiving only 1 dose on Day 1 and
2 g/kg for those receiving the optional Day 3 dose.
Prior to the Day 3 infusion, the Investigator will assess each patient’s
preinfusion platelet count, hematocrit, and hemoglobin. If the Day 3 platelet
count is >50x109/L, the Day 3 infusion will not be administered. If the Baseline
platelet count is still ≤50x109/L, the Day 3 infusion will be administered. If any
of these parameters indicate a clinically relevant change such that, in the
Investigator’s opinion, it is not safe to administer the second infusion the patient
should be withdrawn from study treatment but will be followed for safety through
Day 32.
Assessment Day 5 though Day 22
Patients will return to the study site as indicated in the Flow Chart of
Assessments for continued efficacy and safety evaluations.
Day 32 (End of Study/Early Termination Visit)
Patients will return to the study site on Day 32 for final safety assessments/End
of Study (EOS) visit. Patients withdrawn early from the study will be encouraged
to return to the study site and complete the EOS assessments.
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Statistical Analysis: 
All data collected will be presented descriptively. The time to reach the desired
increase in platelet count as well as the duration of response will be presented
in listings and summarized in statistical tables. Individual profiles of platelet
count over time will be presented as Trellis plots. The primary endpoint for this
study is the proportion of patients with an increase in platelet count to ≥50x109/L
at least once within 7 days after the first infusion. This proportion will be
assessed and presented together with its associated 95% confidence interval
to facilitate comparison with results from other studies and published data.
Because of the limited number of patients, no formal hypothesis test will be
performed; any p-value or confidence interval presented is to be understood in
the exploratory sense.
All safety data, including tolerability assessments, abnormal laboratory values,
and AEs will also be listed and summarized statistically.
Statistical presentations will be fit to the nature of individual data items and
include sample characteristics, frequency counts and rates. Product-limit
survival function estimates (Kaplan-Meier Plots), confidence intervals and
graphs will be included as appropriate.
The following populations will be considered for the statistical analysis:
•
Safety Analysis Set (SAF): All patients who received at least part of one
infusion of PANZYGA.
•
Full Analysis Set (FAS): All patients in the SAF who satisfy all major
eligibility criteria and for whom any post-baseline data is available. This
is the set of eligible patients with treatment effects measured, according
to the intention-to-treat (ITT) principle.
•
Per-Protocol Set I (PP1): All patients in the FAS, excluding those with
significant protocol deviations before the primary efficacy assessment on
day 8 is completed, and which may have an impact on the evaluation of
the primary endpoint.
•
Per-Protocol Set II (PP2): All patients in the FAS, excluding those with
significant protocol violations potentially affecting the (secondary)
efficacy evaluations. 
Only protocol deviations with the potential to significantly affect the study results 
or to invalidate the interpretation of the data obtained will lead to exclusion of
patients from the PP sets. The inclusion of each patient in the respective
analysis populations will be determined before database lock in a data review
meeting by a panel consisting of a medical expert from the Sponsor, the clinical
study manager, the data manager, and the study statistician.
A detailed Statistical Analysis Plan (SAP) will be compiled as a separate 
document. 
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FLOW CHART OF ASSESSMENTS 
Table 1: 
Flow Chart of Assessments 
ASSESSMENTS 
Scr / BL1 
Day 
1 
Day 
3 
Day 
512
Day 
812 
Day 
1512 
Day 
2212 
Day 
3213
Visit Window (Days) 
-7
0 
0 
±1 
±1 
±3 
±3 
±5 
Informed Consent 
X 
Inclusion / Exclusion Criteria Review 
X 
X 
Demographics 
X 
Medical and Surgical History2 
X 
Body Weight and Height 
X 
Physical Examination 
X3 
X3 
X3 
X4 
X4 
X4 
X4 
X3 
Urine or Blood Pregnancy Test (females of 
child-bearing potential) 
X 
X 
Hematology: CBC with white blood cell 
(WBC) differential, hematocrit, hemoglobin, 
platelet counts1, reticulocytes  
X1 
X5,6 
X5,6,7 
X 
X 
X 
X 
X 
Hemolysis: total, direct, and indirect bilirubin 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry: ALT, AST, creatinine, Na, 
Ca, K, BUN, LDH 
X 
X 
X 
X 
X 
X 
Viral markers (HIV, HCV, HBV nucleic acid 
test [NAT]) 
X7 
Receive Sponsor written approval prior to 
enrollment 
X 
PANZYGA INFUSIONS 
X 
X8 
Vital Signs: heart rate, blood pressure, 
temperature, respiratory rate 
X 
X9 
X9 
X 
AE Monitoring10 
X 
X 
X 
X 
X 
X 
X 
Prior and Concomitant Therapy (drug and 
non-drug)11
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: BL = Baseline, Scr = Screening 
1) All Screening Period / Baseline evaluations must be completed within 7 days of Day 1 with the following exception:
Baseline samples for platelet counts must be drawn and evaluated by the Investigator no more than 2 days before the
Day 1 infusion. Note: If Screening/Baseline and Day 1 Visits occur on the same day, the Day 1 investigations need not
be repeated.
2) Medical History will be collected for the previous year and will include the onset date of ITP. Surgical history will include
the date of splenectomy (if applicable), and any other surgical procedures in the previous year.
3) Brief Physical Examination: general appearance, skin, heart, lungs, abdomen, extremities.
4) Targeted  Physical Examination: limited to targeted body systems per Investigator discretion.
5) Pre-infusion 
6) Platelet count, hematocrit, and hemoglobin results must be available and reviewed by the Investigator prior to start of
the infusion. 
7) HIV/HCV/HBV NAT Test: Infusions may begin before the results are back if the Investigator is not aware of, and the
patient isn’t exhibiting clinical signs of, any viral infection. 
8) If the Day 3 preinfusion platelet count is >50x109/L, the Day 3 infusion will not be administered. If the Baseline platelet
count is still ≤50x109/L, the Day 3 infusion will be administered.
9) Vital Signs: at the start of the infusion and every 60 minutes (±15 minutes) thereafter until the end of the infusion. In
addition, vital sign measurements will be recorded just prior to every infusion rate change (-10 minutes), 15 minutes
(+15 minutes) after each infusion rate change, and approximately 30 minutes (+15 minutes) after the end of the
infusion. 
10) The start date and start time will be collected for any adverse events starting at Day 1 through Day 32/EOS visit. 
11) Prior medications will be collected for the 3 months. The start date and start time will be collected for any concomitant
medications taken on Day 1 through Day 32/EOS visit.
12) Days 5, 8, 15, and 22 visits may be performed locally by patient’s primary care physician or a local laboratory service
upon agreement with the site Principal Investigator, the IRB, and the Sponsor.
13) Day 32 visit will correspond to the Early Termination visit for patients who are withdrawn early from the study. 
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PROTOCOL SIGNATURES 
This study is intended to be conducted in compliance with the protocol, 
Go. od Clinical Practice an
 
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Oberlaaerstr . 235, A-1100 Vienna, Austria 
Tel:
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Date 
0 7 MAY 
2020 
Date 
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TABLE OF CONTENTS 
STUDY OUTLINE ............................................................................................................. 2
FLOW CHART OF ASSESSMENTS ............................................................................. 10
PROTOCOL SIGNATURES .......................................................................................... 11
TABLE OF CONTENTS ................................................................................................. 12
TABLE OF TABLES ...................................................................................................... 15
LIST OF ABBREVIATIONS ........................................................................................... 16
1
INTRODUCTION.................................................................................................... 18
1.1
RATIONALE FOR CONDUCTING THE STUDY ..................................................... 19
1.2
DOSE RATIONALE.......................................................................................... 19
1.3
BENEFIT-RISK STATEMENT............................................................................ 19
2
STUDY OBJECTIVES............................................................................................ 21
2.1
PRIMARY OBJECTIVES ................................................................................... 21
2.2
SECONDARY OBJECTIVES.............................................................................. 21
3
INVESTIGATIONAL PLAN.................................................................................... 22
3.1
PRIMARY AND SECONDARY ENDPOINTS......................................................... 22
3.1.1
Primary Endpoint ............................................................................. 22
3.1.2
Secondary Endpoints....................................................................... 22
3.2
OVERALL STUDY DESIGN AND PLAN .............................................................. 22
3.3
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP(S)........... 23
3.3.1
Study Design.................................................................................... 23
3.3.2
Control Group(s).............................................................................. 24
3.3.3
Study Parameters............................................................................ 24
4
STUDY POPULATION........................................................................................... 25
4.1
POPULATION BASE ........................................................................................ 25
4.1.1
Inclusion Criteria .............................................................................. 25
4.1.2
Exclusion Criteria............................................................................. 25
4.2
PRIOR AND CONCOMITANT THERAPY ............................................................. 27
4.2.1
Allowed Pre-medications................................................................. 27
4.2.2
Prohibited Medications .................................................................... 27
4.3
WITHDRAWAL AND REPLACEMENT OF PATIENTS ............................................ 28
4.3.1 Premature Patient Withdrawal ......................................................... 28 
4.3.2 Patient Replacement Policy ............................................................. 28 
4.4
ASSIGNMENT OF PATIENTS TO TREATMENT GROUPS ..................................... 28
4.5
RELEVANT PROTOCOL DEVIATIONS ............................................................... 28
4.6
SUBSEQUENT THERAPY ................................................................................. 28
5 
INVESTIGATIONAL MEDICINAL PRODUCT ...................................................... 29
5.1
CHARACTERIZATION OF INVESTIGATIONAL PRODUCT ..................................... 29
5.2
PACKAGING AND LABELLING .......................................................................... 29
5.3
CONDITIONS FOR STORAGE AND USE ............................................................ 30
5.4
DOSE AND DOSING SCHEDULE ...................................................................... 30
5.5
PREPARATION AND METHOD OF ADMINISTRATION .......................................... 31
5.6
BLINDING, EMERGENCY ENVELOPES, AND BREAKING THE STUDY BLIND ........ 31
5.7
TREATMENT COMPLIANCE ............................................................................. 31
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5.7.1 Drug Dispensing and Accountability................................................ 31 
5.7.2 Assessment of Treatment Compliance ........................................... 32 
6 
STUDY CONDUCT ................................................................................................ 33
6.1 
OBSERVATIONS BY VISIT ............................................................................... 33
6.1.1 Baseline Visit/Screening Period ...................................................... 33 
6.1.2 Day 1 ................................................................................................ 33 
6.1.3 Day 3 ................................................................................................ 34 
6.1.4 Day 5 and Day 8 (± 1 day) ............................................................... 35 
6.1.5 Day 15 and Day 22 (± 3 days) ......................................................... 35 
6.1.6 Day 32 (End of Study Visit) (± 5 days) ............................................ 35 
6.1.7
Visit Windows Used in this Study, including Tolerances ................ 36
6.2 
DURATION OF STUDY ..................................................................................... 36
6.2.1
Planned Duration for an Individual Patient...................................... 36
6.2.2
Planned Duration for the Study as a Whole.................................... 36
6.2.3
Premature Termination of the Study ............................................... 36
7
ASSESSMENTS AND METHODS ........................................................................ 38
7.1
DEMOGRAPHIC AND BASELINE INFORMATION................................................. 38
7.1.1
Demographic and Baseline characteristics..................................... 38
7.1.2
Medical and Surgical history............................................................ 38
7.1.3
Viral Marker Tests............................................................................ 38
7.1.4
Prior and Concomitant Medication Use........................................... 38
7.2
EFFICACY ASSESSMENTS .............................................................................. 38
7.3
SAFETY ASSESSMENTS ................................................................................. 39
7.3.1
Assessments for Safety Evaluations............................................... 39
7.3.2
Adverse Events................................................................................ 39
7.3.3
Serious Adverse Events .................................................................. 42
7.3.4
SAE Reporting Timelines ................................................................ 43
7.3.5
Laboratory Tests.............................................................................. 43
7.3.6
Vital Signs........................................................................................ 44
7.3.7
Physical Examination including Height and Body Weight............... 44
7.3.8
Other Relevant Safety Information.................................................. 45
7.4
OTHER ASSESSMENTS .................................................................................. 46
7.5
APPROPRIATENESS OF MEASUREMENTS........................................................ 46
8
DATA HANDLING AND RECORD KEEPING ...................................................... 47
8.1
DOCUMENTATION OF DATA............................................................................ 47
8.1.1 Source Data and Records ............................................................... 47 
8.1.2 Electronic Case Report Forms ........................................................ 47 
8.1.3 Changes to Electronic Case Report Form Data .............................. 47 
8.2
INFORMATION TO INVESTIGATORS .................................................................. 48
8.3
RESPONSIBILITIES ......................................................................................... 48
8.4
INVESTIGATOR’S SITE FILE ............................................................................ 48
8.5
PROVISION OF ADDITIONAL INFORMATION ...................................................... 49
8.6
INDEPENDENT DATA MONITORING COMMITTEE .............................................. 49
9 
STATISTICAL METHODS AND SAMPLE SIZE ................................................... 50
9.1
DETERMINATION OF SAMPLE SIZE.................................................................. 50
9.2
STATISTICAL ANALYSIS .................................................................................. 50
9.2.1 Populations for Analysis .................................................................. 51 
9.2.2 Efficacy Analysis Plan ...................................................................... 51 
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Page 14 of 60 
9.2.3 Safety Analysis Plan ........................................................................ 52 
9.2.4 Handling of Missing Data ................................................................. 53 
9.3 
RANDOMIZATION, STRATIFICATION, AND CODE RELEASE ............................... 53 
9.4 
INTERIM ANALYSIS ......................................................................................... 53 
10 
ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ............ 54 
10.1 ETHICAL/REGULATORY FRAMEWORK ............................................................. 54 
10.2 APPROVAL OF STUDY DOCUMENTS................................................................ 54 
10.3 PATIENT INFORMATION AND INFORMED CONSENT .......................................... 54 
10.4 PROTOCOL AMENDMENTS ............................................................................. 55 
10.5 CONFIDENTIALITY OF PATIENT DATA .............................................................. 55 
11 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................... 56 
11.1 PERIODIC MONITORING ................................................................................. 56 
11.2 AUDIT AND INSPECTION ................................................................................. 56 
12 
REPORTING AND PUBLICATION ....................................................................... 57 
12.1 CLINICAL STUDY REPORT .............................................................................. 57 
12.2 PUBLICATION POLICY..................................................................................... 57 
13 
LIABILITIES AND INSURANCE ........................................................................... 58 
14 
REFERENCES ....................................................................................................... 59 
15 
APPENDICES ........................................................................................................ 60 
 
 
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Page 15 of 60 
TABLE OF TABLES 
Table 1: 
Flow Chart of Assessments ............................................................... 10 
Table 2: 
Prohibited Medications....................................................................... 27 
Table 3: 
Qualitative and Quantitative Composition of PANZYGA .................. 29 
Table 4: 
Visit Windows Used in this Study ...................................................... 36 
Table 5: 
Laboratory Tests and Time Points..................................................... 44 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine Aminotransferase 
ASH 
American Society of Hematology 
AST 
Aspartate Aminotransferase 
CIDP 
Chronic Inflammatory Demyelinating Poly(radiculo)neuropathy 
CRO 
Contract Research Organisation 
DEHP 
Diethylhexylphthalate 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOS 
End of Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus
IB 
Investigator’s Brochure
ICH 
International Conference on Harmonisation
IDMC 
Independent Data Monitoring Committee
IEC 
Independent Ethics Committee
ifas 
4-letter meaningless suffix assigned by FDA at the end of newly 
approved biologics
IgA 
immunoglobulin A
IMP 
Investigational Medicinal Product 
IRB
Institutional Review Board 
ITP 
Immune Thrombocytopenia 
ITT
Intention-to-Treat 
IUD 
Intrauterine device 
IGIV
Intravenous Immunoglobulin 
LDH 
lactase dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMN 
Multifocal Motor Neuropathy 
NAT 
Nucleic Acid Test 
PMR 
Post-Marketing Requirement 
PREA 
Pediatric Research Equity Act 
PP 
Per-Protocol 
PP1 
Per-Protocol Set 1 
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Abbreviation 
Description 
PP2 
Per-Protocol Set II 
PVC 
Polyvinyl Chloride 
SAE 
Serious Adverse Event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SDV 
Source Data Verification 
SLE 
systemic lupus erythematosus 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-emergent Adverse Event 
TNBP 
tri-n-butyl phosphate 
TPO-RA 
Thrombopoietin Receptor Agonists 
ULN 
Upper Limit of Normal 
USC 
United States Code 
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Page 18 of 60 
1 
INTRODUCTION 
Since more than five decades immunoglobulins have been used to provide 
antibodies for the prevention of viral and bacterial diseases (replacement 
therapy) in immunocompromised patients. Within the last 25 years intravenous 
immunoglobulin (IGIV) has been proven to be useful in a wide variety of clinical 
conditions other than replacement therapy of immunocompromised patients, in 
which IGIV exhibits an immunomodulatory effect. These include Idiopathic 
Thrombocytopenic (ITP) in children and adults at high risk of bleeding or prior to 
surgery to correct the platelet count, Kawasaki disease, and Guillain-Barré 
syndrome (GBS). More recently, single IGIV brands have also been licensed for 
Multifocal Motor Neuropathy (MMN) and Chronic Inflammatory Demyelinating 
Poly(radiculo)neuropathy (CIDP). Experimental off-label use of IGIV mostly in 
other neurological and dermatological indications is widespread. 
ITP is an immune-mediated (disorder characterized by increased platelet 
destruction. The reason for platelet destruction is the development of 
autoantibodies to platelet-membrane antigens. These antibodies are particularly 
produced in the spleen which is also the major site of platelet destruction [1]. In 
patients suffering from ITP, several studies have shown IGIV effective in 
increasing platelet counts to prevent or control bleeding [2-4] The mechanism of 
action in ITP is not fully elucidated but includes immunomodulatory effects, 
particularly the modulation of cytokines, soluble cytokine receptors and cytokine 
receptor antagonists with anti-inflammatory effects as well as complement 
modulation. 
Broadly, 2 categories of agents are available for the treatment of ITP: 1) those 
that rapidly and transiently interfere with the process of platelet destruction for 
management of acute bleeding or bleeding risk (front-line therapies), and 
2) those with potential to provide a more durable improvement in the platelet 
count (second-line therapies). Corticosteroids, IGIV, and anti-D immune globulin 
remain the mainstay of front-line treatment of acute bleeding symptoms in both 
adults and children [5]. Although corticosteroids remain the most commonly used 
ITP therapy, controversy still exists surrounding selection of agent, dosing, and 
duration of therapy. For treatment with prednisone, it is generally accepted that 
shorter courses are preferable to chronic therapy. The 2010 International 
Consensus Report on the investigation and management of primary ITP 
developed by an international working group address three classes of second-
line therapies: splenectomy, rituximab, and the thrombopoietin receptor agonists 
(TPO-RA). Due to a relative lack of data, their use was recommended only in 
patients who were refractory to splenectomy and other therapies. Further study 
results in 2016 demonstrated that TPO-RA agents are being used in children with 
ITP of varying duration and severity. The response was similar to clinical trials, 
but the sustainability of response varied. Future studies need to focus on the ideal 
timing and rationale for these medications in pediatric patients [6]. 
PANZYGA is a human immunoglobulin solution with 10% protein content for 
intravenous administration. PANZYGA is made from a pool of at least 
1000 donations of human fresh-frozen plasma per batch.  
PANZYGA was granted a US approval by the US Food and Drug Administration 
(FDA) in August 2018. The license in 2 indications (primary humoral 
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Page 19 of 60 
immunodeficiency diseases and chronic immune thrombocytopenia) was granted 
based on 2 completed studies. The first study in Primary Immune Deficiency 
included 51 children and adults from ages 2 years to 65 years who were dosed 
at 200 mg/kg to 800 mg/kg body weight every 3 to 4 weeks for 360 days. The 
second study in Immune Thrombocytopenia included 40 adults with chronic ITP 
receiving 2 gm/kg body weight over 2 consecutive days. Of the 36 subjects in the 
full analysis set, 29 patients (81%: 95% CI: 64% to 92%) responded to PANZYGA 
with a rise in platelet count to at least 50x109/L within 7 days after the first 
infusion. 
Further information can be found in the Investigator’s Brochure (IB). 
1.1 Rationale for Conducting the Study 
Under the Pediatric Research Equity Act (PREA) (21 United States Code [USC] 
355c) all applications for new active ingredients, new indications, new dosage 
forms, new dosing regimens or new routes of administration are required to 
contain an assessment of the safety and effectiveness of the product for the 
claimed indication in pediatric patients unless this required is waived, deferred or 
inapplicable.  
This post-marketing requirement (PMR) study was requested by the US FDA 
after PANZYGA received marketing approval in the United States. The rationale 
for conducting this PMR study is to investigate the efficacy and safety of 
PANZYGA in children suffering from primary ITP. 
The study will be conducted in compliance with the protocol, International 
Conference on Harmonisation-Good Clinical Practice (ICH-GCP), US FDA Code 
of Federal Regulations, and other local regulatory requirements. 
1.2 Dose Rationale 
According to recent guidelines, IGIV is recommended for patients with platelet 
counts <30x109/L in case of severe bleeding and/or mucous membrane bleeding. 
Standard doses should be studied (0.8 g/kg to1 g/kg on Day 1, which may be 
repeated once within 3 days, or 0.4 g/kg/day for 2 to 5 days). If other dosage 
regimens are to be applied for, they should be supported by clinical data. [7,8]. 
The dose option for this study is within the recommended guidelines. 
1.3 Benefit-Risk Statement 
The safety profile of IGIV is well characterized and, in general, the same type of 
adverse reactions may be expected for PANZYGA. No new or unknown safety 
problems are expected to emerge which are not already described in the 
Investigator's Brochure. 
Data obtained from the clinical trials conducted with PANZYGA in the adult ITP 
population clearly met the recommended clinical response criteria for efficacy as 
set out in the relevant FDA and EU guidelines. These data are comparable with 
available literature data on other commercial IVIGs and formed the basis for 
marketing authorization in Europe and the US. The safety profile of PANZYGA is 
satisfactory and the number of infusional AEs are below the levels as 
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Page 20 of 60 
recommended by the FDA for products of this class. Efficacy and safety data with 
PANZYGA in 3 clinical studies in 51 patients (also including pediatric patients) 
with primary immunodeficiency (PID) and in 40 patients with immune 
thrombocytopenia (ITP) are available. Available data are sufficient to expect 
favorable benefit-risk profile of PANZYGA in the pediatric ITP population. 
Expected clinical benefit of using PANZYGA in this study is an increase in 
platelets level to control or prevent bleeding. The main known risks are listed 
below: 
• Thrombosis may occur with immune globulin intravenous (IGIV) products, 
including PANZYGA. Risk factors may include: advanced age, prolonged 
immobilization, hypercoagulable conditions, history of venous or arterial 
thrombosis, 
use 
of 
estrogens, 
indwelling 
vascular 
catheters, 
hyperviscosity, and cardiovascular risk factors. 
• Renal dysfunction, acute renal failure, osmotic nephropathy, and death 
may occur with the administration of IGIV products in predisposed 
patients. Renal dysfunction and acute renal failure occur more commonly 
in patients receiving IGIV products containing sucrose. PANZYGA does 
not contain sucrose. 
• For patients at risk of thrombosis, renal dysfunction, or renal failure, 
administer PANZYGA at the minimum infusion rate practicable. Ensure 
adequate hydration in patients before administration. Monitor for signs and 
symptoms of thrombosis and assess blood viscosity in patients at risk for 
hyperviscosity. 
• Standard measures are taken to prevent infections resulting from the use 
of medicinal products prepared from human blood or plasma. Despite this, 
when medicinal products prepared from human blood or plasma are 
administered, the possibility of transmitting infective agents cannot be 
totally excluded. During the manufacturing process of PANZYGA, 
significant viral reduction is obtained. 
Inclusion and exclusion criteria, recommendations on the rate of infusion, 
dosage, and monitoring procedures provided in this protocol sufficiently mitigate 
above mentioned risks and must be adhered to.  
No new or unknown safety problems are expected to emerge in pediatric ITP 
population, which are not listed above or described in the Investigator's Brochure. 
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2 
STUDY OBJECTIVES 
2.1 Primary Objectives 
The primary objective is to evaluate the efficacy of PANZYGA in increasing the 
platelet count in pediatric patients with chronic ITP. 
2.2 Secondary Objectives 
The secondary objectives of this study are to: 
•
Assess safety of up to 2 g/kg PANZYGA (1 g/kg PANZYGA on Day 1 and
an optional dose of 1 g/kg PANZYGA on Day 3) infused in the pediatric
population within the scope of the clinical study
•
Determine the time to reach a platelet count of 50x109/L
•
Determine duration of time during which the platelet count is maintained
at the level ≥50х109/L
•
Determine the maximum platelet count during the study
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3 
INVESTIGATIONAL PLAN 
3.1 Primary and Secondary Endpoints 
3.1.1 Primary Endpoint 
The primary efficacy parameter is defined as an increase in platelet count at least
once to ≥50x109/L within 7 days after the first infusion, ie, by Day 8 (increase
must occur at least once on any day up to and including Day 8). This definition of
clinical response will serve as the basis for the primary endpoint, the response
rate (ie, the proportion of patients with an elevation of platelet count at least once
to 50x109/L within 7 days [ie, Day 8] after the first infusion).
3.1.2 Secondary Endpoints 
Secondary endpoints are defined to further evaluate the efficacy and safety of
the PANZYGA infused in the pediatric population.
The following parameters will be used to for efficacy assessments:
•
Time to reach a platelet count of 50x109/L
•
Duration of platelet response defined as the number of days the platelet
count remains above 50x109/L
•
Maximum platelet count during the study
The following parameters will be used for safety assessments:
•
AEs
•
Vital signs (blood pressure, heart rate, temperature, respiratory rate)
•
Physical examination
•
Laboratory parameters: hematology (including reticulocytes), hemolysis,
platelet count, serum chemistry (including lactase dehydrogenase [LDH])
3.2
Overall Study Design and Plan
This is a prospective, open-label, single-arm, multicenter, Phase 4 study
evaluating the efficacy and safety of the investigational product, PANZYGA, in
pediatric patients with chronic ITP.
The study will enroll at least 20 patients 1 year to <18 years old and will not be
stratified by age group. A patient is considered enrolled into the study after
successfully completing all baseline assessments and receiving at least a partial
dose of PANZYGA.
Patients with a confirmed diagnosis of chronic ITP, without evidence of active 
major bleeding, may be enrolled in the study after written approval of the patient 
by the Sponsor has been obtained. Study procedures will only begin after written 
informed consent (from parent or guardian) and assent (from the patient, as age 
appropriate per Institutional Review Board [IRB] requirements) have been 
obtained. Patients who meet all of the inclusion and none of the exclusion criteria 
may receive the first infusion of PANZYGA within 2 days after Baseline 
investigations have been completed. 
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Each patient will be administered PANZYGA by intravenous infusion at a dose of 
1 g/kg body weight PANZYGA on Day 1 and optionally another dose of 1 g/kg 
PANZYGA on Day 3; body-weight dependent doses will be based on each 
patient’s weight collected at Baseline. Total PANZYGA doses will be 1 g/kg for 
patients receiving only 1 dose on Day 1 and 2g/kg for those receiving the optional 
Day 3 dose. Prior to the Day 3 infusion, Investigators will assess each patient’s 
preinfusion platelet count, hematocrit, and hemoglobin. Patients whose platelet 
count is >50x109/L, the Day 3 infusion will not be administered. If the Baseline 
platelet count is still ≤50x109/L, the Day 3 infusion will be administered. If any 
parameters indicate a clinically relevant change such that, in the Investigator’s 
opinion, it is not safe to administer the second infusion, the patient should be 
withdrawn from study treatment; however, the patient will be followed for safety 
through Day 32.  
Study interventions and procedures will be performed at predefined timepoints 
(see Section 6.1 and the Flow Chart of Assessments [Table 1]) including (but are 
not limited to): blood draws for safety evaluations, vital signs, body weight, 
physical examinations, AE monitoring, and changes in concomitant medication 
use. Patients will have clinic visits on Days 1, 3, 5, 8, 15, and 22. They will return 
to the clinic for a final safety follow-up evaluation at Day 32/End of Study (EOS) 
Visit.  
PANZYGA infusions may be stopped or interrupted at any time if, in the 
Investigator’s opinion, it is not safe to continue or is not in the patient’s best 
interest. Patients who have received a partial dose of PANZYGA should be 
followed for safety evaluations through Day 32/EOS.  
The study is planned to begin screening procedures Q1 2020 at up to 8 sites in 
the USA, with recruitment lasting approximately 24 months, and is anticipated to 
complete in Q1 2022. The study duration for a single patient will be approximately 
39 days, including up to a 1-week Screening period.  
3.3 Discussion of Study Design and Choice of Control Group(s) 
3.3.1 Study Design 
This study was designed to meet the US FDA’s requirements under the PREA 
(21 USC 355c) for a post-approval study of PANZYGA in the pediatric population. 
US FDA is requiring a pediatric study for the treatment of ITP to evaluate 
PANZYGA for the treatment of ITP in patients ages ≥1 year to <18 years. All of 
the US FDA’s recommendations have been incorporated into the protocol.  
This study design is also in line with study protocols evaluating NGAM in adults, 
with the frequency of blood draws and number of visits reduced to accommodate 
a pediatric population. Because of the limited number of patients that will be 
enrolled in this study, along with the increased blood volume and additional site 
visits that would be required to meet the full recommendations in the European 
Medicines Agency (EMA) Guideline for confirmatory visits and blood draws, the 
secondary efficacy endpoints were selected to allow efficacy evaluations in this 
patient population. 
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3.3.2 Control Group(s) 
A placebo control group will not be included in this post-approval study. An active 
control group is not considered relevant, as the objective of this study is to 
evaluate the efficacy and safety of PANZYGA in the pediatric population, not to 
compare the efficacy and safety of PANZYGA versus another IGIV treatment. 
3.3.3 Study Parameters 
The primary therapeutic target for ITP treatment is an increase in the platelet 
count. Therefore, the primary endpoint chosen for the study, namely the response 
rate (ie, the proportion of patients with an increase in platelets at least once to 
≥50x109/L within 7 days after the first infusion), is appropriate to adequately 
describe the efficacy of treatment of PANZYGA in the pediatric population. 
To assess the efficacy of PANZYGA in correcting the platelet count, this response 
rate has been chosen as the primary endpoint. There are several definitions of 
response published in guidelines and commonly used for the evaluation of ITP 
treatment; however, an increase in platelets to ≥50x109/L is the most established 
definition of response [7] and as such has been chosen for this post-marketing 
approval study.  
The secondary efficacy endpoints chosen are in accordance with the primary 
endpoint, in order to further characterize the effect on the increase in platelet 
count. 
The safety assessments, including AE, vital signs, laboratory results, and 
physical examination are appropriate and commonly used parameters to monitor 
the of IGIV treatment during a clinical study. 
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4 
STUDY POPULATION 
4.1 Population Base 
At least 20 female or male patients 1 year to <18 years old with chronic ITP will 
be eligible for this study.  
4.1.1 Inclusion Criteria 
Patients who meet all of the following criteria are eligible for the study: 
1. Females and males aged from 1 year to <18 years old 
Note: Patients who turn 18 years old during study participation must 
be re-consented at their next study visit with an adult informed consent 
form.  
2. Confirmed diagnosis of Chronic Immune Thrombocytopenia (ITP) 
according to American Society of Hematology (ASH 2019) guidelines 
3. Platelets count <30x109/L at the Baseline Visit 
4. Voluntarily given written informed consent (provided by patient’s 
parent or legal guardian) and assent (provided by patient) 
5. Sexually active females who have been using at least 1 acceptable 
form of birth control for a minimum of 30 days (or a minimum of 
3 months for hormonal contraceptives) prior to the Screening visit, 
and must agree to use at least 1 acceptable method of contraception 
throughout the study and for 30 days after the last dose of 
PANZYGA. Acceptable methods include: intrauterine device (IUD), 
hormonal contraception, male or female condom, spermicide gel, 
diaphragm, sponge, or cervical cap. For non-sexually active females 
who have begun menstruating, abstinence is considered an 
acceptable method of birth control. 
6. Parent or legal guardian must agree and be willing to assist the 
participant attend study visits, and to follow all protocol requirements 
and instructions of the study doctor 
4.1.2 Exclusion Criteria 
Patients who meet any of the following criteria are not eligible for the study: 
1. Thrombocytopenia secondary to other diseases (such as Acquired 
Immunodeficiency Syndrome [AIDS] or systemic lupus 
erythematosus [SLE]), drug-related thrombocytopenia, or congenital 
thrombocytopenia 
2. Administration of intravenous immunoglobulin (IGIV) or anti-D 
immunoglobulin within 3 weeks (±3 days) before enrollment 
3. Administration of thrombopoietin receptor agonists when the dose 
has NOT been stable within 3 weeks before enrollment and a dosage 
change is planned before Day 32 
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4. Administration of oral immunosuppressants when the dose has NOT
been stable during the preceding 2 months (2 weeks for long-term
corticosteroid therapy) and a dosage change is planned before
Day 32 (Note: topical agents and inhaled corticosteroid therapy use is
permitted)
5. Administration of long-term anti-prolific agents or attenuated
androgen therapy when the dose has NOT been stable during the
preceding 2 months and a dosage change is planned before Day 32
6. Consistently nonresponsive to previous treatment with IGIV or anti-D
immunoglobulin
7. Evidence of an active major bleeding episode at Screening
8. Splenectomy in the previous 3 months or planned splenectomy 
throughout the study period
9. Evans syndrome (experiencing active disease with 2 out of 3 of the
following: autoimmune thrombocytopenia, autoimmune hemolytic 
anemia, and/or autoimmune neutropenia)
10.Known or suspected human immunodeficiency virus (HIV),
hepatitis B virus (HBV), and/or hepatitis C virus (HCV) infections
11.Emergency surgery in the previous 4 weeks
12.Severe liver and/or kidney disease (alanine aminotransferase [ALT]
>3x upper limit of normal (ULN), aspartate aminotransferase [AST]
>3x upper limit of normal (ULN), and/or creatinine >120 µmol/L)
13.History of severe hypersensitivity to blood or plasma derived
products, or any component of the PANZYGA
14.Known immunoglobulin A (IgA) deficiency and antibodies against IgA
15.History of, or suspected, alcohol or drug abuse in the previous year
16.Females who are pregnant or nursing
17.Unable or unwilling to comply with the study protocol
18.Receipt of any other investigational medicinal product within
3 months before study entry
19. Risk factors* for thromboembolic events in whom the risks outweigh
the potential benefit of PANZYGA treatment.
20. Any other condition(s), that in the Investigator’s opinion, make it
undesirable for the patient to participate in the study or may interfere
with protocol compliance.
* Risk factors include, but are not limited to: obesity, advanced age, hypertension,
diabetes, a history of atherosclerosis/vascular disease or thrombotic events,
hyperlipidemia, multiple cardiovascular risk factors, acquired or inherited
thrombophilic 
disorders, 
prolonged 
periods 
of 
immobilization, 
severe
hypovolemia, central venous catheterization, active malignancy and/or known or
suspected hyperviscosity.
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4.2 Prior and Concomitant Therapy 
Details on medications taken within the previous 3 months prior to the Baseline 
Visit and any concomitant medications taken during the study must be recorded 
in the electronic case report form (eCRF). 
4.2.1 Allowed Pre-medications 
Use of H-1 blockers or antipyretics are allowed for patients who have history of 
hypersensitivity to IGIV treatment; this may minimize the severity of possible 
infusion-related reactions in patients already predisposed to hypersensitivity 
reactions. All pre-medications administered prior to PANZYGA administration 
must be recorded in the eCRF.  
4.2.2 Prohibited Medications 
Use of the following medications are forbidden during the study as specified 
below except if used on or after Day 8 for patient safety in the event of treatment 
failure (ie, platelet count has not reached >50x109/L) (Table 2): 
Table 2: 
Prohibited Medications 
Medication 
Time Window  
IGIV 
prohibited for 3 weeks prior to Baseline Visit 
through Day 32 
anti-D immunoglobulin 
prohibited for 3 weeks prior to Baseline Visit 
through Day 32 
oral immunosuppressants  
prohibited during Screening Period through 
Day 32 unless patients have been receiving 
a stable dose for 2 months (2 weeks for long-
term corticosteroid therapies) prior to 
Screening Visit 
thrombopoietin receptor agonists 
prohibited during Screening Period through 
Day 32 unless patients have been receiving 
stable dose for 3 weeks prior to Screening 
Visit 
long-term anti-prolific agents or 
attenuated androgen therapy 
prohibited during Screening Period through 
Day 32 unless patients have been on a 
stable dose for 2 months prior to Screening 
Visit 
any other blood or plasma-derived 
product* 
prohibited during Screening Period through 
Day 32  
receipt of any other investigational 
product 
prohibited within 3 months prior to Baseline 
Visit through Day 32 
* Patients who are non-responders or requiring emergent ITP treatment (other than PANZYGA specified in this protocol) 
will be followed for safety and complete all assessments through Day 32.  
Trade names of drugs corresponding to the categories provided in Table 2 will 
be provided in the Investigator Site Binder.  
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4.3 Withdrawal and Replacement of Patients 
4.3.1 Premature Patient Withdrawal 
Patients have the right to withdraw from the study at any time for any reason, 
without the need to justify their decision; parents or legal guardians also have the 
right to withdraw a patient on the patient’s behalf. The Investigator also has the 
right to withdraw patients in case of AEs, poor compliance, or other reasons. 
Because an excessive rate of withdrawals can render the study noninterpretable, 
any unnecessary withdrawal of patients should be avoided. 
For any withdrawals after study entry, the Investigator will obtain all the required 
details and document the reason(s) for discontinuation. If the reason for 
withdrawal of a patient is an AE, the main specific event or laboratory test will be 
recorded, and the Investigator will make thorough efforts to clearly document the 
outcome. Patients should return to the study site and have all safety evaluations, 
including safety laboratory tests, completed as specified at the Day 32 visit 
(See Section 6.1.6).  
4.3.2 Patient Replacement Policy 
Patients withdrawn from the study will not be replaced. Under no circumstances 
will patients who enroll in the study be permitted to re-enroll after study 
completion. Patients who fail during the Screening Period (also referred to as 
Screen Failures) may be re-screened upon written approval from the Sponsor. 
4.4 Assignment of Patients to Treatment Groups 
This is an open-label non-randomized study. All patients will receive PANZYGA.  
4.5 Relevant Protocol Deviations 
In case of any major protocol deviation, the Investigator and Octapharma will 
decide on the further participation of the patient in this study after having 
discussed all relevant aspects. 
A list of all included patients with all deviations from the intended study 
procedures and other criteria that may affect the patient's data validity for 
statistical analysis will be prepared upon clinical completion of the study. This will 
also be discussed by a panel consisting of the clinical study manager, a medical 
expert of the Sponsor, the data manager and the study statistician. This panel 
will decide upon the membership of the patient in the Full Analysis Set (FAS), Per 
Protocol (PP) Set 1 (PP2), PP Set 2 (PP2), and Safety Analysis Set for statistical 
analysis. 
4.6 Subsequent Therapy 
If a patient withdraws from the study or is withdrawn by the Investigator by their 
parent/legal guardian, he/she will receive treatment by the Investigator or 
personal physician according to institutional standard of care.  
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5 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1 Characterization of Investigational Product 
Name of Medicinal Product: 
PANZYGA 
Active ingredient of PANZYGA: Immune globulin human-ifas 
Table 3: 
Qualitative and Quantitative Composition of PANZYGA 
Name of Ingredient 
Amount 
Total protein  
9.0 – 11.0 g/100 mL 
Protein composition 
≥95% Ig (≥96% Ig)* 
IgG content  
86 – 110 mg/mL 
Glycine 
15.0 – 19.5 mg/mL (17.3 mg/mL)*  
Water for Injection 
ad 1mL  
* Depending on regulatory requirements 
PANZYGA is a solvent/detergent (S/D)-treated, sterile preparation of highly 
purified immunoglobulin G (IgG) derived from large pools of human plasma. 
PANZYGA is a solution for infusion to be administered intravenously.  
This preparation contains approximately 100 mg of protein per mL (10%), of 
which not less than 96% is normal human immunoglobulin G. PANZYGA contains 
not more than 3% aggregates, not less than 90% monomers and dimers, and not 
more than 3% fragments. On average, the product contains 100 μg/mL of IgA, 
and lower amounts of IgM.  
PANZYGA contains only trace amounts of sodium, and the pH is between 4.5 
and 5.0. The osmolality is in the range of 240 to 310 mosmol/kg.  
The manufacturing process for PANZYGA isolates IgG without additional 
chemical or enzymatic modification, and the Fc portion is maintained intact. 
PANZYGA contains the IgG antibody activities present in the donor population. 
IgG subclasses are fully represented with the following approximate percentages 
of total IgG: IgG1 is 65%, IgG2 is 28%, IgG3 is 3% and IgG4 is 4%.  
PANZYGA contains a broad spectrum of IgG antibodies against bacterial and 
viral agents that are capable of opsonization and neutralization of microbes and 
toxins. PANZYGA contains glycine (15.0 to 19.5 mg/mL), but no preservatives or 
sucrose.  
All units of human plasma used in the manufacture of PANZYGA are provided by 
FDA-approved blood and plasma establishments, and are tested by FDA-
licensed serological tests for HBsAg, antibodies to HCV and HIV and Nucleic Acid 
Test (NAT) for HCV and HIV-1 and found to be non-reactive (negative).  
5.2 Packaging and Labelling 
PANZYGA for investigational use only will be labeled according to US FDA 
regulations. Details of the labeling will be included in the Pharmacy Manual. 
The batch number(s) used will be recorded in the study documentation and EDC. 
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5.3 Conditions for Storage and Use 
PANZYGA must be stored and transported light-protected at +2°C (36°F) to +8°C 
(46°F) and must be brought to room temperature before use.  
Storage temperature must be maintained at +2°C (36°F) to +8°C (46°F) and will 
be monitored for the duration of the study by reviewing the temperature logs. 
PANZYGA must not be frozen prior to use. 
PANZYGA must not be used after its expiry date.  
PANZYGA must not be mixed with other medicinal products. 
Each PANZYGA bottle is for single use only. 
Authorized personnel at the individual study sites will ensure that PANZYGA is 
stored in appropriate conditions in a secure refrigerator with restricted access and
in compliance with national regulations.
5.4 Dose and Dosing Schedule 
PANZYGA will be administered by intravenous infusion. Patients should be
adequately hydrated prior to infusion.
Patients will receive a dose of 1 g/kg body weight PANZYGA given on Day 1 and
optionally another dose of 1 g/kg PANZYGA given on Day 3; body-weight
dependent doses will be based on each patient’s weight collected at Baseline. 
Total PANZYGA doses will be 1 g/kg for patients receiving only 1 dose on Day 1 
and 2 g/kg for those receiving the optional Day 3 dose. If the Day 3 platelet count
is >50x109/L, the Day 3 infusion will not be administered. If the Baseline platelet
count is ≤50x109/L, the Day 3 infusion will be administered. 
PANZYGA will
be
delivered
by intravenous infusion
according
to
the
recommended flow rates:
•
Initial infusion rate of 0.01 mL/kg/min (60 mg/kg/hr) for the first 30 minutes
(±5 minutes)
•
If tolerated, increase to 0.02 mL/kg/min (120 mg/kg/hr) for the second
30 minutes (±5 minutes)
•
If tolerated, increase to 0.04 mL/kg/min (240 mg/kg/hr) for the third
30 minutes (±5 minutes)
•
If tolerated, increase to 0.08 mL/kg/min (480 mg/kg/hr) for the remainder
of the infusion
Infusion rates should not exceed 0.08 mL/kg/min and should not exceed 
8.0 mL/min.  
If a Grade 2 (moderate) or higher infusion-related adverse event (AE) occurs 
during infusion, the PANZYGA infusion will be stopped. After infusion-related 
symptoms subside, the infusion may be resumed at a lower rate. The infusion 
rate may be gradually increased as tolerated by the patient. 
If a Grade 1 (mild) infusion-related AE occurs during infusion, the infusion rate 
should be reduced to half the rate at which the event occurred, or the infusion 
should be interrupted until symptoms subside. The infusion may then be resumed 
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at an infusion rate tolerated by the patient. The infusion rate may be gradually 
increased as tolerated by the patient.  
5.5 Preparation and Method of Administration 
All patients will be infused at the study site under the surveillance of authorized 
study site staff.  
After calculating the volume required for the dose using the patient’s Baseline
body weight (see Section 5.4), the appropriate number of vials will be removed
from the refrigerator. Vials of different sizes may be combined to reach the
required amount of IgG. The dose will be administered, and the empty and
partially used vials will be retained by the site for drug accountability and dose
verification. 
PANZYGA vials must be allowed to warm to room or body temperature before
infusion. After PANZYGA vials have been brought to room or body temperature,
they should be inspected visually for particulate matter and discoloration prior to
administration. The solution should be clear or slightly opalescent. DO NOT USE 
IF
TURBID,
DISCOLORATION
IS 
OBSERVED,
AND/OR
FLOATING
PARTICLES ARE PRESENT. Solutions that are cloudy or vials that have a
deposit must not be used and must be discarded according to local policy.
Aseptic technique must be used throughout the entire procedure.
The contents of bottles must be pooled under aseptic conditions into sterile
infusion bags and administered immediately after pooling. Ideally polyvinyl
chloride (PVC)-free, diethylhexylphthalate (DEHP)-free and latex–free, infusion
bags can be used. Once pooled, a label will be applied on the infusion bag. 
Detailed instructions of this process and an example label will be included in the
Pharmacy Manual.
PANZYGA will be infused into a vein using standard infusion supplies provided
by the individual site. Standard procedures should be followed to prime the
infusion line with a priming solution (eg, normal saline). At the end of each
infusion, the infusion line will be flushed with normal saline solution or with the
site’s routine flushing solution.
Additional information regarding PANZYGA preparation and infusion procedures
will be provided in a pharmacy manual.
Please refer to special warnings and precautions for use provided in the
PANZYGA Investigator Brochure.
5.6 Blinding, Emergency Envelopes, and Breaking the Study Blind 
Not applicable. 
5.7 Treatment Compliance 
5.7.1 Drug Dispensing and Accountability 
The Sponsor or designee will provide and deliver all PANZYGA to participating 
Investigators. A Drug Inventory and Dispensing Log will be kept current by the 
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Investigator, detailing the dates and quantities of PANZYGA received, dispensed 
to each patient, and the quantity remaining at the study site.  
The Drug Inventory and Dispensing Log will be available to the monitor to verify 
drug accountability during the study. The study monitor will inventory all empty 
and partially used vials of PANZYGA and will cross-check this inventory versus 
the patient source documentation (records), eCRF, and the Drug Inventory and 
Dispensing Log. 
Unused and partially used vials may be destroyed at the study site or returned to
the Sponsor for destruction according to institutional practice. Vials may be
destroyed only after drug accountability has been verified and fully reconciled by
the monitor and after the Sponsor has granted written approval of destruction.
Additional information regarding PANZYGA drug accountability procedures will
be provided in a pharmacy manual.
If a study site pharmacy is required to follow their own drug dispensing and
accountability procedures, adherence to these activities will take precedence
over this protocol-specific guidance and will not be considered a protocol
deviation.
5.7.2 Assessment of Treatment Compliance 
All patients will be infused at the study site under the surveillance of authorized
study personnel. Infusion details will be documented together with the batch
number(s) in the source data and eCRF.
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6 
STUDY CONDUCT  
Procedures performed at each study visit are presented in the Flow Chart of 
Assessments (see Table 1). Time windows and tolerances are provided in Table 
4. 
6.1 Observations by Visit 
6.1.1 Baseline Visit/Screening Period (Day -7 to Day 1) 
The following assessments will be performed during the Screening Period. The 
Screening Period can last up to 1 week (to accommodate patient schedules and 
the informed consent/assent process); however, all Baseline evaluations should 
be completed within 2 days before the first administration of PANZYGA. 
Note: The Baseline/Screening and Day 1 Visits may occur on the same day 
(see Section 6.1.2).  
• Obtaining voluntarily given, written (signed and dated) informed consent 
and assent (as age appropriate) 
• Inclusion and exclusion criteria 
• Demographic and baseline characteristics 
• Medical and surgical history (previous 1 year) 
• Splenectomy history 
• Brief physical examination  
• Vital signs 
• Height 
• Body weight 
• Blood samples for serum chemistry, hematology, and hemolysis analytes 
Note: platelet evaluations must be completed within 2 days prior to 
Day 1 visit.  
• Blood or urine pregnancy test (females of childbearing potential, only) 
• Blood samples for viral markers 
• Documentation of prior medications (previous 3 months), including 
administration of pre-medication(s) as appropriate (see Section 4.2.1) 
6.1.2 Day 1 
All Baseline/Screening evaluations must be completed no more than 7 days prior 
to the Day 1 Visit. Patients MAY NOT BE ENROLLED until after receiving written 
approval by the Sponsor. Note: If the Baseline/Screening and Day 1 Visits occur 
on the same day, the Baseline/Screening investigations do not need to be 
repeated. If the Baseline/Screening evaluations are completed more than 2 days 
before Day 1, only the platelet count must be repeated and evaluated by the 
Investigator prior to initiating the first infusion. 
Before the administration/infusion of PANZYGA, patient eligibility will be re-
evaluated. The following assessments/activities will be performed before 
PANZYGA infusion: 
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•
Confirmation of inclusion and exclusion criteria
•
Brief physical examination
•
Vital signs
•
Blood samples for serum chemistry, hematology, and hemolysis analytes
•
Administration of pre-medication(s) as appropriate (see Section 4.2.1)
The following activities will be performed during or after PANZYGA infusion: 
•
PANZYGA infusion
•
Vital signs (at the start of the infusion and every 60 minutes (±15 minutes)
thereafter until the end of the infusion. In addition, vital sign measurements
will be recorded just prior to every infusion rate change (-10 minutes),
15 minutes (+15 minutes) after each
infusion
rate
change,
and
approximately 30 minutes (+15 minutes) after the end of the infusion
•
Monitoring for AEs
•
Documentation of concomitant medication use
6.1.3 Day 3 
The following assessments/activities will be performed before PANZYGA
infusion:
•
Brief physical examination
•
Vital signs
•
Blood samples for serum chemistry, hematology, and hemolysis analytes
•
NOTE: platelet, hemoglobin and hematocrit results must be available and
reviewed by the Investigator prior to initiating the Day 3 infusion
•
Administration of pre-medication(s) as appropriate (see Section 4.2.1)
The Investigator will assess each patient’s Day 3 preinfusion platelet count,
hematocrit, and hemoglobin. If the Day 3 platelet count shows evidence of clinical
response, as indicated by the platelet count being >50x109/L, the Day 3 infusion
will not be administered. If the Baseline platelet count is still ≤50x109/L, the Day 3 
infusion will be administered. In the event that the Day 3 infusion is not
administered, all other Day 3 assessments will still be completed. If any of these
hematology parameters indicate a clinically relevant change such that, in the
Investigator’s opinion, it is not safe to administer the second infusion the patient
should be withdrawn from study treatment but will be followed for safety through
Day 32.
The following activities will be performed during or after PANZYGA infusion: 
•
PANZYGA infusion
•
Vital signs (at the start of the infusion and every 60 minutes (±15 minutes)
thereafter until the end of the infusion. In addition, vital sign measurements
will be recorded just prior to every infusion rate change (-10 minutes),
15 minutes (+15 minutes) after each infusion rate change, and
approximately 30 minutes (+15 minutes) after the end of the infusion
•
Monitoring for AEs
•
Documentation of concomitant medication use
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6.1.4 Day 5 and Day 8 (± 1 day) 
Day 5 and Day 8 visits and assessments may be performed locally (by patient’s 
primary care physician or local laboratory services) upon agreement with the site 
Principal Investigator, the IRB, and the Sponsor. Required interactions and 
communication channels between the primary care physician and the Principal 
Investigator (eg, telemedicine or other means of electronic communication) will 
be outlined in the Investigator Site Binder. 
The following assessments will be performed at Day 5 and Day 8: 
• Targeted physical examination  
• Blood samples for serum chemistry, hematology, and hemolysis analytes 
• Monitoring for AEs 
• Documentation of concomitant medication use 
6.1.5 Day 15 and Day 22 (± 3 days) 
Day 15 and Day 22 visits and assessments may be performed locally (by patient’s 
primary care physician or local laboratory services) upon agreement with the site 
Principal Investigator, the IRB, and the Sponsor. Required interactions and 
communication channels between the primary care physician and the Principal 
Investigator (eg, telemedicine or other means of electronic communication) will 
be outlined in the Investigator Site Binder. 
The following assessments will be performed at Day 15 and Day 22: 
• Targeted physical examination 
• Blood samples for hematology and hemolysis analytes 
• Monitoring for AEs 
• Documentation of concomitant medication use 
6.1.6 Day 32 (End of Study Visit) (± 5 days) 
Patients will return to the study site on Day 32 for final safety assessments/EOS 
Visit. Patients who were withdrawn early from the study should return to the study 
site for a final safety assessment. The following assessments will be performed:  
• Brief physical examination 
• Vital signs 
• Blood samples for serum chemistry, hematology, and hemolysis analytes 
• Blood or urine pregnancy test (females of childbearing potential, only) 
• Monitoring for AEs 
• Documentation of concomitant medication use 
After Day 32, the clinical study is considered completed for the patient. No further 
study-related assessments will be performed, unless safety concerns 
(eg, ongoing AEs) require follow-up. 
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6.1.7 Visit Windows Used in this Study, including Tolerances 
In this study, the following time windows and tolerances apply (Table 4): 
Table 4: 
Visit Windows Used in this Study 
Time point 
Tolerance 
Screening/Baseline Evaluations 
7 days prior to Day 1 
Baseline Platelets1 
2 days prior to Day 1 
Day 1 
none 
Day 3 
none 
Day 5 
±1 day 
Day 8  
±1 day 
Day 15 and Day 22 
±3 days 
Day 32 
± 5 days 
1) Baseline platelet evaluations must be completed and evaluated by the Investigator no more than 2 days 
prior to the Day 1 visit. 
6.2 Duration of Study 
6.2.1 Planned Duration for an Individual Patient 
The duration of the entire study for each patient will be approximately 39 days, 
including a 7-day Screening Period. 
6.2.2 Planned Duration for the Study as a Whole 
The study will be considered completed when all patients have completed the 
Day 32 EOS Visit. 
The estimated start of the study (enrollment of first patient) is Q1 2020, and the 
estimated end of the study (last visit of last patient) is Q1 2022. 
6.2.3 Premature Termination of the Study 
Both the responsible Investigators and the Sponsor reserve the right to terminate 
the study at any time. Should this be necessary, study close-out procedures will 
be arranged on an individual site basis after review and consultation by both 
parties. In terminating the study, the Sponsor and the Investigator will ensure that 
adequate consideration is given to the protection of the patients' interests. 
Furthermore, the Investigator should promptly inform the IRB and provide a 
detailed written explanation. Pertinent regulatory authorities and IRBs will be 
informed in accordance with applicable regulatory requirements. 
6.2.3.1 Early Termination of the Entire Clinical Study 
At any time, the study as a whole will be terminated prematurely if: 
• New toxicological or pharmacological findings or safety reports invalidate 
the earlier positive benefit-risk-assessment for the pediatric population 
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• Any other reason rendering the continuation of the study impossible for 
the Sponsor 
6.2.3.2 Early Termination at an Individual Study Site 
At any time, the study can be terminated at an individual study site if: 
• The site cannot comply with the requirements of the protocol 
• The site cannot comply with GCP or other regulatory standards 
• The site does not meet the required recruitment rate 
Should the study be prematurely terminated, all study materials, including 
PANZYGA, must be returned to the Sponsor. 
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7 
ASSESSMENTS AND METHODS 
7.1 Demographic and Baseline Information 
Demographic and baseline information will be recorded during the Screening 
Period: 
7.1.1 Demographic and Baseline characteristics 
The demographic and baseline characteristics are sex, age, race and ethnic 
origin, height, and weight. 
7.1.2 Medical and Surgical history 
The medical history will be collected for the previous year and will be obtained by 
interviewing the patient. Records of past diseases and treatments (eg, hospital 
discharge letters) will be obtained for the study files, if available. The onset date 
of ITP will be recorded. 
Surgical history will include the date of splenectomy (if applicable) and any other 
surgical procedures in the previous year.  
7.1.3 Viral Marker Tests 
At the Screening Visit, blood samples for viral markers (HIV, HCV, HBV NAT) will 
be collected and tested at the local laboratory according to the site’s standard 
procedures, to rule out secondary infections that may cause ITP. Infusions may 
begin before the results are back if the Investigator is not aware of, and the patient 
isn’t exhibiting clinical signs of, any viral infection. 
7.1.4 Prior and Concomitant Medication Use 
Prior medication use will be obtained by interview and review of patient charts 
(if available). Patients will be queried specifically for use of H-1 blockers or 
antipyretics as pre-medications prior to previous IGIV treatments.  
Concomitant medication use, defined as medications with a start date and time 
after the start of the Day 1 infusion, will be collected throughout the study. The 
start date and time of medication use will be collected on Day 1 and throughout 
the study.  
7.2 Efficacy Assessments 
All efficacy assessments will be based on platelet counts performed throughout 
the study.  
Platelet counts will be performed at Baseline (within 2 days prior to the first 
PANZYGA infusion), at Day 1 and Day 3 prior to planned PANZYGA infusions, 
and then at all remaining study visits (Days 5, 8, 15, 22, and 32). 
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7.3 Safety Assessments 
7.3.1 Assessments for Safety Evaluations 
The following assessments will be performed to evaluate the safety of PANZYGA 
in the pediatric population: 
• AEs and Serious Adverse Events (SAEs) 
• Clinical laboratory tests 
• Vital signs 
• Physical examinations 
• Pregnancies 
7.3.2 Adverse Events  
7.3.2.1 Definitions 
• Adverse event (AE): An AE is any untoward medical occurrence in a 
study /patient receiving an investigational medicinal product (IMP) and 
which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IMP, whether or not related to the IMP. 
• Adverse drug reaction (ADR): An ADR is any noxious and unintended 
response to an IMP related to any dose. The phrase ‘response to an IMP’ 
means that a causal relationship between the IMP and an AE carries at 
least a reasonable possibility (ie, the relationship cannot be ruled out). 
• Other significant AEs: Any marked laboratory abnormalities or any AEs 
that lead to an intervention, including withdrawal of drug treatment, dose 
reduction, or significant additional concomitant therapy. 
• Treatment-emergent AE (TEAE): Any AE that newly appeared, 
increased in frequency, or worsened in severity following the time of the 
first IMP infusion until the end of the safety follow-up period. 
• Infusional AE: Any AE that occurs from the time of infusion and within the 
72 hour period after end of infusion. 
• Withdrawal due to AE/ADR: AE/ADR leading to discontinuation of 
treatment with IMP. Any such events will be followed up by the Investigator 
until the event is resolved or until the medical condition of the patient is 
stable. All follow-up information collected will be made available to the 
Sponsor. 
7.3.2.2 Collection of AEs 
AEs will be collected from the start of the first infusion on Day 1. Any illnesses 
captured between signing the ICF and the first infusion will be captured under 
medical history. The condition of the patient will be monitored throughout the 
study. At each visit, whether scheduled or unscheduled, AEs will be elicited using 
a standard nonleading question such as “How have you been since the last 
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visit/during the previous study period?” In addition, the Investigator will check the 
patient diaries (if applicable) for any documented event. 
Any AE or ADR which occurs during the study will be noted in detail on the 
appropriate pages of the eCRF. If the patient reports several signs or symptoms 
representing a single syndrome or diagnosis, the diagnosis should be recorded 
in the eCRF. The Investigator will grade the severity of all AEs or ADRs (mild, 
moderate, or severe), the seriousness (non-serious or serious), and the causality 
as defined in Section 7.3.2.3, Section 7.3.3, and Section 7.3.2.4, respectively. 
The Sponsor is responsible for assessing the expectedness of each ADR 
(expected or unexpected) as defined in Section 7.3.2.5. 
In the event of clinically significant abnormal laboratory findings, the tests will be 
confirmed and the patient followed until the laboratory values have returned to 
normal and/or an adequate explanation for the abnormality has become 
available. 
Diseases, signs and symptoms, and/or laboratory abnormalities already present 
before the first administration of IMP will not be considered AEs unless an 
exacerbation in intensity or frequency (worsening) occurs. 
The Investigator will provide detailed information about any abnormalities and 
about the nature of and reasons for any action taken as well as any other 
observations or comments that may be useful for the interpretation and 
understanding of an AE or ADR. 
7.3.2.3 Severity of AEs 
The intensity/severity of AEs will be graded as follows: 
• Mild: an AE, usually transient, which causes discomfort but does not 
interfere with the patient’s routine activities 
• Moderate: an AE which is sufficiently discomforting to interfere with the 
patient’s routine activities 
• Severe: an AE which is incapacitating and prevents the pursuit of the 
patient’s routine activities 
The grading of an AE is up to the medical judgement of the Investigator and will 
be decided on a case-by-case basis. 
7.3.2.4 Causality of AEs 
The relationship of AEs to the administered IMP will be assessed by the 
Investigator: 
• Probable: reports including good reasons and sufficient documentation to 
assume a causal relationship, in the sense of plausible, conceivable, likely, 
but not necessarily highly probable. A reaction that follows a reasonable 
temporal sequence from administration of the IMP; or that follows a known 
or expected response pattern to the suspected medicine; or that is 
confirmed by stopping or reducing the dosage of the medicine and that 
could not reasonably be explained by known characteristics of the 
patient’s clinical state. 
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• Possible: reports containing sufficient information to accept the possibility 
of a causal relationship, in the sense of not impossible and not unlikely, 
although the connection is uncertain or doubtful, for example because of 
missing data or insufficient evidence. A reaction that follows a reasonable 
temporal sequence from administration of the IMP; that follows a known 
or expected response pattern to the suspected medicine; but that could 
readily have been produced by a number of other factors. 
• Unlikely: reports not following a reasonable temporal sequence from IMP 
administration. An event which may have been produced by the patient’s 
clinical state or by environmental factors or other therapies administered. 
• Not related (unrelated): events for which sufficient information exists to 
conclude that the etiology is unrelated to the IMP. 
• Unclassified: reports which for one reason or another are not assessable. 
7.3.2.5 Classification of ADRs by Expectedness 
ADRs will be classified by the Sponsor as either expected or unexpected: 
• Expected: an ADR that is listed in the current edition of the Investigator’s 
Brochure or other reference safety information. 
• Unexpected: an ADR that is not listed in the current edition of the 
Investigator’s Brochure or other reference safety information, or that differs 
because of greater severity or greater specificity. 
7.3.2.6 Outcome of AEs 
The outcome of all reported AEs will be documented as follows: 
1. Recovered, resolved 
2. Recovering, resolving 
3. Not recovered, not resolved 
4. Recovered, resolved with sequelae 
5. Fatal 
6. Unknown 
NOTE: A patient’s death per se is not an event, but an outcome. The event which 
resulted in the patient’s death must be fully documented and reported, even in 
case the death occurs within 4 weeks after IMP treatment end and regardless of 
whether or not it is considered treatment-related. 
7.3.2.7 Action(s) taken 
AEs requiring action or therapy must be treated with recognized standards of 
medical care to protect the health and well-being of the patient. Appropriate 
resuscitation equipment and medicines must be available to ensure the best 
possible treatment in an emergency situation. 
The action taken by the Investigator must be documented: 
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a) General actions taken in the event of an AE 
– None 
– Medication (other than IMP) or other (eg, physical) therapy started 
– Test performed 
– Other (to be specified) 
b) IMP-related actions taken in the event of an AE 
– None 
– Product withdrawn 
– Dose reduced 
– Dose increased 
The Investigator will follow up on each AE until it has resolved or until the medical 
condition of the patient has stabilized. Any relevant follow-up information will be 
reported to the Sponsor. 
7.3.2.8 Managing Hypersensitivity Reactions 
Severe hypersensitivity reactions may occur during PANZYGA infusions [9]. In 
the case of any subject exhibiting clinical signs of severe hypersensitivity 
reactions to PANZYGA, the PANZYGA infusion must be immediately stopped. 
Each site must have Epinephrine readily available and follow their institution’s 
standard procedure for Epinephrine administration and monitoring. If a subject 
develops severe hypersensitivity or anaphylactoid reactions, any further 
PANZYGA administration should be discontinued and not resumed. 
7.3.3 Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
• results in death 
• is life-threatening (see below) 
• requires hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is another important medical event 
NOTE: The term ‘life-threatening’ refers to an event in which the patient was, in 
the view of the reporting Investigator, at immediate risk of death at the time of the 
event; it does not refer to an event which may hypothetically have caused death 
had it been more severe. 
In deciding whether an AE/ADR is serious, medical judgment should be 
exercised. Thus, important AEs/ADRs that are not immediately life-threatening or 
do not result in death or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the other outcomes listed in the definitions 
above should also be considered serious.  
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In addition, although not classified under the seriousness criteria, all suspected 
transmissions of an infectious agent should be reported as SAE. A suspected 
virus transmission means that virus antigen has been detected in the patient. A 
passive transmission of antibodies alone does not constitute a suspected virus 
transmission. 
7.3.4 SAE Reporting Timelines 
All SAEs, whether or not they are suspected to be related to study treatment, are 
to be reported immediately by telephone, fax, or email to the Clinical Project 
Manager or designee with the contact detailed provided to each site in the 
Investigator Site Binder. The contact details will also be communicated at the 
study initiation visit. 
In addition, within 24 hours after recognition of the event, an Octapharma Serious 
Adverse Event Report must be completed and submitted to: 
Octapharma’s Corporate Drug Safety Unit 
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
Fax: 
 
E-mail: 
 
24 hours emergency telephone numbers: 
 or  
 
The Investigator must update the Octapharma Serious Adverse Event Report as 
soon as any additional information becomes available. The Investigator must also 
report SAEs to the IRB/IEC as required by local and national laws. The 
Investigator must maintain documentation of all communications to and from the 
IRB/IEC. 
In accordance with 21 CFR 312.32 and local authorities, the Sponsor will submit 
to the FDA unexpected adverse reactions within 15 calendar days. Unexpected 
fatal or life-threatening adverse reactions will be submitted within 7 calendar 
days. 
Waivers the from SAE Reporting Requirement 
Waivers from the SAE reporting requirement include surgeries that are elective 
or were planned before study entry or prolongations of existing hospitalizations 
for economic or social, but not medical, reasons. Such surgeries or prolongations 
of hospitalizations should not be considered SAEs. 
7.3.5 Laboratory Tests 
Clinical laboratory parameters will be investigated during the study at the time 
points specified in the Flow Chart of Assessments (Table 1).  
All of the study-specific laboratory tests will be performed at the local laboratories 
for each study site. The laboratory test and sample collection timing are specified 
below (Table 5). 
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Table 5: 
Laboratory Tests and Time Points 
Test 
Timing 
Hematology (complete blood count, WBC 
differential, hematocrit, hemoglobin, platelet 
counts, reticulocytes) 
During Screening (Baseline evaluation), at 
Days 1, 3, 5, 8, 15, 22, and at Day 32/EOS 
Hemolysis (total, direct, and indirect 
bilirubin)  
During Screening (Baseline evaluation), at 
Days 1, 3, 5, 8, 15, 22, and at Day 32/EOS 
Serum chemistry (ALT, AST, creatinine, Na, 
Ca, K, BUN, LDH) 
During Screening (Baseline evaluation), 
Days 1, 3, 5, 8, and at Day 32/EOS 
Blood or Urine pregnancy test (females of 
childbearing potential) 
During Screening (Baseline evaluation) and 
Day 32/EOS 
Virology: HIV, HCV, HBV NAT 
During Screening (Baseline evaluation, see 
Section 7.1.3)  
Investigational sites will follow all site and local laboratory standard operating 
procedures for sample collection and handling and will provide the Sponsor with 
normal reference ranges and laboratory certification certificates. Upon 
agreement with site Principal Investigator, the IRB, and the Sponsor, Days 5, 8, 
15, and 22 visits may be performed locally by the patient’s primary care physician. 
Laboratory samples may be collected by a patient’s primary care physician or by 
a local laboratory service (that draws, processes, and reports laboratory results) 
that is in the proximity of the patient’s home; these samples must be analyzed 
according to the chosen laboratory’s standard operating procedures. Normal 
reference ranges and laboratory certification certificates of any laboratories will 
also be provided to the Sponsor and the Form FDA 1572 must be updated to 
include the laboratory. 
The methods of determination and normal ranges for each parameter from each 
local laboratory will be provided in the clinical study report.  
7.3.6 Vital Signs 
Vital signs will be collected at the time points specified in the Flow Chart of 
Assessments (Table 1) are blood pressure, body temperature, pulse rate, and 
respiratory rate. 
On Day 1 and Day 3, vital sign measurements will be recorded before the start 
of the infusion and every 60 minutes (±15 minutes) thereafter until the end of the 
infusion. In addition, vital sign measurements will be recorded just prior to every 
infusion rate change (-10 minutes), 15 minutes (+15 minutes) after every infusion 
rate change, and approximately 30 minutes (+15 minutes) after the end of the 
infusion. 
7.3.7 Physical Examination including Height and Body Weight.  
Physical examinations will be performed at the visits specified in the Flow Chart 
of Assessments (Table 1). A “Brief Physical Examination” will include 
examinations of the patient’s general appearance, skin, heart, lungs, abdomen, 
and extremities. A “Targeted Physical Examination” will be limited to targeted 
body systems per Investigator discretion. 
Both height and weight will be measured at Baseline, only.  
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7.3.8 Other Relevant Safety Information 
a) Post-study related safety reports 
Any SAE which occurs during the study (ie, within 4 weeks after the last 
PANZYGA administration, which for most patients will be up to and including 
Day 32) will be reported by the Investigator to the Sponsor. Proactive monitoring 
for post-study SAEs is not required. 
In case a post-study SAE is identified, the Investigator should complete an SAE 
form and also state the relation to the clinical study in the report. 
Deaths occurring during the study (ie, within 4 weeks after the last PANZYGA 
administration, which for most patients will be up to and including Day 32) should 
also be reported, regardless of whether or not they are considered treatment-
related. 
b) Pregnancies  
Every effort will be made to avoid a pregnancy during the use of an IMP. 
Pregnancies occurring during the study (fetal exposure to PANZYGA) need to be 
reported.  
In case of pregnancy during the study, the Investigator should complete the 
Pregnancy Notification Form and send or fax it to the Clinical Project Manager or 
designee (Section 7.3.4). 
Follow-up information on the outcome of both mother and fetus will be requested 
by a Sponsor representative. 
c) Overdose, interaction, medication error and lack of efficacy 
The following safety relevant information should be reported as an AE or, if the 
reaction fulfills one of the criteria for seriousness, as SAE. 
d) Drug overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose 
higher than specified in the protocol and higher than the known therapeutic dose 
that is of clinical relevance. The reaction must be clearly identified as an 
overdose. 
e) Drug interaction 
A drug interaction is a situation in which a substance or medicinal product affects 
the activity of an IMP, ie, increases or decreases its effects, or produces an effect 
that none of the products would exhibit on its own. The reaction must be clearly 
identified as a drug interaction. 
f) Medication error 
A medication error involves the inadvertent administration or unintended use of a 
medicinal product which may be caused by the naming, presentation of 
pharmaceutical form/packaging, or instructions for use/labelling. The reaction 
must be clearly identified as a medication error. 
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g) Lack of efficacy 
Lack of efficacy is suspected when the therapeutic result is not as expected. One 
example of lack of efficacy could be platelets not increasing following the correct 
administration of IVIG. 
7.4 Other Assessments 
No additional assessments have been identified. 
7.5 Appropriateness of Measurements 
For efficacy evaluations, platelet counts provide a direct measure of the response 
to IGIV treatment in ITP patients and has been widely used for this purpose in 
many clinical trials of similar nature. The test is performed routinely at each 
hospital and is considered to be a reliable and robust parameter. 
The definition of response used for the primary endpoint is the most established 
procedure to obtain a dichotomy of success/failure that can be used to calculate 
the response rate. It is also acceptable to US FDA and was used as the primary 
efficacy endpoint in their approval of PANZYGA in the treatment of chronic ITP 
in adults and is thus expected to best facilitate their review of the efficacy of 
PANZYGA in this pediatric population. 
Monitoring AEs, vital signs, laboratory safety tests, and physical examinations 
are standard procedures used to evaluate the safety of investigational products 
in clinical studies.  
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8 
DATA HANDLING AND RECORD KEEPING 
8.1 Documentation of Data 
8.1.1 Source Data and Records 
Source data are defined as all information related to clinical findings, 
observations, or other activities in the study; written down in original records or 
certified copies of original records; or electronic medical records; allowing 
reconstruction and evaluation of the clinical study. 
The Investigator will maintain adequate source records (eg, case histories or 
patient files for each patient enrolled). Source records should be preserved for 
the maximum period of time required by local regulations. 
For each patient enrolled, the Investigator will indicate in the source record(s) that 
the patient is participating in this study. 
All data entered in the eCRF must be supported by source data in the patient 
records. 
The Investigator will permit study-related monitoring, audit(s), IEC/IRB review(s), 
and regulatory inspection(s), by providing direct access to the source 
data/records. 
The Investigator may authorize site staff (eg, sub-Investigators, research nurses) 
to enter study data into the eCRF. This must be documented in the Delegation of 
Authority Log signed by the Investigator. 
8.1.2 Electronic Case Report Forms 
For each patient enrolled, an eCRF will be completed within the Electronic Data 
Capture (EDC) system and approved by the Investigator or an authorized sub-
Investigator.  
Study site staff (eg, research nurse, study coordinator, Investigator) will be 
responsible for entering patient data into the validated EDC system. All study site 
personnel will be trained on the EDC system and study-specific eCRFs prior to 
receiving access to the live database for data entry. 
The study site will be provided with the approved eCRF Completion Guidelines 
to assist in data entry and data issues/questions. The study site will be notified 
once the eCRF is active to begin data entry. Additional site training may be 
provided as refreshers throughout the study, if needed. All persons allowed to 
enter or change eCRF data must be listed in the Delegation of Authority Log. 
8.1.3 Changes to Electronic Case Report Form Data 
Monitors will perform source data verification (SDV) as defined for the study. 
If any errors or discrepancies in the eCRFs are found during data entry or review, 
discrepancies will be generated programmatically within the EDC system, and 
‘manual’ queries will be generated by either a monitor or Data Management.  
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Discrepancies and queries can only be corrected by the Investigator(s) or other 
authorized site personnel. An audit trail documents all changes to the data over 
the entire study period. If the reason for a change is not obvious, a comment must 
be supplied in the query’s response, stating the reason for the change, prior to 
closing. The study monitor should provide guidance to Investigator(s) and the 
Investigator(s)’ designated representatives on making such corrections.  
Once queries have been resolved by the site staff, the resolutions are assessed 
by Data Management. If the query response provided confirms the data as 
correct, the discrepancy will be closed. If the response does not adequately 
address the question raised, a new query will be issued for further clarification. 
Manual checks will be performed, and electronic data check programs run, 
throughout the study until the data is clean and the database is ready for lock. All 
discrepancies will be resolved prior to database lock. There will be a final run of 
the programmed checks to ensure all discrepancies are closed out, SDV will be 
confirmed as complete by the monitor, and all eCRFs will be approved by the 
Investigator prior to database lock. 
8.2 Information to Investigators 
An IB will be handed out to the Investigator before the start of the study. The IB 
contains all information in the Sponsor’s possession necessary for the 
Investigator to be fully and accurately informed about the safety of the IMP under 
evaluation and the respective benefit-risk ratio. 
The IB will be updated by the Sponsor at regular intervals and whenever relevant 
new information concerning PANZYGA becomes available. 
All participating investigators will be informed about relevant study procedures, 
about the methods for rating relevant study outcomes, and how to enter data into 
the eCRF in order to reduce discrepancies. At the study initiation visit, the eCRF 
will be explained to all study site staff entitled to document data in the eCRF. 
The Investigator will be kept informed of important data that relate to the safe use 
of PANZYGA as the study proceeds. 
8.3 Responsibilities 
The Principal Investigator is accountable for the conduct of the clinical study. 
Responsibilities may be delegated to appropriately qualified persons. 
A Delegation of Authority Log will be filled in and signed by the Principal 
Investigator. In accordance with this authority log, study site staff (eg, sub-
Investigators, research nurses) are authorized to perform tasks relating to the 
study. 
8.4 Investigator’s Site File 
At each study site, the Investigator is responsible for maintaining all records to 
enable the conduct of the study to be fully documented. Essential documents as 
required by GCP guidelines and regulations (eg, copies of the protocol, study 
approval letters, all original informed consent and assent forms, site electronic 
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versions of all eCRFs, drug dispensing and accountability logs, correspondence 
pertaining to the study) should be filed accurately and kept by the Investigator for 
the maximum period of time required by local regulations. 
The Investigator is responsible for maintaining a confidential patient identification 
code list, which provides the unique link between named source records and 
eCRF data for the Sponsor. The Investigator must arrange for the retention of 
this confidential list for the maximum period of time required by local regulations. 
No study document should be destroyed without prior written agreement between 
the Investigator and the Sponsor. Should the Investigator elect to assign the 
study documents to another party, or move them to another location, the Sponsor 
must be notified in writing. 
8.5 Provision of Additional Information 
On request, the Investigator will supply the Sponsor with additional data relating 
to the study, or copies of relevant source records, ensuring that the patient’s 
confidentiality is maintained. This is particularly important when source 
documents are illegible or when errors in data transcription are encountered.  
In the event of particular issues or governmental queries, it is also necessary to 
have access to the complete study records, provided that the patient’s 
confidentiality is protected in accordance with applicable regulations. 
8.6 Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC) will be established by the 
Sponsor. The IDMC will be composed of recognized experts in the fields of 
hematology and/or critical care who are not actively recruiting patients. 
The IDMC will review relevant data periodically during the study and will give 
advice on the continuation, modification, or termination of the study. A written 
study-specific procedure will define in detail the composition, responsibilities, and 
procedures of the IDMC. 
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9 
STATISTICAL METHODS AND SAMPLE SIZE 
Statistical analysis will be delegated under an agreement of transfer of 
responsibilities to an external contract research organization (CRO). All 
Octapharma procedures and policies must be met by this CRO. Discrepancies or 
exceptions will be approved by the Sponsor's Manager of Biometrics. 
9.1 Determination of Sample Size 
At least 20 patients who meet all eligibility criteria will be enrolled in the study. 
The purpose of this study is to evaluate the efficacy and safety of PANZYGA in
pediatric patients with chronic ITP; the chosen number of 20 patients to be
enrolled is not derived from statistical considerations of power but driven by
feasibility constraints with respect to finding pediatric ITP patient eligible and
willing to participate in this study.
We expect the true proportion of responders to be comparable to results from
similar studies in adult patients, as there is no published data or expert statement
that
would
indicate
otherwise.
Looking
at
possible
outcome
scenarios,
20 evaluable patients give the following picture from a statistical point of view:
Power Considerations for 20 Evaluable Patients:
Even though the chosen number of 20 pediatric patients is thus not sufficient ‘to
power’ the study, it will still allow the Sponsor to gather enough clinical evidence
to obtain a sound and meaningful medical assessment of the efficacy and safety 
of PANZYGA in pediatric patients with chronic ITP.
9.2
Statistical Analysis
A formal statistical analysis plan describing all details of the analyses to be
performed will be prepared by the study statistician and approved by the Sponsor
prior to the start of the statistical analysis.
No confirmatory statistical analysis will be performed; the results of this study will 
be presented at the descriptive level only. 
In general, and if not detailed otherwise in the Statistical Analysis Plan (SAP), all 
statistical presentations will be fit to the nature and type of the individual data 
items: 
•
Binary data (whether or not an event has occurred): counts and
proportions
•
Count data (the frequency of an event in a set time period): rate (count per
unit time)
Exact 95% 
Hypothetical power to show that the true response 
-
o=o.s -
o=o.6 
Responders 
Confidence Limits 
r.ate is above 6 (l~sided, a •0.025), given that it is in 
fact equal to the observed proportion 
100.. 
Number 
Proportion 
Lower 
Upper 
6=0.5 
6=0.6 
"°" 
11 
55% 
3 1,5% 
76,9% 
5,5% 
'°" 
12 
60% 
36,1% 
80,9% 
12,6% 
2,1% 
'°" 
'""' 
13 
65% 
40,8% 
84,6% 
24,5% 
4,4% 
j '°" 
14 
70% 
45,7% 
88,1% 
41,6% 
10,7% 
g '°" 
15 
75% 
50,9% 
91,3% 
61,7% 
22,5% 
'°" 
16 
80% 
56,3% 
94,3% 
80,4% 
41,1% 
2°" 
17 
85% 
62,1% 
96,8% 
93,3% 
64,8% 
10,0 
°" 
18 
90% 
68,3% 
98,8% 
98,9% 
86,7% 
'°" -
""' 
'°" 
9("' 
100.. 
19 
95% 
75,1% 
99,9% 
100,0% 
98,4% 
True Pfoportion 
20 
100% 
83,2% 
100,0% 
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• Continuous data (measurements on a continuous scale, including quasi-
continuous variables): arithmetic mean, standard deviation, median, lower 
and upper quartile, minimum, maximum 
• Scales data (Ordinal and Non-ordinal): absolute and relative frequencies 
• Time-to-event data (how long it takes to observe the outcome of interest, 
e.g. the initial treatment response): time to event or last evaluation 
(censored data in case subjects are lost to follow-up) and event rate. Such 
parameters may also be presented as Kaplan-Meier plots of the product-
limit survival function estimates. 
9.2.1 Populations for Analysis 
The following populations will be considered for the statistical analysis: 
• Safety Analysis Set (SAF): All patients who received at least part of 
1 infusion of PANZYGA. 
• Full Analysis Set (FAS): All patients in the SAF who satisfy all major 
eligibility criteria and for whom any post-baseline data is available. This is 
the set of eligible patients with treatment effects measured, according to 
the intention-to-treat (ITT) principle. 
• Per-Protocol Set I (PP1): All patients in the FAS, excluding those with 
significant protocol deviations before the primary efficacy assessment on 
Day 8 is completed, and which may have an impact on the evaluation of 
the primary endpoint. 
• Per-Protocol Set II (PP2): All patients in the FAS, excluding those with 
significant protocol violations potentially affecting the (secondary) efficacy 
evaluations. 
Only protocol deviations with the potential to significantly affect the study results 
or to invalidate the interpretation of the data obtained will lead to exclusion of 
patients from the PP sets. The inclusion of each patient in the respective analysis 
populations will be determined before database lock in a data review meeting by 
a panel consisting of a medical expert from the Sponsor, the clinical study 
manager, the data manager, and the study statistician. 
The analysis of safety will be based on the SAF. 
The evaluation of the primary objective will be performed for the FAS 
(ITT analysis) and for the PP1 set (PP analysis) to assess the robustness of the 
results. The primary analysis will be the ITT analysis. 
For secondary objectives ITT and PP2 analyses will be carried out; again the 
ITT analysis is considered the primary analysis and will be presented first in the 
report. 
9.2.2 Efficacy Analysis Plan 
The primary and secondary efficacy parameters will be determined on the basis 
of the patient's platelet concentration, listed individually, and presented 
descriptively. 
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Duration of platelet response is defined as the number of days the platelet count 
remains above ≥ 50x109/L. Patients who do not drop below 50x109/L after 
achieving ≥ 50x109/L will be censored at the last evaluable assessment. Note 
that only patients who are responders will be included in this analysis. Though 
this should not occur, patients receiving emergent ITP treatment other than 
PANZYGA after achieving a platelet count ≥50x109/L will be censored at the time 
of emergent ITP treatment if the medication is administered while the patient’s 
platelet count is ≥50x109/L. Patients receiving emergent ITP treatment other than 
PANZYGA prior to achieving a platelet count ≥50x109/L will not be included in 
this analysis. 
The number and proportion of responders will be presented, together with the 
associated exact 95% confidence intervals. 
The time to reach the desired increase in platelet count as well as the duration of 
response and the maximum platelet levels will be presented in listings and 
summarized in statistical tables. 
Individual profiles of platelet count over time will be presented as Trellis plots. 
9.2.3 Safety Analysis Plan 
The safety analysis will comprise descriptive statistics, tabulations, and listings of 
all TEAEs, safety laboratory results, vital signs, and physical examination 
findings. All reported AEs will be coded according to the Medical Dictionary for 
Regulatory Activities) MedDRA. 
An AE is defined as treatment-emergent if first onset or worsening is after start 
of the first infusion of PANZYGA. Only TEAEs are accounted for in the analysis. 
AEs will be record at the start of the fist infusion of PANZYGA. AEs that occur 
between informed consent/assent and the start of the first PANZYGA infusion will 
be recorded under Medical History.  
Incidences of treatment-emergent AEs will be given as the number and 
percentage of patients who experienced any or a particular AE, including serious 
and drug-related AEs. 
The summary tables for AEs will be given by system organ class and preferred 
term. Additionally, AEs will be summarized by severity and relationship to study 
treatment. In addition to the tables presenting incidences including all AEs, 
incidences will be determined for the subset of SAEs and drug-related AEs. 
Incidences of infusional AEs will be given as the number and percentage of 
patients who experienced any or a particular infusional AE, including serious and 
drug-related AEs.  
The summary tables for infusional AEs will be given by system organ class and 
preferred term. Additionally, infusional AEs will be summarized by severity and 
relationship to study treatment. In addition to the tables presenting incidences 
including all infusional AEs, incidences will be determined for the subset of SAEs 
and drug-related AEs. 
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Narratives will be prepared describing each death, other SAEs, and other 
significant AEs that are judged to be of special interest because of clinical 
importance. 
For each routine laboratory parameter at each visit the actual result, the change 
from baseline, the out-of-range flag and the assessment of clinical relevance will 
be summarized descriptively. 
Vital signs include systolic and diastolic blood pressure, pulse rate, body 
temperature and the respiratory rate; descriptive tables on the sampling statistics 
of these parameters at each time point will be provided for the values as well as 
for their changes to baseline. 
9.2.4 Handling of Missing Data 
No replacement of missing data values is planned, but only observed results (and 
platelet counts) will be included in the analyses. 
9.3 Randomization, Stratification, and Code Release 
This is an open-label non-randomized study; therefore, no randomization code 
list or procedure for code release are required. Patients will not be stratified by 
age group.  
9.4 Interim Analysis  
No interim analysis is planned.  
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10 ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE 
ASPECTS 
10.1 Ethical/Regulatory Framework 
This study will be conducted in accordance with the ethical principles laid down 
in the Declaration of Helsinki. The study protocol and any subsequent 
amendment(s) will be submitted to an IEC/ IRB and to the Regulatory Authority. 
The study will be conducted in compliance with the protocol, GCP guidelines, and 
applicable regulatory requirements. 
The regulatory application or submission for regulatory approval will be made by 
the Sponsor or designated third party (eg, CRO) as required by national law. 
10.2 Approval of Study Documents 
The study protocol, a sample of the patient information and informed consent 
form, assent form, any other materials provided to the patient and their 
parent/legal guardian, and further requested information will be submitted by the 
Sponsor or the Investigator to the appropriate IEC/IRB and the Regulatory 
Authority. The study must be approved by the IEC/IRB and the Regulatory 
Authority before any IMP may be shipped to the study sites and any patient is 
exposed to a study-related procedure. 
The Sponsor, the Investigator, and any third party (eg, CRO) involved in obtaining 
approval must inform each other in writing that all ethical and legal requirements 
have been met before the first patient is enrolled in the study. 
10.3 Patient Information and Informed Consent 
The Investigator will obtain freely given written consent from each the patient after 
an appropriate explanation of the aims, methods, anticipated benefits, potential 
hazards, and any other aspect of the study which is relevant to the patient’s 
decision to participate. The informed consent form must be signed, with name 
and date and time noted by the patient, before the patient is exposed to any 
study-related procedure, including screening tests for eligibility. 
For patients not qualified to give legal consent, written consent must be obtained 
from the legal parent/guardian. If children are old enough to understand the risks 
and benefits of the study, they should also be informed and provide their written 
consent using an assent form. 
The Investigator will explain that the patients are completely free to refuse to enter 
the study or to withdraw from it at any time, without any consequences for their 
further care and without the need to justify. The Investigator will complete the 
informed consent section of the CRF for each patient enrolled. 
Each patient (and parent/legal guardian, as appropriate) will be informed that 
his/her medical (source) records may be reviewed by the study monitor, a quality 
assurance auditor, or a health authority inspector, in accordance with applicable 
regulations, and that these persons are bound by confidentiality obligations. 
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10.4 Protocol Amendments 
Any prospective change to the protocol will be agreed between the Investigator 
(Co-ordinating Investigator in multi-center studies) and the Sponsor prior to its 
implementation. Any such amendments will be submitted to the any competent 
IEC/IRB and/or competent authority responsible as required by applicable 
regulations. 
IEC/IRB approval will, at a minimum, be requested for any change to this protocol 
which could affect the safety of the patients, the objective/design of the study, 
any increase in dosage or duration of exposure to the IMP, an increase in the 
number of patients treated, the addition of a new test or procedure, or the 
dropping of a test intended to monitor safety. 
10.5 Confidentiality of Patient Data 
The Investigator will ensure that the patient’s confidentiality is preserved. On 
eCRFs or any other documents submitted to the Sponsor, the patients will not be 
identified by their names, but by a unique patient identifier. Documents not 
intended for submission to the Sponsor, ie, the confidential patient identification 
code list, original consent and assent forms, and source records, will be 
maintained by the Investigator in strict confidence. 
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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Periodic Monitoring 
The monitor will contact and visit the Investigator periodically to review all study-
related source data/records, verify the adherence to the protocol and the 
completeness, correctness and accuracy of all CRF entries compared to source 
data. The Investigator will cooperate with the monitor to ensure that any 
discrepancies identified are resolved. 
For this study, the first monitoring visit shall take place shortly after the inclusion 
of the first patient. Thereafter, monitoring frequency will depend on study 
progress and in accordance with the study clinical monitoring plan. 
The monitor must be given direct access to source documents (original 
documents, data, and records). Direct access includes permission to examine, 
analyze, verify, and reproduce any records and reports that are important to the 
evaluation of the clinical study. Source data will be available for all data in the 
eCRFs, including all laboratory results. 
In the event that federal, local, or institutional regulations or policies temporarily 
restrict monitors from conducting on site visits, the assigned Octapharma monitor 
may conduct remote monitoring visits. If this occurs, it will be documented in the 
monitoring reports. The Clinical Monitoring Plan will describe the requirements 
for remote monitoring procedures. 
11.2 Audit and Inspection 
The Investigator will make all study-related source data and records available to 
a qualified quality assurance auditor mandated by the Sponsor, or to 
IEC/IRB/regulatory inspectors, after reasonable notice. The main purposes of an 
audit or inspection are to confirm that the rights and welfare of the patients have 
been adequately protected, and that all data relevant for the assessment of safety 
and efficacy of PANZYGA have been reported to the Sponsor. 
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12 REPORTING AND PUBLICATION 
12.1 Clinical Study Report 
A clinical study report (in accordance with relevant guidelines and the Sponsor’s 
Standard Operating Procedures [SOPs]) will be prepared by the Sponsor after 
completion of the study. The Co-ordinating Investigator will approve the final 
study report after review. 
12.2 Publication Policy 
The results of this study may be published or presented at scientific meetings. 
If the Investigator wants to publish or present study results, the Investigator 
agrees to inform the Sponsor and to submit all manuscripts or abstracts to the 
Sponsor before submission to an editorial board or scientific review committee. 
This will allow the Sponsor to protect proprietary information and to provide 
comments based on information that may not yet be available to the Investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will 
support publication of multi-center studies only in their entirety and not as 
individual center data. Authorship will be determined by mutual agreement. 
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13 LIABILITIES AND INSURANCE 
In order to cover any potential damage or injury occurring to a patient in 
association with PANZYGA or participation in the study, the Sponsor will contract 
insurance in accordance with local regulations. 
The Investigator is responsible for dispensing PANZYGA according to this 
protocol and for its secure storage and safe handling throughout the study. 
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14 REFERENCES 
1. Diagnosis and treatment of idiopathic thrombocytopenic purpura: 
recommendations of the American Society of Hematology. The American 
Society of Hematology ITP Practice Guideline Panel. Ann.Intern.Med. 
1997;126:319-326. 
2. Brenner B: Clinical experience with Octagam, a solvent detergent (SD) 
virus inactivated intravenous gammaglobulin. Clin.Exp.Rheumatol. 
1996;14:S115-S119. 
3. Imbach P: Immune thrombocytopenic purpura and intravenous 
immunoglobulin. Cancer. 1991;68:1422-1425. 
4. Newland AC, Burton I, Cavenagh JD, et al: Vigam-S, a solvent/detergent-
treated intravenous immunoglobulin, in idiopathic thrombocytopenic 
purpura. Transfus.Med. 2001;11:37-44. 
5. Despotovic JM: Emerging therapies in immune thrombocytopenia. 
American Society of Hematology. The Hematologist, ASH News and 
Reports. 2018:15:4;1-7.  
6. Neunert C, Despotovic J, Haley K, et. al. Thrombopoietin receptor agonist 
use in children: data from the pediatric ITP consortium of North America 
ICON2 study. Pediatric Blood & Cancer. 2016:63(8), 1407-1413. 
doi:10.1002/pbc.26003 
7. European Medicines Agency, Guideline on the clinical investigation of 
human normal immunoglobulin for intravenous administration (IVIg). 
EMA/CHMP/BPWP/94033/2007 
rev. 
3. 
Retrieved 
from: 
https://www.ema.europa.eu/documents/scientific-guideline/guideline-
clinical-investigation-human-normal-immunoglobulin-intravenous-
administration-ivig-rev-3_en.pdf 
8. American Society of Hematology 2019 Clinical Practice Guideline on the 
Evaluation and Management of Immune Thrombocytopenia (ITP), Quick 
Reference Guide.  
9. PANZYGA [package insert]. Hoboken, NJ: Octapharma USA Inc; 2018. 
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15 APPENDICES 
Not applicable. 
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