A Phase III, Multicenter, Open-Label Study to Evaluate the Pharmacokinetics and Safety of Subgam-VF in Primary Immunodeficiency Diseases
Phase: PHASE3
Conditions: Primary Immune Deficiency Disorders, Common Variable Immunodeficiency, X-linked Agammaglobulinaemia, Hyperimmunoglobulin M Syndrome
Sponsor: Bio Products Laboratory

Study Protocol SCIG03, Version 6, 22 March 2017  
 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 1 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 
CLINICAL STUDY PROTOCOL 
 
 
A Phase III, Multicenter, Open-Label Study to Evaluate 
the Pharmacokinetics and Safety 
 of Subgam-VF in Primary Immunodeficiency Diseases (PID)  
 
 
 
 
 
 
 
 
 
Protocol Number 
SCIG03 
Date 
22 March 2017 
Version 
6
Name of Investigational Product
Subgam-VF
Name and Address of Sponsor 
Bio Products Laboratory Limited (Ltd.) 
Dagger Lane, Elstree 
Hertfordshire,  
WD6 3BX, UK. 
Tel:  +44 (0) 20 8957 2200 
IND No. 
15599 
 
 
 
 
 
 
 
 
  
 
 

Study Protocol SCIG03, Version 6, 22 March 2017  
 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 2 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 

Study Protocol SCIG03, Version 6, 22 March 2017  
 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 3 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
VERSION HISTORY  
 
Version 
Date 
Changes  
Version 3 
19 March 2015 
First version approved by regulatory and IRBs 
(not implemented in any region) 
Version 4 
29 June 2015 
Amendment to: 
 Add measles testing at follow up visit.  
 Clarify adverse event reporting for 
infusion site reactions (section 10.3).  
Version 5 
28 April 2016 
 Correction to analysis of adverse 
events 
 Increase in maximum number of 
subjects, to allow flexibility in 
enrolment during the trial. 
 Clarification of the pharmacokinetic 
assessments to be performed. 
 Updates in line with protocol 
clarification letters 
 Updates or clarifications of study 
assessments / procedures 
 Allowance for a PK sample to be taken 
the week following the PK assessment 
if required 
 Minor changes to the safety analyses  
 Administrative changes 
Version 6 
22 March 2017 
 Change in Chief Medical Officer at 
BPL 
 Number of pediatric subjects updated 
in line with updated Pediatric Study 
Plan. 
 Update to statistical analysis 
populations 
 Clarification of the definition of an 
adverse reaction 
 Update to the pharmacokinetic analysis
Re-emphasis on infusion timing prior 
to PK sampling.

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 4 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
1. 
TABLE OF CONTENT 
1. 
TABLE OF CONTENT ................................................................................................................ 4 
2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .............................................. 7 
3. 
PROTOCOL SYNOPSIS ............................................................................................................. 9 
4. 
INTRODUCTION ....................................................................................................................... 16 
4.1. 
Background ............................................................................................................... 16 
4.2. 
Clinical trial data ....................................................................................................... 17 
4.3. 
Benefit / Risk Statement ........................................................................................... 17 
5. 
STUDY OBJECTIVES ............................................................................................................... 18 
5.1. 
Primary Objective ..................................................................................................... 18 
5.2. 
Secondary Objectives ................................................................................................ 18 
5.3. 
Exploratory Objective ............................................................................................... 18 
6. 
STUDY POPULATION .............................................................................................................. 18 
6.1. 
Inclusion Criteria ...................................................................................................... 18 
6.2. 
Exclusion Criteria ..................................................................................................... 19 
7. 
STUDY DESIGN AND PLAN ................................................................................................... 21 
7.1. 
Study Visits ............................................................................................................... 22 
7.2. 
Infusions .................................................................................................................... 24 
7.3. 
Pharmacokinetics ...................................................................................................... 25 
7.4. 
Clinical Laboratory Tests .......................................................................................... 25 
7.4.1. 
Effects on Hepatic, Renal, and Hematologic Function ..................................... 26 
7.4.2. 
Direct Coombs’ Test ......................................................................................... 26 
7.4.3. 
Virology Testing ............................................................................................... 27 
7.4.4. 
Reserve Samples ............................................................................................... 28 
7.4.5. 
Archive Sample ................................................................................................. 28 
7.5. 
Informed Consent...................................................................................................... 28 
7.6. 
Medical History ........................................................................................................ 28 
7.7. 
Physical Examination................................................................................................ 29 
7.8. 
Monitoring for thromboembolic events (TEE) ......................................................... 29 
7.9. 
Concomitant Medication ........................................................................................... 30 
7.10.  Chest X-Ray .............................................................................................................. 30 
7.11.  Vital Signs ................................................................................................................. 30 
7.12.  IgG - Blood Levels of the Previous IgG Preparation ................................................ 31 
7.13.  IgG Subclasses-Blood Levels of the Previous IgG Preparation ............................... 32 
7.14.  Specific Antibody Function ...................................................................................... 32 
7.15.  IgA and IgM Levels .................................................................................................. 32 
7.16.  Routine Pre-medications ........................................................................................... 32 
7.17.  Data Recording ......................................................................................................... 33 
7.18.  Subject Study Diary .................................................................................................. 33 
7.19.  Subject Withdrawal ................................................................................................... 33 
7.19.1. 
Evaluations at Early Withdrawal ...................................................................... 34 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 5 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
7.20.  Study Termination .................................................................................................... 34 
8. 
DESCRIPTION OF TREATMENT ADMINISTERED ......................................................... 34 
8.1. 
Investigational Product ............................................................................................. 34 
8.1.1. 
Identification and Batch Numbers .................................................................... 34 
8.1.2. 
Packaging and Labeling .................................................................................... 35 
8.1.3. 
Conditions for Storage and Use ........................................................................ 35 
8.2. 
Investigational Treatment ......................................................................................... 35 
8.2.1. 
Dosing Schedule and Rationale ........................................................................ 35 
8.2.2. 
Product Preparation ........................................................................................... 35 
8.2.3. 
Method of Administration................................................................................. 36 
8.2.4. 
Product Accountability ..................................................................................... 37 
8.3. 
Treatment Compliance .............................................................................................. 37 
9. 
ASSESSMENT OF EFFICACY ................................................................................................ 37 
9.1. 
Primary Efficacy Variables ....................................................................................... 37 
10. 
ASSESSMENT OF SAFETY AND TOLERABILITY ....................................................... 37 
10.1.  Safety Variables ........................................................................................................ 37 
10.2.  Adverse Events ......................................................................................................... 38 
10.3.  Infusion Site Reactions ............................................................................................. 39 
11. 
ASSESSMENT OF PHARMACOKINETICS ..................................................................... 39 
11.1.  Pharmacokinetics of Subgam-VF for Total IgG Levels ........................................... 39 
11.2.  Other Pharmacokinetic Parameters ........................................................................... 40 
12. 
INTERIM ANALYSIS ........................................................................................................... 40 
13. 
STATISTICAL METHODS .................................................................................................. 40 
13.1.  Sample Size Determination ....................................................................................... 41 
13.2.  Analysis Population .................................................................................................. 41 
13.2.1. 
Intent-to-treat (ITT) Population ........................................................................ 41 
13.2.2. 
PK population ................................................................................................... 41 
13.3.  Efficacy Analyses ..................................................................................................... 42 
13.4.  Safety Analysis ......................................................................................................... 42 
13.4.1. 
Adverse Events ................................................................................................. 42 
13.4.2. 
Other Safety Analyses ....................................................................................... 43 
13.5.  IgG subclasses and IgG antibodies ........................................................................... 43 
13.6.  Pharmacokinetic Analyses ........................................................................................ 43 
13.6.1. 
Primary Statistical Analysis .............................................................................. 44 
13.6.2. 
Secondary Statistical Analyses ......................................................................... 44 
13.6.3. 
Exploratory Analysis ........................................................................................ 44 
14. 
PROVISION OF ADDITIONAL INFORMATION ............................................................ 45 
15. 
INVESTIGATOR AGREEMENT ........................................................................................ 46 
16. 
REFERENCES ........................................................................................................................ 47 
APPENDIX I: ADVERSE EVENT DEFINITIONS AND REPORTING ...................................... 49 
APPENDIX II - ADMINISTRATIVE REQUIREMENTS .............................................................. 60 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 6 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
APPENDIX III - LOCAL INVESTIGATOR’S RESPONSIBILITIES BASED ON THE ICH 
GUIDELINES FOR GOOD CLINICAL PRACTICE ..................................................................... 74 
APPENDIX IV- VISIT SCHEDULE ................................................................................................. 83 
APPENDIX V- MAXIMUM BLOOD WITHDRAWAL VOLUMES ............................................ 87 
 
LIST OF TABLES 
Table 1 Recommended infusion flow rates for Subgam-VF 
Table 2 Schedule of Assessments 
Table 3 Pharmacokinetic Assessment Schedule for Subgam-VF (Week 21 to Week 22) 
Table 4 IRB Maximum Allowable Total Blood Draw Volumes (Clinical + Research) 
 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 7 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
2. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AEs 
Adverse Events 
ALT 
Alanine Transaminase 
ANC 
Absolute Neutrophil Count 
Anti-D 
Anti-D immunoglobulin 
AST 
Aspartate Transaminase 
AUC 
Area under the curve 
AUC(0-) 
Area under the plasma concentration-time curve of the dosing interval 
sAUC(0-)   
Area under the plasma concentration-time curve of the dosing interval 
standardized to one week 
BMI 
Body Mass Index 
BPL 
Bio Products Laboratory Limited (Ltd.) (the Sponsor and manufacturer) 
BUN 
Blood Urea Nitrogen 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CL 
Systemic clearance (PK) 
Cmax 
Maximum concentration in plasma 
CFR 
Code of Federal Regulations 
CRO 
Contract Research Organization 
Cryo-Store 
Archive Facility for Laboratory Samples  
CV 
Coefficient of Variation 
DVT 
Deep Vein Thrombosis  
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
U.S. Food & Drug Administration  
HAV 
Hepatitis A Virus 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICH  
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IGIV 
Immunoglobulin Intravenous  
IgM 
Immunoglobulin M 
IMP/IP 
Investigational Medicinal Product / Investigational Product (EU / US) 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat (population) 
IV 
Intravenous 
LDH 
Lactate Dehydrogenase 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 8 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
MOsmol 
MilliOsmolae 
mL 
Milliliter 
NAT 
Nucleic acid Amplification Test (PCR) 
PA 
Posterior-Anterior 
PaO2 
Partial pressure of Oxygen in arterial blood 
PCR 
Polymerase Chain Reaction 
PID 
Primary Immunodeficiency Diseases 
PK 
Pharmacokinetic 
PVC 
Polyvinyl Chloride 
RNA 
Ribosenucleic Acid 
SAE 
Serious Adverse Event 
SC 
Subcutaneous 
SCIG 
Subcutaneous IgG 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE(s) 
Treatment-emergent Adverse Event(s) 
TEE 
Thrombo-embolic events 
tmax 
Time to reach the maximum concentration in plasma 
UK 
United Kingdom 
US 
United States 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 9 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
 
3. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
Bio Products Laboratory Ltd. (BPL) 
Dagger Lane, Elstree 
Hertfordshire, WD6 3BX.  UK. 
Name of Manufacturer: 
Bio Products Laboratory Ltd. (BPL) 
Dagger Lane, Elstree 
Hertfordshire, WD6 3BX.  UK. 
Name of Finished Product: 
Subgam-VF 
Protocol identification code: 
SCIG03
Name of Active Ingredient: 
Immune Globulin (Human)
Protocol Synopsis version and date: 
Version 6, 22 March 2017
Title of study:  A Phase III, Multicenter, Open-Label Study to Evaluate the Pharmacokinetics and Safety of Subgam-VF in 
Primary Immunodeficiency Diseases (PID) 
Indication:  Primary immunodeficiency diseases 
Study centers:  This will be a multicenter study planned for the US, but depending upon the availability of suitable subjects 
may be extended into other countries. 
Development phase: III 
Objectives:   
Primary Objective 
 
To determine the PK profile of Subgam-VF and compare the AUC(0-) with historical AUC data (all standardized to 
one week at steady state) from Gammaplex 5% IGIV PID studies (GMX01 and GMX04).  
Secondary Objectives 
 
To assess the safety of Subgam-VF, including the incidence of adverse events and site infusion reactions in subjects 
with PID.  
 
To refine the dose adjustment coefficient for Subgam-VF  
Exploratory Objective 
 
To explore PK modelling for alternative dosing schedules.  
 
Study design:   
This will be a Phase III, multicenter, open-label, non-randomized study. 
 
Following a screening period, eligible subjects will commence weekly Subgam-VF treatment; this is a 16% 
subcutaneous IgG product.  
 
Subjects will receive Subgam-VF for 26 weeks during which time safety will be assessed. 
 
After Week 21, PK sampling will commence to measure AUC(0- ).  
 
The patient populations will be as similar as possible to that of the historical studies (GMX01 and GMX04) as per 
similar inclusion/exclusion criteria. 
 
Comparable methods will be used to determine PK concentrations to that of the historical studies and the AUC 
measured will be at steady state.      
 
Follow-up visit (one week after the last Subgam-VF infusion, Week 27). All AEs will be monitored up to 28 days after 
the last Subgam-VF infusion by telephone contact (Week 30). 
 
The initial weekly dose of Subgam-VF administered will be calculated by taking the average weekly equivalent of the 
subject’s IGIV dose (should be stable, as in same mg/kg +/- 5%), divided by the average dosing interval in weeks (i.e. 3 
or 4), multiplied by 1.37, a dose adjustment coefficient based on other licensed subcutaneous IgG products. If the 
subject was already receiving a weekly SCIG IgG there will be no dose adjustment.  
 
Oral and parenteral steroids as concomitant medication are allowed if the average daily dose is < 0.15 mg of prednisone 
equivalent/kg body weight per day.   

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 10 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
Name of Sponsor/Company: 
Bio Products Laboratory Ltd. (BPL) 
Dagger Lane, Elstree 
Hertfordshire, WD6 3BX.  UK. 
Name of Manufacturer: 
Bio Products Laboratory Ltd. (BPL) 
Dagger Lane, Elstree 
Hertfordshire, WD6 3BX.  UK. 
Name of Finished Product: 
Subgam-VF 
Protocol identification code: 
SCIG03
Name of Active Ingredient: 
Immune Globulin (Human)
Protocol Synopsis version and date: 
Version 6, 22 March 2017
 
Routine premedication to reduce potential adverse effects associated with SCIG infusions are discouraged.  Exceptions; 
 
Premedication will be permitted if a subject has reported systemic adverse events on two Subgam-VF 
infusions.   
 
Local anesthetics (e.g. an analgesic cream) can be used before Subgam-VF infusion to reduce the potential pain 
associated with needle insertion if required. 
 
Subgam-VF will be administered subcutaneously using infusion pumps.  
 
Subjects will be given diaries to record adverse event data as well as any infusions administered at home. In addition 
there will be a telephone follow up by an appropriately qualified site staff member on day 3 after each site administered 
and home administered infusion to check for any adverse reactions including infusion site reactions and remind subjects 
to document these in their subject study diary.  The date of infusion is considered to be Day 0. If Day 3 is to fall on a 
weekend or public holiday then this telephone follow up call should be performed on the closest working day after Day 
3 as possible. 
 
Screening/Baseline 
After informed consent/assent (as appropriate): 
Screening/baseline – subjects receive their usual dose of IGIV/SCIG and have all safety screening tests performed, including 
biochemistry, hematology, virology, vital signs and serum IgG trough levels.   
 
Treatment Period (Weeks 1 to 26) 
Eligible subjects return 7 days (+/- 1 day) after the Screening/Baseline visit for their first Subgam-VF dose (Week 1 visit).   
Weekly dosing with Subgam-VF will be administered for 26 weeks during which time safety will be assessed.   
Week 21 to Week 22: Subjects will undergo PK sampling between two treatment visits to measure AUC(0- ) (sample taken 
pre dose, then at 1, 2, 3, 5 and 7 days post dose, defined as Steady State Day 0, Steady State Day 1, Steady State Day 2, 
Steady State Day 3, Steady State Day 5, Steady State Day 7).  If the PK sampling cannot be completed at Week 21 (eg. due 
to patients work/vacation schedule) then this can be delayed to start at Week 22, 23, 24 or 25; however, the patient should 
still visit the office/hospital for their week 21 infusion and complete the other assessments scheduled for Visit 8, if possible. 
Week 22 assessments (Visit 9) will normally coincide with the PK sampling Day 7.  However, if PK sampling is delayed, 
Visit 9 will also be delayed. 
If the subject is not already receiving IgG via the subcutaneous route, it is planned that home infusion will begin on Week 3 
(3rd infusion of Subgam-VF), following training by the site during the preceding Subgam-VF visits. However, if the subject 
requires further assistance this will be provided (i.e. it is not mandatory that the infusions are performed at home).   
The subject will return to the clinic every four weeks for a safety assessment (haematology, chemistry, pre and post dose 
vital signs and physical exam). Their regular Subgam-VF infusion will be given whilst the subject is at the clinic and 
additional Subgam-VF vials will be dispensed.  Trough levels will also be measured at the clinic visits.  
 
Follow-up visit  
Final safety assessments will be carried out approximately seven days after the final study infusion.  All AEs will be 
monitored up to 28 days after the last Subgam-VF infusion by telephone contact. 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 11 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
Name of Sponsor/Company: 
Bio Products Laboratory Ltd. (BPL) 
Dagger Lane, Elstree 
Hertfordshire, WD6 3BX.  UK. 
Name of Manufacturer: 
Bio Products Laboratory Ltd. (BPL) 
Dagger Lane, Elstree 
Hertfordshire, WD6 3BX.  UK. 
Name of Finished Product: 
Subgam-VF 
Protocol identification code: 
SCIG03
Name of Active Ingredient: 
Immune Globulin (Human)
Protocol Synopsis version and date: 
Version 6, 22 March 2017
 
Number of subjects 
Plan to enroll up to 50 subjects to ensure 30 evaluable subjects.  At least 18 enrolled subjects will be adults (16-75 years) 
and 12 enrolled subjects will be children with a minimum of four enrolled in each of the following age groups: 2-5 years, 6-
11 years and 12 to 15 years.  All subjects who receive at least one infusion of Subgam-VF will be included in the safety 
analysis. 
The total number of subjects (adults plus children) evaluable for PK analysis will be at least 30. Data will be compared to 
historical data from previous Gammaplex IGIV studies. 
 
Assuming no true difference exists in average exposure compared with the historical data, 30 evaluable subjects will give 
greater than 98% power of concluding equivalence assuming a between-subject coefficient of variation (CV) of 18.2 % 
(equivalently, a standard deviation of logged data of 0.181).  If there is a true difference of 10%, power drops to 86%. 
 
Study variables and criteria for evaluation:  
 
Pharmacokinetic Variables 
The following PK variables for total IgG levels will be determined for the PK population:   
 
AUC(0- )- area under the plasma concentration-time curve of the dosing interval; 
 
sAUC(0-) - area under the plasma concentration-time curve of the dosing interval standardized to one week. This 
will be calculated for the historical data only 
 
Cmax – maximum concentration in plasma;  
 
tmax – time to reach the maximum concentration in plasma;  
 
CL– systemic clearance.  
 
The following additional PK variables will also be determined for the ITT population:   
 
Trough serum IgG levels (measured before every infusion administered at the study site); 
 
Trough levels of IgG, and IgG subclasses will be measured prior to certain infusions; 
 
Levels of specific antibodies (Haemophilus influenzae B, Streptococcus pneumonia, Measles) will be measured 
prior to certain infusions; 
 
Safety Variables  
The variables used to assess safety will be the following: number and percent of adverse events (AEs); adverse reactions, 
vital signs; clinical laboratory tests and Direct Coombs’ Test; markers of virus transmission; physical examination. 
 
Statistical Methodology:   
ITT Population: 
All subjects who receive at least one infusion of Subgam-VF will be included in the intent-to-treat (ITT) population.  The 
ITT population will be used for the safety analysis.  
 
PK Population:  
This comprises the Subgam PK population (subset of the ITT population) and Gammaplex PK population (from historical 
Gammaplex 5% IGIV PID studies). In addition, the PK Dose-Adjustment population is the subset of the PK population 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 12 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
Name of Sponsor/Company: 
Bio Products Laboratory Ltd. (BPL) 
Dagger Lane, Elstree 
Hertfordshire, WD6 3BX.  UK. 
Name of Manufacturer: 
Bio Products Laboratory Ltd. (BPL) 
Dagger Lane, Elstree 
Hertfordshire, WD6 3BX.  UK. 
Name of Finished Product: 
Subgam-VF 
Protocol identification code: 
SCIG03
Name of Active Ingredient: 
Immune Globulin (Human)
Protocol Synopsis version and date: 
Version 6, 22 March 2017
which excludes subjects in the Subgam PK population who had prior treatment with another subcutaneous weekly IgG 
product. 
 
Safety:  The number and percent of infusions with at least one adverse event (AE), irrespective of causality, that occurs 
during the infusion or within 72 hours after completion of the infusion will be calculated.  A 1-sided 95% upper confidence 
bound for this percent will be derived.  If the upper bound is less than 40%, excluding local infusion site reactions, the 
incidence of infusion-related AEs associated with Subgam-VF will be considered acceptable.  In addition, the number and 
percent of subjects who report any AEs and the number and percent of subjects who report any AEs at least possibly related 
to Subgam-VF will be calculated, and the upper bound of the 95% confidence interval for the percentages will be presented.  
AEs occurring during the infusion and within 1, 24, 48 and 72 hours after the infusion completion will also be summarized. 
   
AEs that occur during an infusion will be summarized by the infusion rate at which the AEs are reported.  If necessary, 
infusion rates will be grouped into different levels. 
 
Serious adverse events (SAEs) and suspected unexpected serious adverse reactions (SUSARs) will be summarized with all 
AEs, and separate listings will be provided for SAEs and SUSARs.  
 
All other safety assessments will be summarized descriptively for each treatment group. 
 
An adverse reaction will be defined as any TEAE (irrespective of causality) that occurs during the infusion or within 72 
hours after completion of the infusion, any AE classed as product related or any AE with unknown causality. 
 
 
Pharmacokinetics:   
The pharmacokinetics (PK) of Subgam-VF will be described by using a non-compartmental method.  The trough levels of 
total IgG will be summarized descriptively for all the Intent-to-Treat (ITT) subjects and compared with historical data for 
Gammaplex 5%.  Pharmacokinetic variables will be summarized descriptively.  The primary PK parameter will be sAUC(0-
).  
 
All PK parameters will be calculated based on absolute (uncorrected) and baseline-adjusted (i.e. trough-adjusted at steady 
state) concentrations. 
 
IgG subclasses and IgG antibodies: 
The trough levels of IgG subclasses and IgG antibodies against specified antigens will be summarized descriptively for all 
the Intent-to-Treat (ITT) subjects.   
 
Primary Statistical Analysis 
Data will be pooled with historical data and a treatment variable defined (Subgam-VF or Gammaplex IGIV).  Log 
transformed sAUC(0-),  (AUC(0-) standardized to one week) will be analyzed using a mixed model fitted including treatment, 
and allowing for variability to be different between treatment groups.  The mean difference (Subgam-VF or Gammaplex 
IGIV) between treatments with 90% Confidence Interval (CI) will be back transformed to give an estimate of the ratio 
(Subgam-VF/ Gammaplex IGIV) of sAUC(0-). If the resulting 90% CI for the ratio lies within the equivalence limit of 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 13 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
Name of Sponsor/Company: 
Bio Products Laboratory Ltd. (BPL) 
Dagger Lane, Elstree 
Hertfordshire, WD6 3BX.  UK. 
Name of Manufacturer: 
Bio Products Laboratory Ltd. (BPL) 
Dagger Lane, Elstree 
Hertfordshire, WD6 3BX.  UK. 
Name of Finished Product: 
Subgam-VF 
Protocol identification code: 
SCIG03
Name of Active Ingredient: 
Immune Globulin (Human)
Protocol Synopsis version and date: 
Version 6, 22 March 2017
(0.80, 1.25), it will be concluded that there is equivalence in sAUC(0-)  and thus the dosing factor of 1.37 for Subgam-VF (in 
addition to the adjustment for dosing interval) gives equivalent exposure at steady state to Gammaplex IGIV.   
 
Secondary Statistical Analyses 
i. 
The primary analysis method will be repeated with data derived from baseline-adjusted concentrations. 
ii. 
A term for dosing interval within treatment will be included in the model described in the primary analysis so that 
ratios with 90% CI can be presented for Subgam-VF relative to both the 21 day and 28 day dosing interval 
regimens of Gammaplex. 
iii. 
The primary analysis model will be extended to include any significant (at the 10% level) covariates or covariate by 
treatment interactions.  Covariates considered for inclusion will include age category, weight, BMI and sex. 
iv. 
The effect of previous treatment (SCIG or IGIV) on AUC(0-) in the Subgam PK population will be analysed. If the 
resulting 90% CI for the ratio lies within the equivalence limit of (0.80, 1.25), it will be concluded that the previous 
treatment does not affect exposure at steady state. If this is the case then the refined dose adjustment with 90% CI 
will be presented on the full PK population (in addition to on the PK Dose Adjustment population described 
below).  
v. 
In addition, the data from the current study will be restricted to a PK Dose Adjustment population  and analysed as 
per the primary analysis. A refined dose adjustment will be estimated as 1.37/the ratio (Subgam-VF / Gammaplex 
IGIV) of geometric means for sAUC(0-)  and presented with 90% CI. 
Exploratory Analysis 
PK modelling will be performed to explore alternative dosing schedules. 
 
Subject selection criteria:  
Inclusion criteria:   
1) Aged between 2 and 75 years (at time of initial consent). 
2) Body Mass Index (BMI) < 46 for adults (aged 16 years and older), and BMI < 28 for children. 
3) Diagnosed with primary immunodeficiency disease e.g. common variable immunodeficiency, X-linked and autosomal 
forms of agammaglobulinaemia, hyper-IgM syndrome, Wiskott-Aldrich syndrome. 
4) Currently receiving a licensed (or investigational stage III, IIIb) IGIV or SCIG and  
a) IGIV dose is between 300 and 800 mg/kg/month.  SCIG dose is between 110 and 300 mg/kg/week; 
b) Dose is stable for at least the past three months (i.e. consistent mg/kg +/- 5%); 
c) The infusion interval is every 21 or 28 days for IGIV and seven days for SCIG;   
d) Has a documented trough level of ≥ 6 g/L (600 mg/dL) on current IgG therapy.  If not available can be obtained at 
the screening visit, Visit 1 (Week 0).   
5) Female subjects who are (or become) sexually active must practice contraception by using a method of proven 
reliability for the duration of the study.  
6) Females of child-bearing potential, (defined from the onset of menstruation to one year post menopause), must have a 
negative result on a urine HCG-based pregnancy test.   
7) Willing to comply with all aspects of the protocol, including blood sampling, for the duration of the study.  
8) Signed an informed consent form. In the case of subjects under the legal age the parent/guardian will sign an informed 
consent form and where appropriate the subject will sign an assent form.

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 14 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
Name of Sponsor/Company: 
Bio Products Laboratory Ltd. (BPL) 
Dagger Lane, Elstree 
Hertfordshire, WD6 3BX.  UK. 
Name of Manufacturer: 
Bio Products Laboratory Ltd. (BPL) 
Dagger Lane, Elstree 
Hertfordshire, WD6 3BX.  UK. 
Name of Finished Product: 
Subgam-VF 
Protocol identification code: 
SCIG03
Name of Active Ingredient: 
Immune Globulin (Human)
Protocol Synopsis version and date: 
Version 6, 22 March 2017
 
Exclusion Criteria:   
1) Has a history of any severe anaphylactic reaction to blood or any blood-derived product. 
2) Has selective IgA deficiency or has a history of antibodies to IgA. 
3) Has clinically significant impairment of cellular or innate immunity at the discretion of the Investigator 
4) Has evidence of an active infection at the time of enrolment (i.e. on day of first infusion). Subjects who are 
asymptomatic but have not completed their course of antibiotics are eligible.  
5) Has previously completed or withdrawn from this study. 
6) Is currently receiving, or has received, any investigational agent within the prior three months, unless it is an 
investigational stage III, IIIb IGIV or SCIG. 
7) Is pregnant (confirmed by a positive result on an HCG-based pregnancy test) or is nursing. 
8) Is positive for any of the following at screening: 
 
Serological test for HIV 1&2, HCV, or HBsAg 
9) Has levels at screening greater than 2.5 times the upper limit of normal as defined at the central laboratory of any of the 
following: 
 
Alanine transaminase (ALT) 
 
Aspartate transaminase (AST) 
10) Has severe renal impairment (defined as serum creatinine greater than two times the upper limit of normal or BUN 
greater than two times the upper limit of normal for the range of the laboratory doing the analysis); the subject is on 
dialysis; or has a history of acute renal failure.  
11) Is known to abuse alcohol, opiates, psychotropic agents, or other chemicals or drugs, or has done so within the past 12 
months. 
12) Has a history of DVT, or thrombotic complications of IgG therapy, or a prior diagnosis of thrombophilia. 
13) Suffers from any acute or chronic medical condition, (e.g. renal disease or predisposing conditions for renal disease, 
coronary artery disease, or protein losing state, proteinuria) that the Investigator feels may interfere with the conduct of 
the study. 
14) Has an acquired medical condition, such as chronic lymphocytic leukemia, lymphoma, multiple myeloma, chronic or 
recurrent neutropenia (ANC < 1 x 109/L). 
15) Is receiving the following medication: 
 
Steroids (long-term daily, > 0.15 mg of prednisone equivalent/kg/day).  Requirement for short or intermittent 
courses of > 0.15mg/kg/day would not exclude a subject. 
 
Immunosuppressive drugs 
 
Immunomodulatory drugs 
16) If ≥ 18 years of age, has non-controlled arterial hypertension (systolic blood pressure > 160 mmHg and/or diastolic 
blood pressure > 100 mmHg). For younger subjects refer to current guidelines for diagnosis of blood pressure1. 
17) Has anemia (hemoglobin < 10 g/dL) at screening.  
18) Has severe dermatitis that would preclude sites for safe product administration.  
 
1. The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents. Pediatrics 
2004 Aug;114 (Suppl 2:) 555-76. 
Test product, dose/mode of administration, batch number(s)   
 
Subgam-VF is a 16% IgG and will be administered  weekly, by subcutaneous infusion: 
 
The initial weekly dose of Subgam-VF administered will be calculated by taking the average weekly equivalent of 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 15 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
Name of Sponsor/Company: 
Bio Products Laboratory Ltd. (BPL) 
Dagger Lane, Elstree 
Hertfordshire, WD6 3BX.  UK. 
Name of Manufacturer: 
Bio Products Laboratory Ltd. (BPL) 
Dagger Lane, Elstree 
Hertfordshire, WD6 3BX.  UK. 
Name of Finished Product: 
Subgam-VF 
Protocol identification code: 
SCIG03
Name of Active Ingredient: 
Immune Globulin (Human)
Protocol Synopsis version and date: 
Version 6, 22 March 2017
the subject’s IGIV dose (should be stable, as in same mg/kg +/- 5%), multiplied by 1.37, a dose adjustment 
coefficient based on other licensed subcutaneous IgG products.  If the subject was already receiving a weekly SCIG 
IgG there will be no dose adjustment. 
 
It is planned to use one batch of Subgam-VF in this study.  Additional batches may be used if required.  The following 
infusion rates will be followed. 
 
Subgam-VF infusions will be administered in accordance with the table below: 
 
 
 
Table 1 Volume and Rate of Subgam-VF infusions 
 
Volume
Rate 
First infusion 
20 mL/site
20 mL/hr/site 
Maximum at 
subsequent 
infusions 
Up to 30 mL/site 
Up to 30 mL/hr/site 
 
Up to 6 infusion sites can be used simultaneously. Subjects weighing ≥100 kg may use up to 8 sites if necessary. If 
more sites are required, these must be used consecutively (during the same infusion).   
 
Any increase in flow rate or number of sites should first be tried whilst the subject is in the clinic. However, the 
infusions must be administered at the volume and rate outlined in Table 1 throughout the entire infusion.  Titration 
during the infusion is not allowed. 
 
For young children or adults of below average weight, lower flow rates may be used, depending on tolerability.  
 
Duration of treatment:  
The total duration of treatment will be for 26 weeks.   
 
Compliance Statement 
This trial will be conducted in accordance with the protocol, EU Clinical Trial Directives 2001/20/EC and 2005/28/EC and 
applicable local regulatory requirements. 
 
The study will be performed in accordance with the guidelines of the Declaration of Helsinki on biomedical research 
involving human subjects and in accordance with ICH GCP guidelines, European Union (EU) Directives 2001/20/EC, 
2005/28/EC and United States Title 21 Code of Federal Regulations (CFR) as well as the demands of national drug and data 
protection laws, other applicable regulatory requirements, and any new directives or regulations that become enforceable 
during the course of the study. 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 16 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
4. 
INTRODUCTION 
4.1. 
Background 
The primary immunodeficiency diseases are a heterogeneous group of disorders in which 
there is an intrinsic defect in the tissues, cells, and/or proteins of the immune system resulting 
in immune deficiency. Many of these disorders are characterized by hypogammaglobulinemia 
and/or defective antibody production and, as a consequence, increased susceptibility to 
infection. 
 
Replacement therapy with immunoglobulin G (IgG) purified from pools of plasma from 
multiple donors has been used since the early 1950s.  The initial products were administered 
intramuscularly, but were of limited efficacy because of the relatively small quantities that 
could be administered by that route.  Beginning in the 1980s, intravenous immunoglobulin 
(IGIV) became available in the United States (US) and had become the main choice of 
treatment in the US3,4,5. 
 
Subgam-VF is a newly developed, highly purified, unmodified human immunoglobulin G 
(IgG) product intended for subcutaneous (SC) administration, and is manufactured by Bio 
Products Laboratory Ltd., (BPL), UK.  The target indication is the treatment of primary 
immunodeficiency states, such as congenital agammaglobulinemia, common variable 
immunodeficiency, and X-linked agammaglobulinemia. 
 
Subgam-VF is manufactured from plasma from healthy US donors who are subjected to 
medical examinations, laboratory tests, and a review of their medical history before being 
allowed to donate plasma by apheresis.  Each donation must be non-reactive for hepatitis B 
surface antigen (HBsAg), anti-HIV-1 and HIV-2 antibodies, and anti-HCV antibodies.  
Furthermore, plasma minipools (512 donations per pool) undergo nucleic acid amplification 
(NAT) testing for HIV, HBV, HCV, HAV, and parvovirus B19.  Manufacturing pools are 
tested for HBsAg and HIV antibodies; HIV, HBV, HCV, HAV and parvovirus B19 are also 
tested using NAT.  
 
Subgam-VF is a ready-prepared solution for SC administration that contains per mL 0.16 g 
IgG6. Immunoglobulin G purity reaches 100%, the pH is typically 6.6 to 6.8 but in the range 
of 6.4 to 7.2, and osmolality is not less than 240 mOsmol/kg.  The immunoglobulins present 
are virtually 100% IgG, and the distribution of the four IgG subclasses is approximately 64% 
IgG1, 30% IgG2, 5% IgG3, and 1% IgG4.  The content of IgA is lower than 50 µg/mL.  The 
Anti-A, Anti-B and Anti-D content of the final product is monitored and controlled to 
specification.   

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Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 17 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
Subgam-VF was developed from BPL’s SCIG product, Subgam®, and introduces a 20nm 
virus filtration processing stage common to BPL’s IGIV product, Gammaplex®, which was 
licensed in the UK and US in 2009.  Subgam® is also licensed in Cyprus since 2007 and 
Columbia from 2009.  Subgam-VF is manufactured by using an identical process to that for 
Gammaplex, apart from an increase in IgG concentration at the end of processing to allow for 
subcutaneous administration.  Subgam-VF contains the same active protein as the licensed 
IgG product, Gammaplex, but differs in terms of concentration (16% and 5% respectively).  In 
addition Subgam-VF is glycine based compared with Gammaplex which is sorbitol based.   
The efficacy of Gammaplex has been investigated in prior studies therefore a PK and safety 
study will be performed with Subgam-VF and compared with historical Gammaplex data, as 
the two products are essentially identical apart from their relative concentrations, excipients 
and route of delivery.  
 
4.2. 
Clinical trial data 
Subgam®, the precursor non-virus filtered product to Subgam-VF, has been evaluated in a 
Phase III efficacy study involving 50 pediatric and adult subjects with Primary 
Immunodeficiency Disease.  The primary efficacy outcome to achieve target IgG trough 
levels over a minimum of 12 months was met; 85% of adults/teenagers and 93% of children 
achieved target serum IgG levels at all observation time points.  Subgam® was safe and well 
tolerated during the study.  There were 82 reports of infusion site reactions in 25 of the 50 
patients. The most common product-related adverse events were headache (8 reports in 7 
patients), pruritus (7 reports in 2 patients) and vomiting (5 reports in 3 patients).  There were 
no withdrawals due to adverse events or safety considerations and no product-related SAEs6. 
Since licensure in the UK 2004 till 31 May 2014 BPL has received a total of 34 spontaneous 
reports of product-related adverse events (20 non-serious and 14 serious). There have been no 
reports of virus transmission.   
There is no clinical trial data currently available on Subgam-VF. 
 
4.3. 
Benefit / Risk Statement 
Published data has shown that subcutaneous IgG (SCIG) use in subjects with PID provides 
protection which is comparable to that found with IGIV therapy7,8,9,10.  
 
Infusions of IgGs given subcutaneously (SCIG) were initially used in patients who were 
unable to tolerate IgG administered either through intravenous (IV) or intramuscular (IM) 
routes10. SCIG has the advantage in that it can be self-administered at a time and location 
more suitable to the individual and without the need for assistance from a trained professional 
(other than during the initial training period).  This convenience has been associated with an 
improvement in quality of life11,12.  
 
This form of infusion requires no venous access.  Unlike IGIV which is infused directly into 
the intravascular compartment, SCIG must diffuse first into the lymphatic system and is then 

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Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 18 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
subsequently carried into the blood stream via the thoracic duct8,13,14,15, therefore with SCIG 
the intravascular concentration of IgG increases more gradually, peaking at 48-72 hours.  The 
rate IgG enters the circulation appears to be the main driver of systemic tolerability and as 
such the incidence of systemic adverse events appears to be much lower with SCIG therapy13 
than with IV infusion.  Also division of the dose into weekly fractions produces more 
consistent IgG levels without the peaks and troughs experienced with monthly IGIV infusions.  
However, with SCIG therapy because some of the IgG is already equilibrating into the 
extracellular fluid before all of the IgG has entered the bloodstream; and also due to binding 
and/or degradation of the IgG in subcutaneous tissue, the maximum serum concentration of 
IgG can be on average 61% of the level achieved with IGIV16,17,18. 
 
As with any blood product, viral safety is a concern.  Subgam-VF undergoes a stringent multi-
step process, including solvent/detergent treatment, nanofiltration, and a terminal low pH 
incubation of the finished product, to reduce the risk of potential viral contaminants and 
enhance the safety of the product.  
 
5. 
STUDY OBJECTIVES 
5.1. 
Primary Objective  
 To determine the PK profile of Subgam-VF and compare the AUC(0-) with 
historical AUC data (all standardized to one week at steady state) from 
Gammaplex 5% IGIV PID studies (GMX01 and GMX04).  
5.2. 
Secondary Objectives 
 To assess the safety of Subgam-VF, including the incidence of adverse events 
and site infusion reactions in subjects with PID.  
 To refine the dose adjustment coefficient for Subgam-VF  
5.3. 
Exploratory Objective 
 To explore PK modelling for alternative dosing schedules.  
 
6. 
 STUDY POPULATION 
6.1. 
Inclusion Criteria  
In order to qualify for entrance into the study, each subject must satisfy all criteria listed 
below: 
1. Aged between 2 and 75 years old (at time of initial consent)  
2. Body Mass Index (BMI) < 46 for adults (aged 16 years and older), and BMI < 28 for 
children. 
3. Diagnosed with primary immunodeficiency disease e.g. common variable 
immunodeficiency, X-linked and autosomal forms of agammaglobulinaemia, 
hyper-IgM syndrome, Wiskott-Aldrich syndrome. 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 19 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
4. Currently receiving a licensed (or investigational stage III, IIIb) IGIV or SCIG and 
a. IGIV dose is between 300 and 800 mg/kg/month. SCIG dose is between 
110 and 300 mg/kg/week;  
b. Dose is stable for at least the past three months (i.e. consistent mg/kg +/- 
5%);   
c. The infusion interval is every 21 or 28 days for IGIV and seven days for 
SCIG;  
d. Has a documented trough level of ≥ 6 g/L (600 mg/dL) on current IgG 
therapy.  If not available can be obtained at the screening visit, Visit 1 
(Week 0).     
5. Female subjects who are (or become) sexually active must practice contraception by 
using a method of proven reliability for the duration of the study   
6. Females of child-bearing potential, (defined from the onset of menstruation to one year 
post menopause), must have a negative result on a urine  HCG-based pregnancy test   
7. Willing to comply with all aspects of the protocol, including blood sampling, for the 
duration of the study   
8. Signed an informed consent form. In the case of subjects under the legal age the 
parent/guardian will sign an informed consent form and where appropriate the subject 
will sign an assent form. 
 
6.2. 
Exclusion Criteria 
Subjects will be excluded if any of the following exclusion criteria are met: 
 
1. 
Has a history of any severe anaphylactic reaction to blood or any blood-derived 
product. 
2. 
Has selective IgA deficiency or has a history of antibodies to IgA.  
3. 
Has clinically significant impairment of cellular or innate immunity at the discretion 
of the Investigator. 
4. 
Has evidence of an active infection at the time of enrolment (i.e. on day of first 
infusion). Subjects who are asymptomatic but have not completed their course of 
antibiotics are eligible. 
5. 
Has previously completed or withdrawn from this study. 
6. 
Is currently receiving, or has received, any investigational agent within the prior 
three months unless it is an investigational stage III, IIIb IGIV or SCIG. 
7. 
Is pregnant (confirmed by a positive result on an HCG-based pregnancy test) or is 
nursing. 
8. 
Is positive for any of the following at screening: 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 20 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
 
Serological test for HIV 1&2, HCV, or HBsAg 
9. 
Has levels at screening greater than 2.5 times the upper limit of normal as defined at 
the central laboratory of any of the following: 
 
Alanine transaminase (ALT) 
 
Aspartate transaminase (AST) 
10. Has severe renal impairment (defined as serum creatinine greater than two times the 
upper limit of normal or BUN greater than two times the upper limit of normal for 
the range of the laboratory doing the analysis); the subject is on dialysis or has a 
history of acute renal failure.  
11. Is known to abuse alcohol, opiates, psychotropic agents, or other chemicals or drugs, 
or has done so within the past 12 months. 
12. Has a history of DVT, or thrombotic complications of immunoglobulin therapy, or a 
diagnosis of thrombophilia. 
13. Suffers from any acute or chronic medical condition (e.g. renal disease or 
predisposing conditions for renal disease, coronary artery disease, or protein losing 
state, proteinuria) that the Investigator feels may interfere with the conduct of the 
study. 
14. Has an acquired medical condition, such as chronic lymphocytic leukemia, 
lymphoma, multiple myeloma, chronic or recurrent neutropenia (ANC < 1 x 109/L). 
15. Is receiving the following medication: 
 
Steroids (long-term daily, > 0.15 mg of prednisone equivalent/kg/day).  
Requirement for short or intermittent courses of > 0.15mg/kg/day would 
not exclude a subject. 
 
Immunosuppressive drugs 
 
Immunomodulatory drugs 
16. If ≥ 18 years of age, has non-controlled arterial hypertension (systolic blood pressure 
> 160 mmHg and/or diastolic blood pressure > 100 mmHg). For younger subjects 
refer to current guidelines for diagnosis of blood pressure 1. 
17. Has anemia (hemoglobin < 10 g/dL) at screening.  
18. Has severe dermatitis that would preclude sites for safe product administration.  
1. The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents. Pediatrics 2004 
Aug;114 (Suppl 2:) 555-76. 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 21 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
 
7. 
STUDY DESIGN AND PLAN 
 
This will be a Phase III, multicenter, open-label, non-randomized study.  Up to 50 subjects 
will be enrolled to ensure 30 evaluable subjects.  At least 18 subjects will be adults1 (aged 16-
75 years) and 12 will be children split between the age groups 2 to 5 years (i.e. not reached 
their 6th birthday), 6 to 11 years (i.e. not reached their 12th birthday) and 12 to 15 years (i.e. 
not reached their 16th birthday), with a minimum of 4 in each age group.    
 
All children who receive at least one infusion of Subgam-VF will be included in the safety 
analysis. Due to the potential for early withdrawals, PK data may not be available on all 12 
children and there may be fewer than 12 evaluable children in the PK analysis. The total 
number of subjects (adults plus children) evaluable for PK analysis will be at least 30.  
 
Subjects will receive 26 infusions (weeks) of Subgam-VF at a weekly dose equivalent to 1.37 
of their IGIV dose (expressed as mg/kg/week).  If the subject was already receiving a weekly 
SCIG IgG there will be no dose adjustment.  Pharmacokinetics and safety of Subgam-VF will 
be assessed. 
 
All subjects will undergo a pharmacokinetic (PK) profile after the 21st infusion of Subgam-VF 
(see PK Assessment Schedule, Table 3).  Where an appropriately qualified member of the 
study team is available, arrangements will be made to collect the PK samples from Steady 
State Day 1 (24 hours post-infusion) onwards at the subject’s home to reduce the number of 
visits to the sites. Alternatively a Home Health Agency may be utilized to take the PK 
samples outside of the investigational site. The subject would be required to sign an extra 
IRB/EC approved consent form to permit the site to share the subject’s details with the agency 
in order for them to collect the sample. 
 
In the case of younger children it is important not to exceed the maximum blood withdrawal 
volumes stated in Appendix V.  Therefore smaller volumes of blood will be taken.  See the 
Laboratory Manual for details. 
 
 Following a screening period, eligible subjects will commence weekly Subgam-VF 
treatment; this is a 16% subcutaneous IgG product.  
 Subjects will receive Subgam-VF for 26 weeks during which time safety will be 
assessed 
                                                 
1 The definition of an adult as ≥ 16 years is as per the FDA guidance for PK studies2. Note 
this does not affect the requirements for consent/assent, for which each site should follow 
their IRB guidelines.   
 
 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
Page 22 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
 After Week 21, PK sampling will commence to measure AUC(0- ) over 7 days. 
 The patient populations will be as similar as possible to that of the historical studies 
(GMX01 and GMX04) as per similar inclusion/exclusion criteria. 
 Comparable methods will be used to determine PK concentrations to that of the 
historical studies and the AUC measured will be at steady state. 
 Follow-up visit Week 27 (one week after the last Subgam-VF infusion).   
 Follow-up telephone call Week 30 (four weeks after the last Subgam-VF infusion). 
 The initial weekly dose of Subgam-VF administered will be calculated by taking the 
average weekly equivalent of the subject’s IGIV dose (should be stable, as in same 
mg/kg +/- 5%), multiplied by 1.37, a dose adjustment coefficient based on historical 
data for other subcutaneous IgG products.  If the subject was already receiving a 
weekly SCIG IgG there will be no dose adjustment.  
 Oral and parenteral steroids as concomitant medication are allowed if the average 
daily dose is < 0.15 mg prednisone equivalent/kg body weight per day.  Short or 
intermittent courses of > 0.15 mg/kg/day are allowed if required.  
 Routine premedication to reduce potential adverse effects associated with SCIG 
infusion are discouraged.  Exceptions:   
 Premedication will be permitted if a subject has reported systemic adverse events 
on two Subgam-VF infusions. 
 Local anesthetics (e.g. an analgesic cream) can be used before any Subgam-VF 
infusion to reduce the potential pain associated with needle insertion if required. 
 Subgam-VF will be administered subcutaneously using infusion pumps.  
 Subjects will be given diaries to record adverse event data as well as any infusions 
administered at home.  
 
7.1. 
Study Visits 
For details of which procedure will be performed at any specific visit, see the schedule of 
assessments (Table 2) in Appendix IV. 
 
Screening/Baseline 
After informed consent/assent (as appropriate): 
 Screening/baseline – subjects receive their usual dose of IGIV/SCIG and have all 
safety screening tests performed, including biochemistry, hematology, virology, vital 
signs and serum IgG trough levels.   
 
Treatment Period (Weeks 1 to 26) 
 Eligible subjects then return seven days (+/- 1 day) after the Screening/Baseline visit 
for their first Subgam-VF dose (Week 1 visit).  Weekly dosing will be administered 
for 26 weeks during which time safety will be assessed.  Site visits (Weeks 1, 2, 5, 9, 

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CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
13, 17, 21, 22 and 26) – subjects will attend the clinic at specific points and they will 
receive their Subgam-VF infusion at the clinic.  There will also be routine safety 
assessments, which will include blood sampling.  After the Week 2 visit and if an 
appropriately qualified member of the study team or the subject’s carer is available, 
then arrangements may be made to conduct some of the visits at the subject’s home to 
reduce the number of visits to the sites. Alternatively a Home Health Agency may be 
utilized. The subject would be required to sign an IRB/EC approved consent form to 
permit the site to share the subject’s details with the agency in order for them to collect 
the samples/conduct the assessments. 
 If the subject is not already receiving IgG via the subcutaneous route, following 
training by the site during the preceding Subgam-VF visits it is planned that home 
infusions will begin on Week 3 (3rd infusion of Subgam-VF).  For home infusions, 
subjects (or care givers) will infuse Subgam-VF themselves and will record any 
concomitant medications, date and time of any adverse events (including inspecting 
the infusion site for reactions) and record details of their Subgam-VF dose.  If the 
subject requires further assistance this will be provided (i.e. it is not mandatory that 
these infusions are performed at home).   
 There will be a telephone follow up by an appropriately qualified site staff member on 
day 3 after each site administered and home administered infusion to check for any 
adverse reactions including infusion site reactions and remind subjects to document 
these in their subject study diary.  The date of infusion is considered to be Day 0. If 
Day 3 is to fall on a weekend or public holiday then this telephone follow up call 
should be performed on the closest working day after Day 3 as possible. 
 The subject will return to the clinic every four weeks for a safety assessment 
(hematology, chemistry, pre and post dose vital signs and physical exam).  Their 
regular Subgam-VF infusion will be given whilst the subject is at the clinic and 
additional Subgam-VF vials will be dispensed.  IgG trough levels will also be 
measured at the clinic visit every four weeks.  
 PK sampling – This will occur on Week 21 (defined as Steady State Day 0 to 7), and 
will continue over the subsequent seven days to allow calculation of AUC (see the PK 
schedule, Table 3,  Appendix IV). If the PK sampling cannot be completed at Week 21 
(eg. due to patients work/vacation schedule) then this can be delayed to start at Week 
22, 23, 24 or 25; however, the patient should still visit the office/hospital for their 
week 21 infusion and complete the other assessments scheduled for Visit 8, if possible. 
Week 22 assessments (Visit 9) will normally coincide with the PK sampling Day 7.  
However, if PK sampling is delayed, Visit 9 will also be delayed. All PK blood 
samples will be taken at the study site.  However, if an appropriately qualified member 
of the study team is available, arrangements to collect the remaining PK samples from 
Steady State Day 1 onwards at the subject’s home could be made, to help reduce the 
number of visits to the sites. Alternatively a Home Health Agency may be utilized to 
take the PK samples outside of the investigational site.  

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
 In exceptional circumstances, and with prior Sponsor approval, if one of the following 
PK samples if lost, unevaluable, or not taken it may be taken at the same timepoint 
during the week following the PK assessment, as long as the same dose in mg/kg has 
been given: 
o 1 day (24 hours ± 2 hours) 
o 2 days (48 hours ± 4 hours) 
o 3 days (72 hours ± 6 hours) 
o 5 days (120 hours ± 8 hours). 
 
Follow-up visit and end of study 
 
Follow-up visit (Week 27) – A follow up visit will occur seven days (+/- 1 day) after 
the last Subgam-VF infusion has been completed, to carry out assessments for 
safety.  Blood samples will be taken at this visit.  This visit must occur prior to 
administration of a new IgG product.  
 
Telephone follow-up (Week 30) – 28 days (+/- 1 day) after the last Subgam-VF 
infusion the subject will be contacted by the site via the telephone to check for any 
AEs. 
 
It is expected that any given subject will complete all treatments and follow-up assessments 
within approximately 30 weeks, (26 weeks on Subgam-VF, plus four weeks follow-up).  The 
end of the trial will be after the last subject’s last visit (which will be the telephone follow-up 
(Week 30) visit for the last subject).    
 
7.2. 
Infusions  
Subjects will receive 26 infusions of Subgam-VF subcutaneously on a weekly schedule using 
the supplied infusion pumps. 
 
Rescheduling of Infusions (visit windows) 
If absolutely necessary (e.g. because of unavoidable conflicts) Subgam-VF infusions can be 
rescheduled +/- 1 days.  The reason why this visit was rescheduled should be recorded in the 
eCRF.  If there is a deviation from the scheduled visit/ visit windows, the study monitor 
should be contacted, and the deviation must be documented appropriately.  These 
circumstances must not become routine.  If an infusion is rescheduled the other planned study 
assessments should also be rescheduled so that these are performed on the day of infusion. 
 
If the infusion just prior to PK sampling has to be rescheduled, then the PK sampling should 
be postponed to ensure that the PK samples are collected seven days after the last Subgam-VF 
infusion and the sampling times in Table 3 are adhered to.  
 

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CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
7.3. 
Pharmacokinetics 
All subjects will participate in the pharmacokinetic (PK) segment of the study (if blood 
withdrawal volumes allow), see Appendix IV, Table 3.  In the case of younger subjects, 
pediatric blood volumes will need to be taken to ensure the maximum blood withdrawal 
volumes specified in Appendix V are adhered to (see Laboratory Manual for more details).  
 
 
 
In exceptional circumstances, and with prior Sponsor approval, if one of the following PK samples if 
lost, unevaluable, or not taken it may be taken at the same timepoint during the week following the PK 
assessment, as long as the same dose in mg/kg has been given: 
o 1 day (24 hours ± 2 hours) 
o 2 days (48 hours ± 4 hours) 
o 3 days (72 hours ± 6 hours) 
o 5 days (120 hours ± 8 hours). 
 
Where possible, arrangements to collect PK samples at the subject’s home, from Steady State 
Day 1 onwards, by a suitably qualified member of the study may be made. 
 
IMPORTANT: If the infusion just prior to PK sampling has to be rescheduled, then the 
PK sampling should be postponed to ensure that the PK samples are collected seven 
days after the last Subgam-VF infusion and the sampling times in Table 3 are adhered 
to.  
 
7.4. 
Clinical Laboratory Tests 
All blood samples collected for the study will be processed by a central laboratory.  Once the  
results are made available, eligibility should be checked by the Investigator and eligible 
subjects may be enrolled into the study. 
 
Samples for clinical laboratory testing should be taken before certain infusions, unless 
otherwise indicated, as per the Schedule of Assessments (Appendix IV Table 2) and will 
include: 
 
 Biochemistry –including: alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), creatinine, blood urea nitrogen (BUN), lactate dehydrogenase (LDH), sodium, 
potassium, total bilirubin, alkaline phosphatase, glucose and gamma-glutamyl 
transpeptidase (GGT). 
 
 Hematology - Complete Blood Count (CBC) with differential – including: hematocrit, 
hemoglobin, red blood cells (RBC), platelet count and white blood cells (neutrophils, 
lymphocytes, monocytes, eosinophils, and basophils). 
 
 Tests for hemolysis 

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CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
o Direct Coombs’ Test (Direct Antiglobulin test – DAT) 
o Haptoglobin 
o Plasma free hemoglobin 
o Urine hemosiderin 
Tests for bilirubin and serum LDH in the standard biochemistry panel is also 
considered a test for hemolysis. 
 
 Specific antibody function to test for antibodies against the following antigens: 
o Haemophilus influenzae B 
o Streptococcus pneumoniae.  
o Measles  
 
 Virology testing 
o Serological tests for HBsAg, HCV, HIV 1 & 2 at screening for eligibility and 
at Week 27 Follow up visit  
o Nucleic Acid Testing (NAT) for HCV, HIV at Week 27 Follow up only  
o Parvovirus B19 NAT and serology at Infusion 1, 2 and Week 27 Follow up 
visit.  
 
 Urinalysis – that will include microscopic examination. 
 
 Pregnancy testing - all females of child-bearing potential will receive a urine-based, 
human chorionic gonadotropin (HCG) pregnancy test regardless of claimed inability to 
conceive (including patients who have undergone surgical sterilization). 
 
7.4.1. 
Effects on Hepatic, Renal, and Hematologic Function 
If the results of any blood test demonstrate a rise to 2.5 times the upper limit of normal in 
AST, ALT, or bilirubin, these laboratory results will be documented as an AE.   
 
A blood test demonstrating a change in renal or hematologic function will be documented as 
an AE if considered clinically significant by the Investigator.  
 
7.4.2. 
Direct Coombs’ Test 
Blood samples for Direct Coombs’ Tests and tests for hemolysis (bilirubin, haptoglobin, 
serum LDH, plasma free hemoglobin and urine hemosiderin) will be drawn at various times 
during the study (as detailed in Appendix IV, Table 2).    Tests for bilirubin and LDH are 
included in the biochemistry panel. 
In the event that a Direct Coombs’ Test result is positive, the following procedures should be 
followed:   
 
The laboratory will notify the Investigator and the designated CRO within two 
business days of receiving the abnormal result. 

Study Protocol SCIG03, Version 6, 22 March2017 
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CONFIDENTIAL 
 
Page 27 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
 
Subjects with a positive result will be flagged by the laboratory, and those subjects 
will have a Direct Coombs’ Test and other tests for hemolysis (as detailed above)  
before every subsequent infusion given during a clinic visit  and at the follow-up 
visit.   
 
Upon receiving a first report of a positive direct Coombs’ test on any subject, the 
Investigator will contact the subject to return for additional laboratory testing for 
haptoglobin, serum LDH, plasma free hemoglobin bilirubin, and urine hemosiderin 
as soon as practically possible (generally within three business days) and will assess 
the subject in order to determine if there is any clinically significant hemolysis. 
Thereafter, further tests for hemolysis may be done if clinically indicated and at the 
discretion of the investigator. 
 
All positive Direct Coombs’ tests will be reported as adverse events. 
 
 
Other criteria for hemolysis: 
 If the Direct Coombs’ Test is negative, but other hemolysis tests are indicative of 
hemolysis, the Investigator should conduct further tests to confirm hemolysis as 
clinically indicated and at the discretion of the Investigator.  This may include repeat 
Direct Coombs’ Test, haptoglobin, serum LDH, plasma free hemoglobin, bilirubin and 
urine hemosiderin. 
 A drop in hemoglobin of 2 g/dL or greater, in conjunction with both a drop in serum 
haptoglobin to below the lower limit of normal and a rise in serum LDH from 
baseline, would suggest intravascular hemolysis: 
 Investigator should review all results with reference to above criteria, and in 
conjunction with patient medical history to determine if there is clinically 
significant hemolysis.  Investigator should conduct further tests as clinically 
indicated and at the discretion of the Investigator.  This may include repeat 
Direct Coombs’ Test, haptoglobin, serum LDH, plasma free hemoglobin, 
bilirubin and urine hemosiderin. 
 Clinically significant hemolysis should be diagnosed taking into account the above 
criteria (drop in hemoglobin of 2 g/dL or greater, in conjunction with both a drop in 
serum haptoglobin to below the lower limit of normal and a rise in serum LDH from 
baseline) and any additional tests, as applicable. 
 Clinically significant hemolysis will be reported as an adverse event.  Subjects with 
clinically significant hemolysis should have a Direct Coombs’ test and other tests for 
hemolysis (as detailed above) before every subsequent infusion at the clinic. 
 
7.4.3. 
Virology Testing 
If the tests for HBV, HCV, HIV, or Parvovirus B19 suggest a change in viral status of the 
subject, the tests will be repeated by the central laboratory.  If a change in viral status is 
confirmed by a second independent test, the reserve sample taken before the first infusion of 
Subgam-VF will be retested in the same laboratory in the same batch as a retest of the suspect 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
sample.  The central laboratory will inform the Sponsor and the designated CRO within one 
business day of a confirmed report of a change in viral status. 
 
7.4.4. 
Reserve Samples 
Reserve plasma and serum samples will be collected at all relevant time points, for reanalysis 
if needed, e.g. if an original sample is spoiled or if results are discrepant.  Where necessary an 
additional blood sample will be collected; at other time points plasma or serum aliquots will 
be split so that a reserve plasma or serum sample can be retained at site.  See Appendix IV 
and Laboratory Manual.   
 
Reserve samples should be sent to the central laboratory within one month of collection where 
they will be stored at -70°C for the duration of the study.  Reserve samples may be kept until 
the licence for Subgam-VF is granted by the relevant regulatory authorities and will be used, 
if required, for repeat assays at the request of a regulatory agency.  For full details, please see 
separate Laboratory Manual. 
 
Table 4 (Appendix V) displays the suggested maximum blood withdrawal for children.  If the 
volume of blood withdrawn within 30 days is expected to exceed that specified on Table 4, 
then the Sponsor/Contract Research Organization (CRO) should be contacted to discuss order 
of priority for blood sampling.  In these cases it will likely be the reserve samples that will not 
be taken so as to not exceed the maximum blood volumes allowed.  The deviation must be 
documented appropriately on the eCRF. 
 
7.4.5. 
Archive Sample 
A blood sample will be collected from each subject immediately before the first infusion of 
Subgam-VF and at the follow-up (week 27) visit before another IgG product is given and sent 
at the end of the study (after all subjects have completed) to the central laboratory for onward 
dispatch to Cryo-store for long-term storage.  Serum will be stored in tubes at -70°C for a 
minimum of 15 years after the trial is complete19.  Samples will be used for serology and NAT 
testing if required in the future.  The handling and shipping of these samples will be 
coordinated by the central laboratory. 
 
7.5. 
Informed Consent 
Written informed consent (and assent when appropriate) must be obtained from the subject 
and where appropriate by the subject’s parent/legal guardian and signed by a suitable qualified 
and trained person, first in the protocol and the legal and ethical requirements of the study, 
before any study procedures are carried out (see Appendix II, Section 2).   
 
7.6. 
Medical History 
A complete medical history of the subject including demographics will be taken at Screening 
and an interval medical history (adverse events) will be taken at subsequent clinic visits.  

Study Protocol SCIG03, Version 6, 22 March2017 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
Special attention should be paid to any aspect of the medical history or any clinical/laboratory 
feature that may serve to exclude the subject from participation.   
 
Chronic infections and conditions that may require intermittent or continuous treatment during 
the study and/or could potentially change in frequency or severity during the study such as: 
cough, chronic bronchitis, chronic sinusitis, and arthritis and the type and frequency of 
treatment required should also be assessed and recorded so that symptoms of these conditions 
can be distinguished from treatment emergent adverse events (TEAEs) as the study 
progresses.   
 
Any elective procedures that are planned for pre-existing conditions should be recorded. 
 
Previous immunologic data that document the specific immunologic diagnosis will be 
recorded. 
 
The medical history must include the use of prior IGIV and SCIG treatments received and 
how they were tolerated if available.  The previous use of an IGIV and SCIG product must be 
documented in the subject’s eCRF. 
 
7.7. 
Physical Examination 
Physical examination will be performed by an appropriately qualified member of staff at the 
study site.  The physical examination is also a safety variable. 
 
Elements of the examination should include:   
 
General appearance 
 
Head, eyes, ears, nose, throat 
 
Cardiovascular 
 
Respiratory 
 
Skin 
 
Other body systems examined should be specified in the eCRF.  
 
Height will be measured at screening and weight will be measured at screening and at every 
clinic visit.  
 
Any clinically significant change from baseline in any system will be recorded as an AE 
(Appendix I). 
 
7.8. 
 Monitoring for thromboembolic events (TEE) 
Monitoring for thromboembolic events (TEE) will be performed at screening (baseline) and at 
the Week 27 follow up visit (as well as when clinically indicated); this will include 
assessment of lower extremities for pain, swelling, tenderness or redness, also a respiratory 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
examination for any sudden onset of shortness of breath and any associated signs or 
symptoms of pulmonary embolus.   
 
Assessment is particularly important in patients at high risk of TEE including prolonged 
immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of 
estrogens, indwelling central vascular catheters, hyperviscosity and cardiovascular risk 
factors. 
 
Subjects will be educated about the risk of TEE events and the signs and symptoms that they 
should look out for.  This information will be included in the written instructions for home 
infusions. Subjects will be instructed to contact the site immediately should they experience 
any symptoms of concern. 
 
Any clinically significant change from baseline in any system will be recorded as an AE (see 
Appendix I). 
 
7.9. 
Concomitant Medication 
All concomitant prescription and non-prescription medications received by the subject should 
be documented in the source notes, eCRF and study diary (when away from the site). 
 
The following concomitant medications are excluded during the study: 
• 
Steroids (long term daily, ≥ 0.15 mg of prednisone equivalent/kg/day). Requirement 
for short or intermittent courses of steroids would not exclude a subject. 
• 
Immunosuppressive drugs. 
• 
Immunomodulatory drugs. 
• 
Vaccination with live attenuated virus vaccines during the trial (ie. until final follow 
up visit).   
 
7.10. 
Chest X-Ray 
A baseline chest X-ray (posterior-anterior and lateral) will be obtained on all subjects unless a 
chest X-ray taken within the previous 12 months is available to be used as a baseline. 
 
7.11. 
Vital Signs 
Vital signs assessed by qualified personnel will be entered on the eCRF.  The vital signs to be 
observed will be: 
 diastolic blood pressure (mmHg) 
 systolic blood pressure (mmHg)  
 pulse rate (beats/min)  
 respiration rate (breaths/min) 
 temperature (°C)   
 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
The subject must be in the same position each time vital signs are obtained.  Temperature 
must be recorded using the same method every time e.g. orally, under the arm or via another 
common method.   
 
Any clinically significant changes in vital signs will be reported as AEs as described in 
Section 10.2.   
 
Clinically significant hypotension and/or anaphylactic reactions (significant hypotension with 
generalized hives/angioedema or bronchospasm) warrant discontinuation of the infusion and 
administration of appropriate supportive care as deemed necessary by the investigator (this 
may include: epinephrine, antihistamine, corticosteroids, supplemental oxygen, expansion of 
the plasma volume as necessary, etc.).  These occurrences must be recorded on the eCRF as 
AEs.  At the discretion of the investigator, the subject may be withdrawn from the study, but 
will complete the follow-up visits.   
 
If a subject has been assessed as being dehydrated and is given intravenous fluids before 
beginning the subcutaneous study infusion, the baseline vital signs will be taken after the re-
hydration fluids have been given but before infusion of investigational product. 
 
Vital signs will be recorded once during the screening and follow up visits. 
 
Vital signs will be recorded during site visits at the following times:  
 
10 minutes before the start of each Subgam-VF infusion (+/- 5 minutes) 
 
30 minutes after stopping the Subgam-VF infusion (+/- 15 minutes)   
Vital signs are also an important safety variable. 
 
If any AE of moderate or severe intensity occurs, the rate of the infusion at which this AE 
occurred will be recorded, and the infusion rate will be reduced appropriately, depending upon 
the severity of the AE symptoms.  The infusion may then be resumed at a rate tolerated by the 
subject.  Also see the most current Subgam-VF Investigator Brochure (IB) for a list of 
common product-related AEs6. 
 
Before listing changes in vital signs as AEs, each change should be assessed for clinical 
relevance. 
 
7.12. 
IgG - Blood Levels of the Previous IgG Preparation 
As screening is likely to be performed during the same visit where the subject will receive 
their regularly scheduled infusion of a licensed  (or investigational stage III, IIIb) IGIV or 
SCIG), the sample to determine trough IgG levels must be drawn before the infusion is 
started.  Trough IgG levels must be documented to demonstrate that the subject is in a steady 
state.  The minimum target trough level of IgG is 600 mg/dL.  In addition, the dose, treatment 
interval, method of administration (IV/SC) and trade name or investigational reference of their 
current preparation must be recorded. 

Study Protocol SCIG03, Version 6, 22 March2017 
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CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
 
Samples will also be collected as per the Schedule of Assessments (Appendix IV, Table 2), 
and should always be taken before administration of the product.   
 
7.13. 
IgG Subclasses-Blood Levels of the Previous IgG Preparation 
Samples will also be collected as per the Schedule of Assessments (Appendix IV, Table 2) to 
determine the survival of the IgG subclasses during treatment with Subgam-VF. Samples 
should always be taken before administration of the product.   
 
7.14. 
Specific Antibody Function 
A sample will be taken prior to certain infusions (see Appendix IV, Table 2) to test for 
antibodies against the following antigens: 
 Haemophilus influenzae B (screening and follow up [Week27]) 
 Streptococcus pneumoniae (screening and follow up [Week27]) 
 Measles (follow up [Week27])  
 
7.15. 
IgA and IgM Levels 
If levels of IgA and IgM in serum measured within the previous 12 months are not available, 
blood samples for IgA and IgM levels will be obtained.  Samples should be taken at screening 
only. 
 
7.16. 
Routine Pre-medications 
Routine premedication to reduce potential adverse effects associated with the SCIG infusion 
are discouraged. Exceptions: 
 Premedication will be permitted if a subject has reported systemic adverse events on 
two Subgam-VF infusions. 
 If required, local anesthesia (for example Emla cream) is also allowed before any 
infusion to reduce the pain associated with needle insertion.  
 
The routine long-term use of corticosteroids is not allowed.  Oral and parenteral steroids are 
allowed if the average daily dose is < 0.15 mg prednisone equivalent/kg/day.  Short or 
intermittent courses of > 0.15 mg/kg/day are allowed if required. 
 
If a subject who previously required premedication before infusion with a licensed or 
experimental (Phase III or IIIb) IgG product is enrolled, their previous use of premedication, 
as well as associated side-effects must be recorded on the eCRF.  
 
 

Study Protocol SCIG03, Version 6, 22 March2017 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
7.17. 
Data Recording 
All data from the study collected at site will be entered into the eCRF.  Subjects will record 
the data listed in 7.18 directly into the study diary, which will be reviewed by the study site at 
each visit.  All key data must be entered into the subjects’ medical record before they are 
entered into the eCRF (also see Appendix II, section 12.4).  Subject diary data will not be 
transcribed but will be used as source data for home infusions, adverse events and 
concomitant medication. 
 
7.18. 
Subject Study Diary  
The subject or parent/guardian will complete a study diary daily between visits, starting after 
the Screening Visit.  The data from the study diary will be reviewed at each site visit by  
qualified site personnel.  The data to be recorded in the study diary are as follows: 
 
AEs (including time [24 hour clock] and date of onset/stop date and any AEs 
following infusion site inspection).   
 
Concomitant medication, especially antibiotics 
 
Subgam-VF infusion details including:  
o Batch number 
o Date of infusion 
o Start and stop times of the infusion 
o Volume of Subgam-VF infused and number of vials used  
o Infusion rate 
o Infusion sites used and any associated infusion site reactions.  
For children and adolescents the parent/legal guardian is required to oversee that the diary is 
completed accurately and legibly.  
 
The study staff will review the data from the subject study diary at each visit, to ensure the diary 
is completed correctly. If there is any discrepancies or missing data this will be discussed with the 
subject and then if required corrected by the subject. These discussions will be documented in the 
subject’s medical notes. 
 
7.19. Subject Withdrawal  
If more than five subjects withdraw prematurely from the study then a sufficient number of 
subjects will be replaced to ensure data for 30 evaluable subjects.  
 
Subjects can be withdrawn from the study for any of the following reasons: 
 
The subject or parent/legal guardian withdraws consent for the study. 

Study Protocol SCIG03, Version 6, 22 March2017 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
 
The subject or parent/legal guardian is uncooperative and non-compliant (defined as 
the subject missing two consecutive or three overall study visits) with respect to 
provisions of the protocol.  
 
The subject misses two scheduled infusions 
 
The subject has a serious AE (SAE) while participating in the study and, at the 
discretion of the site investigator, is withdrawn. 
 
The subject becomes pregnant while participating in the study (the pregnancy will 
not be recorded as an SAE, but will be captured on a Pregnancy Report Form and 
followed through until delivery or elective/spontaneous termination). 
 
The subject requires treatment with any of the medications listed in the exclusion 
criteria. 
Investigators may withdraw subjects at any time if they feel it is not in the subject’s best 
interests to continue.  Reasonable efforts will be made to contact the parent/legal guardian and 
subject.  If the subject is lost to follow-up, this will be documented in the subject’s medical 
records.  
In exceptional circumstances relating to safety, the sponsor may withdraw subjects at any 
time. 
Data and samples collected up until a subject’s withdrawal from the study will be used in the 
analysis.  Subjects who have completed the study and subjects who have withdrawn cannot 
participate in the study for a second time. 
 
7.19.1. 
Evaluations at Early Withdrawal 
If a subject withdraws from the study or is dropped from the study for any reason, all tests 
identified for the end of study follow-up visit will be performed.  If subjects have stopped 
Subgam-VF treatment and started another product, this will be taken into consideration in the 
analysis of the data.  
 
7.20. 
Study Termination 
Conditions for early termination are detailed in Appendix II, section 8. 
 
8. 
DESCRIPTION OF TREATMENT ADMINISTERED 
8.1. 
Investigational Product 
8.1.1. 
Identification and Batch Numbers 
It is planned to use one batch of Subgam-VF in this study.  Additional batches may be used if 
required.  The batch number(s) of Subgam-VF will be documented in the Certificate of 
Analysis that will be filed in the Trial Master File.  The actual batch number will be 

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CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
documented in the eCRF for each infusion.  A list of all batches used and the subjects who 
received them will be included in the final study report.   
8.1.2. 
Packaging and Labeling 
Subgam-VF will be manufactured, packed, and labeled by BPL.  The product will be supplied 
in glass vials (10 mL per vials containing 1600 mg of IgG = 16%) and each vial will be 
packed in a carton.  The vials and the cartons will be labelled with identifying and contact 
information for BPL.  The label will also include the identity, total quantity and volume, 
concentration, batch number, expiry date, and storage requirements of the product.  
 
8.1.3. 
Conditions for Storage and Use 
Subgam-VF should be stored in a refrigerator in a safe area of limited access or a Pharmacy.  
The product must be protected from light and maintained at a temperature of 36°F to 46°F 
(2°C to 8°C).  Product that has been stored out of a fridge for one period of up to one week at 
temperatures up to 77°F (25°C) may be returned to the fridge with no change to the expiry 
date. Subgam-VF must not be frozen (inadvertently or on purpose).  A log of daily 
temperatures in the Pharmacy storage area must be maintained to demonstrate that the product 
has been stored under the specified conditions. 
 
Once fully trained, subjects will be issued with Subgam-VF for home use.  The study staff 
will ensure that all subjects and parents/guardians are familiar with the correct storage 
conditions and provided with written storage instructions before any product is dispensed. 
 
8.2. 
Investigational Treatment 
8.2.1. 
Dosing Schedule and Rationale 
Subgam-VF is a 16% subcutaneous IgG product. The weekly dose of Subgam-VF 
administered will be calculated by taking the weekly equivalent of the subject’s stable IGIV 
dose, multiplied by 1.37, a dose adjustment coefficient based on other licensed subcutaneous 
IgG products.  If the subject was already receiving a weekly SCIG IgG there will be no dose 
adjustment. The Subgam-VF dose should remain the same throughout the study, if a subject’s 
weight changes by >5% compared with baseline (screening) or the previous visit, the dose 
should be adjusted accordingly with the aim of maintaining a stable dose in terms of mg/kg.   
If the dosage needs to be increased to achieve the required trough IgG level, then this should 
first be discussed with the CRO Medical Monitor, who will, if needed, discuss with the 
Sponsor. 
 
8.2.2. 
Product Preparation 
Before use, all vials must be inspected visually for discoloration, particles and fibers; if the 
contents of a vial is cloudy or contain particulate material, the vial must not be used.  
Subgam-VF is to be infused at room temperature (vial not cold when touched). 
 

Study Protocol SCIG03, Version 6, 22 March2017 
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CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
8.2.3. 
Method of Administration 
Subgam-VF should only be infused subcutaneously using an infusion pump.  Subgam-VF can 
be infused into the following sites: abdomen, thigh, upper arm and/or lateral hip. 
 
The dose of Subgam-VF can be given into multiple infusion sites (although this should be no 
more than six sites, and eight sites for subjects ≥100 kg).  If more sites are needed to achieve a 
full dose, then the sites can be used consecutively, but the infusions should be at least two 
inches apart.   
 
Only one batch of Subgam-VF should be infused during any one infusion session.  
 
Subgam-VF infusions will be administered in accordance with the table below, the maximum 
volumes and flow rates may be reduced according to tolerability. 
 
Table 1 – Recommended infusion flow rates for Subgam-VF  
 
 
Volume
Rate
First infusion 
20 mL/site
20 mL/hr/site 
Maximum at 
subsequent infusions 
Up to 30 mL/site 
Up to 30 mL/hr/site 
 
 Up to six infusion sites can be used simultaneously. Subjects weighing ≥100 kg may 
use up to eight sites if necessary. If more sites are required, these must be used 
consecutively (during the same infusion).  
 Any increase in flow rate or number of sites should first be tried whilst the subject is in 
the clinic.  However, the infusions must be administered at the volume and rate 
outlined in Table 1 throughout the entire infusion.  Titration during the infusion is 
not allowed. 
  
 For young children or adults of below average weight lower flow rates may be used, 
depending on tolerability.  
Details on how to prepare and administer the Subgam-VF infusion can be found in the Patient 
Medication Guide.  
Full training must be provided to the subject prior to self-administration at home or other 
appropriate setting. It is aimed to start home-therapy at Week 3, however if the subject 
requires further training this will be provided (i.e. it is not mandatory that the infusions are 
performed at home from Week 3).   
 
Lack of tolerance at any given rate must be recorded as an AE at that rate.  If a subject has had 
the same treatment related AE at the same rate twice, and those AEs have been recorded, then 
subsequent infusion rate should be halted at the previously highest tolerated rate.  

Study Protocol SCIG03, Version 6, 22 March2017 
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CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
 
If any AE(s) occur, these will be documented as detailed in section 10.3.  The infusion may 
then be resumed at a rate tolerated by the subject. 
 
8.2.4. 
Product Accountability 
The Investigator is responsible for the accountability of all used and unused product utilized 
in the study.  Product accountability must be maintained as detailed in the Pharmacy Manual. 
 
An IP accountability log for Subgam-VF must be kept current by the site.  
 
The Pharmacy Manual will contain further information on IP accountability during the study, 
including disposal.  
 
Subgam-VF must not be used outside of this protocol and must not be used for subjects who 
are not in this study. 
 
8.3. 
Treatment Compliance 
Subgam-VF will be administered subcutaneously both at the study site and also by 
self-administration at home.  Subjects will be required to keep diaries and records of Subgam-
VF usage.  Site staff will check at each study site visit that the product is being stored 
appropriately, administered correctly and safely and the correct volume infused. 
 
9. 
ASSESSMENT OF EFFICACY  
9.1. 
Primary Efficacy Variables 
As this is a pharmacokinetic and safety study, no formal efficacy analyses are planned. 
10. 
ASSESSMENT OF SAFETY AND TOLERABILITY 
10.1. 
Safety Variables 
Safety endpoints include assessment of adverse events and adverse drug reactions, significant 
changes in vital signs, safety laboratory parameters (including kidney and liver function and 
Direct Coombs’ test), virology, physical examination or medical history during the study. 

Study Protocol SCIG03, Version 6, 22 March2017 
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CONFIDENTIAL 
 
Page 38 of 87 
This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
 
The variables used to assess safety will be the following: 
 
Adverse Events 
 
The number and percent of adverse events (AEs) including infusion site 
reactions. 
 The number and percent of infusions associated with one or more AEs that begin 
during the infusion, up to one hour, 24 hours, 48 hours or within 72 hours after 
completion of the infusion.  
 An adverse reaction will be defined as any TEAE (irrespective of causality) that 
occurs during the infusion or within 72 hours after completion of the infusion, any 
AE classed as product related or any AE with unknown causality. 
 Thrombotic events  
 Nature, severity, and frequency of AEs (tolerability) 
 Suspected unexpected serious adverse reactions (SUSARs), if any 
 
Vital signs 
 
Clinical laboratory tests including tests for hemolysis 
 
Transmission of viruses 
 
Physical examination 
 
10.2. 
Adverse Events 
 The definitions and procedures for reporting AEs is detailed in Appendix I.    AEs will 
be documented from the date the Informed Consent Form or Assent Form is signed 
until the follow-up visit and then monitored up to 28 days after the last dose of 
Subgam-VF is infused.  AEs will be reviewed and documented by collecting the 
diaries at each visit and by direct observation during each infusion. In addition there 
will be a telephone follow up by an appropriately qualified site staff member on day 3 
after each site administered and home administered infusion to check for any adverse 
reactions including infusion site reactions and remind subjects to document these in 
their subject study diary.  The date of infusion is considered to be Day 0. If Day 3 is to 
fall on a weekend or public holiday then this telephone follow up call should be 
performed on the closest working day after Day 3 as possible. 
 
The investigator will attempt to establish a diagnosis of the AE based on signs, symptoms, 
and/or other clinical information.  It is the diagnosis that should be documented as the AE and 
not the individual symptoms. 
 
An adverse reaction will be defined as any TEAE (irrespective of causality) that occurs during 
the infusion or within 72 hours after completion of the infusion, any AE classed as product 

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CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
related or any AE with unknown causality..  Also see the most current Subgam-VF 
Investigator’s Brochure listing common product-related AEs6. 
 
10.3. 
Infusion Site Reactions 
Infusion site reactions will be assessed during the study site infusion visits by the investigator 
or delegated study staff, but also rated by the subjects during home infusions and recorded in 
the subject diaries.   
 
Subjects will inspect infusion sites and record any infusion site reactions (including date and 
time) into their study diary.  Subjects will use the following criteria to grade all infusion site 
reactions in their study diary: 
 
Mild: no limitation to normal activities 
Moderate: some limitation to normal activities 
Severe: inability to carry out normal activity. 
All Infusion site reactions will be recorded in the eCRF. However the Investigator will 
determine if these should be recorded as AEs. Infusion site reactions will be recorded as AEs 
when the symptoms/signs lead to infusion stop, require concomitant medication, or have an 
impact on the general condition of the subject as judged by the Investigator. The Investigator 
will also use their judgment to record the severity of the AE and may use the subjects diary 
grading to aid that decision. 
11. 
ASSESSMENT OF PHARMACOKINETICS 
11.1. 
Pharmacokinetics of Subgam-VF for Total IgG Levels 
All subjects will undergo a PK assessment (see Appendix IV, Table 2 and 3 for the sampling 
time points). 
  
Where possible, samples from Steady State Day 1 (24 hours after the infusion at Week 21 or 
if delayed, up to Week 25) onwards may be collected at the subject’s home by an 
appropriately qualified member of the study team.  Alternatively a Home Health Agency may 
be utilized to take the PK samples outside of the investigational site. The subject would be 
required to sign an IRB/EC approved consent form to permit the site to share the subject’s 
details with the agency in order for them to collect the sample. 
 
The following PK variables for total IgG levels will be determined for the PK population: 
 AUC(0- )  - area under the plasma concentration-time curve of the dosing interval.   
 sAUC(0-) - area under the plasma concentration-time curve of the dosing interval 
standardized to one week. This will be calculated for the historical data only. 

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CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
 Cmax – maximum concentration in plasma.  
 tmax – time to reach the maximum concentration in plasma.  
 CL– systemic clearance.  
The timing of the collection of blood samples for PK should be as per Table 2.  The 
scheduling has been selected to ensure achievement of steady state of Subgam-VF.   
 
A variation of <10% is allowed in the timing for samples as follows: 
Steady State Day 1 (24 hours) ± 2 hours,  
Steady State Day 2 (48 hours) ± 4 hours  
Steady State Day 3 (72 hours) ± 6 hours 
Steady State Day 5 (120 hours) ± 8 hours  
Steady State Day 7 (168 hours) ± 12 hours.   
 
All PK parameters will be calculated based on absolute (uncorrected) and baseline-adjusted 
(i.e. trough-adjusted at steady state) concentrations.  
 
Details of the PK methods will be outlined in a PK Analysis Plan.  The PK Analysis Plan will 
be finalized before database lock. 
 
11.2. 
Other Pharmacokinetic Parameters 
The following PK parameters will be listed and summarized descriptively for the ITT 
population: 
 
 Trough serum IgG levels (measured before every infusion administered at the study 
site). 
 Trough levels of serum IgG subclasses will be measured prior to certain infusions. 
 Levels of specific antibodies (Haemophilus influenzae B, Streptococcus pneumoniae, 
Measles) will be measured prior to certain infusions.  The measles assay is for research 
purposes only and will not be reported to the investigational site. 
 
12. 
INTERIM ANALYSIS 
There is no planned interim analysis for this study, however after sufficient adult PK data has 
been collected, a review of the blood sampling schedules for children will be performed and 
the PK sampling will be optimized and reduced if possible. 
 
13. 
STATISTICAL METHODS  
Details of the statistical methods will be outlined in the Statistical Analysis Plan.  The 
Statistical Analysis Plan will be finalized before database lock. 
 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
13.1. 
Sample Size Determination 
This study will enroll up to 50 subjects to ensure 30 evaluable subjects.  A sample size of 
approximately 18 adults (aged 16-75 years) and 12 children (aged between or equal to 2 and 
15 years), has been decided as recommended by the FDA guidance for IGIV products2.  For 
this study, the children will be enrolled across the age groups of 2 to 5 years, 6 to 11 years, 
and 12 to 15 years with a minimum of four in each age group. All children who receive at 
least one infusion of Subgam-VF will be included in the safety analysis. Due to the potential 
for early withdrawals, PK data may not be available on all 12 children and there may be less 
than 12 evaluable children in the PK analysis. The total number of subjects (adults plus 
children) evaluable for PK analysis will be at least 30.  
 
 Data will be compared to historical data from previous Gammaplex IGIV studies.  All the 
subjects will undergo a PK assessment.   
 
Assuming no true difference exists in average exposure compared with the historical data, 30 
evaluable subjects will give greater than 98% power of concluding equivalence assuming a 
between-subject coefficient of variation (CV) of 18.2 % (equivalently, a standard deviation of 
logged data of 0.181).  If there is a true difference of 10%, power drops to 86%. 
 
13.2. 
Analysis Population 
13.2.1. 
Intent-to-treat (ITT) Population 
All subjects who receive at least one infusion of Subgam-VF will be included in the intent-to-
treat (ITT) population.  The ITT population will be used for all safety analyses, summaries of 
demography and the following PK parameters: trough serum IgG levels, IgG subclasses and 
specific antibodies.  
13.2.2. 
PK population 
The PK population will comprise of subjects in the Subgam PK population and subjects in the 
Gammaplex PK population as described below.   
13.2.2.1. Subgam PK population 
All subjects in the ITT population who have a pre-dose sample at steady state and at least four 
post-dose samples at steady state, one of them should be the Steady State Day 7 PK sample.  
In the case of a subject who provides IgG levels at the PK assessment but does not meet the 
criteria for inclusion in the Subgam PK population, data will be listed only. 
 
13.2.2.2. Gammaplex PK population 
All subjects from Gammaplex 5% IGIV PID studies (GMX01 and GMX04) who had an 
evaluable AUC0-τ.   
 
 

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CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
13.2.2.3. PK Dose-Adjustment population 
The PK Dose-Adjustment population is the subset of the PK population which excludes 
subjects in the Subgam PK population who had prior treatment with another subcutaneous 
weekly IgG product. Thus the PK Dose-Adjustment population includes all the Gammaplex 
PK population and those in the Subgam PK population who had previous treatment with 
IGIV. This population is analysed to estimate a refined dose adjustment factor. 
 
13.3. 
Efficacy Analyses 
As this is a pharmacokinetic and safety study, no formal efficacy analyses are planned. 
 
13.4. 
Safety Analysis 
13.4.1. 
Adverse Events 
Summaries of AEs will be based on treatment-emergent AEs (TEAEs), defined as those 
events with onset date between the first infusion date and 28 days after the last infusion.  
 
The number and percent of infusions associated with one or more AEs (irrespective of 
causality) that occur during the infusion or within 72 hours after completion of the infusion 
will be calculated.  A 1-sided 95% upper confidence bound for this percent will be derived.  If 
the upper bound is less than 40%, excluding local infusion site reactions, the incidence of 
infusion-related AEs associated with Subgam-VF will be considered acceptable.  In addition, 
the number and percent of subjects who report any AEs and the number and percent of 
subjects who report any AEs at least possibly related to Subgam-VF will be calculated, and 
the upper bound of the 95% confidence interval for the percentages will be presented.  AEs 
occurring during the infusion and within 1, 24, 48 and 72 hours after the infusion completion 
will also be summarized.   
 
An adverse reaction will be defined as any AE occurring during the infusion and within 72 
hours after the infusion completion OR any AE classed as product-related or with unknown 
causality. 
 
AEs that occur during an infusion will be summarized by the infusion rate at which the AEs 
are reported.  If necessary, infusion rates will be grouped into different levels. 
 
SAEs and SUSARs will be summarized with all AEs, and separate listings will be provided 
for SAEs and SUSARs. 
 
All other safety assessments will be summarized descriptively for each treatment group. 
 
Further summaries of AEs will be detailed in the Statistical Analysis Plan. 
 

Study Protocol SCIG03, Version 6, 22 March2017 
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CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
13.4.2. 
Other Safety Analyses 
All other safety assessments will be summarized descriptively. 
 
13.5. 
IgG subclasses and IgG antibodies 
The trough levels of IgG subclasses and IgG antibodies against specified antigens will be 
summarized descriptively for all the Intent-to-Treat (ITT) subjects.  This analysis will be 
conducted for subjects 2 to 5 years of age, 6 to 11 years of age, 12 to 15 years of age, all 
pediatric subjects (2 to 15 years of age), all adult subjects (aged 16 years and over), then for 
all subjects. 
   
13.6. 
Pharmacokinetic Analyses 
The pharmacokinetics of Subgam-VF will be based on absolute and baseline-adjusted (trough 
adjusted at steady state) values and will be described using a non-compartmental method.  
Actual sample times rather than nominal times will be used to calculate pharmacokinetic 
parameters.   
 
The following PK parameters will be calculated for the Subgam PK population: The 
maximum observed concentration (Cmax), the time at which Cmax was apparent (tmax), the area 
under the concentration versus time curve within a dosing interval (AUC0-τ) and the systemic 
clearance (CL). 
 
Pharmacokinetic variables will be summarized descriptively.  This analysis will be conducted 
for subjects 2 to 5 years of age, 6 to 11 years of age, 12 to 15 years of age, all pediatric 
subjects (2 to 15 years of age), all adult subjects (aged 16 years and over), then for all 
subjects. 
 
For the Gammaplex PK population, sAUC0-τ will be calculated as the area under the 
concentration versus time curve within a dosing interval (21 or 28 days), standardized to one 
week i.e. AUC0- (21 day)/3 or AUC0- (28 day)/4. For the Subgam PK population, sAUC0- is 
equivalent to AUC0- (i.e. no standardization required as dosing is weekly). 
 
All PK data collected on all subjects in the Subgam PK population will be listed.  The PK 
population i.e. Subgam PK population combined with the Gammaplex PK population 
(historical data following administration of Gammaplex 5% IGIV) will be used for the 
primary and secondary statistical PK analyses.  
 
The trough levels of total IgG will be summarized descriptively for all the subjects in the ITT 
population.  Trough levels in the ITT population will be compared with those from the 
Gammaplex PK population.   
 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
13.6.1. 
Primary Statistical Analysis 
Data will be pooled with historical data and a treatment variable defined (Subgam-VF or 
Gammaplex IGIV).  Log transformed sAUC(0-),  (AUC(0-) standardized to one week) will be 
analyzed using a mixed model fitted including treatment, and allowing for variability to be 
different between treatment groups.  The mean difference (Subgam-VF or Gammaplex IGIV) 
between treatments with 90% Confidence Interval (CI) will be back transformed to give an 
estimate of the ratio (Subgam-VF/ Gammaplex IGIV) of sAUC(0-).  If the resulting 90% CI 
for the ratio lies within the equivalence limit of (0.80, 1.25), it will be concluded that there is 
equivalence in sAUC(0-)  and thus the dosing factor of 1.37 for Subgam-VF (in addition to the 
adjustment for dosing interval) gives equivalent exposure at steady state to  Gammaplex 
IGIV.    
13.6.2. 
Secondary Statistical Analyses 
i. 
The primary analysis method will be repeated with data derived from baseline-
adjusted concentrations. 
ii. 
A term for dosing interval within treatment will be included in the model described 
in the primary analysis so that ratios with 90% CI can be presented for Subgam-VF 
relative to both the 21 day and 28 day dosing interval regimens of Gammaplex. 
iii. 
The primary analysis model will be extended to include any significant (at the 10% 
level) covariates or covariate by treatment interactions.  Covariates considered for 
inclusion will include age category, weight, BMI and sex. 
iv. 
The effect of previous treatment (SCIG or IGIV) on AUC(0-) in the Subgam PK 
population will be analysed. If the resulting 90% CI for the ratio lies within the 
equivalence limit of (0.80, 1.25), it will be concluded that the previous treatment 
does not affect exposure at steady state. If this is the case then the refined dose 
adjustment with 90% CI will be presented on the full PK population (in addition to 
on the PK Dose Adjustment population described below).  
v. 
In addition, the data from the current study will be restricted to a PK Dose 
Adjustment population and analysed as per the primary analysis.  A refined dose 
adjustment will be estimated as 1.37/the ratio (Subgam-VF / Gammaplex IGIV) of 
geometric means for sAUC(0-) and presented with 90% CI. 
13.6.3. 
Exploratory Analysis 
PK modelling will be performed to explore alternative dosing schedules. For example; PK 
modelling and simulation will be carried out to compare weekly administration to a biweekly 
schedule at double the weekly dose and assess IgG exposure. 
 
Full details of the PK and associated statistical methods will be described in a PK Analysis 
Plan. 
 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
14. 
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.  In case of particular issues or governmental queries, it is 
also necessary to have access to the complete study records, provided that the subject's 
confidentiality is protected in accordance with applicable regulations. 

Study Protocol SCIG03, Version 6, 22 March2017 
Bio Products Laboratory Ltd. 
CONFIDENTIAL 
 
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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall 
be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to 
any person not involved in the study. 
 
15. 
INVESTIGATOR AGREEMENT 
 
 
A Phase III, Multicenter, Open-Label Study to Evaluate 
the Pharmacokinetics and Safety 
of Subgam-VF in Primary Immunodeficiency Diseases  
(Protocol Number SCIG03) 
 
I have been adequately informed about the development of the investigational product to date 
and agree that this study protocol contains all the information required to conduct the study. 
 
I will provide copies of the study protocol and all product information relating to prior product 
experience furnished to me by the Sponsor/CRO to all staff responsible to me who participate 
in this study.  I will discuss this material with them to ensure that they are fully informed 
regarding the product and the conduct of the study. 
 
The information contained in this document is CONFIDENTIAL and, except to the extent 
necessary to obtain informed consent, may not be disclosed, unless such disclosure is required 
by government regulation or applicable laws.  Persons to whom the information is disclosed 
must be informed that the information is CONFIDENTIAL and cannot be disclosed by them. 
 
By my signature below I agree to conduct this clinical trial in accordance with the protocol, 
ICH Good Clinical Practice, the Declaration of Helsinki and relevant/applicable national drug 
laws regulations. 
 
 
I agree to ensure the confidentiality of the subjects enrolled under my care; however, I agree 
to make their medical records available to authorized representatives of the CRO; authorized 
representatives of Bio Products Laboratory Ltd., the Sponsor of this clinical trial; and relevant 
regulatory authorities.  
 
I have read the Investigator’s Brochure (IB) and protocol, and I am aware of my 
responsibilities as Investigator as stated on FDA Form 1572. 
 
Site Investigator: 
 
Investigator name: 
 
Site Name:
 
 
 
 
Signature: 
 
Date:
 

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reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 
16. 
REFERENCES 
1. The Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood 
Pressure in Children and Adolescents. Pediatrics 2004 Aug;114 (Suppl 2:) 555-
76. 
 
2. FDA guidance, Safety, Efficacy, and Pharmacokinetic Studies to Support 
Marketing of Immune Globulin Intravenous (Human) as Replacement Therapy for 
Primary Humoral Immunodeficiency (Jun 2008).  
 
3. Liese JG, Wintergerst U, Tympner KD, Belohradsky BH.  High-vs. low-dose 
immunoglobulin 
therapy 
in 
the 
long-term 
treatment 
of 
X-linked 
agammaglobulinemia.  Am J Dis Child 1992; 146(3): 335-339. 
 
4. Roifman CM, Lederman, HM, Lavi S, Stein LD, Levison H, Gelfand EW. 
Benefit of intravenous IgG replacement in hypogammaglobulinemic patients 
with chronic sinopulmonary disease.  Am J Med 1985; 79(2): 171-174. 
 
5. Cunningham-Rundles C, Siegal FP, Smithwick EM, Lion-Boule A, 
Cunningham-Rundles S, O’Mally J, et al.  Efficacy of intravenous 
immunoglobulin in primary humoral immunodeficiency disease.  Ann Intern 
Med 1984; 101(4): 435-439. 
 
6. Current version of the Subgam-VF Investigator’s Brochure (IB) for primary 
immunodeficiency disease. 
 
7. Jolles S, Bernatowska E, de Gracia J, Borte M, Cristea V, Peter H, Belohradsky 
B, Wahn V, Neufang-Huber J, Zanket O, Grimbacher B. Efficacy and safety of 
Hizentra® in patients with primary immunodeficiency after a dose-equivalent 
switch from intravenous or subcutaneous replacement therapy. Clin Immunol 
2011; 141:90-102. 
 
8. Berger, M. Subcutaneous administration of IgG in immunoglobulin 
replacement therapy for primary immunodeficiency. Immunol Allergy Clin 
North Am 2008; 28: 779-802 viii. 
 
9. Gardulf A Nicolay U, Asensio O, Bernatowska E, Bock A, Costa-carvalho B, 
Granert C, Haag S, Hernandez D, Kiessling P, Kus J, Pons J, Niehues T, 
Schmidt S, Schulze I, Borte M. Rapid subcutaneous IgG replacement therapy is 
effective and safe in children and adults with primary immunodeficiencies-a 
prospective, multi-national study. J Clin Immunol 2006;26:177-185. 
 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
10. Ochs HD, Gupta S, Kiessling P, Nicolay U, Berger M. Safety and efficacy of 
self-administered subcutaneous immunoglobulin in patients with primary 
immunodeficiency diseases. J Clin Immunol 2006; 26(3): 265-273 
 
11. Gardulf A, Bjorvell H., Gusfafton L., Hammarstrom l., Smith C. Safety of rapid 
subcutaneous gammaglobulin infusions in patients with primary antibody 
deficiency. Immunodeficiency 1993; 4:81-84. 
 
12. Gardulf A, Nicolay U, Asensio O, Bernatowska E, Bock A, Costa-carvalho B, 
Granert C, Haag S, Hernandez D, Kiessling P, Kus J, Matamoros N, Niehues T, 
Schmidt S, Schulze I, Borte M.  Children and adults with primary antibody 
deficiencies gain quality of life by subcutaneous IgG self-infusions at home. J 
Allergy Clin Immunol 2004;114:936-942  
 
13. Berger, M. Choices in IgG replacement therapy for primary immune deficiency 
diseases: subcutaneous IgG vs. intravenous IgG and selecting an optimal dose.  
Curr Opin Allergy Clin Immunol 2011; 11: 532-538 
 
14. Bexon M, Rojavin M, Jolles S et al. The construction of pharmacokinetic model 
to describe intravenous and subcutaneous supplementation of IgG in patients 
with primary immunodeficiency. J Allergy Clin Immunol 2011; 127: AB16 
 
15. Bonilla FA. Pharmacokinetics of immunoglobulin administered via intravenous 
or subcutaneous routes. Immunol Allergy Clin N Am 2008; 28: 803-819 
 
16. Wasserman RL, Melamed I, Kobrynski L et al. efficacy, safety and 
pharmacokinetics of 10% liquid immune globulin preparation (GAMMAGARD 
LIQUID, 10%) administered subcutaneously in subjects with primary 
immunodeficiency disease. J Clin Immunol 2011; 31: 323-331 
 
17. Hagan JB, Fasano MB, Spector S et al. Efficacy and safety of a new 10% 
immunoglobulin preparation for subcutaneous administration, IgPro20, in 
patients with primary immunodeficiency. J Clin Immunol 2010; 30: 734-745. 
18. Orange JS, Belohradsky BH, Berger M, Borte M, Hagan J, Jolles S, Wasserman 
RL, Baggish JS, Saunders R, Grimbacher B. Evaluation of correlation between 
dose and clinical outcomes in subcutaneous immunoglobulin replacement 
therapy. Clin Exp Immunol 2012; 169: 172-181. 
 
19. European Medicines Agency. Committee for Medicinal Products for Human 
Use (CHMP). Guideline on the clinical inestigation of human normal 
immunoglobulin for intravenous administration (IVIg). London, 22 July 2010. 
EMA/CHMP/BPWP/94033/2007. 
 
 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
APPENDIX I: ADVERSE EVENT DEFINITIONS AND REPORTING 
 
ABBREVIATIONS 
AE 
Adverse Event
BPL 
Bio Products Laboratory Limited
CRF 
Case Report Form
CRO 
Contract Research Organization
ECG 
Electrocardiogram
eCRF 
Electronic Case Report Form
FDA 
US Food and Drug Administration
ICF 
Informed Consent Form
IEC 
Independent Ethics Committee
IMP/IP 
Investigational Medicinal Product/Investigational Product 
IRB 
Institutional Review Board
SAE 
Serious Adverse Event
SmPC 
Summary of Product Characteristics
SUSAR 
Suspected Unexpected Serious Adverse Reaction
 
1. 
Definitions of Adverse Events 
 
1.1 
Adverse Events 
Definition: Adverse event means any untoward medical occurrence associated with the 
use of a drug in humans, whether or not considered drug related.  
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug, and does not imply any judgment about causality. An 
adverse event can arise with any use of the drug (e.g., off-label use, use in combination 
with another drug) and with any route of administration, formulation, or dose, including 
an overdose. 
 
All AEs, whether or not considered by the Investigator to be related to the IMP (test 
product, comparator or placebo), must be described and recorded on the appropriate 
Adverse Event forms in the case report form (CRF)/electronic case report form (eCRF). 
Where possible, a diagnosis should be made. Anticipated fluctuations of preexisting 
conditions, including the disease under study, that do not represent a clinically significant 
exacerbation or worsening need not be considered AEs. 
Infusion-Related Adverse Events 
All AEs that occur from the start of the infusion until 72 hours from the end of the 
infusion will be recorded as temporally related to the infusion. 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
Clinical Laboratory and Other Adverse Events 
A laboratory result that is considered by the Investigator to be clinically significant or 
have a clinically significant pathological change from baseline should be recorded as an 
AE. 
 
Other abnormal results (e.g. x-rays, scans, physical examination findings) that worsen 
from baseline and/or are considered clinically significant should also be recorded as AEs. 
The Investigator will exercise his or her medical and scientific judgment in deciding 
whether an abnormal laboratory finding or other abnormal assessment is clinically 
significant. 
 
Reporting 
Adverse events should be reported and documented in accordance with the procedures 
outlined in this section. All AEs occurring during the study must be documented on the 
relevant CRF/eCRF pages. The following data should be documented for each AE: 
 
 Description of the symptom event 
 Classification of "serious" or "not serious" 
 Severity 
 Date of first occurrence and date of resolution (if applicable) 
 Action taken 
 Causal relationship 
 Outcome of event (unknown, recovered, not yet recovered, recovered with 
sequelae, death [with date and cause reported]) 
Pregnancy 
Subjects will be instructed that a known or suspected pregnancy occurring during the 
study should be reported to the Investigator. The Investigator should also be notified of a 
pregnancy occurring during the study but confirmed after completion of the study. If a 
subject is found to be pregnant after inclusion in the study, the subject must be withdrawn 
from the study. Any pregnancy will be followed to term and the status of mother and 
child will be reported to the Sponsor after delivery. 
 
Full details of any pregnancy will be recorded on the AE page of the CRF/eCRF, and a 
Pregnancy Report Form will be completed. A copy of the Pregnancy Report Form must 
be faxed to the CRO within 24 hours. 
 
At the end of the study, it is expected that subjects will continue treatment with other 
immunoglobulin products.  Any adverse events which occur after last study visit are more 
likely related to the continued treatment with non-study immunoglobulin products and 
therefore extended use of contraception and follow-up of pregnancies occurring after end 
of study visit are not appropriate in this study.  Subjects of child bearing potential should 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
be advised of the risks of pregnancy in accordance with the relevant product information 
for their ongoing therapy. 
 
1.2  
Suspected Adverse Reaction 
 
Definition: Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event. For the purposes of IND 
safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal 
relationship between the drug and the adverse event. A suspecte d adverse reaction 
implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
 
The following are examples of types of evidence that would suggest a causal relationship 
between the drug and the adverse event to determine Reasonable possibility.  
 
 A single occurrence of an event that is uncommon and known to be strongly 
associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson 
Syndrome)  
 
 One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g. 
tendon rupture)  
 
 An aggregate analysis of specific events observed in a clinical trial (such as 
known consequences of the underlying disease or condition under investigation or 
other events that commonly occur in the study population independent of drug 
therapy) that indicates those events occur more frequently in the drug treatment 
group than in a concurrent or historical control group  
 
Suspected adverse reactions are the subset of all adverse events for which there is a 
reasonable possibility that the drug caused the event. Inherent in this definition, and in the 
requirement to report suspected adverse reactions, is the need for the Sponsor to evaluate the 
available evidence and make a judgment about the likelihood that the drug actually caused 
the adverse event.  
 
1.3 
Adverse Reaction  
Definition: An adverse reaction means any adverse event caused by a drug. Adverse 
reactions are a subset of all suspected adverse reactions where there is re ason to 
conclude that the drug caused the event.  
 
 
1.4 
Serious Adverse Event or Suspected Adverse Reaction 
Definition: An adverse event or suspected adverse reaction is considered “serious” if, 
in the view of either the investigator or Sponsor, it results in any of the following 
outcomes:  

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 Death,  
 A life-threatening adverse event, [See Section 1.5] 
 Inpatient hospitalization or prolongation of existing hospitalization,  
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions,  
 A congenital anomaly/birth defect.  
 Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse. 
 
Hospitalization does not include hospitalizations for elective procedures for pre-existing 
conditions that did not worsen from baseline)  
 
If either the Sponsor or investigator believes that the event is serious, the event must be 
considered serious and evaluated by the Sponsor for expedited reporting. 
 
The following events of special interest will always be regarded as serious:: 
 
 Anaphylaxis or anaphylactoid reaction 
 Myocardial infarction 
 Stroke 
 Pulmonary embolism 
 Any thromboembolic event (TEE) 
 Laboratory documented infection with blood borne virus 
 Acute renal failure 
 Any transmissible spongiform encephalopathy 
 
In general, information that might materially affect the risk-benefit assessment of a 
medicinal product or that would suggest changes in the way it is to be administered or to 
the way a clinical investigation should be conducted should be reported in an expedited 
manner. Examples include the following: 
 
 
Single case reports of an expected adverse reaction with an unexpected outcome 
(e.g. fatal outcome) 
 
For an expected serious adverse reaction, an increase in the rate of occurrence that 
is judged to be clinically important 
 
A significant hazard to the patient population, such as lack of efficacy in treating 
life-threatening diseases or an event which is significant enough to lead to 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
important changes in the way a medicine is developed (e.g. change in dose, 
monitoring, consent forms). 
 
A major new safety finding from a newly completed animal study 
 
An SAE associated with a study procedure that could modify the conduct of the 
trial 
 
1.5.  
Life-Threatening 
Definition: An adverse event or suspected adverse reaction is co nsidered “life-
threatening” if, in the view of either the investigator or Sponsor, its occurrence places 
the patient or subject at immediate risk of death. It does not include an adverse event or 
suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death. 
 
As with the definition of serious, the determination of whether an adverse event is life-
threatening can be based on the opinion of either the investigator or Sponsor. Thus, if either 
believes that it meets the definition of life-threatening, it must be considered life-threatening 
for reporting purposes 
 
1.6 
Unexpected Adverse Event or Suspected Adverse Reaction 
 
Definition: An adverse event or suspected adverse reaction is considered “unexpected” 
if it is not listed in the investigator brochure or is not listed at the specificity or severity 
that has been observed; or, if an Investigator’s Brochure is not required or available, is 
not consistent with the risk information described in the general investigational plan or 
elsewhere in the current application, as amended. For example, under this definition, 
hepatic necrosis would be unexpected (by virtue of greater severity) if the Investigator’s 
Brochure referred only to elevated hepatic enzymes or hepatitis. Similarly, cerebral 
thromboembolism and cerebral vasculitis would be unexpected (by virtue of greater 
specificity) if the Inve stigator’s Brochure listed only cerebral vascular accidents. 
"Unexpected," as used in this defini tion, also refers to adverse events or suspected 
adverse reactions that are mentioned in the Investigator’s Brochure as occurring with 
a class of drugs or as anticipated from the pharmacological properties of the drug, but 
are not specifically mentioned as occurring with the particular drug under 
investigation. 
 
1.7 
Serious and Unexpected Suspected Adverse Reaction (SUSAR)  
The Sponsor must report any suspected adverse reaction to study treatment (i.e. including 
active comparators) that is both serious and unexpected.  The Sponsor needs to ensure 
that the event meets all three of the definitions:  
 
Suspected adverse reaction  
 
Serious  
 
Unexpected 
 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
The Sponsor (or designated Contract Research Organization [CRO]) shall ensure that all 
relevant information about a SUSAR is reported to the Competent Authorities and to the 
independent ethics committees (IECs)/institutional review boards (IRBs) concerned. 
 
2. 
Detecting Adverse Events 
Subjects will be carefully monitored for adverse events that occur after the Informed 
Consent Form (ICF) has been signed until the 28 days after the last infusion of study 
medication. At site visits, the Investigator or delegate will question the subjects about 
AEs using a nonleading question such as “How are you feeling?” The Investigator will 
also record AEs reported spontaneously by the subjects, including AEs recorded in the 
patient diary. Clinically significant changes in the findings of physical examination and 
clinically significant abnormalities in the result of objective tests (e.g. laboratory 
variables, ECG) should be recorded as AEs.  
. 
 
2.1 
Causality (Assessment of Relationship) 
All AEs will be recorded in the CRF/eCRF, whether considered to be related or unrelated 
to the treatment. The record will include the following: a brief description of event 
(preferably a diagnosis), date and time started and stopped, severity, outcome, actions 
taken, and classification of the AE. The Investigator should also evaluate the probability 
of a causal relationship of the AE to the study medication according to the following 
criteria: 
 
 
Unrelated: Clinical event with an incompatible time relationship to IMP 
administration, or that could be explained by underlying disease or other drugs or 
chemicals, or is incontrovertibly not related to the IMP 
 
Unlikely: Clinical event whose time relationship to IMP administration makes a 
causal connection improbable, but that could plausibly be explained by 
underlying disease or other drugs or chemicals 
 
Possible: Clinical event with a reasonable time relationship to IMP 
administration, but that could also be explained by concurrent disease or other 
drugs or chemicals 
 
Probable: Clinical event with a reasonable time relationship to IMP 
administration, and is unlikely to be attributed to concurrent disease or other 
drugs or chemicals 
 
Very likely/certain: Clinical event with plausible time relationship to IMP 
administration and that cannot be explained by concurrent disease or other drugs 
or chemicals 
 
Study medication is defined as those investigational compounds or their controls used in 
a study. 
 
It will be assumed that for all AEs classified as having a “possible”, “probable” or “very 
likely/certain” relationship to the study medication, there is reasonable likelihood that the 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
AE was causally related to the product. All such AEs will be regarded as “causally 
related” to the study medication. 
 
2.2 
Outcome of Adverse Events 
The outcome of the AE should be documented as: 
 
1. Recovered / resolved 
2. Recovering / resolving 
3. Not recovered / not resolved 
4. Recovered / resolved with sequelae 
5. Fatal 
6. Unknown 
 
2.3 
Action Taken 
The action taken by the Investigator or study staff should be documented as: 
 
1. Drug withdrawn 
2. Dose reduced 
3. Dose increased 
4. Dose not changed 
5. Unknown 
6. Not applicable 
 
2.4 
Severity of Adverse Event 
Severity refers to the grading of adverse events to assess the severity of symptoms as 
evaluated by the Investigator or as experienced by the subject. The severity grading is 
independent of seriousness; in other words, a severe event is not necessarily serious. The 
Investigator will make an assessment of severity (e.g. mild, moderate, severe) for each 
AE and SAE reported during the study in accordance with the following definitions: 
 
Mild: A non-serious adverse drug experience that is usually transient and requires no 
special treatment or intervention.  The experience does not generally interfere with usual 
daily activities.  This includes transient laboratory test alterations. 
 
Moderate: A non-serious adverse drug experience that is alleviated with simple 
therapeutic treatments.  The experience impacts usual daily activities.  This includes 
laboratory test alterations indicating injury, but without long-term risk. 
 
Severe: A non-serious adverse drug experience that requires therapeutic intervention.  
The experience interrupts usual daily activities.  If hospitalization is required for 
treatment, it becomes a serious adverse event. 
 
3. 
Adverse Event Follow-up 
All adverse events will be followed: 
 To resolution; or 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 Until an underlying condition has been diagnosed; or 
 Until the patient’s condition has stabilized; or 
 For a period of 28 days following the last administration of the study drug. 
 
Any new or unresolved AEs noted at the last study visit will be followed up for a further 
28 days unless they fulfil the above criteria. 
 
If the subject becomes pregnant while participating in the study, the pregnancy will not 
be recorded as an SAE, but will be captured on the AE page of the CRF/eCRF and in a 
Pregnancy Report Form and followed through until delivery or elective/spontaneous 
termination. Any birth defects will be reported as in the procedures for SAEs (see 
Sections 1 and 4). 
 
4. 
Reporting Serious Adverse Events 
When an AE occurs that fulfils the definition of serious (see Section 1.3), the Investigator 
must: 
 
Complete and sign the Serious Adverse Event Form and send it to the CRO within 
24 hours.The CRO will then inform the Sponsor within 24 hours of receiving the 
SAE notification. 
 
SAE FAX  
 
 
1 866 851 9318 
 
Medical coverage for urgent queries relating to AEs will be provided on a 24-hour/7-day 
a week basis by contacting the safety office at the following number and the call will be 
routed to the Medical Monitor: 
 
Telephone Number   
1 888 619 3216 
 
The Investigator is responsible for expedited reporting of all Serious Adverse Events 
immediately to the CRO.  This reporting requirement covers any SAEs that develop at 
any point between the date when a subject provides Informed Consent and up to 28 days 
after the last administration of the investigational medicinal product. The Investigator is 
also responsible for reporting to the CRO any SAEs with an onset date more than 28 days 
after the last administration of the product if he/she judges the SAE to be possibly, 
probably or very likely/certainly related to the product. 
 
The immediate report should contain the following as a minimum: 
 
1. Suspected investigational medicinal product 
2. Study subject number 
3. Details of the serious adverse event 
4. Classification of SAE 
5. Causality of SAE (if available) 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 
The immediate SAE form should be followed by a detailed, complete SAE form as soon 
as possible. The immediate report and follow-up reports shall identify subjects by unique 
code numbers assigned to the latter. 
 
Adverse events and/or laboratory abnormalities identified in the protocol as critical to the 
evaluation of safety must be reported to the designated CRO by the Investigator 
according to the reporting requirements within the time periods specified in this protocol. 
 
The Investigator must not wait to receive additional information to document fully the 
event before notification of a SAE, though additional information may be requested. 
Where applicable, information from relevant laboratory results, hospital case records and 
autopsy reports should be obtained. 
 
Instances of death, congenital abnormality or an event that is of such clinical concern as 
to influence the overall assessment of safety, if brought to the attention of the Investigator 
at any time after cessation of IMP administration and linked by the Investigator to this 
study should be reported to the designated CRO/Sponsor. 
 
The Sponsor or designated CRO will promptly notify all relevant Investigators and 
regulatory authorities of findings that could adversely affect the safety of patients, affect 
the conduct of the study, or alter the approval/favorable opinion of the study by the 
IEC/IRB. In addition, the Sponsor (or designated CRO) will expedite the reporting of all 
AEs that are serious, unexpected, and, in the opinion of the Investigator, related to the 
IMP to all concerned Investigators, the IEC/IRB, where required, and the regulatory 
authorities. 
 
The Investigator will comply with local requirements related to the reporting of SAEs, 
IND Safety Notification Letters, and other safety information related to the trial to their 
local IRB. 
 
For reported deaths of a subject, the Investigator shall supply BPL or designated CRO and 
the Research Ethics Committee with any additional information requested. 
 
Completing Serious Adverse Event Forms 
Serious Adverse Event (SAE) forms must be completed in a timely manner and contain 
the following information: 
 
 Subject number, sex, age, study center, trial code 
 Description of event (where possible a diagnosis should be made rather than just 
listing symptoms) 
 Study drug, indication for use, batch number, dose, route, date and time of last 
dose 
 Date and time of adverse event 

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shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 All concomitant medication 
 Causal relationship to study medication (as in Section 2.1) 
 Outcome (as in Section 2.2) 
 Action taken and treatment given (as in Section 2.3) 
 Severity (as in Section 2.4) 
 Classification of serious adverse event (as in Section 1.4) 
 
The SAE form must be signed and dated by the person reporting the SAE. The final report 
must be signed and dated by the Principal Investigator from the site. 
 
5. 
Sponsor’s Responsibilities 
The Sponsor and/or the designated CRO  will be responsible for reporting all relevant 
safety information (including a listing of all SUSARs) to the regulatory authorities and to 
the IRBs/IECs concerned. Safety reports will be issued in accordance with local relevant 
procedures (as a minimum on an annual basis). 
 
The Sponsor and/or the designated CRO will inform the relevant Competent 
Authority(ies), in line with regulatory guidelines, of AEs occurring during the trial. The 
Investigator retains the right to inform the relevant Competent Authority(ies) if he/she so 
desires but must inform the Sponsor and/or designated CRO so that duplicate reports to 
the Competent Authority(ies) can be highlighted. 
 
The Sponsor and/or designated CRO will inform all Investigators of all SUSARs 
occurring during the study or findings that could adversely affect the safety of subjects. 
 
6. Summary of Investigator and Sponsor Reporting Responsibilities1 
 
Term  
Investigator 
Responsibility 
Sponsor 
Responsibility 
Final Determination  
Responsibility 
Serious  
(or life-
threatening)  
Yes  
(Investigator must 
report all serious 
adverse events to the 
Sponsor 
immediately) 
Yes  
An event is considered 
serious or life-threatening, 
based on either the 
Investigator’s or Sponsor’s 
opinion.  
Unexpected  
No  
(No requirement to 
assess 
“expectedness”)  
Yes  
The Sponsor is responsible 
for determining whether 
event meets the definition 
of “unexpected,” based on 
whether the event is listed 
in the Investigator’s 
Brochure; or if an 
Investigator’s Brochure is 
not required or available, is 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
not consistent with the risk 
information described 
elsewhere in the general 
investigational plan or 
elsewhere in the current 
application.  
Suspected Adverse 
Reaction – 
(causality 
assessment standard 
- “reasonable 
possibility”)  
Yes  
(Investigator must 
provide Sponsor with 
an assessment of 
causality)  
Yes (Sponsor’s 
assessment 
determines 
reportability, 
regardless of 
Investigator’s 
assessment)  
The Sponsor is responsible 
for determining whether 
there is a reasonable 
possibility that the drug 
caused the adverse event, 
taking into consideration 
the Investigator’s 
assessment  
 
7. 
Reference 
1. Guidance for Industry and Investigators. Safety Reporting Requirements for INDs 
and BA/BE Studies. U.S. Department of Health and Human Services. Food and 
Drug Administration, December 2012. 
 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
APPENDIX II - ADMINISTRATIVE REQUIREMENTS 
 
 
ABBREVIATIONS AND DEFINITIONS 
ARSAC 
- Administration of Radioactive Substances Committee 
BPL 
 
- Bio Products Laboratory Limited (Ltd.) 
CA 
 
- Competent Authority 
CI 
 
- Chief Investigator 
 
COI 
- Coordinating Investigator 
CRA  
- Clinical Research Associate 
CRO  
- Contract Research Organization 
CFR 
 
- Code of Federal regulation 
CV 
 
- Curriculum Vitae 
DQF  
- Data Query Form 
eCRF   
- Electronic Case Record Form 
EU 
 
- European Union 
FDA  
- Food and Drug Administration 
GCP 
 
- Good Clinical Practice 
GMC  
- General Medical Council 
ICH 
 
- International Conference on Harmonisation 
ID 
 
- Identification 
IEC 
 
- Independent Ethics Committee 
IMP/IP 
- Investigational Medicinal Product 
IRB 
 
- Institutional Review Board 
PI 
 
- Principal Investigator 
R&D  
- Research and Development 
SOP 
 
- Standard Operating Procedure 
USA  
- United States of America 
 
CA – ‘Competent Authority’, synonymous with ‘Regulatory Authority’: the 
Government body that has the power to regulate.  In the context of ICH GCP, the 
term ‘Competent Authority’ includes the authorities that review submitted clinical 
data and those that conduct inspections. 
 
CI – ‘Chief Investigator’: in relation to a clinical trial conducted at a single trial 
site, the Investigator for that site.  In relation to a clinical trial conducted at more 
than one trial site, the authorized health care professional, whether or not he/she is 
an Investigator at any particular site, who takes primary responsibility for the 
conduct of the trial. 
 
COI – ‘Coordinating Investigator’: an investigator assigned the responsibility for 
the coordination of investigations at different centers participating in a multicenter 
trial.  
 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
PI - ‘Principal Investigator’: a doctor or person following a profession for 
investigations because of the scientific background and the experience in subject 
care it requires.  The Principal Investigator is responsible for the conduct of the 
trial at the trial site.  If a trial is conducted by a team of individuals at a trial site, 
the Principal Investigator is the leader responsible for the team.   
 
IEC – ‘Independent Ethics Committee’:  a review board or a committee, 
institutional, regional, national or supranational, constituted of medical/scientific 
professionals and non-medical/non-scientific members, whose responsibility it is 
to ensure the protection of the rights, safety and well-being of human subjects 
involved in a clinical trial and to provide public assurance of that protection, by, 
among other things, reviewing and approving / providing favourable opinion on, 
the trial protocol, the suitability of the investigator(s), facilities and the methods 
and material to be used in obtaining and documenting informed consent of the 
trial subjects. 
 
IRB – ‘Institutional Review Board’: an independent body constituted of medical, 
scientific and non-scientific members, whose responsibility is to ensure the 
protection of the rights, safety and well-being of human subjects involved in a 
clinical trial by, among other things, reviewing, approving and providing 
continuing review of the trial protocol and amendments and of the methods and 
material to be used in obtaining and documenting informed consent of the trial 
subjects. 
 
IMP – ‘Investigational Medicinal Product’: a pharmaceutical form of an active 
substance or placebo being tested or used as a reference in a clinical trial, 
including products already with a marketing authorization but used or assembled 
in a way different from the authorized form, or when used for an unauthorized 
indication, or when used to gain further information about the authorized form. 
 
1. ETHICAL CONSIDERATIONS 
The study will be performed in accordance with the guidelines of the Declaration of 
Helsinki on biomedical research involving human subjects and in accordance with 
GCP guidelines (ICH), EU Directives 2001/20/EC1, 2005/28/EC2 and FDA’s Code of 
Federal Regulations (CFR)3 as well as the demands of national drug and data 
protection laws, other applicable regulatory requirements and any new directives or 
regulations which become enforceable during the course of the study.   
 
Before the study can begin the Investigator must have submitted to an Independent 
Ethics Committee (IEC) / Institutional Review Board (IRB) the study protocol, 
Investigator’s Brochure, subject information leaflet, parent/guardian information 
sheets, assent form, consent form (and any updates), subject recruitment procedures 
and any other relevant study documentation as outlined in the guidance document 
(‘Detailed guidance on the application format and documentation to be submitted in 
an application for an Ethics Committee opinion on the clinical trial on medicinal 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
products for human use’, ENTR/CT 2) for EU Directive 2001/20/EC1 and FDA’s 
Code of Federal Regulations (CFR)3.  Written approval of the study must be obtained 
before the study center can be initiated or the investigational medicinal product (IMP) 
can be released to the Investigator.  Any necessary extensions or renewals of IEC / 
IRB approval must be obtained, in particular, for changes to the study such as 
modification of the protocol, the informed consent form, the written information 
provided to subjects and/or other procedures. 
 
The Investigator will report promptly to the IEC / IRB any new information that may 
adversely affect the safety of the subjects or the conduct of the study.  The 
Investigator will submit written summaries of the study status to the IEC / IRB 
annually, or more frequently if requested by the IEC / IRB, in accordance with local 
regulatory requirements.  On completion of the study, the Sponsor and /or designated 
CRO will notify the IEC/IRB that the study has ended. 
 
2. INFORMED CONSENT 
No study-related procedures will be performed prior to the subject’s and subject’s 
parent/legal guardian’s (if applicable) signed consent to participate in the study being 
obtained.  Before the decision to participate, the Investigator or a duly authorized 
deputy will provide both an oral and a written full explanation of the study and the 
subject’s rights.  The written consent must be given by the subject and the 
parent/legal guardian (if applicable) of the subject, after detailed information about 
the study has been given as outlined above in EU Directive 2001/20/EC1, FDA’s 
Code of Federal Regulations (CFR)3 and in accordance with any national provisions 
on the protection of clinical study subjects.  The verbal explanation will cover all the 
elements specified in the written information provided for the subject.   
 
For subjects not qualified to give legal consent, written consent must be obtained 
from the subject's parent/legal guardian.  If appropriate, children old enough to 
understand the risks and benefits of the study (generally for children above 6 years of 
age) should also be informed and provide their written assent.  In addition, the 
subject/subject’s parent or legal guardian will sign a consent and child’s assent form 
authorizing release of the subject’s HIV test results to appropriate authorities.  All 
consent and assent forms must be approved in advance by the IRB/IEC. 
 
If the legal guardian is unable to read, an impartial witness should be present 
during the entire informed consent discussion.  After the informed consent form 
and any other written information is provided, read, and explained to the subject 
or their legal guardian, and after oral consent has been obtained, if capable of 
doing so, the subject’s legal guardian should sign and date the informed consent 
form, and where appropriate written assent should be obtained from the subject.  
The witness should also sign and date the consent form.  In addition, the subject’s 
legal guardian should, if possible, sign an additional form confirming that the 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
materials provided have been read and explained to them. The witness should also 
sign and date this additional form. 
 
The Investigator or designated personnel will inform the subject and 
parents/guardians of the subject about the objectives, methods, anticipated benefits 
and potential risks and inconveniences of the study.  The subject and parent/legal 
guardian (if applicable) must be given every opportunity to clarify any points they do 
not understand and, if necessary, to ask for more information.  At the end of the 
interview, the subject and parent/legal guardian (if applicable) will be given time to 
consider the study if this is required, or if they request more time.  Subjects and 
parents/legal guardians (if applicable) will be required to sign and date the informed 
consent form.  After signatures are obtained, the informed consent forms will be kept 
and archived by the Investigator in the Investigator’s Study File for possible 
inspection by regulatory authorities, the IEC or IRB, BPL or BPL’s representative’s 
personnel, auditors.  The subject will keep an identical signed copy.  A letter will be 
sent to the subject’s primary care physician informing him/her that the subject is to 
participate in the study, as appropriate. 
 
It should be emphasized to the subject that he/she is at liberty to withdraw from the 
study at any time, without penalty or loss of benefits to which the subject is otherwise 
entitled.  Subjects who withdraw consent should not continue in the study, but will be 
asked to attend an end-of-study visit, if possible. 
 
Should the study require the completion of a subject study diary, for subjects 
under the age of 18, the parent/legal guardian will oversee that the diary is 
completed accurately and legibly. 
 
The IEC / IRB will review and approve the subject information sheet and informed 
consent form.  If the Investigator intends to use his/her own information leaflet (for 
non-interventional studies only) he/she must ensure that it contains all the 
information outlined in Section 4.8 of the ICH-GCP guidelines. 
 
 
3. CONFIDENTIALITY 
The Investigator will ensure that the subject's anonymity is preserved.  
 
In order to protect the subject’s identity, identification codes will be used in lieu of 
subject’s name.  Personal information will be treated as confidential but may need to 
be reviewed by BPL or BPL’s representatives such as the CRA or auditor, or by 
representatives of IEC / IRBs or regulatory authorities.  The subject’s consent to 
direct access to their personal notes must be obtained prior to participation in the 
trial.  Each subject’s Primary Care Physician will be informed of the nature and 
timing of the study, as appropriate. 
 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
All unpublished documents including the protocol, the electronic case record form 
(eCRF) and the Investigator’s Brochure are confidential.  Those documents cannot be 
disclosed to a third party without the written consent of BPL.  However, submission 
of those documents to the IEC / IRB is expressly permitted. 
 
4. COMPENSATION/INDEMNITY 
Compensation will be paid by BPL according to the Guidelines drawn up by the 
Association of the British Pharmaceutical Industry if a subject is injured as a result of 
being in this study. 
 
Compensation will not be provided for injury or medical conditions that are unrelated 
to this study. 
 
BPL will indemnify the Institute and the Investigator with respect to any claim for 
personal injury or death brought against it resulting from the administration to 
subjects, of source materials supplied by BPL, provided that the protocol and 
Investigator Agreement have been adhered to, and the event has not been occasioned 
by malpractice or negligence.  BPL will take out private insurance in respect of its 
liability.   
 
5. PROTOCOL ADHERENCE 
Adherence to the protocol is a fundamental part of the conduct of the study.  
Deviations from the protocol, including deviations from the inclusion / exclusion 
criteria, might erode the scientific and ethical value of the protocol and its 
authorization and might have an impact on the processes put in place for the care and 
safety of the study subjects. 
Deviations from the protocol must not be made without the prior written approval 
of BPL and the IEC / IRB and the CA except where there are logistical or 
administrative changes (non-substantial amendments), or where they are 
implemented to eliminate an immediate threat or hazard to health or safety of the 
subject.  Where a deviation has been made to eliminate an immediate hazard the 
Investigator must submit a report of the implemented deviation and the reasons for it 
to the IEC / IRB and must notify relevant members of the Medical Department of 
BPL or designated Contract Research Organization (CRO).  All deviations must 
be adequately documented. 
 
6. PROTOCOL AMENDMENTS 
A decision will first be made by BPL as to whether a protocol amendment is 
‘Substantial’ or ‘Non-substantial’.  Amendments to the protocol are regarded as 
‘Substantial’ where they are likely to have significant impact on: 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 
The safety or physical or mental integrity of the subjects 
 
The scientific value of the trial 
 
The conduct or management of the trial 
or 
 
The quality or safety of any investigational medicinal product (IMP) used in 
the trial 
 
Competent Authority (CA) and IEC / IRB written approval (if applicable) will be 
obtained prior to any protocol amendment being adopted.   
When a Sponsor and/or Investigator must take urgent safety measures to protect the 
trial subjects from immediate hazard BPL (or designated CRO) must be notified 
within 24 hours and the IEC / IRB and CA must be notified within 3 calendar days 
after appropriate safety measures have been taken.  For any period during which a 
disease is pandemic and is a serious risk to human health or potentially a serious risk 
to human health, the IEC/IRB and CA should be informed as soon as possible.  
Where the amendment affects the risk/benefit ratio of continued participation for 
subjects already enrolled in the study, informed consent should be obtained again 
from such subjects using the new information leaflet/consent form.  The updated 
version of the information leaflet/consent form should be used for all new subjects 
recruited on to the trial. 
 
7. SERIOUS BREACHES 
Reporting of Serious Breaches is not applicable as the study is not planned to be 
conducted in the UK. 
 
8. TRIAL TERMINATION 
BPL reserve the right to stop the trial if: 
 
Recruitment is too slow to allow accrual of an adequate number of subjects 
within a reasonable length of time 
 
Evidence is gained that the subjects are being exposed to an unacceptable risk 
 
For any reason, it is not possible to continue to supply trial material 
 
An advancement in knowledge makes the trial redundant 
 
If the study is terminated, BPL, the CRO and the Investigator will ensure that 
adequate consideration is given to the protection of the subjects' interests. 
 
9. MONITORING VISITS 
The designated Clinical Research Associate (CRA) or representative CRA will 
monitor the study by telephone, correspondence, and regular visits to the 
investigational sites.  In accordance with ICH-GCP guidelines, the study monitor will 
carry out source document verification at regular intervals to ensure that the data 
collected in the eCRF are accurate, to carry out drug accountability and to ensure all 
documentation and study procedures comply with the protocol and with ICH-GCP.  

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
The frequency of monitoring visits will be determined by the rate of subject 
recruitment.  
 
The CRA will ensure that: 
 
The facilities remain adequate 
 
The Investigator adheres to the protocol and ethical responsibilities 
 
Source documents are legible and agree with entries in the eCRF 
 
Adverse events are adequately documented and reported 
 
Investigational medicinal product is properly stored and accountability is 
being maintained 
 
Laboratory samples are identified, handled and stored appropriately 
 
The Investigator must permit the CRA, the IEC / IRB, BPL appointed auditors and 
representatives from regulatory authorities direct access to all study-related 
documents and pertinent hospital or medical records for confirmation of data 
contained within the eCRFs.  The Investigator will agree to make himself/herself 
available to correct or discuss any discrepancies.  Subject confidentiality will be 
protected at all times. 
 
A “Site Delegation List and Signature Log" will be completed and signed by the 
responsible Investigator.  In accordance with this authority log, study site staff (e.g. 
co-Investigators and nurses) will be authorized to enter data into the eCRF.  The 
monitor will visit the study centers as required. 
 
10. AUDIT/INSPECTION 
Access to documentation and facilities used during the study may be required by BPL 
appointed auditors or by regulatory authorities. 
In the event that the regulatory authorities schedule an audit the Investigator must 
notify BPL (or the designated CRO) immediately.  BPL will in turn notify the 
Investigator if they are informed of an audit at an Investigator’s site. 
The main purposes of an audit or inspection are to confirm that the rights and welfare 
of the subjects have been adequately protected, and that all data relevant for the 
assessment of safety and effectiveness of the investigational product have been 
reported to the Sponsor.  
 
The verification of the eCRF data may be performed by direct inspection of source 
documents, after the Investigator has protected all confidential personal subject 
information not related to the study, in accord with local regulations. 
 
11. REQUIRED PRE-STUDY DOCUMENTATION 
Before the start of the study, BPL will require, as a minimum, the following 
documentation: 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
1. 
A signed copy of the protocol and signed amendments approved by 
the IEC/IRB 
2. 
A signed Clinical Trial Agreement, including any host R&D 
approval 
3. 
Other signed financial agreements (e.g. laboratory, pharmacy) 
4. 
Signed Confidentiality Agreements for study team 
5. 
A signed Secrecy Agreement (if applicable) 
6. 
A completed Investigator Financial Disclosure / Certification 
Statement and a Statement of Investigator (Form FDA 1572), if 
applicable 
7. 
An Indemnity Form signed and dated by both parties unless 
indemnity is covered by other signed agreements for the study 
8. 
Insurance policy or statement that this is not required. 
9. 
IEC / IRB written approval 
10. Assurance that the IEC / IRB is organized and operates according to 
GCP and the applicable laws and regulations 
11. ARSAC approval (if applicable) 
12. CA Approval 
13. Signed CVs of Investigators and sub-Investigators showing current 
position and GMC registration number, as appropriate 
14. Normal Ranges for: 
 Laboratory parameters 
 Medical or technical procedures 
 Tests included in the protocol 
15. Evidence of validation of procedures/tests to be performed e.g.: 
 Accreditation 
 Certification 
 SOPs for specialized tests 
16. IEC / IRB approved subject information sheet and consent forms, 
identified with version number and date, plus any other written 
information given to subjects 
17. Investigator’s Brochure, the edition clearly identified plus any updates 
18. Master randomization list (if appropriate) 
19. Decoding procedures for blinded trials 
20. Sample case record form 
 
If any of these documents are issued in a language other than English then 
verified translations are required. 
 
 
 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
12. COMPLETION AND RETURN OF CASE RECORD FORMS AND 
DATA QUERY FORMS  
 
12.1 Recording data in Case Record Forms (eCRF) and Data Query Forms 
(DQFs) 
 
All study data will be recorded on eCRF provided by BPL or designated CRO.  These 
must be completed by the Investigator or a duly authorized assistant.   
 
Electronic CRF 
In the case of eCRF, errors occurring in the eCRFs will be corrected directly in the 
data field of the eCRF.  An audit trail capturing the original entry, the new entry, the 
user ID of the entry personnel, and the date and time of each action will be 
maintained in the data capture system.  Likewise, the interchange of queries between 
the CRO and the site, as well as query replies, will be maintained within the audit trail 
of the data capture system.  Any changes to the data in the data capture system that 
occur after the Investigator or authorized co-Investigator have electronically signed 
the eCRF will require that the Investigator or authorized co-Investigator review and 
re-sign the eCRF. 
 
12.2. Signing off eCRFs/DQFs and return to BPL or designated CRO 
The Investigator must: 
 Sign the completed eCRF/DQFs to confirm the validity of the data 
 Return the completed eCRF/DQFs as instructed 
 Retain a copy in the Investigator File 
 
In the case of eCRF for each subject enrolled, eCRFs will be completed and signed 
electronically by the Investigator or an authorized co-Investigator.  All paper source 
documents will be filled out using an indelible pen, and must be legible.  
 
12.3. Handling of Clinical Trial Data 
All clinical trial data will be recorded, handled and stored in such a way that it can 
be accurately reported, interpreted and verified, whilst maintaining the 
confidentiality of the subjects’ records. 
 
12.4. Source Documents 
Source data are defined as all information related to clinical findings, observations, or 
other activities in the study, written in original records or consisting of certified 
copies of original records.  The Investigator will permit trial-related monitoring, 
audit(s), IRB review(s) and regulatory inspection(s). 
 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
Source documents or data to be entered directly into the Case Record Form will be 
defined prior to study start in an appropriate plan e.g. definition of source data 
document. 
 
 
13. MAINTENANCE AND ARCHIVING OF STUDY RECORDS 
 
13.1. Investigator Site File 
The Investigator will be supplied with an Investigator Site File by BPL, or the 
designated CRO, at the start of the study, containing copies of required pre-study 
essential documents.  It is the responsibility of the Investigator and study team 
members at site to maintain these essential documents and ensure their secure 
storage.  The Investigator file will comprise the following documentation, 
although certain sections may be kept in a separate file with certain study team 
members e.g. laboratory or pharmacy staff: 
 
1. 
Agreements 
 Signed Confidentiality Agreements for study team 
 Signed Clinical Trial Agreement, including any host R&D approval (and 
submission documentation where applicable) detailing versions of 
documents approved 
 Other signed financial agreements specific to the site (e.g. laboratory, 
pharmacy) 
 Indemnity Form (if used) signed and dated by both parties, unless 
indemnity is covered by other signed agreements for the study 
 Insurance statement if applicable 
 A completed Investigator Financial Disclosure / Certification Statement 
and a Statement of Investigator (Form FDA 1572), if applicable 
2. 
Protocol 
 A signed copy of the protocol and signed amendments approved by the 
IEC/IRB 
3. 
Product Information 
 Investigator’s Brochure, the edition clearly identified plus any updates 
 Supporting publications and information 
 Safety updates from BPL, including any aggregated line listings of 
SUSARs and summary safety reports, in accordance with local 
regulatory requirements 
4. 
e-CRF and Supporting Information 
 Sample case record form 
 Other blank forms used in the study e.g. study diary  
 Data transmittal forms 
5. 
CVs 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 Signed CVs of Investigators and sub-Investigators showing current 
position and registration number, as appropriate 
 Case Record Form Signature and Study Duties Log 
 Reference to training records of study site personnel 
6. 
Ethics Committee 
 IEC / IRB written approval 
 CA Approval 
 ARSAC approval (if applicable) 
 Relevant correspondence with IEC/IRB 
 Copies of progress reports to IEC/IRB 
 Copies of annual safety reports to IEC/IRB, in accordance with local 
regulatory requirements 
 Copies of IEC/IRB approved consent forms 
 Copies of IEC/IRB approved information leaflets 
 Final letter and report to IEC/IRB documenting study completion 
7. 
Laboratory Details 
 Central laboratory manual, if applicable 
 Local laboratory normal ranges both current and previous if changed 
during study, if applicable 
 Local laboratory certification / accreditation both current and any 
updates, if applicable 
 Local laboratory validation or SOPs for specialized tests both current 
and any updates, if applicable 
 Sample storage log 
 Local sample handling procedures, unless included in a central 
laboratory manual 
 Laboratory parameters 
 Medical or technical procedures 
 Tests included in the protocol 
8. 
Subject Details 
 Master randomization list (if appropriate). 
 Subject screening log (if appropriate) 
 Subject enrolment log (if appropriate) 
 Signed informed consent forms; informed consent checklist, if used 
 Template of letter to primary physician 
 If applicable, completed subject identification code list for randomized 
studies (at study completion) 
9. 
Adverse Events 
 Reports of Serious Adverse Events and SUSARs 
 Correspondence relating to SAEs and SUSARs 
 Notification of SUSARs to IEC/IRB 
10. General Correspondence 
11. Investigational Medicinal Product 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 IMP receipt forms. 
 Procedure for temperature monitoring 
 Certificates of Analysis, if requested 
 IMP accountability records 
 Instructions for handling IMP 
 Example prescription form (if applicable) 
 Documentation of destruction of IMP 
 Randomization code location (if not kept in Investigator Site File) 
12. Monitoring 
  Pre-study and Initiation Site Visit Report forms 
 Case Record Form correction notes 
 Data query forms  
13. Reports 
 Any interim clinical study report 
 The final clinical study report. A synopsis will suffice 
14. Completed eCRFs 
 Copies of completed eCRFs or reference if stored separately 
 Copy of any eCRF and data query tracking and acknowledgement forms 
15. Meetings 
 Minutes of meetings, agenda and correspondence relating to meetings 
16. Publications 
 Any publications of trial results available before site closure 
 
If any of these documents are issued in a language other than English then verified 
translations are required. 
13.2. Subject Notes 
The Investigator must maintain adequate records of subject participation for the 
duration of the study.  These records must be available for inspection upon 
reasonable request by the Sponsor, members of the regulatory authorities or other 
authorized individuals.  The Investigator must detail in the subject notes that the 
subject is eligible for the study prior to enrolment.  The Investigator must also ensure 
that worksheets provided for the study that form part of the source data must always 
be included in the subject notes.  
13.3. Availability of Data for Inspection 
The Investigator is obliged to provide BPL, or BPL’s representative, with complete 
test results and all data and reports within the timeframe agreed by both parties. 
After completion of the study, all documents and data relating to the study will be 
kept in an orderly manner by the Investigator in a secure study file.  This file will be 
available for inspection by the Sponsor or its representatives.   
 
 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
13.4. Archiving Study Documentation 
The Investigator must make proper provision for archiving study documentation.  
Essential documents must be retained in accordance with ICH-GCP.  Essential 
documents must be retained for two years after the last marketing approval in an ICH 
region or until at least two years have elapsed since the discontinuation of clinical 
development of the IMP.  It is BPL’s responsibility to inform the Investigator or 
Institute as to when these documents no longer need to be retained.  It is the 
Investigator’s responsibility to notify BPL, or BPL’s representative, in writing if they 
are unable to make suitable provisions for archiving study documents at the study 
center.  Prior to archive, subject ID codes should be kept in a suitable place to enable 
easy access at the Investigator site.  Subject ID codes must be retained for a period of 
at least 15 years after issue of the final study report.  Subject consent forms and other 
study related documentation must be retained for a maximum period of time 
permitted by the hospital, institution or private practice 
Essential documents from trials which are not to be used in regulatory submissions 
should be retained for at least five years after completion of the trial.  These 
documents should be retained for a longer period if required by the applicable 
regulatory requirements or by agreement with BPL. 
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. 
 
14. REPORT AND PUBLICATION 
 
BPL’s standard report and publication policy is detailed below.  In the case of the 
agreement between BPL and the Investigator differing from this policy, what is stated 
in the agreement will override what is stated below.  
 
BPL recognizes that the Investigator might wish to publish the results of the study.  
The Investigator and members of the Investigator’s team engaged in the study shall 
not be permitted to present at symposia and professional meetings or to publish 
journals, theses or dissertations, or otherwise of their choosing, methods and results 
of the Study (all of which hereinafter referred to as “the Publication”) without the 
consent of BPL. 
 
In the case that the Investigator or members of the Investigator’s team engaged in the 
study wish to pursue the Publication, the Investigator shall furnish BPL with copies 
of the Publication at least two months in advance of the intended date of whichever is 
the earliest submission of the Publication or presentation of the Publication or 
publication of the Publication or the making of a commitment to do any of the 
foregoing.  The Investigator agrees, if BPL requests a meeting between the 
Investigator and BPL, to discuss in good faith the comments. 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 
BPL shall have two months, after receipt of said copies, to object to such proposed 
Publication on reasonable grounds.  For the avoidance of doubt the grounds that the 
subject matter is patentable or commercially sensitive shall constitute reasonable 
grounds. 
 
Authorship should reflect work done by the Investigators and BPL personnel, in 
accordance with generally recognized principles of scientific collaboration. 
 
 
15. REFERENCES 
 
1. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 
2001 on the approximation of the laws, regulations and administrative provisions 
of the Member States relating to the implementation of good clinical practice in 
the conduct of clinical trials on medicinal products for human use. 
 
2. Commission Directive 2005/28/EC of 8 April 2005 laying down principles and 
detailed guidelines for good clinical practice as regards investigational medicinal 
products for human use, as well as the requirements for authorization of the 
manufacturing or importation of such products. 
 
3. FDA guidelines CFR 21 (ww.w.fda.gov) which dictates the regulations and 
principles for conducting clinical trials in the USA, detailed guidelines are also 
provided. 
 
 
 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 
APPENDIX III - LOCAL INVESTIGATOR’S RESPONSIBILITIES 
BASED ON THE ICH GUIDELINES FOR GOOD CLINICAL 
PRACTICE 
 
1. 
LOCAL INVESTIGATOR 
 
1.1 
Investigator’s Qualifications and Agreements 
 
1.1.1 
The Investigator(s) should be qualified by education, training, and experience to assume 
responsibility for the proper conduct of the study, should meet all the qualifications 
specified by the applicable regulatory requirement(s), and should provide evidence of 
such qualifications through up-to-date curriculum vitae and/or other relevant 
documentation requested by the Sponsor, the IRB/EC, and/or the regulatory 
authority(ies). 
 
1.1.2 
The Investigator should be thoroughly familiar with the appropriate use of the 
investigational product(s), as described in the protocol, in the current Investigator’s 
Brochure, in the product information and in other information sources provided by the 
Sponsor. 
 
1.1.3 
The Investigator should be aware of, and should comply with, GCP and the applicable 
regulatory requirements. 
 
1.1.4 
The Investigator should permit monitoring and auditing by the Sponsor, and inspection 
by the appropriate regulatory authority(ies). 
 
1.1.5 
The Investigator should maintain a list of appropriately qualified persons to whom the 
Investigator has delegated significant study-related duties. 
 
1.2 
Adequate Resources 
 
1.2.1 
The Investigator should be able to demonstrate (e.g. based on retrospective data) a 
potential for recruiting the required number of suitable subjects within the agreed 
recruitment period. 
 
1.2.2 
The Investigator should have sufficient time to properly conduct and complete the study 
within the agreed study period. 
 
1.2.3 
The Investigator should have available an adequate number of qualified staff and 
adequate facilities for the foreseen duration of the study to conduct the study properly and 
safely. 
 
1.2.4 
The Investigator should ensure that all persons assisting with the study are adequately 
informed about the protocol, the investigational product(s), and their study-related duties 
and functions. 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 
1.3 
Medical Care of Study Subjects 
 
1.3.1 
A qualified physician (or dentist, when appropriate), who is an Investigator or a sub-
Investigator for the study, should be responsible for all study-related medical (or dental) 
decisions. 
 
1.3.2 
During and following a subject’s participation in a study, the Investigator should ensure 
that adequate medical care is provided to a subject for any adverse events, including 
clinically significant laboratory values, related to the study.  The Investigator should 
inform a subject when medical care is needed for intercurrent illness(es) of which the 
Investigator becomes aware. 
 
1.3.3 
It is recommended that the Investigator inform the subject’s primary physician about the 
subject’s participation in the study if the subject has a primary physician and if the 
subject agrees to the primary physician being informed. 
 
1.3.4 
Although a subject and their Parent(s)/Guardian(s) are not obliged to give their reason(s) 
for withdrawing prematurely from a study, the Investigator should make a reasonable 
effort to ascertain the reason(s), while fully respecting the subject’s rights. 
 
1.4 
Communication with IRB/EC 
 
1.4.1 
Before initiating a study, the Investigator should have written and dated 
approval/favorable opinion from the IRB/EC for the study protocol, written informed 
consent form, consent form updates, subject recruitment procedures (e.g. advertisements), 
and any other written information to be provided to subjects. 
 
1.4.2 
During the study the Investigator should provide to the IRB/EC all documents subject to 
review. 
 
1.5 
Compliance with Protocol 
 
1.5.1 
The Investigator should conduct the study in compliance with the protocol agreed by the 
Sponsor and, if required, by the regulatory authority(ies) and which was given 
approval/favorable opinion by the IRB/EC.  The Investigator and the Sponsor should sign 
the protocol, or an alternative contract, to confirm agreement. 
 
1.5.2 
The Investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented approval/favorable 
opinion from the IRB/EC of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g. change in monitor(s), change of telephone 
number(s)). 
 
1.5.3 
The Investigator, or person designated by the Investigator, should document and explain 
any deviation from the approved protocol. 
 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
1.5.4 
The Investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to study subjects without prior IRB/EC 
approval/favorable opinion.  As soon as possible, the implemented deviation or change, 
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted. 
 
a) 
to the IRB/EC for review and approval/favorable opinion, 
 
b) 
to the Sponsor for agreement and, if required, 
a) 
to the regulatory authority(ies). 
 
1.6 
Investigational Product(s) 
 
1.6.1 
Responsibility for investigational product(s) accountability at the study site(s) rests with 
the Investigator. 
 
1.6.2 
Where allowed/required, the Investigator may/should assign some or all of the 
Investigator’s duties for investigational product(s) accountability at the study site(s) to an 
appropriate pharmacist or another appropriate individual who is under the supervision of 
the Investigator. 
 
1.6.3 
The Investigator and/or a pharmacist or other appropriate individual, who is designated 
by the Investigator, should maintain records of the product’s delivery to the study site, the 
inventory at the site, the use by each subject, and the return to the Sponsor or alternative 
disposition of unused product(s).  These records should include dates, quantities, 
batch/serial numbers expiration dates (if applicable), and the unique code numbers 
assigned to the investigational product(s) and study subjects.  Investigators should 
maintain records that document adequately that the subjects were provided the doses 
specified by the protocol and reconcile all investigational product(s) received from the 
Sponsor. 
 
1.6.4 
The investigational product(s) should be stored as specified by the Sponsor and in 
accordance with applicable regulatory requirement(s). 
 
1.6.5 
The Investigator should ensure that the investigational product(s) are used only in 
accordance with the approved protocol. 
 
1.6.6 
The Investigator, or a person designated by the Investigator, should explain the correct 
use of the investigational product(s) to each subject/Parent(s)/Guardian(s) and should 
check, at intervals appropriate for the study, that each subject/Parent(s)/Guardian(s) are 
following the instructions properly. 
 
1.7 
Randomization Procedures and Unblinding 
 
The Investigator should follow the study’s randomization procedures, if any, and should 
ensure that the code is broken only in accordance with the protocol.  If the study is 
blinded, the Investigator should promptly document and explain to the Sponsor any 
premature unblinding (e.g. accidental unblinding, unblinding due to a serious adverse 
event) of the investigational product(s). 
 
 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
1.8 
Informed Consent of Study Subjects 
 
1.8.1 
In obtaining and documenting informed consent, the Investigator should comply with the 
applicable regulatory requirement(s), and should adhere to GCP and to the ethical 
principles that have their origin in the Declaration of Helsinki.  Prior to the beginning of 
the study, the Investigator should have the IRB/EC written approval/favorable opinion of 
the written informed consent form and any other written information to be provided to 
subject/Parent(s)/Guardian(s). 
 
1.8.2 
The written informed consent form and any other written information to be provided to 
subjects/Parent(s)/Guardian(s) should be revised whenever important new information 
becomes available that may be relevant to the subject’s/Parent(s)/Guardian(s)’ consent.  
Any revised written informed consent form, and written information should receive the 
IRB/EC approval/favorable opinion in advance of use.  The subject or the subject’s 
legally acceptable representative should be informed in a timely manner if new 
information 
becomes 
available 
that 
may 
be 
relevant 
to 
the 
subject’s/Parent(s)/Guardian(s)’ willingness to continue participation in the study.  The 
communication of this information should be documented. 
 
1.8.3 
Neither the Investigator, nor the study staff, should coerce or unduly influence a 
subject/Parent(s)/Guardian(s) to participate or to continue to participate in a study. 
 
1.8.4 
None of the oral and written information concerning the study, including the written 
informed consent form, should contain any language that causes the subject or the 
subject’s legally acceptable representative to waive or to appear to waive any legal rights, 
or that releases or appears to release the Investigator, the institution, the Sponsor, or their 
agents from liability for negligence. 
 
1.8.5 
The Investigator, or a person designated by the Investigator, should fully inform the 
subject or, if the subject is unable to provide informed consent, the subject’s legally 
acceptable representative, of all pertinent aspects of the study including the written 
information given approval/favorable opinion by the IRB. 
 
1.8.6 
The language used in the oral and written information about the study, including the 
written informed consent form, should be as non-technical as practical and should be 
understandable to the subject or the subject’s legally acceptable representative and the 
impartial witness, where applicable. 
 
1.8.7 
Before informed consent may be obtained, the Investigator, or a person designated by the 
Investigator, should provide the subject or the subject’s legally acceptable representative 
ample time and opportunity to inquire about details of the study and to decide whether or 
not to participate in the study.  All questions about the study should be answered to the 
satisfaction of the subject or the subject’s legally acceptable representative. 
 
1.8.8 
Prior to a subject’s participation in the study, the written informed consent form should 
be signed and personally dated by the subject or by the subject’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. 
 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
1.8.9 
If a subject is unable to read or if a legally acceptable representative is unable to read, an 
impartial witness should be present during the entire informed consent discussion.  After 
the written informed consent form and any other written information to be provided to 
subjects, is read and explained to the subject or the subject’s legally acceptable 
representative, and after the subject’s legally acceptable representative has orally 
consented to the subject’s participation in the study and, if capable of doing so, has 
signed and personally dated the informed consent form, the witness should sign and 
personally date the consent form.  By signing the consent form, the witness attests that 
the information in the consent form and any other written information was accurately 
explained to, and apparently understood by, the subject or the subject’s legally acceptable 
representative, and that informed consent was freely given by the subject or the subject’s 
legally acceptable representative. 
 
1.8.10 Both the informed consent discussion and the written informed consent form and any 
other written information to be provided to subjects should include explanations of the 
following: 
 
 
a) 
That the study involves research. 
 
 
b) 
The purpose of the study. 
 
 
c) 
The study treatment(s) and the probability for random assignment to each treatment. 
 
 
d) 
The study procedures to be followed, including all invasive procedures. 
 
 
e) 
The subject’s/Parent(s)/Guardian(s)’ responsibilities. 
 
 
f) 
Those aspects of the study which are experimental. 
 
 
g) 
The reasonably foreseeable risks or inconveniences to the subject and, when 
applicable, to an embryo, fetus, or nursing infant. 
 
h) 
The reasonably expected benefits.  When there is no intended clinical benefit to 
the subject, the subject/Parent(s)/Guardian(s) should be made aware of this. 
 
 
i) 
The alternative procedure(s) or course(s) of treatment that may be available to the 
subject, and their important potential benefits and risks. 
 
 
j) 
The compensation and/or treatment available to the subject/Parent(s)/Guardian(s) 
in the event of study-related injury. 
 
 
k) 
The anticipated prorated payment, if any, to the subject/Parent(s)/Guardian(s) for 
participating in the study. 
 
 
l) 
The anticipated expenses, if any, to the subject/Parent(s)/Guardian(s) for  
 
 
participating in the study. 
 
 
m) 
That the subject’s participation in the study is voluntarily through its 
Parent(s)/Guardian(s) and that the subject/Parent(s)/Guardian(s) may refuse to 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
participate or withdraw from the study, at any time, without penalty or loss of 
benefits to which the subject/Parent(s)/Guardian(s) are otherwise entitled. 
 
 
n) 
That the monitor(s), the auditor(s), IRB, and the regulatory authority(ies) will be 
granted direct access to the subject’s original medical records for verification of 
clinical study procedures and/or data, without violating the confidentiality of the 
subject, to the extent permitted by the applicable laws and regulations and that, 
by signing a written informed consent form, the subject or the subject’s legally 
acceptable representative is authorizing such access. 
 
 
o) 
That records identifying the subject will be kept confidential and, to the extent 
permitted by the applicable laws and/or regulations, will not be made publicly 
available.  If the results of the study are published, the subject’s identity will 
remain confidential. 
 
 
p) 
That the subject or the subject’s legally acceptable representative will be 
informed in a timely manner if information becomes available that may be 
relevant to the subject’s willingness to continue participation in the study. 
 
 
q) 
The person(s) to contact for further information regarding the study and the rights 
of study subjects, and whom to contact in the event of study-related injury. 
 
 
r) 
The foreseeable circumstances and/or reasons under which the subject’s 
participation in the study may be terminated. 
 
 
s) 
The expected duration of the subject’s participation in the study. 
 
 
t) 
The approximate number of subjects involved in the study. 
 
1.8.11 Prior to participation in the study, the subject or the subject’s legally acceptable 
representative should receive a copy of the signed and dated written informed consent 
form and any other written information provided to the subjects.  During a subject’s 
participation in the study, the subject or the subject’s legally acceptable representative 
should receive a copy of the signed and dated consent form updates and a copy of any 
amendments to the written information provided to subjects. 
 
1.8.12 When a clinical study (therapeutic or non-therapeutic) includes subjects who can only be 
enrolled in the study with the consent of the subject’s legally acceptable representative 
(e.g. minors, or patients with severe dementia), the subject should be informed about the 
study to the extent compatible with the subject’s understanding and, if capable, the 
subject should sign and personally date the written informed consent. 
 
1.8.13 Except as described in 1.8.14, a non-therapeutic study (i.e. a study in which there is not 
anticipated direct clinical benefit to the subject), should be conducted in subjects who 
personally give consent and who sign and date the written informed consent form. 
 
1.8.14 Non-therapeutic studies may be conducted in subjects with consent of a legally 
acceptable representative provided the following conditions are fulfilled: 
 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 
a) 
The objectives of the study cannot be met by means of a study in subjects who 
can give informed consent personally. 
 
 
b) 
The foreseeable risks to the subjects are low. 
 
 
c) 
The negative impact on the subject’s well-being is minimized and low. 
 
 
d) 
The study is not prohibited by law. 
 
e) 
The approval/favorable opinion of the IRB/EC is expressly sought on the 
inclusion of such subjects, and the written approval/favorable opinion covers this 
aspect. 
 
Such studies, unless an exception is justified, should be conducted in patients having a 
disease or condition for which the investigational product is intended.  Subjects in these 
studies should be particularly closely monitored and should be withdrawn if they appear 
to be unduly distressed. 
 
1.8.15 In emergency situations, when prior consent of the subject is not possible, the consent of 
the subject’s legally acceptable representative, if present, should be requested.  When 
prior consent of the subject is not possible, and the subject’s legally acceptable 
representative is not available, enrolment of the subject should require measures 
described in the protocol and/or elsewhere, with documented approval/favorable opinion 
by the IRB/EC, to protect the rights, safety and well-being of the subject and to ensure 
compliance with applicable regulatory requirements.  The subject or the subject’s legally 
acceptable representative should be informed about the study as soon as possible and 
consent to continue and other consent as appropriate (see 1.8.10) should be requested. 
 
1.9 
Records and Reports 
 
1.9.1 
The Investigator should ensure the accuracy, completeness, legibility, and timeliness of 
the data reported to the Sponsor in the CRFs and in all required reports. 
 
1.9.2 
Data reported on the CRF that are derived from source documents should be consistent 
with the source documents or the discrepancies should be explained. 
 
1.9.3 
Any change or correction to a CRF should be dated, initialed, and explained (if 
necessary) and should not obscure the original entry (i.e. an audit trail should be 
maintained): this applies to both written and electronic changes or corrections (see 1.18.4 
(n)).  Sponsors should provide guidance to Investigators and/or the Investigators’ 
designated representatives on making such corrections.  Sponsors should have written 
procedures to assure that changes or corrections in CRFs made by Sponsor’s designated 
representatives are documented, are necessary, and are endorsed by the Investigator.  The 
Investigator should retain records of the changes and corrections. 
 
1.9.4 
The Investigator should maintain the study documents as specified in Essential 
Documents for the Conduct of a Clinical Study and as required by the applicable 
regulatory requirement(s).  The Investigator should take measures to prevent accidental 
or premature destruction of these documents. 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 
1.9.5 
Essential documents should be retained until at least two years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least two years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These 
documents should be retained for a longer period however if required by the applicable 
regulatory requirements or by an agreement with the Sponsor.  It is the responsibility of 
the Sponsor to inform the Investigator as to when these documents no longer need to be 
retained. 
 
1.9.6 
The financial aspects of the study should be documented in an agreement between the 
Sponsor and the Investigator. 
 
1.9.7 
Upon request of the monitor, auditor, IRB, or regulatory authority, the Investigator 
should make available for direct access all requested study-related records. 
 
1.10 
Progress Reports 
 
1.10.1 The Investigator should submit written summaries of the study status to the IRB/EC 
annually, or more frequently, if requested by the IRB/EC. 
 
1.10.2 The Investigator should promptly provide written reports to the Sponsor, the IRB/EC and, 
where applicable, the institution on any changes significantly affecting the conduct of the 
study, and/or increasing the risk to subjects. 
 
1.11 
Safety Reporting 
1.11.1 All serious adverse events (SAEs) should be reported immediately to the Sponsor except 
for those SAEs that the protocol or other document (e.g. Investigator’s Brochure) 
identifies as not needing immediate reporting.  The immediate reports should be followed 
promptly by detailed, written reports.  The immediate and follow-up reports should 
identify subjects by unique code numbers assigned to the study subjects rather than by the 
subjects’ names, personal identification numbers, and/or addresses.  The Investigator 
should also comply with the applicable regulatory requirement(s) related to the reporting 
of unexpected serious adverse drug reactions to the regulatory authority(ies) and the 
IRB/EC. 
 
1.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical to 
safety evaluations should be reported to the Sponsor according to the reporting 
requirements and within the time periods specified by the Sponsor in the protocol. 
 
1.11.3 For reported deaths, the Investigator should supply the Sponsor and the IRB/EC with any 
additional requested information (e.g. autopsy reports and terminal medical reports). 
 
1.12 
Premature Termination or Suspension of a Study 
 
 
If the study is prematurely terminated or suspended for any reason, the Investigator 
should promptly inform the study subjects/Parent(s)/Guardian(s), should assure 
appropriate therapy and follow-up for the subjects, and, where required by the applicable 
regulatory requirement(s), should inform the regulatory authority(ies).  In addition: 

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This protocol or information contained in this document will be treated as confidential at all times and may not be 
reproduced or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It 
shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 
1.12.1 If the Investigator terminates or suspends a study without prior agreement of the Sponsor, 
the Investigator should inform the institution where applicable, and the Investigator 
should promptly inform the Sponsor and the IRB/EC, and should provide the Sponsor 
and the IRB/EC a detailed written explanation of the termination or suspension. 
 
1.12.2 If the Sponsor terminates or suspends a study, the Investigator should promptly inform 
the institution where applicable and the Investigator should promptly inform the IRB/EC 
and provide the IRB/EC a detailed written explanation of the termination or suspension. 
 
1.12.3 If the IRB/EC terminates or suspends its approval/favorable opinion of a study, the 
Investigator should inform the institution where applicable and the Investigator should 
promptly notify the Sponsor and provide the Sponsor with a detailed written explanation 
of the termination or suspension. 
 
1.13 
Final Report(s) by Investigator 
 
Upon completion of the study, the Investigator, where applicable, should inform the 
institution: the Investigator should provide the IRB/EC with a summary of the study’s 
outcome, and the regulatory authority(ies) with any reports required. 
 
 

Study Protocol SCIG03, Version 6, 22March 2017 
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Bio Products Laboratory Ltd. 
CONFIDENTIAL 
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This protocol or information contained in this document will be treated as confidential at all times and may not be reproduced or communicated to a third party without the 
written permission of Bio Products Laboratory Ltd. (BPL).  It shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
APPENDIX IV- VISIT SCHEDULE 
Table 2 Schedule of Assessments 
Assessment 
 
 
(Wk) 
Screen 
1a 
2 
3 
to 
4 
5 
6 
to 
8 
9 
10 
to 
12 
13 
14 
to 
16 
17 
18 
to 
20 
21 
22 
23 to 
25 
26 
27 
FUb 
30  
Telephone 
FUc 
Clinic Visit No. 
1 
2  
3 
 
4 
 
5 
 
6 
 
7 
 
8 
9 
 
10 
11 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion /Exclusion Criteria / 
Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Weight 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
Chest X-ray – if not available in 
previous 12 months 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signsd 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
Infusion with Subgam-VF 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Infusion Site Inspection for 
reactions 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event reportinge 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
TEE examination f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Hematology 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Biochemistry 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
HCG urine pregnancy test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IgG trough levels 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
IgA, IgM g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IgG subclasses 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Specific anti-bodies h 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 

Study Protocol SCIG03, Version 6, 22March 2017 
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CONFIDENTIAL 
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This protocol or information contained in this document will be treated as confidential at all times and may not be reproduced or communicated to a third party without the 
written permission of Bio Products Laboratory Ltd. (BPL).  It shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
Assessment 
 
 
(Wk) 
Screen 
1a 
2 
3 
to 
4 
5 
6 
to 
8 
9 
10 
to 
12 
13 
14 
to 
16 
17 
18 
to 
20 
21 
22 
23 to 
25 
26 
27 
FUb 
30  
Telephone 
FUc 
Clinic Visit No. 
1 
2  
3 
 
4 
 
5 
 
6 
 
7 
 
8 
9 
 
10 
11 
 
Virology i 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Parvovirus B19  j 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Direct Coombs’ Test k 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Haptoglobin, plasma free 
hemoglobin, urine hemosiderin l 
 
X 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
PK assessment m 
 
 
 
 
 
 
 
 
 
 
 
  
X 
X 
 
 
 
 
Study Diary issue 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Reserve sample 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
 
Archive: Store at –70°C for 15 
years  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
 
a  
Eligible subjects return 7 days (+/- 1 day) for their first Subgam-VF dose. Infusion visits will be scheduled every 7 days. Individual infusions may be 
administered at ± 1 day of the planned schedule, if absolutely necessary (e.g. because of unavoidable conflicts, see section 7.2 for details)  
b  
Week 27 Follow-up visit will occur seven days (+/- 1 day) after the last Subgam-VF infusion. This visit must occur prior to administration of a new IgG 
 
product.  
c  
Week 30 Telephone follow-up will occur 28 days (+/- 1 day) after the last Subgam-VF infusion to check for AEs. 
d  
Vital signs will be recorded once during the screening and follow up visits.  During Subgam-VF infusion site visits vital signs will be collected 10 
minutes before the start of each infusion (+/- 5 minutes) and 30 minutes after stopping the infusion (+/- 15 minutes). 
e 
AEs will be documented from the date of consent until the last follow-up visit.  AEs will be collected in subject diaries and by direct observation during 
each site visit. In addition there will be a telephone follow up by the site on day 3 after each infusion to check for any adverse reactions including 
infusion site reactions.   The date of infusion is considered to be Day 0. If Day 3 is to fall on a weekend or public holiday then this telephone follow up 
call should be performed on the closest working day after Day 3 as possible. 
f  
 
Thromboembolic event (TEE) monitoring to be performed at screening and at the follow-up visit- refer to section 7.8 for details  
g  
IgA, IgM - testing for IgA and IgM will only occur in those subjects where results are not available for the previous 12 months  
h  
Specific anti-bodies for Streptococcus pneumoniae and Haemophilus influenzae B will be measured at screening and FU visit. Anti-bodies for measles 
will be measured at FU visit (this visit must occur prior to administration of a new IgG product as a trough sample is required). 
i  
Virology - Serological tests for HBsAg, HCV, HIV 1 & 2 performed at screening and Week 27 FU visit, NAT for HCV and HIV only performed at 
Week 27 FU visit. 
j  
Parvovirus B19 – PCR/NAT and serology 
k  
Direct Coombs’ Test and tests for hemolysis will be repeated for the subject at each subsequent clinic visit if the result is positive at any visit 

Study Protocol SCIG03, Version 6, 22March 2017 
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Bio Products Laboratory Ltd. 
CONFIDENTIAL 
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This protocol or information contained in this document will be treated as confidential at all times and may not be reproduced or communicated to a third party without the 
written permission of Bio Products Laboratory Ltd. (BPL).  It shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
l  
Haptoglobin, plasma free hemoglobin, urine hemosiderin – tests for hemolysis will be repeated for the subject at each subsequent clinic visit if the 
result is positive at any visit 
m  
PK sampling will begin on Week 21 (prior to 21st infusion of Subgam-VF), with the last sample taken on Week 22 just before the next (22nd) infusion 
given at the site. Where possible, PK samples and assessments from Steady State Day 1 onwards could be conducted at the subject’s home by an 
appropriately qualified member of the study team, or a Home Health Agency.  See Table 3 for PK schedule. If the PK sampling cannot be completed at 
Week 21 (eg.. due to patients work/vacation schedule) then this can be delayed to start at Week 22, 23, 24 or 25; however, the patient should still visit 
the office/hospital for their week 21 infusion and complete the other assessments scheduled for Visit 8, if possible. Week 22 assessments (Visit 9) will 
normally coincide with the PK sampling Day 7.  However, if PK sampling is delayed, Visit 9 will also be delayed. 
n  
Archive sample should be collected before an infusion of another product 
 
N.B. The non-shaded columns represent infusions that may be performed at the subject’s home.  After the Week 2 visit and if an appropriately qualified member 
of the study team or the subject’s care giver is available, then arrangements may be made to conduct some of the visits at the subject’s home to reduce the 
number of visits to the sites. Alternatively a Home Health Agency may be utilized. The subject would be required to sign an extra IRB/EC approved consent 
form to permit the site to share the subject’s details with the agency in order for them to collect the samples/conduct the assessments. 

Study Protocol SCIG03, Version 6, 22March 2017 
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Bio Products Laboratory Ltd. 
CONFIDENTIAL 
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This protocol or information contained in this document will be treated as confidential at all times and may not be reproduced or communicated to a third party without the 
written permission of Bio Products Laboratory Ltd. (BPL).  It shall be used for the sole information of the Investigator’s team and Staff must undertake not to disclose any such 
information to any person not involved in the study. 
 
Table 3 
Pharmacokinetic Assessment Schedule for Subgam-VF (Week 21 to Week 22a, b, d) 
Evaluation  
Before start of 
infusion 
Day 0  
 
Time after end of infusion 
Approx. 
-30 min 
1 day 
(24 hours) 
± 2 hours 
2 days 
(48 hours) 
± 4 hours 
3 days 
(72 hours) 
± 6 hours 
5 days 
(120 hours) 
± 8 hours 
7 daysc 
(168 hours) 
± 12 hours 
IgG  
X 
X 
X 
X  
X 
X 
Reserve sample 
X 
X 
X 
X  
X 
X 
 
a If the PK sampling cannot be completed at Week 21 (eg. due to patients work/vacation schedule) then this can be delayed to start at Week 22, 23, 24 or 25; 
however, the patient should still visit the office/hospital for their week 21 infusion and complete the other assessments scheduled for Visit 8, if possible. Week 22 
assessments (Visit 9) will normally coincide with the PK sampling Day 7.  However, if PK sampling is delayed, Visit 9 will also be delayed.. 
 
b If the infusion just prior to PK sampling has to be rescheduled, then the PK sampling should be postponed to ensure that the PK samples are collected seven 
days after the last Subgam-VF infusion and the sampling times in Table 3 are adhered to.  
 
c The PK sample must be collected before the infusion scheduled for that day is started. 
 
d In exceptional circumstances, and with prior Sponsor approval, if one of the following PK samples if lost, unevaluable, or not taken it may be taken at the same 
timepoint during the week following the PK assessment, as long as the same dose in mg/kg has been given: 
o 1 day (24 hours ± 2 hours) 
o 2 days (48 hours ± 4 hours) 
o 3 days (72 hours ± 6 hours) 
o 5 days (120 hours ± 8 hours). 
 
 

Study Protocol SCIG03, Version 6, 22March 2017
Bio Products Laboratory Ltd. 
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This protocol or information contained in this document will be treated as confidential at all times and may not be reproduced 
or communicated to a third party without the written permission of Bio Products Laboratory Ltd. (BPL).  It shall be used for 
the sole information of the Investigator’s team and Staff must undertake not to disclose any such information to any person not 
involved in the study. 
APPENDIX V- MAXIMUM BLOOD WITHDRAWAL VOLUMES 
 
 
Table 4  IRB Maximum Allowable Total Blood Draw Volumes (Clinical + Research) 
 
Body 
Wt 
(Kg) 
Body Wt 
(lbs) 
Total blood 
volume 
(mL) 
 
Maximum 
allowable volume 
(mL) in one 
blood draw 
( = 2.5% of total 
blood volume) 
Total volume 
(clinical + 
research)     
maximum 
volume  (mL) 
drawn in a 30-
day period 
Minimum 
Hgb required 
at time of 
blood draw 
Minimum Hgb 
required at time 
of blood draw if 
subject has 
respiratory/CV 
compromise 
1 
2.2 
100 
2.5 
5
7.0
9.0 -10.0 
2 
4.4 
200 
5 
10
7.0
9.0-10.0 
3 
6.3 
240 
6 
12
7.0
9.0-10.0 
4 
8.8 
320 
8 
16
7.0
9.0-10.0 
5 
11 
400 
10 
20
7.0
9.0-10.0 
6 
13.2 
480 
12 
24
7.0
9.0-10.0 
7 
15.4 
560 
14 
28
7.0
9.0-10.0 
8 
17.6 
640 
16 
32
7.0
9.0-10.0 
9 
19.8 
720 
18 
36
7.0
9.0-10.0 
10 
22 
800 
20 
40
7.0
9.0-10.0 
11-15 
24-33 
880-1200
22-30 
44-60
7.0
9.0-10.0 
16-20 
35-44 
1280-1600
32-40 
64-80
7.0
9.0-10.0 
21-25 
46-55 
1680-2000
42-50 
64-100
7.0
9.0-10.0 
26-30 
57-66 
2080-2400
52-60 
104-120
7.0
9.0-10.0 
31-35 
68-77 
2480-2800
62-70 
124-140
7.0
9.0-10.0 
36-40 
79-88 
2880-3200
72-80 
144-160
7.0
9.0-10.0 
41-45 
90-99 
3280-3600
82-90 
164-180
7.0
9.0-10.0 
46-50 
101-110 
3680-4000
92-100
184-200
7.0
9.0-10.0 
51-55 
112-121 
4080-4400
102-110
204-220
7.0
9.0-10.0 
56-60 
123-132 
4480-4800
112-120
224-240
7.0
9.0-10.0 
61-65 
134-143 
4880-5200
122-130
244-260
7.0
9.0-10.0 
68-70 
145-154 
5280-5600
132-140
264-280
7.0
9.0-10.0 
71-75 
156-185 
5680-6000
142-150
284-300
7.0
9.0-10.0 
76-80 
167-176 
6080-6400
152-160
304-360
7.0
9.0-10.0 
81-85 
178-187 
6480-6800
162-170
324-340
7.0
9.0-10.0 
86-90 
189-198 
6880-7200
172-180
344-360
7.0
9.0-10.0 
91-95 
200-209 
7280-7600
182-190
364-380
7.0
9.0-10.0 
96-100 
211-220 
7680-8000
192-200
384-400
7.0
9.0-10.0 
Source: Tables used by the Committee on Clinical Investigations, Children’s Hospital in Los Angeles, CA; Baylor College of Medicine, 
Dallas, TX; and Cincinnati Children’s Hospital Institutional Review Board, OH