Clinical trial NCT03907241
Conditions: Primary Immunodeficiency
Sponsor: Octapharma
Start date: 2016-03-01; Completion date: 2019-09-05
Enrollment: 27 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Summary for SCGAM-03: Clinical phase III study to monitor the safety, tolerability and efficacy of subcutaneous human immunoglobulin (Octanorm) in patients with primary immunodeficiency diseases who have completed the SCGAM-01 trial.

Summary for SCGAM-03 in Canada: Clinical phase III study to monitor the safety, tolerability and efficacy of subcutaneous human immunoglobulin (octanorm) in patients with primary immunodeficiency diseases, including (but not limited to) those who have completed the SCGAM-01 trial

Detailed description:

Arms: arm 1: octanorm 16.5%, human normal immunoglobulin for subcutaneous (SC) administration.
Interventions: intervention 1: Octanorm 16.5%
Intervention descriptions: intervention 1: Human normal immunoglobulin

Protocol documents:
Prot_002.pdf: 
CLINICAL STUDY PROTOCOL 
CLINICAL PHASE III STUDY TO MONITOR THE SAFETY, 
TOLERABILITY AND EFFICACY OF SUBCUTANEOUS 
HUMAN IMMUNOGLOBULIN (OCTANORM) 
IN PATIENTS WITH PRIMARY IMMUNODEFICIENCY 
DISEASES, INCLUDING (BUT NOT LIMITED TO) THOSE 
WHO HAVE COMPLETED THE SCGAM-01 TRIAL 
Investigational Product: 
Octanorm 
Indication: 
Primary immunodeficiency diseases 
Study Design: 
Prospective, open-label, non-controlled, single-arm, 
multicentre phase III study 
Sponsor: 
OCTAPHARMA Pharmazeutika Prod.Ges.m.b.H., 
Oberlaaer Strasse 235, 1100 Vienna, Austria 
Study Number: 
SCGAM-03 
BB-IND Number: 
15617 
ClinicalTrials.gov ID: 
NCT02627300 
Development Phase: 
Phase III 
Planned Clinical Start: 
2nd quarter 2016 
Planned Clinical End: 
4th quarter 2018 
Date of Protocol: 
25 October 2017 
Version: 
05 - Canada 
Coordinating Investigator: 
<To be added> 
NOTE: This document contains confidential and proprietary information of Octapharma PPG. 
Do not copy or distribute without written permission. 
090-CSP-SCGAM-03-v5/DOC ID 2684
This document contains confidential and proprietary information of Octapharma. Copying or
distribution of this document is only permitted with the written permission of Octapharma. Any
commercial use of the information is subject to the permission of Octapharma and a license fee.


Study Protocol SCGAM-03 Version 05 - Canada  
CONFIDENTIAL 
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-03 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Edition / Date of Protocol: 
05 - Canada 
Title of Study: 
Clinical phase III study to monitor the safety, tolerability and efficacy of subcutaneous human 
immunoglobulin (octanorm) in patients with primary immunodeficiency diseases, including (but not 
limited to) those who have completed the SCGAM-01 trial 
Indication: 
Primary immunodeficiency (PI) diseases. 
Number of Study Centre(s): 
5-7 selected study sites in the United States and Canada that have participated in the SCGAM-01 
trial. 
Study Duration: 2016 to 2018 
Development Phase: III 
Objectives: 
Primary: 
To assess the medium-to-long-term safety and tolerability of octanorm. 
Secondary: 
To assess the effect of octanorm on quality-of-life (QoL) measures. 
To obtain further data on the efficacy of octanorm. 
Study Design: 
The study is a prospective, open-label, non-controlled, single-arm, multicentre phase III study.  
Number of Patients: 
Approximately 45 patients are planned in total: 
• 
Patients will be taken from the cohort of patients who completed the main study SCGAM-01 
in the USA and Canada. The theoretical maximum number of SCGAM-01 patients will be 
approximately 35 (the expected number in the main study).  
• 
Approximately 10 de novo patients who are under other SCIG treatment, but did not 
participate in the main study SCGAM-01 are planned in Canada. 
No statistical sample-size estimation was performed for this extension study. 
Patient Selection Criteria: 
Inclusion Criteria: 
Either: 
SCGAM-01 patients (United States, Canada): 
1 
Completion of the main study SCGAM-01, with good tolerance of octanorm (as determined 
by the investigator). 
Or: 
De novo patients (Canada only): 
1C-a 
Age of ≥18 years and ≤75 years. 
1C-b 
Confirmed diagnosis of PI as defined by ESID and PAGID and requiring immunoglobulin 
replacement therapy due to hypogammaglobulinaemia or agammaglobulinaemia. The exact 
type of PI should be recorded. 
1C-c 
Availability of the IgG trough levels of 2 previous SCIG infusions before enrolment, and 
maintenance of ≥5.0 g/L in the trough levels of these 2 previous infusions. 
And: 
 
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Study Protocol SCGAM-03 Version 05 - Canada  
CONFIDENTIAL 
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-03 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Edition / Date of Protocol: 
05 - Canada 
2. For adult patients: freely given written informed consent. For patients below the legal age 
of majority: freely given written informed consent from parents/legal guardians and written 
informed assent from the child/adolescent in accordance with local requirements. 
3. For female patients of child-bearing potential, a negative result in a urine pregnancy test 
conducted at the Screening Visit. 
4. Willingness to comply with all aspects of the protocol, including blood sampling, for the 
duration of the study. 
 
Exclusion Criteria: 
Either: 
SCGAM-01 patients (United States, Canada): 
1 
Subject being without any IgG treatment for period greater than 5 weeks between the last 
infusion of octanorm in the SCGAM-01 study and the first infusion of octanorm in the 
SCGAM-03 study. 
Or: 
De novo patients (Canada only): 
1C-a 
Acute infection requiring intravenous antibiotic treatment within 2 weeks prior to and 
during the screening period. 
1C-b 
Known history of adverse reactions to IgA in other products. 
1C-c 
Patients with body mass index >40 kg/m2. 
1C-d 
Ongoing history of hypersensitivity or persistent reactions to blood or plasma derived 
products, or any component of the investigational product (such as Polysorbate 80). 
1C-e 
Requirement of any routine premedication for IgG administration. 
1C-f 
History of malignancies of lymphoid cells and immunodeficiency with lymphoma. 
1C-g 
Severe liver function impairment (ALAT 3 times above upper limit of normal). 
1C-h 
Known protein-losing enteropathies or proteinuria. 
1C-i 
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). 
1C-j 
Treatment with oral or parenteral steroids for ≥30 days or when given intermittently or as 
bolus at daily doses ≥0.15 mg/kg. 
1C-k 
Treatment with immunosuppressive or immunomodulatory drugs. 
1C-l 
Live viral vaccination (such as measles, rubella, mumps and varicella) within the last 
2 months prior to first infusion of octanorm. 
And: 
2. Exposure to blood or any blood product or plasma derivatives, other than SCIG used for 
regular PID treatment, within the 3 months before the first infusion of octanorm in this 
study. 
3. Pregnant or nursing women or planned pregnancy during the course of the study. 
4. Treatment with any investigational medicinal product (other than that of SCGAM-01) 
within 3 months prior to first infusion of octanorm. 
5. Presence of any condition, that is likely to interfere with the evaluation of study medication 
or satisfactory conduct of the trial. 
6. Known or suspected to abuse alcohol, drugs, psychotropic agents or other chemicals within 
the past 12 months prior to first infusion of octanorm. 
7. Known or suspected HIV, HCV, or HBV infection. 
 
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Study Protocol SCGAM-03 Version 05 - Canada  
CONFIDENTIAL 
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-03 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Edition / Date of Protocol: 
05 - Canada 
Test Product, Dose, Mode of Administration, and Batch Number(s): 
Octanorm, human normal immunoglobulin for subcutaneous (SC) administration. 
Octanorm is to be administered subcutaneously every week (±2 days). 
If, during the study, the patient's body weight changes by > 5%, the dose is to be adjusted to keep 
the dose constant on a ‘milligram per kilogram body weight’ basis. 
 
SCGAM-01 patients: The patients will continue receiving the same octanorm dose in milligram per 
kilogram body weight as was administered at the Week 64 infusion of the SCGAM-01-study. 
De novo patients: The same dose as with the previous SCIG product before study entry will be used. 
 
The patients' octanorm dose can be individualised, if considered necessary by the investigator, by 
titrating upward or downward. 
Batch (lot) numbers will be reported in the final report of the study. 
Duration of Treatment: 
Patients may remain in the trial until octanorm becomes commercially available in the USA or 
Canada, respectively, or until the Sponsor terminates the trial.  
USA: A patient will remain in the trial for up to 2.5 years. 
Canada: The individual treatment duration in Canada will be approximately 12 months. 
Reference Therapy, Dose, Mode of Administration, and Batch Number(s): 
Not applicable. 
Study Outcome Parameters: 
Safety (primary assessment): 
•  Occurrence of all treatment-emergent adverse events (TEAEs) 
•  Occurrence of temporally associated TEAEs 
•  TEAEs by speed of infusion 
•  Local injection-site reactions 
•  Vital signs (blood pressure, pulse, body temperature, respiratory rate) 
•  Laboratory parameters (haematology, clinical chemistry, basic urinalysis) 
Efficacy: 
Measurement of trough total IgG levels; monitoring for infectious diseases. 
 Occurrence of serious bacterial infections (SBIs). 
 
Quality of life: 
USA: For QoL assessments, each patient will continue using the same questionnaire as before. That 
is, the parent or guardian of patients who were below 14 years of age when they entered the main 
study SCAM-01 will continue using the Child Health Questionnaire-Parent Form (CHQ-PF50), and 
patients who were ≥ 14 years of age when they entered the main study will continue using the SF-
36 Health Survey. 
Canada: The patients will use the SF-36 Health Survey. 
Summary of Study Procedures and Statistical Analysis Plan: 
Study Procedures: 
Patients will be enrolled only after written informed consent has been obtained by the patient or 
their legal guardian. For patients under the legal age of majority, written consent must be obtained 
from the parents or legal guardians. In addition, when required by the local regulatory authorities or 
Institutional Review Board (IRB), written assent must be obtained from children and adolescents 
based upon local requirements. 
 
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Study Protocol SCGAM-03 Version 05 - Canada  
CONFIDENTIAL 
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-03 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Edition / Date of Protocol: 
05 - Canada 
Screening assessments, to be performed before the first octanorm infusion, will include: physical 
examination (including weight); blood sampling for haematology, clinical chemistry, viral markers 
and trough total IgG; urine sample for urinalysis and urine pregnancy test (females of childbearing 
potential only); completion of the QoL Questionnaire. 
 
SCGAM-01 patients (United States, Canada): 
The first study (Screening) visit of SCGAM-03 with the first octanorm infusion will be the same 
visit as the visit in Week 65 (End-of-Study Visit) of the study SCGAM-01. 
 
Eligible patients who have completed the SCGAM-01 study and were treated with any other 
commercially available SCIG before the start of the SCGAM-03 study (e.g. owing to a delay in 
local IRB approval for SCGAM-03) are permitted to enter the SCGAM-03 study. 
The maximum allowed intermission of IgG treatment after completion of the SCGAM-01 study 
and before the start of treatment in the SCGAM-03 study is 5 weeks.  
 
Patients for whom the Week 65 visit of the SCGAM-01 study is not identical to the first visit of 
the SCGAM-03 study will undergo a separate Screening Visit with relevant screening procedures.  
 
Note that screening examinations will, for most patients, be performed within the framework of 
the main study SCGAM-01 (End-of-Study Visit, in Week 65), in which case they need not be 
repeated at the same visit for SCGAM-03). 
 
De novo patients (Canada only): 
Patients will undergo a full Screening Visit, including recording of demographic data, medical 
history and previous/ongoing therapies.  
One week later, the patients will attend the site for Visit N. This will be the first Treatment Visit 
with octanorm (without urine pregnancy test). 
 
Only after the patient's successful Screening and Enrolment into SCGAM-03 study will the first 
infusion of octanorm be permitted. 
 
Patients will stay at the study site during the infusion, vital signs will be measured just before the 
start of each infusion given at the study site, then within 1 hour after the end of the infusion. 
The Patient's Diary for the coming period of the home treatment will be issued to the patients. 
Ongoing adverse events and any PID relevant concomitant medications will be recorded. 
 
At all subsequent study visits, the patients will undergo the following examinations at the site 
before the start of infusion: physical examination (including the body weight), blood sampling for 
haematology and trough total IgG, clinical chemistry, urine sample for urinalysis with a urine 
pregnancy test if indicated. The Patient's Diary will be collected and reviewed.  
 
One week after the last infusion, for both regular or premature termination, a Termination Visit 
will be performed at the site with the following assessments: physical examination (including vital 
signs and weight), blood sample for haematology, clinical chemistry, viral markers and trough 
total IgG; urine sample for urinalysis and urine pregnancy test (females of childbearing potential 
only); completion of the QoL Questionnaire; collection and review of the Patient's Diary. 
AEs and any changes in concomitant medications will be recorded throughout the study period. 
 
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Study Protocol SCGAM-03 Version 05 - Canada  
CONFIDENTIAL 
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-03 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Edition / Date of Protocol: 
05 - Canada 
Up to 45 qualifying patients based on the inclusion and exclusion criteria will be enrolled into the 
SCGAM-03 study. An Independent Data Monitoring Committee will periodically review relevant 
data with emphasis on thromboembolic events (TEEs). 
 
Statistical Analysis: 
The following populations will be considered for the statistical analysis: 
The safety analysis set consisting of all patients who received at least part of one infusion of 
octanorm. 
The full analysis set (FAS) is defined according to the intention-to-treat principle and consists of all 
patients of the safety analysis 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. 
The per-protocol (PP) set consists of all patients of the FAS excluding those with major protocol 
deviations which may have an impact on the analysis of the primary endpoint. This is the set of 
patients who participated in the study as intended and for whom the primary endpoint can be 
evaluated as planned. 
 
Only major protocol deviations with the potential to significantly affect the study results or to 
invalidate the interpretation of the data obtained will lead to exclusion of patients from the PP set. 
The membership of each patient in the respective analysis populations will be determined before 
statistical analysis in a data review meeting by a panel consisting of a medical expert from the 
Sponsor, the clinical study manager, the data manager and the study statistician. 
 
Safety Analysis Plan: 
The safety analysis will comprise descriptive statistics, tabulations and listings of all TEAEs, safety 
laboratory results, vital signs and physical examination findings. All reported AEs will be coded 
according to MedDRA. 
For this extension study, any AE is regarded as treatment-emergent if the patient migrated from the 
main to the extension study without being treated with another IgG product. For de novo patients 
from Canada or if another product was used between the two studies, an AE in the extension study 
is classified as treatment-emergent if onset or worsening is after start of the infusion of octanorm. 
Only TEAEs are accounted for in the analysis. 
 
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. 
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. 
• Infusion rate at the onset of temporally associated TEAEs (frequencies and percentages). 
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. 
The QoL data will be presented descriptively by visit, along with the change from screening (defined 
as the first infusion). 
 
 
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Study Protocol SCGAM-03 Version 05 - Canada 
 
CONFIDENTIAL 
FLOW CHART OF STUDY EVENTS 
Assessments 
Screening – 
First visit 
(Week 65 of 
SCGAM-01) 
Octanorm Treatment Visits 
Termination 
Site visit number 
1 
N4 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 (early) 
Termination 
visit 
Study week number  
1 
2 
12 
24 
36 48 60 72 
84 
96 
108 
One week after 
last infusion 
Informed consent, In-/exclusion criteria3 (De novo patients: 
Demographics, medical history, prior/ongoing therapies3) 
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Body weight3 
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Physical examination3, vital signs1 
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IgG trough levels3 
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Haematology3 (CBC, WBC differential, haematocrit, 
haemoglobin) 
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Clinical Chemistry3 (sodium, potassium, glucose, ALAT, 
ASAT, LDH, total bilirubin, blood urea nitrogen, creatinine) 
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Urine analysis3: pH, glucose, ketones, leukocytes, haemoglobin 
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Viral markers3: HAV, HBV, HCV, HIV 
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Urine pregnancy test2; 3 
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Infusion of IMP (on site)  
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Check for local injection-site reaction 
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Patient Diary hand-out and check (other visits) 
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Quality-of-life Questionnaire 
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Concomitant medication (PID relevant) 
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Adverse events 
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1. Measurements of the vital signs will be carried out before and after the infusion of IMP (if applicable).      2. For females of child-bearing potential.      3. Procedures are to be conducted before the IMP administration 
(if applicable).      4. De novo patients (in Canada only).   5. SCGAM-01 patients only
 
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Study Protocol SCGAM-03 Version 05 - Canada 
CONFIDENTIAL 
 
 
Signature of the Principal Coordinating Investigator 
 
This study is intended to be conducted in compliance with the protocol, 
Good Clinical Practice and the applicable regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dr.  <to be added> 
_____________________________________________________________________ 
Coordinating Investigator 
 
 
 
Signature 
 
 
Date 
 
 
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Study Protocol SCGAM-03 Version 05 - Canada 
CONFIDENTIAL 
 
TABLE OF CONTENTS 
 
PROTOCOL SIGNATURES .................................................................................................. 8 
TABLE OF CONTENTS ....................................................................................................... 10 
LIST OF ABBREVIATIONS ................................................................................................ 13 
1 
INTRODUCTION .......................................................................................................... 14 
1.1 BACKGROUND ............................................................................................................... 14 
1.2 RATIONALE FOR CONDUCTING THE STUDY ................................................................... 16 
1.3 BENEFIT-RISK STATEMENT ........................................................................................... 17 
2 
STUDY OBJECTIVES .................................................................................................. 17 
2.1 PRIMARY OBJECTIVE ..................................................................................................... 17 
2.2 SECONDARY OBJECTIVES .............................................................................................. 17 
3 
INVESTIGATIONAL PLAN ........................................................................................ 18 
3.1 PRIMARY AND SECONDARY ENDPOINTS ........................................................................ 18 
3.1.1 Primary Endpoint ................................................................................................. 18 
3.1.2 Secondary Endpoints ............................................................................................ 18 
3.2 OVERALL STUDY DESIGN AND PLAN............................................................................. 18 
3.3 DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP(S) .......................... 20 
3.3.1 Study Design ......................................................................................................... 20 
3.3.2 Dosing .................................................................................................................. 20 
3.3.3 Control Group(s) .................................................................................................. 20 
3.3.4 Target Parameters ................................................................................................ 20 
3.3.5 Statistical Considerations .................................................................................... 20 
4 
STUDY POPULATION ................................................................................................. 21 
4.1 POPULATION BASE ........................................................................................................ 21 
4.1.1 Inclusion Criteria ................................................................................................. 21 
4.1.2 Exclusion Criteria ................................................................................................ 21 
4.2 PRIOR AND CONCOMITANT THERAPY ............................................................................ 22 
4.2.1 Permitted Concomitant Therapy .......................................................................... 23 
4.2.2 Forbidden Concomitant Therapy ......................................................................... 23 
4.3 WITHDRAWAL AND REPLACEMENT OF PATIENTS .......................................................... 23 
4.3.1 Premature Patient Withdrawal ............................................................................ 23 
4.3.2 Patient Replacement Policy ................................................................................. 24 
4.4 ASSIGNMENT OF PATIENTS TO TREATMENT GROUPS .................................................... 24 
4.5 RELEVANT PROTOCOL DEVIATIONS .............................................................................. 24 
4.6 SUBSEQUENT THERAPY ................................................................................................. 25 
5 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ................................................. 25 
5.1 CHARACTERISATION OF INVESTIGATIONAL PRODUCT(S) .............................................. 25 
5.2 PACKAGING AND LABELLING ........................................................................................ 25 
5.3 CONDITIONS FOR STORAGE AND USE ............................................................................ 26 
5.4 DOSE AND DOSING SCHEDULE ...................................................................................... 27 
5.5 PREPARATION AND METHOD OF ADMINISTRATION ....................................................... 27 
5.6 BLINDING, EMERGENCY ENVELOPES AND BREAKING THE STUDY BLIND ..................... 28 
 
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5.7 TREATMENT COMPLIANCE ............................................................................................ 28 
5.7.1 Drug Dispensing and Accountability ................................................................... 28 
5.7.2 Assessment of Treatment Compliance .................................................................. 29 
5.8 RESCUE MEDICATION/ RISK MANAGEMENT.................................................................. 29 
6 
STUDY CONDUCT ....................................................................................................... 29 
6.1 OBSERVATIONS BY VISIT .............................................................................................. 29 
6.1.1 Screening Visit ...................................................................................................... 29 
6.1.2 Treatment and Assessment Visits; Termination Visit ........................................... 30 
6.1.3 Interpretation of Time Windows in This Study ..................................................... 31 
6.2 DURATION OF STUDY .................................................................................................... 32 
6.2.1 Planned Duration for an Individual Patient ........................................................ 32 
6.2.2 Planned Duration for the Study as a Whole ......................................................... 32 
6.2.3 Premature Termination of the Study .................................................................... 32 
7 
ASSESSMENTS AND METHODS .............................................................................. 33 
7.1 BACKGROUND / BASELINE INFORMATION ..................................................................... 33 
7.2 EFFICACY ASSESSMENTS ............................................................................................... 33 
7.3 SAFETY ASSESSMENTS .................................................................................................. 36 
7.3.1 Adverse Events ..................................................................................................... 36 
7.3.1.1 
Definitions .............................................................................................................. 36 
7.3.1.2 
Collection ................................................................................................................ 37 
7.3.1.3 
Severity ................................................................................................................... 37 
7.3.1.4 
Causality ................................................................................................................. 37 
7.3.1.5 
Outcome .................................................................................................................. 38 
7.3.1.6 
Action(s) taken ........................................................................................................ 39 
7.3.2 Local Reactions .................................................................................................... 39 
7.3.3 Serious Adverse Events ........................................................................................ 39 
7.3.4 Laboratory Safety Tests ........................................................................................ 40 
7.3.5 Viral Safety Tests .................................................................................................. 41 
7.3.6 Vital Signs ............................................................................................................ 41 
7.3.7 Physical Examination ........................................................................................... 41 
7.3.8 Other Relevant Safety Information ....................................................................... 42 
7.4 OTHER ASSESSMENTS ................................................................................................... 42 
7.4.1 Drug Concentration Measurements ..................................................................... 42 
7.4.2 Quality of Life Assessment ................................................................................... 42 
7.5 APPROPRIATENESS OF MEASUREMENTS ........................................................................ 43 
8 
DATA HANDLING AND RECORD KEEPING ........................................................ 43 
8.1 DOCUMENTATION OF DATA .......................................................................................... 43 
8.1.1 Source Data and Records ..................................................................................... 43 
8.1.2 Electronic Case Report Forms (eCRF) ................................................................ 44 
8.1.3 Changes to Case Report Form Data .................................................................... 44 
8.1.4 Handling of Missing Data .................................................................................... 44 
8.2 INFORMATION OF INVESTIGATORS................................................................................. 45 
8.3 RESPONSIBILITIES.......................................................................................................... 45 
8.4 INVESTIGATOR’S SITE FILE ........................................................................................... 45 
8.5 PROVISION OF ADDITIONAL INFORMATION ................................................................... 46 
8.6 INDEPENDENT DATA MONITORING COMMITTEE ........................................................... 46 
9 
STATISTICAL METHODS AND SAMPLE SIZE .................................................... 46 
 
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9.1 DETERMINATION OF SAMPLE SIZE ................................................................................. 46 
9.2 STATISTICAL ANALYSIS ................................................................................................ 46 
9.2.1 Population for Analysis ........................................................................................ 46 
9.2.2 Efficacy Analysis Plan .......................................................................................... 47 
9.2.3 Safety Analysis Plan ............................................................................................. 48 
9.2.3.1 
Adverse Events ....................................................................................................... 48 
9.3 RANDOMISATION / STRATIFICATION / CODE RELEASE .................................................. 48 
9.4 INTERIM ANALYSIS ....................................................................................................... 48 
10 ETHICAL / REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ...... 48 
10.1 ETHICAL / REGULATORY FRAMEWORK ......................................................................... 48 
10.2 APPROVAL OF STUDY DOCUMENTS ............................................................................... 49 
10.3 PATIENT INFORMATION AND INFORMED CONSENT ........................................................ 49 
10.4 PROTOCOL AMENDMENTS ............................................................................................. 49 
10.5 CONFIDENTIALITY OF PATIENTS’ DATA ........................................................................ 50 
11 QUALITY CONTROL AND QUALITY ASSURANCE ........................................... 50 
11.1 PERIODIC MONITORING ................................................................................................. 50 
11.2 AUDIT AND INSPECTION ................................................................................................ 50 
12 REPORTING AND PUBLICATION ........................................................................... 51 
12.1 CLINICAL STUDY REPORT ............................................................................................. 51 
12.2 PUBLICATION POLICY .................................................................................................... 51 
13 LIABILITIES AND INSURANCE ............................................................................... 51 
14 REFERENCES ............................................................................................................... 51 
 
 
 
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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 
CHQ-PF50 
Child Health Questionnaire-Parent Form 
CI 
Confidence interval 
CRO 
Contract research organisation 
CSF 
Cerebrospinal fluid 
DCF 
Dosing conversion factor 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FAS 
Full analysis set 
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 
IDMC 
Independent Data Monitoring Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVIG 
Intravenously administered immunoglobulin 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
PI 
Primary immunodeficiency  
PID 
Primary immunodeficiency diseases 
PK 
Pharmacokinetic(s) 
PP 
Per protocol 
QoL 
Quality of life 
SAE 
Serious adverse event 
SBI 
Serious bacterial infection 
SC 
Subcutaneous 
SCIG 
Subcutaneously administered immunoglobulin 
SF-36 Health Survey 
36-Item Short Form Survey-Adult QoL Questionnaire 
TEAE 
Treatment-emergent adverse event 
TEE 
Thromboembolic event 
Tmax 
Time to maximum plasma concentration 
WBC 
White blood cell 
 
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1 
INTRODUCTION 
1.1 
Background 
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 the 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 become 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 subcutaneous 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 PK 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 single IVIG dose administered every 3 [or 4] weeks is split into 3 [or 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 40–50% 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 SCIG 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 (SBIs) was the most common primary efficacy endpoint in these studies. Secondary 
endpoints included overall infections (i.e. infections not meeting SBI criteria), missed days at 
work or school, days in hospital and days on antibiotics. Definitions of overall infections and 
SBI were not standardised across studies. In 6 studies, SBIs 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 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] 
 
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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 product (IMP) in this study, is an immunoglobulin preparation 
from human normal plasma and is manufactured by Octapharma. It contains 16.5% 
(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. 
1.2 
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 can easily be learned by the 
patients, which is another advantage of SC administered immunoglobulins (SCIG). It may 
remarkably improve the patient’s quality of life 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. 
Post-dose peak levels of SCIG are reached usually 3–6 days after infusion. It has been shown 
that after infusion, exogenous IgG is distributed relatively rapidly between plasma and 
extravascular fluid until approximately half is partitioned in the extravascular space. Therefore, 
a rapid initial drop in serum IgG is to be expected. Several factors such as the endogenous 
production, the actual catabolism rate, the underlying disease or inter-patient variability help to 
explain the wide range observed for terminal half-lives. PK data are required for each new 
 
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product to ensure that it will not behave differently from existing preparations, in terms of 
appropriate dose and timing of the infusions. 
The rationale for conducting the main clinical study (SCGAM-01) was to investigate the PK 
characteristics, efficacy, and safety of octanorm, and to provide guidance on the dosing when 
switching patients from IV to SC treatment in patients suffering from PI. 
The principal purpose of the present (extension) study is to acquire additional safety and 
tolerability data for patients treated in the medium-to-long term with octanorm. At the same 
time, efficacy and quality-of-life (QoL) data will also be acquired. 
The rationale for the new protocol version 03 - Canada is to include an estimated 10 adult 
patients from Canada (both SCGAM-01 patients and de novo patients), to collect further safety, 
quality-of-life and efficacy data.  
The individual treatment duration in Canada will be approximately 12 months.  
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. 
Standard measures are taken to prevent infections resulting from the use of medicinal products 
prepared from human blood or plasma. Despite this, when medicinal products prepared from 
human blood or plasma are administered, the possibility of transmitting infective agents cannot 
totally be excluded. The virus inactivation methods for octanorm are described in the 
Investigator's Brochure. 
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 terms of efficacy, it can reasonably be assumed that octanorm exhibits the same effectiveness 
as other SCIG brands. 
Results from the main study (SCGAM-01) have been analysed in an interim analysis and none 
of the results or data acquired in that study affect the above benefit–risk assessment. 
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of the study is to assess the medium-to-long-term safety and tolerability of 
octanorm. 
2.2 
Secondary Objectives 
The secondary objectives of the study are: 
• 
To assess the effect of octanorm on quality-of-life measures. 
• 
To obtain further data on the efficacy of octanorm. 
 
 
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3 
INVESTIGATIONAL PLAN 
3.1 
Primary and Secondary Endpoints 
3.1.1 Primary Endpoint 
There is no single primary endpoint in this present extension study. The primary objective is to 
assess safety and tolerability in medium-to-long-term administration, and this will be assessed 
by means of the following variables: 
• Occurrence of all treatment-emergent AEs (TEAEs) throughout the entire treatment 
period starting with the first infusion of IMP. 
• Occurrence of temporally associated TEAEs. 
• TEAEs by speed of infusion. 
• Local injection-site reactions. 
• Vital signs (blood pressure, pulse, body temperature, respiratory rate). 
• Laboratory parameters (haematology, clinical chemistry and tests for viral safety). 
 
3.1.2 Secondary Endpoints 
Secondary assessment criteria will be for quality of life and efficacy: 
• QoL assessments using the CHQ-PF50 from parent or guardian of patients <14 years of 
age and the SF-36 Health Survey in patients ≥14 years of age. 
• Occurrence of serious bacterial infections (SBIs) as defined in Section 7.2. 
• The annual rate of all infections of any kind or seriousness. 
• Time to resolution of infections. 
• Use of antibiotics (number of days and annual rate). 
3.2 
Overall Study Design and Plan 
The study is a prospective, open-label, non-controlled, single-arm, multicentre phase III safety 
study with observation of patients receiving weekly doses of octanorm over a period of up to 
two and half years. 
The study will be conducted at study sites in the United States and in Canada that already 
participated in the SCGAM-01 trial. 
In the United States only patients who have completed the main study (SCGAM 01) may be 
enrolled. In Canada adult de novo patients may also be enrolled. 
 
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SCGAM-01 patients only: 
Most patients will migrate directly from the main study to the present extension study. 
However, some patients are expected to complete the main study before the commencement of 
the extension study.  
Eligible patients who have completed the SCGAM-01 study and were treated with any other 
commercially available SCIG before the start of the SCGAM-03 study (e.g. owing to a delay 
in local IRB approval for SCGAM-03) are permitted to enter the SCGAM-03 study 
In the intervening interval they must have received the commercially available SCIG at the 
approximately same dose which the patient had received in study SCGAM-01. For these 
patients, the screening visit will be regarded as a fresh start and all screening procedures are to 
be conducted. 
The maximum allowed interval without any IgG treatment before the start of treatment in the 
SCGAM-03 study is approximately 5 weeks.  
Each patient will be treated weekly with octanorm, either at the investigation site (on study visit 
days) or else at home. A final examination will be performed 1 week after the last infusion, for 
both regular and premature termination of the patient's study participation. 
The study will be ended when octanorm becomes commercially available in the respective 
country (i. e. USA or Canada) or the sponsor decides to terminate the trial at an earlier date. In 
the USA, the maximum total duration of the study for an individual patient will be 
approximately 2.5 years. 
Study-related procedures will begin only after written informed consent has been obtained from 
the patient. For patients who are minors (USA only), written consent must be obtained from the 
parents or legal guardians. In addition, when required by the local regulatory authorities or 
Institutional Review Board (IRB), written assent must be obtained from children and 
adolescents based upon the age requirements established by those institutions. 
The numbers of patients from the United States to be enrolled in each age group will follow the 
numbers emerging from the main study SCGAM-01 and willing and eligible to continue 
treatment. At the time of preparation of this protocol these numbers are at most: 
• ≥2 years and <5 years of age: up to 5 patients 
• ≥5 years and <12 years of age: up to 5 patients 
• ≥12 years and <16 years of age: up to 10 patients 
• ≥16 years and ≤75 years of age: up to 30 patients 
• Total: approximately 45 (maximum 50) patients. 
An Independent Data Monitoring Committee will periodically review relevant data with 
emphasis on thromboembolic events (TEEs). 
The following interventions and procedures will be performed at predefined time points (see 
Section 6.1.2): Drawing of blood samples, determination of body weight, review of the Patient's 
Diary, physical examination including vital sign assessments, QoL assessments, assessments 
of local injection-site reactions, urine sampling, and urine pregnancy tests. 
AEs and any changes in concomitant medications will be recorded throughout the study period. 
 
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3.3 
Discussion of Study Design and Choice of Control Group(s) 
3.3.1 Study Design 
The designs of the main study SCGAM-01 and of this extension study take into account the 
FDA’s comments and requests included in the clinical hold letter (dated April 27, 2012) for 
IND 15019 for another SCIG of Octapharma (gammanorm 16.5%). 
The study design is also in line with similar study protocols conducted with other SCIG 
brands.[18,20] 
3.3.2 Dosing 
SCGAM-01 patients (United States, Canada): 
The patients will continue receiving the same octanorm dose (in mg per kg body weight) as was 
administered at the Week 64 infusion of the SCGAM-01-study. 
De novo patients (Canada only): 
The patients will continue receiving the same octanorm dose (in mg per kg body weight) as 
with their previous SCIG product before the study entry. 
Dosing will take place on site at study visits, and otherwise at the patient's home, by self-
administration or with assistance (relative, carer etc.). 
3.3.3 Control Group(s) 
Does not apply in this study: all patients will receive active treatment with octanorm. 
3.3.4 Target Parameters 
The outcome measures in this study are consistent with previous studies of other IVIG or SCIG 
products and are also in compliance with the FDA Guidance for Industry.[22] 
The QoL Questionnaires are standardised, validated instruments that have been widely used in 
clinical studies, including PI. 
3.3.5 Statistical Considerations 
The FDA Guidance for Industry suggests that, based on historical data, a statistical 
demonstration of a serious infection rate per person-year less than 1.0 is adequate to provide 
substantial evidence of efficacy.[22] Therefore, the 99% CI for this rate will be calculated at a 
descriptive level, without formal statistical testing (statistical tests may be performed on an ad 
hoc basis if this is considered appropriate). 
Because a single patient may experience more than one SBI, the calculation of this confidence 
interval will take into account such intra-patient correlation, following a compound Poisson 
process model. 
 
 
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4 
STUDY POPULATION 
4.1 
Population Base 
Approximately 45 male or female patients suffering from PI will be eligible for inclusion to 
this clinical study. 
4.1.1 Inclusion Criteria 
Patients who meet of the following criteria may be enrolled: 
Either: 
SCGAM-01 patients (United States, Canada): 
1 
Completion of the main study SCGAM-01, with good tolerance of octanorm (as 
determined by the investigator). 
Or: 
De novo patients (Canada only): 
1C-a Age of ≥18 years and ≤75 years. 
1C-b Confirmed diagnosis of PI as defined by ESID and PAGID and requiring 
immunoglobulin 
replacement 
therapy 
due 
to 
hypogammaglobulinaemia 
or 
agammaglobulinaemia. The exact type of PI should be recorded. 
1C-c Availability of the IgG trough levels of 2 previous SCIG infusions before enrolment, 
and maintenance of ≥5.0 g/L in the trough levels of these 2 previous infusions. 
 
And: 
2. For adult patients: freely given written informed consent. For patients below the legal 
age of majority: freely given written informed consent from parents/legal guardians and 
written informed assent from the child/adolescent in accordance with local 
requirements. 
3. For female patients of child-bearing potential, a negative result in a urine pregnancy test 
conducted at the Screening Visit. 
4. Willingness to comply with all aspects of the protocol, including blood sampling, for 
the duration of the study. 
 
4.1.2 Exclusion Criteria 
Patients who meet one (or more) of the following criteria are excluded from the study: 
Either: 
SCGAM-01 patients (United States, Canada): 
1 
Subject being without any IgG treatment for period greater than 5 weeks between the 
last infusion of octanorm in the SCGAM-01 study and the first infusion of octanorm in 
the SCGAM-03 study. 
Or: 
 
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De novo patients (Canada only): 
1C-a Acute infection requiring intravenous antibiotic treatment within 2 weeks prior to and 
during the screening period. 
1C-b Known history of adverse reactions to IgA in other products. 
1C-c Patients with body mass index >40 kg/m2. 
1C-d Ongoing history of hypersensitivity or persistent reactions to blood or plasma derived 
products, or any component of the investigational product (such as Polysorbate 80). 
1C-e Requirement of any routine premedication for IgG administration. 
1C-f 
History of malignancies of lymphoid cells and immunodeficiency with lymphoma. 
1C-g Severe liver function impairment (ALAT 3 times above upper limit of normal). 
1C-h Known protein-losing enteropathies or proteinuria. 
1C-i 
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). 
1C-j 
Treatment with oral or parenteral steroids for ≥30 days or when given intermittently or 
as bolus at daily doses ≥0.15 mg/kg. 
1C-k Treatment with immunosuppressive or immunomodulatory drugs. 
1C-l 
Live viral vaccination (such as measles, rubella, mumps and varicella) within the last 
2 months prior to first infusion of octanorm. 
And: 
2. Exposure to blood or any blood product or plasma derivatives, other than SCIG used 
for regular PID treatment, within the 3 months before the first infusion of octanorm in 
this study. 
3. Pregnant or nursing women or planned pregnancy during the course of the study. 
4. Treatment with any investigational medicinal product (other than that of SCGAM-01) 
within 3 months prior to first infusion of octanorm. 
5. Presence of any condition, that is likely to interfere with the evaluation of study 
medication or satisfactory conduct of the trial. 
6. Known or suspected to abuse alcohol, drugs, psychotropic agents or other chemicals 
within the past 12 months prior to first infusion of octanorm. 
7. Known or suspected HIV, HCV, or HBV infection. 
4.2 
Prior and Concomitant Therapy 
Details of any PID relevant concomitant medication (antibiotics, corticosteroids, premedication 
(if used), immunosuppressive or immunomodulatory drugs, blood or any blood product or 
derivative, IVIG, SCIG other than octanorm taken within 8 weeks before the SCGAM-03 study 
etc.) must be recorded in the electronic case report form (eCRF).  
 
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SCGAM-01 patients only (United States, Canada): 
Prior medication will be inferred from the study data of the main study SCGAM-01. For patients 
with an intermission between the studies SCGAM-01 and SCGAM-03 any additional 
medications taken in the intervening period are to be recorded. 
4.2.1 Permitted Concomitant Therapy 
Local anaesthetics (Emla or L-Max (lidocaine) cream, plaster, or similar product) to reduce 
pain associated with needle insertion are allowed. The use of such medication(s) must be 
recorded. 
Routine premedication to alleviate potential tolerability problems is not allowed during the 
study. However, patients who experience (or experienced in the SCGAM-01 study) 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 should 
be avoided.  
4.2.2 Forbidden Concomitant Therapy 
Treatment with any IMP (other than IgG products) within 3 months before first infusion of 
octanorm in SCGAM-03 study, or during the study, is forbidden. 
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 study. 
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 oral 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 and immunomodulatory 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. The responsible Investigator also has the right to withdraw patients from the study in 
case of AEs, poor compliance, or administrative reasons. 
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 the patient's discontinuation. 
• 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. 
 
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• 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 this extension study. A pregnancy 
test is mandatory at the Screening Visit, at the visits in Weeks 12, 36, 60, 84 and 108, 
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’s Central Drug Safety Unit must be informed. 
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 for any reason will not be replaced. 
4.4 
Assignment of Patients to Treatment Groups 
SCGAM-01 patients only: 
In the main study SCGAM-01, patients were recruited into four age strata: ≥2 years and <5 
years, ≥5 years and <12 years, ≥12 years and <16 years, and ≥16 and ≤75 years. In the present 
extension study, they will remain in the strata that they were in for analysis in the main study 
(irrespective of whether their age changed such as to imply a change of age stratum). Each 
patient will be identified by this previously allocated number throughout the trial; no additional 
patient or randomisation number will be used for this extension study. 
 
De novo patients only: 
The patients will not be recruited in age strata. The new 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 system 
to the Investigator, the contract research organization (CRO) and the Sponsor. 
All patients enrolled in this study will be treated with octanorm. 
Patients who participated in this study and discontinued are not permitted to re-enrol. 
4.5 
Relevant Protocol Deviations 
In the case of any major deviation from this study protocol, 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. 
 
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4.6 
Subsequent Therapy 
If a patient decides to withdraw from the study or is withdrawn by the Investigator, he/she may 
be switched back to the treatment that he/she received before participation in the study or to 
another commercially available IVIG or SCIG. 
 
5 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
5.1 
Characterisation of Investigational Product(s) 
Name of Medicinal Product: 
Octanorm 
Active ingredient of octanorm: Human normal immunoglobulin 
Table 1 
Biochemical Characteristics of octanorm 
Parameter 
 
Total protein (of which ≥96% is human IgG) 
150 – 180 mg per mL 
Maltose 
70 – 90 mg per mL 
Octoxynol 
≤5 µg per mL 
TNBP  
≤1 µg per mL 
IgA 
≤0.6 mg per mL 
Polysorbate 80 
10 – 60 µg per mL 
pH 
5.0 – 5.8 
Osmolality 
310 – 380 mosmol/kg 
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 3,500 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 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. The label on the octanorm vial will be in the respective 
language(s) of the country and will be in accordance with local regulations. Label terminology 
may vary according to local regulations, and country-specific remarks will be added as needed. 
Sample labels will be filed in the TMF. Each octanorm vial will be labelled approximately as 
follows: 
 
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Master Label Canada 
 
 
Master Label USA 
Caution: New Drug - Limited by Federal (or United States) Law to Investigational Use 
Octanorm 
Study: SCGAM-03 
Unit size: ____ mL 
1 mL contains: 165 mg protein of which ≥96% is human normal immunoglobulin G. 
Solution for subcutaneous injection. 
To be stored at 36 °F to 46 °F, 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 before administration. 
Solutions that are cloudy or have a deposit must not be used. 
To be warmed up to room or body temperature before use. After first opening, use immediately. 
Patient No.: |___|___|___|___| 
Dosage: Please refer to the handling instruction provided. 
BB-IND number: 15617 
Sponsor: OCTAPHARMA Pharmazeutika Prod.Ges.m.b.H.; Oberlaaerstr. 235, 1100 Vienna, 
Austria, Tel: 
 
Batch No.: ______________ Expiry date: ________ 
5.3 
Conditions for Storage and Use 
Octanorm must be stored and transported light-protected at 36 °F to 46 °F (2 °C to +8 °C) and 
must not be frozen. 
 
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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). A minimum interval 
of 4 days must be observed between two single subcutaneous infusions. If, during the study, 
the body weight changes by >5%, the dose is to be adjusted to keep the dose constant on a ‘mg 
per kg body weight’ basis.  
SCIG infusions will be (self-)administered at home. The infusion is to be given at the study site 
at Week 1, (Week 2, de novo patients only), Week 12, Week 24, Week 36, Week 48, Week 60, 
Week 72, Week 84, Week 96, and Week 108.  
Each of these study visit dates may deviate ± 2 weeks from the planned date. (Visit N for de 
novo patients may deviate ± 2 days.) However, the deviations must not cumulate. 
SCGAM-01 patients only: 
The patients will continue receiving the same octanorm dose in milligram per kilogram body 
weight as was administered at the Week 64 infusion of the SCGAM-01-study. 
 
De novo patients only: 
The same dose as with the previous SCIG product before study entry will be used. 
The patients' octanorm dose can be individualised, if considered necessary by the investigator, 
by titrating upward or downward and should be based on the difference between each patient's 
measured serum total IgG trough levels while on octanorm and each patient's individual target 
serum total IgG trough level.  
5.5 
Preparation and Method of Administration 
Vials of octanorm must be allowed to warm to room or body temperature before 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 
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 discharged. 
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 before 
administration. The solution should be clear or slightly opalescent. Solutions that are cloudy or 
have a deposit must not be used. 
The patient or his/her relative or caregiver will be instructed at the clinic/doctor's office or at 
the infusion centre in the use of the following: 
• syringe driver, 
• infusion techniques, 
 
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• keeping of a Patient Diary and 
• measures to be taken in case of severe AEs. 
 
Infusion sites:  
The maximum number of infusion sites used simultaneously should not exceed 6. 
Infusion sites should be at least 2 inches (approx. 5 cm) apart. The actual sites of infusion should 
be changed with each weekly administration. 
Volume: 
o Adults: The infusion volume can be up to a maximum of 60 mL/per one infusion site. 
o Children (≥5 years of age): The volume can be up to a maximum of 35 mL/site. 
o Small children (<5 years of age): The volume may be up to 20 mL/site. 
 
Infusion (flow) rate: The maximum recommended flow rate per 1 infusion site is 60 mL per 
hour. 
o For children for all infusion sites TOGETHER the maximum flow rate should not 
exceed a total of 80 mL per hour. 
o For adult patients only: The maximum flow rate for all infusion sites together can be 
(gradually) increased up to 150 mL per hour if the previous rate is well tolerated. 
 
5.6 
Blinding, Emergency Envelopes and Breaking the Study Blind 
Not applicable for this open-label study. 
5.7 
Treatment Compliance 
5.7.1 Drug Dispensing and Accountability 
All IMP provided to the site will be accounted for. This includes IMP received at the site, 
dispensed to patients, and IMP returned unused by the subject/patient. 
Sponsor or designee will deliver octanorm to the participating investigators. Investigator will 
keep current drug inventory and dispensing log, detailing the dates, batch (lot) numbers, and 
quantities of IMP received and dispensed to each patient and the remaining quantity. 
The inventory and drug dispensing log will be available to the monitor to verify drug 
accountability during the study. The study monitor will review all empty and partially used 
vials of IMP and will cross-check versus the patient source documentation (records), eCRF, 
and drug dispensing log.  
After this check, and after the sponsor has granted written approval of destruction, empty or 
partially used vials should be destroyed at the study site following local policies. The 
destruction must be documented. 
For their home treatment, sufficient amount of octanorm will be handed out to the patients. The 
Investigator or his 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 
 
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return used or expired vials to the study site at their on-site visits and the (early) Termination 
Visit. 
5.7.2 Assessment of Treatment Compliance 
Patients will receive infusions at the study site and at home (administered at home by the patient 
or his/her relative or carer). 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/school/kindergarten/day 
care, 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. 
5.8 
Rescue Medication/ Risk Management 
In the event of a (serious) AE, infection(s), treatment failure and or if the patient does not 
tolerate the treatment, the Investigator will direct the patient for an immediate unscheduled visit 
to ensure their safety and wellbeing.    
 
If a patient decides to withdraw from the study or is terminated by the Investigator for treatment 
failure or any reason, the patient may switch back to their previous treatment prior to 
participating in the study or to any other commercially available IVIG or SCIG treatment as 
determined by their physician.  
 
In the event of potential risk of allergic reaction, adequate rescue medication will be provided 
by Investigator to the patient; for example, Epipen (epinephrine injection), Antihistamines and 
or any other similar medication as determined by the Investigator.  In the case of an adverse 
reaction, patients will be trained by the Investigator on how and when to use the emergency 
medication and will be instructed to immediately seek emergency medical assistance.   
 
 
6 
STUDY CONDUCT 
6.1 
Observations by Visit 
6.1.1 Screening Visit 
SCGAM-01 patients only (United States, Canada): 
The Screening (First) Visit will in most cases be the same as the last study visit (Termination 
Visit scheduled in week 65, the End-of-study visit) of the main study SCGAM-01 (since most 
patients will migrate directly from the main study SCGAM-01 to the present extension study; 
Section 3.2). Screening procedures are to be conducted before the IMP administration for that 
visit. 
If the treatment with octanorm was interrupted between the SCGAM-01 and extension 
(SCGAM-03) studies (for details see Section 3.2), then all screening procedures (see study flow 
chart) are to be conducted at the new Screening visit. 
 
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Study-related procedures will begin only after written informed consent has been obtained by 
the patient or their legal guardian. At the Screening Visit the following activities will be 
performed: 
• Written informed consent. 
• Check of inclusion and exclusion criteria. 
• Recording of demographic data (de novo patients only). 
• Documentation of medical history (SCGAM-01 patients: including all adverse 
conditions that have occurred after the end of the SCGAM-01 study). 
• Recording of all previous/ongoing drug and non-drug therapies (SCGAM-01 patients: 
only those administered after the end of the SCGAM-01 study). 
• General physical examination, including body weight and 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). 
• Infusion of octanorm (SCGAM-01 patients only). 
• Check for injection-site reaction and assessment if necessary. 
• Issue of Patient's Diary (SCGAM-01 patients only). 
• Completion of QoL Questionnaire. 
• Recording of any concomitant medication and adverse events (SCGAM-01 patients: 
only new ones, not previously recorded in the SCGAM-01). 
6.1.2 Treatment and Assessment Visits; Termination Visit 
De novo patients only (Canada): 
One week after Screening Visit, all patients will attend the site for Visit N. This will be the first 
Treatment Visit with octanorm (without laboratory tests). 
 
On study visit days, administration will be performed on site; otherwise, at home 
(Section 3.3.2). 
At the study visits, the following activities will be performed before IMP administration: 
• General physical examination, including body weight and vital signs (every visit). 
• Drawing of blood samples for total IgG trough level (every visit, except Visit N for de 
novo patients). 
• Drawing of blood samples for safety laboratory parameters (Visits 2, 4, 6, 8, 10 and the 
Termination Visit). 
• Drawing of blood samples for viral markers (Visit 6 and the Termination Visit). 
• Urine sampling including urine pregnancy test (in females of childbearing potential 
only; Visits 2, 4, 6, 8, 10). 
 
During or after IMP administration 
• Completion of QoL Questionnaire (Visit 6 and the Termination Visit). 
 
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• Collection of the Patient Diary. The Investigator will review the Diary entries and will 
ask the patient about any AEs that may have occurred and any changes in concomitant 
therapies (medication and non-drug therapy). Any concomitant medication and adverse 
events will be recorded. Relevant Diary data will be transferred to the eCRF. 
Discrepancies between Patient Diary entries and eCRF entries must be explained by the 
Investigator (every visit).  
• Infusion of octanorm (every visit). 
• Check for injection-site reaction and assessment if any reaction is present (every visit). 
 
For laboratory testing please refer to Section 7.3.4. 
Termination Visit: 
One week after the last infusion (study visit 10 in Week 108, or sooner if a patient withdraws 
prematurely from the study or if the study is ended earlier by one of the events described in 
Section 3.2), a Termination Visit will be performed including the following assessments: 
• General physical examination (including vital signs). 
• Drawing of blood samples for safety laboratory parameters including viral markers. 
• Drawing of blood samples for total IgG trough level. 
• Urine sampling including urine pregnancy test (in females of childbearing potential 
only). 
• Completion of QoL Questionnaire. 
• Collection and review of the Patient Diary as at the earlier visits (Section 6.1.2) with 
recording of any AEs and changes in concomitant medications. 
• Assessment of any local infusion-site reactions. 
After the final examination, 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. 
 
Unscheduled visits: 
Investigators will be encouraged to perform unscheduled visits, whenever necessary for a 
patient's safety and welfare. This shall be considered in particular for de novo patients from 
Canada.  
Unscheduled visits will be documented on the eCRF. 
 
6.1.3 Interpretation of Time Windows in This Study 
For this study the following time windows apply: 
Time point 
Time stated 
Tolerance 
On site visit N  
(de novo patients only) 
Week 2 
± 2 days 
 
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On site Visits 2, 3, 4, 5, 6, 7, 8, 9, 10  Weeks 12, 24, 36, 48, 60, 72, 84, 96, 
108 
± 2 weeks 
 
Interval between Last Treatment 
Visit and (early) Termination Visit 
1 week 
± 5 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 
USA: The maximum total duration of the study for an individual patient will be approximately 
2.5 years. 
Canada: The individual treatment duration in Canada will be approximately 12 months. 
6.2.2 Planned Duration for the Study as a Whole 
USA: The study started enrolling in the second quarter of 2016. Completion of the study by the 
last patient is expected for approximately fourth quarter of 2018. The total study duration will 
be approximately 2.5 years. 
Canada: The study is planned to start enrolling in the fourth quarter of 2017. Completion of the 
study by the last patient is expected for approximately fourth quarter of 2018. The total study 
duration will be approximately 12 months.  
This period may be shorter if the sponsor decides to end the trial earlier, or when octanorm 
becomes commercially available in the respective country (for details see Section 3.2). 
6.2.3 Premature Termination of the Study 
Both the responsible Investigators and the Sponsor reserve the right to terminate the study at 
any time. Should this be necessary, the procedures will be arranged on an individual study basis 
after review and consultation by both parties. In terminating the study, the Sponsor and the 
Investigator will ensure that adequate consideration is given to the protection of the patients' 
interests. Premature termination will be notified in accordance with applicable regulatory 
requirements. 
Furthermore, the Investigator should promptly inform the IRB and provide a detailed written 
explanation. The pertinent regulatory authorities and IRBs are to be informed according to 
national regulations. 
Early termination of the study as a whole or centre-wise may apply for the following reasons: 
Clinical Study 
• At any time the study as a whole will be terminated prematurely if e.g.: 
o New toxicological or pharmacological findings or safety reports invalidate the 
earlier positive benefit-risk-assessment. 
o If more than 2 TEEs (i.e. ischemic stroke, transient ischemic attack, cerebral 
infarction, cerebrovascular accident, cerebral thrombosis, embolic infarctions, 
 
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[acute] myocardial infarction, deep vein thrombosis, pulmonary embolism, 
venous thrombosis excluding thrombophlebitis) are observed fulfilling the 
following criteria: 
 assessed as probably or possibly related to octanorm treatment by 
Investigator and/or Sponsor; 
 confirmed by the Independent Data Monitoring Committee (IDMC). 
o Any other reason rendering the continuation of the study impossible for the 
Sponsor. 
Study Centre 
• At any time the study can be terminated at an individual centre if e.g.: 
o The centre cannot comply with the requirements of the protocol. 
o The centre cannot comply with applicable standards. 
o The required recruitment rate is not met. 
Should the study be prematurely terminated, all study materials (completed, partially completed 
and blank forms, IMP, etc.) must be returned to the Sponsor. 
 
7 
ASSESSMENTS AND METHODS 
7.1 
Background / Baseline Information 
The following general or background assessments will be performed during the study at 
predefined time points: 
Demographic data: All demographic data (age, weight, height, calculated body mass index, 
ethnic origin, ABO Rhesus blood type) will be taken over from the main study SCGAM-01 
(SCGAM-01 patients) or recorded at Screening Visit (de novo patients). 
Medical history: All medical history (conditions and surgical treatment) will likewise be taken 
over from the main study SCGAM-01 (SCGAM-01 patients) or recorded at Screening Visit (de 
novo patients). 
Previous and ongoing therapies: Similarly, previous drug and non-drug therapies (e.g. 
physiotherapy) will be taken over from the main study SCGAM-01 (SCGAM-01 patients) or 
recorded at Screening Visit (de novo patients). 
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. 
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 (primary endpoint). 
 
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• 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. 
• Number of days of use and annual rate of antibiotics (oral, parenteral, oral plus 
parenteral, prophylactic and therapeutic), along with type and dosage of antibiotic. 
• QoL assessments. 
For the collection of data for the above measurements, each patient will be provided with an 
individual Diary to be filled in by the patient during the home therapy time. The Patient's Diary 
will be checked for accuracy of the data by the Investigator and collected at each study visit. 
The data will be then 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. 
For the purpose of this study the following events will be considered as SBIs, to be included in 
the primary efficacy analysis: 
• Bacterial pneumonia. 
• Bacteraemia/sepsis. 
• Osteomyelitis/septic arthritis. 
• Visceral abscess. 
• Bacterial meningitis. 
The presence of any of these infections should be verified by the specific differentiated 
diagnostic examinations [22] given in the following table: 
Table 2 
Diagnostic Criteria for Serious Infection Types 
Infection: Bacteraemia/sepsis a 
• 
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 b, leukocytosis (white blood cell (WBC) count 
>12,000/mm3), differential WBC count demonstrating >10% immature (band) neutrophils, 
leukopenia, thrombocytopenia, coagulopathy, lactic acidosis. 
Infection: 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 c, CSF leukocytosis with 
neutrophil predominance, decrease in CSF glucose. 
 
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Infection: 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. 
Infection: Bacterial Pneumonia d 
• 
Symptoms: productive cough/change in character of sputum, dyspnoea or tachypnoea, chills, 
chest pain, rigors, headache, fatigue, sweats, anorexia, myalgia. 
• 
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 e, 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) 
Infection: 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 
Notes to Table 2: 
Items in bold are considered essential diagnostic features. 
a 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. For paediatric 
patients, the definition of sepsis using age-specific criteria as recommended by the International Consensus 
Conference on Paediatric Sepsis should be employed.[23] 
b 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 patients without indwelling catheters 
or vascular access devices, a single blood culture positive for a pathogenic organism will meet the diagnostic 
criteria for bacteraemia. Patients meeting criteria for positive blood culture but without 2 or more of the sepsis 
criteria listed above will be classified as having bacteraemia. 
 
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c 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. 
d 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. To establish the diagnosis of bacterial 
pneumonia for paediatric patients, most of the same diagnostic criteria listed may be used, with the following 
exceptions: Because paediatric patients may not produce a sputum specimen for culture, blood cultures or 
serology may be substituted to identify the etiologic bacterial pathogen. In infants age 3 to 24 months, who tend 
to have a higher baseline temperature, fever is defined as a rectal temperature >38.3 °C (101 °F). In children 
>2 years, fever is more commonly defined as a rectal temperature >38 °C (100.4 °F). In paediatric patients, 
elevations of WBC counts >15,000/mm3 are frequent but could be variable in patients with bacterial pneumonia, 
or leukopenia with WBC count <5000/mm3 may be observed, usually associated with severe infection. 
e 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. 
7.3 
Safety Assessments 
Any of the following drug safety information shall be collected: Adverse events (AEs) and 
serious adverse events (SAEs) temporally associated with administration of IMP. 
7.3.1 Adverse Events 
7.3.1.1 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. 
An AE is defined as treatment-emergent (TEAE), if the event began or worsened after the start 
of first infusion of trial medication: 
• For patients who migrate into the extension study without interruption of octanorm 
treatment (see Section 3.2), all adverse events occurring in the extension study will be 
considered treatment-related. An adverse event recorded in the main study will not be 
recorded again in the present one. 
• For patients who receive any other IgG brand between the main and the extension studies 
(Section 3.2), “treatment-emergent” will refer to events with onset after the start of the 
infusion with octanorm at the screening visit of the extension study. 
• For de novo patients in Canada who received another IgG brand before this study, 
“treatment-emergent” will refer to events with onset after the start of the infusion with 
octanorm at Visit N of the study. 
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 non-serious AE or marked laboratory abnormality that results in: 
 
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• withdrawal of IMP treatment, 
• and/or dose reduction, 
• and/or initiation of significant additional concomitant therapy (i.e. medications given 
intravenously). 
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. 
7.3.1.2 Collection 
The condition of the patient will be monitored throughout the study. At each visit, whether 
scheduled or unscheduled, AEs will be elicited using a standard non-leading question such as 
“How have you been since the last visit / during the previous study period?” For minor patients 
not understanding the question, the answer must be obtained from parents or legal guardians. 
In addition, the Patient Diaries (if applicable) will be checked by the Investigator for any 
documented event. 
Any AE which occurs during the study will be noted in detail on the appropriate pages of the 
eCRF. If the patient reports several signs or symptoms representing one syndrome or diagnosis, 
the diagnosis should be recorded in the eCRF. The Investigator will grade the severity of all 
AEs (mild, moderate or severe), the seriousness (non-serious or serious) and causality, as 
defined below (Sections 7.3.1.3, 7.3.1.4, and 7.3.2). The Sponsor is responsible to assess the 
expectedness of each ADR (expected or unexpected), as defined below (Section 7.3.1.4). 
In the event of clinically significant abnormal laboratory findings, the tests will be confirmed 
and followed-up until they have returned to normal and/or an adequate explanation is available. 
Diseases, signs and symptoms and/or laboratory abnormalities already existing before the first 
administration of IMP are not considered as AEs when observed at a later stage unless they 
represent an exacerbation in intensity or frequency (worsening). 
The Investigator should always provide detailed information concerning any abnormalities and 
the nature of, and reasons for any necessary action(s), as well as any other observations or 
comments, which are useful for the interpretation and understanding of the patients’ AEs. 
7.3.1.3 Severity 
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. 
7.3.1.4 Causality 
The relationship of AEs to the administered IMP will be assessed by the Investigator: 
 
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• 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). 
Classification of ADRs: 
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 for 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. 
7.3.1.5 Outcome 
The outcome of an AE has to be classified as follows: 
• recovered, resolved 
• recovering, resolving 
• not recovered, not resolved 
• recovered, resolved with sequelae 
• fatal 
• unknown 
NOTE: A patient’s death per se is not an event, but an outcome. The event which resulted into 
a patient’s death must be fully documented and reported, even in case the death occurs within 
4 weeks after IMP treatment end, and without respect of being considered treatment-related or 
not. 
 
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7.3.1.6 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) in general 
• none 
• medication (other than IMP) or other (e.g., physical) therapy started 
• test performed 
• other (to be specified) 
b) on IMP 
• none 
• product withdrawn 
• treatment interrupted 
• dose reduced 
• dose increased 
The Investigator will follow up each AE until it is resolved or until the medical condition of the 
patient is stable, and all relevant follow-up information will be reported to the Sponsor. 
7.3.2 Local 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 after each 
infusion using a 4-point rating scale: 0=none, 1=mild, 2=moderate, 3=severe. 
Investigators have to evaluate local reactions within approximately 1 hour after infusion at 
every study visit, 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 stitch(es); 
• 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, bleedings (other than small blood drops 
caused by the needle stitch), 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. 
7.3.3 Serious Adverse Events 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• results in death, 
• is life-threatening, 
 
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• 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. 
 
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 (surgical) procedure for which the date was scheduled before inclusion in 
the study 
• prolongation of the existing hospitalisation due to economical or social, but not due to 
medical reasons. 
 
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 hypothetically might have caused death if it were more severe. 
Medical judgment should be exercised in deciding whether an AE/ADR is serious in other 
situations: 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. 
SAE reporting timelines 
All SAEs, whether suspected to be related to study treatment or not, are to be reported by 
telephone, fax or e-mail immediately to the Clinical Project Manager or designee. 
Contact details will be communicated at the study initiation visit. 
An Octapharma "Serious Adverse Event Report" must be completed and submitted within 
24 hours after recognition of the event. 
All SAEs should be reported to the CRO responsible for the USA and Canada (Premier 
Research), telephone number 
 
Octapharma's 24-hour emergency telephone number is 
 
7.3.4 Laboratory Safety Tests 
For children the trial-related blood loss (including any losses in the manoeuvre) should not 
exceed 3% of the total blood volume during a period of 4 weeks and should not exceed 1% at 
any single draw. The total volume of blood is estimated at 80 mL/kg body weight. 
The following laboratory tests will be performed during the course of the study to investigate 
the efficacy and safety and tolerability of octanorm. At each visit, laboratory tests are to be 
performed before infusion of octanorm at the study site. 
 
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Table 3 
Laboratory Tests and Time Points 
Test 
Timing 
Laboratory 
Total serum IgG trough levels 
At screening and at all subsequent treatment 
visits. 
Local 
Haematology (complete blood count, 
WBC differential, haematocrit, 
haemoglobin) 
At screening, at Visits 2, 4, 6, 8 and 10, and 
at the Termination Visit. 
Local 
Clinical chemistry (sodium, potassium, 
glucose, ALAT, ASAT, LDH, total 
bilirubin, blood urea nitrogen or blood 
urea, creatinine) 
At screening, at Visits 2, 4, 6, 8 and 10, and 
at the Termination Visit. 
Local 
Urinalysis: pH, glucose, ketones, 
leukocytes, haemoglobin. 
At screening, at Visits 2, 4, 6, 8 and 10, and 
at the Termination Visit. 
Local 
Urine pregnancy test (women of 
childbearing potential) 
At screening, at Visits 2, 4, 6, 8 and 10, and 
at the Termination Visit. 
Local 
Virology: HAV, HBV, HCV, HIV 
At screening, at Visit 6, and at the 
Termination Visit. 
Local 
WBC, white blood cells; ALAT, alanine aminotransferase; ASAT, aspartate aminotransferase; LDH, lactate 
dehydrogenase; HAV/HBV/HCV, hepatitis A/B/C virus; HIV, human immunodeficiency virus. 
Laboratory determinations will be done at the individual study sites according to local 
procedures.  
The normal ranges of each determination at each laboratory involved will be provided in the 
Clinical Report. 
7.3.5 Viral Safety Tests 
At the Screening Visit, viral markers will be taken before the octanorm infusion, and will be 
tested at the local laboratory according to the site’s standard procedures. For patients positive 
in Hepatitis A virus at screening, follow-up samples may be omitted. 
Further viral marker samples will be taken, in Week 60 and at the (early) Termination Visit. 
7.3.6 Vital Signs 
To evaluate short-term tolerance, monitoring of vital signs including blood pressure, body 
temperature, pulse and respiratory rate will be performed at visits taking place at the clinic/study 
site; the Screening Visit, then at all subsequent study visits, and finally at the Termination Visit 
(irrespective of whether termination is regular or premature). 
Measurements will be carried out before the infusion and approximately within 1 hour after the 
infusion of IMP (not applicable for de novo patients at Screening Visit). 
7.3.7 Physical Examination 
A general physical examination will be performed at the Screening Visit according to routine 
procedures and will be as comprehensive as necessary to detect relevant abnormalities. If any 
findings are abnormal (SCGAM-01 patients: only the findings that newly occurred since end 
of the SCGAM-01 study), the Investigator will document the start date and whether or not the 
abnormal finding is still present at the start of treatment. The physical examination will be 
repeated at all subsequent study visits, and finally at the Termination Visit (irrespective of 
whether termination is regular or premature). Clinically relevant worsening from the status at 
screening will be documented as an AE. 
 
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7.3.8 Other Relevant Safety Information 
Post study related safety reports 
Any SAE which occurs up to four weeks after the completion of the study should be reported 
by the Investigator to the sponsor if the investigator becomes aware of it. Proactive monitoring 
for post-study SAEs is not required. If a post study SAE is identified, the investigator should 
complete a SAE form. Relation to the clinical study should be stated on the report. 
If a patient dies within 4 weeks after the last IMP administration, this should be reported as 
well, irrespective of whether or not it is considered treatment-related. 
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 is asked to complete the pregnancy 
notification form and to send it (by fax or email) to the Sponsor. Follow-up information on the 
outcome of both mother and foetus will be requested by a Sponsor representative. 
Overdose, interaction and medication error 
The following safety relevant information should be reported as AE or as SAE, if the reaction 
fulfils one of the criteria for seriousness (see Section 7.3.3). 
Drug overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
that specified in the protocol, and higher than the known therapeutic dose and of clinical 
relevance. The reaction must be clearly identified as an overdose. 
Interaction 
A drug interaction is a situation in which a substance/medicinal product affects the activity of 
an IMP, i.e. the effects are increased or decreased, or they produce an effect that none of the 
products exhibits on its own. The reaction must be clearly identified as drug interaction. 
Medication error 
Medication error involves the inadvertent administration or unintended use of a medicinal 
product which may be caused by the naming, presentation of pharmaceutical form/packaging, 
instructions for use/labelling. The reaction must be clearly identified as a medication error. 
7.4 
Other Assessments 
7.4.1 Drug Concentration Measurements 
Samples for total IgG trough levels measurements will be taken at the Screening Visit, before 
any infusion given at the study site and at the (early) Termination Visit; these samples will 
analysed at the local laboratory. 
7.4.2 Quality of Life Assessment 
QoL assessments will be made using the Child Health Questionnaire-Parent Form (CHQ-PF50) 
from parent or guardian of patients <14 years of age and the SF-36 Health Survey in patients 
≥14 years of age. The QoL assessments will take place at the Screening Visit, at Week 60 (Visit 
6), and at the (early) Termination Visit. 
 
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7.5 
Appropriateness of Measurements 
Safety will be monitored by standard assessment. 
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 Questionnaires are standardised, validated instruments that have been widely used in 
clinical studies, including studies with PI patients. 
 
8 
DATA HANDLING AND RECORD KEEPING 
To ensure that data in the CRFs are accurate and complete and in accordance with source 
records, source data verification will be performed in accordance with Octapharma standards. 
The extent of source data verification will be defined in detail in the monitoring manual. 
8.1 
Documentation of Data 
8.1.1 Source Data and Records 
Source data are defined as all of the information related to clinical findings, observations, or 
other activities in the study, written down in original records or certified copies of original 
records. The investigator will maintain adequate source records (e.g., case histories or 
subject/patient files for each subject/patient enrolled). Source records should be preserved for 
the maximum period of time required by local regulations. 
For each subject/patient enrolled, the investigator will indicate in the source record(s) that the 
subject/patient participates in this study. 
All data entered in the CRF must be supported by source data in the subject/patient records with 
the 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 source data/records. 
The investigator may authorize site staff (e.g., sub-investigators, nurses) to enter study data into 
the CRF. This must be documented in the „Delegation of Authority Log“, signed by the 
investigator. 
The following data must be verifiable from the source records: patient’s inclusion in Study 
SCGAM-03, patient number, sex, weight, date of birth, written informed consent, medical 
history, main inclusion and exclusion criteria,  local laboratory test results, PID relevant 
concomitant therapies (medication and non-drug therapy), any AE occurring in the course of 
the study, details of infusions (batch number, number of vials used, date, dose, rate and site(s)), 
date and reason for premature withdrawal (if applicable). As part of the source records, 
laboratory data will be reviewed by the Investigator, assessed as to their clinical significance, 
signed and dated. 
 
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8.1.2 Electronic Case Report Forms (eCRF) 
For each patient enrolled, an eCRF will be completed within the electronic data capture (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 
eCRF before 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 appear on the delegation of authority log. 
The following data may be entered directly into the EDC system, without prior record of source 
data, turning the eCRF into source: dates of blood sampling, vital signs. 
If any errors in the eCRFs are found during the data review process discrepancies will be 
generated programmatically within the EDC system, and ‘manual’ queries will be generated by 
either a monitor or Data Management. The programmed checks fire automatically once an 
eCRF page is saved within the system. The outputs of the programmed checks are referred to 
as ‘discrepancies’. Discrepancies are generated by the input of illogical eCRF data with the 
purpose to clarify the context or insertion of illogical or missing data with the site or designee. 
All discrepancies (programmed and manual) will be submitted to the site personnel or monitor 
for the site within the EDC system. Once the site responds to a discrepancy, Data Management 
or the monitor will review the new or changed data to ensure an appropriate response and close 
the discrepancy within the system. 
 
8.1.3 Changes to Case Report Form Data 
Monitors will perform source data verification (SDV) as defined for the study. 
Errors occurring on the EDC system can only be corrected by the investigator(s) or authorised 
site personnel. An audit trail documents all changes to the data over the entire study period. If 
data is changed as a result of a query, a comment must be supplied within the query’s text, 
stating the reason for the change, before closing. In addition, any changes to a previously saved 
eCRF page that has not had a query generated will need to have a reason specified for the data 
change. 
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 
(all discrepancies resolved) and the database is ready for lock. Source data verification will be 
confirmed as complete by the monitor, and all eCRFs will be approved by the Investigator 
before database lock. 
8.1.4 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, the 
 
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last available weight measurement will be used for calculating the dose per kg bodyweight (last 
observation carried forward). 
If missing values occur in the confirmatory analysis of the primary endpoints, they will be 
imputed by worst observed values and thus be ranked at the end of the list for the Wilcoxon-
Mann-Whitney test. Last-observation-carried-forward (LOCF) and observed-cases (OC) 
analyses will be applied as well as mixed models to explore the sensitivity of the results with 
regard to imputation techniques. 
8.2 
Information of Investigators 
An Investigator’s Brochure will be handed out to the Investigator before the start of the study, 
unless the investigator is already in possession of the current Investigator’s Brochure. This 
brochure 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 Investigator’s Brochure will be updated by the Sponsor at regular intervals and in case 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 investigators will be kept informed of important information related to the safe use of the 
investigational product as the study proceeds. 
8.3 
Responsibilities 
The principal Investigator is accountable for the conduct of the clinical study. Responsibilities 
may be delegated to appropriately qualified persons. 
A “Delegation of Authority Log“ will be filled in and signed by the Investigator. In accordance 
with this authority log study-site staff (e.g., sub-investigators, nurses) is authorised to perform 
tasks relating to the study. 
The Investigator is responsible for coordinating the study locally. 
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, drug dispensing and accountability logs, correspondence pertaining to 
the study, etc.) should be filed accurately and kept by the Investigator for the maximum period 
of time required by local regulations. 
The Investigator is responsible for maintaining a confidential patient identification code list, 
which provides the unique link between named source records and eCRF data for the Sponsor. 
The Investigator must arrange for the retention of this confidential list for the maximum period 
of time required by local regulations. 
 
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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 
The Sponsor will establish an IDMC. During the study, the IDMC will periodically review 
relevant data and will give advice on the continuation, modification or termination of the study 
(see Section 6.2.3). A study-specific Charter will define in detail the composition, 
responsibilities and procedures of the IDMC. 
 
9 
STATISTICAL METHODS AND SAMPLE SIZE 
The statistical analysis will be delegated under an agreement of transfer of responsibilities to 
an external 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 
Approximately 45 patients are planned in total: 
• All the patients who complete the main study SCGAM-01 in the USA or in Canada and 
who are willing and eligible to continue study treatment will be included in the present 
extension study. At the time of preparation of this protocol is it anticipated that 
approximately 35 patients will take part in the extension study (Section 3.2).  
• Approximately 10 de novo patients who are under other SCIG treatment, but did not 
participate in the main study SCGAM-01 are planned in Canada. 
No further sample-size considerations apply. 
9.2 
Statistical Analysis 
No confirmatory statistical analysis will be performed; the results of this extension study will 
be presented at the descriptive level only. 
9.2.1 Population for Analysis 
The following populations will be considered for the statistical analysis: 
The safety analysis set consists of all patients who received at least part of one infusion of 
octanorm within this extension study. 
 
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The full analysis set (FAS) is defined according to the intention-to-treat principle and consists 
of all patients of the safety analysis set who satisfy all eligibility criteria and for whom any post 
screening data in this extension study are available. It is expected that the FAS will coincide 
with the safety set. 
The per-protocol (PP) set consists of all patients of the FAS excluding those with major protocol 
violations which may have an impact on the analysis of the primary endpoint. This is the set of 
patients who participated in the study as intended and for whom the primary endpoint can be 
evaluated as planned. 
Only major protocol deviations with the potential to affect the study results significantly or to 
invalidate the interpretation of the data obtained will lead to exclusion of patients from the PP 
set; protocol deviations to be considered will include (but will not be limited to): 
• Violations of the study entry criteria. 
• Administration of any other blood or plasma-derived product or of any other 
immunoglobulin preparations during the SCGAM-03 study. 
• Any prohibited concomitant medication (including long term corticosteroids, daily, 
≥0.15 mg of prednisone or equivalent/kg/day, immunosuppressive and 
immunomodulatory drugs). 
• Failure to attend two scheduled consecutive visits OR three or more scheduled visits 
during the study for reasons other than clinical reasons. 
Efficacy endpoints will be analysed on the basis of FAS. 
Analysis of the safety endpoints will be based on the safety set. 
The membership of each patient in the respective analysis populations will be determined 
before the statistical analysis in a data review meeting by a panel consisting of a medical expert 
from the Sponsor, the clinical study manager, the data manager and the study statistician. 
All statistical analyses will be repeated on modified populations, i. e. excluding the 'de novo' 
patients. 
All data will be summarised for all patients overall and by age group. 
9.2.2 Efficacy Analysis Plan 
No confirmatory efficacy analysis will be performed. 
The rate of SBI per person-year (bacterial pneumonia, bacteraemia/sepsis, osteomyelitis/septic 
arthritis, visceral abscess, bacterial meningitis) during the treatment period with octanorm will 
be presented as point estimates of the rate along with a 99% CI. Calculation of this CI will 
account for intra-patient correlation in incidents following a compound Poisson process model. 
Furthermore, all observed SBIs will be listed individually and in full detail. 
The duration of infection will be summarised by standard descriptive statistics by type of 
infection and by severity. The individual characteristics of each infection, including the time to 
resolution will be listed. 
The use of antibiotics will be reported as a detailed list of all such medications, and the number 
of patients treated with antibiotics, the number of treatment episodes and the number of 
treatment days will be tabulated. 
 
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The FDA Guidance for Industry suggests that, based on historical data, a statistical 
demonstration of a serious infection rate per person-year less than 1.0 is adequate to provide 
substantial evidence of efficacy.[22] Therefore, this background information will be used for a 
descriptive evaluation of the serious infection rate in this extension study. Exploratory statistical 
testing may be performed if considered appropriate. 
The QoL data will be presented descriptively by visit, along with the change from baseline 
(defined as the first 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. 
9.2.3.1 Adverse Events 
All reported AEs will be coded according to 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. 
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. 
• Infusion rate at the onset of temporally associated TEAEs  
• 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. 
9.3 
Randomisation / Stratification / Code Release 
There is no randomisation in this study. 
9.4 
Interim Analysis 
No interim analysis is planned. 
 
10 ETHICAL / REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS 
10.1 Ethical / Regulatory Framework 
This study will be conducted in accordance with the ethical principles that have their origins in 
the Declaration of Helsinki. Before submission of the study protocol to the IRB and Competent 
Authority, the study will be registered in ClinicalTrials.gov. The study protocol and any 
 
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subsequent substantial amendment(s), as well as a sample of the information sheet and informed 
consent form, any other materials provided to the patients, and further requested information 
will be submitted to the IRB and the Competent Authority. The study will be conducted in 
compliance with the protocol, GCP and the applicable regulatory requirements. 
In addition, the study will be conducted under a US Investigational New Drug (IND) 
application, and therefore must meet the applicable FDA requirements including Statement of 
Investigator Form 1572 and financial disclosure statement. 
The regulatory application or submission for regulatory approval will be made by the Sponsor 
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 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, and further 
requested information will be submitted to the appropriate IRB and the competent Authority. 
The study approval letter must be available before any patient is exposed to a study-related 
procedure. 
The Sponsor, the Investigator and any third party (e.g. CRO) involved in obtaining approval, 
must inform each other in writing that all ethical and legal requirements have been met before 
the first patient is enrolled in the study. 
10.3 Patient Information and Informed Consent 
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. 
For minor patients, freely given written consent must be obtained from parents or legal 
guardians. In addition, when required by the local regulatory authorities, IRBs, written assent 
must be obtained from children and adolescents based upon the age requirements established 
by those institutions. 
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 their withdrawal. The Investigator will date and sign the 
informed consent form of each patient enrolled. 
Each patient, or his parents/legal guardians, will give written consent that his/her source records 
may be reviewed by study monitors, quality assurance auditors and/or health authority 
inspectors, in accordance with applicable regulations. These persons are bound by 
confidentiality obligations. 
10.4 Protocol Amendments 
Any prospective change to the protocol will be agreed between the Investigator (Coordinating 
Investigator in multicentre studies) and the Sponsor before its implementation. Any such 
 
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amendments will be submitted to the IRB and/or Competent Authority responsible as required 
by applicable regulations. 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 Patients’ Data 
The Investigator will ensure that the patient's confidentiality will be preserved. On eCRFs or 
any other documents submitted to the Sponsor, the patients will not be identified by their names, 
but by an identification code, consisting of a centre number and a patient number. Documents 
that are not for submission to the Sponsor, i.e. the confidential patient identification list, original 
informed consent forms and source records, will be maintained by the responsible Investigator 
in strict confidence. 
 
 
11 QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Periodic Monitoring 
The monitor will contact and visit the investigator periodically to review all study-related 
source data/records, verify the adherence to the protocol and the completeness, correctness and 
accuracy of all CRF entries compared to source data. The investigator will 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 
subject/patient. Thereafter, monitoring frequency will depend on study progress but is expected 
to be approximately every 10-18 weeks. 
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 IRB / Regulatory Authority inspectors, 
after reasonable notice. The main purposes of an audit or inspection are to confirm that the 
rights and welfare of the patients have been adequately protected, and that all data relevant for 
the assessment of safety and effectiveness of the IMP have been reported to the Sponsor. 
 
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12 REPORTING AND PUBLICATION 
12.1 Clinical Study Report 
The Sponsor will prepare a clinical study report (in accordance with relevant guidelines and 
Octapharma Standard Operating Procedures) timely after the completion of the study. The 
Coordinating Investigator will approve the final study report after review. 
12.2 Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
envisaged by an Investigator, the Investigator agrees to inform the Sponsor and to submit all 
manuscripts or abstracts to the Sponsor before submission to an editorial board or scientific 
review committee. This will allow the Sponsor to protect proprietary information and to provide 
comments based on information that may not yet be available to the Investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will support publication 
of multicentre studies only in their entirety and not as individual centre data. Authorship will 
be determined by mutual agreement. 
 
13 LIABILITIES AND INSURANCE 
To cover any damage or injury occurring to a patient in association with the investigational 
medicinal product or the participation in the study, the Sponsor will contract insurance in 
accordance with local regulations. 
All participating investigators are responsible for dispensing the IMP in adherence to this 
protocol, and for its secure storage and safe handling throughout the study. 
 
14 REFERENCES 
 
 1.  Berger M: Choices in IgG replacement therapy for primary immune deficiency diseases: 
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 
preparation for subcutaneous administration, IgPro20, in patients with primary 
immunodeficiency. J Clin Immunol 2010;30:734-745. 
 6.  Wasserman RL, Irani AM, Tracy J, et al: Pharmacokinetics and safety of subcutaneous immune 
globulin (human), 10% caprylate/chromatography purified in patients with primary 
immunodeficiency disease. Clin Exp Immunol 2010;161:518-526. 
 
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CONFIDENTIAL 
 
 7.  Wasserman RL, Melamed I, Kobrynski L, et al: Efficacy, Safety, and Pharmacokinetics of a 
10% Liquid Immune Globulin Preparation (GAMMAGARD LIQUID, 10%) Administered 
Subcutaneously in Subjects with Primary Immunodeficiency Disease. J Clin Immunol 2011;DOI 
10.1007/s10875-011-9512-z- 
 8.  Berger M, Rojavin M, Kiessling P, et al: Pharmacokinetics of subcutaneous immunoglobulin 
and their use in dosing of replacement therapy in patients with primary immunodeficiencies. 
Clinical immunology (Orlando, Fla.) 2011;doi:10.1016/j.clim.2011.01.006- 
 9.  Berger M: Subcutaneous Administration of IgG. Immunol.Allergy Clin.North Am. 
2008;28:779-802. 
 10.  Orange JS, Grossman WJ, Navickis RJ, et al: Impact of trough IgG on pneumonia incidence in 
primary immunodeficiency: A meta-analysis of clinical studies. Clin Immunol 2010;137:21-30. 
 11.  Gardulf A, Hammarstrom L, Smith CI: Home treatment of hypogammaglobulinaemia with 
subcutaneous gammaglobulin by rapid infusion. Lancet 1991;338:162-166. 
 12.  Borte M, Bernatowska E, Ochs HD, et al: Efficacy and safety of home-based subcutaneous 
immunoglobulin replacement therapy in paediatric patients with primary immunodeficiencies. 
Clin Exp Immunol 2011; 
 13.  Borte M, Quinti I, Soresina A, et al: Efficacy and Safety of Subcutaneous Vivaglobin® 
Replacement Therapy in Previously Untreated Patients with Primary Immunodeficiency: A 
Prospective, Multicenter Study. Journal of Clinical Immunology 2011;DOI 10.1007/s10875-
011-9588-5- 
 14.  Gardulf A, Bjorvell H, Gustafson R, et al: Safety of rapid subcutaneous gammaglobulin 
infusions in patients with primary antibody deficiency. Immunodeficiency 1993;4:81-84. 
 15.  Gardulf A, Bjorvell H, Andersen V, et al: Lifelong treatment with gammaglobulin for primary 
antibody deficiencies: the patients' experiences of subcutaneous self-infusions and home 
therapy. J.Adv.Nurs. 1995;21:917-927. 
 16.  Gardulf A, Moller G, Jonsson E: A comparison of the patient-borne costs of therapy with 
gamma globulin given at the hospital or at home. Int.J.Technol.Assess.Health Care 
1995;11:345-353. 
 17.  Gardulf A, Hammarstrom L: Subcutaneous Administration of Immunoglobulins: What Are the 
Advantages? Clin Immunother 1996;6:108-116. 
 18.  Hagan JB, Fasano MB, Spector S, et al: Efficacy and Safety of a New 20% Immunoglobulin 
Preparation for Subcutaneous Administration, IgPro20, in Patients With Primary 
Immunodeficiency. Journal of Clinical Immunology 2010;DOI 10.1007/s10875-010-9423-4- 
 19.  Jolles S, Bernatowska E, de GJ, et al: Efficacy and safety of Hizentra((R)) in patients with 
primary immunodeficiency after a dose-equivalent switch from intravenous or subcutaneous 
replacement therapy. Clin Immunol 2011;doi:10.1016/j.clim.2011.06.002- 
 20.  Wasserman RL, Melamed I, Nelson RP, et al: Pharmacokinetics of Subcutaneous IgPro20 in 
Patients with Primary Immunodeficiency. Clin Pharmacokinet. 2011;50:405-414. 
 21.  Ochs HD, Gupta S, Kiessling P, et al: Safety and efficacy of self-administered subcutaneous 
immunoglobulin in patients with primary immunodeficiency diseases. J.Clin.Immunol. 
2006;26:265-273. 
 22.   Guidance for Industry - Safety, Efficacy, and Pharmacokinetic Studies to Support Marketing of 
Immune Globulin Intravenous (Human) as Replacement Therapy for Primary Humoral 
Immunodeficiency. 2008. 
 23.  Goldstein B, Giroir B, Randolph A: International pediatric sepsis consensus conference: 
definitions for sepsis and organ dysfunction in pediatrics 
18. Pediatr.Crit Care Med. 2005;6:2-8. 
 24.  Taylor E: Intravenous immune globulin (IVIG): hemolytic reactions. Can Adv Reaction 
Newsletter 2009;19:1-3. 
 
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 25.  Chapel HM, Spickett GP, Ericson D, et al: The comparison of the efficacy and safety of 
intravenous versus subcutaneous immunoglobulin replacement therapy. J.Clin.Immunol. 
2000;20:94-100. 
 26.  Brown BW, Brauner C, Chan A, et al: STPLAN Version 4.3, Calculations for Sample Sizes and 
Related Problems. n.a. 2006;1-184. 
 
 
 
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SAP_003.pdf: 
ocfophormo
Statistical Analysis Plan
Study lD
Study title
Study phase
SCGAM-03
Clinical phase lll study to monitor the safety, tolerability
and efficacy of subcutaneous human immunoglobulin
(octanorm) in patients with primary immunodeficiency
diseases who have completed the SCGAM-OItrial.
ilt
Document author
Document version
 
, Manager Biometrics, Octapharma
2.0
Supersedes
Effective date
17-Jul-20I9
Doc lD
2964
Protocol version this
SAP is based upon
Version 07, dated 04-October-201-8 (US)
Version 05, dated 25-October-2OL8 (Canada)
Approved by
Name
Function, affiliation
Date and signoture
Manager Biometrics, Octapharma
 
tf
Vice President Clinical R&D lmmunology
& Critical Care, Octapharma
lil
090-SAP-SCGAM -03_V2.d ocx
Doc lD: 2964
1 7. JULI
Ll24
This document contains confidential and proprietary information of Octapharma. 
Copying or distribution of this document is only permitted with the written permission 
of Octapharma. Any commercial use of the information is subject to the permission of 
Octapharma and a license fee.


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Document History 
Version 
Date 
Author 
Description 
Final v1.0 14-Dec-2015 
 
New Document 
Final v1.1 21-Dec-2015 
 
Correction of clerical errors due to problems with the use of 
Word fields in the pdf conversion: Wrong study id in header, 
Faulty page numbers, wrong date of protocol on page 5  
Final v2.0 17-Jul-2019 
 
Ensure conformance with the latest protocol versions (v 7.0 
for the US, v 5.0 for Canada) and decisions made with respect 
to the analysis of the predecessor study SCGAM.-01  
Abbreviations 
AE 
Adverse Event 
 
IMP 
Investigational Medicinal Product 
ALAT 
Alanine Aminotransferase 
 
ITT 
Intention-To-Treat 
ASAT 
Aspartate Aminotransferase 
 
IVIG 
Intravenous Immunoglobulin 
BMI 
Body Mass Index 
 
LDH 
Lactate Dehydrogenase 
CBC 
Complete Blood Count 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
CHQ-PF50 
Child Health Questionnaire - Parent Form 
 
NAT 
Nucleic Acid Test 
CI 
Confidence Interval 
 
PI 
Primary Immunodeficiency  
CSR 
Clinical Study Report 
 
PP 
Per Protocol 
(e)CRF 
(Electronic) Case Report Form 
 
PT 
Preferred Term 
ELISA 
Enzyme-Linked Immunosorbent Assay 
 
QoL 
Quality of Life 
FAS 
Full Analysis Set 
 
TEAE 
Treatment Emergent Adverse Event 
FDA 
Food and Drug Administration 
 
TEE 
Thromboembolic Event 
GCP 
Good Clinical Practice 
 
WBC 
White Blood Cell 
HBV 
Hepatitis B Virus 
 
SAF 
Safety Set 
HCV 
Hepatitis C Virus 
 
SAP 
Statistical Analysis Plan 
HIV 
Human Immunodeficiency Virus 
 
SBI 
Serious Bacterial Infections 
ICH 
International Conference on Harmonisation 
 
SOC 
System Organ Class 
IgG 
Immunoglobulin G 
 
 
 


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Table of Contents 
1. 
Preface ............................................................................................................................................. 5 
2. 
Purpose ............................................................................................................................................ 6 
3. 
Study Objectives and Endpoints ...................................................................................................... 7 
3.1. 
Study Objectives ...................................................................................................................... 7 
3.1.1. 
Primary Objective ............................................................................................................ 7 
3.1.2. 
Secondary Objectives ...................................................................................................... 7 
3.2. 
Study Endpoints (Target Variables) ......................................................................................... 7 
3.2.1. 
Primary Target Variables ................................................................................................. 7 
3.2.2. 
Secondary Target Variables ............................................................................................. 7 
4. 
Study Methods ................................................................................................................................ 8 
4.1. 
Overall Study Design and Plan ................................................................................................. 8 
4.2. 
Age groups ............................................................................................................................... 8 
4.3. 
Selection of Study Population ................................................................................................. 9 
5. 
Sequence of Planned Analyses ...................................................................................................... 10 
5.1. 
Final Analyses and Reporting ................................................................................................ 10 
6. 
Sample Size Determination ........................................................................................................... 11 
6.1. 
Patient Replacement Policy ................................................................................................... 11 
6.2. 
Premature Termination of the Study .................................................................................... 11 
7. 
Analysis Populations ...................................................................................................................... 12 
8. 
General Issues for Statistical Analysis ........................................................................................... 13 
8.1. 
Analysis Software .................................................................................................................. 13 
8.2. 
Withdrawals .......................................................................................................................... 13 
8.3. 
Handling of Missing Data....................................................................................................... 13 
8.4. 
Derived and Computed Variables ......................................................................................... 13 
9. 
Study Subjects and Demographics ................................................................................................ 15 
9.1. 
Disposition of Subjects and Withdrawals .............................................................................. 15 
9.2. 
Protocol Violations ................................................................................................................ 15 
9.3. 
Demographics and Other Baseline Characteristics ............................................................... 15 
9.4. 
Measurement of Treatment Compliance .............................................................................. 16 
10. Efficacy Analysis............................................................................................................................. 17 
11. Safety and Tolerability Analyses .................................................................................................... 18 
11.1. Adverse Events ...................................................................................................................... 18 
11.2. Infusions with One or More Temporally Associated AEs ...................................................... 18 
11.3. Infusion Site Reactions .......................................................................................................... 18 
11.4. Clinical Laboratory Evaluations ............................................................................................. 18 
11.5. Viral Markers ......................................................................................................................... 19 
11.6. Vital Signs .............................................................................................................................. 19 
11.7. Further Safety Evaluations .................................................................................................... 20 
11.7.1. 
Physical Examination ..................................................................................................... 20 
12. Reporting Conventions .................................................................................................................. 21 
12.1. General Reporting Conventions ............................................................................................ 21 


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12.2. Population Summary Conventions ........................................................................................ 21 
13. References ..................................................................................................................................... 23 
14. Tables, Listings and Figures ........................................................................................................... 24 
 
 
 
 


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1. Preface 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for Octapharma 
Protocol SCGAM-03: 
Study title for the USA: Clinical phase III study to monitor the safety, tolerability and efficacy of 
subcutaneous human immunoglobulin (octanorm) in patients with primary immunodeficiency 
diseases who have completed the SCGAM-01 trial 
Study title for Canada: Clinical phase III study to monitor the safety, tolerability and efficacy of 
subcutaneous human immunoglobulin (octanorm) in patients with primary immunodeficiency 
diseases, including (but not limited to) those who have completed the SCGAM-01 trial  
This phase III study is conducted to monitor the safety, tolerability and efficacy  properties of 
octanorm in patients with a confirmed diagnosis of Primary Immunodeficiency (PI) Disease as defined 
by the WHO and requiring immunoglobulin replacement therapy due to hypogammaglobulinaemia 
or agammaglobulinaemia. 
Study SCGAM-03 was initally designed as an extension of study SCGAM-01 in the sense that patients 
were to be taken exclusively from the cohort of patients who completed study SCGAM-01 in the USA; 
this was changed by allowing enrollment of Canadian patients who did not participate in the 
predecessor study. The primary focus of SCGAM-03 is to assess the medium-to-long-term safety and 
tolerability of octanorm. 
The structure and content of this SAP provides sufficient detail to meet the requirements identified 
by the FDA and International Conference on Harmonization (ICH) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use: Guidance on Statistical Principles in Clinical Trials1.  
The following documents were reviewed in preparation of this SAP: 
• 
Clinical Study Protocol SCGAM-03, Final Version 07, dated October 4, 2018 (for the US), and 
Final Version 05, dated October 25, 2017 (for Canada) respectively. 
The reader of this SAP is encouraged to also read the clinical protocol for details on the planned 
conduct of this study. Operational aspects related to collection and timing of planned clinical 
assessments are not repeated in this SAP unless relevant to the planned analyses. 
                                                          
1 International Conference on Harmonization. (1998). Guidance on Statistical Principles. ICH Topic E9 (Statistical 
Principles for Clinical Trials) (p. 37). London: International Conference on Harmonization. 


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2. Purpose 
This SAP outlines all statistical analyses to be performed on data collected in study SCGAM-03, and 
the resulting output that will be compiled to support the completion of the Clinical Study Report 
(CSR). 
The planned analyses identified in this SAP will be included in regulatory submissions and/or future 
manuscripts. Exploratory analyses not necessarily identified in this SAP may be performed to support 
the clinical development program. Any post-hoc or unplanned analyses performed that are not 
identified in this SAP will be clearly identified in the respective CSR. 
The statistical output provided to the medical writer of the CSR will closely follow the ICH guideline 
for industry on topic E3 (Structure and Content of Clinical Study Reports2) to facilitate the 
subsequent compilation of the CSR. 
This statistical output will consist of tables, figures and listings, including 
• 
Tables, figures and listings used or referenced in, or appended to the CSR as detailed in the 
remainder of this SAP (section 14 of the CSR) 
o Demographic data summary figures and tables 
o Efficacy data summary figures and tables 
o Safety data summary figures and tables 
• 
Listings provided as appendices to the CSR 
o Patient data listings (section 16.2 of the CSR) 
o Individual patient data listings (section 16.4 of the CSR) will be covered by inclusion 
of SAS datasets into the electronic submission to the authorities 
A detailed list of all tables, figures and listings will be supplied in a separate document later when all 
feedback from authorities will be available. 
                                                          
2 International Conference on Harmonization. (1996). Structure and Content of Clinical Study Reports. Structure 
and Content of Clinical Study Reports (Guideline for Industry) (S. 37). London: International Conference on 
Harmonization. 


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3. Study Objectives and Endpoints 
3.1. 
Study Objectives  
3.1.1. 
Primary Objective 
The primary objective of the study is to assess the medium-to-long-term safety and tolerability of 
octanorm.  
3.1.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• 
To assess the effect of octanorm on quality-of-life (QoL) measures. 
• 
To obtain further data on the efficacy of octanorm. 
3.2. 
Study Endpoints (Target Variables) 
3.2.1. 
Primary Target Variables 
There is no single primary endpoint in this present extension study. The primary objective is to assess 
safety and tolerability in medium-to-long-term administration, and this will be assessed by means of 
the following outcome variables: 
• 
Occurrence of treatment-emergent AEs (TEAEs) throughout the entire treatment period 
starting with the first infusion of IMP. 
• 
Occurrence of temporally associated TEAEs. 
• 
TEAEs by speed of infusion. 
• 
Local injection-site reactions. 
• 
Vital signs (blood pressure, pulse, body temperature, respiratory rate). 
• 
Physical examination. 
• 
Laboratory parameters (haematology, clinical chemistry and tests for viral safety). 
3.2.2. 
Secondary Target Variables 
Secondary assessment criteria will be for quality of life and efficacy: 
• 
QoL assessments using the CHQ-PF50 from parent or guardian of patients <14 years of age and 
the SF-36 Health Survey in patients ≥14 years of age. Age here refers to the age at enrollment 
into study SCGAM-01, so that each patient will continue using the same questionnaire as 
before. 
• 
Total IgG trough levels. 
• 
Occurrence of serious bacterial infections (SBIs) as defined in Section 10. 
• 
The annual rate of all infections of any kind or seriousness. 
• 
Time to resolution of infections. 
• 
Use of antibiotics (number of days and annual rate). 
• 
Missed days from work/school/kindergarten/day care. 


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4. Study Methods 
4.1. 
Overall Study Design and Plan 
Study SCGAM-03 is designed as a prospective, open-label, non-controlled, single-arm, multicentre 
phase III safety follow-up study with observation of patients receiving weekly or bi-weekly doses of 
octanorm over a period of up to two years.  
The study will be conducted at study sites in the United States that already participated in the SCGAM-
01 trial, and at study sites in Canada enrolling ‘de novo’ patients who are under other SCIG treatment. 
Most US patients will migrate directly from the main study to the present extension study. However, 
some patients are expected to complete the main study before the commencement of the extension 
study. Therefore, the following rules are instituted: 
a) Patients who complete the main study after the start of the extension study will be required to 
migrate directly into the extension study, so that treatment with octanorm is not interrupted. 
(For these patients, the screening visit in the extension study will be the same as the final visit in 
the main study; extension-study screening tests that also constitute main-study tests for that visit 
do not need to be duplicated.) Use of an IgG product other than octanorm between the main and 
extension studies will disqualify a patient from entry to the extension study. 
b) Patients who completed the main study before the start of this extension study will be allowed to 
continue IgG treatment with any commercially available SCIG until the time when they can be 
treated within the extension study. In the intervening interval they must have received the 
commercially available SCIG at the approximately same  dose which the patient had received in 
study SCGAM-01. (For these patients, the screening visit will be regarded as a fresh start and all 
screening procedures are to be conducted.) 
Each patient will be treated weekly or bi-weekly with octanorm, either at the investigation site (on 
study visit days) or else at home. Patients may remain in the trial until Octanorm becomes 
commercially available in the USA, the Sponsor decides to terminate the trial, or December 2020 
(whichever comes first). A patient may remain in the trial for up to approximately 4.5 years, i.e. 
receiving a total of approximately 234 Octanorm infusions (or less, if the infusions will be administered 
bi-weekly) A final examination will be performed 1 week after the last infusion, for both regular and 
premature termination of the patient's study participation. 
4.2. 
Age groups 
As of protocol version 9 of the predecessor study SCGAM-01, the age ranges for the four age strata 
were revised to: ≥2 years and <6 years, ≥6 years and <12 years, ≥12 years and <17 years, ≥17 
years and ≤75 years. In the present extension study, patients will remain in the strata that they were 
in for analysis in the main study (irrespective of whether their age changed such as to imply a change 
of age stratum). The maximum patient numbers in each age group will thus be the same as in the 
main study SCGAM-01. The analyses will reflect these age strata unless the number of patients per 
stratum is too low for reasonable statistical summaries; if this happens adjacent strata might be 
combined as indicated by the data. 
In addition, and to align the analysis with the results of the SCGAM-01 study, a different definition of 
age groups (2 to < 12, 12 to < 17, 17 to 65, and > 65 years) will be evaluated, and also a comparison 
of male vs. female subjects will be performed for primary and secondary endpoints. 
 


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4.3. 
Selection of Study Population 
The study population consists of patients of both sexes who completed study SCGAM-01. All patients 
therefore have a confirmed diagnosis of PI and require immunoglobulin replacement therapy due to 
hypogammaglobulinaemia or agammaglobulinaemia. All patients have been on stable treatment 
with octanorm during the SCGAM-01 study, possibly followed by a comparatively short period of 
compatible SCIG treatment with another (commercially available) SCIG product. 
 
 


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5. Sequence of Planned Analyses 
5.1. 
Final Analyses and Reporting 
As stated in section 4.1, each patient is treated with octanorm over a total periodof up to 4.5 years; 
one week after the last infusion a follow-up visit is performed, and the patient will be switched to a 
commercially available immunoglobulin product at the discretion of the investigator. Once the last 
patient has completed the study, data validation will be completed and the database will be locked 
according to the applicable standard operating procedures. This process includes a data review, the 
identification and classification of any protocol violations as detailed in section 7, and thus the 
patient disposition with respect to the analysis populations. All final, planned, analyses identified in 
the protocol and in this SAP will be performed only after the last patient has completed the study, 
the subject disposition has been agreed and documented, and the final SAP has been approved. 
Key statistics and study results will be made available to the study team following database lock and 
prior to completion of the final CSR by means of tables, figures and listings. 
Any, post-hoc, exploratory analyses completed to support planned study analyses, which were not 
identified in the final SAP, will be documented and reported in appendices to the CSR. Any results 
from these unplanned analyses will also be clearly identified in the text of the CSR. 


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6. Sample Size Determination 
Approximately 45 patients are planned in total: 
• 
Patients will be taken from the cohort of patients who completed the main study SCGAM-01 
in the USA and Canada. The theoretical maximum number of SCGAM-01 patients will be 
approximately 35 (the expected number in the main study). 
• 
Approximately 10 de novo patients who are under other SCIG treatment, but did not 
participate in the main study SCGAM-01 are planned in Canada. 
No further sample-size considerations apply. 
6.1. 
Patient Replacement Policy 
Patients withdrawn from the study for any reason will not be replaced.  
6.2. 
Premature Termination of the Study 
Both, the responsible Investigators and the Sponsor, reserve the right to terminate the study as a 
whole or centre-wise at any time. Should this be necessary, the procedures will be arranged on an 
individual study basis after review and consultation by both parties. In terminating the study, the 
Sponsor and the Investigator will ensure that adequate consideration is given to the protection of the 
patients' interests. Premature termination will be notified in accordance with applicable regulatory 
requirements. Please refer to the protocol for further details on premature termination. 
 
 


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7. Analysis Populations 
The following populations will be considered for the statistical analysis: 
The safety analysis set (SAF) consists of all patients who received at least part of one infusion of 
octanorm within this extension study. 
The full analysis set (FAS) is defined according to the intention-to-treat principle and consists of all 
patients of the SAF who satisfy all eligibility criteria and for whom any post screening data in this 
extension study are available. It is expected that the FAS will coincide with the safety set. 
The per-protocol (PP) set consists of all patients of the FAS excluding those with major protocol 
violations which may have an impact on the analysis of the primary endpoint. This is the set of patients 
who participated in the study as intended and for whom the primary endpoint can be evaluated as 
planned. 
Only major protocol deviations with the potential to affect the study results significantly or to 
invalidate the interpretation of the data obtained will lead to exclusion of patients from the PP set; 
protocol deviations to be considered will include (but will not be limited to): 
• 
Violations of the study entry criteria. 
• 
Administration of any other blood or plasma-derived product or of any other 
immunoglobulin preparations during the SCGAM-03 study. 
• 
Any prohibited concomitant medication (including long term corticosteroids, daily, ≥0.15 mg 
of prednisone or equivalent/kg/day, immunosuppressive and immunomodulatory drugs). 
• 
Failure to attend two scheduled consecutive visits OR three or more scheduled visits during 
the study for reasons other than clinical reasons. 
Analysis of the safety endpoints will be based on the safety set. 
Efficacy endpoints will be analysed on basis of the FAS. 
Any analysis might be repeated on basis of the PP analysis set if indicated by the data or in case the PP 
population differs from the FAS by 3 patients or more, to allow for an assessment of the robustness of 
the results with respect to protocol violations. 
The membership of each patient in the respective analysis populations will be determined before the 
statistical analysis in a data review meeting by a panel consisting of a medical expert from the Sponsor, 
the clinical study manager, the data manager and the study statistician. 
All protocol violations documented during the conduct of the study or identified at the data review 
process prior to DB lock will be reviewed and classified as minor or major and with respect to its 
effect on the planned analysis. Only major protocol violations with the potential to significantly affect 
the study results or to invalidate the interpretation of the data obtained will lead to exclusion of 
patients from the PP set. This classification of protocol violations 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. 


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8. General Issues for Statistical Analysis 
Descriptive summaries will be presented for each of the primary and secondary variables. In general, 
summaries will be completed for all patients overall and by age group as described in section 4.2.  
Continuous, quantitative variable summaries will in general include the number of patients with non-
missing values (N), mean, standard deviation, median, minimum and maximum, 1st and 3rd quartile. 
Categorical, qualitative variable summaries will include the frequency and percentage of patients 
who are in the particular category. In general the denominator for the percentage calculation will be 
based upon the total number of patients in the analysis population unless otherwise specified. 
Whenever appropriate, the analyses will be stratified according to the predefined age groups taken 
from the SCGAM-01 study (2 to <6 | ≥6 to <12 | ≥12 to <17 | ≥17 to ≤75). 
Additionally, for primary and secondary endpoints, the following subgroups will be investigated: 
• 
Male vs female subjects 
• 
A different definition of age groups: 2 to < 12, 12 to < 17, 17 to 65, and > 65 years 
8.1. 
Analysis Software 
Statistical analyses will be performed using SAS Software version 9.1 or higher. 
8.2. 
Withdrawals 
Patients who withdraw from the study prematurely will be considered in all data presentations for 
which they contribute data; in particular for the analysis of annual rates they will be considered with 
their actual observation periods. 
8.3. 
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. 
For missing weight measurements the last available body weight will be used for all calculations 
related to dosing; in individual patient data listings missing data will however not be replaced by 
imputed values. 
No analyses of the patterns of missing data will be done. 
For adverse events the following will be applied: 
An Adverse Event (AE) is defined as treatment-emergent, if first onset or worsening is after start of 
the first infusion of octanorm. 
If the start date and time of an AE are partially or completely missing, the AE will be assumed to be 
treatment-emergent if it cannot be definitely shown that the AE did not occur or worsen during the 
treatment emergent period (worst case approach). Missing dates and times will not be replaced. 
For medications the following will be applied: A medication will be assumed to be concomitant if it 
cannot be definitely shown that the medication was not administered during the octanorm 
treatment period as defined in section 8.4 below. Missing dates will not be replaced. 
8.4. 
Derived and Computed Variables 
The following derived and computed variables have been initially identified as important for the 
analysis of the primary and secondary target variables. It is expected that additional variables will be 


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required. The SAP will not be amended for additional variables that are not related to the primary 
target or key secondary target variables. Any additional derived or computed variables will be 
identified and documented in the SAS programs that create the analysis files. If the SAP is not 
amended, further derivations related to primary and secondary target variables will be described in 
the CSR. 
• 
Age will be derived according to the usual definition that a person is n years old until she or 
he has completed her or his (n+1)th year of life, using the date of informed consent as the 
reference date. This is also the definition that will be applied for evaluation of the age related 
inclusion criteria, and the stratification into the four predefined age groups 
[Unit: years] 
• 
Body Mass Index: BMI = (Body weight) / Height2 
[Unit: kg/m2] 
• 
The octanorm treatment period is defined as the period between the day of first treatment 
with study drug to the end of the observation period. This will usually be the termination 
visit. 
• 
The rate of serious bacterial infections per year during regularly repeated treatment with 
octanorm will be calculated as r = (Total number of serious bacterial infections occurring in 
the treatment period) / (Duration of treatment period) 
[Unit: 1/years] 
• 
The rate of other infections will be derived using the same method 
Calculation of the confidence intervals of these rates will account for intra-patient correlation in 
incidents following a compound Poisson process model.[1]  
With Ci infections for the ith patient, and C total infections, the adjusted 2-sided 98% CI is 
calculated by:  
൦𝑒𝑒
ln(𝑟𝑟)−2.33∙ඨ∑𝐶𝐶𝑖𝑖
2
𝐶𝐶2 ; 𝑒𝑒
ln(𝑟𝑟)+2.33∙ඨ∑𝐶𝐶𝑖𝑖
2
𝐶𝐶2 ൪ 
• 
The rate of infusions with one or more temporally associated AEs will be calculated for each 
patient as r = (Number of infusions with one or more temporally associated AEs) / (Number 
of infusions started). An AE is defined as a temporally associated if, and only if, the onset (or 
worsening) is either during an infusion of study medication or within 72 hours of the end of 
the infusion. 
[Unit: N/A] 
• 
The rate of absence from work or school will be based on the assumption of 200 
working/school days per year, i.e. the rate is to be calculated as R = (1/200)*(Number of days 
absent from work or school) / (Patient years on octanorm treatment)  
[Unit: 1/years] 


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9. Study Subjects and Demographics 
9.1. 
Disposition of Subjects and Withdrawals 
All patients enrolled in the study will be accounted for. Descriptive summaries of population data will 
be provided overall and by age group; these will include 
• 
The frequency and percent of patients in each analysis population, age strata and enrollment 
group  
• 
The disposition of patients (including number of patients enrolled, number of patients 
treated, number of completers) 
• 
study withdrawals by reason of withdrawal 
9.2. 
Protocol Violations 
Protocol violations will be checked on complete data for all relevant patients prior to defining the 
analysis populations. Relevant in this context means: 
• 
All patients for the final analysis 
The final decision regarding inclusion/exclusion of patients from the analysis sets will be taken based 
on protocol adherence reports during data review meetings before database lock, data release and 
final analysis applying the definitions in section 7. 
Major protocol violations will be summarized by type of violation. Individual patients with these 
protocol violations will be listed. 
9.3. 
Demographics and Other Baseline Characteristics 
Descriptive summaries of the demographic and other baseline characteristics will be completed for 
the populations specified below, overall and by age group as applicable; these include: 
• 
Demographics (Age, Gender, Race/Ethnicity, Height, Weight, BMI (calculated), ABO Rhesus 
blood type) 
(SAF, FAS, PP) 
• 
Medical History (SAF) 
Medical history will be coded with the Medical Dictionary for Regulatory Activities (MedDRA, 
according to the version specified in the Data Management Plan). Incidences of findings in 
medical history will be summarized by MedDRA system organ class (SOC) and preferred term 
(PT)  
• 
Prior and Concomitant Medications (SAF) 
Medications will be coded using the WHO Drug Dictionary (according to the version specified 
in the Data Management Plan). Incidences of prior and concomitant medications will be 
summarized by ATC level 2 and ATC level 4 
• 
Baseline Physical Examination, including vital signs (SAF) 
General patient characteristics and background assessments already available in the SCGAM-01 
database will be copied to the SCGAM-03 database for analysis; this includes demographics, medical 
history, previous and ongoing therapies. 


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9.4. 
Measurement of Treatment Compliance 
The following parameters will be listed and summarized per patient and/or per infusion: 
• 
Body weight 
• 
Actual dose (total and per kg body weight, based on the latest available weight 
measurement) 
• 
Total dose of octanorm administered 
• 
Total number of infusions administered 
• 
Total volume of solution administered 
• 
Infusion times 
• 
Overall amount of product administered (only included in data listings) 
• 
Maximal volume administered (in total and per kg body weight) 
• 
Infusion  flow rates (overall and per site) (center visits only) 
• 
Number of infusion parts administered per infusion (center visits only) 
• 
Number of infusion lines used simultenously  (center visits only) 
 
Deviations from the planned treatment schedule will be summarized by counting the number of 
infusions that deviate from the scheduled intervals by more than 2 days, and by listing all cases with 
more than two days deviation individually. 


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10. 
Efficacy Analysis 
No confirmatory efficacy analysis will be performed. 
The rate of SBI per person-year (bacterial pneumonia, bacteraemia/sepsis, osteomyelitis/septic 
arthritis, visceral abscess, bacterial meningitis) during the treatment period with octanorm will be 
presented as point estimates of the rate along with a two-sided 98% CI. Calculation of this CI will 
account for intra-patient correlation in incidents following a compound Poisson process model. 
Furthermore, all observed SBIs will be listed individually and in full detail. 
In case no serious bacterial infections are observed, it is not possible to calculate a confidence interval 
with the originally planned method using compound Poisson process model; if this happens, two 
additional analyses will be presented as sensitivity analyses: 
1. The originally planned two sided 98% confidence interval will be calculated for the worse case 
that one bacterial infections would have been observed. 
2. The confidence interval will be calculated using a standard Poisson distribution; this second 
model will also be used as a sensitivity analysis if a very small number of serious bacterial 
infections is observed, as within patient correlations are negligible for small number of serious 
bacterial infections. 
The annual rate of all infections of any kind or seriousness will also be presented as point estimate, 
but along with the two-sided 90% CI. This CI will be calculated using a compound Poisson process 
model to account for intra-patient correlation in incidents as described above; in addition, and as a 
sensitivity analysis, the same CI will be calculated using the overdispersed Poisson regression model 
by means of the SAS procedure GENMOD. 
The duration of infection will be summarised by standard descriptive statistics by type of infection and 
by severity. The individual characteristics of each infection, including the time to resolution will be 
listed. 
The use of antibiotics will be reported as a detailed list of all such medications, and the number of 
patients treated with antibiotics, the number of treatment episodes and the number of treatment days 
will be tabulated. 
The QoL data will be presented descriptively by visit, along with the change from baseline (i.e. 
screening visit). 
All absences from work or school will be listed with duration and reason for absence. The individual 
absence rates per person-year will calculated and summarized by descriptive statistics, including the 
two-sided 90% confidence interval, again calculated on basis of the compound Poisson process model. 
All hospitalizations will be listed with duration and indication for the inpatient hospital stay. The 
individual hospitalizations days per person-year will calculated and summarized by descriptive 
statistics, including the two-sided 90% confidence interval, again calculated on basis of the compound 
Poisson process model. 


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11. 
Safety and Tolerability Analyses 
The safety analysis will comprise descriptive statistics, tabulations and listings of all TEAEs, safety 
laboratory results, viral markers, vital signs and physical examination findings. 
11.1. 
Adverse Events 
All reported AEs will be coded according to MedDRA. 
An AE is defined as treatment-emergent, if first onset or worsening is during the octanorm treatment 
period. Only treatment-emergent AEs (TEAEs) are accounted for in the analysis. 
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. 
All reported events will be listed and tabulated in full detail, in particular the following key figures will 
be presented: 
• 
Total number of TEAEs reported. 
• 
Number of temporally associated TEAEs. 
• 
Infusion rate at the onset of temporally associated TEAEs  
• 
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. 
11.2. 
Infusions with One or More Temporally Associated AEs 
The number of infusions with at least one temporally associated adverse event (including AEs judged 
not to be related to octanorm by the investigator) over the total number of infusions will be 
calculated for each patient, and the ratio will be presented, including the associated upper one-sided 
95% confidence limit. The calculation of this confidence interval will take into account the observed 
intra-patient correlation - this is necessary because each patient may experience more than one 
infusion with an associated AE; it can therefore not be assumed that the observed events are 
statistically independent. 
11.3. 
Infusion Site Reactions 
Infusion Site Reactions are captured on a separate eCRF page; summaries will be prepared for 
• 
Number of patients with infusion site reactions by severity and by type of reaction 
• 
Number of infusions with infusion site reactions by severity, by type of reaction and by week 
11.4. 
Clinical Laboratory Evaluations 
The following laboratory tests will be performed during the course of the study to investigate the 
safety and tolerability of octanorm; for the timing of these lab panels and tests please refer to the 
flow chart of study events and sections 6.1 (Observations by Visit) and 7.3.4 (Laboratory Safety Tests) 
of the protocol: 
• 
Standard hematology 
o Complete blood count [CBC] 
o WBC differential 
o Hematocrit 
o Hemoglobin 
• 
Clinical chemistry 
o Sodium 


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o Potassium 
o Glucose 
o Alanine aminotransferase [ALAT] 
o Aspartate aminotransferase [ASAT] 
o Lactate dehydrogenase [LDH] 
o Total bilirubin 
o Blood urea nitrogen 
o Creatinine 
• 
Urinalysis 
o pH 
o Glucose 
o Ketones 
o Leukocytes 
o Hemoglobin 
o Urine pregnancy test (women of childbearing potential) 
All laboratory assessments will be done at the local laboratories according to the site’s standard 
procedures. 
Total serum IgG trough levels will be determined by the local laboratories.  
All laboratory data will be converted to standard units during the Data Management process. The 
laboratory data will be listed with suitable flags indicating abnormal values (L=Lower than reference 
range, H=Higher than reference range). 
Summary statistics for the laboratory values as well as their changes from baseline at each time will 
be tabulated for all laboratory parameters. 
11.5. 
Viral Markers 
Virology markers will be assessed at the screening visit, at visit 6 and at the (early) termination visit, 
and will include: HAV, HBV, HCV, HIV. 
These data will be listed as well with suitable flags indicating positive results. Furthermore shift 
tables will be presented to show any changes in the viral status during the study. 
11.6. 
Vital Signs 
To evaluate short-term tolerance, monitoring of vital signs including blood pressure, body 
temperature, pulse and respiratory rate will be performed at visits taking place at the clinic/study site; 
the Screening Visit, then at all subsequent study visits (at 12-weekly intervals), and finally at the 
Termination Visit (irrespective of whether termination is regular or premature). 
Measurements will be carried out before the infusion and (approximately) within 1 hour after the 
infusion of IMP. 
Vital signs parameters will be summarized by visit and measurement time, using the standard set of 
summary statistics for both absolute values and changes from baseline, where the baseline value is 
the pre-infusion measurement. 


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11.7. 
Further Safety Evaluations 
11.7.1. 
Physical Examination 
A general physical examination will be performed at the Screening Visit according to routine 
procedures and will be as comprehensive as necessary to detect relevant abnormalities. If any findings 
are abnormal (only the findings newly occurred since end of the SCGAM-01 study), the Investigator 
will document the start date and whether or not the abnormal finding is still present at the start of 
treatment. The physical examination will be repeated at all subsequent study visits (at 12-weekly 
intervals), and finally at the Termination Visit (irrespective of whether termination is regular or 
premature). Clinically relevant worsening from the status at screening will be documented as an AE. 
 
 


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12. 
Reporting Conventions 
The following reporting conventions will be adopted for the presentation of study data. These 
conventions will enhance the review process and help to standardize presentation with common 
notations. 
12.1. 
General Reporting Conventions 
• 
All tables and data listings will be developed in landscape orientation, unless presented as 
part of the text in a CSR. 
• 
Figures will in general also be presented in landscape orientation, unless presented as part of 
the text in a CSR. Exceptions are the Trellis plots that will be presented in portrait 
orientation. 
• 
Legends will be used for all figures with more than one variable or item displayed. 
• 
Figures will be in black and white, unless color figures have been identified as useful for 
discriminating presentation in the figure. Lines in figures should be wide enough to view the 
line after being photocopied. 
• 
Specialized text styles, such as bolding, italics, borders, shading, superscripted and 
subscripted text will not be used in tables, figures and data listings unless they add significant 
value to the table, figure, or data listing. 
• 
Only standard keyboard characters should be used in tables and data listings. Special 
characters, such as non-printable control characters, printer specific, or font specific 
characters, will not be used on a table, figure, or data listing. Hexadecimal character 
representations are allowed (e.g., μ, α, β). 
• 
The ICH numbering convention is to be used for all tables, figures and data listings. 
• 
All footnotes will be left justified and placed at the bottom of a page. Footnotes must be 
present on the page where they are first referenced. Footnotes should be used sparingly and 
must add value to the table, figure, or data listing. If more than four footnote lines are 
planned then a cover page may be used to display footnotes. 
• 
Missing values for both numeric and character variables will be presented as blanks in a table 
or data listing. A zero (0) may be used if appropriate to identify when the frequency of a 
variable is not observed. 
• 
All date values will be presented as DDMMMYYYY (e.g., 29AUG2001) format. 
• 
All observed time values will be presented using a 24-hour clock HH:MM format (e.g. 15:26). 
• 
Time durations will be reported in HH:MM notation. The use of decimal notation to present 
(display) time durations should be avoided (e.g. 0.083h = 5min) unless it is necessary to show 
the computation of time differences in a table, figure, or data listing, in which case both 
notations may be used to display the time duration. 
• 
All tables, figures and data listings will have the name of the program, and a date stamp on 
the bottom of each output. 
12.2. 
Population Summary Conventions 
• 
Population(s) represented on the tables or data listings will be clearly identified in the title as 
“Population: <name of population>” where <name of population> is any of the analysis 
population names or abbreviations defined in section 7 (safety analysis set (SAF), full analysis 
set (FAS or ITT), per-protocol set (PP). 


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• 
Sub-population(s) or special population(s) descriptions will provide sufficient detail to ensure 
comprehension of the population (e.g., ITT Females, Per-Protocol Males >60 years of age) 
used for analysis in a table or figure. 
• 
Population sizes may be presented for each treatment or dosing category as totals in the 
column header as (N=xxx), where appropriate. 
• 
Population sizes shown with summary statistics are the samples sizes (n) of patients with 
non-missing values. 
• 
All population summaries for continuous variables will include: N, mean, SD, median, Q1, Q3, 
minimum and maximum. 
• 
All percentages are rounded and reported to a single decimal point (xx.x%). 
 


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13. 
References 
[1]  Kegler SR (2007) Applying the compound Poisson process model to the reporting of injury-
related mortality rates. Epidemiologic Perspectives & Innovations 2007, 4:1 
 


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14. 
 Tables, Listings and Figures 
To be supplied in a separate document later when all feedback from authorities will be available. 

Prot_004.pdf: 
090-CSP- SCGAM-03-v07
CLINICAL STUDY PROTOCOL 
CLINICAL PHASE III STUDY TO MONITOR THE SAFETY, 
TOLERABILITY AND EFFICACY OF SUBCUTANEOUS 
HUMAN IMMUNOGLOBULIN (OCTANORM) IN PATIENTS 
WITH PRIMARY IMMUNODEFICIENCY DISEASES WHO 
HAVE COMPLETED THE SCGAM-01 TRIAL 
Investigational Product: 
Octanorm 
Indication: 
Primary immunodeficiency diseases 
Study Design: 
Prospective, open-label, non-controlled, single-arm, multicenter 
phase III study 
Sponsor: 
OCTAPHARMA Pharmazeutika Prod.Ges.m.b.H., Oberlaaer 
Strasse 235, 1100 Vienna, Austria 
Study Number: 
SCGAM-03 
BB-IND Number: 
15617 
ClinicalTrials.gov ID: 
NCT02627300 
Development Phase: 
Phase III 
Planned Clinical Start: 
2nd quarter 2016 
Planned Clinical End: 
4th quarter 2020 
Date of Protocol: 
October 04, 2018 
Version: 
07 
This document contains confidential and proprietary information of Octapharma AG. 
Do not copy or distribute without written permission 
This document contains confidential and proprietary information of Octapharma. Copying or 
distribution of this document is only permitted with the written permission of Octapharma. Any 
commercial use of the information is subject to the permission of Octapharma and a license fee.


Study Protocol No. SCGAM-03 Version 07 
CONFIDENTIAL 
 
 
Page 2/61 
04 OCT 2018 
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-03 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Edition / Date of Protocol: 
October 04, 2018 
Title of Study: 
Clinical phase III study to monitor the safety, tolerability and efficacy of subcutaneous human 
immunoglobulin (Octanorm) in patients with primary immunodeficiency diseases who have 
completed the SCGAM-01 trial. 
Indication: 
Primary immunodeficiency (PI) diseases 
Number of Study Center(s): 
4–6 selected study sites in the United States. 
Study Duration: 2016 to 2020 
Development Phase: III 
Objectives: 
Primary: 
To assess the medium-to-long-term safety and tolerability of Octanorm. 
Secondary: 
• 
To assess the effect of Octanorm on quality-of-life (QoL) measures.  
• 
To obtain further data on the efficacy of Octanorm. 
Study Design: 
The study is a prospective, open-label, non-controlled, single-arm, multicenter phase III study. 
Number of Patients: 
Patients will be taken exclusively from the cohort of patients who completed the main study 
SCGAM-01 in the USA, with no restrictions as regards age or treatment regimen. Therefore, the 
theoretical maximum number of patients will be approximately 35 (the expected number in the 
main study). No statistical sample-size estimation was performed for this extension study. 


Study Protocol No. SCGAM-03 Version 07 
CONFIDENTIAL 
 
 
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04 OCT 2018 
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-03 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Edition / Date of Protocol: 
October 04, 2018 
Subject/Patient Selection Criteria: 
Inclusion Criteria: 
1. Completion of the main study SCGAM-01, with good tolerance of Octanorm (as 
determined by the investigator). 
2. For adult patients: freely given written informed consent. For patients below the legal age 
of majority: freely given written informed consent from parents/legal guardians and written 
informed assent from the child/adolescent in accordance with local requirements. 
3. For female patients of child-bearing potential, a negative result in a urine pregnancy test 
conducted at the Screening visit. 
4. Willingness to comply with all aspects of the protocol, including blood sampling, for the 
duration of the study. 
Exclusion Criteria: 
1. Subject being without any IgG treatment for period greater than approximately 5 weeks 
between the last infusion of Octanorm in the SCGAM-01 study and the first infusion of 
Octanorm in the SCGAM-03 study. 
2. Exposure to blood or any blood product or derivative, other than IgG used for regular PID 
treatment, within the 3 months before the first infusion in this study. 
3. Planned pregnancy during the course of the study. 
Test Product, Dose, Mode of Administration, and Batch Number(s): 
Octanorm, human normal immunoglobulin for subcutaneous (SC) administration. 
Octanorm will be administered subcutaneously every week (±2 days) or every second week 
(±2 days) at the doubled weekly dose.  
If, during the study, the patient's body weight changes by > 5%, the dose is to be adjusted to keep 
the dose constant on a ‘milligram per kilogram body weight’ basis. 
The patients will continue receiving the same Octanorm dose in milligram per kilogram body 
weight as was administered at the Week 64 infusion of the SCGAM-01-study. 
The ‘corrected’ dosing conversion factor (DCF) will be calculated in the main study SCGAM-01 
study, after recruitment of all planned patients for pharmacokinetic assessment. If the ‘corrected’ 
DCF is already known, then it will be used to calculate the dose in the extension study. Otherwise a 
value of 1.5 will be used. Later on the ‘corrected’ DCF may be used (for all patients). 
The patients' Octanorm dose can be individualized, if considered necessary by the investigator, by 
titrating upward or downward. This individualization of dosing should take precedence over 
applying the corrected DCF. 
Batch (lot) numbers will be reported in the final report of the study. 


Study Protocol No. SCGAM-03 Version 07 
CONFIDENTIAL 
 
 
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04 OCT 2018 
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-03 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Edition / Date of Protocol: 
October 04, 2018 
Duration of Treatment: 
Patients may remain in the trial until Octanorm becomes commercially available in the USA, the 
Sponsor decides to terminate the trial, or December 2020 (whichever comes first). A patient may 
remain in the trial for up to approximately 4.5 years, i.e. receiving a total of approximately 
234 Octanorm infusions (or less, if the infusions will be administered bi-weekly) 
Reference Therapy, Dose, Mode of Administration: 
Not applicable. 
Study Outcome Parameters (Primary and Secondary Endpoints): 
Safety (primary assessment): 
• 
Occurrence of all treatment-emergent adverse events (TEAEs), 
• 
Occurrence of temporally associated TEAEs, 
• 
TEAEs by speed of infusion, 
• 
Local injection-site reactions, 
• 
Vital signs (blood pressure, pulse, body temperature, respiratory rate), 
• 
Laboratory parameters (hematology, clinical chemistry, basic urinalysis, and tests for viral 
safety). 
Efficacy: 
• 
Measurement of trough total IgG levels; monitoring for infectious diseases. 
• 
Occurrence of serious bacterial infections (SBIs). 
Quality of Life: 
For QoL assessments, each patient will continue using the same questionnaire as before. That is, the 
parent or guardian of patients who were below 14 years of age when they entered the main study 
SCGAM-01 will continue using the Child Health Questionnaire-Parent Form (CHQ-PF50), and 
patients who were ≥ 14 years of age when they entered the main study will continue using the 
SF-36 Health Survey. 
Summary of Study Procedures and Statistical Analysis Plan 
Study Procedures: 
Patients will be enrolled only after written informed consent has been obtained by the patient or 
their legal guardian. For patients under the legal age of majority, written consent must be obtained 
from the parents or legal guardians. In addition, when required by the local regulatory authorities or 
Institutional Review Board (IRB), written assent must be obtained from children and adolescents 
based upon local requirements. 


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04 OCT 2018 
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-03 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Edition / Date of Protocol: 
October 04, 2018 
The first study (Screening) visit of SCGAM-03 with the first Octanorm infusion will be the same 
visit as the visit in Week 65 (End-of-Study Visit) of the study SCGAM-01. 
Eligible patients who have completed the SCGAM-01 study and were treated with any other 
commercially available SCIG before the start of the SCGAM-03 study (e.g. owing to a delay in 
local IRB approval for SCGAM-03) are permitted to enter the SCGAM-03 study. 
The maximum allowed intermission of IgG treatment after completion of the SCGAM-01 study and 
before the start of treatment in the SCGAM-03 study is 5 weeks.  
Patients for whom the Week 65 visit of the SCGAM-01 study is not identical to the First visit of the 
SCGAM-03 study will undergo a separate Screening visit with relevant screening procedures. Only 
after the patient's successful Screening and enrolment into SCGAM-03 study will the first infusion 
of Octanorm be permitted. 
Screening visit assessments, to be performed before the First infusion, will include: physical 
examination (including weight); blood sampling for hematology, clinical chemistry, viral markers 
and trough total IgG, urine sample for urinalysis and urine pregnancy test (females of childbearing 
potential only), and completion of the same QoL questionnaire as used in the SCGAM-01 study. 
Note that these examinations will, for most patients, be performed within the framework of the 
main study SCGAM-01 (End-of-Study Visit in Week 65), in which case they need not be repeated 
at the same visit for SCGAM-03.  
Patients will stay at the study site during the infusion, vital signs will be measured just before the 
start of each infusion given at the study site, then within 1 hour after the end of the infusion. 
The patient's diary for the coming period of the home treatment will be issued to the patients. 
Ongoing adverse events and any relevant concomitant medications will be recorded. 
At all subsequent study visits, the patients will undergo the following examinations at the site 
before the start of infusion: physical examination (including weight), blood sampling for 
hematology and trough total IgG, clinical chemistry, urine sample for urinalysis, with a urine 
pregnancy test if indicated. The patient's diary will be collected and reviewed. Other study 
assessments will be performed as indicated in the Flow Chart of Study Events. 
One week after the last infusion, for both regular or premature termination, a termination visit will 
be performed at the site with the following assessments: physical examination (including vital signs 
and weight), blood sample for hematology, clinical chemistry, viral markers, and trough total IgG; 
urine sample for urinalysis and urine pregnancy test (females of childbearing potential only); 
completion of the QoL questionnaire; collection and review of the patient's diary. 
AEs and any changes in concomitant medications will be recorded throughout the study period.  


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04 OCT 2018 
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-03 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Edition / Date of Protocol: 
October 04, 2018 
Up to 35 qualifying patients based on the inclusion and exclusion criteria will be enrolled into the 
SCGAM-03 study. An Independent Data Monitoring Committee will periodically review relevant 
data with emphasis on thromboembolic events (TEEs). 
Statistical Analysis: 
The following populations will be considered for the statistical analysis: 
• 
The safety analysis set consisting of all patients who received at least part of one infusion 
of Octanorm. 
• 
The full analysis set (FAS) is defined according to the intention-to-treat principle and 
consists of all patients of the safety analysis 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. 
• 
The per-protocol (PP) set consists of all patients of the FAS excluding those with major 
protocol deviations which may have an impact on the analysis of the primary endpoint. This 
is the set of patients who participated in the study as intended and for whom the primary 
endpoint can be evaluated as planned. 
Only major protocol deviations with the potential to significantly affect the study results or to 
invalidate the interpretation of the data obtained will lead to exclusion of patients from the PP set. 
The membership of each patient in the respective analysis populations will be determined before 
statistical analysis in a data review meeting by a panel consisting of a medical expert from the 
Sponsor, the clinical study manager, the data manager and the study statistician 
Safety Analysis Plan: 
The safety analysis will comprise descriptive statistics, tabulations and listings of all TEAEs, safety 
laboratory results, vital signs and physical examination findings. All reported AEs will be coded 
according to MedDRA. 
For this extension study, any AE is regarded as treatment-emergent if the patient migrated from the 
main to the extension study without being treated with another IgG product. If another product was 
used between the two studies, then an AE in the extension study is classified as treatment-emergent 
if onset or worsening is after start of the infusion of Octanorm at the screening visit. Only TEAEs 
are accounted for in the analysis. 
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. 
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. 


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04 OCT 2018 
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-03 
Name of Active Ingredient: 
Human Normal Immunoglobulin 
Edition / Date of Protocol: 
October 04, 2018 
• 
Number of temporally associated TEAEs. 
• 
Infusion rate at the onset of temporally associated TEAEs (frequencies and percentages). 
• 
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. 
The QoL data will be presented descriptively by visit, along with the change from screening 
(defined as the first infusion). 
 


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04 OCT 2018 
FLOW CHART OF STUDY EVENTS 
ASSESSMENTS 
Screening – 
First visit 
(Week 65 of 
SCGAM-01) 
Octanorm Treatment Visits 
Termination (ET) 
SEQUENCE 
--- 
--- 
Every 12 Wks4 
[every 24 wks] 
--- 
Every 12 Wks4 
[every 24 wks] 
--- 
--- 
WEEKS 
1 
12 
24, 36, 48 
[36] 
60 
72, 84, 94, 108, etc 
[84, 108, 132, etc] 
Final Infusion 
Visit 
One week after 
last infusion 
Informed consent, In-/exclusion criteria3 
x 
 
 
 
 
 
 
Body weight3 
x 
x 
x 
x 
x 
x 
 
Physical examination3, vital signs1 
x 
x 
x 
x 
x 
x 
x 
IgG trough levels3 
x 
x 
x 
x 
x 
x 
x 
Hematology3 (CBC, WBC differential, 
hematocrit, hemoglobin) 
x 
x 
[Wk 36, only] 
x 
[every 24 wks] 
 
x 
Clinical Chemistry3 (sodium, potassium, 
glucose, ALT, AST, LDH, total bilirubin, 
blood urea nitrogen, creatinine) 
x 
x 
[Wk 36, only] 
x 
[every 24 wks] 
x 
x 
Urine analysis3: pH, glucose, ketones, 
leukocytes, hemoglobin 
x 
x 
[Wk 36, only] 
x 
[every 24 wks] 
x 
x 
Viral markers3: HAV, HBV, HCV, HIV 
x 
 
 
x 
 
 
x 
Urine pregnancy test2; 3 
x 
x 
[Wk 36, only] 
x 
[every 24 wks] 
x 
x 
Infusion of IMP (on site) 
x 
x 
x 
x 
x 
x 
 
Check for local injection-site reaction 
x 
x 
x 
x 
x 
x 
x 
Patient diary hand-out and check  
x 
x 
x 
x 
x 
x 
x 
Quality-of-life questionnaire 
x 
 
 
x 
 
 
x 
Concomitant medication  
x 
x 
x 
x 
x 
x 
x 
Adverse events 
x 
x 
x 
x 
x 
x 
x 
1 Measurements of the vital signs will be carried out before and after the infusion of IMP. 
2 For females of child-bearing potential. 
3 Procedures are to be conducted before the IMP administration (if applicable). 
4 Procedures marked with an “x” will be performed at every on-site visit which occur every 12-weeks. Procedures marked within brackets (eg, [Week 36] or [every 24 wks]) will only be performed 
at the study week within the brackets, which corresponds to every other on-site study visit. 


Shrdy Protocol No. SCGAM-03 Version 07
CONFIDENTTAL
PROTOCOL SIGNATURES
This study is intended to be conducted in compliance with the protocol,
Cood Clinical Practice and the applicable regulatory requirements.
International Medical Director
Octapharma Pharmazeutika Produktionsgesellschaft mbH
Oberlaaersft . 235, A-ll 00 Vienna, Austria
Tel: 
 
  
 
 
D7 0 cf %lg
4d,7a4?
Date
Director, Clinical Operations
Octapharma USA, Inc.
l2l River Street, Suite 1201
Hobokeru NJ, USA
 
 
 
ll- Ocr--Zo t g
Signahre
Date
Manager Biometrics 
Signature
Octapharma Pharmazeutika Produktions gesellschaft mbH
Oberlaaerst. 235, A-1100 Vienna, Austria
Tel: 
 
  
Date
 
 
 
3 l ll, 
:";' :t
Head of Corporate Drug Safety 
Signature
Octapharma Pharmazeutika Produktionsgesellschaft mbH
Oberlaaersh . 235, A-ll 00 Vienna, Austria
Tel: 
 
  
Date
Page 9/61
04 ocT 2018


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TABLE OF CONTENTS 
STUDY OUTLINE...................................................................................................................2 
FLOW CHART OF STUDY EVENTS ..................................................................................8 
PROTOCOL SIGNATURES ..................................................................................................9 
TABLE OF CONTENTS ......................................................................................................10 
TABLE OF TABLES .............................................................................................................13 
LIST OF ABBREVIATIONS ...............................................................................................14 
1 
INTRODUCTION ..........................................................................................................16 
1.1 
BACKGROUND ........................................................................................................16 
1.2 
RATIONALE FOR CONDUCTING THE STUDY ............................................................18 
1.3 
BENEFIT-RISK STATEMENT ....................................................................................19 
2 
STUDY OBJECTIVES ..................................................................................................20 
2.1 
PRIMARY OBJECTIVE ..............................................................................................20 
2.2 
SECONDARY OBJECTIVES .......................................................................................20 
3 
INVESTIGATIONAL PLAN ........................................................................................21 
3.1 
PRIMARY AND SECONDARY ENDPOINTS .................................................................21 
3.1.1 Primary Endpoint ......................................................................................21 
3.1.2 Secondary Endpoints .................................................................................21 
3.2 
OVERALL STUDY DESIGN AND PLAN .....................................................................21 
3.3 
DISCUSSION OF STUDY DESIGN AND CHOICE OF CONTROL GROUP(S) ...................23 
3.3.1 Study Design..............................................................................................23 
3.3.2 Dosing .......................................................................................................23 
3.3.3 Control Group(s) .......................................................................................23 
3.3.4 Target Parameters ....................................................................................23 
3.3.5 Statistical Considerations .........................................................................24 
4 
STUDY POPULATION ................................................................................................25 
4.1 
POPULATION BASE .................................................................................................25 
4.1.1 Inclusion Criteria ......................................................................................25 
4.1.2 Exclusion Criteria .....................................................................................25 
4.2 
PRIOR AND CONCOMITANT THERAPY .....................................................................25 
4.2.1 Permitted Concomitant Therapy ...............................................................25 
4.2.2 Forbidden Concomitant Therapy ..............................................................26 
4.3 
WITHDRAWAL AND REPLACEMENT OF PATIENTS ...................................................26 
4.3.1 Premature Patient Withdrawal .................................................................26 
4.3.2 Patient Replacement Policy ......................................................................27 


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4.4 
ASSIGNMENT OF PATIENTS TO TREATMENT GROUPS .............................................27 
4.5 
RELEVANT PROTOCOL DEVIATIONS .......................................................................27 
4.6 
SUBSEQUENT THERAPY ..........................................................................................27 
5 
INVESTIGATIONAL MEDICINAL PRODUCT(S) .................................................28 
5.1 
CHARACTERIZATION OF INVESTIGATIONAL PRODUCT(S) .......................................28 
5.2 
PACKAGING AND LABELING ...................................................................................29 
5.3 
CONDITIONS FOR STORAGE AND USE .....................................................................30 
5.4 
DOSE AND DOSING SCHEDULE ...............................................................................30 
5.5 
PREPARATION AND METHOD OF ADMINISTRATION ................................................30 
5.6 
BLINDING, EMERGENCY ENVELOPES AND BREAKING THE STUDY BLIND ..............31 
5.7 
TREATMENT COMPLIANCE .....................................................................................32 
5.7.1 Drug Dispensing and Accountability ........................................................32 
5.7.2 Assessment of Treatment Compliance .......................................................32 
6 
STUDY CONDUCT .......................................................................................................33 
6.1 
OBSERVATIONS BY VISIT .......................................................................................33 
6.1.1 Screening Visit ..........................................................................................33 
6.1.2 Treatment and Assessment Visits ..............................................................34 
6.1.3 Termination Visit .......................................................................................34 
6.1.4 Interpretation of Time Windows in This Study ..........................................35 
6.2 
DURATION OF STUDY .............................................................................................35 
6.2.1 Planned Duration for an Individual Patient .............................................35 
6.2.2 Planned Duration for the Study as a Whole..............................................35 
6.2.3 Premature Termination of the Study .........................................................35 
7 
ASSESSMENTS AND METHODS ..............................................................................37 
7.1 
BACKGROUND / BASELINE INFORMATION ..............................................................37 
7.2 
EFFICACY ASSESSMENTS........................................................................................37 
7.3 
SAFETY ASSESSMENTS ...........................................................................................40 
7.3.1 Adverse Events ..........................................................................................40 
7.3.1.1 Definitions .............................................................................................. 40 
7.3.1.2 Collection................................................................................................ 40 
7.3.1.3 Severity ................................................................................................... 41 
7.3.1.4 Causality ................................................................................................. 41 
7.3.1.5 Outcome.................................................................................................. 42 
7.3.1.6 Action(s) taken ....................................................................................... 42 
7.3.2 Local Reactions .........................................................................................43 
7.3.3 Serious Adverse Events .............................................................................43 
7.3.4 Laboratory Safety Tests.............................................................................44 


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7.3.5 Viral Safety Tests.......................................................................................45 
7.3.6 Vital Signs .................................................................................................45 
7.3.7 Physical Examination................................................................................45 
7.3.8 Other Relevant Safety Information............................................................46 
7.4 
OTHER ASSESSMENTS ............................................................................................47 
7.4.1 Drug Concentration Measurements ..........................................................47 
7.4.2 Quality of Life Assessment ........................................................................47 
7.5 
APPROPRIATENESS OF MEASUREMENTS .................................................................47 
8 
DATA HANDLING AND RECORD KEEPING ........................................................48 
8.1 
DOCUMENTATION OF DATA ...................................................................................48 
8.1.1 Source Data and Records..........................................................................48 
8.1.2 Electronic Case Report Forms (eCRF) .....................................................48 
8.1.3 Changes to Case Report Form Data .........................................................49 
8.1.4 Handling of Missing Data .........................................................................49 
8.2 
INFORMATION OF INVESTIGATORS .........................................................................50 
8.3 
RESPONSIBILITIES ..................................................................................................50 
8.4 
INVESTIGATOR’S SITE FILE ....................................................................................50 
8.5 
PROVISION OF ADDITIONAL INFORMATION ............................................................51 
8.6 
INDEPENDENT DATA MONITORING COMMITTEE ....................................................51 
9 
STATISTICAL METHODS AND SAMPLE SIZE ....................................................52 
9.1 
DETERMINATION OF SAMPLE SIZE .........................................................................52 
9.2 
STATISTICAL ANALYSIS .........................................................................................52 
9.2.1 Population for Analysis .............................................................................52 
9.2.2 Efficacy Analysis Plan...............................................................................53 
9.2.3 Safety Analysis Plan ..................................................................................53 
9.2.3.1 Adverse Events ....................................................................................... 53 
9.3 
RANDOMIZATION / STRATIFICATION / CODE RELEASE ...........................................54 
9.4 
INTERIM ANALYSIS ................................................................................................54 
10 ETHICAL / REGULATORY, LEGAL AND ADMINISTRATIVE ASPECTS ......55 
10.1 ETHICAL / REGULATORY FRAMEWORK ..................................................................55 
10.2 APPROVAL OF STUDY DOCUMENTS ........................................................................55 
10.3 PATIENT INFORMATION AND INFORMED CONSENT .................................................55 
10.4 PROTOCOL AMENDMENTS ......................................................................................56 
10.5 CONFIDENTIALITY OF PATIENTS’ DATA .................................................................56 
11 QUALITY CONTROL AND QUALITY ASSURANCE ...........................................57 
11.1 PERIODIC MONITORING ..........................................................................................57 
11.2 AUDIT AND INSPECTION .........................................................................................57 


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12 REPORTING AND PUBLICATION...........................................................................58 
12.1 CLINICAL STUDY REPORT ......................................................................................58 
12.2 PUBLICATION POLICY.............................................................................................58 
13 LIABILITIES AND INSURANCE ..............................................................................59 
14 REFERENCES ...............................................................................................................60 
 
TABLE OF TABLES 
Table 1: 
Biochemical Characteristics of Octanorm ........................................................................ 28 
Table 2: 
Infusion Volume and Flow Rate by Patient Weight ......................................................... 31 
Table 3: 
Time Windows Used in this Study ................................................................................... 35 
Table 4: 
Diagnostic Criteria for Serious Infection Types ............................................................... 38 
Table 5: 
Laboratory Tests and Time Points .................................................................................... 45 


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LIST OF ABBREVIATIONS 
Abbreviation 
Description 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration–time curve 
CHQ-PF50 
Child Health Questionnaire-Parent Form 
CI 
Confidence interval 
CRO 
Contract research organization 
CSF 
Cerebrospinal fluid 
DCF 
Dosing conversion factor 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
FAS 
Full analysis set 
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 
IDMC 
Independent Data Monitoring Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IV 
Intravenous 
IVIG 
Intravenously administered immunoglobulin 
LDH 
Lactate dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
PI 
Primary immunodeficiency 
PK 
Pharmacokinetic(s) 
PP 
Per protocol 
QoL 
Quality of life 
SAE 
Serious adverse event 
SBI 
Serious bacterial infection 


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Abbreviation 
Description 
SC 
Subcutaneous 
SCIG 
Subcutaneously administered immunoglobulin 
SF-36 
Short Form Health Survey, 36 item 
TEAE 
Treatment-emergent adverse event 
TEE 
Thromboembolic event 
Tmax 
Time to maximum plasma concentration 
WBC 
White blood cell 


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1 INTRODUCTION 
1.1 Background 
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 characterized 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 hospitalization. 
In the 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 become 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 subcutaneous 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 PK 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: 


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• 1:1 dosing: The single IVIG dose administered every 3 [or 4] weeks is split into 
3 [or 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. 
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 40–50% 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 SCIG 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 (SBIs) was the most common primary efficacy endpoint in these studies. 
Secondary endpoints included overall infections (i.e. infections not meeting SBI criteria), 
missed days at work or school, days in hospital and days on antibiotics. Definitions of overall 
infections and SBI were not standardized across studies. In 6 studies, SBIs were defined by 


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FDA criteria and included bacterial pneumonia, meningitis, sepsis, osteomyelitis or visceral 
abscess. In 2 studies, a SBI was defined as an infection requiring hospitalization.[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 
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 (also known as Cutaquig), the investigational product (IMP) in this study, is an 
immunoglobulin preparation from human normal plasma and is manufactured by 
Octapharma. It contains 16.5% (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. 
1.2 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 can easily be learned by 
the patients, which is another advantage of SC administered immunoglobulins (SCIG). It 
may remarkably improve the patient’s quality of life and compliance as it reduces the 
frequency of hospitalizations and the need for home care. Administration of IgG via the SC 


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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 lifesaving. 
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. 
Post-dose peak levels of SCIG are reached usually 3–6 days after infusion. It has been shown 
that after infusion, exogenous IgG is distributed relatively rapidly between plasma and 
extravascular fluid until approximately half is partitioned in the extravascular space. 
Therefore, a rapid initial drop in serum IgG is to be expected. Several factors such as the 
endogenous production, the actual catabolism rate, the underlying disease or inter-patient 
variability help to explain the wide range observed for terminal half-lives. PK data are 
required for each new product to ensure that it will not behave differently from existing 
preparations, in terms of appropriate dose and timing of the infusions. 
The rationale for conducting the main clinical study was to investigate the PK characteristics, 
efficacy, and safety of Octanorm, and to provide guidance on the dosing when switching 
patients from IV to SC treatment in patients suffering from PI. 
The principal purpose of the present (extension) study is to acquire additional safety 
and tolerability data for patients treated in the medium-to-long term with Octanorm. At 
the same time, efficacy and quality-of-life (QoL) data will also be acquired. 
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. 
Standard measures are taken to prevent infections resulting from the use of medicinal 
products prepared from human blood or plasma. Despite this, when medicinal products 
prepared from human blood or plasma are administered, the possibility of transmitting 
infective agents cannot totally be excluded. The virus inactivation methods for Octanorm are 
described in the Investigator's Brochure. 
The safety profile of SCIG is well characterized. 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 terms of efficacy, it can reasonably be assumed that Octanorm exhibits the same 
effectiveness as other SCIG brands. 
Results from the main study (SCGAM-01) have been analyzed in Q1 2017 and none of the 
results or data acquired in that study affect the above benefit–risk assessment. 


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2 STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective of the study is to assess the medium-to-long-term safety and 
tolerability of Octanorm. 
2.2 Secondary Objectives 
The secondary objectives of the study are: 
• To assess the effect of Octanorm on quality-of-life measures. 
• To obtain further data on the efficacy of Octanorm. 


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3 INVESTIGATIONAL PLAN 
3.1 Primary and Secondary Endpoints 
3.1.1 Primary Endpoint 
There is no single primary endpoint in this present extension study. The primary objective is 
to assess safety and tolerability in medium-to-long-term administration, and this will be 
assessed by means of the following variables: 
• Occurrence of all treatment-emergent AEs (TEAEs) throughout the entire treatment 
period starting with the first infusion of IMP. 
• Occurrence of temporally associated TEAEs. 
• TEAEs by speed of infusion. 
• Local injection-site reactions. 
• Vital signs (blood pressure, pulse, body temperature, respiratory rate). 
• Laboratory parameters (hematology, clinical chemistry and tests for viral safety). 
3.1.2 Secondary Endpoints 
Secondary assessment criteria will be for quality of life and efficacy: 
• QoL assessments using the CHQ-PF50 from parent or guardian of patients <14 years 
of age and the SF-36 Health Survey in patients ≥14 years of age. 
• Occurrence of serious bacterial infections (SBIs) as defined in Section 7.2. 
• The annual rate of all infections of any kind or seriousness. 
• Time to resolution of infections. 
• Use of antibiotics (number of days and annual rate). 
3.2 Overall Study Design and Plan 
The study is a prospective, open-label, non-controlled, single-arm, multicenter phase III 
safety follow-up study with observation of patients receiving weekly (or bi-weekly at 
double the weekly dose) doses of Octanorm over a period of up to approximately 4.5 years 
The study will be conducted at study sites in the United States that already participated in the 
SCGAM-01 trial. 
Only patients who have completed the main study (SCGAM-01) may be enrolled.  
Most patients will migrate directly from the main study into the present extension study. 
However, some patients are expected to complete the main study before the commencement 
of the extension study. 


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Eligible patients who have completed the SCGAM-01 study and were treated with any other 
commercially available SCIG before the start of the SCGAM-03 study (e.g. owing to a delay 
in local IRB approval for SCGAM-03) are permitted to enter the SCGAM-03 study. 
In the intervening interval they must have received the commercially available SCIG at the 
approximately same dose which the patient had received in study SCGAM-01. For these 
patients, the screening visit will be regarded as a fresh start and all screening procedures are 
to be conducted. 
The maximum allowed interval without any IgG treatment before the start of treatment in the 
SCGAM-03 study is approximately 5 weeks. 
Each patient will be treated weekly (or bi-weekly at double the weekly dose) with 
Octanorm, either at the investigation site (on study visit days) or else at home. Thus the 
maximum number of study infusions of Octanorm may be up to 234 for each patient (or less 
if treated bi-weekly). A final examination will be performed 1 week after the last 
infusion, for both regular and premature termination of the patient's study participation. 
The study will be ended when Octanorm becomes commercially available in the USA, the 
sponsor decides to terminate the trial, or December 2020 (whichever comes first). The 
maximum total duration of the study for an individual patient may be approximately 4.5 
years. Study-related procedures will begin only after written informed consent has been 
obtained from the patient. For patients who are minors, written consent must be obtained 
from the parents or legal guardians. In addition, when required by the local regulatory 
authorities or Institutional Review Board (IRB), written assent must be obtained from 
children and adolescents based upon the age requirements established by those institutions. 
The numbers of patients to be enrolled in each age group will follow the numbers emerging 
from the main study SCGAM-01 and willing and eligible to continue treatment. At the time 
of preparation of this protocol these numbers are at most: 
• ≥2 years and <5 years of age: up to 5 patients 
• ≥5 years and <12 years of age: up to 5 patients 
• ≥12 years and <16 years of age: up to 10 patients 
• ≥16 years and ≤75 years of age: up to 30 patients 
• Total: approximately 35 patients. 
An Independent Data Monitoring Committee will continue to periodically review relevant 
data with emphasis on thromboembolic events (TEEs). 
The following interventions and procedures will be performed at predefined time points 
(see Section 6.1.2): Drawing of blood samples, determination of body weight, review of the 
patient's diary, physical examination including vital sign assessments, QoL assessments, 
assessments of local injection-site reactions, urine sampling, and urine pregnancy tests. 
AEs and any changes in concomitant medications will be recorded throughout the study 
period. 


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3.3 Discussion of Study Design and Choice of Control Group(s) 
3.3.1 Study Design 
The designs of the main study SCGAM-01 and of this extension study take into account the 
FDA’s comments and requests included in the clinical hold letter (dated April 27, 2012) for 
IND 15019 for another SCIG of Octapharma (gammanorm 16.5%). 
The study design is also in line with similar study protocols conducted with other SCIG 
brands.[18,20] 
3.3.2 Dosing 
The equivalent monthly dose of IgG is usually determined in one of two ways: 
• 1:1 dosing, wherein the monthly IVIG dose is split into four equal weekly SCIG 
infusions; 
• AUC dosing, in which the SCIG dose is calculated from PK data to provide a 
monthly exposure to IgG equivalent to that with IVIG. 
The former is common in Europe, while the latter is a requirement of the US FDA for SCIG 
labelling studies. For AUC dosing, the SCIG dose has been 1.3 or 1.5 times higher than the 
previous IVIG dose.[3,18,21] 
Compared with weekly administration, PK modelling and simulation (completed in May 
2017) predicted that administration of Octanorm 16.5% on a biweekly basis at double the 
weekly dose results in comparable IgG exposure [slightly higher IgG peak (Cmax) and 
slightly lower trough (Cmin)]. 
Therefore, the proposed study design with respect to weekly or bi-weekly dosing is 
acceptable, having in mind that a corrected DCF will be applied once available. Appropriate 
dose levels will be maintained by regular monitoring of IgG trough levels. 
If the exact DCF is not known, then a value of 1.5 will be used. 
The patients will continue receiving the same Octanorm dose (in mg per kg body weight) as 
was administered at the Week 64 infusion of the SCGAM-01-study. 
Dosing will take place on site at study visits, and otherwise at the patient's home, by self- 
administration or with assistance (relative, care giver etc.). 
3.3.3 Control Group(s) 
Does not apply in this extension study: all patients will continue the active treatment with 
Octanorm that they received in the main study SCGAM-01. 
3.3.4 Target Parameters 
The outcome measures in this study are consistent with previous studies of other IVIG or 
SCIG products and are also in compliance with the FDA Guidance for Industry.[22] 
The QoL questionnaires are standardized, validated instruments that have been widely used 
in clinical studies, including PI. 


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3.3.5 Statistical Considerations 
The FDA Guidance for Industry suggests that, based on historical data, a statistical 
demonstration of a serious infection rate per person-year less than 1.0 is adequate to provide 
substantial evidence of efficacy.[22] Therefore, the 99% CI for this rate will be calculated at 
a descriptive level, without formal statistical testing (statistical tests may be performed on an 
ad hoc basis if this is considered appropriate). 
Because a single patient may experience more than one SBI, the calculation of this 
confidence interval will take into account such intra-patient correlation, following a 
compound Poisson process model. 


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4 STUDY POPULATION 
4.1 Population Base 
Approximately 35 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. Completion of the main study SCGAM-01, with good tolerance of Octanorm (as 
determined by the investigator). 
2. For adult patients: freely given written informed consent. For patients below the legal 
age of majority: freely given written informed consent from parents/legal guardians 
and written informed assent from the child/adolescent in accordance with local 
requirements. 
3. For female patients of child-bearing potential, a negative result in a urine pregnancy 
test conducted at the Screening visit. 
4. Willingness to comply with all aspects of the protocol, including blood sampling, for 
the duration of the study. 
4.1.2 Exclusion Criteria 
Patients who meet one (or more) of the following criteria are excluded from the study: 
1. Subject being without any IgG treatment for period greater than 5 weeks between the 
last infusion of Octanorm in the SCGAM-01 study and the first infusion of Octanorm 
in the SCGAM-03 study. 
2. Exposure to blood or any blood product or derivative, other than IgG used for regular 
PID treatment, within the 3 months before the first infusion in this study. 
3. Planned pregnancy during the course of the study. 
4.2 Prior and Concomitant Therapy 
Details of any relevant concomitant medication (antibiotics, corticosteroids, premedication 
(if used), immunosuppressive or immunomodulatory drugs, blood or any blood product or 
derivative, IVIG other than Octanorm taken after the SCGAM-01 and before the SCGAM-03 
study etc.) must be recorded in the electronic case report form (eCRF). Prior medication will 
be inferred from the study data of the main study SCGAM-01. For patients with an 
intermission between the studies SCGAM-01 and SCGAM-03 any additional medications 
taken in the intervening period are to be recorded. 
4.2.1 Permitted Concomitant Therapy 
Local anesthetics (EMLA or L-Max (lidocaine) cream, plaster, or similar product) to reduce 
pain associated with needle insertion are allowed. The use of such medication(s) must be 
recorded. 


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Routine premedication to alleviate potential tolerability problems is not allowed during the 
study. However, patients who experience (or experienced in the SCGAM-01 study) 
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 should be avoided. 
4.2.2 Forbidden Concomitant Therapy 
Treatment with any IMP (other than IgG products) within 3 months before first infusion of 
Octanorm in SCGAM-03 study, or during the study, is forbidden. 
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 study. 
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 oral 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 and immunomodulatory 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. The responsible Investigator also has the right to withdraw patients from the 
study in case of AEs, poor compliance, or administrative reasons. 
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 the patient's discontinuation. 
• 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 this extension study. A 
pregnancy test is mandatory for all females of child bearing potential at the Screening 
Visit, Week 12 Visit, and then every 24-weeks at scheduled study visits following the 


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Week 12 Visit until 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’s Central Drug Safety Unit must be informed. 
If a patient is withdrawn, the Investigator will organize 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 for any reason will not be replaced. 
4.4 Assignment of Patients to Treatment Groups 
In the main study SCGAM-01, patients were recruited into four age strata: ≥2 years and 
<5 years, ≥5 years and <12 years, ≥12 years and <16 years, and ≥16 and ≤75 years. In the 
present extension study, they will remain in the strata that they were in for analysis in the 
main study (irrespective of whether their age changed such as to imply a change of age 
stratum). Their maximum patient numbers will thus be the same as in the main study 
SCGAM-01. Each patient will be identified by this previously allocated number throughout 
the trial; no additional patient or randomization number will be used for this extension study. 
All patients enrolled in this study will be treated with Octanorm. 
Under no circumstances are patients who participate in this extension study and left it 
permitted to re-enroll. 
4.5 Relevant Protocol Deviations 
In the case of any major deviation from this study protocol, 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 
If a patient decides to withdraw from the study or is withdrawn by the Investigator, he/she 
may be switched back to the treatment that he/she received before participation in the main 
study or to another commercially available IVIG or SCIG. 


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5 INVESTIGATIONAL MEDICINAL PRODUCT(S) 
5.1 Characterization of Investigational Product(s) 
Name of Medicinal Product:  
Octanorm 
Active ingredient of Octanorm: 
Human normal immunoglobulin 
Table 1: 
Biochemical Characteristics of Octanorm 
Parameter 
 
Total protein (of which ≥96% is human IgG) 
150 – 180 mg per mL 
Maltose 
70 – 90 mg per mL 
Octoxynol 
≤5 µg per mL 
TNBP 
≤1 µg per mL 
IgA 
≤0.6 mg per mL 
Polysorbate 80 
10 – 60 µg per mL 
pH 
5.0 – 5.8 
Osmolality 
310 – 380 mOsmol/kg 
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 3,500 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 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. 


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5.2 Packaging and Labeling 
Octanorm is delivered in glass vials. Each Octanorm vial will be labeled in a booklet style as 
follows: 
Master Label Canada 
 
Master Label US
 
Caution: New Drug - Limited by Federal (or United States) Law to 
Investigational Use Octanorm Study: SCGAM-03 
Unit size: 
mL 
1 mL contains: 165 mg protein of which 96% is human normal immunoglobulin G. 
Solution for subcutaneous injection. 
To be stored at 36 °F to 46 °F, 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 before 
administration. Solutions that are cloudy or have a deposit must not be used. 
To be warmed up to room or body temperature before use. After first opening, use 
immediately. Patient No.: | | 
| 
| 
| 
Dosage: Please refer to the handling instruction 
provided. BB-IND number: 15617 
Sponsor: OCTAPHARMA Pharmazeutika Prod.Ges.m.b.H.; Oberlaaerstr. 235, 
1100 Vienna, Austria, Tel: 
 


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5.3 Conditions for Storage and Use 
Octanorm must be stored and transported light-protected at 36 °F to 46 °F (2 °C to +8 °C) 
and must not be frozen. 
Octanorm must not be used after its expiration date. 
Authorized personnel at the individual study centers 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 is to be administered subcutaneously every week (±2 days) or every second week 
(±2 days) at double the weekly dose. 
A minimum interval of 4 days must be observed between two single subcutaneous infusions.  
If, during the study, the body weight changes by >5%, the dose is to be adjusted to keep the 
dose constant on a ‘mg per kg body weight’ basis. 
SCIG infusions will be administered at the study site or (self-administered) at home.  
The infusion is to be given at the study site at Week 1, Week 12, and then every 12-weeks 
until the Final Infusion Visit. 
Each of these study visit dates may deviate ± 2 weeks from the planned date. However, 
the deviations must not cumulate. 
The patients' Octanorm dose can be individualized, if considered necessary by the 
investigator, by titrating upward or downward and should be based on the difference between 
each patient's measured serum total IgG trough levels while on Octanorm and each patient's 
target serum total IgG trough level as determined below. This individualization of dosing 
should take precedence over applying the corrected DCF. 
5.5 Preparation and Method of Administration 
Vials of Octanorm must be allowed to warm to room or body temperature before 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 
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 discharged. 
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 before 
administration. The solution should be clear or slightly opalescent. Solutions that are cloudy 
or have a deposit must not be used. 


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The patient or his/her relative or caregiver will be instructed at the clinic/doctor's office or at 
the infusion center 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. 
Infusion sites: 
The maximum number of infusion sites used simultaneously should not exceed 6. 
Infusion sites should be at least 2 inches (approximately 5 cm) apart. The actual sites of 
infusion should be changed with each weekly (or bi-weekly) administration. 
Infusion volume: 
The volume can be up to 60 mL/per infusion site. 
Infusion (flow) rate: 
The maximum recommended flow rate is 60 mL/hr/site. 
The maximum infusion rate for all sites combined is 240 mL/hr. 
Increases in infusion rates and volumes may only be introduced if the previous 
2 administrations were well tolerated by the patient. 
The infusion volume and the flow rate should be increased gradually as tolerated to prevent 
infusion site reactions. See the parameters listed in Table 2. 
Table 2: 
Infusion Volume and Flow Rate by Patient Weight 
 
Recommended Increase for 
Patients2 
<40 kg 
Recommended Increase for 
Patients2 
≥40 kg 
Infusion volume 
mL/site per infusion cycle1 
Approximately ≤5mL 
Approximately ≤10 mL 
Infusion flow rate 
mL/hour/site per infusion cycle1 
Approximately ≤5mL 
Approximately ≤10 mL 
1 weekly or biweekly depending on dosing regimen 
2 To account for non-precision flow rates of mechanical pumps, actual flow rate increases will be dependent on tubing size, 
number of infusion sites and needle gauge. Minor deviations in excess flow rates (<2 mL/site) would not be considered 
protocol deviations. 
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 
All IMP provided to the site will be accounted for. This includes IMP received at the site, 
dispensed to patients, and IMP returned unused by the subject/patient. 
Sponsor or designee will deliver Octanorm to the participating investigators. Investigator will 
keep current drug inventory and dispensing log, detailing the dates, batch (lot) numbers, and 
quantities of IMP received and dispensed to each patient and the remaining quantity. 
The inventory and drug dispensing log will be available to the monitor to verify drug 
accountability during the study. The study monitor will review all empty and partially used 
vials of IMP and will cross-check versus the patient source documentation (records), eCRF, 
and drug dispensing log. 
After this check, and after the sponsor has granted written approval of destruction, empty or 
partially used vials should be destroyed at the study site following local policies. The 
destruction must be documented. 
For their home treatment, sufficient amount of Octanorm will be handed out to the patients. 
The Investigator or his 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 the (early) 
Termination Visit. 
5.7.2 Assessment of Treatment Compliance 
Patients will receive infusions at the study site and at home (administered at home by the 
patient or his/her relative or caregiver). 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/school/kindergarten/day care, 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 
6.1 Observations by Visit 
6.1.1 Screening Visit 
The Screening (First) Visit will in most cases be the same as the last study visit (Termination 
Visit scheduled in week 65, the End-of-study visit) of the main study SCGAM-01 (since 
most patients will migrate directly from the main study SCGAM-01 to the present extension 
study; Section 3.2). Screening procedures are to be conducted before the IMP administration 
for that visit. 
If the treatment with Octanorm was interrupted between the SCGAM-01 and extension 
(SCGAM-03) studies (for details see Section 3.2), then all screening procedures (see study 
flow chart) are to be conducted at the new Screening visit. 
Study-related procedures will begin only after written informed consent has been obtained by 
the patient or their legal guardian. At the Screening Visit the following activities will be 
performed (as stated above, these need NOT be duplicated at a single visit): 
• Written informed consent. 
• Check of inclusion and exclusion criteria. 
• Documentation of medical history including all adverse conditions that have occurred 
after the end of the SCGAM-01 study. 
• Recording of all previous drug and non-drug therapies administered after the end of 
the SCGAM-01 study. 
• General physical examination, including body weight and 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). 
• Infusion of Octanorm 
• Check for injection-site reaction and assessment if necessary 
• Issue of patient's diary 
• Completion of QoL questionnaire. 
• Recording of any concomitant medication and adverse events (only new ones, not 
previously recorded in the SCGAM-01). 


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6.1.2 Treatment and Assessment Visits 
Each patient who stays in the study for the whole period may receive up to 234 weekly 
infusions of Octanorm (or less, if infused bi-weekly). On study visit days, administration will 
be performed on site; otherwise, at home (Section 3.3.2). 
At the study visits, the following activities will be performed before IMP administration: 
• General physical examination, including body weight and vital signs (every visit). 
• Drawing of blood samples for total IgG trough level (every visit). 
• Drawing of blood samples for safety laboratory parameters (Week 12 Visit, every 
24-weeks at scheduled study visits following the Week 12 Visit, and the Final 
Infusion Visit). 
• Drawing of blood samples for viral markers (Week 60 Visit and the Termination 
Visit). 
• Urine sampling including urine pregnancy test (in females of childbearing potential 
only; Week 12 Visit, every 24-weeks at scheduled study visits following the Week 12 
Visit, and the Final Infusion Visit). 
During or after IMP administration: 
• Completion of QoL questionnaire (Week 60 Visit). 
• Collection of the patient diary. The Investigator will review the diary entries and will 
ask the patient about any AEs that may have occurred and any changes in 
concomitant therapies (medication and non-drug therapy). Any concomitant 
medication and adverse events will be recorded. Relevant diary data will be 
transferred to the eCRF. Discrepancies between patient diary entries and eCRF entries 
must be explained by the Investigator (every visit). 
• Infusion of Octanorm (every visit). 
• Check for injection-site reaction and assessment if any reaction is present (every 
visit). 
For laboratory testing please refer to Section 7.3.4. 
6.1.3 Termination Visit 
One week after the Final Infusion Visit (after patient withdrawal or study termination by one 
of the events described in Section 6.2.3), a Termination Visit will be performed including the 
following assessments: 
• General physical examination (including vital signs). 
• Drawing of blood samples for safety laboratory parameters including viral markers. 
• Drawing of blood samples for total IgG trough level. 
• Urine sampling including urine pregnancy test (in females of childbearing potential 
only). 


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• Completion of QoL questionnaire. 
• Collection and review of the patient diary as at the earlier visits (Section 6.1.2) with 
recording of any AEs and changes in concomitant medications. 
• Assessment of any local infusion-site reactions. 
After the final examination, 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. 
6.1.4 Interpretation of Time Windows in This Study 
For this study the following time windows apply (see Table 3): 
Table 3: 
Time Windows Used in this Study 
 
Time point 
Time stated 
Tolerance 
On site Visits beginning with Week 12 
Weeks 12, 24, 36, 48, 60, and 
each subsequent 12 week visit. 
± 2 weeks 
Interval between Last Treatment Visit 
and (early) Termination Visit 
1 week 
± 5 days 
Blood and urine sampling 
before IMP administration 
-1 day 
Octanorm infusions at patient’s home 
every week (= every 7 days) 
or bi-weekly (= every 14 days) 
at double the weekly dose 
±2 days 
±2 days 
6.2 Duration of Study 
6.2.1 Planned Duration for an Individual Patient 
Patients will receive weekly (or bi-weekly) infusions until Octanorm becomes commercially 
available in the USA, or the Sponsor decides to terminate the study, or December 2020 
(whichever comes first). The total number of infusions will vary for each patient based on the 
date the patient entered into Study SCGAM-03.  
6.2.2 Planned Duration for the Study as a Whole 
The study started enrolling in the second quarter of 2016. Completion of the study by the last 
patient is expected in December 2020, giving total study duration of approximately 4.5 years. 
This duration may be shorter if the sponsor decides to end the trial earlier, or when Octanorm 
becomes commercially available in the USA (for details see Section 3.2). 
6.2.3 Premature Termination of the Study 
Both the responsible Investigators and the Sponsor reserve the right to terminate the study at 
any time. Should this be necessary, the procedures will be arranged on an individual study 
basis after review and consultation by both parties. In terminating the study, the Sponsor and 
the Investigator will ensure that adequate consideration is given to the protection of the 


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patients' interests. Premature termination will be notified in accordance with applicable 
regulatory requirements. 
Furthermore, the Investigator should promptly inform the IRB and provide a detailed written 
explanation. The pertinent regulatory authorities and IRBs are to be informed according to 
national regulations. 
Early termination of the study as a whole or center-wise may apply for the following reasons: 
Clinical Study:  
• At any time the study as a whole will be terminated prematurely if e.g.: 
o 
New toxicological or pharmacological findings or safety reports invalidate the 
earlier positive benefit-risk-assessment. 
o 
If more than 2 TEEs (i.e. ischemic stroke, transient ischemic attack, cerebral 
infarction, cerebrovascular accident, cerebral thrombosis, embolic infarctions, 
[acute] myocardial infarction, deep vein thrombosis, pulmonary embolism, 
venous thrombosis excluding thrombophlebitis) are observed fulfilling the 
following criteria: 
▪ 
assessed as probably or possibly related to Octanorm treatment by 
Investigator and/or Sponsor; 
▪ 
confirmed by the Independent Data Monitoring Committee (IDMC). 
o 
Any other reason rendering the continuation of the study impossible for the 
Sponsor. 
Study Center: 
• At any time the study can be terminated at an individual center if e.g.: 
o 
The center cannot comply with the requirements of the protocol.  
o 
The center cannot comply with applicable standards. 
o 
The required recruitment rate is not met. 
Should the study be prematurely terminated, all study materials (completed, partially 
completed and blank forms, IMP, etc.) must be returned to the Sponsor. 


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7 ASSESSMENTS AND METHODS 
7.1 Background / Baseline Information 
The following general or background assessments will be performed during the study at 
predefined time points: 
Demographic data: All demographic data (age, weight, height, calculated body mass index, 
ethnic origin, ABO Rhesus blood type) will be taken over from the main study SCGAM-01. 
Medical history: All medical history (conditions and surgical treatment) will likewise be 
taken over from the main study SCGAM-01. 
Previous and ongoing therapies: Similarly, previous drug and non-drug therapies 
(e.g. physiotherapy) will be taken over from the main study SCGAM-01. 
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. 
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 (primary endpoint). 
• Number of episodes of any other infections (including acute sinusitis, exacerbation of 
chronic sinusitis, acute otitis media, acute bronchitis, infectious diarrhea etc.), along 
with type and severity of infection, and time to resolution. 
• Number of days of use and annual rate of antibiotics (oral, parenteral, oral plus 
parenteral, prophylactic and therapeutic), along with type and dosage of antibiotic. 
• QoL assessments. 
For the collection of data for the above measurements, each patient will be provided with an 
individual diary to be filled in by the patient during the home therapy time. The patient's 
diary will be checked for accuracy of the data by the Investigator and collected at each study 
visit. The data will be then 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. 
For the purpose of this study the following events will be considered as SBIs, to be included 
in the primary efficacy analysis: 
• Bacterial pneumonia. 
• Bacteremia/sepsis. 
• Osteomyelitis/septic arthritis. 
• Visceral abscess. 


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• Bacterial meningitis. 
The presence of any of these infections should be verified by the specific differentiated 
diagnostic examinations [22] given in Table 4: 
Table 4: 
Diagnostic Criteria for Serious Infection Types 
 
Infection: Bacteremia/sepsis a 
• 
Symptoms: chills, rigors. 
• 
Physical findings: fever, hypothermia, tachycardia, tachypnea, 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 b, leukocytosis (white blood cell (WBC) count 
>12,000/mm3), differential WBC count demonstrating >10% immature (band) 
neutrophils, leukopenia, thrombocytopenia, coagulopathy, lactic acidosis. 
Infection: 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 c, CSF 
leukocytosis with neutrophil predominance, decrease in CSF glucose. 
Infection: Osteomyelitis/Septic Arthritis 
• 
Symptoms: pain, decreased range of motion, tenderness, edema, 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. 
Infection: Bacterial Pneumonia d 
• 
Symptoms: productive cough/change in character of sputum, dyspnea or tachypnea, chills, 
chest pain, rigors, headache, fatigue, sweats, anorexia, myalgia. 
• 
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 e, positive culture with or without 


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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) 
Infection: 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 
 
Notes to Table 4: 
Items in bold are considered essential diagnostic features. 
a. 
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. For pediatric patients, the definition of sepsis using age-specific criteria as recommended by 
the International Consensus Conference on Pediatric Sepsis should be employed.[23] 
b. 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 patients without 
indwelling catheters or vascular access devices, a single blood culture positive for a pathogenic organism 
will meet the diagnostic criteria for bacteremia. Patients meeting criteria for positive blood culture but 
without 2 or more of the sepsis criteria listed above will be classified as having bacteremia. 
c. 
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. 
d. 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. To establish the 
diagnosis of bacterial pneumonia for pediatric patients, most of the same diagnostic criteria listed may be 
used, with the following exceptions: Because pediatric patients may not produce a sputum specimen 
for culture, blood cultures or serology may be substituted to identify the etiologic bacterial pathogen. In 
infants age 3 to 24 months, who tend to have a higher baseline temperature, fever is defined as a rectal 
temperature >38.3 °C (101 °F). In children >2 years, fever is more commonly defined as a rectal 
temperature >38 °C (100.4 °F). In pediatric patients, elevations of WBC counts >15,000/mm3 are frequent 
but could be variable in patients with bacterial pneumonia, or leukopenia with WBC count <5000/mm3 may 
be observed, usually associated with severe infection. 
e. 
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. 


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7.3 Safety Assessments 
Any of the following drug safety information shall be collected: Adverse events (AEs) and 
serious adverse events (SAEs) temporally associated with administration of IMP. 
7.3.1 Adverse Events 
7.3.1.1 Definitions 
Adverse event (AE): An AE is any untoward medical occurrence in a study patient receiving 
an IMP and which does not necessarily have a causal relationship with this treatment. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of an IMP, whether or not 
related to the IMP. 
An AE is defined as treatment-emergent (TEAE), if the event began or worsened after the 
start of first infusion of trial medication: 
• For patients who migrate into the extension study without interruption of Octanorm 
treatment (Section 3.2), all adverse events occurring in the extension study will be 
considered treatment-related. An adverse event recorded in the main study will not be 
recorded again in the present one. 
• For patients who receive any other IgG brand between the main and the extension 
studies (Section 3.2), “treatment-emergent” will refer to events with onset after the 
start of the infusion with Octanorm at the screening visit of the extension study. 
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 non-serious AE or marked laboratory abnormality that results in: 
• withdrawal of IMP treatment, 
• and/or dose reduction, 
• and/or initiation of significant additional concomitant therapy (i.e. medications given 
intravenously). 
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. 
7.3.1.2 Collection 
The condition of the patient will be monitored throughout the study. At each visit, whether 
scheduled or unscheduled, AEs will be elicited using a standard non-leading question such as 
“How have you been since the last visit / during the previous study period?” For minor 


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patients not understanding the question, the answer must be obtained from parents or legal 
guardians. In addition, the patient diaries (if applicable) will be checked by the Investigator 
for any documented event. 
Any AE which occurs during the study will be noted in detail on the appropriate pages of the 
eCRF. If the patient reports several signs or symptoms representing one syndrome or 
diagnosis, the diagnosis should be recorded in the eCRF. The Investigator will grade the 
severity of all AEs (mild, moderate or severe), the seriousness (non-serious or serious) and 
causality, as defined below (Section 7.3.1.3, Section 7.3.1.4, and Section 7.3.2). The Sponsor 
is responsible to assess the expectedness of each ADR (expected or unexpected), as defined 
below (Section 7.3.1.4). 
In the event of clinically significant abnormal laboratory findings, the tests will be confirmed 
and followed-up until they have returned to normal and/or an adequate explanation is 
available. 
Diseases, signs and symptoms and/or laboratory abnormalities already existing before the 
first administration of IMP are not considered as AEs when observed at a later stage unless 
they represent an exacerbation in intensity or frequency (worsening). 
The Investigator should always provide detailed information concerning any abnormalities 
and the nature of, and reasons for any necessary action(s), as well as any other observations 
or comments, which are useful for the interpretation and understanding of the patients’ AEs. 
7.3.1.3 Severity 
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. 
7.3.1.4 Causality 
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 


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is uncertain or doubtful, for example because of missing data or insufficient evidence. 
A reaction that follows a reasonable temporal sequence from administration of the 
IMP; that follows a known or expected response pattern to the suspected medicine; 
but that could readily have been produced by a number of other factors. 
• Unlikely: reports not following a reasonable temporal sequence from IMP 
administration. An event which may have been produced by the patient’s clinical 
state or by environmental factors or other therapies administered. 
• Not related (unrelated): events for which sufficient information exists to conclude that 
the etiology is unrelated to the IMP. 
• Unclassified: reports which for one reason or another are not yet assessable, e.g. 
because of outstanding information (can only be a temporary assessment). 
Classification of ADRs: 
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 for 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. 
7.3.1.5 Outcome 
The outcome of an AE has to be classified as follows: 
• recovered, resolved 
• recovering, resolving 
• not recovered, not resolved 
• recovered, resolved with sequelae 
• fatal 
• unknown 
NOTE: A patient’s death per se is not an event, but an outcome. The event which resulted 
into a patient’s death must be fully documented and reported, even in case the death occurs 
within 4 weeks after IMP treatment end, and without respect of being considered treatment-
related or not. 
7.3.1.6 Action(s) taken 
AEs requiring action or therapy must be treated with recognized standards of medical care to 
protect the health and well-being of the patient. Appropriate resuscitation equipment and 
medicines must be available to ensure the best possible treatment in an emergency situation. 
The action taken by the Investigator must be documented: 


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a. in general 
– none 
– medication (other than IMP) or other (e.g., physical) therapy started 
– test performed 
– other (to be specified) 
b. on IMP 
– none 
– product withdrawn 
– treatment interrupted 
– dose reduced 
– dose increased 
The Investigator will follow up each AE until it is resolved or until the medical condition of 
the patient is stable, and all relevant follow-up information will be reported to the Sponsor. 
7.3.2 Local 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 after each 
infusion using a 4-point rating scale: 0=none, 1=mild, 2=moderate, 3=severe. 
Investigators have to evaluate local reactions within approximately 1 hour after infusion at 
every study visit, 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 sticks; 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, bleedings (other than small blood 
drops caused by the needle stick), 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. 
7.3.3 Serious Adverse Events 
A serious AE (SAE) is any untoward medical occurrence that at any dose: 
• results in death, 
• is life-threatening, 
• requires hospitalization or prolongation of existing hospitalization, 
• results in persistent or significant disability/incapacity, 


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• is a congenital anomaly/birth defect, 
• is another important medical event. 
Hospitalization is NOT considered an SAE in case of: 
• hospitalization because of study-related procedures; hospitalization due to hospital 
standard measures (hospitalization for the first infusion of study drug etc.) 
• an elective (surgical) procedure for which the date was scheduled before inclusion in 
the study 
• prolongation of the existing hospitalization due to economic or social, but not due to 
medical, reasons. 
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 hypothetically might have caused death if it were more severe. 
Medical judgment should be exercised in deciding whether an AE/ADR is serious in other 
situations: Important AEs/ADRs that are not immediately life-threatening or do not result in 
death or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definitions above, should also be considered serious. 
In addition, although not classified under the seriousness criteria, all suspected transmissions 
of an infectious agent should be reported as SAE. A suspected virus transmission means that 
virus antigen has been detected in the patient. A passive transmission of antibodies alone 
does not constitute a suspected virus transmission. 
SAE reporting timelines 
All SAEs, whether suspected to be related to study treatment or not, are to be reported by 
telephone, fax or e-mail immediately to the Clinical Project Manager or designee. 
Contact details will be communicated at the study initiation visit. 
An Octapharma "Serious Adverse Event Report" must be completed and submitted within 
24 hours after recognition of the event. 
All SAEs should be reported via fax to the CRO responsible for the USA (Premier Research), 
fax number 
 
Octapharma's 24-hour emergency telephone number is 
. 
7.3.4 Laboratory Safety Tests 
For children the trial-related blood loss (including any losses in the maneuver) should not 
exceed 3% of the total blood volume during a period of 4 weeks and should not exceed 1% at 
any single draw. The total volume of blood is estimated at 80 mL/kg body weight. 
The following laboratory tests will be performed during the course of the study to investigate 
the efficacy and safety and tolerability of Octanorm (Table 5). At each visit, laboratory tests 
are to be performed before infusion of Octanorm at the study site. 


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Table 5: 
Laboratory Tests and Time Points 
Test 
Timing 
Laboratory 
Total serum IgG trough levels 
At screening and at all subsequent treatment 
visits. 
Local 
Hematology (complete blood count, WBC 
differential, hematocrit, hemoglobin) 
At screening, at Week 12, continue every 
24 weeks until the Final Infusion Visit, and at 
the Termination Visit. 
Local 
Clinical chemistry (sodium, potassium, 
glucose, ALT, AST, LDH, total bilirubin, 
blood urea nitrogen or blood urea, 
creatinine) 
At screening, at Week 12, continue every 
24 weeks until the Final Infusion Visit, and at 
the Termination Visit. 
Local 
Urinalysis: pH, glucose, ketones, 
leukocytes, hemoglobin. 
At screening, at Week 12, continue every 
24 weeks until the Final Infusion Visit, and at 
the Termination Visit. 
Local 
Urine pregnancy test (women of 
childbearing potential) 
At screening, at Week 12, continue every 
24 weeks until the Final Infusion Visit, and at 
the Termination Visit. 
Local 
Virology: HAV, HBV, HCV, HIV 
At screening, at Week 60, and at the 
Termination Visit.  
Local 
WBC, white blood cells; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LDH, lactate dehydrogenase; 
HAV/HBV/HCV, hepatitis A/B/C virus; HIV, human immunodeficiency virus. 
Local laboratory determinations will be done at the individual study sites according to local 
procedures. 
The normal ranges of each determination at each laboratory involved will be provided in the 
Clinical Report. 
7.3.5 Viral Safety Tests 
At the Screening Visit, viral markers will be taken before the Octanorm infusion, and will be 
tested at the local laboratory according to the site’s standard procedures. For patients positive 
in Hepatitis A virus at screening, follow-up samples may be omitted. 
Further viral marker samples will be taken in Week 60 and at the (early) Termination Visit. 
7.3.6 Vital Signs 
To evaluate short-term tolerance, monitoring of vital signs including blood pressure, body 
temperature, pulse and respiratory rate will be performed at visits taking place at the 
clinic/study site; the Screening Visit, then at all subsequent study visits (at 12-weekly 
intervals), and finally at the Termination Visit (irrespective of whether termination is regular 
or premature). 
Measurements will be carried out before the infusion and (approximately) within 1 hour after 
the infusion of IMP. 
7.3.7 Physical Examination 
A general physical examination will be performed at the Screening Visit according to routine 
procedures and will be as comprehensive as necessary to detect relevant abnormalities. If any 
findings are abnormal (only the findings newly occurred since end of the SCGAM-01 study), 


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the Investigator will document the start date and whether or not the abnormal finding is still 
present at the start of treatment. The physical examination will be repeated at all subsequent 
study visits (at 12-weekly intervals), and finally at the Termination Visit (irrespective of 
whether termination is regular or premature). Clinically relevant worsening from the status at 
screening will be documented as an AE. 
7.3.8 Other Relevant Safety Information 
a) Post study related safety reports 
Any SAE which occurs up to four weeks after the completion of the study should be reported 
by the Investigator to the sponsor if the investigator becomes aware of it. Proactive 
monitoring for post-study SAEs is not required. If a post study SAE is identified, the 
investigator should complete a SAE form. Relation to the clinical study should be stated on 
the report. 
If a patient dies within 4 weeks after the last IMP administration, this should be reported as 
well, irrespective of whether or not it is considered treatment-related. 
b) Pregnancies 
Every effort will be made to avoid a pregnancy during the use of an IMP. Pregnancies 
occurring during the study (fetal exposure to the IMP) need to be reported. 
In case of pregnancy during the study the Investigator is asked to complete the pregnancy 
notification form and to send it (by fax or email) to the Sponsor. Follow-up information on 
outcome of both mother and fetus will be requested by a Sponsor representative. 
c) Overdose, interaction and medication error 
The following safety relevant information should be reported as AE or as SAE, if the reaction 
fulfils one of the criteria for seriousness (see Section 7.3.3). 
d) Drug overdose 
An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than 
that specified in the protocol, and higher than the known therapeutic dose and of clinical 
relevance. The reaction must be clearly identified as an overdose. 
e) Interaction 
A drug interaction is a situation in which a substance/medicinal product affects the activity of 
an IMP, i.e. the effects are increased or decreased, or they produce an effect that none of the 
products exhibits on its own. The reaction must be clearly identified as drug interaction. 
f) Medication error 
Medication error involves the inadvertent administration or unintended use of a medicinal 
product which may be caused by the naming, presentation of pharmaceutical 
form/packaging, instructions for use/labeling. The reaction must be clearly identified as a 
medication error. 


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7.4 Other Assessments 
7.4.1 Drug Concentration Measurements 
Samples for total IgG trough levels measurements will be taken at the Screening Visit, before 
any infusion given at the study site and at the (early) Termination Visit; these samples will 
analyzed at the local laboratory. 
7.4.2 Quality of Life Assessment 
QoL assessments will be made using the Child Health Questionnaire-Parent Form 
(CHQ-PF50) from parent or guardian of patients <14 years of age and the SF-36 Health 
Survey in patients ≥14 years of age. The QoL assessments will take place at the screening, at 
Week 60, and at the (early) Termination Visit. 
7.5 Appropriateness of Measurements 
Safety will be monitored by standard assessments. 
The therapeutic efficacy, defined as the prevention of SBI, is a very important clinical aspect 
of any IgG replacement therapy and best characterizes 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 questionnaires are standardized, validated instruments that have been widely used 
in clinical studies, including studies with PI patients. 


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8 DATA HANDLING AND RECORD KEEPING 
To ensure that data in the CRFs are accurate and complete and in accordance with source 
records, source data verification will be performed in accordance with Octapharma standards. 
The extent of source data verification will be defined in detail in the monitoring manual. 
8.1 Documentation of Data 
8.1.1 Source Data and Records 
Source data are defined as all of the information related to clinical findings, observations, or 
other activities in the study, written down in original records or certified copies of original 
records. The investigator will maintain adequate source records (e.g., case histories or 
subject/patient files for each subject/patient enrolled). Source records should be preserved for 
the maximum period of time required by local regulations. 
For each subject/patient enrolled, the investigator will indicate in the source record(s) that the 
subject/patient participates in this study. 
All data entered in the CRF must be supported by source data in the subject/patient records 
with the 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 source data/records. 
The investigator may authorize site staff (e.g., sub-investigators, nurses) to enter study data 
into the CRF. This must be documented in the “Delegation of Authority Log”, signed by the 
investigator. 
The following data must be verifiable from the source records: patient’s inclusion in Study 
SCGAM-03, patient number, sex, weight, date of birth, written informed consent, medical 
history, main inclusion and exclusion criteria, local laboratory test results, PID relevant 
concomitant therapies (medication and non-drug therapy), any AE occurring in the course of 
the study, details of infusions (batch number, number of vials used, date, dose, rate and 
site(s)), date and reason for premature withdrawal (if applicable). As part of the source 
records, laboratory data will be reviewed by the Investigator, assessed as to their clinical 
significance, signed and dated. 
8.1.2 Electronic Case Report Forms (eCRF) 
For each patient enrolled, an eCRF will be completed within the electronic data capture 
(EDC) system and approved by the Investigator or an authorized sub-investigator. 
Study-site staff (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 eCRF before 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 appear on the delegation of authority log. 


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The following data may be entered directly into the EDC system, without prior record of 
source data, turning the eCRF into source: dates of blood sampling, vital signs. 
If any errors in the eCRFs are found during the data review process discrepancies will be 
generated programmatically within the EDC system, and ‘manual’ queries will be generated 
by either a monitor or Data Management. The programmed checks fire automatically once an 
eCRF page is saved within the system. The outputs of the programmed checks are referred to 
as ‘discrepancies’. Discrepancies are generated by the input of illogical eCRF data with the 
purpose to clarify the context or insertion of illogical or missing data with the site or 
designee. 
All discrepancies (programmed and manual) will be submitted to the site personnel or 
monitor for the site within the EDC system. Once the site responds to a discrepancy, Data 
Management or the monitor will review the new or changed data to ensure an appropriate 
response and close the discrepancy within the system. 
8.1.3 Changes to Case Report Form Data 
Monitors will perform source data verification (SDV) as defined for the study. 
Errors occurring on the EDC system can only be corrected by the investigator(s) or 
authorized site personnel. An audit trail documents all changes to the data over the entire 
study period. If data is changed as a result of a query, a comment must be supplied within the 
query’s text, stating the reason for the change, before closing. In addition, any changes to a 
previously saved eCRF page that has not had a query generated will need to have a reason 
specified for the data change. 
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 (all discrepancies resolved) and the database is ready for lock. Source data verification 
will be confirmed as complete by the monitor, and all eCRFs will be approved by the 
Investigator before database lock. 
8.1.4 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, 
the last available weight measurement will be used for calculating the dose per kg 
bodyweight (last observation carried forward). 
If missing values occur in the confirmatory analysis of the primary endpoints, they will be 
imputed by worst observed values and thus be ranked at the end of the list for the Wilcoxon- 
Mann-Whitney test. Last-observation-carried-forward (LOCF) and observed-cases (OC) 
analyses will be applied as well as mixed models to explore the sensitivity of the results with 
regard to imputation techniques. 


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8.2 Information of Investigators 
An Investigator’s Brochure will be handed out to the Investigator before the start of the 
study, unless the investigator is already in possession of the current Investigator’s Brochure. 
This brochure 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 Investigator’s Brochure will be updated by the Sponsor at regular intervals and in case 
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 investigators will be kept informed of important information related to the safe use of the 
investigational product as the study proceeds. 
8.3 Responsibilities 
The Principal Investigator is accountable for the conduct of the clinical study. 
Responsibilities may be delegated to appropriately qualified persons. 
A “Delegation of Authority Log” will be filled in and signed by the Investigator. In 
accordance with this authority log study-site staff (e.g., sub-investigators, nurses) is 
authorized to perform tasks relating to the study. 
The Investigator is responsible for coordinating the study locally. 
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, drug dispensing and accountability logs, correspondence pertaining 
to the study, etc.) should be filed accurately and kept by the Investigator for the maximum 
period of time required by local regulations. 
The Investigator is responsible for maintaining a confidential patient identification code list, 
which provides the unique link between named source records and eCRF data for the 
Sponsor. The Investigator must arrange for the retention of this confidential list for the 
maximum period of time required by local regulations. 
No study document should be destroyed without prior written agreement between the 
Investigator and the Sponsor. Should the Investigator elect to assign the study documents to 
another party, or move them to another location, the Sponsor must be notified in writing. 


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8.5 Provision of Additional Information 
On request, the Investigator will supply the Sponsor with additional data relating to the study, 
or copies of relevant source records, ensuring that the patient’s confidentiality is maintained. 
This is particularly important when 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 
The Sponsor will establish an IDMC. During the study, the IDMC will periodically review 
relevant data and will give advice on the continuation, modification or termination of the 
study (see Section 6.2.3). A study-specific Charter will define in detail the composition, 
responsibilities and procedures of the IDMC. 


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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 
All the patients who complete the main study SCGAM-01 and who are willing and eligible 
to continue study treatment will be included in the present extension study. At the 
time of preparation of this protocol is it anticipated that approximately 35 patients will take 
part in the extension study (Section 3.2). No further sample-size considerations apply. 
9.2 Statistical Analysis 
No confirmatory statistical analysis will be performed; the results of this extension study will 
be presented at the descriptive level only. 
9.2.1 Population for Analysis 
The following populations will be considered for the statistical analysis: 
The safety analysis set consists of all patients who received at least part of one infusion of 
Octanorm within this extension study. 
The full analysis set (FAS) is defined according to the intention-to-treat principle and 
consists of all patients of the safety analysis set who satisfy all eligibility criteria and for 
whom any post screening data in this extension study are available. It is expected that the 
FAS will coincide with the safety set. 
The per-protocol (PP) set consists of all patients of the FAS excluding those with major 
protocol violations which may have an impact on the analysis of the primary endpoint. This 
is the set of patients who participated in the study as intended and for whom the primary 
endpoint can be evaluated as planned. 
Only major protocol deviations with the potential to affect the study results significantly or to 
invalidate the interpretation of the data obtained will lead to exclusion of patients from the 
PP set; protocol deviations to be considered will include (but will not be limited to): 
• Violations of the study entry criteria. 
• Administration of any other blood or plasma-derived product or of any other 
immunoglobulin preparations during the SCGAM-03 study. 
• Any prohibited concomitant medication (including long term corticosteroids, daily, 
≥0.15 mg of prednisone or equivalent/kg/day, immunosuppressive and 
immunomodulatory drugs). 
• Failure to attend two scheduled consecutive visits OR three or more scheduled visits 
during the study for reasons other than clinical reasons. 


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Efficacy endpoints will be analyzed on the basis of FAS. Analysis of the safety endpoints 
will be based on the safety set. 
The membership of each patient in the respective analysis populations will be determined 
before the statistical analysis in a data review meeting by a panel consisting of a medical 
expert from the Sponsor, the clinical study manager, the data manager and the study 
statistician. 
All data will be summarized for all patients overall and by age group. 
9.2.2 Efficacy Analysis Plan 
No confirmatory efficacy analysis will be performed. 
The rate of SBI per person-year (bacterial pneumonia, bacteremia/sepsis, osteomyelitis/septic 
arthritis, visceral abscess, bacterial meningitis) during the treatment period with Octanorm 
will be presented as point estimates of the rate along with a 99% CI. Calculation of this CI 
will account for intra-patient correlation in incidents following a compound Poisson process 
model. Furthermore, all observed SBIs will be listed individually and in full detail. 
The duration of infection will be summarized by standard descriptive statistics by type of 
infection and by severity. The individual characteristics of each infection, including the time 
to resolution will be listed. 
The use of antibiotics will be reported as a detailed list of all such medications, and the 
number of patients treated with antibiotics, the number of treatment episodes and the number 
of treatment days will be tabulated. 
The FDA Guidance for Industry suggests that, based on historical data, a statistical 
demonstration of a serious infection rate per person-year less than 1.0 is adequate to provide 
substantial evidence of efficacy.[22] Therefore, this background information will be used for 
a descriptive evaluation of the serious infection rate in this extension study. Exploratory 
statistical testing may be performed if considered appropriate. 
The QoL data will be presented descriptively by visit, along with the change from baseline 
(defined as the first 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. 
9.2.3.1 Adverse Events 
All reported AEs will be coded according to 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. 


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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. 
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. 
• Infusion rate at the onset of temporally associated TEAEs 
• 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. 
9.3 Randomization / Stratification / Code Release 
There is no randomization in this study. The patients will be recruited into 4 age strata 
(≥2 years and <5 years, ≥5 years and <12 years, ≥12 years and <16 years, and ≥16 years and 
≤75 years). 
9.4 Interim Analysis 
No interim analysis is planned. 


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10 ETHICAL / REGULATORY, LEGAL AND 
ADMINISTRATIVE ASPECTS 
10.1 Ethical / Regulatory Framework 
This study will be conducted in accordance with the ethical principles that have their origins 
in the Declaration of Helsinki. Before submission of the study protocol to the IRB and 
Competent Authority, the study will be registered in ClinicalTrials.gov. The study protocol 
and any subsequent substantial amendment(s), as well as a sample of the information sheet 
and informed consent form, any other materials provided to the patients, and further 
requested information will be submitted to the IRB and the Competent Authority. The study 
will be conducted in compliance with the protocol, GCP and the applicable regulatory 
requirements. 
In addition, the study will be conducted under a US Investigational New Drug (IND) 
application, and therefore must meet the applicable FDA requirements including Statement 
of Investigator Form 1572 and financial disclosure statement. 
The regulatory application or submission for regulatory approval will be made by the 
Sponsor 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 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, and 
further requested information will be submitted to the appropriate IRB and the competent 
Authority. The study approval letter must be available before any patient is exposed to a 
study-related procedure. 
The Sponsor, the Investigator and any third party (e.g. CRO) involved in obtaining approval, 
must inform each other in writing that all ethical and legal requirements have been met 
before the first patient is enrolled in the study. 
10.3 Patient Information and Informed Consent 
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. 
For minor patients, freely given written consent must be obtained from parents or legal 
guardians. In addition, when required by the local regulatory authorities, IRBs, written assent 


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must be obtained from children and adolescents based upon the age requirements established 
by those institutions. 
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 their withdrawal. The Investigator will date 
and sign the informed consent form of each patient enrolled. 
Each patient, or his parents/legal guardians, will give written consent that his/her source 
records may be reviewed by study monitors, quality assurance auditors and/or health 
authority inspectors, in accordance with applicable regulations. These persons are bound by 
confidentiality obligations. 
10.4 Protocol Amendments 
Any prospective change to the protocol will be agreed between the Investigator 
(Coordinating Investigator in multicenter studies) and the Sponsor before its implementation. 
Any such amendments will be submitted to the IRB and/or Competent Authority responsible 
as required by applicable regulations. 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 Patients’ Data 
The Investigator will ensure that the patient's confidentiality will be preserved. On eCRFs or 
any other documents submitted to the Sponsor, the patients will not be identified by their 
names, but by an identification code, consisting of a center number and a patient number. 
Documents that are not for submission to the Sponsor, i.e. the confidential patient 
identification list, original informed consent forms and source records, will be maintained by 
the responsible 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 
subject/patient. Thereafter, monitoring frequency will depend on study progress but is 
expected to be approximately every 10-18 weeks. 
The monitor must be given direct access to source documents (original documents, data and 
records). Direct access includes permission to examine, analyze, verify and reproduce any 
records and reports that are important to the evaluation of the clinical study. Source data will 
be available for all data in the CRFs, including all laboratory results. 
11.2 Audit and Inspection 
The Investigator will make all study-related source data and records available to a qualified 
quality assurance auditor mandated by the Sponsor, or to IRB / Regulatory Authority 
inspectors, after reasonable notice. The main purposes of an audit or inspection are to 
confirm that the rights and welfare of the patients have been adequately protected, and that 
all data relevant for the assessment of safety and effectiveness of the IMP have been reported 
to the Sponsor. 


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12 REPORTING AND PUBLICATION 
12.1 Clinical Study Report 
The Sponsor will prepare a clinical study report (in accordance with relevant guidelines and 
Octapharma Standard Operating Procedures) timely after the completion of the study. The 
Coordinating Investigator will approve the final study report after review. 
12.2 Publication Policy 
The results of this study may be published or presented at scientific meetings. If this is 
envisaged by an Investigator, the Investigator agrees to inform the Sponsor and to submit all 
manuscripts or abstracts to the Sponsor before submission to an editorial board or scientific 
review committee. This will allow the Sponsor to protect proprietary information and to 
provide comments based on information that may not yet be available to the Investigator. 
In accordance with standard editorial and ethical practice, the Sponsor will support 
publication of multicenter studies only in their entirety and not as individual center data. 
Authorship will be determined by mutual agreement. 


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13 LIABILITIES AND INSURANCE 
To cover any damage or injury occurring to a patient in association with the investigational 
medicinal product or the participation in the study, the Sponsor will contract insurance in 
accordance with local regulations. 
All participating investigators are responsible for dispensing the IMP in adherence to this 
protocol, and for its secure storage and safe handling throughout the study. 


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