Clinical Phase 3 Study to Evaluate the Efficacy, Tolerability and Safety of Subcutaneous Human Immunoglobulin (Octanorm) in Patients With Primary Immunodeficiency Diseases.
Phase: PHASE3
Conditions: Primary Immune Deficiency Disorder
Sponsor: Octapharma

 
This document contains confidential and proprietary information of Octapharma AG. 
Do not copy or distribute without written permission. 
SCGAM-04 CSP_V2_30Nov2016_/DOC ID 2530 
 
CLINICAL STUDY PROTOCOL 
CLINICAL PHASE 3 STUDY TO EVALUATE THE 
EFFICACY, TOLERABILITY AND SAFETY OF 
SUBCUTANEOUS HUMAN IMMUNOGLOBULIN 
(OCTANORM) IN PATIENTS WITH PRIMARY 
IMMUNODEFICIENCY DISEASES 
 
 
Investigational Product: 
octanorm 
Indication: 
Primary Immunodeficiency Diseases 
Study Design: 
Prospective, open-label, non-controlled, single-arm, 
multicentre phase 3 study 
Sponsor: 
OCTAPHARMA Pharmazeutika Prod.Ges.m.b.H., 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
Study Number: 
SCGAM-04 
EudraCT Number: 
2016-003230-24 
Development Phase: 
Phase 3 
Planned Clinical Start: 
Q2 2017 
Planned Clinical End: 
Q3 2018 
Date of Protocol: 
30-Nov-2016 
Version: 
02 
Co-ordinating Investigator 
Not applicable 
 
 
 
 
 
 

Study Protocol No. SCGAM-04, Version 02 CONFIDENTIAL 
30-Nov-2016 
 
Page 2 of 59 
STUDY OUTLINE  
Name of Sponsor/Company: 
OCTAPHARMA Pharmazeutika Prod.Ges.m.b.H., Oberlaaer Strasse 235, 1100 Vienna, Austria 
Name of Investigational Product: 
octanorm 
Protocol Identification Code: 
SCGAM-04 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Date of Final Protocol: 
30-Nov-2016 
 
Title of Study: 
Clinical phase 3 study to evaluate the efficacy, tolerability and safety of subcutaneous human 
immunoglobulin (octanorm) in patients with primary immunodeficiency diseases. 
Indication: 
Primary immunodeficiency (PI) diseases. 
Number of Study Centre(s): 
Approximately 5 study sites in Russia. 
Objectives: 
• To evaluate the efficacy of octanorm in preventing serious bacterial infections (SBI) 
compared with historical control data. 
• To evaluate the tolerability and safety of octanorm. 
Study Design: 
The study is a prospective, open-label, non-controlled, single-arm, multicentre phase 3 study 
with an 8-week wash-in/wash-out period followed by a 6-month efficacy period. 
Number of Patients: 
Approximately 20 to 25 patients who comply with the inclusion and Non-Inclusion Criteria 
will be enrolled into the study. 
Patient Selection Criteria: 
Inclusion Criteria: 
1. Age of ≥18 years and ≤70 years. 
2. Confirmed diagnosis of PI requiring immunoglobulin replacement therapy due to 
hypogammaglobulinaemia or agammaglobulinaemia. The type of PI should be 
recorded. 
3. Patients with at least 4 infusions on regular treatment with any Intravenous 
Immunoglobulin (IVIG) prior to entering the study. Constant IVIG dose between 200 
and 800 mg/kg body weight (the individual doses of the last 4 infusions should not 

Study Protocol No. SCGAM-04, Version 02 CONFIDENTIAL 
30-Nov-2016 
 
Page 3 of 59 
Name of Sponsor/Company: 
OCTAPHARMA Pharmazeutika Prod.Ges.m.b.H., Oberlaaer Strasse 235, 1100 Vienna, Austria 
Name of Investigational Product: 
octanorm 
Protocol Identification Code: 
SCGAM-04 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Date of Final Protocol: 
30-Nov-2016 
 
vary by more than ±25% of the mean dose for the last 4 infusions). 
4. Availability of at least 2 IgG trough levels with an IgG level of ≥5.0 g/L from the 
period of the last 4 IVIG infusions. 
5. Negative result on a pregnancy test (Human Chorionic Gonadotrophin [HCG]-based 
assay in urine) for women of childbearing potential and use of a reliable method of 
contraception for the duration of the study. Women of non-childbearing potential must 
be post-menopausal (amenorrhoeic for at least 12 months) or surgically sterile. 
Examples for medically acceptable methods of birth control for this study include:  
– Oral, implantable, transdermal or injectable contraceptives 
– Intrauterine device 
– Condoms; diaphragm or vaginal ring with spermicidal jellies or cream 
– Sexual abstinence 
– Vasectomised partner 
6. Patient must freely give written informed consent.  
7. Willingness to comply with all aspects of the protocol, including blood sampling, for 
the duration of the study. 
Non-Inclusion Criteria: 
1. Acute infection requiring intravenous (IV) antibiotic treatment within 2 weeks prior to 
and during the screening period. 
2. Known history of adverse reactions to Immunoglobulin A in other products. 
3. Patients with body mass index >40 kg/m2. 
4. Exposure to blood or any blood product or plasma derivatives, other than IVIG 
treatment of PI, within the past 3 months prior to first infusion of octanorm. 
5. Ongoing history of hypersensitivity or persistent reactions to blood or plasma derived 
products, or any component of the investigational medicinal product (IMP) (such as 
Polysorbate 80). 
6. History of malignancies of lymphoid cells and immunodeficiency with lymphoma. 
7. Severe liver function impairment (ALAT 3 times above upper limit of normal). 
8. Known protein-losing enteropathies or proteinuria. 
9. Presence of renal function impairment (creatinine >120 µM/L or creatinine 
>1.35 mg/dL), or predisposition for acute renal failure (e.g., any degree of pre-existing 
renal insufficiency or routine treatment with known nephritic drugs). 
10. Treatment with enteral or parenteral steroids for ≥30 days or when given intermittently 

Study Protocol No. SCGAM-04, Version 02 CONFIDENTIAL 
30-Nov-2016 
 
Page 4 of 59 
Name of Sponsor/Company: 
OCTAPHARMA Pharmazeutika Prod.Ges.m.b.H., Oberlaaer Strasse 235, 1100 Vienna, Austria 
Name of Investigational Product: 
octanorm 
Protocol Identification Code: 
SCGAM-04 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Date of Final Protocol: 
30-Nov-2016 
 
or as bolus, at daily doses ≥0.15 mg/kg. Inhaled corticosteroids are allowed. 
11. Patients with chronic obstructive pulmonary disease (COPD) stage Global Initiative 
for Chronic Obstructive Lung Disease (GOLD) III or IV. 
12. Treatment with immunosuppressive drugs. 
13. Live viral vaccination (such as measles, rubella, mumps and varicella) within the last 
2 months prior to first infusion of octanorm. 
14. Treatment with any IMP within 3 months prior to first infusion of octanorm. 
15. Presence of any condition that is likely to interfere with the evaluation of study 
medication or satisfactory conduct of the trial. 
16. Known or suspected to abuse alcohol, drugs, psychotropic agents or other chemicals 
within the past 12 months prior to first infusion of octanorm. 
17. Known or suspected human immunodeficiency virus (HIV), hepatitis C virus (HCV), 
or hepatitis B virus (HBV) infection. 
18. Pregnant or nursing women; planned pregnancy during course of the study. 
Test Product, Dose, and Mode of Administration: 
octanorm, human normal immunoglobulin for subcutaneous (SC) administration. 
octanorm has to be administered subcutaneously every week (±2 days). 
The dose will be calculated as follows: 
last IVIG dose (in grams) 
number of weeks between IVIG doses 
If, during the study, the body weight changes by >5% from baseline (Visit 2), the dose is to 
be adjusted to keep the dose constant on a milligram per kilogram body weight basis.  
The dose can also be adjusted if trough levels of IgG during the study are <5 g/L or if there is 
a clinical need for octanorm dose adjustment. 
Duration of Treatment: 
Each patient who stays in the study for the whole period will receive 32 weekly SC infusions 
of octanorm. 
Reference Therapy, Dose, Mode of Administration, 
Not applicable. 

Study Protocol No. SCGAM-04, Version 02 CONFIDENTIAL 
30-Nov-2016 
 
Page 5 of 59 
Name of Sponsor/Company: 
OCTAPHARMA Pharmazeutika Prod.Ges.m.b.H., Oberlaaer Strasse 235, 1100 Vienna, Austria 
Name of Investigational Product: 
octanorm 
Protocol Identification Code: 
SCGAM-04 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Date of Final Protocol: 
30-Nov-2016 
 
Study Outcome Parameters (Primary and Secondary Endpoints): 
Efficacy Parameters: 
The primary efficacy endpoint is the rate of SBI (defined as bacteraemia/sepsis, bacterial 
meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess) per 
person-year on treatment. 
Secondary efficacy endpoints are: 
• The annual rate of all infections of any kind or seriousness. 
• Non-serious infections (total and by category). 
• Time to resolution of infections. 
• Use of antibiotics (number of days and annual rate). 
• Hospitalisations due to infection (number of days and annual rate). 
• Episodes of fever. 
• Days missed from work/study due to infections and their treatment. 
• Quality of life (QoL) assessment using the SF-36 Health Survey. 
• Trough levels of serum total IgG throughout the study. 
Safety Parameters: 
• Occurrence of all treatment emergent AEs (TEAEs) throughout the entire treatment 
period starting with the first infusion of IMP. 
• Proportion of infusions with at least 1 temporally associated AE. 
• Occurrence of adverse drug reactions (ADRs). 
• Local injection site reactions. 
• Vital signs (blood pressure, pulse, body temperature, respiratory rate). 
• Laboratory parameters (haematology, clinical chemistry, and viral status). 
Study Procedures: 
The study consists of a Screening Period (up to 7 weeks) that starts with the signing of the 
informed consent form, an 8-week wash-in/wash-out period followed by a 6-month efficacy 
period. Only patients previously on IVIG treatment may be enrolled. Each patient who stays 
in the study for the whole period will receive 32 octanorm SC weekly infusions. The final 
examinations will be performed 1 week after the end of the last infusion, or 1 week after 
premature withdrawal of the patient from the study, with a telephone follow-up 3 weeks later. 
The total duration of the study for an individual patient will be about 43 weeks (depending on 

Study Protocol No. SCGAM-04, Version 02 CONFIDENTIAL 
30-Nov-2016 
 
Page 6 of 59 
Name of Sponsor/Company: 
OCTAPHARMA Pharmazeutika Prod.Ges.m.b.H., Oberlaaer Strasse 235, 1100 Vienna, Austria 
Name of Investigational Product: 
octanorm 
Protocol Identification Code: 
SCGAM-04 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Date of Final Protocol: 
30-Nov-2016 
 
the IVIG treatment schedule before enrolment). 
Site staff will be trained by the Sponsor in the use of the SC pump. Patients have to be trained 
at the study site (for at least 4 infusions). Thereafter, the patient may continue with octanorm 
infusions at home. Every 4 weeks the infusion is to be given at the study site. A 6-week 
interval may be acceptable exceptionally (e.g., in case of vacation). 
Before starting home treatment, a diary will be provided to the patients for documenting the 
date, volume and speed of infusion, occurrence of infections, AEs and local tissue reactions at 
injection sites, missed days from work/study, inpatient hospital stays, and any changes in 
concomitant therapies between visits. 
Refer to Table 1 for the timings of the interventions and activities during the visits taking 
place at the study site. 
Statistical Analysis Plan: 
A formal statistical analysis plan (SAP) describing all details of the analyses to be performed 
will be prepared by the study statistician and approved by the sponsor before the start of the 
statistical analysis. The following analysis populations will be defined: safety set, full analysis 
set, and per-protocol set. 
Occurrences of SBI and other infections will be presented as absolute numbers and as point 
estimates of the mean rates per person-year. Days of work/study missed, number and days of 
hospitalisations due to infections, the use of antibiotics, number of episodes of fever and QoL 
data will be presented descriptively. 
Trough levels of IgG will be summarised by infusion number and presented graphically as 
time profiles. 
AE rates will be calculated with respect to severity and relationship to IMP administration. 
Short term tolerance parameters (blood pressure, heart rate, temperature, respiratory rate) and 
safety laboratory parameters (haematology, clinical chemistry, and urinalysis) will be 
evaluated and presented descriptively. For categorical parameters frequency tables will be 
presented, whereas appropriate sample statistics will be presented for continuous parameters. 
 
 
 

Study Protocol No. SCGAM-04, Version 02 CONFIDENTIAL 
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Page 7 of 59 
FLOW CHART OF ASSESSMENTS 
Table 1: 
Flow Chart of Assessments Performed Throughout the Study 
ASSESSMENTS 
Screen-
ing 
Weekly octanorm Infusions  
Termin-
ation 
Follow-
up 
 
Wash-in/wash-out period 
Efficacy period 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
Phone 
call 
WEEK 
up to −7 
1 
2 
3 
4 
8 
12 
16 
20 
24 
28 
32 
33 
36 
Informed consent (Screening will start once informed consent is 
obtained)  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria (see Section 4.1) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic & baseline characteristics (see Section 7.1) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and prior medication (see Section 7.1) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Chest x-ray1 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Physical examination (see Section 7.3.7) 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
x 
 
Vital signs(see Section 7.3.7) 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
x 
 
IgG trough levels2 (pre-infusion during octanorm treatment) 
x3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
Haematology2(pre-infusion during octanorm treatment) 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
x 
 
Clinical Chemistry2 (pre-infusion during octanorm treatment) 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
x 
 
Urine analysis: pH, glucose, ketones, leukocytes2 
x 
x 
 
 
x 
 
 
x 
 
 
x 
 
x 
 
Viral markers: NAT: HAV, HBV, HCV, HIV, parvovirus B194 
x 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
Urine pregnancy test (in females of childbearing potential) 
x 
 
 
 
 
 
 
x 
 
 
 
 
x 
 
Infusion of IMP (on site) 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Local injection site reaction 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
Patient diary check 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 
QoL questionnaire 
 
x 
 
 
 
 
 
 
 
 
 
 
x 
 
Adverse event (AE) monitoring (see Section 7.3.2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication (see Section 4.2) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Only if last available chest X-ray (or CT or MRI) is older than 12 months. 
2 Local laboratory; see Section 7.3.6.2. Haematology: complete blood count, WBC differential, haematocrit, haemoglobin; Clinical chemistry: sodium, potassium, glucose, ALAT, ASAT, 
LDH, total bilirubin, blood urea nitrogen or urea, creatinine 
3 Only for those patients who have their last IVIG infusion during the Screening Period. 
4 Local or central laboratory; see Section 7.3.6.1. Additional retention samples will be drawn and shipped to central laboratory at Visit 2 and Termination visit.

Study Protocol No. SCGAM-04, Version 02 CONFIDENTIAL 
30-Nov-2016 
PROTOCOL SIGNATURES 
Signature of the Sponsor's Representatives 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and the ap licable regulatory requirements. 
Wolfgang Frenzel, MD 
International Medical Director 
on behalf of the Sponsor 
Octapharma Pharmazeutika Produktionsgesellschaft mbH 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
Tel: +43 (0) 1 61032-1201 
wolfgang.frenzel@octapharma.com 
FRENZEL 
3 0. NOV. 2016 
ignature 
Date 
Signature of the Author of the Protocol/Clinical Project Manager 
This study is intended to be conducted in compliance with the protocol, Good Clinical 
Practice and applicable regulatory requirements. 
Eva Turpel-Kantor, MD 
Deputy International Medical Director 
Octapharma Pharmazeutika Produktionsgesellschaft mb 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
Tel: +43 (0) 1 61032-1798 
eva. turpel-kantor@octapharma.com 
Page 8 of 59 
Date 

Study Protocol No. SCGAM-04, Version 02 CONFIDENTIAL 
Signature of the Biostatistician 
Laurenz Trawnicek, MSc 
Manager Biometrics 
Signature 
Octapharma Pharmazeutika Produktionsgesellschaft mbH 
Oberlaaerstr. 235, A-1100 Vienna, Austria 
Tel: +43 (0) 1 61032-1827 
laurenz. trawnicek@octapharma.com 
Page 9 of 59 
30-Nov-2016 
3o -N?Jv-.zo,6 
Date 

Study Protocol No. SCGAM-04, Version 02 CONFIDENTIAL 
30-Nov-2016 
 
Page 10 of 59 
TABLE OF CONTENTS 
STUDY OUTLINE .................................................................................................................................2 
FLOW CHART OF ASSESSMENTS ..................................................................................................7 
PROTOCOL SIGNATURES ................................................................................................................8 
TABLE OF CONTENTS .....................................................................................................................10 
LIST OF ABBREVIATIONS ..............................................................................................................13 
1 
INTRODUCTION .......................................................................................................................14 
1.1 
RATIONALE FOR CONDUCTING THE STUDY ............................................................. 16 
1.2 
DOSE RATIONALE ................................................................................................... 17 
1.3 
BENEFIT-RISK STATEMENT..................................................................................... 17 
2 
STUDY OBJECTIVES ...............................................................................................................19 
3 
INVESTIGATIONAL PLAN .....................................................................................................20 
3.1 
PRIMARY AND SECONDARY ENDPOINTS ................................................................. 20 
3.1.1 
Primary Endpoint .................................................................................................20 
3.1.2 
Secondary Endpoints ............................................................................................20 
3.2 
OVERALL STUDY DESIGN AND PLAN ...................................................................... 20 
3.3 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP ........................ 22 
3.3.1 
Study Design .........................................................................................................22 
3.3.2 
Control Group ......................................................................................................22 
3.3.3 
Study Parameters ..................................................................................................22 
4 
STUDY POPULATION ..............................................................................................................23 
4.1 
POPULATION BASE ................................................................................................. 23 
4.1.1 
Inclusion Criteria ..................................................................................................23 
4.1.2 
Non-Inclusion Criteria ..........................................................................................23 
4.2 
PRIOR AND CONCOMITANT THERAPY ..................................................................... 24 
4.2.1 
Permitted Concomitant Therapy ...........................................................................24 
4.2.2 
Forbidden Concomitant Therapy ..........................................................................24 
4.3 
WITHDRAWAL AND REPLACEMENT OF PATIENTS ................................................... 25 
4.3.1 
Premature Patient Withdrawal .............................................................................25 
4.3.2 
Patient Replacement Policy ..................................................................................25 
4.4 
ASSIGNMENT OF PATIENTS TO TREATMENT GROUPS .............................................. 26 
4.5 
RELEVANT PROTOCOL DEVIATIONS ....................................................................... 26 
4.6 
SUBSEQUENT THERAPY .......................................................................................... 26 
5 
INVESTIGATIONAL MEDICINAL PRODUCT ...................................................................27 
5.1 
CHARACTERISATION OF INVESTIGATIONAL PRODUCT ............................................ 27 
5.2 
PACKAGING AND LABELLING ................................................................................. 27 
5.3 
CONDITIONS FOR STORAGE AND USE...................................................................... 28 
5.4 
DOSE AND DOSING SCHEDULE ................................................................................ 28 
5.5 
PREPARATION AND METHOD OF ADMINISTRATION ................................................. 28 
5.6 
BLINDING, EMERGENCY ENVELOPES, AND BREAKING THE STUDY BLIND .............. 29 
5.7 
TREATMENT COMPLIANCE ...................................................................................... 30 

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5.7.1 
Drug Dispensing and Accountability ....................................................................30 
5.7.2 
Assessment of Treatment Compliance ..................................................................30 
6 
STUDY CONDUCT ....................................................................................................................31 
6.1 
OBSERVATIONS BY VISIT ........................................................................................ 31 
6.1.1 
Screening Visit (Visit 1) ........................................................................................31 
6.1.2 
Treatment Visits ....................................................................................................31 
6.1.3 
Study Termination Visit (Visit 13, Week 33) .........................................................32 
6.1.4 
Follow-up Phone Call (Week 36) .........................................................................33 
6.1.5 
Time Windows Used in this Study, including Tolerances .....................................33 
6.2 
DURATION OF STUDY ............................................................................................. 33 
6.2.1 
Planned Duration for an Individual Patient .........................................................33 
6.2.2 
Planned Duration for the Study as a Whole .........................................................33 
6.2.3 
Premature Termination of the Study .....................................................................34 
7 
ASSESSMENTS AND METHODS ...........................................................................................35 
7.1 
DEMOGRAPHIC AND BASELINE INFORMATION ........................................................ 35 
7.2 
EFFICACY ASSESSMENTS ........................................................................................ 35 
7.2.1 
Serious Bacterial Infections ..................................................................................36 
7.3 
SAFETY ASSESSMENTS ........................................................................................... 38 
7.3.1 
Assessments for Safety Endpoints .........................................................................38 
7.3.2 
Adverse Events (AEs) ............................................................................................38 
7.3.3 
Serious Adverse Events (SAEs) .............................................................................41 
7.3.4 
SAE Reporting Timelines ......................................................................................41 
7.3.5 
Local Infusion Site Reactions ...............................................................................42 
7.3.6 
Laboratory Tests ...................................................................................................42 
7.3.7 
Vital Signs and Physical Examination ..................................................................44 
7.3.8 
Other Relevant Safety Information .......................................................................44 
7.4 
OTHER ASSESSMENTS ............................................................................................. 45 
7.4.1 
Quality of Life Assessment ....................................................................................45 
7.5 
APPROPRIATENESS OF MEASUREMENTS ................................................................. 45 
8 
DATA HANDLING AND RECORD KEEPING......................................................................46 
8.1 
DOCUMENTATION OF DATA .................................................................................... 46 
8.1.1 
Source Data and Records .....................................................................................46 
8.1.2 
Case Report Forms ...............................................................................................46 
8.1.3 
Changes to Case Report Form (CRF) Data .........................................................46 
8.2 
INFORMATION TO INVESTIGATORS .......................................................................... 47 
8.3 
RESPONSIBILITIES ................................................................................................... 47 
8.4 
INVESTIGATOR’S SITE FILE ..................................................................................... 47 
8.5 
PROVISION OF ADDITIONAL INFORMATION ............................................................. 48 
8.6 
INDEPENDENT DATA MONITORING COMMITTEE ..................................................... 48 
9 
STATISTICAL METHODS AND SAMPLE SIZE .................................................................49 
9.1 
DETERMINATION OF SAMPLE SIZE .......................................................................... 49 
9.2 
STATISTICAL ANALYSIS .......................................................................................... 49 
9.2.1 
Populations for Analysis .......................................................................................49 
9.2.2 
Efficacy Analysis Plan ..........................................................................................50 
9.2.3 
Safety Analysis Plan..............................................................................................50 

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9.2.4 
Handling of Missing Data .....................................................................................51 
9.3 
RANDOMISATION, STRATIFICATION, AND CODE RELEASE ...................................... 51 
10 
ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ......................52 
10.1 ETHICAL/REGULATORY FRAMEWORK .................................................................... 52 
10.2 APPROVAL OF STUDY DOCUMENTS ........................................................................ 52 
10.3 PATIENT INFORMATION AND INFORMED CONSENT ................................................. 52 
10.4 PROTOCOL AMENDMENTS ...................................................................................... 52 
10.5 CONFIDENTIALITY OF PATIENT DATA ..................................................................... 53 
11 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................................54 
11.1 PERIODIC MONITORING .......................................................................................... 54 
11.2 AUDIT AND INSPECTION .......................................................................................... 54 
12 
REPORTING AND PUBLICATION ........................................................................................55 
12.1 CLINICAL STUDY REPORT ....................................................................................... 55 
12.2 PUBLICATION POLICY ............................................................................................. 55 
13 
LIABILITIES AND INSURANCE ............................................................................................56 
14 
REFERENCES ............................................................................................................................57 
15 
APPENDICES..............................................................................................................................59 
 

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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALAT 
Alanine Aminotransferase 
ASAT 
Aspartate Aminotransferase 
AUC 
Area Under the Concentration-Time Curve 
CRO 
Contract Research Organisation 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FA 
Full Analysis 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HAV 
Hepatitis A Virus 
HBV 
Hepatitis B Virus 
HCG 
Human Chorionic Gonadotrophin 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IMP 
Investigational Medicinal Product 
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
IV 
Intravenous 
IVIG 
Intravenous Immunoglobulin 
LDH 
Lactate Dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
PI 
Primary Immunodeficiency  
PK 
Pharmacokinetic 
PP 
Per-protocol 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
SBI 
Serious Bacterial Infection(s) 
SC 
Subcutaneous 
SCIG 
Subcutaneous Immunoglobulin 
Tmax 
Time to Maximum Plasma Concentration 
WBC 
White blood cell 

Study Protocol No. SCGAM-04, Version 02 CONFIDENTIAL 
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Page 14 of 59 
1 
INTRODUCTION 
The primary therapeutic use of γ-immunoglobulins (IgG) is to provide antibodies to prevent 
viral and bacterial diseases (replacement therapy) in patients with primary immunodeficiency 
(PI) syndromes who have significant defects of antibody formation (humoral immunity).  
The PI syndromes are a heterogeneous group of disorders with an intrinsic defect of the 
tissues, cells, or proteins of the immune system resulting in immune deficiency. Many of 
these disorders are characterised by hypogammaglobulinaemia with or without defective 
antibody production. Children and adults with PI have an increased risk of recurrent bacterial 
and viral infections that typically attack the respiratory tract (sinusitis, bronchitis, pneumonia) 
but can also affect the gastrointestinal tract (gastroenteritis). They can be severe and can lead 
to substantial morbidity. Responses to antibacterial therapy are often poor. At present, most 
PIs are not curable, but immunoglobulins have shown to decrease the total number of severe 
infections and the duration of hospitalisation. 
In earlier years (around 1950), the IgG preparations were administered intramuscularly. This 
route of administration causes substantial discomfort, and restricts the amount of IgG that can 
be given to the patients. During the last 20 years, several IgG preparations have been 
developed for intravenous (IV) and subcutaneous (SC) administration, and their use has 
further contributed to the successful treatment of patients with PI disorders. 
The administration via the SC route offers some advantages over IV infusion from a patient’s 
and a physician’s perspective and therefore became an alternative treatment option to the 
IV treatment. After the introduction of small, portable syringe drivers, this route of 
administration has gained even more popularity in Europe and the US as a practical, effective 
and safe treatment, because home therapy can also be recommended with this kind of 
administration. 
There are two major differences in the pharmacokinetic (PK) characteristics of intravenously 
administered immunoglobulins (IVIG) and subcutaneously administered immunoglobulins 
(SCIG): delayed absorption and reduced bioavailability. 
Following IV administration, the plasma concentration peaks immediately upon termination 
of the infusion, frequently reaching concentrations more than twice as high as the trough 
level. After SC administration, the absorption of IgG into the SC tissue is slower; the IgG 
must be delivered into the blood stream by the lymphatic system. Thus, with SCIG, the 
intravascular IgG concentration increases gradually, peaking at 48–72 hours. Most other 
features of SCIG treatment are consequences of these fundamental differences.[1] 
Studies of the PKs of SCIG have shown a lower bioavailability than IVIG. This decreased 
bioavailability may involve degradation in the tissues and/or local binding in the intercellular 
matrix. Because of this expectation, several studies were designed to directly determine the 
bioavailability of SCIG as compared to IVIG.[2] 
On converting from IVIG to SCIG replacement therapy for PI, the equivalent monthly dose of 
IgG is usually determined in one of two ways: 
• 1:1 dosing: The 3 to 4 weekly IVIG dose is split into 3 to 4 equal weekly SCIG 
infusions. 
• Dosing based on the area under the curve (AUC). The SCIG dose is calculated from 
PK data to provide a monthly exposure to IgG equivalent to that with IVIG. 

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The former is common in Europe, while the latter is a requirement of the US Food and Drug 
Administration (FDA) for SCIG labelling studies.[3] 
No differences have been reported in the half-life of SCIG and IVIG. With modern IgG 
preparations, half-lives have generally been reported to be about 30–35 days. Thus, there is no 
clinically significant difference in the half-life of IgG between the two administration 
routes.[1] 
However, SCIGs are usually given weekly, compared with IVIG regimens in which a large 
dose is given every 3rd or 4th week. The use of smaller doses at more frequent intervals results 
in stable, higher trough IgG serum concentrations which remain constant between consecutive 
SCIG infusions.[4] 
In 3 recent studies comparing IVIG and SCIG in PI patients, the mean peak serum IgG level 
immediately after IV infusions was 2303 mg/dL.[5-7] In contrast, the mean peak with SCIG 
was 1410 mg/dL and the time for the peak IgG concentration (Tmax) was 62.6 h (2.6 days).[8] 
With weekly SCIG administrations, only about 4.5 days elapse between the Tmax of one dose 
and the administration of the next dose. Given the half-life of 30 days this means that the IgG 
plasma concentration has dropped by only about 10 to 20% before the serum level starts to 
rise again. In contrast, with IVIG dosing intervals of 3–4 weeks (about one half-life), the drop 
in plasma concentration will be about 40 to 50% by the time the next dose is due. These 
differences in the dosing intervals used in most SCIG vs. IVIG regimens result in more stable 
serum IgG levels with SCIG.[1,8] 
Pooled data from 7 studies in which equivalent monthly SC IgG doses were given weekly vs. 
IVIG every 21–28 days showed that trough serum IgG levels were 10 to 20% higher with 
weekly SC doses than with the same total monthly IVIG dose. After 6 to 12 weekly infusions, 
near-steady-state IgG levels were achieved with differences between minimum and peak 
concentrations of only 5 to 10% of the overall mean.[1,8] 
No clinical data are available that would allow comparison of the long-term efficacy of SCIG 
versus IVIG administration on the development of bronchiectasis or other changes on lung 
scans, nor on deterioration of pulmonary function in patients who have PI. Similarly, no data 
are available comparing the efficacy of SC versus IVIG on the persistence or progression of 
chronic sinus disease in PI patients with that problem, or on other complications of PI.[9] 
Orange et al (2012) reviewed the clinical efficacy of SCIG and identified 13 clinical studies in 
a total of 482 patients representing more than 27,500 infusions. The rate of serious bacterial 
infections (SBI) was the most common primary efficacy endpoint in these studies. Secondary 
endpoints included overall infections (i.e., infections not meeting SBI criteria), missed days 
from work or school, days in hospital and days on antibiotics. Definitions of overall infections 
and SBI were not standardised across studies. In 6 studies, SBI were defined by FDA criteria 
and included bacterial pneumonia, meningitis, sepsis, osteomyelitis or visceral abscess. In 2 
studies, a SBI was defined as an infection requiring hospitalisation.[3] 
The rate of SBI was reported in 11 studies and varied from 0 to 0.09 events per patient and 
year. Infections were reported in 11 studies and varied from 2 to 5.18 patient and year. These 
figures are overall at least as good as those reported for IVIG studies.  
To provide adequate protection from infection, a serum IgG concentration of >5 g/L 
following IgG therapy has been recommended. Several retrospective studies and one 

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prospective study, however, have shown that higher serum IgG concentrations, resulting from 
higher doses of IVIG, are associated with a decreased incidence of infections.[3] 
A recent meta-analysis in 16 individual studies of IVIG focused on the diagnosis of 
pneumonia, the most comparable endpoint, and demonstrated a statistically significant inverse 
correlation between higher IgG dose and a lower incidence of pneumonia, with a 27% 
decrease in incidence of pneumonia for every 100 mg/kg increase in dose.[10] 
Despite its well-established safety profile, IVIG often leads to undesired symptoms, ranging 
from mild systemic adverse reactions, such as flushing, fever, muscle aches, tiredness, 
headache and dizziness, to severe reactions, manifesting as chest pain, tachycardia, and 
changes in blood pressure, aseptic meningitis, thrombosis or renal failure.[4] 
The slower rate of rise towards the peak and the truncation of its height are believed to be 
responsible for the much lower incidence of systemic adverse events (AEs) with SCIG. This 
is consistent with observations that many AEs of IVIG infusions are rate-related, and has been 
repeatedly confirmed.[9] 
On the other hand local reactions at SC injection sites are common. These reactions are rarely 
severe, and are accepted by most patients. In the meta-analysis by Orange et al. the reporting 
rate varied from 0.028 to 0.697 per infusion demonstrating that the majority of patients 
tolerate SCIG well.[3] 
octanorm, the investigational medicinal product (IMP) in this study, is an immunoglobulin 
preparation from human normal plasma and is manufactured by Octapharma. It contains 
around 165 mg/mL protein. The product is aimed for SC infusion by pump or syringe. 
Further information on the IMP can be found in the Investigator’s Brochure. 
1.1 Rationale for Conducting the Study 
The administration of immunoglobulins via the SC route offers several advantages over IV 
infusion from a patient’s and a physician’s perspective. Replacement therapy by rapid SC 
infusion with a pump was introduced during the late 1980s. Several reports have shown that 
the SC method is feasible, safe, efficient, cost-effective and highly appreciated by the 
patients.[11-19] 
Self-administration at home with small portable pumps or syringes is simple and can easily be 
learned by the patients, which is another advantage of SCIG. It may remarkably improve the 
patient’s quality of life (QoL) and compliance as it reduces the frequency of hospitalisations 
and the need for home care. Administration of IgG via the SC route provides more stable and 
well-balanced IgG plasma levels until the end of the treatment interval, in contrast with the 
peak IgG plasma concentrations attained with IVIG solutions which weaken at the end of 
dose. When effective IVIG therapy cannot be continued because of the lack of peripheral and 
central vein access, SCIG might also be an alternative treatment option. 
Experience has shown that replacement therapy with immunoglobulins is life saving. If 
replacement is started early, and if appropriate amounts are given with sufficient frequency, 
the cycle of recurrent infections and progressive lung damage can be arrested. Near to normal 
serum IgG levels can be easily maintained. 
A clinical study with octanorm (SCGAM-01) is currently being conducted in Czech Republic, 
Slovak Republic, Poland, Hungary, USA and Canada, with the rationale to investigate PK, 

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efficacy and safety in PI patients. In total, 50 patients have been included in this study (of 
whom 10 are children); 18 patients already successfully completed the study, 28 patients are 
ongoing, and 4 patients left the study (none of them due to AEs or SAEs). More than 2200 
weekly SC infusions have been given and were very well tolerated by the patients. No SBI 
occurred. (For more details see the ‘Development Safety Update Report’.) 
The rationale for conducting this clinical study (SCGAM-04) is to investigate the efficacy and 
safety of octanorm in patients with PI to provide efficacy and safety data in Russian patients 
for submission to the national authorities to support marketing authorisation in the Russian 
Federation. 
1.2 Dose Rationale 
On converting from IVIG to SCIG replacement therapy for PI, the equivalent monthly dose of 
IgG is usually determined as 1:1 dosing, wherein the 3 to 4 weekly IVIG dose is split into 3 to 
4 equal weekly SCIG infusions. This is common practice in Europe. 
In this study, the weekly dose of octanorm will be 1:1.  
Throughout the study, the appropriate dose levels will be maintained by regular monitoring of 
IgG trough levels. The octanorm dose can be adjusted (increased) by the Investigator if 
needed (see Section 5.4). 
The manufacture of octanorm is based on the (IVIG) Octagam manufacturing process. The 
process is identical up to the step of the second diafiltration. After this step the product 
solution is concentrated to the octanorm target concentration of 165 g/L. 
The PK characteristics and the safety profile of the IVIG Octagam are well known. Octagam 
has been extensively investigated over the last 15 years. More than 900 patients have been 
enrolled in prospective clinical studies with Octagam 5% or 10%.  
In the Russian Federation and in the EU, the recommended and approved Octagam dose in PI 
is 200 to 800 mg/kg body weight, administered every 3 to 4 weeks. Therefore, in this clinical 
study, the proposed dose of octanorm is within those recommended values. 
1.3 Benefit-Risk Statement 
Patients with PI need life-long treatment with immunoglobulins. Replacement therapy is 
expected to achieve protective trough levels of 5–6 g/L.  
The safety profile of SCIG is well characterised. For octanorm, the same type of adverse 
reactions may be expected. No new or unknown safety problems are expected to emerge for 
octanorm, which are not already described in the Investigator’s Brochure. 
In the ongoing SCGAM-01 study, approximately 50 patients have received more than 2200 
weekly SC infusions of octanorm, and no serious bacterial infections have occurred, 
indicating that octanorm is effective in the treatment of patients with PI syndromes. It can 
reasonably be assumed that octanorm will have at least the same effectiveness as Octagam 
and other IVIG brands. 
The 2200 weekly SC infusions of octanorm were very well tolerated by the patients. Adverse 
events which were assessed by Investigators and sponsor as ‘probably’ or ‘possibly related’ to 
octanorm, were mostly mild or moderate in severity. The majority of them were local 

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reactions just caused by the injected octanorm volume (usually reported as a transient 
‘swelling’, transient redness and infusion site pruritus).  
Two serious adverse events (SAE) were reported, both were considered as ‘not related’ by 
the Investigator: 
1. ‘Appendicitis with appendectomy’: The appendicitis was severe in intensity but 
considered not related to octanorm treatment. 
2. ‘Tumour of thyroid gland’: Histology after surgery confirmed enlargement of the 
thyroid gland without signs of malignancy. The investigator assessed the SAE as mild 
in severity and considered it not related to octanorm. 
No other SAEs were reported until the finalisation of this Protocol. No death occurred. 
No unexpected or unknown safety issues have been detected so far for octanorm. 
Standard measures are taken in order to prevent infections resulting from the use of medicinal 
products prepared from human blood or plasma. Despite this, when such medicinal products 
prepared from human blood or plasma are administered, the possibility of transmitting 
infective agents cannot totally be ruled out. The virus inactivation methods for octanorm are 
described in the Investigator’s Brochure. 

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2 
STUDY OBJECTIVES 
The study objectives are: 
• To evaluate the efficacy of octanorm in preventing SBI compared with historical 
control data. 
• To evaluate the tolerability and safety of octanorm. 
• To assess the effect of octanorm on QoL measures. 

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3 
INVESTIGATIONAL PLAN 
3.1 Primary and Secondary Endpoints 
3.1.1 Primary Endpoint 
The primary efficacy endpoint is the rate of SBI (defined as bacteraemia/sepsis, bacterial 
meningitis, osteomyelitis/septic arthritis, bacterial pneumonia, and visceral abscess) per 
person-year on treatment. 
3.1.2 Secondary Endpoints 
Secondary efficacy endpoints are: 
• The annual rate of all infections of any kind or seriousness. 
• Non-serious infections (total and by category). 
• Time to resolution of infections. 
• Use of antibiotics (number of days and annual rate). 
• Hospitalisations due to infection (number of days and annual rate). 
• Episodes of fever. 
• Days missed from work/study due to infections and their treatment. 
• QoL assessment using the SF-36 Health Survey. 
• Trough levels of serum total IgG throughout the study. 
Secondary safety endpoints are: 
• Occurrence of all treatment emergent AEs (TEAEs) throughout the entire treatment 
period starting with the first infusion of IMP. 
• Proportion of infusions with at least 1 temporally associated AE. 
• Occurrence of adverse drug reactions (ADRs). 
• Local injection site reactions. 
• Vital signs (blood pressure, pulse, body temperature, respiratory rate). 
• Laboratory parameters (haematology, clinical chemistry, and viral status). 
3.2 Overall Study Design and Plan 
The study is a prospective, open-label, non-controlled, single-arm, multicentre phase 3 study 
with an 8-week wash-in/wash-out period followed by a 6-month (6 × 4 weeks) efficacy 
period. 
The study will be conducted at approximately 5 selected study sites in Russia. 
Only patients previously on IVIG treatment may be enrolled. All patients have to undergo the 
8-week wash-in/wash-out period. 
Each patient will be treated with octanorm over a period of about 8 months (8-week wash-
in/wash-out phase and 6-month efficacy phase) (see Figure 1). Each patient who stays in the 
study for the whole period will receive 32 octanorm SC infusions. The final examinations will 

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be performed 1 week after the end of the last infusion, or 1 week after premature withdrawal 
of the patient from the study, with a telephone follow-up 3 weeks later.  
The total duration of the study for an individual patient will be up to 43 weeks (depending on 
the IVIG treatment schedule before enrolment). 
Approximately 20 to 25 patients who comply with the inclusion and Non-Inclusion Criteria 
will be enrolled into the study. Study-related procedures will begin only after written 
informed consent has been obtained from the patient.  
The Screening Period starts with the signing of the informed consent form. Screening can start 
before or after the last (4th) IVIG infusion, up to 7 weeks before the first infusion of 
octanorm. The first infusion of octanorm will be done around the time when the patient’s 
treatment with IVIG is due. 
All results necessary to check the patient’s eligibility must be available before the first IMP 
administration. 
Site staff will be trained by the Sponsor in the use of the SC pump. Patients have to be trained 
at the study site (for at least 4 infusions). Thereafter, the patient may continue with octanorm 
infusions at home. Every 4 weeks the infusion is to be given under oversight of the study 
personnel at the study site. A 6-week interval may be acceptable exceptionally (e.g., in case of 
vacation). Before starting home treatment, a diary will be provided to the patients for 
documenting the date, volume and speed of infusion, occurrence of infections, AEs and local 
tissue reactions at injection sites, missed days from work/study, inpatient hospital stays, and 
any changes in concomitant therapies between visits. 
Refer to Table 1 and Section 6.1 for the timings of the interventions and activities during the 
visits taking place at the study site.  

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Figure 1 
Study Design 
1 Patients must have had at least 4 infusions of IVIG to enrol in the study. The last infusion of IVIG can occur before Screening 
starts or during the Screening Period.  
2 The first administration of octanorm must take place within 7 weeks of the Screening Visit and around the time when the 
patient’s next treatment with IVIG would have been due. 
3.3 Discussion of Study Design and Choice of Control Group 
3.3.1 Study Design 
The inclusion and Non-Inclusion Criteria chosen are considered adequate to ensure that the 
study population will be representative of patients suffering from PI. 
The study design is also in line with similar study protocols conducted with other SCIG 
brands.[18,20] 
3.3.2 Control Group 
Introduction of a placebo group would not be justified for ethical reasons. An active control 
group is not considered relevant, as the efficacy of treatment with SCIG and with octanorm 
has been demonstrated for this indication. 
The historical control data will be based on the standards cited in the Guidance for 
Industry.[22] 
3.3.3 Study Parameters 
The outcome measures in this study are consistent with previous studies of other IVIG or 
SCIG products. 
The QoL questionnaire is a standardised, validated instrument that has been widely used in 
clinical studies, including PI. 
4th (last) IVIG1 
octanorm  s.c. infusion Nr. 
1    2     3     4    5     6      7     8     9… 
Screening 
Period 
8 week wash-in/wash-
out 
6-month efficacy phase 
…28  29…  32 (last s.c.  
      infusion) 
First octanorm infusion2 

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4 
STUDY POPULATION 
4.1 Population Base 
Approximately 20 to 25 adult male or female patients suffering from PI will be eligible for 
inclusion to this clinical study. 
4.1.1 Inclusion Criteria 
Patients who meet all of the following criteria may be enrolled: 
1. Age of ≥18 years and ≤70 years. 
2. Confirmed diagnosis of PI requiring immunoglobulin replacement therapy due to 
hypogammaglobulinaemia or agammaglobulinaemia. The type of PI should be 
recorded. 
3. Patients with at least 4 infusions on regular treatment with any IVIG prior to entering 
the study. Constant IVIG dose between 200 and 800 mg/kg body weight (the 
individual doses of the last 4 infusions should not vary by more than ±25% of the 
mean dose for the last 4 infusions). 
4. Availability of at least 2 IgG trough levels with an IgG level of ≥5.0 g/L from the 
period of the last 4 IVIG infusions. 
5. Negative result on a pregnancy test (Human Chorionic Gonadotrophin [HCG]-based 
assay in urine) for women of childbearing potential and use of a reliable method of 
contraception for the duration of the study. Women of non-childbearing potential must 
be post-menopausal (amenorrhoeic for at least 12 months) or surgically sterile. 
Examples for medically acceptable methods of birth control for this study include:  
– Oral, implantable, transdermal or injectable contraceptives 
– Intrauterine device 
– Condoms; diaphragm or vaginal ring with spermicidal jellies or cream 
– Sexual abstinence 
– Vasectomised partner 
6. Patient must freely give written informed consent.  
7. Willingness to comply with all aspects of the protocol, including blood sampling, for 
the duration of the study. 
4.1.2 Non-Inclusion Criteria 
Patients who meet one (or more) of the following criteria cannot be included in the study: 
1. Acute infection requiring IV antibiotic treatment within 2 weeks prior to and during 
the screening period. 
2. Known history of adverse reactions to Immunoglobulin A in other products. 
3. Patients with body mass index >40 kg/m2. 
4. Exposure to blood or any blood product or plasma derivatives, other than IVIG 
treatment of PI, within the past 3 months prior to first infusion of octanorm. 
5. Ongoing history of hypersensitivity or persistent reactions to blood or plasma derived 
products, or any component of the IMP (such as Polysorbate 80). 

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6. History of malignancies of lymphoid cells and immunodeficiency with lymphoma. 
7. Severe liver function impairment (alanine aminotransferase [ALAT] 3 times above 
upper limit of normal). 
8. Known protein-losing enteropathies or proteinuria. 
9. Presence of renal function impairment (creatinine >120 µM/L or creatinine 
>1.35 mg/dL), or predisposition for acute renal failure (e.g., any degree of pre-existing 
renal insufficiency or routine treatment with known nephritic drugs). 
10. Treatment with enteral or parenteral steroids for ≥30 days or when given intermittently 
or as bolus, at daily doses ≥0.15 mg/kg. Inhaled corticosteroids are allowed. 
11. Patients with chronic obstructive pulmonary disease (COPD) stage Global Initiative 
for Chronic Obstructive Lung Disease (GOLD) III or IV. 
12. Treatment with immunosuppressive drugs. 
13. Live viral vaccination (such as measles, rubella, mumps and varicella) within the last 
2 months prior to first infusion of octanorm. 
14. Treatment with any IMP within 3 months prior to first infusion of octanorm. 
15. Presence of any condition that is likely to interfere with the evaluation of study 
medication or satisfactory conduct of the trial. 
16. Known or suspected to abuse alcohol, drugs, psychotropic agents or other chemicals 
within the past 12 months prior to first infusion of octanorm. 
17. Known or suspected human immunodeficiency virus (HIV), hepatitis C virus (HCV), 
or hepatitis B virus (HBV) infection. 
18. Pregnant or nursing women; planned pregnancy during course of the study. 
4.2 Prior and Concomitant Therapy 
Details on medications taken within 30 days prior to screening and any concomitant 
medications taken during the study and for 4 weeks after the end of the last infusion must be 
recorded in the CRF. This includes non-drug therapy, such as physiotherapy. Previous IVIG 
infusions will be recorded as prior therapy (for those infusions given before Screening) and 
concomitant therapy (if last dose is given within Screening Period), as applicable. 
4.2.1 Permitted Concomitant Therapy 
Routine premedication to alleviate potential tolerability problems is not allowed during the 
study. However, patients who experience 2 consecutive TEAEs that are likely to be prevented 
by premedication are permitted to receive antipyretics, antihistamines, or antiemetic drugs. 
Non-steroidal anti-inflammatory drugs can affect renal function and should be avoided.  
Local anaesthetics (as cream or plaster) to reduce pain associated with needle(s) insertion are 
allowed. Inhaled corticosteroids are allowed. The use of such medication(s) must be recorded. 
4.2.2 Forbidden Concomitant Therapy 
Apart from up to one routine IVIG infusion during the Screening Period (see Figure 1), 
administration of any blood or plasma derived product is forbidden during the study and 
should only be given for emergency reasons. Patients will be withdrawn from the study if IgG 
preparations other than octanorm are administered during the treatment period. 

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Premedication for the study SCIG infusions shall not be given, with the exception of 
permitted therapy as stated above (for patients with 2 consecutive TEAEs). Corticosteroids 
shall not be given as a pre-treatment to alleviate potential tolerability problems. 
Treatment with enteral or parenteral steroids for ≥30 days or when given intermittently or as 
bolus, at daily doses ≥0.15 mg/kg of prednisone or equivalent is forbidden.  
Immunosuppressive drugs are also forbidden. 
octanorm must not be mixed with other medicinal products. 
4.3 Withdrawal and Replacement of Patients 
4.3.1 Premature Patient Withdrawal 
Patients have the right to withdraw from the study at any time for any reason, without the 
need to justify their decision. The responsible Investigator also has the right to withdraw 
patients from the study in case of AEs, poor compliance, or administrative reasons. Since an 
excessive rate of withdrawals can render the study un-interpretable, any unnecessary 
withdrawal of patients should be avoided. 
Reasons for premature patient withdrawal can be the following: 
• Patient’s decision: Should a patient decide to withdraw, the Investigator will make the 
best efforts to complete and report all information available at time of withdrawal. The 
Investigator will document the reason(s) for withdrawal of each patient in the 
electronic case report form (eCRF). 
• Withdrawal for safety reason: If the reason for removal of a patient from the study is 
an AE or an abnormal laboratory test result, this specific event or test will also be 
recorded. If a patient is withdrawn from the study because of an AE, the Investigator 
will make thorough efforts to clearly document the outcome. 
• Administration of other immunoglobulin preparation: If for any reason a patient’s 
therapy is changed to another IVIG or SCIG preparation within this study, the patient 
will be withdrawn from the study. 
• Pregnancy: Pregnant patients may not be included in the study. A pregnancy test is 
mandatory at the Screening Visit, at Week 16 and at the Termination Visit. All female 
patients of childbearing potential are responsible for using effective contraception 
during their study participation. If a pregnancy occurs, treatment with the IMP must be 
stopped immediately and Octapharma must be informed: The Pregnancy Notification 
Form must be completed and sent or faxed to the CRO (see Section 7.3.4 for the 
contact email and fax number). 
If a patient is withdrawn, the Investigator will organise a Termination Visit. At this visit, all 
investigations including laboratory tests should be performed to allow the patient to be 
included in both safety and efficacy evaluations. This Termination Visit is identical to the 
follow-up visit of the last IgG administration. 
4.3.2 Patient Replacement Policy 
Patients withdrawn from the study because of safety or efficacy reasons will not be replaced. 
Patients withdrawn from the study for any other reason, e.g., major protocol violation, 
pregnancy or administrative reasons will also not be replaced. However, if the number of 

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withdrawals exceeds the limit of 15%, the Sponsor will assess the situation and decide on a 
possible replacement policy. Patients who do not satisfy specific entry criteria during 
screening may be rescreened following discussion of the individual case with the Sponsor. 
4.4 Assignment of Patients to Treatment Groups 
The patient numbers will be allocated sequentially in the order in which the patients are 
enrolled. The fact that a patient has been enrolled will be reported immediately and 
automatically by the Electronic Data Capture (EDC) system to the Investigator, the contract 
research organisation (CRO) and the Sponsor. 
All patients enrolled in this study will be treated with octanorm.  
Each patient will be identified by the previously assigned patient number throughout the trial; 
no additional patient or randomisation number will be used. 
Under no circumstances are patients who participate in the study permitted to re-enrol for a 
second time. 
4.5 Relevant Protocol Deviations 
In the case of any critical or major protocol deviation, the Investigator and Octapharma will 
decide on the further participation of the patient in this study, after having discussed all 
relevant aspects. 
A list of all included patients with all deviations from the intended study procedures and other 
criteria that may affect the validity of patient data for statistical analysis will be prepared after 
the clinical phase of the study is completed. The list will be discussed by a panel consisting of 
the clinical study manager, a medical expert of the Sponsor, the data manager and the study 
statistician. This panel will decide upon the inclusion of each patient in the analysis 
populations. 
4.6 Subsequent Therapy 
In case a patient decides to withdraw from the study or is withdrawn by the Investigator, 
he/she may be switched back to the treatment he/she has received before study participation 
or to another commercially available IVIG or SCIG. 

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5 
INVESTIGATIONAL MEDICINAL PRODUCT 
5.1 Characterisation of Investigational Product 
Name of Medicinal Product:  
octanorm 
Active ingredient of octanorm: 
Human normal immunoglobulin 
Table 2 Biochemical Characteristics of octanorm 
Parameter 
 
Total protein (of which ≥95% is human IgG) 
150 – 180 mg per mL 
Maltose 
70 – 90 mg per mL 
Octoxynol 
≤5 µg per mL 
TNBP 
≤1 µg per mL 
Immunoglobulin A 
≤0.6 mg per mL 
Polysorbate 80 
10 – 60 µg per mL 
pH 
5.0 – 5.8 
Polymers + Aggregates 
≤5% of the total chromatogram area 
Monomers + Dimers 
≥90% of the total chromatogram area 
Fragments 
≤5% of the total chromatogram area 
Sodium 
≤30 mMol/L 
Each batch (lot) of octanorm is prepared from at least 1,000 donations of human fresh frozen 
plasma. Effective viral reduction is obtained via a combination of 3 validated manufacturing 
steps: cold-ethanol fractionation, solvent/detergent treatment with TNBP and Octoxynol, and 
pH 4 treatment. The manufacture of octanorm is based on the Octagam manufacturing 
process including an additional adsorption step onto a commercially available and widely 
used chromatography column for the removal of coagulation factor XI. The process is 
identical up to the step of diafiltration. After this step the product solution is concentrated to a 
target concentration of 200 g/L. Polysorbate 80 and maltose are added during final 
formulation to final concentrations of 10-60 µg/mL and 70-90 mg/mL, respectively. 
5.2 Packaging and Labelling 
octanorm is delivered in glass vials. 
Each octanorm vial will be labelled as follows: 

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FOR CLINICAL TRIAL USE ONLY 
Study: SCGAM-04 
octanorm 
Unit size: ____ mL 
1 mL contains: 165 mg protein of which ≥95% is human normal immunoglobulin G. 
Solution for subcutaneous injection. 
To be stored at +2 °C to +8 °C, protected from light. Must not be frozen. Keep out of the 
reach and sight of children. 
Must be inspected visually for particulate matter and discoloration prior to administration. 
Solutions that are cloudy or have a deposit must not be used. 
To be warmed up to room or body temperature before use. 
Dosage: Please refer to the handling instruction provided. 
INVESTIGATOR NAME: ___________________                                   Site No: |___|___| 
Patient No.: |___|___|___|___| 
Manufacturer: OCTAPHARMA Dessau GmbH; Otto-Reuterstrasse 3, 06847 Dessau-Roßlau, 
Germany, Tel: +49 340 55080 
Sponsor: Octapharma Pharmazeutika Prod.Ges.m.b.H., Oberlaaer Strasse 235, 1100 Vienna, 
Austria, Tel: +43 (1)61032-0 
Batch No.: ______________ 
 
Expiry date: ________ 
5.3 Conditions for Storage and Use 
octanorm must be stored and transported light-protected at +2 °C to +8 °C and must not be 
frozen. 
octanorm must not be used after its expiration date. 
Authorised personnel at the individual study centres will ensure that the investigational 
product is stored in appropriate conditions in a secure refrigerator with restricted access. 
5.4 Dose and Dosing Schedule 
octanorm has to be administered subcutaneously every week (±2 days). There must be a 
minimum of 4 days between each SC infusion. If, during the study, the body weight changes 
by >5% from the baseline visit (Visit 2), the dose is to be adjusted to keep the dose constant 
on a milligram per kilogram body weight basis. 
The octanorm dose during the wash-in/wash-out phase is to be calculated as follows: 
last IVIG dose (in grams) 
number of weeks between IVIG doses 
The dose can also be adjusted if IgG trough levels during the study are <5 g/L or if there is a 
clinical need for octanorm dose adjustment; in this case any changes should be discussed 
beforehand with the Octapharma Medical Expert. 
5.5 Preparation and Method of Administration 
Vials of octanorm must be allowed to warm to room or body temperature prior to infusion. 
Thereafter, octanorm should be infused subcutaneously using a syringe driver for precise 
infusion rates and standard infusion materials provided to the patients by the site. The correct 
amount of IgG taken from 12 or 48 mL vials of octanorm will be infused with the aid of a 

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syringe driver. The content of the vials will have to be transferred into the syringes suitable 
for the syringe driver selected. Remaining solution in a vial must be discarded. 
octanorm must not be mixed with other medicinal products. An aseptic technique must be 
used throughout the procedure.  
Each vial must be examined visually for particulate matter and discoloration prior to 
administration. The solution should be clear or slightly opalescent. Solutions that are cloudy 
or have a deposit must not be used. 
The patient will be instructed at the clinic/doctor’s office or at the infusion centre in the use of 
the following: 
• syringe driver,  
• infusion techniques,  
• keeping of a patient diary and  
• measures to be taken in case of severe AEs.  
After training of the patient at the study site (for at least 4 SC administrations), SCIG 
infusions may be (self-)administered at home. Every 4 weeks the infusion is to be given at the 
study site (latest after 6 weeks exceptionally). 
Patients must be monitored for at least 1 hour after all doses of octanorm given at the study 
site. 
Infusion sites: The maximal number of infusion sites used simultaneously should not 
exceed 6. Infusion sites should be approximately 5 cm apart. The actual sites of infusion 
should be changed with each weekly administration. 
Volume: For the first administration, 15 mL per infusion site should not be exceeded. After 
the 4th administration, this may be gradually increased to 25 mL/site, if tolerated, to 
35 mL/site after the 16th administration. Starting with the 24th administration and when the 
previous volumes were well tolerated, the volume can be increased to a maximum of 
40 mL/site. 
Infusion rate: For the first 4 administrations of octanorm, the maximum recommended flow 
rate is 15 mL per hour per site. For subsequent infusions, the flow rate may be gradually 
increased to a maximum of 25 mL per hour per site as tolerated. 
The maximum flow rate is, however, not to exceed a total of 30 mL per hour for all sites for 
the first 4 infusions and 50 mL per hour for all sites up to infusion no. 16 and, if tolerated, 80 
mL per hour for all infusion sites thereafter. Starting with the infusion no.24 (site visit no.10) 
the maximum flow rate can be (gradually) increased up to 100 mL per hour for all infusion 
sites - if the previous rates are well tolerated. 
5.6 Blinding, Emergency Envelopes, and Breaking the Study Blind 
Not applicable for this open-label study. 

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5.7 Treatment Compliance 
5.7.1 Drug Dispensing and Accountability 
Any IMP provided to the site will be accounted for. This includes IMP received at the site, 
IMP dispensed to patients, and IMP returned by the patient. 
A Drug Inventory and Dispensing Log will be kept current by the Investigator, detailing the 
dates and quantities of IMP received and dispensed to each patient and the remaining 
quantity.  
The inventory and dispensing log will be available to the monitor to verify drug 
accountability during the study.  
Unused IMP can be destroyed at the study site or returned to the Sponsor for destruction. 
Destruction can be initiated only after accountability has been verified and fully reconciled by 
the monitor and after the Sponsor has granted written approval of destruction. 
For their home treatment, a sufficient amount of octanorm will be handed out to the patients. 
The Investigator or his/her designee has to document the date, quantities and batch (lot) 
number(s) of IMP handed out including the corresponding patient number. The patients will 
be advised to return used or expired vials to the study site at their on-site visits, and to return 
used and unused vials at the (early) Termination Visit. All used and unused IMP returned by 
the patients must not be stored in the secure IMP refrigerator, must not be re-used and must 
be destroyed after drug accountability is completed. 
5.7.2 Assessment of Treatment Compliance 
After training, for the first 4 weeks patients will receive weekly infusions at the study site 
under the surveillance of authorised study personnel. The patient will then continue with 
SCIG infusions at home, with infusions given at the study site every 4th week. Infusion 
details will be documented together with the batch number(s) in the eCRF. 
Throughout the study, patients will be asked to document on a diary the date, batch (lot) 
numbers, number of vials, speed of infusion, injection site(s), occurrence of infections, 
TEAEs and local tissue reactions at injection sites, missed days from work/study, inpatient 
hospital stays, and any changes in concomitant therapy between visits. The diary will be 
reviewed during the patient’s infusion visit at the study site. 

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6 
STUDY CONDUCT  
The flow chart of assessments by study visit is shown in Table 1, following the study outline. 
6.1 Observations by Visit 
6.1.1 Screening Visit (Visit 1) 
The Screening Period starts with the signing of the informed consent form. The last pre-study 
IVIG infusion can take place before or after the start of the Screening Period. Screening 
results must be known before the first IMP administration. The first administration of IMP 
must take place within 7 weeks of the Screening Visit. 
Study-related procedures will begin only after written informed consent has been obtained 
from the patient. At the Screening Visit the following activities will be performed: 
• Written informed consent. 
• Check of inclusion and Non-Inclusion Criteria. 
• Documentation of demographic data. 
• Documentation of medical history including all adverse conditions that have occurred 
during the last 30 days. Documentation of serious infections (for definition see 
Section 7.2.1) and any IV antibiotics from the previous 12 months. 
• Recording of all other previous drug and non-drug therapies during the last 30 days. 
• General physical examination, including body weight and vital signs. 
• Chest X-ray (only if last available chest X-ray, CT or MRI is older than 12 months). 
• Drawing of blood samples for total IgG trough level (only for those patients who have 
their last IVIG infusion during the Screening Period). 
• Drawing of blood samples for safety laboratory parameters including viral markers. 
• Urine sampling including urine pregnancy test (in females of childbearing potential 
only). 
6.1.2 Treatment Visits 
A patient’s eligibility must be confirmed (e.g., laboratory and viral testing results must be 
available) before dosing with octanorm is started. The first infusion of octanorm will be done 
around the time when the patient’s next treatment with IVIG would have been due. Each 
patient who stays in the study for the whole period will receive 32 octanorm SC weekly 
infusions. After receiving training at the study site, the patient will infuse the first 4 infusions 
at the study site. After this the patient may continue with weekly octanorm SC infusions at 
home. However, every 4 weeks the infusion is to be given at the study site. In exceptional 
circumstances (e.g., vacation), and after discussion with the Sponsor, this interval may be 
extended by up to 2 weeks. 
6.1.2.1 Treatment Visits 2, 5, 8 and 11 (Weeks 1, 4, 16, and 28) 
At each of these visits at the study site, the following activities will be performed: 
• Determination of body weight. 

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• Physical examination including vital signs. 
• Drawing of blood samples for total IgG trough level (before IMP administration). 
• Drawing of blood samples for safety laboratory parameters. Urine sampling.  
• At Visit 8 (Week 16): urine sampling for urine pregnancy test (in females of 
childbearing potential only). 
• QoL assessment will take place before the first infusion at Visit 2. 
• Drawing of blood for viral markers test and retention sample before the first infusion 
at Visit 2. 
• IMP infusion. 
• Assessment of local injection site reactions. 
• Monitoring of AEs. 
• Documentation of concomitant medication 
• At Visits 8 and 11: collection and review of the patient diary. The Investigator will 
evaluate the patient’s diary and will ask the patient about the occurrence of any AEs 
and any changes in concomitant therapies (medication and non-drug therapy). 
Relevant data will be transcribed onto the eCRF. Discrepancies between patient diary 
entries and eCRF entries must be explained by the Investigator. 
6.1.2.2 Treatment Visits 3, 4, 6, 7, 9, 10 and 12 (Weeks 2, 3, 8, 12, 20, 24 and 32) 
At each of these visits at the study site, the following activities will be performed: 
• Determination of body weight. 
• Drawing of blood samples for total IgG trough level (before IMP administration). 
• IMP infusion. 
• Assessment of local injection site reactions. 
• Monitoring of AEs. 
• Documentation of concomitant medication 
• From Visit 6 onwards (i.e., those visits preceded by home treatment phase): Collection 
and review of the patient diary. The Investigator will evaluate the patient’s diary and 
will ask the patient about the occurrence of any AEs and any changes in concomitant 
therapies (medication and non-drug therapy). Relevant data will be transcribed onto 
the eCRF. Discrepancies between patient diary entries and eCRF entries must be 
explained by the Investigator. 
6.1.3 Study Termination Visit (Visit 13, Week 33) 
One week after the last infusion, or sooner if a patient withdraws prematurely from the study, 
a Termination Visit will be performed including the following assessments: 
• Physical examination (including vital signs). 
• Drawing of blood samples for total IgG trough level. 
• Drawing of blood samples for safety laboratory parameters including viral markers. 
• Urine sampling including urine pregnancy test (in females of childbearing potential 
only). 

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• QoL assessment. 
• Collection and review of the patient diary. 
• Changes in concomitant medications. 
• AE monitoring. 
6.1.4 Follow-up Phone Call (Week 36) 
Four weeks after the last dose of IMP (and 3 weeks after the Termination Visit), a phone call 
will be made to the patient to check on any changes regarding AEs and concomitant 
medication. After the phone call, the clinical study is considered completed for the patient. No 
further study-related assessments may be performed, unless safety concerns (e.g., ongoing 
AEs) require follow-up. 
6.1.5 Time Windows Used in this Study, including Tolerances 
There is a time window of ±2 days for all study visits (Visits 2 to 12) including the 
Termination Visit and the follow-up phone call (Table 3). 
Table 3 
Time Windows including Tolerances 
Time point 
Time stated 
Tolerance 
Screening 
Up to 7 weeks before the 
first IMP administration 
None 
octanorm infusions 
Weekly 
±2 days 
On-site Visits 2, 3, 4, 5, 6, 7, 8, 9, 
10, 11, 12, 13 
Weeks 1, 2, 3, 4, 8, 12, 
16, 20, 24, 28, 32 
±2 days 
In exceptional circumstances (e.g., 
vacation) this may be extended by 
up to 2 weeks. Note: visit schedule 
should be calculated based on 
Visit 2 as the baseline, to avoid 
slippage. 
Interval between Last Treatment 
Visit and (early) Termination Visit 
1 week 
±2 days 
Blood and urine sampling 
Before IMP 
administration 
−1 day 
octanorm infusion  
Every week=every 7 days 
±2 days 
6.2 Duration of Study 
6.2.1 Planned Duration for an Individual Patient 
The duration of the entire study for each patient will be approximately 43 weeks. 
6.2.2 Planned Duration for the Study as a Whole 
The study will be considered completed when all patients have completed the planned 
observation period/Final Examination Visit. 
The estimated start of the study (enrolment of first patient) is the second quarter of 2017, and 
the estimated end of the study (last visit of last patient) is the third quarter of 2018. 

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6.2.3 Premature Termination of the Study 
Both the Investigator and the Sponsor reserve the right to terminate the study at any time. In 
this event, any necessary 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. 
Regulatory authorities and independent ethics committees (IECs)/institutional review boards 
(IRBs) should be informed in accordance with national regulations. 
Early termination of the study as a whole or by centre may apply for the following reasons: 
6.2.3.1 Early Termination of the Entire Clinical Study 
At any time, the study as a whole will be terminated prematurely if: 
• New toxicological or pharmacological findings or safety reports invalidate the earlier 
positive benefit-risk-assessment. 
• If more than 2 TEEs (i.e., ischaemic stroke, transient ischaemic attack, cerebral 
infarction, cerebrovascular accident, cerebral thrombosis, embolic infarctions, [acute] 
myocardial infarction, deep vein thrombosis, pulmonary embolism, venous thrombosis 
excluding thrombophlebitis) are observed and are assessed as probably or possibly 
related to octanorm treatment by Investigator and/or Sponsor. 
• Any other reason rendering the continuation of the study impossible for the Sponsor. 
6.2.3.2 Early Termination at an Individual Study Centre 
At any time, the study can be terminated at an individual centre if: 
• The centre cannot comply with the requirements of the protocol. 
• The centre cannot comply with good clinical practice (GCP) standards. 
• The centre’s first patient is not recruited by 10 weeks after initiation of the centre. 
• The required recruitment rate is not met. 
Should the study be prematurely terminated, all study materials (patient diaries, IMPs, etc.) 
must be returned to the Sponsor. 

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7 
ASSESSMENTS AND METHODS 
7.1 Demographic and Baseline Information 
The following general or background assessments will be performed during the study at 
predefined time points: 
Demographic data: Sex, age, weight and height (calculated Body Mass Index), and ethnic 
origin. 
Medical history: All previous medical conditions and surgeries, the exact type of PI, all 
adverse conditions that have occurred during the last 30 days, with special emphasis on, but 
not restricted to, infections. Serious infections during the last 12 months should be recorded. 
Check for history or evidence of alcohol, drug, psychotropic agent or chemical abuse during 
the last 12 months. Obtained by interviewing the patient. 
Previous and ongoing therapies: All previous drug and non-drug therapies (e.g., 
physiotherapy) during the last 30 days and IV antibiotics during the last 12 months. Obtained 
by interviewing the patient. 
General physical examination, including vital signs. The physical examination will be 
performed according to study site’s routine procedures and will be as comprehensive as 
necessary to detect relevant somatic or neurological diseases. 
Chest X-ray. Obtained only if last available chest imaging (X-ray, CT or MRI) is older than 
12 months. 
7.2 Efficacy Assessments 
To study the effectiveness of octanorm in the prevention of infections, the following 
measurements will be recorded throughout the study: 
• Number of episodes of SBI, per person-year on treatment, along with type and severity 
of infection, and time to resolution. 
• Number of episodes of any other infections (including acute sinusitis, exacerbation of 
chronic sinusitis, acute otitis media, acute bronchitis, infectious diarrhoea etc), along 
with type and severity of infection, and time to resolution. 
• Use and number of days of use of antibiotics (oral, parenteral, oral plus parenteral, 
prophylactic and therapeutic), along with type and dosage of antibiotic. 
• Absence and number of days of absence from work or study. 
• Hospitalisations due to infections and number of days of hospitalisation, along with 
reason. 
• Number of episodes of fever. 
• QoL assessment. 
For the collection of the above measurements, each patient will be provided with an 
individual diary to be filled in by the patient during the time in between 2 octanorm infusion 
visits at the site (approximately every 4 weeks). The patient’s diary will be checked for 
accuracy of the data by the Investigator and collected at each visit. The data will be then 

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transferred into the eCRF. A new diary will be handed out to the patient for the following 
period until the next infusion visit at the site. 
7.2.1 Serious Bacterial Infections 
For the purpose of this study the following events will be considered as SBI: 
• Bacterial pneumonia. 
• Bacteraemia/sepsis. 
• Osteomyelitis/septic arthritis. 
• Visceral abscess. 
• Bacterial meningitis. 
The presence of any of these infections should be verified by the following specific 
differentiated diagnostic examinations [22]: 
Table 4 
Diagnostic Criteria for Serious Infection Types 
Bacterial Pneumonia a 
• 
Symptoms: productive cough/change in character of sputum, dyspnoea or tachypnoea, chills, 
chest pain, rigors, headache, fatigue, sweats, anorexia, myalgias. 
• 
Physical findings: rales; pulmonary consolidation as reflected by: dullness on percussion, 
bronchial breath sounds, egophony; fever >38°C oral or >39°C rectal, or <36°C, hypothermia 
(temperature <36°C oral or <37°C rectal). 
• 
Laboratory tests: leukocytosis, differential WBC count of >10% band neutrophils, 
leukopenia, hypoxemia (PaO2 <60 mm Hg on room air), positive blood culture, Gram stain 
and culture of deep expectorated sputum b, positive culture with or without positive Gram 
stain of transtracheal aspirate, pleural fluid culture, lung biopsy, bronchoscopy with 
bronchoalveolar lavage or protected brush sampling. 
• 
Imaging studies: Pulmonary infiltrate with consolidation on chest X-ray (new in 
comparison with baseline chest X-ray) 
Bacteraemia/sepsis c 
• 
Symptoms: chills, rigors. 
• 
Physical findings: fever, hypothermia, tachycardia, tachypnoea, hypocarbia, hypotension 
(systolic blood pressure <90 mm Hg or a reduction of >40 mm Hg from baseline in the 
absence of other causes of hypotension), altered mental status, petechiae, purpura, oligouria, 
cutaneous vasodilation/vasoconstriction. 
• 
Laboratory tests: positive blood culture d, leukocytosis (white blood cell (WBC) count 
>12,000/mm3), differential WBC count demonstrating >10% immature (band) neutrophils, 
leukopenia, thrombocytopenia, coagulopathy, lactic acidosis. 

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Osteomyelitis/Septic Arthritis  
• 
Symptoms: pain, decreased range of motion, tenderness, oedema, redness, warmth over the 
involved site (local inflammatory symptoms/signs may be lacking in adults). 
• 
Physical findings: evidence of soft tissue infection adjacent to the involved bone/joint, 
drainage from sinus tract from involved bone, fever of >38°C oral or >39°C rectal. 
• 
Laboratory tests: positive blood culture, positive probe to bone, positive bone aspirate 
culture, positive bone biopsy culture, positive bone histopathology, positive joint fluid Gram 
stain and culture. 
• 
Imaging studies: positive X-ray, nuclear medicine bone scan, magnetic resonance 
imaging scan, or computed tomography scan showing bony destruction with 
radiolucent areas; for chronic osteomyelitis: sequestra, involucra. 
Visceral Abscess 
• 
Symptoms: abdominal pain, anorexia, weight loss, cough/pleuritic chest pain (hepatic 
abscess), rigors (seldom present). 
• 
Physical findings: intermittent fevers (temperature >38°C oral or >39°C rectal), abdominal 
tenderness, palpable mass, hepatomegaly, jaundice. 
• 
Laboratory tests: positive Gram stain and/or culture from the infected site, with 
isolation of an appropriate pathogen, positive blood culture, leukocytosis with 
accompanying left shift, differential WBC count of >10% immature (band) neutrophils, 
elevated serum amylase concentration (pancreatic abscess), elevated alkaline phosphatase 
concentration (hepatic abscess) pyuria in renal abscess. 
• 
Imaging studies: typical findings on ultrasound, computed tomography scan, magnetic 
resonance imaging scan, or radionuclide scan 
Bacterial Meningitis 
• 
Symptoms: headache, stiff neck, mental status changes, irritability, decreased feeding 
(infants), photophobia, nausea/vomiting, rigors, seizures. 
• 
Physical findings: Kernig’s sign, Brudzinski’s sign, meningococcal rash, fever of >38°C oral 
or >39°C rectal. 
• 
Laboratory tests: positive cerebrospinal fluid (CSF) Gram stain and/or culture and/or 
positive CSF bacterial antigen assay, positive blood culture e, CSF leukocytosis with 
neutrophil predominance, decrease in CSF glucose. 
Note: Items in bold are considered essential diagnostic features. 
a For the diagnosis of pneumonia in adults, commonly at least 2 of the listed symptoms and/or signs should be present in 
conjunction with at least one laboratory and one imaging studies diagnostic element. However, for the purposes of counting 
serious infection episodes in a clinical trial of IVIG, the finding of a new pulmonary infiltrate with consolidation on chest X-ray is 
considered sufficient. 
b It is recommended to obtain a deep expectorated sputum gram stain to demonstrate the presence of microorganisms on 
examination of 10-20 oil immersion microscopic fields and <10 squamous epithelial cells and >25 polymorphonuclear 
leukocytes at 10X low power magnification to determine suitability of sputum culture. 
c Two of the following should be present to make the diagnosis of sepsis in adults: temperature >38°C oral/ >39°C rectal or 
<36°C oral or <37°C rectal; heart rate >90 beats/min; respiratory rate >20 breaths/min, or PaCO2 <32 mm Hg; WBC count 
>12,000/mm3, <4,000/mm3, or >10% immature (band) forms.  
d Indwelling catheter- or vascular access device-related blood-borne infections are not included because evidence is lacking that 
these are preventable with IVIG replacement therapy. For subjects without indwelling catheters or vascular access devices, a 
single blood culture positive for a pathogenic organism will meet the diagnostic criteria for bacteraemia. Subjects meeting 
criteria for positive blood culture but without 2 or more of the sepsis criteria listed above will be classified as having 
bacteraemia.  
e A blood culture positive for growth of Streptococcus pneumoniae, Neisseria meningitides, or Haemophilus influenzae, in 
combination with CSF leukocytosis and/or decrease in CSF glucose, can serve to confirm the diagnosis of acute bacterial 
meningitis.  

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7.3 Safety Assessments 
7.3.1 Assessments for Safety Endpoints 
Any of the following drug safety information shall be collected: 
• Adverse events (AEs) and serious adverse events (SAEs) temporally associated with 
the administration of IMP, comparator, or placebo (for definitions and reporting 
requirements, see Sections 7.3.2, 7.3.3, and 7.3.4) 
• Pregnancies, drug overdose, interaction, medication error, lack of efficacy, and post-
study SAEs (see Section 7.3.8) 
7.3.2 Adverse Events (AEs) 
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 unfavourable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an IMP, whether or not related to the IMP. 
• Adverse drug reaction (ADR): An ADR is any noxious and unintended response to 
an IMP related to any dose. The phrase ‘response to an IMP’ means that a causal 
relationship between the IMP and an AE carries at least a reasonable possibility, i.e., 
the relationship cannot be ruled out. 
• Other significant AEs: Any marked laboratory abnormalities or any AEs that lead to 
an intervention, including withdrawal of drug treatment, dose reduction, or significant 
additional concomitant therapy. 
• Withdrawal due to AE/ADR: AE/ADR leading to discontinuation of treatment 
with IMP. Any such events will be followed up by the Investigator until the event is 
resolved or until the medical condition of the patient is stable. All follow-up 
information collected will be made available to the Sponsor. 
7.3.2.2 Collection of AEs 
The condition of the patient will be monitored throughout the study, i.e., up to 4 weeks after 
the last dose of IMP. At each visit, whether scheduled or unscheduled, AEs will be elicited 
using a standard nonleading question such as “How have you been since the last visit/during 
the previous study period?” In addition, the Investigator will check the patient diaries (if 
applicable) for any documented event. 
Any AE or ADR 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 representing a single 
syndrome or diagnosis, the diagnosis should be recorded in the CRF. The Investigator will 
grade the severity of all AEs or ADRs (mild, moderate, or severe), the seriousness (non-
serious or serious), and the causality as defined in Sections 7.3.2.3, 7.3.3, and 7.3.2.4. The 
Sponsor is responsible for assessing the expectedness of each ADR (expected or unexpected) 
as defined in Section 7.3.2.5. 

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In the event of clinically significant abnormal laboratory findings, the tests will be confirmed 
and the patient followed up until the laboratory values have returned to normal and/or an 
adequate explanation for the abnormality has become available. 
Diseases, signs and symptoms, and/or laboratory abnormalities already present before the first 
administration of IMP will not be considered AEs unless an exacerbation in intensity or 
frequency (worsening) occurs. 
The Investigator will provide detailed information about any abnormalities and about the 
nature of and reasons for any action taken as well as any other observations or comments that 
may be useful for the interpretation and understanding of an AE or ADR. 
7.3.2.3 Severity of AEs 
The intensity/severity of AEs will be graded as follows: 
• Mild: an AE, usually transient, which causes discomfort but does not interfere with 
the patient’s routine activities 
• Moderate: an AE which is sufficiently discomforting to interfere with the patient’s 
routine activities 
• Severe: an AE which is incapacitating and prevents the pursuit of the patient’s routine 
activities 
The grading of an AE is up to the medical judgement of the Investigator and will be decided 
on a case-by-case basis. 
7.3.2.4 Causality of AEs 
The relationship of AEs to the administered IMP will be assessed by the Investigator: 
• Probable: reports including good reasons and sufficient documentation to assume a 
causal relationship, in the sense of plausible, conceivable, likely, but not necessarily 
highly probable. A reaction that follows a reasonable temporal sequence from 
administration of the IMP; or that follows a known or expected response pattern to the 
suspected medicine; or that is confirmed by stopping or reducing the dosage of the 
medicine and that could not reasonably be explained by known characteristics of the 
patient’s clinical state. 
• Possible: reports containing sufficient information to accept the possibility of a causal 
relationship, in the sense of not impossible and not unlikely, although the connection 
is uncertain or doubtful, for example because of missing data or insufficient evidence. 
A reaction that follows a reasonable temporal sequence from administration of the 
IMP; that follows a known or expected response pattern to the suspected medicine; but 
that could readily have been produced by a number of other factors. 
• Unlikely: reports not following a reasonable temporal sequence from IMP 
administration. An event which may have been produced by the patient’s clinical state 
or by environmental factors or other therapies administered. 
• Not related (unrelated): events for which sufficient information exists to conclude 
that the aetiology 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). 

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7.3.2.5 Classification of ADRs by Expectedness 
ADRs will be classified by the Sponsor as either expected or unexpected: 
• Expected: an ADR that is listed in the current edition of the Investigator’s Brochure 
or other reference safety information. 
• Unexpected: an ADR that is not listed in the current edition of the Investigator’s 
Brochure or other reference safety information, or that differs because of greater 
severity or greater specificity. 
7.3.2.6 Outcome of AEs 
The outcome of all reported AEs 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 
the patient’s death must be fully documented and reported, even in case the death occurs 
within 4 weeks after IMP treatment end (i.e., up to the follow-up phone call) and regardless of 
whether or not it is considered treatment-related. 
7.3.2.7 Action(s) taken 
AEs requiring action or therapy must be treated with recognised standards of medical care to 
protect the health and well being of the patient. Appropriate resuscitation equipment and 
medicines must be available to ensure the best possible treatment in an emergency situation. 
The action taken by the Investigator must be documented: 
a) General actions taken in the event of an AE 
– None 
– Medication (other than IMP) or other (e.g., physical) therapy started 
– Test performed 
– Other (to be specified) 
b) IMP-related actions taken in the event of an AE 
– None 
– Product withdrawn 
– Treatment interrupted 
– Dose reduced 
– Dose increased 

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The Investigator will follow up on each AE until it has resolved or until the medical condition 
of the patient has stabilised. Any relevant follow-up information will be reported to the 
Sponsor. 
7.3.3 Serious Adverse Events (SAEs) 
An SAE is any untoward medical occurrence that at any dose: 
• results in death, 
• is life-threatening (see below), 
• requires hospitalisation or prolongation of existing hospitalisation, 
• results in persistent or significant disability/incapacity, 
• is a congenital anomaly/birth defect, 
• is another important medical event. 
NOTE: The term ‘life-threatening’ refers to an event in which the patient was, in the view of 
the reporting Investigator, at immediate risk of death at the time of the event; it does not refer 
to an event which may hypothetically have caused death had it been more severe. 
In deciding whether an AE/ADR is serious, medical judgment should be exercised. Thus, 
important AEs/ADRs that are not immediately life-threatening or do not result in death or 
hospitalisation but may jeopardise the patient or may require intervention to prevent one of 
the other outcomes listed in the definitions above should also be considered serious.  
In addition, although not classified under the seriousness criteria, all suspected transmissions 
of an infectious agent should be reported as SAE. A suspected virus transmission means that 
virus antigen has been detected in the patient. A passive transmission of antibodies alone does 
not constitute a suspected virus transmission. 
Hospitalisation is NOT considered an SAE in case of: 
• hospitalisation because of study-related procedures; hospitalisation due to hospital 
standard measures (hospitalisation for the first infusion of study drug etc.) 
• an elective medical procedure for which the date was scheduled prior to inclusion in 
the study 
• hospitalisation or prolongation of the existing hospitalisation due to economical or 
social, but not due to medical reasons. 
7.3.4 SAE Reporting Timelines 
All SAEs, whether or not they are suspected to be related to study treatment, are to be 
reported within 24 hours after recognition of the event by telephone, fax, or email: 
To CRO: 
• Telephone/Fax Number: +7 812 324 45 13 
Email:  
safety@SMOOTHDD.com 
 

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In addition, within 24 hours after recognition of the event by the site an Octapharma Serious 
Adverse Event Report must be submitted by the CRO to: 
Octapharma’s Corporate 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: +43 1 40 80 500 
The contact details will also be communicated at the study initiation visit. 
7.3.5 Local Infusion Site Reactions 
Local injection site reactions are to be assessed by both patients and investigators. 
Patients have to grade the overall perception of local reactions in their diaries within 
approximately 1 day post-infusion using a 4-point rating scale: 0=none, 1=mild, 2=moderate, 
3=severe). 
Investigators have to evaluate local reactions at within approximately 1 hour post-infusion for 
the first 4 infusions at the study site and at every study site visit thereafter, using a 4-point 
rating scale: 0=none, 1=mild, 2=moderate, 3=severe. 
The following observations must not be reported as local infusion site reactions as all of 
them can be expected in all patients:  
• Local mass (usually reported as "swelling") caused by the injected octanorm volume;  
• Small blood drops at the injection site caused by the needle puncture(s);  
• and short and immediate pain at the injection site caused by the puncture itself.  
Any other local injection site reactions such as redness, pain (other than the pain caused by 
the puncture itself), pruritus, rash or other skin reactions, bleeding (other than small blood 
drops caused by the needle puncture), local thrombosis, induration or swellings (caused by 
other grounds than the injected volume) must be reported on the local injection site reaction 
page in the eCRF. 
7.3.6 Laboratory Tests 
The following laboratory parameters will be investigated during the study at the time points 
specified in Section 6 and shown in the flow chart of assessments in Table 1: 

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Table 5 
Laboratory Tests and Time Points 
Test 
Timing 
Laboratory 
Total serum IgG trough levels 
At Screening (if last IVIG infusion is 
given during Screening Period), before 
any infusion given at the study site and at 
(early) Termination Visit. 
Local 
Hematology (complete blood count, 
WBC differential, haematocrit, 
haemoglobin) 
At Screening, and pre-infusion at Weeks 
1, 4, 16 and 28, and at (early) Termination 
Visit. 
Local 
Clinical chemistry (sodium, 
potassium, glucose, ALAT, ASAT, 
LDH, total bilirubin, blood urea 
nitrogen or blood urea, creatinine) 
At Screening, and pre-infusion at Weeks 
1, 4, 16 and 28, and at (early) Termination 
Visit. 
Local 
Urinalysis: pH, glucose, ketones, 
leukocytes 
At Screening, and pre-infusion at Weeks 
1, 4, 16 and 28, and at (early) Termination 
Visit. 
Local 
Urine pregnancy test (women of 
childbearing potential) 
At Screening, at Week 16, and at (early) 
Termination Visit; at other times if 
indicated. 
Local 
Virology: NAT: HAV, HBV, HCV, 
HIV, parvovirus B19 
At Screening, at Week 1 and at (early) 
Termination Visit. 
Local or 
central 
Retention samples 
At Week 1 and at (early) Termination 
Visit. 
Central 
IgG (immunoglobulin G); WBC (white blood cell); ALAT (alanine aminotransferase); ASAT 
(aspartate aminotransferase); lactate dehydrogenase (LDH); HBsAg (hepatitis B surface antigen); 
NAT (nucleic acid testing); HAV (hepatitis A virus); HBV (hepatitis B virus); HCV (hepatitis C 
virus); HIV (human immunodeficiency virus). 
 
Local laboratory determinations will be done at the individual study sites according to local 
procedures. A laboratory manual detailing the procedures for the central laboratory samples 
will be distributed to all study sites. 
7.3.6.1 Central Laboratory 
Retention samples of all blood draws for virus safety will be kept at ≤−70°C at the central 
laboratory for possible future testing. 
Samples must be frozen at ≤−70°C. At sites where a freezer of −70°C or below is not 
available, samples can be stored at or below −20°C. In such cases, shipment to the central 
laboratory should be performed shortly, but not later than 2 months, after the day of 
collection. 
In case it is not possible to test at the local laboratory, the following laboratory tests will be 
done at a central laboratory: 
• Virology: NAT (Technology of Nucleic Acid testing according to local procedures): 
hepatitis A virus (HAV), HBV, HCV, HIV, parvovirus B19. 

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At the Screening Visit, before the first octanorm infusion, samples will be taken for testing of 
viral markers at a local or central laboratory. A positive result on HIV, HCV or HBV viral 
markers is a non inclusion criterion and the results must be available before the start of IMP 
treatment. For patients positive in parvovirus B19 or HAV at baseline, follow-up samples may 
be omitted.  
For details see the Central Laboratory Manual. 
7.3.6.2 Local Laboratory 
The laboratory tests to be done by the local laboratories of each study site are listed in Table 
5. 
The methods of determination and normal ranges for each parameter will be provided in the 
clinical study report.  
7.3.7 Vital Signs and Physical Examination 
The vital signs obtained at the time points specified in Section 6 are blood pressure, body 
temperature, pulse rate, and respiratory rate. Measurements will be carried out before and 
within 1 hour after the infusion of IMP, except for temperature which will only be measured 
before the infusion.  
Physical examinations will be performed at the visits specified in Section 6. Both height and 
weight will be measured at baseline. In addition, weight will be measured at all visits prior to 
dosing. 
After each on-site dose of octanorm, patients must be monitored at the study site for at least 
one hour. 
7.3.8 Other Relevant Safety Information 
a) Post-study related safety reports 
Any SAE which occurs up to 4 weeks after the last IMP administration will be reported by the 
Investigator to the Sponsor. Proactive monitoring for post-study SAEs is not required. 
In case a post-study SAE is identified, the Investigator should complete an SAE form and also 
state the relation to the clinical study in the report. 
Deaths occurring within 4 weeks after the last IMP administration should also be reported, 
regardless of whether or not they are considered treatment-related. 
b) Pregnancies 
Every effort will be made to avoid a pregnancy during the use of an IMP. Pregnancies 
occurring during the study (foetal exposure to the IMP) need to be reported.  
In case of pregnancy during the study, the Investigator should complete the Pregnancy 
Notification Form and send or fax it to the CRO (see Section 7.3.4 for the contact email and 
fax number). 
Follow-up information on the outcome of both mother and foetus will be requested by a 
Sponsor representative. 

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c) Overdose, interaction, medication error and lack of efficacy 
The following safety relevant information should be reported as AE or, if the reaction fulfils 
one of the criteria for seriousness, as SAE. 
Drug overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
specified in the protocol and higher than the known therapeutic dose that is of clinical 
relevance. The reaction must be clearly identified as an overdose. 
Drug interaction 
A drug interaction is a situation in which a substance or medicinal product affects the activity 
of an IMP, i.e., increases or decreases its effects, or produces an effect that none of the 
products would exhibit on its own. The reaction must be clearly identified as a drug 
interaction. 
Medication error 
A medication error involves the inadvertent administration or unintended use of a medicinal 
product which may be caused by the naming, presentation of pharmaceutical form/packaging, 
or instructions for use/labelling. The reaction must be clearly identified as a medication error. 
7.4 Other Assessments 
7.4.1 Quality of Life Assessment 
The QoL assessment will be made using the SF-36 Health Survey.  
7.5 Appropriateness of Measurements 
The therapeutic efficacy, defined as the prevention of SBI, is a very important clinical aspect 
of any IgG replacement therapy and best characterises benefit to the patient. 
Determination of the pre-next-dose trough level of IgG is a standard method for determination 
of the correct dose for the individual patient. 
The QoL questionnaire is a standardised, validated instrument that has been widely used in 
clinical studies, including studies with PI patients. 

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8 
DATA HANDLING AND RECORD KEEPING 
8.1 Documentation of Data 
8.1.1 Source Data and Records 
Source data are defined as all information related to clinical findings, observations, or other 
activities in the study, written down in original records or certified copies of original records, 
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. 
All data entered in the CRF must be supported by source data in the patient records, with 
exceptions listed in Section 8.1.2. 
The Investigator will permit study-related monitoring, audit(s), IEC/IRB review(s), and 
regulatory inspection(s), by providing direct access to the source data/records. 
The Investigator may authorise site staff (e.g., sub-investigators, nurses) to enter study data 
into the CRF. This must be documented in the Delegation of Authority Log signed by the 
Investigator. 
8.1.2 Case Report Forms 
For each patient enrolled, an eCRF will be completed within the EDC system and approved 
by the Investigator or an authorised sub-investigator. 
Study site staff (e.g., research nurse) will be responsible for entering 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. 
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 be listed in the Delegation 
of Authority Log. 
8.1.3 Changes to Case Report Form (CRF) Data 
Monitors will perform source data verification (SDV) as defined for the study. 
If any errors or discrepancies in the eCRFs are found during data entry or review, 
discrepancies will be generated programmatically within the EDC system, and ‘manual’ 
queries will be generated by either a monitor or Data Management.  
Discrepancies and queries can only be corrected by the Investigator(s) or other authorised site 
personnel. An audit trail documents all changes to the data over the entire study period. If the 
reason for a change is not obvious, a comment must be supplied in the query’s response, 

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stating the reason for the change, prior to closing. The study monitor should provide guidance 
to Investigator(s) and the Investigator(s)’ designated representatives on making such 
corrections.  
Once queries have been resolved by the site staff, the resolutions are assessed by Data 
Management. If the query response provided confirms the data as correct, the discrepancy will 
be closed. If the response does not adequately address the question raised, a new query will be 
issued for further clarification. 
Manual checks 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 
approved by the Investigator prior to database lock. 
8.2 Information to Investigators 
An Investigator’s Brochure (IB) will be handed out to the Investigator before the start of the 
study. The IB contains all information in the Sponsor’s possession necessary for the 
Investigator to be fully and accurately informed about the safety of the IMP under evaluation 
and the respective benefit-risk ratio. 
The IB will be updated by the Sponsor at regular intervals and whenever relevant new 
information concerning the IMP becomes available. 
All participating investigators will be informed about the relevant study procedures, about the 
methods for rating relevant study outcomes and how to complete the eCRF in order to reduce 
discrepancies between participating investigators and study sites. At the study initiation visit, 
the eCRF will be explained to all study site staff entitled to document data in the eCRF. 
The Investigator will be kept informed of important data that relate to the safe use of the IMP 
as the study proceeds. 
8.3 Responsibilities 
The Investigator is accountable for the conduct of the clinical study. Responsibilities may be 
delegated to appropriately qualified persons. 
The Investigator shall maintain a list of appropriately qualified persons to whom he/she has 
delegated significant study-related duties. This “Delegation of Authority Log” will be filled in 
and signed by the Investigator. In accordance with this authority log, study site staff (e.g., 
sub-investigators, nurses) is authorized to perform study related tasks and to enter specific 
data into the eCRF. 
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. 

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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. 
8.5 Provision of Additional Information 
On request, the Investigator will supply the Sponsor with additional data relating to the study, 
or copies of relevant source records, ensuring that the patient’s confidentiality is maintained. 
This is particularly important when source data 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 
An Independent Data Monitoring Committee will not be established for this study. 

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9 
STATISTICAL METHODS AND SAMPLE SIZE 
The statistical analysis will be delegated under an agreement of transfer of responsibilities to 
an external 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 
This uncontrolled study is designed to obtain data on IgG trough levels in PI patients in 
Russia, along with clinical safety and efficacy data. The sample size of approximately 20 to 
25 evaluable patients will provide local data to supplement the PK data from the SCGAM-01 
study that is compliant with the CHMP recommendations for this indication (CHMP Note for 
Guidance EMA/CHMP/BPWP/94033/2007 rev. 2). No formal sample size calculation is 
provided. 
No attempts will be made for a balanced inclusion of male and female patients. 
9.2 Statistical Analysis 
A formal statistical analysis plan (SAP) describing all details of the analyses to be performed 
will be prepared by the study statistician and approved by the Sponsor prior to the start of the 
statistical analysis. 
In addition to the specific analyses detailed in the subsequent sections, all collected efficacy 
and safety assessments and derived endpoints will be presented by means of descriptive 
statistics. 
If not detailed otherwise in the SAP, study parameters will be presented according to their 
data type. The number of subjects in the analysis population and the number of subjects 
contributing to each particular summary will be included in every presentation. 
• Binary data (whether or not an event has occurred): counts and proportions 
• Count data (the frequency of an event in a set time period): rate (count per unit time) 
• Continuous data (measurements on a continuous scale, including quasi-continuous 
variables): arithmetic mean, standard deviation, median, lower and upper quartile, 
minimum, maximum 
Scales data (ordinal and non-ordinal): absolute and relative frequencies. Where appropriate, 
results will be presented grouped by different subject characteristics (e.g., gender) as well as 
in total. 
Additional descriptive and exploratory statistics, such as the geometric mean or confidence 
intervals, will be included as appropriate. If not mentioned otherwise, confidence intervals are 
to be understood as two-sided, 95% confidence intervals. 
9.2.1 Populations for Analysis 
The total set consists of all patients enrolled in the trial including drop-outs. For the statistical 
analyses the following 3 sets will be deployed: 
The safety set consists of all patients who received at least one infusion of IMP; it is the set of 
patients exposed to treatment. 

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The full analysis (FA) set consists of all patients of the safety set who satisfy all major 
eligibility criteria and for whom any post-baseline data is available. It is the set of eligible 
patients with treatment effects measured, according to the intention-to-treat (ITT) principle. 
The per-protocol (PP) set consists of all patients of the FA set excluding those patients with 
major protocol deviations which may have an impact on the analysis of efficacy. This is the 
set of patients who participated in the trial as intended and for whom efficacy can be 
evaluated as planned. 
All protocol deviations documented during the conduct of the study or identified at the data 
review process prior to database lock will be reviewed and classified as minor or major and 
with respect to their significance for the planned analyses. Only significant protocol 
deviations with the potential to affect the study results or to invalidate the interpretation of the 
data obtained will lead to exclusion of subjects from the PP set. This classification of protocol 
deviations is the joint responsibility of the clinical study manager, the study statistician, and 
Octapharma’s responsible medical expert, and will be performed and documented before the 
database is locked and the statistical analyses are performed. 
All efficacy endpoints will be analysed on the basis of both the ITT and the PP analysis sets, 
to allow for an assessment of the robustness of the results with respect to protocol deviations. 
Analysis of the safety endpoints will be based on the safety set. 
9.2.2 Efficacy Analysis Plan 
The efficacy of octanorm in the prevention of infections will be evaluated by the following 
measurements: 
• Number of episodes of SBI, per person-year on treatment, along with type and severity 
of infection, and time to resolution. 
• Number of episodes of any other infections (including acute sinusitis, exacerbation of 
chronic sinusitis, acute otitis media, acute bronchitis, infectious diarrhoea etc), along 
with type and severity of infection, and time to resolution. 
• Use and number of days of use of antibiotics (oral, parenteral, oral plus parenteral, 
prophylactic and therapeutic), along with type and dosage of antibiotic. 
• Absence and number of days of absence from work or study. 
• Hospitalisations due to infections and number of days of hospitalisation, along with 
reason. 
• Number of episodes of fever. 
• The QoL data will be presented descriptively by visit, along with the change from 
baseline (defined as the first infusion). 
Trough levels of IgG will be summarised by infusion number and presented graphically as 
time profiles. In addition, the frequency of pre-next dose IgG trough levels below 5 g/L will 
be presented for each infusion. 
9.2.3 Safety Analysis Plan 
The safety analysis will comprise descriptive statistics, tabulations and listings of all TEAEs, 
safety laboratory results, viral markers, vital signs and physical examination findings. 

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9.2.3.1 Adverse Events 
All reported AEs will be coded according to Medical Dictionary for Regulatory Activities 
(MedDRA). 
An AE is defined as treatment-emergent, if first onset or worsening is after start of the first 
infusion of octanorm. Only TEAEs are accounted for in the analysis. 
AEs that occur between informed consent and the start of the first infusion of octanorm will 
also be documented and will be flagged as pre-treatment AEs. 
For each TEAE, the time relative to the start of the infusion will be calculated and the TEAE 
will be classified as temporally associated if the onset is during the infusion or within 
72 hours after the end of the infusion. 
In addition ADRs are defined as any noxious and unintended response to an IMP related to 
any dose (i.e., a causal relationship between the IMP and an AE carries at least a reasonable 
possibility and a relationship cannot be ruled out). 
All reported events will be listed and tabulated in full detail, in particular the following key 
figures will be presented for each age group and for the study as a whole: 
• Total number of TEAEs reported. 
• Number of temporally associated TEAEs. 
• Number of ADRs. 
• Number and percentage of infusions temporally associated with one or more TEAE. 
• Number of temporally associated TEAEs divided by the total number of infusions. 
• Number of ADRs divided by the total number of infusions. 
Narratives will be prepared describing each death, other SAEs, and other significant AEs that 
are judged to be of special interest because of clinical importance. 
9.2.4 Handling of Missing Data 
In general, missing data will not be imputed. Calculations pertaining to person-year 
computations will be based on observed values only. 
Only in case of missing body weight will the last available weight measurement be used for 
calculating the dose/kg bodyweight for the previous IVIG infusions (last observation carried 
forward, LOCF). 
9.3 Randomisation, Stratification, and Code Release 
Not applicable to this study. 

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10 ETHICAL/REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS 
10.1 Ethical/Regulatory Framework 
This study will be conducted in accordance with the ethical principles laid down in the 
Declaration of Helsinki. The study protocol and any subsequent amendment(s) will be 
submitted to an IEC/IRB and to the Regulatory Authority. The study will be conducted in 
compliance with the protocol, GCP guidelines, and applicable regulatory requirements. 
The regulatory application or submission for regulatory approval will be made by the Sponsor 
or designated third party (e.g., CRO) as required by national law. Study approval must be 
available before any patient is exposed to a study-related procedure. 
The Competent Authorities and the IECs/IRBs will be notified of the end of the clinical study 
in accordance with local regulations. 
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 must be approved by the IEC/IRB and the Regulatory Authority before any IMP may be 
shipped to the study sites and any patient is exposed to a study-related procedure. 
The Sponsor, the Investigator, and any third party (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 
The Investigator will obtain freely given written consent from each patient after an 
appropriate explanation of the aims, methods, anticipated benefits, potential hazards, and any 
other aspect of the study which is relevant to the patient’s decision to participate. The 
informed consent form must be signed, with name and date and time noted by the patient, 
before the patient is exposed to any study-related procedure, including screening tests for 
eligibility. 
The Investigator will explain to each single patient 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 study 
monitors, quality assurance auditors, or health authority inspectors, 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 and the 
Sponsor prior to its implementation. Any such amendments will be submitted to the any 

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competent IEC/IRB and/or competent authority responsible as required by applicable 
regulations. 
IEC/IRB approval will, at a minimum, be requested for any change to this protocol which 
could affect the safety of the patients, the objective/design of the study, any increase in dosage 
or duration of exposure to the IMP, an increase in the number of patients treated, the addition 
of a new test or procedure, or the dropping of a test intended to monitor safety. 
10.5 Confidentiality of Patient Data 
The Investigator will ensure that the patient’s confidentiality is preserved. On eCRFs or any 
other documents submitted to the Sponsor, the patients will not be identified by their names, 
but by a unique patient identifier. Documents not intended for submission to the Sponsor, i.e., 
the confidential subject identification code list, original consent forms, and source records, 
will be maintained by the Investigator in strict confidence. 

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11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Periodic Monitoring 
The monitor will contact and visit the Investigator periodically to review all study-related 
source data/records, verify the adherence to the protocol and the completeness, correctness 
and accuracy of all CRF entries compared to source data. The Investigator will co-operate 
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, but is expected to be 
approximately every 4-6 weeks. A study Initiation Visit and Termination Visit must take 
place. 
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyse, 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 efficacy of the IMP have been reported to the Sponsor. 

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12 REPORTING AND PUBLICATION 
12.1 Clinical Study Report 
A clinical study report (in accordance with relevant guidelines and the Sponsor’s SOPs) will 
be prepared by the Sponsor after completion of the study. The Octapharma International 
Medical Director 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. 
In accordance with standard editorial and ethical practice, the Sponsor will support 
publication of multi-centre studies only in their entirety and not as individual centre data. 
Authorship will be determined by mutual agreement. 

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13 LIABILITIES AND INSURANCE 
In order to cover any potential damage or injury occurring to a patient in association with the 
IMP or participation in the study, the Sponsor 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. 

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14 REFERENCES 
 
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subcutaneous IgG vs. intravenous IgG and selecting an optimal dose. Current opinion in allergy 
and clinical immunology 2011;11:532-538. 
 2.  Berger M, Jolles S, Orange JS, et al: Bioavailability of IgG Administered by the Subcutaneous 
Route. Journal of Clinical Immunology 2013;DOI 10.1007/s10875-013-9876-3- 
 3.  Orange JS, Belohradsky BH, Berger M, et al: Evaluation of correlation between dose and 
clinical outcomes in subcutaneous immunoglobulin replacement therapy. Clin Exp.Immunol 
2012;169:172-181. 
 4.  Misbah S, Sturzenegger MH, Borte M, et al: Subcutaneous immunoglobulin: opportunities and 
outlook. Clin Exp Immunol 2009;158:51-59. 
 5.  Hagan JB, Fasano MB, Spector S, et al: Efficacy and safety of a new 20% immunoglobulin 
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15 APPENDICES 
Not applicable.