An Open-label, Multicenter, Post-Marketing Requirement (PMR) Study to Investigate the Safety, Tolerability and Efficacy of Octaplas in the Management of Pediatric Patients Who Require Replacement of Multiple Coagulation Factors.
Phase: PHASE4
Conditions: Liver Surgery, Liver Dysfunction, Coagulopathy, Cardiac Surgery
Sponsor: Octapharma

 
NOTE: This document contains confidential and proprietary information of Octapharma Pharmazeutika 
Produktionsges.m.b.H. Do not copy or distribute without written permission. 
LAS-212_Protocol V09_19Nov166 
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CLINICAL STUDY PROTOCOL 
An open-label, multicenter, Post-Marketing Requirement 
(PMR) study to investigate the safety, tolerability and efficacy 
of Octaplas in the management of pediatric patients who 
require replacement of multiple coagulation factors. 
 
Investigational Product: 
Octaplas 
Indication: 
Replacement of multiple coagulation factors in pediatric 
patients with acquired deficiencies due to liver disease 
and/or in pediatric patients requiring cardiac surgery or 
liver transplantation. 
Study Design: 
Open-label, multicenter, post-marketing requirement 
study 
Sponsor: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Oberlaaerstrasse 235, 1100 Vienna, Austria 
Study Number: 
LAS-212 
EudraCT and/or IND 
Number: 
BL 125416/0: Required Pediatric Assessment 
Development Phase: 
Phase IV 
Planned Clinical Start: 
Q2 2014 
Planned Clinical End: 
Q4 2017 
Date of Protocol: 
19-Nov-2016 
Version: 
9.0 
Coordinating Investigator: Philip C. Spinella, M.D.  
1 Children’s Place/NWT 10th floor  
St Louis, MO, 63110, USA  
 

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STUDY OUTLINE 
Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
Octaplas 
Protocol Identification Code:  
LAS-212 
Name of Active Ingredient: 
Human Coagulation Active Plasma For 
Infusion, S/D treated 
Date of Final Protocol: 
19-Nov-2016 
Title of Study: 
An open-label, multicenter, Post-Marketing Requirement (PMR) study to investigate the 
safety, tolerability and efficacy of Octaplas in the management of pediatric patients who 
require replacement of multiple coagulation factors. 
Indication: 
Replacement of multiple coagulation factors in pediatric patients with acquired 
deficiencies due to liver disease and/or in pediatric patients requiring cardiac surgery or 
liver surgery (see package insert in Appendix 1).  
Number of Study Center(s): Up to 10 sites in North-America. 
Study Duration: 2nd quarter 2014 to 4th quarter 2017 
Development Phase: IV 
Objectives: 
Primary: 
To assess the safety and tolerability of Octaplas in the pediatric population by monitoring 
serious adverse events (SAEs), adverse drug reactions (ADRs), thrombotic events (TEs), 
thromboembolic events (TEEs) and hyperfibrinolytic events, including laboratory 
parameters for metabolic derangements, renal function, and hematologic implications. 
Secondary: 
To assess the efficacy of Octaplas in the pediatric population by measuring hemostatic 
parameter improvements reflecting changes in hemostasis. 
Study Design: 
Open-label, multicenter, post-marketing requirement Phase IV study. 
Number of Patients: Fifty (50) pediatric patients treated with Octaplas with targeted 
number of patients within the following two age categories: 
1. Neonates/Infants (0-2 years): a maximum of 33 patients 
2. Children > 2 years and ≤ 16 years: a minimum of 17 patients   
Patient Selection Criteria: 
Inclusion Criteria: 
1. Patient requiring liver or cardiac surgery and/or patient with liver dysfunction 
associated with coagulopathy in whom replacement of multiple coagulation factors 

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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
Octaplas 
Protocol Identification Code:  
LAS-212 
Name of Active Ingredient: 
Human Coagulation Active Plasma For 
Infusion, S/D treated 
Date of Final Protocol: 
19-Nov-2016 
is required. 
2. Voluntarily given, written and signed informed consent by the patient’s legal 
representative(s) or guardian(s). Children deemed old enough by the 
Investigator/institution to understand the risks and benefits of the study should also 
be made aware of the risks/benefits of the study and provide written assent. 
3. Male or female patient ≤ 16 years of age. 
Exclusion Criteria: 
1. Patient with known homozygous congenital deficiency of protein S. 
2. Patient has a history of hypersensitivity reaction to blood or plasma-derived 
products or to any excipient of the investigational product. 
3. Patient has an already known IgA deficiency with documented antibodies against 
IgA. 
4. Patient has a congenital factor deficiency or platelet disorder requiring plasma 
treatment. 
5. Patient is currently participating in another study investigating a new drug product 
or another interventional clinical study that may impact coagulation factors or has 
participated during the last three (3) months. 
6. Patient received FFP, FP24 or any other plasma product other than Octaplas within 
the last 72 hours (cryoprecipitate and albumin are not exclusionary) prior to first 
Octaplas infusion. 
7. Patient is on ECMO (Extracorporeal Membrane Oxygenation) when plasma is 
ordered by the treating physician for the first infusion episode. 
8. Patient is pregnant. 
9. Patient is predicted to require massive blood transfusion defined as more than 
40 mL per kilogram of all blood products in a 24-hour period 
10. Patient is receiving plasma exchange, therapeutic plasma exchange (TPE) or 
plasmapheresis. 
11. Patient is a premature neonate defined as less than 37 weeks gestation. 
12. Cardiac surgery patients who develop the need for plasma replacement greater than 
72 hours after the end of the associated cardiac surgery and do not have 
coagulopathy due to hepatic dysfunction. 
Test Product, Dose, Mode of Administration, and Batch Number(s): 
Octaplas infusion solution for IV administration, ABO blood group compatible. 

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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
Octaplas 
Protocol Identification Code:  
LAS-212 
Name of Active Ingredient: 
Human Coagulation Active Plasma For 
Infusion, S/D treated 
Date of Final Protocol: 
19-Nov-2016 
Duration of Treatment: The study infusion(s) of Octaplas will occur over a maximum 
72-hour treatment period.  After the final infusion episode there will be an additional 72-
hour safety follow-up period for monitoring of adverse drug reactions.   
Reference Therapy, Dose, Mode of Administration, and Batch Number(s): 
None. 
Study Outcome Parameters (Primary and Secondary Endpoints): 
Primary Endpoints: 
• Incidence of SAEs, ADRs (e.g., allergic reactions), TEs, TEEs and 
hyperfibrinolytic events, beginning after the start of the first infusion episode until 
the final examination (end of safety follow-up period). 
• Clinically significant changes in laboratory parameters to assess for metabolic 
derangements, renal function, and hematologic implications as measured by the 
following: Chem 7 (metabolic panel), complete blood count (CBC) and ionized 
calcium. 
Secondary Endpoints: 
• Clinically significant changes in hemostatic parameters as measured by the 
following: international normalized ratio (INR), prothrombin time (PT), activated 
partial 
thromboplastin 
time 
(aPTT), 
thromboelastography 
(TEG) 
or 
thromboelastometry (ROTEM). 
• Volume (dose in mL/kg) of Octaplas used per infusion episode for each patient. 
• Medically significant changes in vital signs. 
• Investigator’s assessment of overall safety observed for each patient. 
Summary of Study Procedures and Statistical Analysis Plan (SAP): 
Study Periods: 
Screening: At Screening, informed consent will be obtained from the legal 
representative(s) or guardian(s) of the patient. Children deemed old enough by the 
Investigator/institution to understand the risks and benefits of the study should provide 
written assent. Relevant medical history including relevant prior and on-going 
concomitant medications and demographic data will be recorded. The patient’s eligibility 
will be checked based on the inclusion and exclusion criteria. A physical examination in 
accordance with the site’s routine procedure will be performed. The patient’s ABO blood 
group will be determined for compatibility. A pregnancy test for females at the age of ≥ 
11 years or of childbearing potential (if younger than 11 years old) will be performed 

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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
Octaplas 
Protocol Identification Code:  
LAS-212 
Name of Active Ingredient: 
Human Coagulation Active Plasma For 
Infusion, S/D treated 
Date of Final Protocol: 
19-Nov-2016 
prior to enrollment if it was not previously performed during the current hospital 
admission. Female patients of childbearing potential are excluded from the study if the 
pregnancy test is positive. Per physician discretion, he/she will decide if clinical 
indication for a plasma infusion is necessary and will place the plasma order accordingly. 
The type of surgical procedure indicated and important operative interventions will also 
be recorded. Patients determined to have a reasonable probability to receive intra-
operative plasma transfusion according to the Investigator’s clinical judgment may also 
be approached for consent to participate. If these patients are subsequently not prescribed 
plasma intra-operatively or postoperatively they will be determined to be a screening 
failure and not included in the analysis.  
Pre-Infusion: Within 6 hours prior the start of the first infusion episode, vital signs and 
several laboratory tests will be assessed to measure metabolic derangements and renal 
function.   
72-hour Study Treatment Period: The number of infusion episodes1 and actual total 
volume (dose in mL/kg) of Octaplas administered to a patient within the 72-hour 
treatment period will depend on the clinical setting and physician discretion. The infusion 
rate of Octaplas should not exceed 0.020-0.025 mmol citrate per minute, which is equal to 
Octaplas per kg per minute. This limitation is not applicable for devices used for 
cardiopulmonary bypass or extracorporeal membrane oxygenation or similar. In case 
situations like e.g. a serious hemorrhage necessitates a rapid infusion ≥ 1mL/kg and the 
benefits outweigh the potential risks, the infusion speed can be ≥ 1mL/kg body weight. 
The first infusion dose will be at a minimum of 10 mL/kg or one unit unless a lesser dose 
is medically justified. If infusion episodes are performed and the dose administered is less 
than 10 mL/kg, the medical reason justifying this dosage will be recorded in the case 
report form (CRF), since at least 10 mL/kg are required to significantly increase the 
respective plasma protein levels.  
Post-infusion episode samples should be drawn within 30 to 60 minutes after each 
infusion episode. If the patient requires priming of the cardiopulmonary bypass (CPB) 
circuit with plasma, the post-infusion episode samples should be drawn 30-60 minutes 
after reversal of heparin during the process of coming off CPB. For the first infusion 
episode it is mandatory that pre– and post–infusion episode samples for hemostatic and 
                                                 
 
1 An infusion episode is defined as any amount of Octaplas infusion given, with no more than 60 minutes break 
between 2 Octaplas infusions. If the time interval between the end of one Octaplas infusion and the beginning of 
the next Octaplas infusion is more than 60 minutes this will be counted as 2 different infusion episodes. 

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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
Octaplas 
Protocol Identification Code:  
LAS-212 
Name of Active Ingredient: 
Human Coagulation Active Plasma For 
Infusion, S/D treated 
Date of Final Protocol: 
19-Nov-2016 
laboratory parameters be drawn for testing. If subsequent infusion episodes are performed 
(after the first infusion episode), laboratory testing and vital signs should be performed 
within a maximum of 60 minutes before the start and 60 minutes after the end of each 
infusion episode. If multiple vital sign assessments are taken within 60 minutes before 
and/or after the infusion, the vital signs that are assessed closest before the start and after 
the end of each infusion should be recorded. Pre- and post-infusion episode 
measurements to assess hemostatic and laboratory parameters should be recorded if 
available unless considered not medically necessary by the Investigator (e.g., the timing 
of the pre-infusion episode sample is close to or overlaps with the timing of the post-
infusion episode sample and it is not necessary to perform, or testing is not medically 
appropriate for patient at that time, etc.). In the event that the pre- or post-infusion 
laboratory sample testing is not performed, the reason will be documented in the CRF. 
The study Treatment Period will end after 72 hours from the start of the first infusion of 
Octaplas, or after the end of the last infusion episode if the total duration of Octaplas 
treatment is <72 hours.   
72-hour Safety Follow-up Period: Adverse drug reactions and relevant concomitant 
medications will be monitored for 72 (±6) hours after the last Octaplas transfusion is 
completed. 
Final Examination: At the end of the 72-hour safety follow-up period, a final 
examination will be performed comprising of vital signs, Investigator assessment of 
safety (the safety assessment is to be carried out by the principal or sub-investigator) and 
laboratory testing (Chem 7, CBC and ionized calcium) for monitoring of metabolic 
derangements, renal function, and hematologic implications.  
After the final examination, the clinical phase of the study is considered completed for the 
patient. No further study-related assessments will be performed, unless safety concerns 
(e.g., on-going ADRs) require follow-up. 
 
Statistical Analysis Plan (SAP): 
Due to the complex and highly variable and individual medical circumstances and 
interventions that are to be expected in this study, no single parameter or measurement of 
outcome is chosen as the primary endpoint. All data collected will be summarized and 
presented descriptively to facilitate the review of population homogeneity and general 
patterns within and between patients of similar baseline characteristics or disease 
patterns. No confirmatory hypothesis testing is planned. Any p-value or confidence 
interval presented is to be understood in the exploratory sense. 
To allow a holistic review and interpretation of each course of treatment, all parameters 
relevant for the assessment of safety will be presented descriptively in full detail, by 

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Name of Sponsor/Company: 
Octapharma Pharmazeutika Produktionsges.m.b.H. 
Name of Investigational Product: 
Octaplas 
Protocol Identification Code:  
LAS-212 
Name of Active Ingredient: 
Human Coagulation Active Plasma For 
Infusion, S/D treated 
Date of Final Protocol: 
19-Nov-2016 
subgroups of interest as well as in total. The safety assessment will include the 
occurrence of SAEs, ADRs, TEs, TEEs and hyperfibrinolytic events. To facilitate the 
detection of any possible safety signal, all these events will be characterized and analyzed 
by age (≤ and > 2 years of age respectively), underlying diagnosis, seriousness, severity, 
relation to study drug and timely relationship to study drug administration. In addition to 
these pre-planned categories, the collected data will be examined to identify additional 
characteristics of interest such as particular types of surgeries, relevant concomitant 
medications, or Standardized MedDRA Queries (SMQs) covering a noticeable number of 
events. The occurrences of all specific safety events will be presented for all these 
categories and in total, together with the associated 95% confidence intervals. 
To account for the abovementioned diversity in the study population, individual patient 
profiles will be generated, displaying the baseline characteristics as well as all 
interventions, treatment details and relevant measurements on a time scale. This will 
facilitate the review of each individual course of treatment by the trial medical monitor or 
expert to assess the efficacy of the treatment but also to detect any safety signal that 
might not be reflected in the ADR rates. 
Hemostatic parameters will be presented descriptively per time point, including shift 
tables. Individual courses of hemostatic parameters will be presented graphically as 
Trellis plots. 
Vital sign measurements will be summarized by descriptive statistics, including shift 
tables. All measurements outside age-specific thresholds will be listed and reviewed 
individually. 
All safety laboratory data – absolute values as well as changes from baseline – will be 
presented descriptively per time point. All measurements outside age-specific thresholds 
will be listed and reviewed individually. 
All data will be presented in total as well as in sub–groups reflecting age (≤ and > 2 
years), gender, underlying diagnosis, surgical procedures performed and/or most relevant 
medical history and concomitant medications. 
 

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TABLE OF CONTENTS 
1 
INTRODUCTION .......................................................................................................... 14 
1.1 RATIONALE FOR CONDUCTING THE STUDY ................................................................... 15 
1.2 DOSE RATIONALE .......................................................................................................... 15 
1.3 BENEFIT-RISK STATEMENT ........................................................................................... 15 
2 
STUDY OBJECTIVES .................................................................................................. 17 
2.1 PRIMARY OBJECTIVE ..................................................................................................... 17 
2.2 SECONDARY OBJECTIVE(S) ............................................................................................ 17 
3 
INVESTIGATIONAL PLAN ........................................................................................ 17 
3.1 PRIMARY AND SECONDARY ENDPOINTS ........................................................................ 17 
Primary Endpoint(s) ......................................................................................................... 17 
Secondary Endpoint(s) ..................................................................................................... 17 
3.2 OVERALL STUDY TIMELINE ........................................................................................... 17 
Study Flow Chart .............................................................................................................. 18 
3.3 DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP(S) ........................... 22 
Study Design ..................................................................................................................... 22 
Control Group(s) .............................................................................................................. 22 
Target Parameter(s) ......................................................................................................... 22 
4 
STUDY POPULATION ................................................................................................. 23 
4.1 POPULATION BASE ........................................................................................................ 23 
Inclusion Criteria ............................................................................................................. 23 
Exclusion Criteria ............................................................................................................ 23 
4.2 PRIOR AND CONCOMITANT THERAPY ............................................................................ 24 
Permitted Concomitant Therapy ...................................................................................... 24 
Forbidden Concomitant Therapy ..................................................................................... 24 
4.3 WITHDRAWAL AND REPLACEMENT OF PATIENTS .......................................................... 25 
Premature Patient Withdrawal ......................................................................................... 25 
Patient Replacement Policy .............................................................................................. 25 
4.4 ASSIGNMENT OF PATIENTS TO TREATMENT GROUPS ..................................................... 25 
4.5 RELEVANT PROTOCOL DEVIATIONS .............................................................................. 25 
4.6 SUBSEQUENT THERAPY ................................................................................................. 26 
5 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ................................................. 26 
5.1 CHARACTERIZATION OF INVESTIGATIONAL PRODUCT(S) ............................................... 26 
5.2 PACKAGING AND LABELING .......................................................................................... 26 
5.3 CONDITIONS FOR STORAGE AND USE ............................................................................ 27 
5.4 DOSE AND DOSING SCHEDULE ...................................................................................... 27 
5.5 PREPARATION AND METHOD OF ADMINISTRATION ....................................................... 27 
5.6 BLINDING, EMERGENCY ENVELOPES AND BREAKING THE STUDY BLIND ...................... 28 
5.7 TREATMENT COMPLIANCE ............................................................................................. 28 
Drug Dispensing and Accountability ............................................................................... 28 

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Assessment of Treatment Compliance .............................................................................. 28 
6 
STUDY CONDUCT ....................................................................................................... 28 
6.1 STUDY PERIODS ............................................................................................................. 28 
Screening .......................................................................................................................... 28 
Pre-Infusion (Immediately Before First Infusion Episode) .............................................. 29 
Study Treatment Period .................................................................................................... 29 
Safety Follow-up Period ................................................................................................... 29 
Final Examination ............................................................................................................ 30 
6.2 DURATION OF STUDY .................................................................................................... 30 
Planned Duration for an Individual Patient .................................................................... 30 
Planned Duration for the Study as a Whole ..................................................................... 30 
Premature Termination of the Study ................................................................................ 30 
7 
ASSESSMENTS AND METHODS .............................................................................. 30 
7.1 BACKGROUND / BASELINE INFORMATION ..................................................................... 30 
7.2 EFFICACY ASSESSMENTS ............................................................................................... 31 
7.2.1 Hemostatic Parameters ........................................................................................ 31 
7.3 SAFETY ASSESSMENTS .................................................................................................. 31 
7.3.1 Relevant Drug Safety Information ........................................................................ 31 
7.3.2 Adverse Events and Adverse Drug Reactions ...................................................... 32 
7.3.2.1 
Definitions ...............................................................................................................32 
7.3.2.2 
Collection .................................................................................................................32 
7.3.2.3 
Severity ....................................................................................................................32 
7.3.2.4 
Causality ..................................................................................................................33 
7.3.2.5 
Outcome ...................................................................................................................34 
7.3.2.6 
Action(s) Taken .......................................................................................................34 
7.3.3 Serious Adverse Events (SAEs)............................................................................. 34 
7.3.4 TEs, TEEs and Hyperfibrinolytic Events .............................................................. 35 
7.3.5 Laboratory Tests ................................................................................................... 37 
7.3.5.1 
Determination of Blood Group ................................................................................37 
7.3.5.2 
Pregnancy Testing ...................................................................................................37 
7.3.5.3 
Laboratory Parameters .............................................................................................37 
7.3.6 Physical Examination and Vital Signs.................................................................. 40 
7.3.7 Other Relevant Safety Information ....................................................................... 40 
7.4 APPROPRIATENESS OF MEASUREMENTS ........................................................................ 41 
8 
DATA HANDLING AND RECORD KEEPING ........................................................ 41 
8.1 DOCUMENTATION OF DATA ........................................................................................... 41 
Source Data and Records ................................................................................................. 41 
Case Report Forms ........................................................................................................... 41 
Changes to Case Report Form Data ................................................................................ 42 
8.2 INFORMATION OF INVESTIGATORS ................................................................................. 43 
8.3 RESPONSIBILITIES .......................................................................................................... 43 
8.4 INVESTIGATOR’S SITE FILE ............................................................................................ 43 
8.5 PROVISION OF ADDITIONAL INFORMATION .................................................................... 44 
8.6 INDEPENDENT DATA MONITORING COMMITTEE (IDMC) .............................................. 44 

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9 
STATISTICAL METHODS AND SAMPLE SIZE .................................................... 44 
9.1 DETERMINATION OF SAMPLE SIZE ................................................................................. 44 
9.2 STATISTICAL ANALYSIS ................................................................................................. 44 
Population for Analysis .................................................................................................... 45 
Efficacy Analysis Plan ...................................................................................................... 46 
Safety Analysis Plan ......................................................................................................... 46 
9.3 RANDOMIZATION / STRATIFICATION / CODE RELEASE ................................................... 46 
9.4 INTERIM ANALYSIS (IF APPLICABLE) ............................................................................. 46 
10 ETHICAL / REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ...... 46 
10.1 ETHICAL / REGULATORY FRAMEWORK .......................................................................... 46 
10.2 APPROVAL OF STUDY DOCUMENTS ............................................................................... 47 
10.3 PATIENT INFORMATION AND INFORMED CONSENT/ASSENT .......................................... 47 
10.4 PROTOCOL AMENDMENTS ............................................................................................. 47 
10.5 CONFIDENTIALITY OF PATIENTS’ DATA......................................................................... 48 
11 QUALITY CONTROL AND QUALITY ASSURANCE ........................................... 48 
11.1 PERIODIC MONITORING ................................................................................................. 48 
11.2 AUDIT AND INSPECTION................................................................................................. 48 
12 REPORTING AND PUBLICATION ........................................................................... 48 
12.1 CLINICAL STUDY REPORT.............................................................................................. 48 
12.2 PUBLICATION POLICY .................................................................................................... 48 
13 LIABILITIES AND INSURANCE ............................................................................... 49 
14 REFERENCES ............................................................................................................... 49 
15 APPENDICES ................................................................................................................. 50 
15.1 APPENDIX 1: OCTAPLAS PACKAGE INSERT .................................................................... 50 
 
INDEX OF TABLES 
Table 1: 
Scheme of Decision for Adjudicators ................................................................... 36 
Table 2: 
Laboratory Parameters .......................................................................................... 37 
Table 3: 
Hemostatic Parameters ......................................................................................... 38 
 

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LIST OF ABBREVIATIONS 
ADR 
Adverse Drug Reaction 
AE(s) 
Adverse Event(s) 
aPTT 
Activated Partial Thromboplastin Time 
BUN 
Blood Urea Nitrogen 
BW 
Body Weight 
CBC 
Complete Blood Count 
CDSU 
Central Drug Safety Unit 
CFT 
Clot Formation Time 
CPB 
Cardiopulmonary bypass 
CPM 
Clinical Project Manager 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Clotting Time 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EPL 
Estimated percentage lysis 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
FFP 
Fresh Frozen Plasma 
FP24 
Plasma frozen within 24 hours of collection 
GCP 
Good Clinical Practice 
HAV 
Hepatitis A Virus 
HEENT 
Head, Ears, Eyes, Nose and Throat 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
Intravenous 
ITT 
Intent-to-Treat 
K-time 
time from the end of R until the clot reaches 20 mm 
MA 
Maximum Amplitude 

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MCF 
Maximum Clot Firmness 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
ML 
Maximum lysis 
NIH 
National Institute of Health 
PMR 
Post-Marketing Requirement 
PP 
Per-Protocol 
PT 
Prothrombin Time 
RBC 
Red Blood Cell 
RDW 
Red Cell Distribution Width 
ROTEM 
Thromboelastometry 
R-time 
Reaction time 
SADR 
Serious Adverse Drug Reaction 
SAE(s) 
Serious Adverse Event(s) 
SAF 
Safety Population 
SAP 
Statistical Analysis Plan 
S/D 
Solvent/Detergent 
SDP 
Solvent/Detergent (S/D) Treated and Pooled 
SMQ 
Standardized MedDRA Query 
TE 
Thrombotic Event 
TEE 
Thromboembolic Event 
TEG 
Thromboelastography 
TNBP 
Tri(n-butyl)phosphate 
TPE 
Therapeutic Plasma Exchange 
WBC 
White Blood Cell 
 

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1 
INTRODUCTION 
Octaplas is a solvent/detergent (S/D) treated and pooled (SDP) human plasma prepared from 
units of fresh frozen plasma (FFP) pooled according to their ABO blood group. It contains the 
normal constituents of plasma. Octaplas is a further development of octaplas® which is 
marketed in Europe since 1992. In January of 2013, Octaplas received regulatory approval by 
the Food and Drug Administration (FDA) for the US market. For Octaplas, a new prion 
affinity column was introduced in the manufacturing process of the product to eliminate 
potential prion proteins. Furthermore, the time of S/D treatment in the manufacturing process 
has been shortened from 4–4.5 hours to 1–1.5 hours. These measures increase the 
concentration of plasmin inhibitor and slightly increase the concentration of protein S 
compared with octaplas®. Octaplas has received marketing authorization in Australia, 
Germany, Portugal, the U.K., Ireland, Belgium, the Netherlands, Luxemburg, Sweden, 
Finland, Switzerland, Malta, and Canada. octaplas® is registered in 21 countries and Octaplas 
is registered in 13 countries including the United States.  
Octaplas is labeled in the United States with the proprietary name octaplasTM. In case the 
study will be conducted in countries outside of the United States where the product is licensed 
under the name Octaplas and the product octaplas is recognized as the predecessor product 
this could lead to mismatch or misunderstanding. Therefore the name Octaplas is used in the 
current protocol.  
Octaplas does not contain red blood cells (RBCs), leukocytes and platelets. The RBCs and 
cell fragments are removed in several filtration steps during the production process. 
Therefore, adverse reactions caused by the presence of these cells (e.g., immunization against 
RBC antigens or febrile non-hemolytic reactions from cytokines liberated by leukocytes) are 
not expected to be associated with the infusion of this product. 
Virus inactivation is performed using the S/D treatment method using the virus inactivating 
reagents 1% tri(n-butyl)phosphate (TNBP) and 1% Triton X-100 (Octoxynol). This virus 
inactivation 
procedure 
is 
effective 
against 
enveloped 
viruses 
such 
as 
human 
immunodeficiency virus, hepatitis B virus and hepatitis C virus. The efficacy of this virus 
inactivation procedure has been extensively validated according to current international 
guidelines. The S/D treatment has no effect on non-enveloped viruses such as hepatitis A 
virus (HAV) and parvovirus B19. However, the presence of neutralizing antibodies towards 
HAV and B19 in the starting plasma and the final product, result in immune neutralization 
and passive immunization which both serve to limit or prevent virus replication and thereby 
infection in recipients. [1]  
The virus inactivating reagents (TNBP and Octoxynol) may remain in trace amounts in the 
final product. Toxicity studies performed in rats and dogs have shown that these levels are of 
no toxicological relevance to humans. Furthermore, no teratogenic, embryotoxic or mutagenic 
effects of TNBP and Octoxynol were observed in the toxicity studies performed. 
In total, 15 prospective clinical studies and 9 retrospective studies with octaplas have been 
conducted. Of the 15 prospective studies, 2 were focused on safety aspects only, and of the 9 
retrospective trials, 3 were mainly studying efficacy. In total, about 495 patients have been 
enrolled in the pro- and retrospective efficacy studies, including one observational study, and 
the patients were exposed to 2592 infusion episodes with octaplas/Octaplas or Uniplas (a 
plasma formulation compatible with all ABO blood groups). 

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Octaplas was developed as an alternative to plasma in order to prevent virus transmission. In 
addition, the product was developed to meet the request for a standardized, cell free plasma 
for infusion that contains high levels of pro- and anti-coagulants, in order to improve the 
therapeutic efficacy and reduce adverse reactions.   
1.1 
Rationale for Conducting the Study 
This post-marketing requirement (PMR) study was requested by the FDA after Octaplas 
received marketing approval in the United States. This PMR study is planned to be conducted 
in 50 pediatric patients from 0 to ≤ 16 years of age with acquired deficiencies due to liver 
disease and/or who require cardiac surgery or liver transplantation in whom replacement of 
multiple coagulation factors is required. 
The study is intended to obtain additional safety information on Octaplas in a routine clinical 
setting via the assessment of adverse drug reactions (ADRs), serious adverse events (SAEs) 
thrombotic events (TEs), thromboembolic events (TEEs) and hyperfibrinolytic events, and 
will be conducted in compliance with the protocol, ICH-GCP and other regulatory 
requirements.  
1.2 
Dose Rationale 
Octaplas is for intravenous use only. Please refer to the package insert of Octaplas for further 
information regarding dose (Appendix 1).  
1.3 
Benefit-Risk Statement 
There are several benefits associated with the administration of Octaplas. Octaplas has 
undergone additional steps for viral inactivation and removal. The combination of the S/D 
treatment and immune neutralization ensures a high degree of viral safety for this product. 
Antibodies against white blood cells are diluted and neutralized which abolishes the risk for 
immune Transfusion Related Acute Lung Injury (one of the most serious complications of 
transfusions today); this is a very favorable feature of Octaplas compared to plasma. Because 
cells and cellular debris are completely removed by multiple size exclusion filtration steps, 
adverse reactions attributable to residual blood cells, especially white blood cells, are not 
expected in conjunction with the use of Octaplas. The dilution effect on cytokines and 
allergens from the pooling of multiple units of single-donor FFP units diminishes the number 
and severity of adverse reactions that can occur due to the presence of allergens/soluble 
substances in plasma. Additionally, Octaplas has uniform and stable levels of both pro- and 
anti-coagulation factors. The combination of the uniformity of these factors in Octaplas and 
the consistent size of each unit could produce a more predictable hemostatic response 
following Octaplas transfusion compared to standard plasma. Comprehensive biochemical 
studies confirmed that Octaplas produced with the new column possesses a biochemical 
quality identical to its predecessor, octaplas®, with the advantage of offering an enhanced 
safety profile in terms of prion disease transmission such as Variant Creutzfeldt-Jakob 
Disease. 
The adverse reactions that were observed in ≥ 1% of subjects who received octaplas were 
mild and included pruritus, urticaria, nausea, headache, and paresthesia. [2] Serious adverse 

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reactions that were associated with octaplas transfusion included anaphylactic shock, citrate 
toxicity and severe hypotension. 
Other possible adverse reactions that may occur with the use of Octaplas are excessive 
bleeding caused by hyperfibrinolysis due to low levels of plasmin inhibitor in the product, 
thrombosis due to low levels of protein S, and citrate toxicity (hypocalcemia). The infusion 
rate should not exceed 1 mL/kg/min. Symptoms attributable to citrate toxicity can include 
fatigue, paresthesia and muscle spasms, especially in patients with liver function disorders. 
Because Octaplas is made from human plasma, it may carry a risk of transmitting certain 
infectious agents such as viruses and Variant Creutzfeldt-Jakob Disease. Other adverse 
reactions that have been reported in the post-marketing experience include hypersensitivity 
reactions including anaphylactoid and allergic type of reactions, alkalosis, cardiac arrest, 
circulatory overload, thromboembolism, tachycardia, respiratory arrest or failure, 
bronchospasm, pulmonary edema, dyspnea, tachypnea, abdominal pain, vomiting, rash, 
erythema, fever and/or chills, chest discomfort or pain, and seroconversions (passive transfer 
of antibodies). 
High volumes or infusion rates may induce Transfusion Associated Volume Overload that is 
manifested dyspnea, hypoxia, and increasing oxygen demands. Pulmonary edema can often 
be seen on chest X-ray. High infusion rates may rarely cause cardiovascular effects as a result 
of citrate toxicity (fall in ionized calcium), especially in patients with liver function disorders. 
Octaplas should be used with caution in patients with risks for thrombotic complications 
because of the potential for increased risk of venous thromboembolism. In order to reduce the 
risk for venous thromboembolism, appropriate measures should be considered in all patients 
at risk for thrombotic complications subjected to coagulation factor support for an extended 
period of time (e.g., during long-term, large-volume therapeutic plasma exchange [TPE]) 
using Octaplas. 
Administration of Octaplas must be based on ABO-blood group compatibility with the 
recipient. Hemolytic reactions can occur with ABO blood group mismatches. In emergency 
cases, blood group AB can be regarded as the universal plasma since it can be given to all 
patients. 
Octaplas should not be used in patients with: 
• Immunoglobulin A (IgA) deficiency 
• Severe deficiency of protein S 
• History of hypersensitivity to FFP or to plasma-derived products 
• History of hypersensitivity reaction to Octaplas 

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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective is to assess the safety and tolerability of Octaplas in the pediatric 
population by monitoring SAEs, ADRs, TEs, TEEs and hyperfibrinolytic events, including 
laboratory parameters for metabolic derangements, renal function, and hematologic 
implications. 
2.2 
Secondary Objective(s) 
The secondary objective is to assess the efficacy of Octaplas in the pediatric population by 
measuring hemostatic parameter improvements reflecting changes in hemostasis. 
3 
INVESTIGATIONAL PLAN 
3.1 
Primary and Secondary Endpoints 
Primary Endpoint(s) 
• Incidence of SAEs, ADRs (e.g., allergic reactions; refer to Section 7.3.2.1 for 
definition), TEs, TEEs and hyperfibrinolytic events, beginning after the start of the 
first infusion episode until the final examination (end of safety follow-up period). 
• Clinically significant changes in laboratory parameters to assess for metabolic 
derangements, renal function, and hematologic implications as measured by the 
following: Chem 7 (metabolic panel), complete blood count (CBC) and ionized 
calcium (refer to Section 7.3.5.3 for definition). 
Due to the complex and highly variable and individual medical circumstances and 
interventions that are to be expected in this study, no single parameter or measurement of 
outcome is chosen as the primary endpoint. 
Secondary Endpoint(s) 
• Clinically significant changes in hemostatic parameters as measured by the following: 
international normalized ratio (INR), prothrombin time (PT), activated partial 
thromboplastin time (aPTT), thromboelastography (TEG), or thromboelastometry 
(ROTEM). 
• Volume (dose in mL/kg) of Octaplas used per infusion episode for each patient. 
• Medically significant changes in vital signs. 
• Investigator’s assessment of overall safety observed for each patient. 
3.2 
Overall Study Timeline 
The study started in the second quarter 2015 and is planned for completion by 4th quarter of 
2017. The end of the study is defined as the last visit of the last patient participating in the 
study. 

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Study Flow Chart 
Time-Points 
Screening/ 
Pre-Infusion 
(within 7 days prior to 
start of first infusion1) 
72-Hour Study 
Treatment Period 
(Infusion 
Episode(s)2, 3 
 
72-Hour Safety 
Follow-up Period3,4 
Final 
Examination 
72 hours after end of last study 
infusion episode2 
Inclusion/Exclusion criteria 
X 
 
 
 
Informed consent/assent 
X 
 
 
 
Physical examination5  
X 
 
 
 
Medical history (incl. prior and current relevant concomitant 
medications6) 
X 
 
 
 
Vital signs7 
X 
X  
 
X 
Documentation of the type of surgical procedure indicated8 
X 
 
 
 
Demographic data 
X 
 
 
 
Blood group determination 
X 
 
 
 
Hemostatic parameters9 
X 
X 
 
 
Laboratory parameters (Chem 7, CBC and ionized calcium)9 
X 
X 
 
X 
Pregnancy test10 
X 
 
 
 
Ordering of plasma 
X 
 
 
 
Administration of Octaplas 
 
X 
 
 
Investigator Assessment of Safety11 
 
 
 
X 
Monitoring of SAEs and ADRs 
 
←------------------Continuously-----------------→ 
Monitoring of TEs, TEEs, and hyperfibrinolytic events (regardless 
of causality)12 
 
Monitoring concomitant medication 
 
 
 
 

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1. 
Screening time window of -7 days does not apply for informed consent/assent procedure. 
2. 
An infusion episode is defined as any amount of Octaplas given, with no more than 60 minutes break between 2 Octaplas infusions. If the time interval between the end of 
one Octaplas infusion and the beginning of the next Octaplas infusion is more than 60 minutes this will be counted as 2 different infusion episodes. For patients on CPB 
who are primed with plasma, a transfusion episode will begin with the initiation of the circuit with plasma and will end when the heparin is reversed during the 
process of coming off CPB. The study Treatment Period will end after 72 hours from the start of the first infusion of Octaplas, or after the end of the last infusion 
episode if the total duration of Octaplas treatment is <72 hours. 
3. 
Single donor plasma (e.g. FFP, FP24, thawed plasma, etc.) should be avoided during the Treatment and Follow-up study periods. Patients receiving single donor plasma during 
the Treatment or Follow-up periods will be withdrawn from the trial. Plasma exchange, TPE or plasmapheresis is not permitted during the Treatment or Follow-up periods. 
Patients who develop the need for and undergo plasma exchange or plasmapheresis will be withdrawn from the trial. 
4. 
The permitted visit window for the Safety Follow-up period and Final Examination is 72 hours (± 6 hours) after the end of the last Octaplas infusion. The Follow-up 
procedures (e.g., Investigator assessment of safety) may be performed sooner if it will not be practical to obtain at the 72-hour post final examination visit. If it is not medically 
feasible to obtain the final examination visit assessments at the 72 hours (± 6 hours) time point, the reason must be documented (e.g., patient discharged prior to 72 hours after 
the end of the last infusion, etc.).  
5. 
A physical examination will be performed at the screening visit in accordance with the site’s local standard procedures. This may include examination of dermatological and 
lymphatic system, head, eyes, ears, nose, throat [HEENT], respiratory tract, cardiovascular and gastrointestinal system, musculoskeletal system, neurological system, and 
endocrinological systems. 
6. 
Details of any relevant prior (up to 7 days before the first administration of Octaplas) and concomitant medications administered during the trial period will be recorded on the 
case report form (CRF). All other transfusion products (e.g., albumin, cryoprecipitate, platelets) must be captured individually in the CRF. Routine medications that are 
considered standard and/or that have little or no impact on the study data results are not to be entered into the CRF (e.g., anesthesia medications, beta blockers, etc.). For details 
please see Section 4.2. 
7. 
Vital signs will include heart rate, respiratory rate, temperature, arterial saturation and blood pressure assessment. Vitals should be assessed within a maximum of 6 hours 
before the start and 60 minutes after the end of the first infusion episode. All subsequent assessments should be accomplished within 60 minutes before and 60 minutes after 
each infusion episode. If multiple vital sign assessments are taken within 60 minutes before and/or after the infusion, the vital signs that are assessed closest before the start and 
after the end of each infusion should be recorded. 
8. 
The type of surgical procedure indicated as well as start and stop dates and times of the procedure, estimated blood loss, use of ECMO and/or CPB will be recorded on the 
CRF.  
9. 
Pre- and post-infusion episode samples for hemostatic and laboratory parameters will be tested. Pre-infusion samples for the first infusion episode should be drawn within 
6 hours prior to the start of the first infusion episode (all the subsequent pre-infusion assessments are to be done within 60 minutes prior the infusion episode). Post-
infusion episode samples should be drawn within 30 to 60 minutes after the end of each infusion. If the patient requires priming of the cardiopulmonary bypass (CPB) 
circuit with plasma, the post-infusion episode samples should be drawn 30-60 minutes after reversal of heparin during the process of coming off CPB. For the first 
infusion episode it is mandatory that, pre– and post–infusion episode samples for hemostatic and laboratory parameters be tested. If subsequent infusion episodes are 
performed, pre- and post-infusion episode laboratory tests should be performed  unless considered not medically necessary by the Investigator (e.g., the timing of the pre-
infusion episode sample is close to or overlaps with the timing of the post-infusion episode sample and it is not necessary to perform, etc.). In the event the pre- or post-
infusion laboratory sample(s) are not drawn, the reason for not obtaining the sample(s) will be recorded on the CRF. If multiple hemostatic and laboratory parameters may 
be assessed before and/or after the infusion, the hemostatic and laboratory parameters that are assessed closest before the start and after the end of each infusion should be 
entered in the eCRF. TEG with Kaolin activation or ROTEM EXTEM testing should be performed as defined in Section 7.3.5.3. 

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10. Females ≥ 11 years old or females of childbearing potential (if younger than 11 years old) must have a negative pregnancy test prior to the first infusion episode to qualify for 
the study.  
11. This Assessment of Safety should be performed by the principal investigator or sub-investigator. 
12. For this trial a “clinically relevant hyperfibrinolytic event” is defined by one of the following test results in the presence of a bleed that requires intervention: 
• 
Kaolin TEG – estimated percentage lysis (EPL) > 7.5% at 30 min (after starting assay). 
• 
ROTEM EXTEM – maximum lysis (ML) > 7.5% at 30 min (after starting assay). 

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Laboratory Evaluations Flow Chart1 
Time-Points 
Pre-Infusion 
Post-Infusion 
Final 
Examination 
Before infusion episode 
Between 30 and 60 minutes after each 
infusion episode 
72 hours after end of last 
study infusion episode 
Hemostatic parameters: 
INR, PT, aPTT, TEG or ROTEM  
X 
X 
 
Laboratory parameters: 
• Chem 7 panel: BUN, CO2 (bicarbonate), serum 
chloride, serum creatinine, glucose, serum 
potassium, and serum sodium. 
• CBC: WBC, RBC, platelets, hemoglobin, 
hematocrit, MCV, MCH, MCHC, and RDW. 
• Ionized calcium 
X 
X 
X 
1. 
The following blood volume limits for sampling are recommended, if an Investigator decides to deviate from these, this should be justified. NIH Clinical Center Guidelines for 
Blood Drawn for Research Purposes in the Clinical Center (M95-9) rev 06/05/2009: For pediatric patients, no more than 5 mL/kg may be drawn for research purposes in a 
single day, and no more than 9.5 mL/kg may be drawn over any eight-week period. 
 

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3.3 
Discussion of Study Design and Choice of Control Group(s) 
Study Design 
This is an open-label, multicenter, PMR study in 50 pediatric patients with acquired 
deficiencies due to liver disease and/or pediatric patients requiring cardiac surgery or liver 
surgery who require replacement of multiple coagulation factors. The substitution of 
coagulation factors is also applicable for young children who require cardiac surgery and 
require priming of the cardiopulmonary by-pass circuit due to the dilution of the increased 
volume of the by-pass circuit relative to the circulating blood volume of the child. The study 
will be conducted in up to 10 sites in North America. The following number of patients is 
planned to be enrolled: 
1. Neonates/Infants (0-2 years): a maximum of 33 patients 
2. Children > 2 years and ≤ 16 years: a minimum of 17 patients   
Taking into consideration the small size of the target population of children with this disease 
condition and intervention indication, the proposed sample size of 50 children seems 
appropriate to obtain sufficient safety information in a reasonable amount of time.  
Control Group(s) 
This is an open-label study of Octaplas to investigate its safety, tolerability and efficacy in the 
management of pediatric patients who require replacement of multiple coagulation factors; 
there is no control group. 
Since the sole aim of this PMR study is the gathering of information on the safety and 
efficacy of Octaplas in the indicated study population, it is reasonable to omit a concurrent 
control group. 
Target Parameter(s) 
The selection of the endpoints listed in Section 3.1 is considered adequate to provide the most 
relevant information on the safety and efficacy aspects of Octaplas in this setting. Therefore, 
these target parameters are in congruence with the study rationale. 

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4 
STUDY POPULATION 
4.1 
Population Base 
In total, 50 pediatric patients who require replacement of multiple coagulation factors are 
expected to be enrolled according to the following inclusion and exclusion criteria.  
Inclusion Criteria 
Patients who meet all of the following criteria are eligible for the study: 
1. Patient requiring liver or cardiac surgery and/or patient with liver dysfunction 
associated with coagulopathy in whom replacement of multiple coagulation factors is 
required. 
2. Voluntarily given, written and signed informed consent by the patient’s legal 
representative(s) 
or 
guardian(s). 
Children 
deemed 
old 
enough 
by 
the 
Investigator/institution to understand the risks and benefits of the study should also be 
made aware of the risks/benefits of the study and provide written assent. 
3. Male or female patient ≤ 16 years of age. 
Exclusion Criteria 
Patients who meet any of the following criteria are not eligible for the study: 
1. Patient with known homozygous congenital deficiency of protein S. 
2. Patient has a history of hypersensitivity reaction to blood or plasma-derived products 
or to any excipient of the investigational product. 
3. Patient has an already known IgA deficiency with documented antibodies against IgA. 
4. Patient has a congenital factor deficiency or platelet disorder requiring plasma 
treatment. 
5. Patient is currently participating in another study investigating a new drug product or 
another interventional clinical study that may impact coagulation factors or has 
participated during the last three (3) months. 
6. Patient received FFP, FP24 or any other plasma product other than Octaplas within the 
last 72 hours (cryoprecipitate and albumin are not exclusionary) prior to first Octaplas 
infusion. 
7. Patient is on ECMO (Extracorporeal Membrane Oxygenation) when plasma is ordered 
by the treating physician for the first infusion episode. 
8. Patient is pregnant. 
9. Patient is predicted to require massive blood transfusion defined as more than 40 mL 
per kilogram of all blood products in a 24-hour period  
10. Patient is receiving plasma exchange, TPE or plasmapheresis. 
11. Patient is a premature neonate defined as less than 37 weeks gestation. 
12. Cardiac surgery patients who develop the need for plasma replacement greater than 72 
hours after the end of the associated cardiac surgery and do not have coagulopathy due 
to hepatic dysfunction. 

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4.2 
Prior and Concomitant Therapy 
Details of relevant current and concomitant medications administered during the trial period 
will be recorded on the CRF. Relevant medications are defined as follows: 
• Plasma products (e.g., octaplas™, regular plasma products, etc.) and all other blood 
products that are administered. 
• Antifibrinolytics (ε-aminocaproic acid or tranexamic acid) and any other 
pharmaceutical pro- or anti-coagulants such as recombinant activated factor VII, any 
of the prothrombin complex concentrates, or fibrinogen concentrates. 
• Vaso-active 
agents 
(epinephrine, 
norepinephrine, 
vasopressin, 
Milrninone, 
phenylepherine, Antidiuretics (desmopressin, DDAVP, DesmoMelt, Stimate, Minirin, 
etc.). 
• Colloids (e.g., albumin, hydroxyethyl starches). 
• Medications (including steroids) taken to treat or prevent ADRs (to Octaplas) 
• Other medications that the Investigator considers relevant to report for this trial. 
Routine medications that are considered standard and/or that have little or no impact on the 
study data results are not to be entered into the CRF (e.g., anesthesia medications, beta 
blockers, etc.). Any concomitant medications or changes thereof must be recorded. If the 
change influences the patients’ eligibility to continue in the trial, the Sponsor must be 
informed. 
Permitted Concomitant Therapy 
The following concomitant medications are permitted: 
• calcium-gluconate given IV in case of hypocalcemia (due to citrate toxicity), 
• antihistamines and glucocorticoids given IV in case of anaphylactoid reactions, and 
• red blood cells, platelet units if medically indicated. 
It is permitted for patients to receive Octaplas or other plasma products (please see exceptions 
below) during the 72-hour follow-up period if medically indicated.  
Although patient’s requiring ECMO at study entry are excluded, ECMO is permitted therapy 
while on study if it is determined to be medically indicated after the start of the first infusion.  
Forbidden Concomitant Therapy 
Single donor plasma (e.g., FFP, FP24, thawed plasma, etc.) should be avoided during the 
Treatment and Follow-up study periods. Patients receiving single donor plasma during the 
Treatment or Follow-up periods should be withdrawn from the trial. 
Plasma exchange, TPE or plasmapheresis is not permitted during the study. Patients who 
develop the need for and undergo plasma exchange or plasmapheresis during the Treatment or 
Follow-up periods will be withdrawn from the trial. 

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4.3 
Withdrawal and Replacement of Patients 
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. The Investigator also has the right to withdraw patients in case 
of ADRs, protocol violations, or other reasons. Since an excessive rate of withdrawal can 
render the study non-interpretable, the unnecessary withdrawal of patients must be avoided. 
For any discontinuation after study entry, the Investigator will obtain all the required details 
and document the reason(s) for discontinuation in the CRF. If the reason for withdrawal of a 
patient is an ADR, the main specific event or laboratory test will be recorded in the CRF, and 
the Investigator will make thorough efforts to clearly document the outcome. 
Moreover a patient may be withdrawn from the study prior to completion for any of the 
following reasons: 
• Whenever the patient/legal representative(s)/guardian(s) decides it is in the patient’s 
best interest to withdraw 
• Whenever the Investigator decides it is in the patient’s best interest to be withdrawn 
• Pregnancy 
For any premature patient withdrawal after study entry, the Investigator will obtain all the 
required details and document the reason(s) for discontinuation in the CRF. Data of patients 
withdrawn prematurely will be included in the safety analysis. 
Patients consented (enrolled) into the study pre-operatively for cardiac and liver surgery will 
be considered screening failures if they do not receive Octaplas intra-operatively or post-
operatively. Patients who are consented but do not receive Octaplas intra-operatively will be 
eligible for study treatment while they remain in the intensive care unit. Patients who are 
discharged from the intensive care unit without being treated with Octaplas will be considered 
a screening failure. 
Patient Replacement Policy 
There is no patient replacement policy defined for this protocol. Fifty (50) pediatric patients 
will be treated in the study. 
4.4 
Assignment of Patients to Treatment Groups 
All patients enrolled in this study will be treated with Octaplas. The Investigator will inform 
the Sponsor of new patients enrolled by the submission of patient entry information.  
4.5 
Relevant Protocol Deviations 
If deviations from the protocol occur, the Investigator should promptly inform the monitor 
and the nature of the deviation must be reviewed and discussed. Any deviation must be 
documented, stating the reason and date, the action taken, and the impact for the patient 
and/or the trial. The documentation must be kept in the Investigator’s Trial File and the 
Sponsor’s Trial File. In case of any major protocol deviation the Investigator and the Sponsor 
will decide on whether the patient should be withdrawn from this study. 

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4.6 
Subsequent Therapy 
After the study treatment period has ended, subsequent therapy is at the treating physician’s 
discretion. 
5 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
5.1 
Characterization of Investigational Product(s) 
For Octaplas, a new prion affinity column was introduced in the manufacturing process of the 
product to eliminate potential prion proteins. Furthermore, the time of S/D treatment in the 
manufacturing process has been shortened from 4–4.5 hours to 1–1.5 hours. These measures 
increase the concentration of plasmin inhibitor and slightly increase the concentration of 
protein S compared with octaplas®. 
The virus safety of Octaplas was maintained as shown by virus validation studies. With a total 
inactivation to below the detection limit, the shortened S/D procedure has a time-safety-
margin of >98.3% versus >99.5% for the predecessor product. 
5.2 
Packaging and Labeling 
Octaplas is delivered frozen in sterile, pyrogen free plastic bags containing 200 mL. The bags 
are vacuum sealed in a clear plastic wrap and delivered in cartons of 10 units. 
Each octaplas™ bag will be labeled as shown below (for blood group A). 
NDC 68209-952 – 01 
Octaplas™ 
Pooled Plasma (Human), Solvent/Detergent Treated 
For intravenous use only. 
Rx only. 
200 mL contain 9 - 14 g human plasma proteins, 0.88 - 1.48 g sodium citrate dihydrate, 0.06 - 0.24 g sodium 
dihydrogen phosphate dihydrate, 0.80 - 1.20 g glycine, ≤0.4 mg TNBP and ≤1.0 mg Octoxynol. This product 
contains no preservative. 
Store at ≤–18°C (–0.4oF) protected from light. 
Thawed product should be used immediately and must not be refrozen. 
Do not use product that is cloudy or has deposits. 
Unused product must be discarded. 
Caution: New Drug--Limited by Federal (or United States) law to investigational use 
Exp. Date: 
Lot No.: 
U.S. License No. 1646 
Manufactured by:  
 
Octapharma AB 
 
Elersvägen 40 
 
SE-112 75, Sweden 
Distributed by:  

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Octapharma USA Inc. 
 
Hoboken, NJ 07030 
 
866-766-4860 
Final labeling will comply with the national requirements of each country where the study is 
to be conducted. 
Octaplas is labeled in the United States with the proprietary name octaplasTM. In case the 
study will be conducted in countries outside of the United States where the product is licensed 
under the name Octaplas and the product octaplas is recognized as the predecessor product 
this could lead to mismatch or misunderstanding. Therefore the name Octaplas is used in the 
current protocol.  
5.3 
Conditions for Storage and Use 
The shelf-life of Octaplas is 36 months when stored at ≤ -18°C (≤ -0.4°F) and protected from 
light. After thawing, the product must be used within 24 hours when stored at 1-6°C (33.8°F 
to 42.8°F) or within 8 hours when stored at room temperature 20 to 25°C (68°F to 77°F). See 
package insert in Appendix 1. 
The Investigator/authorized personnel at the site will ensure that the product is stored in 
appropriate conditions with restricted access and in compliance with national regulations. 
5.4 
Dose and Dosing Schedule 
The actual volume of Octaplas administered to a patient will depend on the clinical setting.  
If the time interval between the end of one Octaplas infusion and the beginning of the next 
Octaplas infusion is no longer than 60 minutes, then this will be regarded as 1 infusion 
episode. If the time interval is more than 60 minutes, this will be counted as 2 different 
infusion episodes. For patients on CPB who are primed with plasma, a transfusion episode 
will begin with the initiation of the circuit with plasma and will end when the heparin is 
reversed during the process of coming off CPB. 
The infusion rate of Octaplas should not exceed 0.020-0.025 mmol citrate per kilogram per 
minute, which is equal to <1 mL Octaplas per kg per minute. This limitation is not applicable 
for devices used for cardiopulmonary bypass or extracorporeal membrane oxygenation or 
similar. In case situations like e.g. a serious hemorrhage necessitates a rapid infusion ≥ 
1mL/kg and the benefits outweigh the potential risks, the infusion speed can be ≥ 1mL/kg 
body weight. The dose (mL) of Octaplas to be infused will depend on the age and BW of the 
patient. The first infusion dose will be at a minimum of 10 mL/kg or one unit unless a lesser 
dose is medically justified. If infusions are performed and the dose administered is less than 
10 mL/kg the medical reason justifying this dosage will be recorded in the CRF, since at least 
10 mL/kg are required to significantly increase the respective plasma protein levels  
5.5 
Preparation and Method of Administration 
Octaplas will be used per the approved labeling for the product (see Appendix 1). Octaplas 
will be administered based on ABO-blood group compatibility. In urgent cases and in the 
circumstances that no same blood group is available (type A donor plasma for type A 

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recipient), patient can be administered plasma that is compatible to recipient’s blood group 
(e.g., donor AB plasma can be administered to recipient with blood group A). 
5.6 
Blinding, Emergency Envelopes and Breaking the Study Blind 
Not applicable. This is an open-label study. 
5.7 
Treatment Compliance 
Drug Dispensing and Accountability 
Octaplas will be supplied by the Sponsor. A drug dispensing and accountability log will be 
kept up-to-date at the Investigator's site, detailing the dates and quantities of the 
investigational medicinal product (IMP) received at the site and dispensed and administered 
to each patient. The inventory will be made available to the monitor to verify drug 
accountability during the study. Unused trial medication will be returned to the Sponsor 
designated clinical supplies depot or, if approved by the Sponsor in advance, may be 
destroyed at the Investigator site following local policies for destruction of biologic supplies. 
Empty bags will not have to be returned and will be destroyed at the study site following local 
policies after appropriate documentation. 
Assessment of Treatment Compliance 
Having in mind the setting and the fact that study drug administration will exclusively take 
place at the investigational site, full compliance is expected. 
6 
STUDY CONDUCT 
6.1 
Study Periods 
Screening 
The following assessments will be performed at Screening: 
• Obtaining voluntarily given, written (signed and dated) informed consent by the 
patient’s legal representative(s) or guardian(s). Children deemed old enough by the 
Investigator/institution to understand the risks and benefits of the study should also be 
made aware of the risks/benefits of the study and provide written assent. Patients 
determined to have a reasonable probability to receive intra-operative plasma 
transfusion according to the Investigator’s clinical judgment may also be approached 
for consent to participate. If these patients are subsequently not prescribed plasma 
intra-operatively or postoperatively they will be determined to be a screening failure 
and not included in the analysis. 
• Review of inclusion and exclusion criteria. 
• Physical examination (see Section 7.3.6). 
• Relevant medical history including prior medications (taken within 7 days prior to 
time 0 (study drug given) and on-going concomitant medication(s). 
• Demographic data (height, BW, gender, date of birth, ethnicity). 
• Determination of ABO blood group for compatibility. 

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• Pregnancy testing for females at the age of ≥ 11 or of childbearing potential (if 
younger than 11 years old). Results must be negative for the female patient to be in the 
study. 
• Documentation of type of surgical procedure indicated for the patient and important 
operative interventions. 
• Ordering of plasma if clinically indicated per physician discretion. 
Pre-Infusion (Immediately Before First Infusion Episode) 
The following assessments will be performed before the first infusion episode: 
• Vital signs (see Section 7.3.6). 
• Blood sample(s) for hemostatic parameters (see Section 7.2.1). 
• Blood sample(s) for laboratory parameters (see Section 7.3.5.3). 
Study Treatment Period 
The number of infusion episodes and actual total volume (dose in mL/kg) of Octaplas 
administered to a patient within the 72-hour treatment period will depend on the clinical 
setting and physician discretion. After 72 hours from the start of the first infusion of Octaplas, 
the study treatment period will end. The following procedures will be performed during the 
study treatment period: 
• Administration/infusion of Octaplas. 
• Vital signs. 
• Monitoring of ADRs (refer to Section 7.3.2.1 for definition), TEs, TEEs, 
hyperfibrinolytic events and concomitant medications. 
• Pre- and post-infusion episode samples for hemostatic and laboratory parameters will 
be tested. The pre-infusion episode laboratory samples should be drawn within 6 hours 
before the start of the first infusion episode and within 60 minutes prior to the start of 
subsequent infusion episodes. Post-infusion episode samples should be drawn within 
30 to 60 minutes after the end of each infusion episode. If the patient requires priming 
of the cardiopulmonary bypass (CPB) circuit with plasma, the post-infusion episode 
samples should be drawn 30-60 minutes after reversal of heparin during the process of 
coming off CPB. For the first infusion episode it is mandatory that pre- and -post-
infusion episode laboratory testing is performed. If subsequent infusion episodes are 
performed, pre- and post-infusion episode laboratory tests should be performed unless 
considered not medically necessary by the Investigator (e.g., the timing of the pre-
infusion episode sample is close to or overlaps with the timing of the post-infusion 
episode sample and it is not necessary to perform, etc.). In the event pre- or post-
infusion laboratory sample(s) are not performed, the reason will be documented in the 
CRF. If multiple hemostatic and laboratory parameters may be assessed before and/or 
after the infusion, the hemostatic and laboratory parameters that are assessed closest 
before the start and after the end of each infusion should be entered in the eCRF. 
Safety Follow-up Period 
• ADRs, TEs, TEEs, hyperfibrinolytic events and concomitant medications will be 
monitored for 72 hours (± 6 hours) after the last Octaplas transfusion is completed.  

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Final Examination 
Seventy-two hours (± 6 hours) after the end of the last study infusion episode, a Final 
Examination will be performed that consists of the following assessments: 
• Vital signs (see Section 7.3.6). 
• Physician Assessment of Safety (Section 7.3.1). 
• Blood sample(s) for laboratory parameters (see Section 7.3.5.3). 
• Monitoring of ADRs (refer to Section7.3.2 for definition), TEs, TEEs, 
hyperfibrinolytic events and concomitant medications. 
After the Final Examination, the clinical phase of the study is considered completed for the 
patient. No further study-related assessments will be performed, unless safety concerns (e.g., 
on-going ADRs) require follow-up. 
6.2 
Duration of Study 
Planned Duration for an Individual Patient 
There will be a maximum 72-hour study treatment period followed by a 72-hour follow-up 
period. 
Planned Duration for the Study as a Whole 
The study will be considered completed when all patients have completed the Final 
Examination. 
The start of the study (enrollment of first patient) is 2nd quarter 2014 and the estimated end of 
the study is 4th quarter 2017. 
Premature Termination of the Study 
Both the Investigator and the Sponsor reserve the right to terminate the study at any time. 
Should this be necessary, the procedures will be arranged on an individual study 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 Independent Ethics Committee 
(IEC)/Institutional Review Board (IRB) and provide a detailed written explanation. The 
pertinent regulatory authorities should be informed according to national regulations. 
Should the study be prematurely terminated, all study materials (completed, partially 
completed and blank CRFs, investigational product, etc.) must be returned to the Sponsor. 
7 
ASSESSMENTS AND METHODS 
7.1 
Background / Baseline Information 
The following information will be captured upon enrollment: 
• Physical examination with vital signs (see Section 7.3.6). 
• Relevant Medical History including relevant prior medications (taken within 7 days 
prior to time 0 (study drug given)) and on-going relevant concomitant medications. 

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• Demographic data including height, BW, gender, date of birth, and ethnicity. 
• Blood group determination. 
• Blood samples for hemostatic and laboratory parameters (see Sections 7.2.1 and 
7.3.5.3, respectively). 
• Pregnancy testing for females ≥ 11 years old or of childbearing potential (if younger 
than 11 years old). 
• Type of surgical procedure indicated and use of ECMO and/or CPB 
7.2 
Efficacy Assessments 
7.2.1 Hemostatic Parameters 
The secondary objective of this study is to assess the efficacy of Octaplas in the pediatric 
population by measuring hemostatic parameter improvements reflecting changes in 
hemostasis. 
The following hemostatic parameters will be assessed: INR, PT, aPTT, TEG with Kaolin 
activation or ROTEM EXTEM testing. 
7.3 
Safety Assessments 
7.3.1 Relevant Drug Safety Information 
Any of the following drug safety information shall be collected after the start of the first 
infusion episode: 
• SAEs 
• ADRs temporally associated with administration of the investigational product 
(definitions and reporting requirements see Sections 7.3.2 and 7.3.3)  
• AEs that fall into the category of TEs, TEEs and hyperfibrinolytic events 
• Post-treatment related safety reports, pregnancies, drug overdose, interaction, abuse, 
misuse, medication error, lack of efficacy (see Section 7.3.7) 
Non-serious AEs observed during the trial will not be captured in the CRF (except for TEs, 
TEEs, and hyperfibrinolytic events as explained above). 
Post-treatment, the Investigator will provide an overall Assessment of Safety observed for 
each patient by indicating his or her opinion of one of the following 3 categories best 
describing the patient’s experience with treatment while on study: 
• Excellent: defined as the treatment was well tolerated by the patient 
• Moderate: defined as adverse drug reaction(s) were observed, but easily resolved or 
not clinically significant 
• Poor: Defined as adverse drug reaction(s) were observed requiring significant medical 
intervention 

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7.3.2 Adverse Events and Adverse Drug Reactions 
7.3.2.1 Definitions  
Adverse event (AE): An AE is any untoward medical occurrence in a study patient receiving 
an 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 adverse event carries at least a reasonable possibility, i.e., the 
relationship cannot be ruled out. 
Withdrawal due to ADR/AE: Is a patient whose treatment with IMP is discontinued because 
of an ADR. 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 
The condition of the patient will be monitored throughout the study. ADRs/AEs will be 
elicited using a standard non-leading question such as “How have you been since the last 
evaluation?” If children or adolescent patients are unable to adequately understand and 
respond to this question, the information will be obtained from the patient’s guardian and/or 
Investigator or study nurse. 
Any ADR or above defined AE after the first administration of study drug which occurs 
during the study will be noted in detail on the appropriate pages of the CRF. If the patient 
reports several signs or symptoms, which represent a single syndrome or diagnosis, the latter 
should be recorded in the CRF. The Investigator responsible will grade the severity of all 
ADRs/AEs (mild, moderate or severe), the seriousness (non-serious or serious) and causality, 
as defined below (Sections 7.3.2.3, 7.3.2.4, and 7.3.3). The Sponsor is responsible to assess 
the expectedness of each ADR/AE (expected or unexpected), as defined below (Section 
7.3.2.4). 
 
Diseases, signs and symptoms and/or laboratory abnormalities already existing before the first 
administration of IMP are not considered as ADRs/AEs when observed at a later stage unless 
they represent an exacerbation in intensity or frequency (worsening). 
The Investigator responsible should always provide detailed information concerning any 
abnormalities and the nature of, and reasons for any necessary action(s), as well as any other 
observations or comments, which are useful for the interpretation and understanding of the 
patients’ ADRs/AEs. 
7.3.2.3 Severity 
The intensity/severity of all ADRs/AEs will be graded as follows: 

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• mild: an ADR/AE, usually transient, which causes discomfort but does not interfere 
with the patient’s routine activities; 
• moderate: an ADR/AE which is sufficiently discomforting to interfere with the 
patient’s routine activities; 
• severe: an ADR/AE which is incapacitating and prevents the pursuit of the patient’s 
routine activities. 
Grading of an ADR/AE is up to the medical judgment of the Investigator and will be decided 
on a case by case basis. 
7.3.2.4 Causality 
The following causality definitions should be used for classification of each AE: 
Probable:  
Reports or laboratory test abnormality, with reasonable time relationship to 
drug intake. 
 
 
Unlikely to be attributed to disease or other drugs. 
 
 
Response to withdrawal clinically reasonable. 
 
 
Re-challenge not required. 
Possible: 
Reports or laboratory test abnormality, with reasonable time relationship to 
drug intake. 
 
 
Could also be explained by disease or other drugs. 
 
 
Information on drug withdrawal may be lacking or unclear. 
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: 
Reports 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 yet assessable, e.g., because of 
outstanding information (can only be a temporary assessment). 
The following causality definitions should be used for classification of each ADR: 
Probable:  
Reports or laboratory test abnormality, with reasonable time relationship to 
drug intake. 
 
 
Unlikely to be attributed to disease or other drugs. 
 
 
Response to withdrawal clinically reasonable. 
 
 
Re-challenge not required. 
Possible: 
Reports or laboratory test abnormality, with reasonable time relationship to 
drug intake. 
 
 
Could also be explained by disease or other drugs. 
 
 
Information on drug withdrawal may be lacking or unclear. 
Classification of ADRs: 
ADRs will be classified by the Sponsor as either expected or unexpected: 
• expected: an adverse event that is listed in the current edition of the Investigator’s 
Brochure (IB). 
• unexpected: an adverse event that is not listed in the current edition of the IB, or that 
differs because of greater severity or greater specificity. 

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7.3.2.5 Outcome 
The outcome of all reported ADRs/AEs has to 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 
patient’s death must be fully documented and reported, even in case the death occurs within 
four (4) weeks after IMP treatment end, and without respect of being considered treatment-
related or not. 
7.3.2.6 Action(s) Taken 
ADRs/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 of an emergency 
situation. 
The action taken by the Investigator must be documented: 
a) in general 
- none 
- medication (other than IMP) or other (e.g., physical) therapy started 
- test performed 
- other (to be specified) 
b) on IMP 
- none 
- product withdrawn 
- dose reduced 
- dose increased 
The responsible Investigator will follow-up each ADR/AE until it is resolved or until the 
medical condition of the patient is stable and all relevant follow-up information will be 
reported to the Sponsor. 
7.3.3 Serious Adverse Events (SAEs) 
A serious AE is any untoward medical occurrence at any dose: 
• results in death, 
• is life-threatening (this implies that the patient was at an immediate risk of death at the 
time of the event, and not a hypothetical situation of what could or would have 
happened if, for example, no treatment had been administered), 
• requires in-patient hospitalization or prolongation of existing in-patient hospitalization 
(hospitalization does not refer to the treatment of an ADR/AE on an out-patient status 

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or to hospitalization because of study-related procedures (e.g., infusion at two 
consecutive days) or because of an elective surgical procedure for which the date had 
been scheduled earlier), 
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, 
• is another important medical event (e.g., suspected transmission of an infectious agent, 
or other reactions that should be reported in an expedited manner although they did 
not immediately result in one of the above seriousness criteria). 
Medical judgment should be exercised in deciding whether an ADR/AE is serious in other 
situations. Important ADRs/AEs 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.  
SAE reporting timelines 
All SAEs occurring after the start of the first infusion episode are to be reported by telephone, 
fax or e-mail immediately to the Clinical Project Manager (CPM) or designee. Contact details 
will be communicated at the study initiation visit. 
An Octapharma "Serious Adverse Event Report" must be completed and submitted within 
24 hours after recognition of the event. 
All SAEs, TEs, TEEs and hyperfibrinolytic events (Section 7.3.4)should be reported to: 
Octapharma’s Central Drug Safety Unit: 
OCTAPHARMA Pharmazeutika Produktionsges.m.b.H. 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
Fax: +43 1 61032-9949 
E-mail: cdsu@octapharma.com 
24 hours emergency telephone number: +1 (844) 338-7317 or +43 1 40 80 500 
7.3.4 TEs, TEEs and Hyperfibrinolytic Events 
To allow continuous monitoring of the product's safety, all hyperfibrinolytic events, TEs and 
TEEs and other safety information as defined below must be documented and reported to 
Octapharma. All the above mentioned events will be reported regardless of severity or 
relatedness to the product. For this trial a “clinically relevant hyperfibrinolytic event” is 
defined by one of the following test results in the presence of a bleed that requires 
intervention. 
1. Kaolin TEG: estimated percentage lysis (EPL) > 7.5% at 30 min (after starting assay) 
2. ROTEM EXTEM: maximum lysis (ML) > 7.5% at 30 min (after starting assay) 
The following list includes diagnoses and symptoms of possible TEs and TEEs that could be 
expected to be reported: 
Acute myocardial infarction 
Increased heart enzymes* 
Electrocardiogram signs of myocardial infarction* 
Angina pectoris* 
Acute coronary syndrome* 

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Chest pain or pressure* 
Cardiac arrest** 
(Ischemic) Stroke 
Transient ischemic attack  
Cerebrovascular accident 
Vision or speech disorders* 
Unilateral paresis/weakness 
Movement disorders* 
Dysphasia* 
Sudden severe headache* 
Deep vein thrombosis 
Pain or tenderness in leg(s)* 
Pain in calf/calves* 
Swelling calf/calves/lower legs* 
Pulmonary embolism 
Unexplained shortness of breath* 
Sudden chest pain getting worse with a deep breath, coughing, or chest movement* 
Cyanosis* 
Thrombophlebitis 
Infusion site thrombosis 
* Possible sign or symptom of TEE 
** May be outcome of TEE 
To determine/confirm a TE or TEE the following adjudicators will be involved: 
Adjudicator 1 (Investigator) 
On the corresponding safety reporting form of the CRF, the Investigator is specifically asked 
if the reported event is a TE or TEE in his/her opinion. 
Adjudicator 2 (Octapharma Central Drug Safety Unit, CDSU) 
Once a TEE/TE is recorded on the CRF, the event will be forwarded to Octapharma's Drug 
Safety Unit who will process the TEE/TE in routine manner (including assessments of 
expectedness, causality, seriousness, TEE/TE classification of event). 
Adjudicator 3 (Independent Data Monitoring Committee, IDMC) 
The IDMC will receive anonymized case reports and/or lists of all reported adverse reactions. 
Serious cases, probably or possibly related and suspected TEEs/TEs (as determined by 
Adjudicator 1 and/or Adjudicator 2) will be reviewed on an ad-hoc basis; other cases like 
ADRs and not related SAEs will be reviewed on a quarterly basis. The IDMC will then vote 
on all new cases (simple majority), record their judgment and return their decisions back to 
data management. 
In case, the adjudicators disagree, the following scheme will be applied (Table 1):  
Table 1: 
Scheme of Decision for Adjudicators 
Determined as 
TEE/TE by 
Adjudicator 1? 
Determined as 
TEE/TE by 
Adjudicator 2? 
Determined as 
TEE/TE by 
Adjudicator 3? 
Determined as 
TEE/TE in database? 
Yes 
no 
no 
yes 
Yes 
yes 
no 
yes 

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No 
yes 
no 
yes 
No 
no 
yes 
yes 
No 
yes 
yes 
yes 
Yes 
no 
yes 
yes 
Abbreviations: TE=thrombotic event; TEE=thromboembolic event 
7.3.5 Laboratory Tests 
7.3.5.1 Determination of Blood Group 
The blood type will be clarified at Screening for determination of the patient’s ABO blood 
group type compatibility. 
7.3.5.2 Pregnancy Testing 
Pregnancy testing will be done pre-infusion for females ≥ 11 years old or of childbearing 
potential (if younger than 11 years old). Females must have a negative pregnancy test in order 
to be in the study. 
7.3.5.3 Laboratory Parameters2 
The following laboratory parameters (Table 2) will be tested to assess renal, hematologic and 
metabolic function. These tests must be drawn within a maximum of 6 hours before the start 
of the first infusion episode and within 60 minutes before the start of subsequent infusion 
episodes, as well as within 30 to 60 minutes after each infusion episode and at the Final 
Examination. If the patient requires priming of the cardiopulmonary bypass (CPB) circuit 
with plasma, the post-infusion episode samples should be drawn 30-60 minutes after reversal 
of heparin during the process of coming off CPB. 
Table 2: 
Laboratory Parameters 
Chem 7 panel 
CBC 
Ionized Calcium 
BUN 
WBC 
 
CO2 (bicarbonate) 
RBC 
 
Serum Chloride 
Hemoglobin 
 
Serum Creatinine 
Hematocrit 
 
Glucose 
MCV 
 
Serum Potassium 
MCH 
 
                                                 
 
2 The following blood volume limits for sampling are recommended: If an Investigator decides to deviate from 
these, this should be justified. NIH Clinical Center Guidelines for Blood Drawn for Research Purposes in the 
Clinical Center (M95-9) rev 06/05/2009: For pediatric patients, no more than 5 mL/kg may be drawn for 
research purposes in a single day, and no more than 9.5 mL/kg may be drawn over any eight-week period. 

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Serum Sodium 
MCHC 
 
 
RDW 
 
 
Platelets 
 
Abbreviations: BUN=blood urea nitrogen; MCH=Mean Corpuscular Hemoglobin; MCHC=Mean Corpuscular 
Hemoglobin Concentration; MCV=Mean Corpuscular Volume; RDW=Red Cell Distribution Width; 
WBC=White Blood Cell 
The following hemostatic parameters will be assessed (Table 3). 
Table 3: 
Hemostatic Parameters 
INR 
Please be aware that either 
TEG or ROTEM assessment 
is to be carried out 
PT 
aPTT 
TEG with Kaolin activation  
ROTEM EXTEM* 
Abbreviations: aPTT=Activated Partial Thromboplastin Time; INR=International Normalized Ratio; 
PT=Prothrombin Time; TEG=Thromboelastography; ROTEM=Thromboelastometry 
 
For all infusion episodes, the TEG sample results should be recorded if testing is performed 
(e.g., when evaluating a potential hyperfibrinolytic event, or other clinical reason for testing).  
The parameters to be recorded are: reaction time (R-time), time from the end of R until the 
clot reaches 20 mm (K-time), slope between R and K (alpha angle), maximum amplitude of 
clot strength (MA), and EPL at 30 minutes in order to be able to assess the occurrence of a 
potential hyperfibrinolytic event. Heparin may be present in the blood of patients undergoing 

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anticoagulation. If anticoagulation by heparin is known or suspected, heparinase must be used 
to neutralize its effect. Failure to neutralize heparin may result in a lack of significant clot 
formation, and inability to diagnose fibrinolysis. 
For all infusion episodes, the ROTEM with EXTEM assay test results should be recorded if 
testing is performed (e.g., when evaluating a potential hyperfibrinolytic event, or other 
clinical reason for testing). The following ROTEM test parameters (EXTEM) will be 
recorded: clotting time (CT), clot formation time (CFT), alpha angle, Maximum Clot 
Firmness (MCF), and ML at 30 minutes. 
Please be aware that is sufficient to either assess kaolin TEG or ROTEM EXTEM samples. 
 
In cases where the maximum blood volume drawn for lab testing becomes an issue, it is at the 
investigator’s discretion to determine which laboratory assessments he/she sees most 
necessary to be done with this limited amount of blood volume based on the best interest of 
the patients care. If the laboratory testing is being drawn strictly for the study, and no other 
laboratory testing is needed to manage the patient clinically at the time of the sampling then 
this is the general order of importance for this trial:  TEG/ROTEM, INR, PT, aPTT, Ionized 
Ca, Chem 7, CBC.  In situations where lab tests are omitted due to maximum blood volume 
restrictions per protocol, an explanation should be added to the source notes and eCRF 
describing this. 
The investigator classifies any result that is not within its respective normal result range as 
either clinically significant (CS) or not clinically significant (NCS). Medical judgement is 
required. For example, the investigator may not classify an abnormal result as CS unless it 
exceeds a certain level or appears in conjunction with other observations. An abnormal lab 

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value should be deemed clinically significant by the investigator if for instance either of the 
following conditions is met: 
• The abnormality suggests a disease and/or organ toxicity that is new or has worsened 
from baseline 
• The abnormality is of a degree that requires additional active management, e.g., 
change of dose, discontinuation of the drug, close observation, more frequent follow-
up assessments, of further diagnostic investigation. 
In the event of clinically significant abnormal laboratory findings, the tests will be repeated 
and followed-up until they have returned to normal and/or an adequate explanation is 
available. 
7.3.6 Physical Examination and Vital Signs 
At Screening, a physical examination will be performed. 
A physical examination will be performed in accordance with the site’s routine procedures. 
This may include examination of dermatological and lymphatic system, HEENT, respiratory 
tract, cardiovascular and gastrointestinal system, musculoskeletal system, and neurological 
system. 
Vital signs will include heart rate, respiratory rate, temperature, arterial saturation, and blood 
pressure assessment. Vitals should be assessed within a maximum of 6 hours before the start 
of the first infusion episode and within 60 minutes before the start of subsequent infusion 
episodes, as well as within 30 to 60 minutes after each infusion episode and at the Final 
Examination. If multiple vital sign assessments are taken before and/or after the infusion, the 
vital signs that are assessed closest before the start and after the end of each infusion should 
be recorded. 
7.3.7 Other Relevant Safety Information 
Post study related safety reports: Any ADR which occurs after the completion of the study 
should be reported by the Investigator. The usual procedure for reporting post marketing 
safety information should be followed, but relation to the clinical study should be stated on 
the report. 
If the Investigator becomes aware that a patient has died within four (4) weeks after the last 
IMP administration, this should be reported as well, without being considered treatment 
related or not. 
Pregnancies: Every effort will be made to avoid a pregnancy during the use of an IMP. 
Pregnancies occurring during the study (fetal exposure to the IMP) need to be reported.  
In case of pregnancy during the study, the Investigator is asked to complete the pregnancy 
notification form and to send it (by fax) to the CPM / designee. 
Follow-up information on the outcome of both mother and fetus will be requested by a 
Sponsor representative. 
Overdose, interaction, abuse, misuse and medication error: 
The following safety relevant information should be reported as an ADR or, if the reaction 
fulfils one of the criteria for seriousness, as a SADR. 

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Drug overdose: An overdose is a deliberate or inadvertent administration of a treatment at a 
dose higher than that specified in the protocol, and higher than the known therapeutic dose 
and of clinical relevance. The reaction must be clearly identified as an overdose. Due to the 
study design, no overdose is expected. 
Interaction: A drug interaction is a situation in which a substance/medicinal product affects 
the activity of an IMP, i.e., the effects are increased or decreased, or they produce an effect 
that none of the products exhibits on its own. The reaction must be clearly identified as drug 
interaction. 
Abuse: An abuse is the deliberate use of a medicinal product that may lead to addiction 
accompanied by harmful physical or psychological effects. This is not relevant for the IMP 
but may be applicable for concomitant medications. 
Misuse: Misuse is the deliberate administration or use of the medicinal product outside its 
described indication or outside the current state of the art medical practice (off-label-use). The 
reaction must be clearly identified as misuse. 
Medication error: 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 and instructions for use/labeling. The reaction must be clearly identified as a 
medication error.  
7.4 
Appropriateness of Measurements 
Only standardized measurements that are widely used and generally recognized as reliable, 
accurate, and relevant will be used in this study.  
8 
DATA HANDLING AND RECORD KEEPING 
8.1 
Documentation of Data 
Source Data and Records 
Source data are defined as all the information related to clinical findings, observations, or 
other activities in the study, written down in original records or certified copies of original 
records allowing reconstruction and evaluation of the clinical study. 
The Investigator will maintain adequate source records (e.g., 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 
participates in this study. 
The Investigator will permit study-related monitoring, audit(s), IEC/IRB review(s) and 
regulatory inspection(s), by providing direct access to source data/records. 
Case Report Forms 
The Sponsor will provide the CRFs in electronic format. They will be reviewed against source 
documentation at each monitoring visit. The Investigator should allocate sufficient time and 
space for the review and correction process.  

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For each patient enrolled, an electronic CRF (eCRF) will be completed within the Electronic 
Data Capture (EDC) system and approved by the Investigator or an authorized sub-
investigator.  
Study site staff (e.g., research nurse) will be responsible for entering all of the patient data 
into the validated EDC system. All site personnel will be trained on the EDC system and 
study specific eCRFs prior to receiving access to the live database for data entry, as defined in 
applicable SOPs. The site is also provided with the approved eCRF Completion Guidelines 
which will assist in data entry and data issues/questions. The site will be notified once the 
database 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 
appear on the delegation of authority log. 
If any errors in the eCRFs are found during the data review process, discrepancies will be 
generated programmatically within the EDC system, and ‘manual’ queries will be generated 
by either a monitor or Data Management. The programmed checks fire automatically once an 
eCRF page is saved within the system. The output of the programmed checks is referred to as 
‘discrepancies’. Discrepancies are generated by the input of illogical eCRF data. The purpose 
of these objects is to clarify the use, context, or insertion of illogical or missing data with the 
site or designee. 
All discrepancies (programmed and manual) will be submitted to the site personnel or monitor 
for the site within the EDC system. Once the site responds to a discrepancy, Data 
Management or the monitor will review the new or changed data to ensure an appropriate 
response and close the discrepancy within the system. The Investigator should ensure the 
accuracy, completeness and timeliness of the data reported to the Sponsor in the CRFs and in 
all required reports. 
Changes to Case Report Form Data 
Errors occurring in the EDC system can only be corrected by the Investigator(s) or other site 
personnel. An audit trail documents all changes to the data over the entire study period. If data 
is changed as a result of a query, a comment must be supplied within the query’s text, stating 
the reason for the change, prior to closing. The study monitor should provide guidance to 
investigators and the investigators’ designated representatives on making such corrections. In 
addition, any changes to a previously saved eCRF page that has not had a query generated 
will need to have a reason specified for the data change. This is handled within the EDC 
system and relevant prompts appear once any changes are made. 
Once queries have been resolved by the site staff, the resolutions are assessed by Data 
Management for incomplete or ambiguous resolutions. If the query response provided 
confirms the data as correct, the discrepancy will be closed based on the query response. If the 
response does not adequately address the question raised, a new query will be issued for 
further clarification. 
Manual checks are performed and programs are 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 
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All corrections on a CRF and on the source documents must be made in a way that does not 
obscure the original data. The correct data must be inserted, dated and initialed/authorized by 
trial site personnel. If reason for the change is not obvious, then a reason should be given. The 
Principal Investigator must, at a minimum, sign the final CRF page to attest to the accuracy 
and completeness of all the data. Once the data have been entered into the database, they will 
be checked and any discrepancies will be raised and returned to the Investigator for 
resolution. Data will be monitored and tabulated in accordance with the Data Management 
Plan. 
8.2 
Information of Investigators 
An IB will be handed out to the Investigator before the start of the study. This 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 in case new information 
concerning the IMP becomes available. 
The Investigator will be kept informed of important data that relate to the safe use of the IMP 
as the study proceeds. 
8.3 
Responsibilities 
The Investigator is accountable for the conduct of the clinical study. If any responsibilities are 
delegated, the Investigator should maintain a list of appropriately qualified persons to whom 
he/she has delegated significant study-related duties. 
The Investigator may authorize site staff (e.g., sub-investigators, nurses) to enter study data 
into the CRF. This must be documented in the “Delegation of Authority Log“, filled in and 
signed by the Investigator responsible.  
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 (e.g., copies of the protocol, study approval letters, all original 
informed consent forms, site copies of all CRFs, drug dispensing and accountability logs, 
correspondence pertaining to the study, etc.) 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 CRF 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. 

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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 CRFs are illegible or when errors in data transcription are 
encountered. In case 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 (IDMC) 
An IDMC will be established by the Sponsor. The IDMC will be composed of recognized 
experts in the field of hematology, transfusion medicine, immunology, pediatric surgery 
and/or pediatric critical care who are not actively recruiting patients. 
The IDMC will review relevant quarterly safety line listings and SADR narratives 
periodically during the study and will give advice on the continuation, modification or 
termination of the study. A study specific Standard Operating Procedure will define in detail 
the composition, responsibilities and procedures of the IDMC. 
9 
STATISTICAL METHODS AND SAMPLE SIZE 
The statistical analysis will be delegated under an agreement of transfer of responsibilities to 
an external Contract Research Organization (CRO). All Octapharma procedures and policies 
have to be met by this CRO. Discrepancies or exceptions are to be approved by the Sponsor's 
Manager of Biometrics. 
9.1 
Determination of Sample Size 
A total of 50 pediatric patients are planned to be treated. The following number of patients is 
planned to be enrolled: 
1. Neonates/Infants (0-2 years): a maximum of 33 patients 
2. Children > 2 years and ≤ 16 years: a minimum of 17 patients   
The primary purpose of this study is to assess safety and tolerability of Octaplas in the 
pediatric population by monitoring ADRs, TEs, TEEs and hyperfibrinolytic events, including 
relevant laboratory parameters. All data collected will be explored in full detail and no single 
parameter or measurement of outcome is chosen as the primary endpoint, and no statistical 
hypothesis is to be tested.  
9.2 
Statistical Analysis 
A formal statistical analysis plan describing all details of the descriptive and explorative 
analyses to be performed will be prepared by the study statistician and approved by the 
Sponsor prior to the start of the statistical analysis. 
Due to the complex and highly variable and individual medical circumstances and 
interventions that are to be expected in this study, no single parameter or measurement of 
outcome is chosen as the primary endpoint. All data collected will be summarized and 
presented descriptively to facilitate the review of population homogeneity and general 

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patterns within and between patients of similar baseline characteristics or disease patterns. No 
confirmatory hypothesis testing is planned. Any p-value or confidence interval presented is to 
be understood in the exploratory sense. 
To allow a holistic review and interpretation of each course of treatment all parameters 
relevant for the assessment of safety will be presented descriptively in full detail, by 
subgroups of interest as well as in total. The safety assessment will include the occurrence of 
all SAEs, ADRs, TEs, TEEs, and hyperfibrinolytic events. To facilitate the detection of any 
possible safety signal, all these events will be characterized and analyzed by underlying 
diagnosis, seriousness, severity, relation to study drug and timely relationship to study drug 
administration. In addition to these pre-planned categories, the collected data will be 
examined to identify additional characteristics of interest such as particular types of surgeries, 
relevant concomitant medications, or Standardized MedDRA Queries (SMQs) covering a 
noticeable number of events. The occurrences of all specific safety events will be presented 
for all these categories and in total, together with the associated 95% confidence intervals. 
To account for the abovementioned diversity in the study population, individual patient 
profiles or tabulations will be generated, displaying the baseline characteristics as well as all 
interventions, treatment details and measurements on a time scale. This will facilitate the 
review of each individual course of treatment by the trial medical monitor or expert to assess 
the efficacy of the treatment but also to detect any safety signal that might not be reflected in 
the ADR rates. 
Hemostatic parameters will be presented descriptively per time point, including shift tables. 
Individual courses of hemostatic parameters will be presented graphically as Trellis plots. 
Vital sign measurements will be summarized by descriptive statistics, including shift tables. 
All measurements outside age-specific thresholds will be listed and reviewed individually. 
All safety laboratory data – absolute values as well as changes from baseline – will be 
presented descriptively per time point. All measurements outside age-specific thresholds will 
be listed and reviewed individually. 
All data will be presented in total as well as in sub–groups reflecting age (≤ and > 2 years 
respectively), gender, underlying diagnosis, surgical procedures performed and/or most 
relevant medical history and concomitant medications. 
Population for Analysis 
The Safety (SAF) population will include all patients who received at least one infusion of 
Octaplas. 
The full analysis set (FAS) is defined according to the intent-to-treat (ITT) principle and will 
include all patients of the SAF with any measurements on the primary endpoint variables 
(monitored for ADRs, hemostatic parameters, safety laboratory parameters, vital signs, etc.).  
Patients who are consented (enrolled) to participate prior to an operative procedure and then 
did not get transfused will not be included in the ITT analysis.  
The per-protocol (PP) population will include all patients who have completed the infusion 
episode(s) and the final examination without major protocol deviations, which may have an 
impact on the evaluation of the primary study outcome parameter(s). Examples of protocol 
deviations to be considered in this respect would be dosing errors, the use of prohibited 
concomitant medications, or the occurrence of completely unrelated medical events that 

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require an interruption of the study procedures. The final decision regarding 
inclusion/exclusion of patients from the analysis sets will be taken by a panel including the 
CPM, the study statistician and a medical expert during a data review meeting before database 
lock. The decisions taken will be based on a review of complete data listings, and documented 
before the database is locked and the analysis is performed. 
Efficacy Analysis Plan 
The analysis of the efficacy parameters will be performed for the ITT and PP populations. 
Hemostatic parameters will be presented descriptively per time point, including shift tables. 
Individual courses of hemostatic parameters will be presented graphically as Trellis plots. 
Adjustments for Covariates 
Adjustments for covariates will be discussed in the SAP. 
Data Presentation 
In addition to the sampling statistics of the measurements, graphs showing the time profiles at 
the individual patient and group mean levels will be presented. 
Safety Analysis Plan 
The analysis of the safety parameters will be performed for the SAF population. 
The occurrence of SAEs, ADRs, TEs, TEEs and significant hyperfibrinolytic events will be 
reported. All these events will be characterized and analyzed by underlying diagnosis, 
seriousness, severity, relation to study drug and timely relationship to study drug 
administration. Subgroup analyses will be conducted for hyperfibrinolytic events in patients 
who undergo liver transplant. 
All safety laboratory data – absolute values as well as changes from baseline – will be 
presented descriptively per time point. All measurements outside age-specific thresholds will 
be listed and reviewed individually. 
All data will be presented in total as well as in sub–groups reflecting age (≤ and > 2years), 
gender, underlying diagnosis, surgical procedures performed and/or most relevant medical 
history and concomitant medications. 
9.3 
Randomization / Stratification / Code Release 
Not applicable. 
9.4 
Interim Analysis (if Applicable) 
No interim analysis is planned. 
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 

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submitted to an IEC/IRB and to the Regulatory Authority. The study will be conducted in 
compliance with the protocol, GCP regulations and applicable regulatory requirements. 
The submission for regulatory approval will be made by the Sponsor or designated third party 
(e.g., 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, any other 
materials provided to the patients, and further requested information will be submitted by the 
Sponsor or the Investigator to the appropriate IEC/IRB and the Regulatory Authority. The 
study approval letter must be available before any patient is exposed to a study-related 
procedure. 
The Sponsor, the Investigator and any third party (e.g., 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/Assent 
The Investigator will obtain freely given written consent from each patient’s legal 
representatives or guardians 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’s legal representatives or guardians, before the patient is exposed to 
any study-related procedure, including screening tests for eligibility. 
Children deemed old enough by the Investigator/institution to understand the risks and 
benefits of the study should also be made aware of the risks/benefits of the study and provide 
written assent. 
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 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. 
10.4 Protocol Amendments 
Any prospective change to the protocol will be agreed between the Investigator (coordinating 
investigator in multi-center studies) and the Sponsor prior to its implementation. Any such 
amendments will be submitted to the IEC(s)/IRB(s) 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 
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10.5 Confidentiality of Patients’ Data 
The Investigator will ensure that the patient's confidentiality is preserved. On CRFs or any 
other documents submitted to the Sponsor, the patients will not be identified by their names, 
but by a unique patient number. Documents not for submission to the Sponsor, i.e., the 
confidential subject identification code list, original informed consent forms and source 
records will be maintained by the Investigator in strict confidence. 
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. 
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 CRFs, 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 effectiveness of the IMP have been reported to the Sponsor. 
12 REPORTING AND PUBLICATION 
12.1 Clinical Study Report 
A clinical study report (in accordance with relevant guidelines and Sponsor’s SOPs) will be 
prepared by the Sponsor after the completion of the study. The coordinating 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 this is 
envisaged by an Investigator, the Investigator agrees to inform the Sponsor and to submit all 
manuscripts or abstracts to the Sponsor prior to 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. 

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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. 
13 LIABILITIES AND INSURANCE 
In order to cover any potential damage or injury occurring to a patient in association with the 
IMP or the participation in the study, Octapharma will contract insurance in accordance with 
local regulations. 
The Investigator is responsible for dispensing the IMP according to this protocol, and for its 
secure storage and safe handling throughout the study. 
14 REFERENCES 
1. Rollag H, Solheim BG, Svennevig JL: Viral safety of blood derivatives by immune 
neutralization. Vox Sang 1998; 74 Suppl 1: 213-217. 
2. Octaplas. Annotated prescribing information. Octapharma. Hoboken, New Jersey, 
USA. 

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15 APPENDICES 
15.1 Appendix 1: Octaplas Package Insert 
 

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