A Phase 3, Multicenter, Open-Label Study of the Safety, Tolerability, Efficacy, and PK of ProMetic BioTherapeutics IGIV (Human) 10% in Adults and Children With Primary Immunodeficiency Diseases
Phase: PHASE3
Conditions: Primary Immunodeficiency
Sponsor: Prometic Biotherapeutics, Inc.

Protocol No. 2004C009G 
Version 5 
Immune Globulin Intravenous (Human) 10% 
ProMetic BioTherapeutics, Inc. 
Confidential 
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CLINICAL PROTOCOL 
2004C009G 
 
A Phase 3, Multinational, Multicenter, Open-Label Study of the Safety, Tolerability, 
Efficacy, and Pharmacokinetics of ProMetic BioTherapeutics Immune Globulin 
Intravenous (Human) 10% in Adults and Children 
with Primary Immunodeficiency Diseases 
Clinical Development Phase: 
3 
 
Sponsor: 
ProMetic BioTherapeutics, Inc. 
1330 Piccard Drive, Suite 201 
Rockville, MD 20850 
 
Medical Monitor: 
Joseph Parker, MD 
 
Clinical Study Manager: 
Atlantic Research Group, Inc. 
Issue Date: 
December 22, 2016 
Version: 
Version 5 
 
 
 
 
CONFIDENTIAL – PROPRIETARY INFORMATION 

Protocol No. 2004C009G 
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SIGNATURES 
 
Sponsor Signature 
 
Study Title: 
A Phase 3, Multinational, Multicenter, Open-Label Study of the 
Safety, Tolerability, Efficacy, and Pharmacokinetics of ProMetic 
BioTherapeutics Immune Globulin Intravenous (Human) 10% in 
Adults and Children with Primary Immunodeficiency Diseases 
Study Number: 
2004C009G 
Version/Date: 
Version 5 / December 22, 2016 
 
 
This protocol has been approved by ProMetic BioTherapeutics, Inc. This study will be 
conducted in compliance with the protocol, US Code of Federal Regulations, EU Studies 
Directives, International Conference on Harmonisation (ICH) Guidelines for Good 
Clinical Practice (GCP), and any other applicable requirements. 
 
 
Signed: 
Joseph M. 
Parker, MD 
Digitally signed by Joseph M. Parker, MD 
DN: cn=Joseph M. Parker, MD, 
o=ProMetic BioTherapeutics, ou, 
email=j.parker@prometic.com, c=US 
Date: 2016.12.22 17:44:30 -05'00' 
 
 
Date: 
 

Protocol No. 2004C009G 
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Signature of Principal Investigator 
 
Study Title: 
A Phase 3, Multinational, Multicenter, Open-Label Study of the 
Safety, Tolerability, Efficacy, and Pharmacokinetics of ProMetic 
BioTherapeutics Immune Globulin Intravenous (Human) 10% in 
Adults and Children with Primary Immunodeficiency Diseases 
Study Number: 
2004C009G 
Version/Date: 
Version 5 / December 22, 2016 
 
 
I, the undersigned, have read the protocol and agree to conduct this study in accordance 
with ethical principles that have their origin in the Declaration of Helsinki and are 
consistent with the International Conference on Harmonisation (ICH) guidelines for 
Good Clinical Practice (GCP), EU Studies Directives, and all applicable local and federal 
regulatory requirements. 
I will provide copies of the protocol and access to all information furnished by the 
sponsor to study personnel under my supervision. I will discuss this material with them to 
ensure they are fully informed about the investigational product and the study. I 
understand that the study may be terminated or enrollment suspended at any time by the 
sponsor with or without cause, or by me if it becomes necessary to protect the best 
interests of the study subjects. 
 
 
 
 
Signed: 
Date:   
 
 
Name:    
 
 
Title:   
 
 
Address:   
 
 
 
 
Telephone:    
 

Protocol No. 2004C009G 
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Protocol Synopsis 
 
Name of Sponsor: ProMetic 
BioTherapeutics, Inc. 
Name of Investigational Medicinal Product 
(IMP): 
Immune Globulin Intravenous (Human) 
10% (IGIV) 
Protocol # 2004C009G 
IND# 016287 
Protocol Title: A Phase 3, Multinational, Multicenter, Open-Label Study of the 
Safety, Tolerability, Efficacy, and Pharmacokinetics of ProMetic 
BioTherapeutics Immune Globulin Intravenous (Human) 10% in 
Adults and Children with Primary Immunodeficiency Diseases 
Clinical 
Phase: 
Phase 3 (Pivotal) 
Treatment 
Indication: 
For the treatment of children and adults with primary 
immunodeficiency diseases (PIDD) who require immunoglobulin G 
(IgG) replacement therapy 
Purpose and 
Objectives: 
Purpose 
To assess the tolerability, safety, efficacy and pharmacokinetics (PK) 
of the investigational medicinal product (IMP), ProMetic Immune 
Globulin Intravenous (Human) 10%, in subjects with PIDD. 
Efficacy Objectives 
Primary Objective 
• To examine the rate of clinically documented serious bacterial 
infections (SBIs) in subjects treated with the IMP to achieve a rate 
of less than one SBI per year. 
Secondary Objectives 
To examine the effect of the IMP on the following: 
• Serum trough concentrations of total IgG obtained prior to each 
IMP infusion; 
• Number of episodes of fever (≥100.4°F); 
• Number of days out of work/school/kindergarten/daycare or 
unable to perform normal daily activities due to infections; 
• Number of days of hospitalization due to infections; 
• Number of days of antibiotic use for infection prophylaxis and/or 
treatment; 

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• Incidence of infections other than acute serious bacterial 
infections. 
Safety Objectives 
• To examine the safety and tolerability of the IMP; 
• To collect adverse events (AEs) from the signing of informed 
consent to 21 days (± 2 days) or 28 days (± 2 days) days after the 
last infusion, depending on the subject’s treatment schedule; 
• To examine total AEs and the observed proportion of AEs 
considered by the Sponsor to be IMP related; 
• To examine AEs temporally associated (during and within 
72 hours after the end of the infusion) with the IMP infusion, 
which will be recorded regardless of relationship to the IMP; 
• To examine infusion- and rate-related AEs, regardless of 
relationship to the IMP; 
• To monitor safety approximately 7 days post infusion; 
• To examine long-term safety with virology testing from Screening 
to the Long-Term Safety Visit (LTSV); 
• To monitor for immunogenic reactions by testing for antibodies to 
ß-2 glycoprotein I (ß2GPI) and to ß-2 glycoprotein I domain I 
(β2GPI-DI), from baseline to the LTSV; 
• To monitor for thrombogenicity and hemolysis by performing 
post-infusion clinical evaluations and laboratory testing. 
Pharmacokinetic Sub-study Objectives 
• To determine the steady state serum concentrations of total IgG; 
• To determine the PK profiles for total IgG following 
administration of the IMP. 
Study Plan: 
This is a pivotal phase 3, open-label, single-arm, multinational, 
multicenter study to assess the tolerability, safety, efficacy, and 
pharmacokinetics of the IMP in adults and children with PIDD. The 
study will be conducted at up to 20 sites in the United States and 
Russia. All subjects will be treated as outpatients with ProMetic 
BioTherapeutics Immune Globulin Intravenous Solution 10% (the 
IMP) for approximately 1 year. 
A total of approximately 75 subjects aged 2-80 years will be enrolled 
in the study: approximately 50 subjects aged 17-80 years (Cohort 1) 
and approximately 25 children aged 2 to <17 years (Cohort 2). Only 
subjects 18 years of age and older, treated with commercially licensed 

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immune globulin product, will be enrolled by Russian sites, in 
accordance with Russian national legislation. 
This is an open-label study; no subject or study personnel will be 
blinded. 
A subset of subjects will be asked to participate in a PK sub-study 
(Section 6.13). Subjects who consent to participate in the PK 
sub-study will undergo a series of blood draws to assess the PK 
profile of the IMP before and after Infusion 6 (21-day cycle subjects) 
or Infusion 5 (28-day cycle subjects). 
Safety Precautions at Enrollment 
To enhance subject safety, IMP will initially be given only to subjects 
aged 18-80 years currently treated with a stable dose of immune 
globulin, with the timing of the first IMP infusion at staggered 
intervals in Groups 1 and 2. The study will proceed to Group 3 only 
after evaluation and Food and Drug Administration (FDA) review of 
safety data obtained at Week 4 (or Week 3 for patients on a 3-week 
treatment regimen) after the first IMP infusion in 15 subjects. The 
procedures will be as follows: 
• Group 1: The first IMP infusion in the first five subjects will be 
staggered at 2-week intervals, and blood samples for interim 
safety testing, including the three assays for antibodies to β2GPI 
(two for total β2GPI and one for β2GPI-DI), will be drawn before 
the second infusion (at Week 4 in subjects on a 4-week treatment 
regimen; Week 3 in subjects on a 3-week treatment regimen). 
While these first five subjects continue on IMP and before further 
subjects receive IMP, the results will be evaluated by the 
Investigators and the Data Safety Monitoring Board (DSMB) and 
submitted to the FDA for review. 
• Group 2: Contingent on FDA and DSMB approval after review of 
the interim safety results in Group 1, 10 further subjects will 
receive the first IMP infusion staggered at an interval to be 
determined by the FDA after review of the Group 1 results. As in 
Group 1, blood samples for safety testing will be drawn before the 
second infusion (Week 4 or 3, depending on treatment regimen). 
While these 10 subjects continue on IMP and before further 
subjects receive IMP, the results will be evaluated by the 
Investigators and the DSMB and submitted to the FDA for review. 
• Group 3: Contingent on FDA and DSMB approval after review of 
the interim safety testing in Group 2, the study will continue with 
IMP infusions in approximately 60 further subjects, including 
approximately 35 adults to complete Cohort 1 and approximately 
25 children in Cohort 2. The starting date of the first IMP infusion 
in this group will not be staggered. 

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If special circumstances of clinical management, and anticipated 
treatment cycle scheduled date, make it necessary to reduce the 
2-week staggering interval for subjects in Group 1, the interval 
between subjects may be decreased to a minimum of 10 days. 
To overcome the challenges of scheduling subjects for their first IMP 
infusion to fit their current treatment schedule, all eligible subjects 
will be screened by study sites and enrolled in the study after giving 
informed consent. Enrolled subjects will continue treatment with their 
current commercially licensed immune globulin product under the 
care of the Investigator until the scheduled time of their first IMP 
infusion. Subjects who have previously been receiving immune 
globulin as part of a clinical trial, or coming off of IGSC, will be 
treated with a commercially available IGIV selected by the 
Investigator in consultation with their treating physician. 
Eligible subjects aged 18-80 years will be randomized in a 
1:1:1 fashion to Groups 1, 2, and 3. When 5 subjects have been 
enrolled in Group 1, this group will be closed, and randomization will 
continue 1:1 to Groups 2 and Group 3. Group 2 will be closed when 
10 subjects have been enrolled, and all subjects subsequently enrolled 
in the study will be placed in Group 3. Once the FDA and the DSMB 
has approved the safety profile of Groups 1 and 2, all subjects in 
Group 3 will begin to receive IMP. To be eligible for enrollment, 
subjects must have been treated with a stable dose of commercially 
licensed immune globulin administered intravenously (IGIV) for at 
least 3 consecutive treatments at 21 or 28 day intervals with 
documented trough levels, or subcutaneously (IGSC) for at least 
12 weeks with documented steady state levels, as defined in the 
Inclusion Criteria (Section 4.3.1). The following subjects will not be 
eligible for randomization and will be assigned to Group 3: 
• Subjects receiving treatment with another investigational 
immune globulin at enrollment (SC or IV) 
• Subjects receiving IGSC 
• Subjects aged < 18 years 
This randomization scheme is designed to: 
• Minimize potential selection bias, so that the interim safety 
analyses will be based on randomly assigned subject populations 
• To ensure no child is enrolled into the safety groups and receive 
IMP before the FDA has approved the safety of the product in 
adults 
• To allow subjects currently receiving another Investigational 
Medical Product to be stabilized on an approved commercially- 
available IGIV for at least 3 months prior to receiving IMP 

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• Provide data on adverse events, including episodes of hemolysis 
or thrombosis, as well as immunologic testing (anti-β2GPI and 
anti-β2GPI-DI antibodies) in subjects currently receiving 
commercially licensed IGIV product, as well as in subjects 
receiving the IMP. 
This schema for the staggered administration of IMP will result in the 
following two time periods for each individual subject: 
Waiting Period: This is the elapsed time from enrollment to the first 
administration of IMP. During this time period, subjects will receive 
either their current commercially licensed product (CP) or a CP 
chosen by the Principal Investigator in consultation with their treating 
physician. All relevant safety and efficacy endpoints will be recorded 
and summarized for this time period. 
IMP Treatment Period: For each subject, this is the elapsed time 
from the first administration of IMP to study completion. During this 
time period, subjects will receive the IMP, ProMetic BioTherapeutics 
Immune Globulin Intravenous (Human) 10%. All planned safety and 
efficacy endpoints will be recorded and summarized for this time 
period. All primary and secondary efficacy analysis is restricted to 
data collected during this time frame. 
Treatment 
Waiting Period on Commercial Product 
Subjects who enroll in the study while on commercial immune 
globulin product and who need to wait for the scheduled start of their 
IMP treatment will continue on their usual dose and treatment cycle 
during the Waiting Period on commercial product. 
Subjects who have been receiving another IGIV or IGSC 
investigational product and subjects who have been receiving 
commercial IGSC will be switched to a commercial IGIV product as 
selected by the Investigator in consultation with their treating 
physician on enrollment. 
IMP Treatment Period 
Subjects on commercial IGIV therapy before study entry, who will 
continue on their usual regimen during the Waiting Period, will switch 
to IMP at the same dose and treatment interval. For subjects on IGSC 
therapy before study entry, the IMP dose will be calculated based on 
the current IGSC dose, and the IMP treatment interval will be the 
same as their prior IGIV treatment interval (Section 13.6.1). 
Doses can be adjusted by the Principal Investigator (PI) as described 
in Section 13.6.1 and IMP infusion rates will be adjusted during all 
visits to a tolerable level according to a preset algorithm described in 
Section 13.6.2. 

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Evaluations 
Analyses of all primary and secondary efficacy endpoints will be 
restricted to data collected during the IMP treatment period (Section 5 
and Section 12). However, the same assessments will be recorded and 
summarized for the period on commercial product as for the IMP 
treatment period (Section 6). 
The interim safety evaluations of Groups 1 and 2 will look for 
evidence of immunogenicity, hemolysis and thrombosis based on 
clinical signs and laboratory tests (hematology, blood chemistry, 
urinalysis, hemolysis, d-dimer, protein C and protein S concentrations, 
antibodies to ß2GPI and β2GPI-DI) in samples drawn before the 
second infusion (at Week 4 in subjects on a 4-week treatment cycle; 
Week 3 in subjects on a 3-week treatment cycle) (Section 8.1). 
Subject 
Population: 
Main Study 
To achieve 60 evaluable subjects, approximately 75 eligible subjects 
aged 2 to 80 years will be enrolled. Two cohorts will be separately 
enrolled to ensure an adequate number of subjects in each age group. 
Cohort 1 will enroll approximately 50 subjects aged 17 to 80 years to 
achieve at least 40 evaluable subjects. 
Cohort 2 will enroll approximately 25 subjects to achieve at least 
20 evaluable subjects. Cohort 2 will enroll up to 6 subjects aged 2 to 
<6 years, at least 6 subjects aged 6 to <12 years, and at least 6 subjects 
aged 12 to <17 years. 
Note: Only adult subjects (≥18 years) can be randomized to Groups 1, 
2, and 3 during the Evaluation Period. Pediatric subjects (< 18 years) 
are directly enrolled into Group 3. After randomization is closed for 
Groups 1 and 2, additional subjects, regardless of age, will be enrolled 
in Group 3. 
PK Sub-study 
The PK sub-study will be conducted in a subset of each cohort: 
• Approximately 25 subjects in Cohort 1 will be enrolled to achieve 
18 evaluable subjects for PK analysis. 
• Approximately 18 subjects in Cohort 2 will be enrolled to achieve 
12 evaluable subjects for PK analysis. Up to 6 subjects will be 
analyzed for PK in each of the following age groups: 2 to 
<6 years, 6 to <12 years, and 12 to <17 years. 
Inclusion 
Criteria: 
1. Subject is male or female between the ages of 2 and 80 years 
at Screening. 

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o For Russian sites, only subjects 18 years of age and older, 
treated with commercially licensed immune globulin 
product will be enrolled. 
o For Cohort 1, all subjects will be aged ≥17 to 80 years. 
o For Cohort 2, subjects will be aged 2 to <17 years 
2. Subject or parent(s)/legal guardian has given written informed 
consent/assent (as applicable). Pediatric subjects are defined as 
2 to <17 years of age at study entry and will require assent 
forms as appropriate. 
3. Subject or parent(s)/legal guardian agrees to comply with the 
requirements of the protocol. 
4. Female subjects of childbearing potential must have a negative 
urine pregnancy test documented at the visit at which they 
receive the first infusion of IMP and must agree to employ 
adequate birth control measures, as determined by their 
Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC), for the duration of the study. 
5. The subject must have established one of the following three 
diagnoses (isolated PIDD of other types will be excluded): 
o Common variable immunodeficiency (CVID) 
o X-linked agammaglobulinemia (XLA) 
o Hyper-IgM syndrome and documented low IgG 
levels (< 4.5 mg/mL [< 450 mg/dL]). 
6. Subjects must have been treated with a stable dose of immune 
globulin administered intravenously (IGIV) or subcutaneously 
(IGSC), as defined below. 
o For IGIV, a stable dose is defined as administration of a 
dose of 200-800 mg/kg, with no more than 25% change 
during at least 3 consecutive treatments at 21-day 
(±4 days) or 28-day (±4 days) dosing intervals. 
o For IGSC, a stable dose is defined as administration of a 
dose of 300-900 mg/kg/month IV (or Sub-cutaneous 
equivalent), regardless of dosing schedule, with no more 
than 25% change during at least 12 weeks. 
7. Subjects who are receiving IGSC when they enter the study 
must have received at least one documented IGIV infusion in 
the past without an associated serious adverse event. 
8. Documented trough or steady state levels 
o Subjects who are receiving IGIV when they enter the study 
have at least 2 documented serum IgG trough levels of 

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≥ 5 mg/ mL measured in the prior 6 months. One of these 
can be the serum IgG level at Screening. 
o Subjects who are receiving IGSC have at least 
2 documented serum IgG steady state levels of ≥ 5 mg/mL 
in the prior 24 weeks. One of these can be the serum IgG 
level at Screening. 
9. Authorization to access personal health information. 
Exclusion 
Criteria: 
1. Subject has secondary immunodeficiency or has been diagnosed 
with dysgammaglobulinemia or isolated IgG subclass deficiency. 
2. Subject has ever had a history of severe anaphylactic or 
anaphylactoid reaction to immunoglobulins or other blood 
products. 
3. Subject has a known history of immunoglobulin A (IgA) 
deficiency and known anti-IgA antibodies. (Note that subjects with 
IgA deficiency without known antibodies to IgA may be enrolled.) 
4. Subject has had a thrombotic event, such as deep vein thrombosis, 
myocardial infarction, cerebrovascular accident, pulmonary 
embolism, at any time. 
5. Subject has received blood products except IGIV, IGSC, or 
albumin within the previous 12 months. 
6. Subject has participated in another study (except IGIV, IGSC 
studies) within the previous 4 weeks. 
7. Subject has had cancer in the past 5 years, except for basal cell or 
squamous cell cancers of the skin. 
8. Subject has current or prior diagnosis of malignancies of lymphoid 
cells such as lymphocytic leukemia, non-Hodgkin’s lymphoma, or 
immunodeficiency with thymoma. 
9. Subject has known hypoalbuminemia (< 3 gm/dL), protein-losing 
enteropathy, or nephrotic syndrome. 
10. Subject has had a documented active infection within 7 days prior 
to Screening, or subject is on continuous prophylactic antibiotics. 
Subjects receiving a course of antibiotic treatment for a recent 
bacterial infection, which is controlled, can be enrolled into the 
study. 
11. Subject is positive for human immunodeficiency virus (HIV)-1 or 
HIV-2. 
12. Subject has a positive hepatitis C virus (HCV) or hepatitis B virus 
(HBV) nucleic acid test (NAT) performed by qualitative or 

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quantitative polymerase chain reaction (PCR) in the past 
12 months. 
13. Subject has levels of alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) > 2.5 times the upper limit of normal 
(ULN). 
14. Subject has serum creatinine >1.5 times the ULN or a severe 
chronic condition such as renal failure with proteinuria. 
15. Subject has anemia with a hemoglobin level ≤ 8 g/dL. 
16. Subject has severe neutropenia with neutrophil count 
≤ 1,000 per mm3 or has lymphopenia with < 500 per mm3. 
17. Subject is taking prednisone at a dose ≥ 0.15 mg/kg/day. (Topical 
steroids for skin conditions, steroid eye drops, chronic use of 
inhaled steroids for asthma, and intranasal steroids for rhinitis are 
allowed). Exception: A brief course of systemic steroids above this 
threshold (i.e., a steroid burst) is allowed for treatment of a 
short-term condition such as an asthma exacerbation or poison ivy 
exposure. 
18. Subject is receiving other immunosuppressive drugs or 
chemotherapy. 
19. Subject has known atrial fibrillation requiring anticoagulant 
therapy; congestive heart failure (New York Heart Association 
Class III/IV); cardiomyopathy; or cardiac arrhythmia associated 
with thromboembolic events, unstable or advanced ischemic heart 
disease, or hyperviscosity. 
20. Subject has known decreased Protein C and/or Protein S levels. 
21. Subject is positive for antibodies to β2GPI and/or β2GPI-DI at 
Screening. 
22. Female subject who is pregnant, breast-feeding, or planning a 
pregnancy during the course of the study. 
23. A history of epilepsy or multiple episodes of migraine (defined as 
at least one episode within 6 months of enrolment) not completely 
controlled by medication, or any condition that is likely to 
interfere with evaluation of the IMP or satisfactory conduct of the 
study in the Investigator and Medical Monitor’s opinion. 
Study Sites: 
This study will be conducted at up to 20 sites in the United States and 
Russia. 
Investigational 
Medicinal 
Products, 
Dose, Dosage 
ProMetic BioTherapeutics IGIV is a 10% liquid formulation of 
human IgG in 50 mL vials containing 100 mg/mL of IgG. 

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regimen, 
Treatment 
period, 
Formulation, 
Mode of 
Administration 
The IMP will be administered every 3 or 4 weeks, depending on the 
subject’s previous IGIV treatment schedule, for approximately 
1 year. 
To maintain a trough IgG level of at least 5 mg/mL, the dose of the 
IMP administered will be calculated by the Investigator using the 
subject’s body weight and, for subjects previously receiving IGIV, 
will be consistent with the previous IGIV dose. For determination of 
the IGIV dosage for subjects previously receiving IGSC, the total 
IGSC dose corresponding to one 3- or 4-week cycle will be divided 
by a dose-adjustment coefficient as indicated by package insert (see 
Section 13.6.1). The maximum infusion rate per minute must not 
exceed 8.0 mL/min in any subject. 
Infusion Rate for Infusion 1 and Infusion 2 
The first two infusions will be administered according to the 
following algorithm: For the first 30 minutes, IMP will be initiated at 
an infusion rate of 0.01 mL/kg/min. If, in the Investigator’s opinion, 
the rate is well tolerated, the rate may be increased to 
0.02 mL/kg/min for the next 30 minutes. If the increase is well 
tolerated, the infusion rate may be increased to 0.04 mL/kg/min for 
the next 30 minutes. If well tolerated, the remainder of the infusion 
may be administered at a maximum infusion rate of between 
0.06 mL/kg/min and 0.08 mL/kg/min, depending on the subject’s 
body weight. The maximum infusion rate per minute must not exceed 
8.0 mL/min in any subject. If an AE occurs during the first dose, the 
infusion rate should be adjusted or halted in accordance with 
Section 10.2. 
Infusion Rate for Infusion 3 Onward 
The rate for infusion 3 onward will follow the same algorithm of 
infusion rate increase for the first two doses, but the increases can be 
implemented every 15 minutes instead of 30 minutes. 
Study 
Duration: 
Duration of Subject Participation 
The screening period before administration of the first dose of IMP 
will depend on the subject’s infusion cycle: 21 days for subjects on a 
21-day cycle, 28 days for subjects on a 28-day cycle, and up to 
17 days for subjects on IGSC infusions. 
To cover seasonal variations, all subjects will be treated with the IMP 
for approximately one year. After the last infusion, AEs will be 
monitored for 21 days (±2 days) or 28 days (±2 days) days, depending 
on the infusion cycle, and all subjects will then return for a long-term 
safety visit (LTSV), at Week 51 for subjects on a 21-day cycle and 
Week 52 for those on a 28-day cycle. 

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However, the expected total duration of subject participation from 
enrollment to LTSV will include the Waiting Period on commercial 
product treatment. This period will vary, depending on the date of 
enrollment and the start of IMP treatment in the assigned scheduling 
group. 
The safety evaluation phase (including an evaluation at Week 4 for 
subjects on a 4-week treatment regimen; Week 3 for subjects on a 
3-week treatment regimen after the first IMP infusion in five subjects 
and another at Week 4 or 3, depending on treatment regimen, after the 
first IMP infusion in the next 10 subjects, with the start of IMP 
treatment at staggered intervals) is expected to be completed by 
Study Week 36. Thus, if there is no delay in completing the two 
evaluations, a subject enrolled in the study at the beginning of 
recruitment and assigned to Group 3 (start of IMP after both 
evaluations are complete) would have a Waiting Period on 
commercial product of 36 weeks. The total study duration for this 
subject would be 88 weeks (approximately 21 months). Subjects who 
enroll at a later time and are assigned to Group 3 would have a shorter 
Waiting Period and a correspondingly shorter total study duration. 
Total Study Duration 
This study will be conducted at up to 20 adult and pediatric centers in 
the US and Russia which specialize in treating patients with 
immunodeficiencies. 
The study duration in adults will comprise recruitment, screening, and 
evaluation of the first 15 subjects to receive IMP, as well as continued 
screening during the safety evaluation period, and treatment with 
commercial IGIV product for subjects who must wait for the first 
scheduled IMP infusion. The total study time is expected to be at least 
2 years for Cohort 1. 
Children will not be included in Groups 1 and 2, but they may be 
screened, enrolled into Group 3, and treated with commercial product 
during the evaluation period, and once the safety groups are approved 
by the FDA they can receive the first IMP infusion. 
If the adult cohort finishes before the pediatric cohort, there will be 
two database locks and two clinical study reports, one for adult 
licensure and one for pediatric licensure (Section 12.5). 
Criteria for 
Evaluation: 
Primary Efficacy Endpoints: 
The rate of clinically documented SBIs, defined as: 
• Bacterial pneumonia 
• Bacteremia and septicemia 

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• Osteomyelitis / septic arthritis 
• Bacterial meningitis 
• Visceral abscess 
Secondary Efficacy Endpoints: 
• Total serum IgG trough levels 
• Episodes of fever (≥ 100.4°F) 
• Number of days out of work/school/kindergarten/day care or 
unable to perform normal daily activities due to infection 
• Number of days of hospitalization due to infection 
• Number of days of antibiotic use for infection prophylaxis 
and/or treatment 
• Number and duration of infections other than acute serious 
bacterial infections 
Safety Endpoints: 
• All AEs reported 
• Rate (per infusion per subject), severity, and relatedness of 
AEs 
• Frequency of temporally associated AEs 
• Infusional AEs 
• Assessment of local tolerability to IMP infusions 
• Adverse reactions/suspected adverse reactions 
• Vital sign changes, including changes in systolic and diastolic 
blood pressure, heart rate, respiratory rate, and body 
temperature 
• Changes from Screening in physical examination findings 
• Changes from Baseline in laboratory parameters (blood 
chemistry, hematology, urinalysis, hemolysis, d-dimer, protein 
S, and protein C concentrations, titers of antibodies to ß2GPI 
and β2GPI-DI) 
• Frequency of clinical signs of hemolysis and/or thrombosis 
within 72 hours after infusion of the IMP 
• IGIV-associated hemolysis 
• Changes from Screening in viral markers (HAV, HBV, HCV, 
HIV-1, HIV-2, and B19) 

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• Comparisons of safety variables during treatment with IMP 
and during the Waiting Period on commercial product will be 
made as described in Section 12.3.4. 
Pharmacokinetic Endpoints (sub-study) 
• Total IgG levels 
• Area under the concentration-time curve over 1 dosing interval 
(AUC0-t) 
• Area under the concentration-time curve extrapolated to 0 
concentration (AUC0-inf) 
• Peak serum concentration (Cmax) 
• Time to reach peak serum concentration (Tmax) 
• The volume of distribution at steady-state (Vss) 
• Mean residence time (MRT) 
• Total body clearance (CL) 
• Terminal half-life (t1/2) 
Statistical 
Methods: 
Sample size 
To calculate the approximate power for this study, it is assumed that 
the number of SBIs experienced per subject per year follows a 
negative binomial distribution with mean μ and variance σ2 = μ(1+ϕμ) 
where ϕ represents an overdispersion parameter reflecting possible 
inter-subject variability in the rates of SBIs between subjects. To 
demonstrate efficacy, it is required that the observed mean number of 
SBIs across the study population should have an upper 99% one-sided 
confidence limit below 1 infection per subject per year. This is 
equivalent to testing the one-sided null hypothesis, H0: μ≥1, against 
the alternative hypothesis, H0: μ<1, where μ is the population mean 
rate of SBI’s per subject per year. 
Based on the mean and variance of the negative binomial distribution, 
standard one-sample power calculations for comparison of an 
observed mean with a theoretical alternative hypothesis indicate that 
for a study with 40 subjects (Cohort 1), the probability of the upper 
one-sided 99% confidence limit being less than 1 remains above 80% 
(power≥0.798) for overdispersion ranging from ϕ=0 (corresponding 
to a Poisson distribution with no overdispersion) to ϕ=2 provided that 
the true mean number of SBIs per subject per year in the population 
lies below 0.50. For a sample of 20 subjects (Cohort 2), this 
probability remains at or above 80% (power≥0.798) for 
overdispersion ranging from ϕ=0 to ϕ=2 provided that the true mean 

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number of SBIs per subject per year in the population lies below 0.40 
(or 0.50 in the case when there is no overdispersion). 
For practical purposes, the study should be considered adequately 
powered to demonstrate efficacy for a population in which the true 
incidence of serious acute bacterial infections is below 0.50 per 
subject per year. 
General statistical approach 
Analyses will be presented for the adult cohort (Cohort 1) and the 
pediatric cohort (Cohort 2) regardless of Study Group both separately 
and combined. 
All subjects who are exposed to at least one dose of the IMP will be 
included in the safety analysis set. The primary efficacy analysis will 
be based on the all treated population analysis set, which will be 
identical to the safety set. In addition, a modified per-protocol 
population analysis set will be defined as only subjects who receive at 
least 6 infusions and provide data. 
No data will be imputed. 
 
Efficacy Analysis 
Primary Efficacy Endpoint 
For the primary endpoint, a 99% one-sided (upper) confidence limit 
for the incidence rate of SBIs (scaled to represent 12 months exposure 
if necessary) will be derived, and the objective of demonstrating that 
the true infection rate is below 1 per subject per year will be 
considered established if this upper limit is less than 1. 
To calculate the confidence limit, a negative binomial regression 
model will be used. This model includes an over-dispersion parameter 
to account for possible intra-subject correlation as well as the actual 
time period each subject is on the study as an offset variable. 
The null hypothesis for this analysis is that the true SBI rate is at least 
1 per subject per year, and the alternative hypothesis is that this rate is 
less than 1 per subject per year. Rejection of the null hypothesis is 
therefore equivalent to demonstration of the study objective to show 
that the true rate is less than 1 SBI per subject per year. 
The proposed method of analysis makes appropriate allowance for any 
intra-subject correlation in the incidence of SBIs. Such correlation 
would occur whenever variability in the subject-specific SBI rates 
exceeds what would be expected in the presence of true Poisson 
variability. The proposed statistical test is based on a negative 
binomial model that includes an overdispersion parameter reflecting 
any such inflated variance. 

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Subgroup analyses will be performed based on gender and region 
(USA, Russia). 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be presented using the appropriate 
descriptive statistics and summarized according to treatment time 
periods (Waiting Period, IMP Treatment Period). No hypotheses will 
be tested. 
No formal statistical analyses will be done comparing primary or 
secondary efficacy endpoints between the Waiting Period on 
commercial product and the IMP Treatment Period. However, any 
efficacy endpoints measured during both the Waiting Period on 
commercial product and IMP Treatment Period may be summarized 
side-by-side using the appropriate descriptive statistics. For the 
Waiting Period on commercial product, the summary descriptive 
statistics will be aggregated over all commercially licensed products. 
 
Safety Endpoints 
Evaluation of safety includes the analysis of laboratory investigations 
and the analysis of adverse events. 
Laboratory Data: 
A summary by treatment period (Waiting period, IMP treatment 
period) will be produced for each of the laboratory parameters at each 
visit. These safety summaries will include descriptive summary tables 
and the data will be summarized in the form of frequency count, 
mean, standard deviation, median, minimum and maximum by 
treatment period and visit. 
Adverse Events: 
The seriousness, severity and relationship to the study drug of adverse 
events (AEs) will be observed and recorded on repeated 
administrations of the study drug using the MedDRA dictionary for 
the coding of AEs and serious adverse events (SAEs). 
The number and proportion of subjects who have one or more AEs 
will be tabulated by seriousness, severity, and relationship to 
treatment according to body system and treatment period. Temporally 
associated AEs will be similarly summarized. Rates of AEs will be 
estimated on a per infusion per subject basis and tabulated by 
seriousness, severity, and relationship to treatment according to body 
system and treatment period. 
The observed proportion will be reported for infusions with one or 
more temporally associated (during and within 72 hours after the end 
of the infusion) AEs (including any AEs considered product related). 
Infusional AEs will also be tabulated by the prevailing infusion rate. 

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The number of infusions with a temporally associated AE (including 
any AEs considered product related) will be analyzed using a negative 
binomial regression model with the objective of demonstrating that 
the rate of infusions with one or more temporally associated AEs is 
less than 40 infusions per 100 patient infusions. This will be 
accomplished by fitting an intercept-only negative binomial regression 
model to the data where the response for each subject is the number of 
affected infusions (i.e., the number of infusions with one or more 
temporally-associated AEs). A two-sided 90% confidence limit on the 
intercept will then be computed on the inverse link scale to achieve an 
upper one-sided 95% confidence limit on the on the expected mean 
number of infusions per 100 patient infusions having one or more 
temporally associated AEs. This upper limit should be below 40 in 
order to statistically demonstrate the safety of the infusion process. 
The operational definition of adverse reaction/suspected adverse 
reaction for analysis purposes will be all AEs meeting any of the 
following criteria: (a) the event began during or within 72 hours 
following the last IMP infusion; (b) the event was considered by the 
investigator and/or the sponsor to be at least possibly related to the 
IMP administration; or (c) the causality assessment was missing or 
indeterminate. 
The operational definition of IGIV-associated hemolysis for this 
analysis is defined as any event meeting the following criteria 
occurring within 10 days following IGIV administration: (a) a fall of 
at least 1 g/dL in hemoglobin from the previous value; (b) a positive 
Coombs test (direct anti-globulin test); and (c) at least 2 of the 
following: increased reticulocyte count, increased LDH, low 
haptoglobin, increased bilirubin, increased plasma free hemoglobin, 
increased urine hemosiderin. 
No formal statistical analyses will be done comparing safety endpoints 
between the Waiting Period and the IMP Treatment Period. However, 
all safety endpoints measured during both the Waiting Period and IMP 
Treatment Period will be summarized side-by-side using the 
appropriate descriptive statistics. For the Waiting Period, the summary 
descriptive statistics will be aggregated over all commercially licensed 
products. 
Pharmacokinetics Endpoints 
For all subjects in the PK sub-study, blood samples will be collected 
for the assessment of serum concentrations of total IgG. The serum 
concentrations will be determined as defined in a laboratory assay 
plan. All PK parameters will be estimated by both compartmental and 
non-compartmental analysis using Phoenix® WinNonlin 6.3 
(Pharsight) and summary statistics will be presented. For all subjects 
in the all treated population dataset, prior to each infusion, trough 

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serum IgG concentrations will also be determined. For the PK 
analysis, the data will be baseline (pre-dose) corrected. 

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Table of Contents 
Protocol Synopsis ............................................................................................ 4 
Table of Contents ........................................................................................... 21 
List of In-text Tables ..................................................................................... 26 
List of Figures ................................................................................................ 26 
List of Abbreviations and Definitions of Terms ............................................ 27 
1 
Introduction .......................................................................................... 30 
1.1 
Background .......................................................................................................30 
1.2 
Immunoglobulin Replacement Therapy for PIDD with Antibody 
Deficiency .........................................................................................................32 
1.3 
Benefit/Risk Statement ......................................................................................32 
1.4 
FDA and DSMB Approval of Interim Safety Results for Group 1 and 
Group 2 ..............................................................................................................34 
2 
Study Rationale and Objectives ............................................................ 34 
2.1 
Study Rationale .................................................................................................34 
2.2 
Dosing Rationale ...............................................................................................34 
2.3 
Study Purpose and Objectives ...........................................................................35 
2.3.1 
Purpose ...........................................................................................................35 
2.3.2 
Primary Efficacy Objective.............................................................................35 
2.3.3 
Secondary Efficacy Objectives .......................................................................35 
2.3.4 
Safety Objectives ............................................................................................35 
2.3.5 
Pharmacokinetic Objectives ...........................................................................36 
3 
Study Plan ............................................................................................. 36 
3.1 
Safety Precautions at Enrollment ......................................................................36 
3.2 
Treatment...........................................................................................................39 
3.2.1 
Waiting Period (Commercial Product Period) ................................................39 
3.2.2 
IMP Treatment ................................................................................................39 
3.3 
Evaluations ........................................................................................................39 
3.4 
Study Flow Chart ...............................................................................................40 
3.5 
Study Duration ..................................................................................................42 
3.5.1 
Duration of Subject Participation ...................................................................42 

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3.5.2 
Total Study Duration ......................................................................................42 
4 
Study Population ................................................................................... 46 
4.1 
Main Study ........................................................................................................46 
4.2 
PK Sub-study .....................................................................................................46 
4.3 
Eligibility Criteria ..............................................................................................46 
4.3.1 
Inclusion Criteria ............................................................................................46 
4.3.2 
Exclusion Criteria ...........................................................................................48 
5 
Efficacy, Safety, and Pharmacokinetic Endpoints ............................... 49 
5.1 
Efficacy Endpoints ............................................................................................49 
5.1.1 
Primary Endpoint ............................................................................................49 
5.1.2 
Secondary Efficacy Endpoints ........................................................................49 
5.2 
Safety Endpoints ................................................................................................50 
5.3 
Pharmacokinetic Endpoints ...............................................................................50 
6 
Study Procedures/Evaluations .............................................................. 51 
6.1 
Medical History .................................................................................................51 
6.2 
Subject Diary .....................................................................................................51 
6.3 
Vital Signs .........................................................................................................52 
6.4 
Physical Examination ........................................................................................52 
6.4.1 
Organ Systems ................................................................................................52 
6.4.2 
Evaluation for Infection ..................................................................................52 
6.4.3 
Height and Weight ..........................................................................................53 
6.4.4 
Chest X-ray .....................................................................................................53 
6.5 
Pregnancy Testing .............................................................................................53 
6.6 
Serum IgG Trough Levels .................................................................................53 
6.7 
Viral Safety Markers .........................................................................................53 
6.8 
General Safety Laboratory Assessments ...........................................................54 
6.9 
Hemolysis ..........................................................................................................55 
6.10 
Immunogenicity Testing ....................................................................................55 
6.11 
3-4 Hour Post-infusion Safety Testing – Indicators of Thrombosis ..................56 
6.12 
Post-infusion Clinical Evaluation for AEs, Hemolysis, and Thrombosis .........56 
6.12.1 
AEs .................................................................................................................56 
6.12.2 
One Hour Post Infusion (IMP/CP) .................................................................56 

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6.12.2.1 
Hemolysis Clinical Evaluation ....................................................................56 
6.12.2.2 
Thrombosis Clinical Evaluation ..................................................................57 
6.12.3 
Phone Calls 24 and 72 Hours after IMP/CP Infusion .....................................58 
6.12.3.1 
AEs ..............................................................................................................58 
6.12.3.2 
Hemolysis Clinical Questions .....................................................................58 
6.12.3.3 
Thrombosis Clinical Questions ...................................................................58 
6.13 
Pharmacokinetic Sub-study ...............................................................................59 
6.13.1 
PK Time Points for Cohort 1 (adults) .............................................................59 
6.13.2 
PK Time Points for Cohort 2 (children) .........................................................60 
7 
Study Schedule ..................................................................................... 60 
7.1 
Schedule of Assessments and Study Events ......................................................60 
7.2 
Pre-screening .....................................................................................................69 
7.3 
Screening Visit ..................................................................................................69 
7.4 
Baseline and IMP/CP Infusion 1 .......................................................................73 
7.5 
IMP/CP Infusions 2, 4, and 8 ............................................................................75 
7.6 
IMP/CP Interim Infusion Visits ........................................................................78 
7.7 
Viral testing (IMP Infusion 5 for 21-day cycle / IMP Infusion 4 for 28- 
day cycle) ..........................................................................................................80 
7.8 
Pharmacokinetic Sub-study (IMP Infusion 6 for 21-day cycle / IMP 
Infusion 5 for 28-day cycle) ..............................................................................80 
7.9 
Treatment Completion/Termination Visit (TCTV): IMP Infusion 17 (21- 
day cycle) or IMP Infusion 13 (28-day cycle)...................................................80 
7.10 
Long-Term-Safety-Visit (LTSV): Week 51 (21-day cycle) or Week 52 
(28-day cycle) ....................................................................................................81 
7.11 
Long-Term-Safety-Follow-up visit (LTSF) for subjects who are 
discontinued from IMP due to adverse events and if study is stopped .............82 
8 
Administrative Considerations ............................................................. 83 
8.1 
Interim Analyses and Stopping Rules for Subjects on IMP ..............................83 
8.1.1 
Immunogenic Reactions .................................................................................86 
8.1.2 
Thrombotic Events ..........................................................................................87 
8.1.3 
Hemolysis .......................................................................................................88 
8.1.4 
Other Reasons for Termination ......................................................................88 
8.2 
Withdrawal Criteria and Replacement of Subjects ...........................................89 
8.3 
Screen Failures ..................................................................................................90 

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8.4 
Subject Identification ........................................................................................90 
8.5 
Treatment Compliance ......................................................................................90 
8.6 
Protocol Deviations ...........................................................................................90 
8.7 
Data Safety Monitoring Board (DSMB) ...........................................................91 
9 
Concomitant and Prohibited Medications ............................................ 92 
9.1 
Commercial Product ..........................................................................................92 
9.2 
Concomitant Medications ..................................................................................92 
9.3 
Prohibited Medications ......................................................................................92 
9.4 
Other Restrictions ..............................................................................................92 
10 
Reporting of Adverse Events ................................................................ 93 
10.1 
Definitions .........................................................................................................93 
10.1.1 
Adverse Event .................................................................................................93 
10.1.2 
Adverse Drug Reaction (ADR) .......................................................................93 
10.1.3 
Infusional and Temporally Associated Adverse Events .................................93 
10.1.4 
Serious Adverse Events (SAEs) .....................................................................93 
10.1.5 
Adverse Event Severity ..................................................................................94 
10.1.6 
Adverse Event Relationship to IMP or CP .....................................................94 
10.2 
Handling and Reporting of Infusional and Temporally Related Adverse 
Events ................................................................................................................95 
10.2.1 
Common Temporally Associated AEs or ADRs ............................................95 
10.2.2 
Subject Monitoring .........................................................................................96 
10.2.3 
Reporting Infusional and Temporally Associated AEs ..................................97 
10.3 
Eliciting and Reporting of Other Adverse Events .............................................97 
10.4 
SAE Reporting ..................................................................................................98 
10.4.1 
SAE Reporting to Safety.................................................................................98 
10.4.2 
Institutional Review Board/Independent Ethics Committee ..........................98 
10.4.3 
Expedited Suspected Unexpected Serious Adverse Reaction (SUSAR) 
Reporting (Sponsor Responsibility) ................................................................99 
10.5 
Pregnancy ..........................................................................................................99 
10.6 
Procedure for Breaking the Blind ....................................................................100 
10.7 
Follow-up of Adverse Events ..........................................................................100 
11 
Pharmacokinetic Analysis .................................................................. 100 
12 
Statistical Analysis ............................................................................. 101 

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12.1 
Analysis Populations .......................................................................................101 
12.2 
Handling of Missing Data ...............................................................................101 
12.3 
Statistical Analysis Plan ..................................................................................101 
12.3.1 
Descriptive analyses .....................................................................................101 
12.3.2 
Primary Efficacy Endpoint ...........................................................................102 
12.3.3 
Secondary Efficacy Endpoints ......................................................................102 
12.3.4 
Safety Endpoints ...........................................................................................103 
12.3.5 
Subgroup Analyses .......................................................................................105 
12.4 
Sample Size .....................................................................................................105 
12.5 
Interim Analysis ..............................................................................................106 
13 
Management of Investigational Medicinal Product ........................... 107 
13.1 
Packaging and Labeling ..................................................................................107 
13.2 
Storage .............................................................................................................107 
13.3 
Accountability .................................................................................................107 
13.4 
Shipment, Returns, and Destruction ................................................................108 
13.5 
Preparation.......................................................................................................108 
13.6 
Dose and Administration of IMP ....................................................................110 
13.6.1 
IMP Dose ......................................................................................................110 
13.6.2 
IMP Administration ......................................................................................110 
13.6.2.1 
IMP Infusion Rate for Infusion 1 and Infusion 2 ......................................111 
13.6.2.2 
IMP Infusion Rate for Infusion 3 Onward ................................................111 
14 
Records Management ......................................................................... 112 
14.1 
Direct Access to Source Data/Documents.......................................................112 
14.2 
Data Collection and Management ...................................................................112 
14.3 
Record Keeping ...............................................................................................112 
15 
Quality Control and Quality Assurance.............................................. 113 
15.1 
Quality Control by the Monitoring Team ........................................................113 
15.2 
Quality Assurance by an Audit Team .............................................................113 
15.3 
Quality Assurance by Data Management ........................................................114 
16 
Ethics and Responsibility ................................................................... 114 
16.1 
Investigational Review Board .........................................................................114 
16.2 
Ethical Conduct of the Study ...........................................................................114 

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16.3 
Informed Consent and Assent .........................................................................115 
16.4 
Changes in the Conduct of the Study ..............................................................116 
17 
Confidentiality .................................................................................... 116 
18 
Publication Policy ............................................................................... 117 
19 
Liabilities and Insurance ..................................................................... 117 
20 
References........................................................................................... 118 
21 
Appendices ......................................................................................... 120 
21.1 
Diagnostic Criteria for Serious Infection Types (FDA Guidance, June 
2008) ................................................................................................................120 
21.2 
Declaration of Helsinki ...................................................................................123 
 
 
 
List of In-text Tables 
Table 1. 
Projected Study Duration - Adults .............................................................44 
Table 2. 
Projected Study Duration - Children ..........................................................45 
Table 3. 
Schedule of Assessments and Study Events for Waiting Period on 
Commercial Product Treatment .................................................................61 
Table 4. 
Schedule of Assessments and Study Events for IMP Treatment ...............64 
Table 5. 
Calculations on Statistical Power .............................................................106 
 
 
List of Figures 
Figure 1. 
Safety Evaluation Phase – Randomized Assignment to Scheduling 
Group .........................................................................................................41 
Figure 2. 
Summary of Stopping Rules ......................................................................85 

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List of Abbreviations and Definitions of Terms 
 
Abbreviation 
Explanation 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
AUC 
Area under the curve 
AUC0-t 
Area under the concentration-time curve over 1 dosing interval 
AUC0-inf 
Area under the concentration-time curve extrapolated to zero 
concentration 
ß2GPI 
ß2 Glycoprotein I 
β2GPI-D1 
ß2GPI Domain I 
B19 
Human parvovirus b19 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CK 
Creatinine kinase 
CL 
Total body clearance 
Cmax 
Peak serum concentration 
CRA 
Clinical research associate 
CRO 
Clinical research organization 
CTA 
Clinical trial application 
CVID 
Common variable immune deficiency 
DAT 
Direct anti-globulin test 
DSMB 
Data Safety Monitoring Board 
DVT 
Deep vein thrombosis 
eCRF 
Electronic case report form 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HAV 
Hepatitis A virus 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 

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HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IgA 
Immunoglobulin A 
IgG 
Immunoglobulin G 
IGIV 
Immune globulin intravenous 
IgM 
Immunoglobulin M 
IGSC 
Immune globulin subcutaneous 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LTSF 
Long-term safety follow-up 
LTSV 
Long-term safety visit 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean residence time 
NAT 
Nucleic acid test 
PCR 
Polymerase chain reaction 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PIDD 
Primary immunodeficiency diseases 
PK 
Pharmacokinetics 
PP 
Per protocol 
QA 
Quality assurance 
QC 
Quality control 

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RBC 
Red blood cell 
RDW 
Red (cell) distribution width 
SAE 
Serious adverse event 
SBI 
Serious bacterial infection 
SC 
Subcutaneous 
SD 
Standard deviation 
SUSAR 
Suspected unexpected serious adverse reaction 
T½ 
Terminal half-life 
TCTV 
Treatment completion/termination visit 
TEE 
Thromboembolic event 
Tmax 
Time to reach peak serum concentration 
TRALI 
Transfusion-related acute lung injury 
ULN 
Upper limit of normal 
Vd 
Volume of distribution 
Vss 
Volume of distribution at steady state 
WBC 
White blood cell 
WHO 
World Health Organization 
XLA 
X-linked agammaglobulinemia 

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1 
Introduction 
 
1.1 
Background 
Primary immunodeficiency diseases (PIDD) are a class of disorders in which there is an 
intrinsic defect in the human immune system, in contrast to immune disorders that are 
secondary to infection, chemotherapy, or some other external agent. PIDD include a 
variety of disorders in which the intrinsic immune defect renders patients more 
susceptible to infections. As a consequence, patients are affected by recurrent protozoal, 
bacterial, fungal, and viral infections. Untreated PIDD may be characterized by frequent 
life-threatening infections. 
More than 220 different PIDD are currently recognized by the World Health 
Organization (Immune Deficiency Foundation, 2015). Antibody deficiencies, also 
referred to as B-cell or humoral immunodeficiencies, comprise the largest group of PIDD 
(International Union of Immunological Societies, 1999). Common PIDD include 
disorders of humoral immunity (affecting B-cell differentiation or antibody production), 
T-cell defects and combined B- and T-cell defects, phagocytic disorders, and complement 
deficiencies (Reust, 2013). 
ProMetic proposes to include in the study the following three well-defined types of 
PIDD, which are associated with humoral immune deficiency and are conventionally 
treated with immunoglobulin therapy: 
• Common variable immunodeficiency (CVID) 
• X-linked agammaglobulinemia (XLA) 
• Hyper-immunoglobulin M (IgM) syndrome and documented low immunoglobulin G 
(IgG) levels (< 4.5 mg/mL) 
Although PIDD are often described as rare disorders, remarkably little is known about the 
true incidence or prevalence in any population, either individually or in the aggregate 
(Bonilla, 2008; Boyle & Buckley, 2007). There is no universal screening for these defects 
at birth or at any time during life, anywhere in the world. Overall, there may be as many 
as 500,000 cases in the United States, of which about 50,000 cases are diagnosed each 
year (Schroeder, 2001). Some disorders, such as selective IgA deficiency, are quite 
common and may occur as often as 1 in 400 individuals (Conley, Notarangelo, & Etzioni, 
1999; Cunningham-Rundles & Bodian, 1999). Others may be as rare as one individual 
affected per million. It has been estimated that 40% of cases are diagnosed in the first 
year of life, with another 40% diagnosed by the age of 5, and another 15% by the age of 
16; only 5% of cases are diagnosed in adulthood (Conley & Stiehm, 1996). 
The largest registry available on patients with PIDD is the European Society for 
Immunodeficiencies (ESID) Registry (Grimbacher & ESID Registry Working Party, 

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2014). As of June 2014, 19,355 patients were included. Children younger than age 
15 years represented two-thirds of the subjects. More than half the patients (57%) had an 
antibody disorder, and this was also the group with the greatest number of adult patients. 
Treatment data were available on approximately 14,000 subjects, of whom 6,476 receive 
immunoglobulin treatment. It is believed that the Registry provides incomplete PIDD 
prevalence data; for example, the prevalence varies from 2 per 100,000 in Germany to 
6 per 100,000 in France. The author believes the apparent difference in prevalence is due 
to the fact that in France there are designated documenters, financed by local grants, who 
visit centers to enter patients’ data into the Registry. 
Boyle and Buckley (Boyle & Buckley, 2007) performed a telephone survey of 
10,000 randomly-selected US households and asked an open-ended question: “Has 
anyone in your household ever been diagnosed with a primary immuno-deficiency 
disease, such as common variable immunodeficiency, IgA deficiency, IgG subclass 
deficiency, or any other immunodeficiency?” While admitting the multiple issues 
associated with this survey, the authors estimated a prevalence of diagnosed PIDD at 1 in 
1,200 persons. The specific diagnoses recorded included common variable 
immunodeficiency, IgA deficiency, IgG subclass deficiency, X-linked 
agammaglobulinemia, severe combined immunodeficiency, and chronic granulomatous 
disease. 
Joshi et al (Joshi, Iyer, Hagan, St Sauver, & Boyce, 2009) examined trends in the 
incidence of primary immunodeficiency over 3 decades (1976-2006) in Olmsted County, 
Minnesota, using 27 ICD-9 codes. This study therefore also included multiple types of 
primary immunodeficiency. According to this population-based historical cohort study, 
incidence rates did not differ by sex, but showed an increasing temporal trend in rates 
over the past 31 years. They found the overall incidence to be 4.6 per 100,000 person- 
years, with the incidence increasing with time to reach 10.3 per 100,000 persons in the 
final 5 years of the survey (2001-6). At all periods, the highest incidence of these 
disorders was in the age group 0-5 years. Overall B-cell defects represented 78% of the 
population and combined B- and T-cell defects another 10.5%. Among the B-cell defects, 
IgA deficiency was the most common, accounting for 30% of cases, followed by IgG 
subclass (IgG2, IgG3, and IgG4) deficiency (26%), and hypogammaglobulinemia 
(including IgG1 subclass deficiency) (23%). Common variable immunodeficiency was 
diagnosed in 15% of the cases. 
Infections with encapsulated bacteria such as Haemophilus inﬂuenzae and Streptococcus 
pneumoniae are the most common presenting features of the antibody deﬁciency 
syndromes. Other common infectious presenting features include respiratory tract 
infections (including sinusitis), gastrointestinal infections, meningitis, septic arthritis, and 
osteomyelitis. Infections often respond to standard treatment, but recur once therapy has 
been ﬁnished. Prolonged and recurrent infection can have signiﬁcant consequences: in 

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children poor growth and developmental delay, often as a result of end-organ damage in 
the respiratory tract. A positive family is of course a strong indicator that a congenital 
humoral immune deficiency may be present (Wood, 2009). 
 
1.2 
Immunoglobulin Replacement Therapy for PIDD with Antibody 
Deficiency 
Immunoglobulin replacement therapy is the standard treatment for patients with these 
PIDD. Standard treatment is to administer IgG either intravenously (IV) or 
subcutaneously (SC) at regular intervals, with the aim of maintaining the trough level of 
total IgG above 5 mg/mL. This replacement therapy is effective in preventing most 
infections, resulting in improved quality of life (Eijkhout et al., 2001; Roifman & 
Gelfand, 1988). 
 
1.3 
Benefit/Risk Statement 
Because of advances in our medical understanding and treatment of PIDD, patients who 
in the past would not have survived childhood are now able to live nearly normal lives 
with the lifelong administration of IGIV infusions. In subjects with a compromised 
immune system, prophylactic treatment with IGIV has been shown to increase the time 
between serious bacterial infections, decrease the incidence of overall bacterial 
infections, and reduce the number of hospitalizations required for treatment of infections 
(Boyle and Buckley, 2007; Bruton, 1952; Eijkhout et al., 2001; Roifman & Gelfand, 
1988). 
Replacement immunoglobulin given either IV or SC is standard practice for subjects with 
PIDD. Most patients receive IGIV infusions at intervals of 2, 3, or 4 weeks. Patients 
receiving subcutaneous treatment receive treatment weekly. Reductions in hospitalization 
and infection rates have been well documented in subjects receiving high doses 
(>400 mg/kg every 3 weeks) of IGIV; and maintaining trough levels of IGIV above 
5 mg/mL is considered standard of care (Boyle and Buckley, 2007;Eijkhout et al., 2001; 
Roifman & Gelfand, 1988). 
ProMetic’s Immune Globulin (Human) Intravenous 10% solution is analytically 
comparable to currently marketed IGIV products that are widely used by patients with 
PID. ProMetic’s IGIV is expected to provide similar therapeutic benefits as commercially 
available IGIV products. Since the levels of Anti-A/Anti-B hemagglutinins have been 
reduced by exposure to an Anti-A/Anti-B column, less hemolytic events may be expected 
with the ProMetic IGIV. 
The following adverse reactions are known to be associated with IGIV products: chills, 
headache, fever, vomiting, allergic reactions, infusion site reactions, nausea, arthralgia, 
low blood pressure, and moderate low back pain. Rarely, human normal 
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anaphylactic shock, even when the patient has shown no hypersensitivity to previous 
administration. Cases of reversible aseptic meningitis, isolated cases of reversible 
hemolytic anemia/hemolysis, and rare cases of transient cutaneous reactions have been 
observed with human normal immunoglobulin. An increase in serum creatinine level 
and/or acute renal failure has been observed. 
There have been reports of transfusion-related acute lung injury (TRALI) in patients 
administered IGIV (Rizk, Gorson, Kenney, & Weinstein, 2001). TRALI typically occurs 
within 1-6 hours after infusion and is characterized by severe respiratory distress, 
pulmonary edema, hypoxemia, abnormal left ventricular function, and fever. Patients 
with TRALI may be managed using oxygen therapy with adequate ventilator support. 
Currently, there are no guidelines for the prevention of TRALI. 
Rare occurrences of thromboembolic events, including stroke, myocardial infarction, 
pulmonary embolism, and deep vein thrombosis, have been reported following IGIV 
administration. Many of these rare serious reactions have been reported in patients who 
have significant risk factors or underlying diseases including advanced age, history of 
atherosclerosis, cardiovascular risk factors, hyperviscosity states, hypercoagulable 
disorders, or prolonged immobilization. Recently, impurities such as kallikrein and factor 
XIa (FXIa) have been identified as contributors to thromboembolic events (TEEs) 
following IGIV treatments. The manufacturing of ProMetic BioTherapeutics Immune 
Globulin Intravenous Solution 10% includes chromatography methods which will result 
in lower levels of impurities including kallikrein and FXIa in the final product (Data on 
File, ProMetic Biotherapeutics, Inc). It should be noted that the relationship between 
IVIG and thromboembolic events has been questioned (Basta, 2014). 
ProMetic’s IGIV is not expected to pose any unexpected safety risk to patients. Standard 
safety monitoring procedures will be adopted during the clinical study. Risks related to 
TEEs are minimized by performing the assays described in the Investigator’s Brochure. 
Any signs and symptoms of TEE will be closely monitored during the clinical study. In 
addition, ProMetic’s IGIV product is evaluated for thrombogenicity in the rabbit venous 
stasis model (Wessler assay) as a release assay. ProMetic’s IGIV does not promote 
thrombogenic activity in that model. 
There are three viral inactivation/removal steps in the IGIV process to help to assure 
safety of the patients from viral infectivity. However, as IGIV is a blood product, there is 
also a risk of transmission of unknown blood-borne infections. Hepatitis C transmission 
has been reported; however, there are no reports of transmission of HIV, hepatitis A or 
hepatitis B infection by IGIV therapy. 

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1.4 
FDA and DSMB Approval of Interim Safety Results for Group 1 and 
Group 2 
After reviewing the interim safety data from Group 1, the Data Safety Monitoring Board 
(DSMB) and Food and Drug Administration (FDA) approved dosing of ProMetic’s IGIV 
utilizing a 3-day stagger interval in Group 2; approval dates were May 26, 2016 and June 
16, 2016, respectively. 
After reviewing the interim safety data from Group 2, the DSMB and FDA approved 
dosing of ProMetic’s IGIV in Group 3; approval dates were October 13, 2016 and 
December 20, 2016, respectively. 
 
2 
Study Rationale and Objectives 
 
2.1 
Study Rationale 
Polyclonal immunoglobulin preparations of human origin, including IGIV products, have 
historically been used as replacement therapy to reduce the frequency of serious bacterial 
infections in subjects with PIDD. Prior to the introduction of IGIV therapy, patients 
suffering from hypogammaglobulinemia and agammaglobulinemia due to PIDD 
experienced approximately four or more serious acute bacterial infections each year. 
However, maintenance of trough IgG serum levels ≥5 mg/mL prevents most recurrent 
infections and their chronic complications, which improves the patient’s quality of life 
(Eijkhout et al., 2001; Roifman & Gelfand, 1988). Over the past 20 years, prophylaxis 
with IGIV has become the standard therapy for patients suffering from 
hypogammaglobulinemia and agammaglobulinemia due to PIDD. 
 
2.2 
Dosing Rationale 
The optimal dose and frequency of administration must be determined individually for 
each patient. For patients with PIDD, doses of approximately 300-600 mg/kg infused 
every three to four weeks are commonly used. A number of studies have demonstrated an 
association of a steadily decreasing incidence of infections with an increasing frequency 
of IGIV administration in CVID patients. Each patient may demonstrate his or her own 
individual response to therapy and experience dramatic differences in the frequency and 
severity of infections with moderate changes in the dose of IGIV. Patients suffering from 
a serious acute infection often benefit from booster doses of IGIV. Ultimately, IGIV 
dosage must be individualized based upon the response of the patient (Schroeder, 2001). 

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2.3 
Study Purpose and Objectives 
 
2.3.1 
Purpose 
The purpose of this study is to assess the tolerability, safety, efficacy, and 
pharmacokinetics (PK) of the investigational medicinal product (IMP), ProMetic Immune 
Globulin Intravenous (Human) 10%, in subjects with PIDD. 
 
2.3.2 
Primary Efficacy Objective 
The primary objective is to examine the rate of clinically documented serious bacterial 
infections (SBIs) in subjects treated with the IMP to achieve a rate of less than one SBI 
per year. 
 
2.3.3 
Secondary Efficacy Objectives 
The secondary efficacy objectives for this study are to examine the effects of the IMP on 
the following: 
• Serum trough concentrations of total IgG obtained prior to each IMP infusion; 
• Number of episodes of fever (≥100.4°F); 
• Number of days out of work/school/kindergarten/day care or unable to perform 
normal daily activities due to infections; 
• Number of days of hospitalization due to infections; 
• Number of days of antibiotics use for infection prophylaxis and/or treatment; 
• Incidence of infections other than acute serious bacterial infections. 
 
2.3.4 
Safety Objectives 
The safety objectives are: 
• To examine the safety and tolerability of the IMP 
• To collect adverse events (AEs) from the start of the signing of informed consent to 
21 days (± 2 days) or 28 days (± 2 days) after the last infusion, depending on the 
subject’s treatment schedule 
• To examine total AEs and the observed proportion of AEs considered by the Sponsor 
to be IMP related; 
• To examine AEs temporally associated (during and within 72 hours after the end of 
the infusion) with the IMP infusion, which will be recorded regardless of relationship 
to the IMP 
• To examine infusion and rate-related AEs, regardless of relationship to the IMP 

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• To monitor safety approximately 7 days post infusion 
• To examine long-term safety with virology testing from Screening to the Long-Term 
Safety Visit (LTSV) 
• To monitor for immunogenic reactions by testing for antibodies to β2GPI and 
β2GPI-DI, from baseline to the LTSV 
• To monitor for thrombogenicity and hemolysis by performing post-infusion clinical 
evaluations and laboratory testing 
 
2.3.5 
Pharmacokinetic Objectives 
The PK objectives are: 
• To determine the steady state serum concentrations of total IgG; 
• To determine the PK profiles for total IgG following administration of the IMP. 
 
 
3 
Study Plan 
This is a pivotal phase 3, open-label, single-arm, multinational, multicenter study to 
assess the tolerability, safety, efficacy, and pharmacokinetics of the IMP in adults and 
children with PIDD. The study will be conducted at up to 20 sites in the United States 
and Russia. All subjects will be treated on an outpatient basis with ProMetic 
BioTherapeutics Immune Globulin Intravenous Solution 10% (the IMP) for 
approximately 1 year. 
A total of approximately 75 subjects aged 2-80 years will be enrolled in the study: 
approximately 50 subjects aged 17-80 years (Cohort 1) and approximately 25 children 
aged 2 to <17 years (Cohort 2). Only subjects 18 years of age and older and treated with 
commercially licensed immune globulin product will be enrolled by Russian sites, in 
accordance with Russian national legislation. 
This is an open-label study; no subject or study personnel will be blinded. 
A subset of subjects will be asked to participate in a PK sub-study (Section 6.13). 
Subjects who consent to participate in the PK sub-study will undergo a series of blood 
draws to assess the PK profile of the IMP before and after Infusion 6 (21-day cycle 
subjects) or Infusion 5 (28-day cycle subjects). 
 
3.1 
Safety Precautions at Enrollment 
To enhance subject safety, IMP will initially be given only to adults aged 18-80 years 
treated with a stable dose of immune globulin, with the timing of the first IMP infusion at 
staggered intervals, in Groups 1 and 2. The study will proceed to Group 3 only after 
evaluation and FDA review of safety data obtained at Week 4 (or Week 3 for subjects on 

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a 3-week treatment regimen) after the first IMP infusion in 15 subjects. The procedures 
will be as follows: 
• Group 1: The timing of the first IMP infusion in the first five subjects will be 
staggered at 2-week intervals, and blood samples for interim safety testing, including 
three assays for antibodies to β2GPI (two for total β2GPI and one for β2GPI-DI), will 
be drawn before the second infusion (at Week 4 in subjects on a 4-week treatment 
regimen; Week 3 in subjects on a 3-week treatment regimen). While these first five 
subjects continue on IMP and before further subjects receive IMP, the results will be 
evaluated by the Investigators and the DSMB and submitted to the FDA for review. 
• Group 2: Contingent on FDA and DSMB approval after review of the interim safety 
results in Group 1, 10 further subjects will receive the first IMP infusion staggered at 
an interval to be determined by the FDA after review of the Group 1 results. As in 
Group 1, blood samples for safety testing will be drawn before the second infusion 
(Week 4 or 3, depending on treatment regimen). While these 10 subjects continue on 
IMP and before further subjects receive IMP, the results will be evaluated by the 
Investigators and the DSMB and submitted to the FDA for review. 
• Group 3: Contingent on FDA and DSMB approval after review of the interim safety 
results in Group 2, the study will continue with IMP infusions in approximately 
60 further subjects, including approximately 35 more adults to fill Cohort 1 and 
approximately 25 children in Cohort 2. The starting date of the first IMP infusion in 
this group will not be staggered. 
If special circumstances of clinical management, and anticipated treatment cycle 
scheduled date, make it necessary to reduce the 2-week staggering interval for subjects in 
Group 1, the interval between subjects may be decreased to a minimum of 10 days. 
To overcome the challenges of scheduling subjects for their first infusion contingent on 
infusions in the previous subject, potentially eligible subjects will be screened and 
enrolled in the study as they become available. Enrolled subjects will continue treatment 
with a commercially licensed immune globulin product as selected by the Investigator in 
consultation with their treating physician until the scheduled time of their first IMP 
infusion. Subjects who have previously been receiving immune globulin as part of a 
clinical trial, or coming off of IGSC, will be treated with a commercially available IGIV 
selected by the Investigator in consultation with their treating physician. 
Eligible subjects aged 18 to 80 years will be randomized in a 1:1:1 fashion to Groups 1, 
2, and 3. When 5 subjects have been enrolled in Group 1, this group will be closed, and 
randomization will continue 1:1 to Groups 2 and Group 3. Group 2 will be closed when 
10 subjects have been enrolled, and all subjects subsequently enrolled in the study will be 
placed in Group 3. Once the FDA and the DSMB has approved the safety profile of 
Groups 1 and 2, all subjects in Group 3 will begin to receive IMP. To be eligible for 

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enrollment, subjects must have been treated with a stable dose of commercially licensed 
IGIV for at least 3 consecutive treatments at 21 or 28 day intervals with documented 
trough levels, or subcutaneously (IGSC) for at least 12 weeks with documented steady 
state levels, as defined in the Inclusion Criteria (Section 4.3.1). The following subjects 
will not be eligible for randomization and will be assigned to Group 3: 
• Subjects receiving treatment with another investigational immune globulin at 
enrollment (SC or IV) 
• Subjects receiving IGSC. 
• Subjects aged < 18 years. 
This randomization scheme is designed to: 
• Minimize potential selection bias so that the interim safety analyses will be based on 
randomly assigned subject populations 
• To ensure no child is enrolled into the safety groups and receive IMP before the FDA 
has approved the safety of the product in adults 
• To allow subjects currently receiving another Investigational Medical Product to be 
stabilized on a commercially available immune globulin for at least 3 months prior to 
receiving IMP 
• Provide data on adverse events, including episodes of hemolysis or thrombosis, as 
well as immunologic testing (anti-β2GPI and anti-β2GPI-DI antibodies) in subjects 
currently receiving commercially licensed IGIV product, as well as in subjects 
receiving the IMP. 
This schema for the staggered administration of IMP will result in the following two time 
periods for each individual subject: 
Waiting Period: This is the elapsed time from enrollment to the first administration of 
IMP. During this time period, subjects will receive either their current commercially 
licensed product (CP) or a CP chosen by the Principal Investigator in consultation with 
their treating physician. All relevant safety and efficacy endpoints will be recorded and 
summarized for this time period. 
IMP Treatment Period: For each subject, this is the elapsed time from the first 
administration of IMP to study completion. During this time period, subjects will receive 
the IMP, ProMetic BioTherapeutics Immune Globulin Intravenous (Human) 10%. All 
planned safety and efficacy endpoints will be recorded and summarized for this time 
period. All primary and secondary efficacy analysis is restricted to data collected during 
this time frame. 

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3.2 
Treatment 
 
3.2.1 
Waiting Period (Commercial Product Period) 
Subjects who enroll in the study while on IV infusions of a commercial immune globulin 
product and who need to wait for the scheduled start of their IMP treatment will continue 
on their current product with their usual dose and treatment cycle during the Waiting 
Period. 
Subjects who have been receiving another investigational immune globulin product will 
be switched to commercially available IGIV product as selected by the Investigator at 
enrollment in consultation with their treating physician. 
Subjects on IGSC therapy before study entry will be switched to commercially available 
IGIV product as selected by the Investigator at enrollment in consultation with their 
treating physician. 
For any subjects who are switched from IGSC or investigational immune globulin 
product to a commercial IGIV product, the waiting period on the commercial IGIV will 
be at least 3 cycles prior to IMP infusion 1. 
Any necessary changes in dosage will be determined by the Investigator according to the 
usual standards of care. 
 
3.2.2 
IMP Treatment 
Subjects on IGIV therapy before study entry will receive the IMP at the same dose and 
treatment cycle as in their usual regimen. In subjects on IGSC therapy before study entry, 
the IMP dose will be calculated based on the current IGSC dose, and the IMP treatment 
interval will be based on their previous IGIV treatment interval (Section 13.6). Thus, 
within each age cohort, study visits and infusions will be scheduled either at 21-day or 
28-day intervals. 
Doses can be adjusted by the PI as described in Section 13.6.1 and IMP infusion rates 
will be adjusted during all visits to a tolerable level according to a preset algorithm 
described in Section 13.6.2. 
 
3.3 
Evaluations 
Analyses of all primary and secondary efficacy endpoints will be restricted to data 
collected during the IMP treatment period (Section 5 and Section 12). However, the same 
assessments will be recorded and summarized for the period on commercial product as 
for the IMP treatment period (Section 6). 
The interim safety evaluations of Groups 1 and 2 will look for evidence of 
immunogenicity, hemolysis and thrombosis based on clinical signs and laboratory tests 
(hematology, blood chemistry, urinalysis, hemolysis, d-dimer, protein C and protein S 

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concentrations, antibodies to ß2GPI and β2GPI-DI) in samples drawn before the second 
infusion (at Week 4 in subjects on a 4-week treatment cycle and at Week 3 in subjects on 
a 3-week treatment cycle) (Section 8.1). 
 
3.4 
Study Flow Chart 
A schematic diagram of the study plan is given in Figure 1 below. The rules and 
procedures for suspending or stopping the study and for discontinuation of subjects with 
specific characteristics in the event of safety concerns are explained in Section 8.1. 

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Figure 1. 
Safety Evaluation Phase – Randomized Assignment to Scheduling Group 
 

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3.5 
Study Duration 
 
3.5.1 
Duration of Subject Participation 
The Screening Visit will be conducted 21 days (±2 days) before the Baseline Visit 
(Infusion 1 IMP, or CP for Subjects in Waiting Period) for subjects on a 21-day cycle, 28 
days (±2 days) before Baseline for subjects on a 28-day cycle, or up to 17 days before the 
Baseline Visit for subjects receiving IGSC when they enter the study. 
To cover seasonal variations, all subjects will be treated with the IMP for approximately 
1 year. After the last infusion, AEs will be monitored for 21 days (±2 days) or 28 days 
(±2 days) days, depending on the infusion cycle, and all subjects will then return for a 
long-term safety visit (LTSV), at Week 51 for subjects on a 21-day cycle and Week 52 
for those on a 28-day cycle. 
However, the expected total duration of subject participation from enrollment to LTSV 
will include the Waiting Period on commercial product treatment. This period will vary, 
depending on the date of enrollment and the start of IMP treatment in the assigned 
scheduling group. 
The safety evaluation phase (including an evaluation at Week 4 for subjects on a 4-week 
treatment regimen; Week 3 for subjects on a 3-week treatment regimen after the first IMP 
infusion in 5 subjects and another at Week 4 or 3, depending on treatment regimen, after 
the first IMP infusion in the next 10 subjects, with the start of IMP treatment at staggered 
intervals), is expected to be completed by Study Week 36. Thus, if there is no delay in 
completing the two evaluations, a subject enrolled in the study at the beginning of 
recruitment and assigned to Group 3 (start of IMP after both evaluations are complete) 
would have a Waiting Period on commercial product of 36 weeks. The total study 
duration for this subject would be 88 weeks (approximately 21 months). Subjects who 
enroll at a later time and are assigned to Group 3 would have a shorter Waiting Period 
and a correspondingly shorter total study duration. 
 
3.5.2 
Total Study Duration 
This study will be conducted at up to 20 adult and pediatric centers in the US and Russia 
which specialize in treating patients with immunodeficiencies. 
The study duration in adults will comprise recruitment, screening, and evaluation of the 
first 15 subjects to receive IMP, as well as continued screening during the safety 
evaluation phase, and treatment with commercial IGIV product for subjects who must 
wait for the first scheduled IMP infusion. The total study time is expected to be at least 
2 years for Cohort 1. 

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Children will not be included in Groups 1 and 2, but they may be screened, enrolled into 
Group 3 and treated with commercial product during the evaluation period, and once the 
safety groups are approved by the FDA, they can receive the first IMP infusion. 
If the adult cohort finishes before the pediatric cohort, there will be two database locks 
and two clinical study reports, one for adult licensure and one for pediatric licensure 
(Section 12.5). 

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Table 1. 
Projected Study Duration - Adults 
 
Weeks (Months) 
Study initiation activities (expected time for centralb 
IRB/IEC approval, etc.) 
4 (1) 
Recruitment and screening (minimum total time), including: 
12 (3) 
- Identification of potential subjects from site records 
8 (2) 
- Screening of identified potential subjects before the 
first subject receives IMPa 
4 (1) 
Total study time (minimum time from enrollment of the first 
subject to the last long-term safety visit in the last subject, 
including: 
88 (21) 
- Evaluation period, including 
o Staggered scheduling of first IMP infusion in 
15 subjects (Groups 1 and 2) with interim 
evaluations and FDA review of safety data, and 
o Recruitment, screening, and commercial product 
treatment for subjects waiting for the first 
scheduled IMP infusion 
36 (9) 
- IMP period per subject 
o 48 weeks from first to last IMP infusion 
o long-term safety visit at Wk 51 (3-wk treatment 
schedule) or Wk 52 (4-wk treatment schedule) 
52 (12) 
Close-out time 
8 (2) 
Minimum total time 
112 (27) 
aRecruitment and screening will continue during the 36-week evaluation period, which would allow a 
total of approximately 10months for recruitment after identification of potential subjects. 
bSites with local IRB/IEC may have longer review/approval period. 

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Table 2. 
Projected Study Duration - Children 
 
Weeks (Months) 
Study initiation activities (expected time for centralb 
IRB/IEC approval, etc.) 
4 (1) 
Recruitment and screening (minimum total time), including: 
12 (3) 
- Identification of potential subjects from site records 
8 (2) 
- Screening of identified potential subjects before the 
first subject receives IMPa 
4 (1) 
Total study time (minimum time from enrollment of the first 
subject to the last long-term safety visit in the last subject, 
including: 
100 (24) 
- Recruitment, screening and commercial product 
treatment for subjects waiting for the first scheduled 
IMP infusion (continued during the safety evaluation 
phase for adults) 
36 (9) 
- Extra time for recruitment and screening of children 
12 (3) 
- IMP period per subject 
48 weeks from first to last IMP infusion and long-term 
safety visit at Wk 51 (3-wk treatment schedule) or 
Wk 52 (4-wk treatment schedule) 
52 (12) 
Close-out time 
8 (2) 
Minimum total time 
124 (30) 
aRecruitment and screening will continue during the 36-week evaluation period, and as children may be 
more difficult to recruit an additional 12 weeks (3 months) is allowed. This would push back the start of 
IMP treatment in some pediatric subjects by a further 3 months. The maximum time is 1 year for 
recruitment of children. 
bSites with local IRB/IEC may have longer review/approval period. 

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4 
Study Population 
Subjects with a diagnosis of primary humoral immunodeficiency will be selected for the 
study. To achieve 60 evaluable subjects, approximately 75 eligible subjects aged 2 to 
80 years will be enrolled. Two cohorts (Cohort 1 [adults] and Cohort 2 [children]) will be 
separately enrolled to ensure an adequate number of subjects in each age group. The PK 
sub-study will be conducted in a subset of each cohort. Subjects randomly assigned to 
Groups 1, 2, and 3 during the evaluation period must be from Cohort 1. After 
randomization is closed, both Cohorts 1 and 2 can be enrolled in Group 3. 
 
4.1 
Main Study 
Cohort 1 will enroll approximately 50 subjects aged 17 to 80 years to achieve at least 
40 evaluable subjects. 
Cohort 2 (children) will enroll approximately 25 subjects to achieve at least 20 evaluable 
subjects. Cohort 2 will enroll up to 6 subjects aged 2 to <6 years, at least 6 subjects 6 to 
<12 years, and at least 6 subjects aged 12 to <17 years. 
 
4.2 
PK Sub-study 
Approximately 25 of the subjects in Cohort 1 will be enrolled in the PK sub-study to 
achieve at least18 evaluable subjects for PK analysis. 
Approximately 18 of the subjects from Cohort 2 will be enrolled in the PK sub-study to 
achieve at least 12 evaluable subjects for PK analysis. Up to 6 subjects will be analyzed 
for PK in each of the following age groups: 2 to <6 years, 6 to <12 years, and 12 to 
<17 years. 
 
4.3 
Eligibility Criteria 
 
4.3.1 
Inclusion Criteria 
1. Subject is male or female between the ages of 2 and 80 years at Screening. 
• For Russian sites, only subjects 18 years of age and older, treated with 
commercially licensed immune globulin product will be enrolled. 
• For Cohort 1, all subjects will be aged ≥17 to 80 years. 
• For Cohort 2, subjects will be aged 2 to <17 years 
2. Subject or parent(s)/legal guardian has given written informed consent/assent 
(as applicable). Pediatric subjects are defined as 2 to 17 years of age at study 
entry and will require assent forms as appropriate. 
3. Subject or parent(s)/legal guardian agrees to comply with the requirements of 
the protocol. 

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4. Female subjects of childbearing potential must have a negative urine 
pregnancy test documented at the visit which they receive the first infusion of 
IMP and must agree to employ adequate birth control measures, as determined 
by their IRB/IEC, for the duration of the study. 
5. The subject must have established one of the following three diagnoses 
(isolated PIDD of other types will be excluded): 
• Common variable immunodeficiency (CVID) 
• X-linked agammaglobulinemia (XLA) 
• Hyper-IgM syndrome and documented low IgG levels (<4.5 mg/mL 
[450 mg/dL]). 
6. Subjects must have been treated with a stable dose of immune globulin 
administered intravenously (IGIV) or subcutaneously (IGSC), as defined 
below. 
o For IGIV, a stable dose is defined as administration of a dose of 
200-800 mg/kg with no more than 25% change during at least 
3 consecutive treatments at 21-day (±4 days) or 28-day (±4 days) 
dosing intervals. 
o For IGSC, a stable dose is defined as administration of a dose of 
300-900 mg/kg/month IV (or Sub-cutaneous equivalent), 
regardless of dosing schedule, with no more than 25% change 
during at least 12 weeks. 
7. Subjects who are receiving IGSC when they enter the study must have 
received at least one previous documented IGIV infusion without an 
associated serious adverse event. 
8. Documented trough or steady state levels 
o Subjects who are receiving IGIV when they enter the study have at 
least 2 documented serum IgG trough levels of ≥ 5 mg/ mL 
measured in the prior 6 months. One of these can be the serum IgG 
level at Screening. 
o Subjects who are receiving IGSC have at least 2 documented 
serum IgG steady state levels of ≥ 5 mg/mL in the prior 24 weeks. 
One of these can be the serum IgG level at Screening. 
9. Authorization to access personal health information. 

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4.3.2 
Exclusion Criteria 
1. Subject has secondary immunodeficiency or has been diagnosed with 
dysgammaglobulinemia or isolated IgG subclass deficiency. 
2. Subject has ever had a history of severe anaphylactic or anaphylactoid 
reaction to immunoglobulins or other blood products. 
3. Subject has a known history of immunoglobulin A (IgA) deficiency and 
known anti-IgA antibodies. (Note that subjects with IgA deficiency without 
known antibodies to IgA may be enrolled.) 
4. Subject has had a thrombotic event, such as deep vein thrombosis, 
myocardial infarction, cerebrovascular accident, pulmonary embolism, at any 
time. 
5. Subject has received blood products except IGIV, IGSC, or albumin within 
the previous 12 months. 
6. Subject has participated in another study (except for IGIV, IGSC studies) 
within the previous 4 weeks. 
7. Subject has had cancer in the past 5 years, except for basal cell or squamous 
cell cancers of the skin. 
8. Subject has current or prior diagnosis of malignancies of lymphoid cells such 
as lymphocytic leukemia, non-Hodgkin’s lymphoma, or immunodeficiency 
with thymoma. 
9. Subject has known hypoalbuminemia (<3 gm/dL), protein-losing 
enteropathy, or nephrotic syndrome. 
10. Subject has had a documented active infection within 7 days prior to 
Screening, or subject is on continuous prophylactic antibiotics. Subjects 
receiving a course of antibiotic treatment for a recent bacterial infection, 
which is controlled, can be enrolled into the study. 
11. Subject is positive for human immunodeficiency virus (HIV)-1 or HIV-2. 
12. Subject has a positive hepatitis C virus (HCV) or hepatitis B virus (HBV) 
nucleic acid test (NAT) performed either by qualitative or quantitative 
polymerase chain reaction (PCR) in the past 12 months. 
13. Subject has levels of alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) >2.5 times the upper limit of normal (ULN). 
14. Subject has serum creatinine >1.5 times the ULN or a severe chronic 
condition such as renal failure with proteinuria. 
15. Subject has anemia with a hemoglobin level ≤8 g/dL. 

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16. Subject has severe neutropenia with neutrophil count ≤1000 per mm3 or has 
lymphopenia with <500 per mm3. 
17. Subject is taking prednisone at a dose ≥0.15 mg/kg/day. (Topical steroids for 
skin conditions, steroid eye drops, chronic use of inhaled steroids for asthma, 
and intranasal steroids for rhinitis are allowed.) Exception: A brief course of 
systemic steroids above this threshold (i.e., a steroid burst) is allowed for 
treatment of a short-term condition such as an asthma exacerbation or poison 
ivy exposure. 
18. Subject is receiving other immunosuppressive drugs or chemotherapy. 
19. Subject has known atrial fibrillation requiring anticoagulant therapy; 
congestive heart failure (New York Heart Association Class III/IV); 
cardiomyopathy; or cardiac arrhythmia associated with thromboembolic 
events, unstable or advanced ischemic heart disease, or hyperviscosity. 
20. Subject has known decreased Protein C and/or Protein S levels. 
21. Subject is positive for antibodies to β2GPI and/or β2GPI-DI at Screening. 
22. Female subject who is pregnant, breast-feeding, or planning a pregnancy 
during the course of the study. 
23. A history of epilepsy or multiple episodes of migraine (defined as at least one 
episode within 6 months of enrolment) not completely controlled by 
medication, or any condition that is likely to interfere with evaluation of the 
IMP or satisfactory conduct of the study in the Investigator’s opinion. 
 
5 
Efficacy, Safety, and Pharmacokinetic Endpoints 
 
5.1 
Efficacy Endpoints 
 
5.1.1 
Primary Endpoint 
The rate of clinically documented SBIs, defined as: 
• Bacterial pneumonia 
• Bacteremia and septicemia 
• Osteomyelitis / septic arthritis 
• Bacterial meningitis 
• Visceral abscess 
 
5.1.2 
Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be assessed: 

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• Total serum IgG trough 
• Number of episodes of fever (≥100.4°F) 
• Number of days out of work/school/kindergarten/day care or unable to perform 
normal daily activities due to infection 
• Number of days of hospitalization due to infection 
• Number of days of antibiotic use for infection prophylaxis and/or treatment 
• Number and duration of infections other than acute serious bacterial infections 
 
5.2 
Safety Endpoints 
Safety will be evaluated via the following assessments: 
• All reported AEs 
• Rate (per subject per infusion), severity, and relatedness of AEs 
• Frequency of temporally associated AEs 
• Infusional AEs 
• Assessment of local tolerability to IMP infusions: Reactions at infusion site 
• Adverse reactions/suspected adverse reactions 
• Vital sign changes, including changes in systolic and diastolic blood pressure, heart 
rate, respiratory rate, and body temperature 
• Changes from Screening in physical examination findings 
• Changes from Baseline in laboratory parameters (blood chemistry, hematology, 
urinalysis, hemolysis, d-dimer, protein S, and protein C concentrations, titers of 
antibodies to ß2GPI and β2GPI-DI) 
• Frequency of clinical signs of hemolysis and/or thrombosis within 72 hours after 
infusion of the IMP 
• IGIV-associated hemolysis 
• Changes from Screening in viral safety markers (HAV, HBV, HCV, HIV-1, HIV-2, 
and B19) 
• Comparisons of safety variables during treatment with IMP and during the Waiting 
Period on commercial product will be made as described in Section 12.3.4. 
 
5.3 
Pharmacokinetic Endpoints 
The PK profile will be analyzed for the following endpoints in subjects participating in 
the PK sub-study: 

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• Total IgG levels 
• Area under the concentration-time curve over 1 dosing interval (AUC0-t) 
• Area under the concentration-time curve extrapolated to zero concentration (AUC0-inf) 
• Peak serum concentration (Cmax) 
• Time to reach the peak serum concentration (Tmax) 
• The volume of distribution at steady-state (Vss) 
• Mean residence time (MRT) 
• Total body clearance (CL) 
• Terminal half-life (t1/2) 
 
6 
Study Procedures/Evaluations 
 
6.1 
Medical History 
During Screening, all subjects will provide a relevant medical history including surgeries 
during the past 2 years, serious bacterial infections documented in the last 5 years, 
medications taken in the last 4 weeks, and any adverse drug reactions (ADRs) in the past 
6 months. 
 
6.2 
Subject Diary 
To obtain some of the data for evaluation of secondary endpoints, each subject (or 
parent/guardian, as appropriate) will be asked to fill in a diary throughout the study. The 
diary will be given to the subject at the baseline visit (Infusion 1 IMP/CP), along with 
instructions on how to complete it. The subject will be asked to record the following 
information in the diary from the first study visit until the LTSV: 
• Any episode of fever (≥100.4°F) measured at home with a thermometer provided by 
the study staff 
• The number of days out of work/school/kindergarten/day care or unable to perform 
normal activities due to the underlying PIDD 
• Date and duration of any hospitalizations (in case hospitalization is not at the 
site/location where the subject is being treated in the study) 
• Any antibiotic treatments or other medications and the number of separate occasions 
they are taken during the study period 
• Any other changes in medical history 

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Each time a subject returns to the study site, the Subject Diary will be reviewed for 
completeness and accuracy. Any discrepancies, especially from the phone call 
documentation up to 72 hours will be corrected by the subject at each visit, as necessary. 
Staff will review concomitant medications, AEs, and other safety information contained 
on the Subject Diary prior to administering CP or IMP. In addition, any other safety 
information (for example, laboratory results from prior visits) will also be reviewed prior 
to administration of CP or IMP. The diary will be returned to the subject at each visit 
with instructions to complete the diary and return with the diary at the next visit. 
Thermometers will be replaced only if lost or not functioning. 
 
6.3 
Vital Signs 
Vital signs, including systolic and diastolic blood pressure, heart rate, respiratory rate, 
and body temperature, will be recorded at Screening; at each infusion visit before, during, 
and after each infusion (IMP or CP), and at the LTSV. 
At each infusion visit, vital signs will be measured at rest at the following time points: 
• ≤30 minutes pre-infusion 
• 10 minutes (±3 minutes) after the start of the infusion 
• 10 minutes (±3 minutes) after each increase of the infusion rate 
• 30 minutes post infusion (±5 minutes) 
• 60 minutes post infusion (±15 minutes) 
At the LTSV, vital signs will be recorded before administration of the subject’s standard 
immunoglobulin treatment, but no post measurement is required. 
 
6.4 
Physical Examination 
 
6.4.1 
Organ Systems 
A physical examination will be performed at each visit and will focus on organs or 
systems that are known to be the target of complications in PIDD: skin; head, eyes, ear, 
nose, and throat (HEENT), respiratory, cardiovascular, abdominal, breasts (optional), 
genitourinary (optional), rectal (optional), musculoskeletal, and neurologic. 
 
6.4.2 
Evaluation for Infection 
When a subject is suspected of having an acute serious bacterial infection, the subject 
will be evaluated for the infection according to the FDA Guidance for Industry: Safety, 
Efficacy, and Pharmacokinetic Studies to Support Marketing of Immune Globulin 
Intravenous (Human) as Replacement Therapy for Primary Humoral Immunodeficiency, 
as outlined in Section 21.1. 

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All incidences of acute serious bacterial infection will be recorded in the electronic case 
report form (eCRF) together with the confirmatory tests for the diagnosis. 
 
6.4.3 
Height and Weight 
Height will be recorded at Screening, and weight will be recorded at every visit. 
 
6.4.4 
Chest X-ray 
All subjects will have a chest X-ray performed between the Screening visit and IMP 
Infusion 1, unless a chest X-ray has been performed within 6 months prior to the first 
study drug infusion (CP or IMP) and demonstrates a normal result or has shown no 
indication of active disease process, as determined by the PI/designee. 
 
6.5 
Pregnancy Testing 
For female subjects of childbearing potential, a urine pregnancy test will be performed at 
every visit prior to infusion of IMP/CP. 
 
6.6 
Serum IgG Trough Levels 
IgG trough levels will be determined from blood samples collected from all subjects at 
Screening, during the IMP treatment period prior to each infusion of IMP, and at the 
LTSV before the subject’s standard IgG treatment. Subjects on CP Waiting Period need 
two IgG trough/steady state levels of ≥ 5 mg/ mL documented within 6 months prior to 
IMP Infusion 1. 
 
6.7 
Viral Safety Markers 
Viral safety markers (HAV, HBV, HCV, HIV-1, HIV-2, and B19) will be tested as 
follows: 
• Virology samples drawn at the following time points will be tested using NAT 
(preferably quantitative PCR, if available) and serology assays: 
o Blood samples will be obtained at Screening for determination of the subject’s 
pre-exposure viral status and to exclude subjects with a positive test for any of 
the following viruses: HIV, HCV, or HBV in accordance with the exclusion 
criteria. 
o Prior to IMP dosing at IMP Infusion 1 when subject comes off CP Waiting 
Period 
o Prior to administration of the IMP at Week 12 (Infusion 5 for subjects on the 
21-day cycle; Infusion 4 for subjects on the 28-day cycle) 
o Prior to administration of standard IgG at LTSV 

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• Retention samples for potential later testing will also be drawn prior to administration 
of the IMP/CP at the following visits: 
o Infusion 1 IMP/CP, Baseline for all subjects 
o LTSV 
• Retention samples will be sent to the central laboratory and stored at -20°C or below 
for future viral testing if needed. 
• All viral safety measurements will be performed by the central laboratory. 
 
6.8 
General Safety Laboratory Assessments 
Samples for general laboratory safety assessments will be collected at the following time 
points: 
• All subjects at Screening 
• All subjects before administration of IMP or CP at infusions 1 (baseline value), 2, 3 
and 4 and then before every fourth infusion (8, 12, 16, etc.), TCTV (Treatment 
Completion/Termination Visit) and at the LTSV 
• Post-Infusion IMP treatment for Groups 1 and 2 during Safety Evaluation Phase 
o 7 days (±1 day) after administration of IMP at infusions 1, 2, and 4 and then 
after every fourth IMP infusion (8, 12, 16) when IMP treatment ends; 
• Post-Infusion IMP treatment for Group 3 
o 7 days (±1 day) after administration of IMP at infusions 1 and 4 
If it is difficult for subjects (particularly children) to return to the study site for these 
tests, blood samples may be drawn by a home healthcare nurse. 
General safety laboratory assessments include the following tests: 
Hematology 
CBC, hemoglobin, hematocrit, white blood cell (WBC) count and differential, red blood 
cell (RBC) count, RBC indices (mean corpuscular volume [MCV], mean corpuscular 
hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], red cell 
distribution width [RDW]), and platelets 
Blood chemistry 
Glucose, total bilirubin, creatinine, lactate dehydrogenase (LDH), blood urea nitrogen 
(BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST) 

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Urinalysis 
Protein, glucose, blood, bilirubin, urobilinogen, pH, and ketones by dipstick; sediment 
analysis 
 
6.9 
Hemolysis 
Tests for hemolysis include urine hemosiderin, serum haptoglobin, plasma free 
hemoglobin, Coombs test (direct anti-globulin test). 
Samples for hemolysis assessments will be collected at the following time points: 
• All subjects at Screening 
• All subjects before administration of IMP or CP at infusions 1 (baseline value), 2, 3 
and 4 and then every fourth infusion (8, 12, 16, etc.), TCTV and at the LTSV 
• Post-Infusion IMP treatment for Groups 1 and 2 during Safety Evaluation Phase 
o 2-3 days after administration of IMP after administration of IMP infusions 1 
(baseline value), 2 and 4; 
o 7 days (±1 day) after administration of IMP at infusions 1, 2, and 4 and then 
after every fourth infusion (8, 12, 16) until IMP treatment ends; 
• Post-Infusion IMP treatment for Group 3 
o 7 days (±1 day) after administration of IMP at infusions 1 and 4 
If it is difficult for subjects (particularly children) to return to the study site for these 
tests, blood samples may be drawn by a home healthcare nurse. 
For all subjects, a drop of ≥2.0 g/dL from the pre-infusion hemoglobin level or clinical 
signs of hemolysis between visits will lead to a full hemolysis work-up. 
 
6.10 
Immunogenicity Testing 
Immunogenicity testing for the detection of antibodies to β2GPI and β2GPI -DI will 
include the following tests: 
• β2GPI Domain 1 QUANTA Flash Kit, INOVA Diagnostics 
• β2GPI IgG Ab QUANTA Flash Kit, INOVA Diagnostics 
• β2GPI IgM Ab QUANTA Flash Kit, INOVA Diagnostics 
Blood samples for detection of antibodies to β2GPI and β2GPI -DI will be drawn at the 
following time points: 
• All subjects at Screening 
• All subjects before administration of IMP or CP at infusions 1 (baseline value), 2, 4, 
and 8, LTSV before infusion of the subject’s standard immunoglobulin treatment 

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• Retention samples will be drawn at every visit for subjects on IMP treatment, from 
baseline through the LTSV 
If any subject after receiving IMP seroconverts from negative to positive, with an 
elevated antibody titer at least 12 weeks apart, as defined in Section 8.1.1, then all prior 
retention samples for ß2GPI and/or β2GPI-DI for all subjects should be analyzed. 
 
6.11 
3-4 Hour Post-infusion Safety Testing – Indicators of Thrombosis 
For all subjects, blood samples will be drawn 3-4 hours after the end of IMP/CP infusion 
at Infusion 1, 2, 4, 8, 12 and 16. 
Tests include: 
• D-dimers 
• Retention sample for protein C and protein S determination, in case d-dimer results 
indicate potential thrombosis or the PI determines a need for such testing from his 
evaluation (Note: a retention sample for protein C and protein S will also be taken at 
Screening to allow for a comparison of the subject’s baseline status in the event of a 
later thrombotic episode or thromboembolic vascular event.) 
 
6.12 
Post-infusion Clinical Evaluation for AEs, Hemolysis, and 
Thrombosis 
 
6.12.1 AEs 
All subjects will be observed for 3-4 hours after the first infusion of IMP or CP, and for 
1 hour after all further infusions, and AEs will be recorded by observation and report (see 
Section 10). 
 
6.12.2 One Hour Post Infusion (IMP/CP) 
 
6.12.2.1 
Hemolysis Clinical Evaluation 
For all subjects, at each infusion visit the Investigator will examine the subject within 
approximately one hour (±15 minutes) after IMP/CP infusion to look for the following 
clinical signs of hemolysis: 
1. Abnormal paleness or lack of color of the skin 
2. Jaundice, or yellowing of the skin, eyes, and mouth 
3. Fever 
4. Weakness 
5. Dizziness 
6. Confusion 

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7. Intolerance to physical activity 
8. Enlargement of the spleen and liver 
9. Increased heart rate (tachycardia) 
10. Heart murmur 
Positive assessments will lead to a full hemolysis work-up immediately, according to the 
facility’s standard of care. 
 
6.12.2.2 
Thrombosis Clinical Evaluation 
For all subjects, in addition to the assessment of hemolysis described above, the 
Investigator will also perform an assessment for the following clinical signs of 
thrombosis within approximately one hour (±15 minutes) after each IMP/CP infusion: 
1. Tenderness along line of femoral or popliteal veins (NOT just calf tenderness) 
2. Entire limb swollen 
3. Pitting edema 
4. Lower leg pain 
5. Warmth and redness of limb 
6. Weakness or decreased sensation of one side of the body 
7. Facial droop or decreased sensation 
8. Aphasia 
9. Dizziness or vertigo 
10. Visual loss or blurred vision 
11. Sudden severe headache 
12. Confusion 
13. Chest pain or discomfort 
14. Shortness of breath at rest or with exertion 
15. Pain in the left arm or jaw 
16. Pleuritic chest pain 
17. Syncope 
Positive assessments will lead to an immediate full thrombosis work-up according to the 
facility’s standard of care. If a thromboembolic event is concerned this will trigger testing 
of that subject’s retention samples for β2GPI and β2GPI-DI. 

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6.12.3 Phone Calls 24 and 72 Hours after IMP/CP Infusion 
For all subjects, the study staff will telephone each subject 24 (+6) hours and 
72 (+12) hours after each infusion of IMP/CP. Emails or text messages may be used 
instead as long as every required question is asked and answered. 
 
6.12.3.1 
AEs 
During the phone calls, the staff will ask open-ended questions about the subject’s 
wellbeing and to ensure that AEs are being documented in the Subject Diary. 
The staff will also ask the following specific questions to determine whether a work-up 
for hemolysis and/or thrombosis is necessary: 
 
6.12.3.2 
Hemolysis Clinical Questions 
The study staff will review these specific questions with the subject and ensure subject is 
completing the diary. 
1. Have you noticed your urine is darker than usual? 
2. Are you feeling dizzy or weak? 
3. Are you feeling confused? 
4. Does your skin look pale or discolored? 
5. Have you had a fever above 100.4°F? 
If any of the above questions is answered yes, the study coordinator will report this to the 
PI or sub-investigator immediately. The PI will decide whether the subject should come in 
for a full work-up. If so, the site will call the subject in for a full hemolysis work-up as 
per the facility’s standard of care. 
 
6.12.3.3 
Thrombosis Clinical Questions 
The study staff will review these specific questions with the subject and ensure subject is 
completing the diary. 
1. Do you have pain and/or swelling of an arm or leg with warmth over the affected 
area? 
2. Is there discoloration of an arm or leg? 
3. Is there any numbness or weakness on one side of the body? 
4. Do you have difficulty speaking? 
5. Have you had changes in your vision or new headaches? 
6. Are you experiencing dizziness or a feeling that the room is spinning? 
7. Are you experiencing unexplained shortness of breath? 

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8. Do you have chest pain or discomfort that worsens on deep breathing? 
9. Do you have unexplained rapid heartbeat? 
10. Have you passed out or felt like you might pass out? 
11. Are you experiencing any chest pain or discomfort? 
12. Do you have pain in your left arm or jaw? 
13. Have you experienced nausea and sweating? 
If any of the above questions is answered yes, the study coordinator will report this to the 
PI or sub-investigator immediately. The PI will decide whether the subject should come 
in for a full work-up. If so, the site will call the subject in for a full thrombosis work-up 
as per the facility’s standard of care. In addition, the Central Laboratory will perform the 
full thrombosis work-up tests on retention samples (including testing for antibodies 
to β2GPI and to β2GPI-DI) held for the subject. 
 
6.13 
Pharmacokinetic Sub-study 
Subjects in Cohorts 1 and 2 who consent to participate in the PK sub-study will have 
blood samples drawn for PK analysis before and after Infusion 6 (Week 15 ±2 days) for 
21-day cycle subjects or Infusion 5 (Week 16 ±2 days) for 28-day cycle subjects at the 
time points listed in Section 6.13.1 for Cohort 1 and Section 6.13.2 for Cohort 2 below. 
Total IgG levels will be measured at all time points for the PK study, in addition to being 
measured prior to administration of IMP at all visits for all subjects. 
All attempts will be made to perform the PK blood draws from Day 7 onwards on the 
specified day per protocol, but a window of ±1 day will be allowed. 
 
6.13.1 PK Time Points for Cohort 1 (adults): 
• Pre-dose at 10 to 30 minutes before IMP Infusion 6 for 21-day cycle subjects or IMP 
Infusion 5 for 28-day cycle subjects 
• 15 minutes (±1 minute) after the end of the infusion 
• 1 hour (±5 minutes) after the end of the infusion 
• 4 hours (±15 minutes) after the end of the infusion 
• 24 hours (±1 hour) after the end of the infusion 
• 7 days (±1 day) after the end of the infusion 
• 14 days (±1 days) after the end of the infusion 
• 21 days (±1 days) after the end of the infusion (immediately before infusion at 
Infusion 7 for 21-day cycle subjects) 

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• 28 days (±1 days) after the end of the infusion (immediately before infusion at 
Infusion 6 for 28-day cycle subjects) 
 
6.13.2 PK Time Points for Cohort 2 (children): 
• Pre-dose at 10 to 30 minutes before IMP Infusion 6 for 21-day cycle subjects or IMP 
Infusion 5 for 28-day cycle subjects 
• 15 minutes (±1 minute) after the end of the infusion 
• 4 hours (±15 minutes) after the end of the infusion 
• 24 hours (±1 hour) after the end of the infusion 
• 10 days (±1 day) after the end of the infusion 
• 21 days (±1 day) after the end of the infusion (immediately before infusion at Visit 7 
for 21-day cycle subjects) 
• 28 days (±1 day) after the end of the infusion (immediately before infusion at Visit 6 
for 28-day cycle subjects) 
 
7 
Study Schedule 
 
7.1 
Schedule of Assessments and Study Events 
The schedule of assessments and procedures for the Screening visit is included in Table 3 
and 4. Table 3 gives assessments and procedures for the Waiting Period on commercial 
product (CP) before IMP treatment starts. The schedule of assessments and study events 
for IMP treatment is given in Table 4. Subjects in the Waiting Period on CP will switch 
to IMP at their first scheduled IMP infusion. 

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Table 3. 
Schedule of Assessments and Study Events for Waiting Period on Commercial Product Treatment 
 
Baseline 
Variable Number of CP Infusions Depending on Evaluations in the First 15 Subjects with IMP 
Visit/Infusion a 
Screen 
r 
CP1 
CP 2 
CP3 
CP4 
CP5 
CP6 
CP7 
CP8 
CP9 
CP10 
CP11 
CP12 
CP13 Prior to IMP 
Week (21-day cycle) 
-3 week 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
Week (28-day cycle)a 
-4 week 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Pre-infusion: 
Medical history and prior ADRs 
specific to IgG treatment 
X 
X 
X 
Prior and concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review of eligibility criteria 
X 
X 
X 
Subject diary review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IgG trough levels f 
X 
X 
Anti-β2GPI and 
Anti-β2GPI-DI g 
X 
X 
X 
X 
X 
X 
Viral testing h 
X 
Retention sample for viral 
testing (pre-infusion) i 
X 
X 
Pre-infusion laboratory safety 
assessments – general j 
X 
X 
X 
X 
X 
X 
X 
X 

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Baseline 
Variable Number of CP Infusions Depending on Evaluations in the First 15 Subjects with IMP 
Visit/Infusion a 
Screen 
r 
CP1 
CP 2 
CP3 
CP4 
CP5 
CP6 
CP7 
CP8 
CP9 
CP10 
CP11 
CP12 
CP13 Prior to IMP 
Week (21-day cycle) 
-3 week 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
Week (28-day cycle)a 
-4 week 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
48 
Pre-infusion hemolysis 
assessments q 
X 
X 
X 
X 
X 
X 
X 
X 
CP infusion k 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Post-infusion 
Vital signs b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical evaluation for 
hemolysis & thrombosis: 1h 
after infusion l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
D-dimer: 3-4h after infusion m 
X 
X 
X 
X 
X 
Retention sample for protein C 
& protein S: 3-4h after infusion n 
X 
X 
X 
X 
X 
X 
Phone calls 24 h & 72 h p 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event assessment o 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADR = adverse drug reaction; IgG = immunoglobulin G; NAT = nucleic acid test; PCR = polymerase chain reaction. 
a 
The number of weeks on CP will depend on the timing of recruitment of the first 15 subjects to receive IMP. If safety review of the first 5 subjects is 
satisfactory and the staggering interval for the next 10 subjects (Schedule 2) can be reduced, the number of weeks on CP will be shorter than shown here. 
If recruitment of these subjects does not take place as quickly as planned, the number of weeks on CP may be longer. 
b 
Vital signs will be recorded before, during, and after the infusion at time points listed in Section 6.3. 
c 
Physical examination will focus on organs and systems known to be the target of complications in PIDD: skin, head, eyes, ear, nose, and throat (HEENT), 
respiratory, cardiovascular, abdominal, breasts (optional), genitourinary (optional), rectal (optional), musculoskeletal, neurologic (Section 6.4). Serious 
bacterial infections will be diagnosed as outlined in Section 21.1. Screening visit includes height measurement. 
d 
If at any visit after baseline, a subject’s body weight has changed by 5% or more from the baseline value, the CP dose will be adjusted according to 
standards of care. 

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e 
Female subjects of childbearing potential. 
f 
For subjects receiving IGIV at entry, baseline IgG levels are trough levels; for those receiving IGSC at entry, baseline IgG levels are steady state levels. 
Subjects on CP Waiting Period need two IgG trough/steady state levels of ≥ 5 mg/ mL documented within 6 months prior to IMP Infusion 1. 
g 
Antibody titers for anti-β2GPI and anti-β2GPI-DI will be determined at Screening, before the CP infusion 1 as the baseline value, then before CP infusions 
2, 4, and 8. 
h 
Viral testing includes HAV, HBV, HCV, HIV-1, HIV-2, and B19 using nucleic acid test (NAT) or preferably quantitative PCR, if available, and serology 
assays. 
i 
Viral testing includes HAV, HBV, HCV, HIV-1, HIV-2, and B19 using nucleic acid test (NAT) or preferably quantitative PCR, if available, and serology 
assays. Performed prior to IMP dosing at IMP Infusion 1 when subject comes off Waiting Period. Retention sample also collected prior to Infusion 1 
IMP/CP baseline for all subjects. 
j 
Pre-infusion general laboratory safety tests include hematology, blood chemistry, and urinalysis. For subjects in the Waiting Period, testing will be done 
on samples collected before administration of the first four CP infusions (1, 2, 3, 4) and then before every fourth CP infusion (8, 12, 16, etc.) as long as the 
subject is in the Waiting Period. 
k 
Infusion rate is adjusted according to standard care. CP infusions will continue until the subject’s first scheduled IMP infusion can occur. 
l 
Approximately 1 hour after each infusion, the Investigator will examine the subject to look for clinical signs of hemolysis and thrombosis (Section 6.12.2). 
Positive assessments will lead to a full work-up for hemolysis or thrombosis, as appropriate, according to the facility’s standard of care. 
m 
Approximately 3-4 hours after CP infusions 1, 2, 4, 8, 12, 16 a blood sample will be drawn for measuring d-dimer levels. 
n 
Approximately 3-4h after CP infusions 1, 2, 4, 8, 12, 16 a retention sample will be drawn for testing of protein C and protein S in case d-dimer results after 
the first infusion indicate potential thrombosis or the PI determines a need for protein C and protein S testing based on his evaluation (Section 6.11). A 
retention sample will be drawn at Screening pre-infusion for later testing of protein C and protein S in case d-dimer results are positive after first infusion 
of CP. 
o 
Subjects are monitored for infusional AEs during CP infusions, for 3-4 hours after the first infusion, and for 1 hour after further infusions. Other AEs are 
recorded in the subject diaries and collected and reviewed at each visit (Section 10). All subjects are monitored for temporally associated AEs in the 24- 
hour and 72-hour phone calls from staff to the subject. 
p 
The study staff will call subjects 24 hours (+6 hours) and 72 hours (+12) after each infusion to evaluate the potential for hemolysis, thrombosis, and any 
other AEs. Positive answer on any of the five hemolysis questions or on any of the thrombosis questions will be reported to the PI for a decision as to 
whether a full work-up is necessary (Section 6.12.3). 
q 
Pre-infusion hemolysis laboratory tests will include urine hemosiderin, serum haptoglobin, plasma free hemoglobin, Coombs test (direct anti-globulin 
test). Pre-infusion hemolysis testing will be done for all subjects before administration of CP at infusions 1 (baseline value), 2, 3, 4 and then every fourth infusion (8, 
12, 16, etc.). For all subjects, a drop of ≥2.0 g/dL from the pre-infusion hemoglobin level or clinical signs of hemolysis between visits will lead to a full 
hemolysis work-up (Section 6.9). 
r Screening visit will include demographics. Subjects treated with commercial IGIV or IGSC may receive their current treatment infusion either before the 
screening visit or at the screening visit if screening laboratory samples are taken prior to the infusion. Subjects receiving IGSC when they enter the study 
will have their screening visit up to 17 days prior to the Baseline Visit. 

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Table 4. 
Schedule of Assessments and Study Events for IMP Treatment 
 
Baseline 
Treatment with IMP 
TCa 
LTSV bb 
Visit/Infusion 
Screen 
Visit aa 
IMP 
1e 
IMP 
2 
IMP 
3 
IMP 
4 
IMP 
5 
IMP 
6 
IMP 
7 
IMP 
8 
IMP 
9 
IMP 
10 
IMP 
11 
IMP 
12 
IMP 
13b 
IMP 
14b 
IMP 
15b 
IMP 
16b 
IMP 
17c 
Standard 
18d 
Week (21-day cycle) 
-3 weeks 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
39 
42 
45 
48 
51 
Visit/Infusion 
Screen 
Visit aa 
IMP 
1e 
IMP 
2 
IMP 
3 
IMP 
4 
IMP 
5 
IMP 
6 
IMP 
7 
IMP 
8 
IMP 
9 
IMP 
10 
IMP 
11 
IMP 
12 
- 
- 
- 
- 
IMP 
13c 
Standard 
14d 
Week (28-day Cycle) 
-4 weeks 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
- 
- 
- 
- 
48 
52 
Pre-infusion 
Medical History and 
prior ADRs to IgG 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review eligibility 
criteria 
X 
X 
Subject diary review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy test i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IgG trough levels j 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-β2GPI and 
Anti-β2GPI-DI k 
X 
X 
X 
X 
X 
X 
Retention sample for 
immunogenicity l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Baseline 
Treatment with IMP 
TCa 
LTSV bb 
Visit/Infusion 
Screen 
Visit aa 
IMP 
1e 
IMP 
2 
IMP 
3 
IMP 
4 
IMP 
5 
IMP 
6 
IMP 
7 
IMP 
8 
IMP 
9 
IMP 
10 
IMP 
11 
IMP 
12 
IMP 
13b 
IMP 
14b 
IMP 
15b 
IMP 
16b 
IMP 
17c 
Standard 
18d 
Week (21-day cycle) 
-3 weeks 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
39 
42 
45 
48 
51 
Visit/Infusion 
Screen 
Visit aa 
IMP 
1e 
IMP 
2 
IMP 
3 
IMP 
4 
IMP 
5 
IMP 
6 
IMP 
7 
IMP 
8 
IMP 
9 
IMP 
10 
IMP 
11 
IMP 
12 
- 
- 
- 
- 
IMP 
13c 
Standard 
14d 
Week (28-day Cycle) 
-4 weeks 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
- 
- 
- 
- 
48 
52 
Viral testing m,e 
X 
X e 
X m 
X m 
X 
Retention sample for 
viral testing e 
X 
X 
Pre-infusion laboratory 
safety assessments n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pre-infusion hemolysis 
assessments y,z 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IMP infusion o 
Xo 
Xo 
X p 
X p 
X p 
X p 
X p 
X p 
X p 
X p 
X p 
X p 
X p 
X p 
X p 
X p 
X p 
Post-infusion 
Vital signs f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X f 
Clinical evaluation for 
hemolysis & thrombosis: 
1 h post infusion q 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
D-dimer: 3-4 h post- 
infusion r 
X r 
X 
X 
X 
X 
X 
Retention sample for 
protein C & protein S: 
3-4 h post-infusion r 
X 
X r 
X 
X 
X 
X 
X 
Phone calls 24 h & 72 h t 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Baseline 
Treatment with IMP 
TCa 
LTSV bb 
Visit/Infusion 
Screen 
Visit aa 
IMP 
1e 
IMP 
2 
IMP 
3 
IMP 
4 
IMP 
5 
IMP 
6 
IMP 
7 
IMP 
8 
IMP 
9 
IMP 
10 
IMP 
11 
IMP 
12 
IMP 
13b 
IMP 
14b 
IMP 
15b 
IMP 
16b 
IMP 
17c 
Standard 
18d 
Week (21-day cycle) 
-3 weeks 
0 
3 
6 
9 
12 
15 
18 
21 
24 
27 
30 
33 
36 
39 
42 
45 
48 
51 
Visit/Infusion 
Screen 
Visit aa 
IMP 
1e 
IMP 
2 
IMP 
3 
IMP 
4 
IMP 
5 
IMP 
6 
IMP 
7 
IMP 
8 
IMP 
9 
IMP 
10 
IMP 
11 
IMP 
12 
- 
- 
- 
- 
IMP 
13c 
Standard 
14d 
Week (28-day Cycle) 
-4 weeks 
0 
4 
8 
12 
16 
20 
24 
28 
32 
36 
40 
44 
- 
- 
- 
- 
48 
52 
7-day post-infusion lab 
safety assessments – 
general u 
X 
X 
X 
X 
X 
X 
2-3 day and 7-day post- 
infusion lab safety 
assessments–hemolysis v 
X 
X 
X 
X v 
X v 
X v 
PK sub-study 
X w 
X w 
Adverse event 
assessment x 
X x 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADR = adverse drug reaction; IgG = immunoglobulin G; LTSV = long-term safety visit; LTSF = long-term safety follow-up; NAT = nucleic acid test; PCR = 
polymerase chain reaction; PK = pharmacokinetics; TC = treatment completion or termination visit. 
a 
For subjects who terminate the study before the planned treatment completion visit, all procedures should be performed at the final scheduled visit. If a 
subject is terminating early and will be unable to return for the LTSV visit, additional procedures for LTSV (safety laboratory test, viral testing, and 
retention sample) must also be performed at the final visit. 
b 
21-day cycle only 
c 
Subjects on the 21-day cycle will receive 17 infusions of the IMP, and subjects on the 28-day cycle will receive 13 infusions of the IMP in one year. 
d 
Subjects resume standard IgG treatment. 
e 
Viral testing includes HAV, HBV, HCV, HIV-1, HIV-2, and B19 using nucleic acid test (NAT) or preferably quantitative PCR, if available, and serology 
assays. Subjects coming off of Waiting Period must have viral testing prior to IMP Infusion 1. 
f 
Vital signs will be recorded before, during, and after the IMP infusion at time points listed in Section 6.3. At the LTSV, vital signs will be recorded before 
administration of the subject’s standard immunoglobulin treatment, but no post-infusion measurement is required. 

Protocol No. 2004C009G 
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g 
Physical examination will focus on organs and systems known to be the target of complications in PIDD: skin; head, eyes, ear, nose, and throat (HEENT); 
respiratory, cardiovascular, abdominal, breasts (optional), genitourinary (optional), rectal (optional), musculoskeletal, neurologic (Section 6.4). Serious 
bacterial infections will be diagnosed as outlined in Section 21.1. A chest X-ray will be performed between the Screening visit and the IMP Infusion 1, 
unless a chest X-ray has been performed within 6 months prior to the first study infusion (CP or IMP) and demonstrates a normal result. Screening visit 
includes height measurement. 
h 
If at any visit after baseline, a subject’s body weight has changed by 5% or more from the baseline value, the IMP dose will be adjusted accordingly 
(Section 13.6.1). 
i 
Female subjects of childbearing potential. 
j 
For subjects receiving IGIV at study entry, IgG levels are trough levels; for those receiving IGSC at study entry, baseline IgG levels are steady state levels. 
Subjects (including those coming off of the CP Waiting Period) need two IgG trough/steady state levels of ≥ 5 mg/ mL documented within 6 months prior 
to IMP Infusion 1. 
k 
Antibody titers for anti-β2GPI and anti-β2GPI-DI, will be done at Screening, before IMP infusion 1 as the baseline value, then before infusions 2, 4, and 8, 
and at the LTSV. 
l 
Retention samples for anti-β2GPI and anti-β2GPI-DI antibodies will be taken at every infusion visit. 
m 
Interim viral testing will be performed at Week 12 (IMP Infusion 5 for subjects on the 21-day cycle; IMP Infusion 4 for subjects on the 28-day cycle). 
Retention sample also collected prior to Infusion 1 IMP/CP baseline for all subjects. Final viral testing will be performed at the LTSV (Section 6.7). 
n 
Pre-infusion general laboratory safety tests include general safety (hematology, blood chemistry, and urinalysis) (Section 6.8). 
o 
Infusion rate is adjusted every 30 minutes based on tolerability as described in Section 13.6.2.1. 
p 
Infusion rate is adjusted every 15 minutes based on tolerability as described in Section 13.6.2.2. 
q 
Approximately 1 hour after each infusion, the Investigator will examine the subject to look for clinical signs of hemolysis and thrombosis (Section 6.12.2). 
Positive assessments will lead to a full work-up for hemolysis (Section 6.12) or thrombosis, as appropriate, according to the facility’s standard of care. 
r 
Approximately 3-4 hours after the first IMP infusion (IMP baseline), a blood sample will be drawn for measuring d-dimer levels, and a retention sample 
will also be drawn for testing of protein C and protein S in case d-dimer results indicate potential thrombosis or the PI determines a need for protein C and 
protein S testing based on his evaluation (Section 6.11). A retention sample will be drawn at Screening pre-infusion for later testing of protein C and 
protein S in case d-dimer results are positive after the first infusion of IMP. 
t The study staff will call subjects 24 hours (+6 hours) and 72 hours (+12 hours) after each infusion to evaluate the potential for hemolysis, thrombosis, and 
any other AEs. Positive answer on any of the five hemolysis questions or on any of the thrombosis questions will be reported to the PI for a decision as to 
whether a full work-up is necessary (Section 6.12.3). 
u 
Post-infusion general laboratory safety tests will include hematology, blood chemistry, and urinalysis (Section 6.8). For Groups 1 and 2, post-infusion 
general safety laboratory testing will be done while receiving IMP, 7 days (±1 day) after IMP Infusions 1, 2, and 4, and then 7 days (±1 day) after every 
fourth infusion (8, 12, 16). For Group 3, post-infusion general safety laboratory testing will be done while receiving IMP, 7 days (±1 day) after IMP 
Infusions 1 and 4. 

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v 
Post-infusion hemolysis laboratory tests will include urine hemosiderin, serum haptoglobin, plasma free hemoglobin, Coombs test (direct anti-globulin 
test) (Section 6.9). For Groups 1 and 2, post-infusion hemolysis testing will be done while receiving IMP, 2-3 days and again 7 days (±1 day) after IMP 
Infusions 1, 2, and 4, and then 7 days (±1 day) after every fourth infusion (8, 12, 16). For Group 3, post-infusion hemolysis testing will be done while 
receiving IMP, 7 days (±1 day) after IMP Infusions 1 and 4. 
w 
Subjects who participate in the PK sub-study will have blood samples drawn before and after IMP Infusion 6 (21-day cycle subjects) or IMP Infusion 5 
(28-day cycle subjects) at time points listed in Section 6.13. 
x 
Subjects are monitored for infusional AEs during the IMP infusions, for 3-4 hours after the first infusion, and for 1 hour after further infusions. Other AEs 
are recorded in the subject diaries and collected and reviewed at each visit (Section 10). All subjects are monitored for temporally associated AEs in the 
24-hour and 72-hour phone calls from staff to the subject as described above. 
y 
Pre-infusion hemolysis laboratory tests will include urine hemosiderin, serum haptoglobin, plasma free hemoglobin, Coombs test (direct anti-globulin test) 
(Section 6.9). Pre-infusion hemolysis testing will be done for all subjects before administration of IMP at infusions 1 (baseline value), 2, 3, 4 and every 
fourth infusion (8, 12, 16), TCTV and at the LTSV. For all subjects, a drop of ≥2.0 g/dL from the pre-infusion hemoglobin level or clinical signs of 
hemolysis between visits will lead to a full hemolysis work-up (Section 6.9) 
z 
All subject groups will have pre-infusion hemolysis testing prior to IMP/CP infusion 1. For all subjects, a drop of ≥2.0 g/dL from the pre-infusion 
hemoglobin level or clinical signs of hemolysis between visits will lead to a full hemolysis work-up (Section 6.9) 
aa Screening visit will include demographics. Subjects treated with commercial IGIV or IGSC may receive their current treatment infusion either before the 
screening visit or at the screening visit if screening laboratory samples are taken prior to the infusion. Subjects receiving IGSC when they enter the study 
will have their screening visit up to 17 days prior to the Baseline Visit. 
bb 
For subjects who discontinue IMP due to events (hemolysis, thrombosis, anti-β2GPI immunogenicity), and for all subjects if study is stopped, follow-up 
LTSF will continue for additional cycles (Section 7.11). For subjects who discontinue IMP due to anti-β2GPI immunogenicity, subject will continue to be 
followed up and have the LTSF performed until immunogenicity titers are stabilized (or dropping) over 3 consecutive treatment cycles (21-day cycle/ 
28-day cycle). (Section 7.11) 

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7.2 
Pre-screening 
To identify subjects who meet the eligibility criteria, Investigators will review their 
patient files according to their own center’s procedures for pre-screening, ensuring that 
they comply with national regulations (in the United States, Health Insurance Portability 
and Accountability Act [HIPAA]). De-identified data will be recorded on a pre-screening 
log (Section 8.4). Prior to Screening, sites will prescreen subjects for general eligibility 
and seek approval from the CRO to screen. Enrollment will be competitive. Because 
there are required numbers of subjects in the different groups (scheduling groups, adults, 
children, PK, non-PK), subjects must receive approval from the CRO to ensure that there 
are adequate numbers of subjects in each group and that over-enrollment does not occur. 
 
7.3 
Screening Visit 
Once approval for screening has been granted, the Screening Visit will be conducted 
21 days (±2 days) before the Baseline Visit (Infusion 1 IMP, or CP for Subjects in 
Waiting Period) for subjects on a 21-day cycle, 28 days (±2 days) before Baseline for 
subjects on a 28-day cycle, or up to 17 days before the Baseline Visit for subjects 
receiving IGSC when they enter the study. 
Informed Consent or Assent 
Before any study procedures are performed, informed consent will be obtained from 
eligible subjects and parent(s) or legal guardians, and if applicable, assent will be 
obtained from subjects younger than 18 years, according to the procedures outlined in 
Section 16.3. 
Once informed consent and/or assent has been obtained, subjects will undergo a 
screening visit to ascertain their eligibility. All subjects will be offered participation in 
the PK sub-study until the planned number of subjects is reached. 
Demographic Information 
Demographic information will be collected to include the subject’s date of birth, race, 
ethnicity, and sex. 
Complete Medical History 
Subjects will give a relevant medical history including surgeries during the past two years 
and serious bacterial infections documented in the last 5 years. 
Prior and Current Medications 
Prior and Current Immunoglobulin Treatment 
Documentation of prior use of immunoglobulin treatment (IGIV or IGSC), including the 
regimen cycle and rate/dose, will be reviewed so that selection criteria are met 
(Section 4.3.1). To be eligible for enrollment, subjects must have been treated with a 

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stable dose of commercially licensed immune globulin, administered intravenously 
(IGIV), for at least 3 consecutive treatments at 21 or 28 day intervals with at least 
2 documented trough levels, or administered subcutaneously (IGSC) for at least 12 weeks 
with at least 2 documented steady state levels, as defined in the inclusion criteria 
(Section 4.3.1). In addition, subjects must have had at least two documented IgG trough 
or steady state levels of ≥5 mg/mL measured in the 6 months prior to IMP treatment. 
Subjects who switch from an investigational immune globulin or IGSC are not part of the 
randomization scheme and will be automatically assigned to Group 3. These subjects are 
required to receive a stable dose of a commercial IGIV product for at least 3 cycles 
during the Waiting Period before they can be given the IMP. In addition, subjects must 
have had at least two documented IgG trough or steady state levels of ≥ 5 mg/mL 
measured in the 6 months prior to IMP treatment. 
For subjects who are receiving IGIV, the current IGIV dose will be documented for use 
in calculating the starting dose for the baseline infusion, and for those who are receiving 
IGSC, the current IGSC dose will be documented for use in calculating the starting IGIV 
dose for the baseline infusion (see Section 13.6.1). As required by inclusion criteria 
(Section 4.3.1), at least one IGIV infusion in the past without an associated serious 
adverse event must be documented for such subjects. 
Prior Adverse Drug Reactions to Immunoglobulin Treatment 
If available in the documentation, data will be captured of known Adverse Drug 
Reactions the subjects previously exhibited when being treated with immunoglobulins 
(IV or SC). The subject will be queried about adverse reactions in the last 6 months. 
Miscellaneous Medications 
Information on prior and current medication will be collected including non-prescription, 
prescription, herbal medications, and transfusions. All routes, doses, schedules, infusions 
rates, and indications will be recorded as appropriate. Data will be collected for the past 
4 weeks before the screening visit. 
As the use of pre-medication for pain relief and/or diphenhydramine prior to an IMP 
infusion is only permitted if the subject is using these pre-medications as part of routine 
IGIV or IGSC treatment. 
Vital Signs 
Vital signs will be collected to include body temperature, blood pressure, respiratory rate, 
and heart rate prior to infusion. 
Physical Examination 
The physical examination will focus on organs or systems are known to be the target of 
complications in PIDD as described in Section 6.4. 

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Height and weight will be recorded. 
Laboratory Assessments 
As noted below, subjects are allowed to receive their last IGIV or IGSC dose(s) at the 
screening visit as long as screening laboratory samples are taken prior to the infusion. 
Specimens for the following laboratory analyses will be obtained to ascertain whether the 
subject meets eligibility criteria. 
• Urine pregnancy test, if applicable (Section 6.5) 
• Serum IgG trough level (Section 6.6) 
• Viral testing (Section 6.7) 
• Safety assessments, including general safety (hematology, blood chemistry, and 
urinalysis) (Section 6.8) 
• Laboratory hemolysis testing, including urine hemosiderin, serum haptoglobin, 
plasma free hemoglobin, Coombs test (direct anti-globulin test) (Section 6.9) 
• Retention sample for protein C and protein S to allow for a comparison of the 
subject’s baseline status in the event of a later thrombotic episode or thromboembolic 
vascular event (Section 6.11) 
• Immunogenicity sample (Section 6.10), testing for antibodies to β2GPI and 
β2GPI-DI. 
• Chest X-ray will be performed between the Screening visit and IMP Infusion 1, 
unless a chest X-ray has been performed within 6 months prior to the first study 
infusion (CP or IMP) and demonstrates a normal result or has shown no indication of 
active disease process, as determined by the PI/designee. 
Review of Eligibility Criteria and Randomization 
The medical history, prior medication, physical exam, and other collected tests/data and 
safety parameters will be reviewed to ascertain whether the subject meets all inclusion 
criteria and does not meet any of the exclusion criteria. The Investigator will ascertain 
whether the subject is eligible to participate and will follow the protocol throughout the 
subject’s participation in the study. 
Randomization codes for the three scheduling groups described in Section 3.1 will be 
assigned as subjects become eligible for randomization. If a subject withdraws from 
participation in the study, then his or her enrollment/randomization code cannot be 
reused. 
Children, subjects treated with IGSC, and subjects on another investigational product at 
enrollment will not be part of the randomization scheme and will be assigned to Group 3. 

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All subjects enrolled after Groups 1 and 2 have been closed will also be assigned to 
Group 3. 
The Sponsor will produce the randomization code and scheme. Once the subject has been 
assessed for all inclusion/exclusion criteria and deemed eligible for the study, the study 
coordinator will log into an interactive response technology (IRT), such as interactive 
web response system (IWRS), and enter the subject ID. The IRT/IWRS will randomize 
the subject and assign the randomization number and enrollment group, which will 
include the group number at the end of the Subject Identification Number. 
 
Infusion of Current Immunoglobulin Product (if needed) 
Subjects treated with commercial IGIV or IGSC may receive their current treatment 
infusion either before the screening visit or within 1 day after all screening-related 
laboratory assessments are completed. The first study infusion visit (whether the start of 
ProMetic IMP or continuation of CP during the Waiting Period) will be scheduled 
according to the subject’s usual treatment cycle. (Subjects on another IGIV or IGSC 
investigational product at study entry may receive the last administration of that product 
at screening. They will not be part of the randomization scheme and will be assigned to 
Group 3 and switched to commercially licensed IGIV selected by the Investigator in 
consultation with their treating physician. They will continue CP for the duration of the 
Waiting Period and at a minimum of 3 months in order to satisfy requirement for 
3 months on a stable dose of commercial product prior to first IMP infusion.) 
Safety Evaluation Phase (Groups 1 and 2) 
The safety evaluation phase includes an evaluation of Group 1 and then Group 2. Interim 
safety testing will be performed prior to the second infusion (at Week 4 in subjects on 
28 day cycle, and Week 3 in subjects on 21 day cycle) in five subjects starting IMP 
treatment at staggered 2-week intervals (Group 1). The results from these 5 subjects are 
evaluated by the Investigators and the DSMB and submitted to the FDA for review. 
These subjects will continue on IMP while awaiting review, but no further subjects will 
be started on IMP. Contingent on FDA and DSMB approval after review of the interim 
safety results in Group 1, 10 further subjects (Group 2) will receive the first IMP infusion 
staggered at an interval to be determined by the FDA. The safety evaluation phase 
continues for Group 2 with interim safety testing as done in Group 1, and the results from 
these next 10 subjects are evaluated by the Investigators and the DSMB and submitted to 
the FDA for review. Contingent on FDA and DSMB approval after review of the interim 
safety testing in Group 2, IMP infusions for the next 60 subjects, including 35 adults 
(Cohort 1) 25 children (Cohort 2) will start. The starting date of the first IMP infusion in 
this last group will not be staggered. 

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7.4 
Baseline and IMP/CP Infusion 1 
For subjects on a 21-day cycle, this visit will occur 21 days (±2 days) after the Screening 
Visit. For subjects on a 28-day cycle, this visit will occur 28 days (±2 days) after the 
Screening Visit. For IGSC subjects this visit must occur within up to 17 days after the 
Screening Visit. 
Medical History and Medication Review 
A review of medical history and current medication will be performed to assess for any 
changes or missing information. For subjects entering the study, laboratory results from 
Screening will be reviewed to assess safety and to ascertain baseline levels. For subjects 
starting IMP after the Waiting Period on CP, events and laboratory results from the CP 
period will be reviewed. 
Adverse Event Assessment 
Any and all adverse events will be captured starting from the Screening Visit. 
Review of Eligibility Criteria 
For subjects entering the study, the eligibility criteria, including results of screening 
laboratory tests, will be reviewed and updated, and eligibility will be assessed and 
verified. For subjects starting IMP after the Waiting Period on CP, any changes in 
eligibility will be evaluated. Subject will again be queried about any adverse drug 
reactions prior to treatment with immunoglobulins. 
Subject Diary Distribution and Completion Instructions 
The Subject Diaries and thermometers will be distributed, along with instructions for 
recording the data, as described in Section 6.2. Staff will review concomitant 
medications, AEs, and other safety information contained on the Subject Diary at each 
visit prior to administering CP or IMP for all subjects. 
Pre-infusion Vital Signs 
Vital signs will be collected within 30 minutes prior to Infusion 1 (IMP or CP) to include 
body temperature, blood pressure, respiratory rate, and heart rate (Section 6.3). 
Physical Examination 
The physical examination will focus on organs or systems that are known to be the target 
of complications in PIDD and the subject will be evaluated for infection as described in 
Section 6.4. 
The subject’s weight will be measured as a basis for calculating the IMP or CP dose 
(Section 13.6.1). 

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Chest X-Ray 
A chest X-ray will be performed between the Screening visit and IMP Infusion 1, unless 
a chest X-ray has been performed within 6 months prior to the first study infusion (CP or 
IMP) and demonstrates a normal result or has shown no indication of active disease 
process, as determined by the PI/designee. 
Pre-Infusion Laboratory Assessments 
Blood samples for the following laboratory tests will be obtained prior to administration 
of the IMP/CP: 
• Urine pregnancy test, if applicable (Section 6.5) 
• Serum IgG trough level prior to Infusion of IMP (Section 6.6) 
• Antibodies to β2GPI and β2GPI-DI (Section 6.10) 
• Retention sample for potential future immunogenicity testing (Section 6.10), only for 
subjects receiving IMP infusions 
• Viral testing (Section 6.7) for subjects coming off of CP Waiting Period 
• Retention blood sample for potential future virology testing (Section 6.7) 
• Safety assessments, including general safety (hematology, blood chemistry, and 
urinalysis) (Section 6.8) 
• Hemolysis assessment, including urine hemosiderin, serum haptoglobin, plasma free 
hemoglobin, Coombs test (direct anti-globulin test) (Section 6.9). 
• For all subjects, a drop of ≥2.0 g/dL from the pre-infusion hemoglobin level or 
clinical signs of hemolysis between visits will lead to a full hemolysis work-up 
(Section 6.9). 
Infusion of IMP or CP 
The dose and volume of the IMP to be administered to each subject will be calculated 
based on the subject’s weight (Section 13.6.1). The IMP should be prepared and 
administered according to the instructions in Sections 13.5 and 13.6.2. 
The dose and administration of CP will be determined by the Investigator in consultation 
with their treating physician, as in the subject’s usual care. 
Vital Signs, Post-infusion 
Vital signs (body temperature, blood pressure, respiratory rate, and heart rate) will be 
recorded at the time intervals outlined in Section 6.3. 

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Post-infusion Clinical Evaluation for AEs, Hemolysis, and Thrombosis (All Groups) 
• Subjects will be observed for AEs directly during the first IMP/CP infusion and for 
3-4 hours after the infusion, and AEs will be recorded by observation and report (see 
Section 10.1 for definitions of infusional and temporally associated AEs and Section 
10.3 for instructions on eliciting and reporting AEs). 
• The Investigator will examine the subject approximately 1 hour (±15 minutes) after 
the first IMP/CP infusion to look for clinical signs of hemolysis and thrombosis as 
described in Section 6.12.2. 
• Study staff will call the subjects 24 (+6) hours and 72 (+12) hours after the first 
IMP/CP infusion to ask open-ended questions about their wellbeing and to ensure that 
any AEs are being documented in the Subject Diary. 
• During the 24- and 72-hour phone calls after the first IMP/CP infusion, study staff 
will also ask questions as described in Section 6.12.3 to determine whether a work-up 
for hemolysis and/or thrombosis is necessary 
3-4 Hour Post-infusion Laboratory Thrombosis Indicators (All Groups) 
Samples for the following tests will be drawn 3-4 hours after the end of infusion (Section 
6.11): 
• D-dimer 
• Retention sample for protein C and protein S determination, in case d-dimer results 
indicate potential thrombosis or the PI determines a need for such testing 
2- to 3-Day Post-infusion Hemolysis Testing (Groups 1 and 2 while on IMP) 
Post-infusion hemolysis laboratory tests will include urine hemosiderin, serum 
haptoglobin, plasma free hemoglobin, Coombs test (direct anti-globulin test) (Section 
6.9). This 2-3 day post infusion testing will only be done for Group 1 and 2 subjects 
receiving IMP. 
7-Day (±1 day) General Laboratory Safety Testing (Groups 1, 2, and 3 while on 
IMP) 
Post-infusion general laboratory safety tests including hematology, blood chemistry, and 
urinalysis (Section 6.8), and hemolysis laboratory tests (Section 6.9), will be done 7 days 
(±1 day) after the IMP infusions for Groups 1, 2, and 3. If it is difficult for subjects 
(particularly children) to return to the study site for these tests, blood samples can be 
drawn by a home healthcare nurse. 
 
7.5 
IMP/CP Infusions 2, 4, and 8 
Subjects on a 21-day cycle may have infusions scheduled within ± 2 days of the 21-day 
cycle infusion time points throughout the study. 

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Subjects on a 28-day cycle may have infusions scheduled within ± 2 days of the 28-day 
cycle infusion time points throughout the study 
Adverse Event Assessment and Concomitant Medication Review 
A review of adverse events, laboratory results and current medication will be performed. 
Subject Diary Review 
The Subject Diary will be reviewed as described in Section 6.2. 
Vital Signs Pre-Infusion 
Vital signs (body temperature, blood pressure, respiratory rate, and heart rate) will be 
recorded before the IMP infusion at the time intervals outlined in Section 6.3. 
Physical Examination 
The physical examination will focus on organs or systems that are known to be the target 
of complications in PIDD and the subject will be evaluated for infection as described in 
Section 6.4. 
The subject’s weight will be measured, and if the subject has gained or lost ≥5% body 
weight since baseline, the amount of IMP for infusion must be adjusted accordingly. 
Pre-Infusion (IMP/CP) Laboratory Assessments 
The following laboratory samples will be obtained prior to administration of IMP/CP: 
• Urine pregnancy test, if applicable (Section 6.5) 
• Serum IgG trough levels will be measured prior to each Infusion of IMP (Section 6.6) 
• Safety assessments, including general safety (hematology, blood chemistry, and 
urinalysis) (Section 6.8) 
• Antibodies to β2GPI and β2GPI-DI (Section 6.10) 
• Retention sample for potential future immunogenicity testing (Section 6.10), only for 
subjects receiving IMP infusions 
• Hemolysis assessment, including urine hemosiderin, serum haptoglobin, plasma free 
hemoglobin, Coombs test (direct anti-globulin test) (Section 6.9). 
• For all subjects, a drop of ≥2.0 g/dL from the pre-infusion hemoglobin level or 
clinical signs of hemolysis between visits will lead to a full hemolysis work-up 
(Section 6.9). 
Infusion (IMP or CP) 
The dose and volume of the IMP to be administered to each subject will be calculated 
based on the subject’s weight (Section 13.6.1). The IMP should be prepared and 
administered according to the instructions in Sections 13.5 and 13.6.2. 

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The dose and administration of CP will be based on the subject’s usual treatment and 
determined by the Investigator in consultation with the treating physician. 
Post-infusion Vital Signs 
Vital signs (body temperature, blood pressure, respiratory rate, and heart rate) will be 
recorded after the infusion at the time intervals outlined in Section 6.3. 
Post-infusion Clinical Evaluation for AEs, Hemolysis, and Thrombosis (All Groups) 
• Subjects will be observed for AEs during the IMP/CP infusions and for 
approximately 1 hour (±15 minutes) after the infusion, and AEs will be recorded by 
observation and report (see Section 10.1 for definitions of infusional and temporally 
associated AEs and Section 10.3 for instructions on eliciting and reporting AEs). 
• The Investigator will examine the subject approximately 1 hour (±15 minutes) after 
the IMP/CP infusions to look for clinical signs of hemolysis and thrombosis as 
described in Section 6.12.2. 
• Study staff will call the subjects 24 (+6) hours and 72 (+12) hours after IMP/CP 
infusions to ask open-ended questions about their wellbeing and to ensure that any 
AEs are being documented in the Subject Diary. 
• During the 24- and 72-hour phone calls after IMP/CP infusions, study staff will also 
ask questions as described in Section 6.12.3 to determine whether a work-up for 
hemolysis and/or thrombosis is necessary and/or testing of any retention samples for 
immunogenicity are required. 
• All other AEs should be recorded in the subject diaries and collected and reviewed, 
along with any concomitant medications, at each visit (Section 10) 
3-4 Hour Post-infusion Laboratory Thrombosis Indicators (All Groups) 
Samples for the following tests will be drawn 3-4 hours after the end of infusion (Section 
6.11): 
• D-dimer 
• Retention sample for protein C and protein S determination, in case d-dimer results 
indicate potential thrombosis or the PI determines a need for such testing 
2- to 3-Day Post-infusion Hemolysis Testing (Groups 1 and 2 while on IMP) 
Post-infusion hemolysis laboratory tests will include urine hemosiderin, serum 
haptoglobin, plasma free hemoglobin, Coombs test (direct anti-globulin test) (Section 
6.9). This 2-3 day post infusion testing will only be done for Group 1 and 2 subjects after 
receiving IMP Infusions 2 and 4. 

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7-Day (±1 day) General Laboratory Safety and Hemolysis Testing (Groups 1, 2, and 
3 while on IMP) 
Post-infusion general laboratory safety tests including hematology, blood chemistry, 
urinalysis (Section 6.8), and hemolysis laboratory tests (Section 6.9) will be done 7 days 
(±1 day) after IMP infusions 2, 4, and 8 for Groups 1 and 2 and after IMP infusion 4 for 
Group 3 while receiving IMP. 
If it is difficult for subjects (particularly children) to return to the study site for these 
tests, blood samples can be drawn by a home healthcare nurse. 
 
7.6 
IMP/CP Interim Infusion Visits 
Subjects on a 21-day cycle may have infusions scheduled within ± 2 days of the 21-day 
cycle infusion time points throughout the study. 
Subjects on a 28-day cycle may have infusions scheduled within ± 2 days of the 28-day 
cycle infusion time points throughout the study 
Adverse Event Assessment and Concomitant Medication Review 
A review of adverse events, laboratory results and current medication will be performed. 
Subject Diary Review (Interim Infusion Visits) 
The Subject Diary will be reviewed as described in Section 6.2. 
Vital Signs Pre-Infusion (Interim Infusion Visits) 
Vital signs (body temperature, blood pressure, respiratory rate, and heart rate) will be 
recorded before the IMP infusion at the time intervals outlined in Section 6.3. 
Physical Examination (Interim Infusion Visits) 
The physical examination will focus on organs or systems that are known to be the target 
of complications in PIDD and the subject will be evaluated for infection as described in 
Section 6.4. 
The subject’s weight will be measured, and if the subject has gained or lost ≥5% body 
weight since baseline, the amount of IMP for infusion must be adjusted accordingly. 
Pre-Infusion Laboratory Assessments (Interim Infusion Visits) 
The following laboratory samples will be obtained prior to administration of IMP/CP 
Infusion: 
• Urine pregnancy test, if applicable, prior to each Infusion of IMP/CP (Section 6.5) 
• Serum IgG trough will be measured prior to each Infusion of IMP (Section 6.6) 
• Retention sample for potential future immunogenicity testing (Section 6.10), only for 
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• Safety assessments, including general safety (hematology, blood chemistry, and 
urinalysis) (Section 6.8) at IMP/CP Infusions 3, 12, and 16 
• Hemolysis assessment, including urine hemosiderin, serum haptoglobin, plasma free 
hemoglobin, Coombs test (direct anti-globulin test) (Section 6.9) at IMP/CP 
Infusions 3, 12, and 16. 
• For all subjects, a drop of ≥2.0 g/dL from the pre-infusion hemoglobin level or 
clinical signs of hemolysis between visits will lead to a full hemolysis work-up 
(Section 6.9). 
Infusions (Interim Infusion Visits) 
The dose and volume of the IMP to be administered to each subject will be calculated 
based on the subject’s weight. The IMP should be prepared and administered according 
to the instructions in Sections 13.5 and 13.6. 
The dose and administration of CP will be determined by the Investigator in consultation 
with the treating physician, as in the subject’s usual care. 
Post-infusion Vital Signs (Interim Infusion Visits) 
Vital signs (body temperature, blood pressure, respiratory rate, and heart rate) will be 
recorded after the infusion at the time intervals outlined in Section 6.3. 
Post-infusion Clinical Evaluation for AEs, Hemolysis, and Thrombosis (Interim 
Infusion Visits) 
• Subjects will be observed directly during each infusion and for 1 hour (±15 minutes) 
after each infusion, and AEs will be recorded by observation and report (see Section 
10.1 for definitions of infusion and temporally associated AEs and Section 10.3 for 
instructions on eliciting and reporting AEs). 
• The Investigator will examine the subject approximately 1 hour (±15 minutes) after 
each infusion to look for clinical signs of hemolysis and thrombosis as described in 
Section 6.12.2. 
• Study staff will call the subjects 24 (+6) hours and 72 (+12) hours after each IMP/CP 
infusion to ask open-ended questions about their wellbeing and to ensure that any 
AEs are being documented in the Subject Diary. 
• During the 24- and 72-hour phone calls after each IMP/CP infusion, study staff will 
also ask questions as described in Section 6.12.3 to determine whether a work-up for 
hemolysis and/or thrombosis is necessary and/or testing of any retention samples for 
immunogenicity are required. 
• All other AEs should be recorded in the subject diaries and collected and reviewed, 
along with any concomitant medications, at each visit (Section 10). 

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3-4 Hour Post-infusion Laboratory Thrombosis Indicators (All Groups) 
Samples for the following tests will be drawn 3-4 hours after the end of infusion (Section 
6.11) at IMP/CP infusions 12 and 16 (all subjects): 
• D-dimer 
• Retention sample for protein C and protein S determination, in case d-dimer results 
indicate potential thrombosis or the PI determines a need for such testing 
7-Day (±1 day) General Laboratory Safety and Hemolysis Testing (Groups 1 and 2 
while on IMP) 
Post-infusion general laboratory safety tests including hematology, blood chemistry, 
urinalysis (Section 6.8), and hemolysis laboratory tests (Section 6.9) will be done 7 days 
(±1 day) after IMP infusions 12 and 16 for Groups 1 and 2 while receiving IMP. 
If it is difficult for subjects (particularly children) to return to the study site for these 
tests, blood samples can be drawn by a home healthcare nurse. 
 
7.7 
Viral testing (IMP Infusion 5 for 21-day cycle / IMP Infusion 4 for 28- 
day cycle) 
Viral safety markers (HAV, HBV, HCV, HIV-1, HIV-2, and B19) laboratory test sample 
will be obtained prior to administration of the IMP at Week 12 (Infusion 5 for subjects on 
the 21-day cycle; Infusion 4 for subjects on the 28-day cycle) as described in Section 6.7. 
 
7.8 
Pharmacokinetic Sub-study (IMP Infusion 6 for 21-day cycle / IMP 
Infusion 5 for 28-day cycle) 
Subjects who participate in the PK sub-study will have PK blood samples drawn for 
Infusion 6 (Week 15 ±2 days) for 21-day cycle subjects or Infusion 5 (Week 16 ±2 days) 
for 28-day cycle subjects as described in Section 6.13. 
D-dimer and retention samples for protein C & S are drawn at time-points outlined in 
Section 6.11 and Tables 3 and 4. 
 
7.9 
Treatment Completion/Termination Visit (TCTV): IMP Infusion 17 (21- 
day cycle) or IMP Infusion 13 (28-day cycle) 
All study procedures at the TCTV are the same as those performed at Infusion 3, Interim 
Visit (Section 7.6). 
If treatment is terminated before the TCTV (Infusion 17 for the 21-day cycle, Infusion 13 
for the 28-day cycle), then all procedures for the TCTV should be performed at the final 
scheduled visit. 
In addition, if the subject is terminating the study early and is unable to return for the 
LTSV, the procedures required for the LTSV, including safety laboratory assessments 

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(hematology, chemistry, and urinalysis) and virology testing, with a retention sample, 
should also be completed at this visit. 
 
7.10 Long-Term-Safety-Visit (LTSV): Week 51 (21-day cycle) or Week 52 
(28-day cycle) 
Subjects on the 21-day cycle will return for the LTSV 21 days (±2 days) after their last 
infusion of IMP, and subjects on the 28-day cycle will return for the LTSV 28 days (±2 
days) after their last infusion of IMP. The LTSV will be conducted prior to the 
administration of the subject’s standard IgG treatment. The visit will consist of the 
following: 
Adverse Event Assessment and Concomitant Medication Review 
A review of adverse events, laboratory results and current medication will be performed. 
Current IgG treatment will be included under concomitant medication. 
Subject Diary Review 
The Subject Diary will be reviewed and collected as described in Section 6.2. 
Vital Signs Pre-Infusion 
Vital signs (body temperature, blood pressure, respiratory rate, and heart rate) will be 
recorded before the IMP infusion at the time intervals outlined in Section 6.3. 
Physical Examination 
The physical examination will focus on organs or systems that are known to be the target 
of complications in PIDD and the subject will be evaluated for infection as described in 
Section 6.4. 
The subject’s weight will be measured, and if the subject has gained or lost ≥5% body 
weight since baseline, the amount of IgG for infusion must be adjusted accordingly per 
standard care. 
Pre-Infusion Laboratory Assessments 
The following laboratory samples will be obtained prior to administration of IMP/CP: 
• Urine pregnancy test, if applicable (Section 6.5) 
• Serum IgG trough levels will be measured prior to each Infusion of IMP (Section 6.6) 
• Virology testing (Section 6.7), with a retention sample for future virology testing if 
necessary 
• Retention blood sample for potential future virology testing (Section 6.7) 
• Safety assessments, including general safety (hematology, blood chemistry, and 
urinalysis) (Section 6.8) 

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• Hemolysis assessment, including urine hemosiderin, serum haptoglobin, plasma free 
hemoglobin, Coombs test (direct anti-globulin test) (Section 6.9). 
• For all subjects, a drop of ≥2.0 g/dL from the pre-infusion hemoglobin level or 
clinical signs of hemolysis between visits will lead to a full hemolysis work-up 
(Section 6.9). 
• Antibodies to β2GPI and β2GPI-DI (Section 6.10) and retention sample. 
 
7.11 Long-Term-Safety-Follow-up visit (LTSF) for subjects who are 
discontinued from IMP due to adverse events and if study is stopped 
For subjects who are discontinued from study drug due to thrombotic or hemolytic 
events, and for all subjects if the study is stopped, subject will continue to be followed up 
and have the LTSF performed for 2 additional cycles (21-day cycle/28-day cycle) after 
LTSV, for a total approximate 3-month safety follow-up. The assessments will be 
conducted prior to the administration of the subject’s standard IgG treatment. 
For subjects who are discontinued from study drug due to anti-β2GPI immunogenicity, 
subject will continue to be followed up and have the LTSF performed after LTSV until 
immunogenicity titers are stabilized (or dropping) over 3 consecutive treatment cycles 
(21-day cycle/28-day cycle) after their last IMP infusion, and while on the subject’s 
standard IgG treatment. The assessments will be conducted prior to the administration of 
the subject’s standard IgG treatment. A follow-up phone call with the subject will take 
place approximately 8 weeks after the last LTSF performed for a review of laboratory 
assessments, including immunogenicity β2GPI and β2GPI-DI, adverse events and 
concomitant medication. 
Adverse Event Assessment and Concomitant Medication Review 
A review of adverse events, laboratory results and current medication will be performed. 
Current IgG treatment will be included under concomitant medication. 
Subject Diary Review 
The Subject Diary will be reviewed and collected as described in Section 6.2. 
Vital Signs Pre-Infusion 
Vital signs (body temperature, blood pressure, respiratory rate, and heart rate) will be 
recorded before the IMP infusion at the time intervals outlined in Section 6.3. 
Physical Examination 
The physical examination will focus on organs or systems that are known to be the target 
of complications in PIDD and the subject will be evaluated for infection as described in 
Section 6.4. 

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The subject’s weight will be measured, and if the subject has gained or lost ≥5% body 
weight since baseline, the amount of IgG for infusion must be adjusted accordingly per 
standard care. 
Pre-Infusion Laboratory Assessments 
The following laboratory samples will be obtained prior to administration of IMP/CP: 
• Urine pregnancy test, if applicable (Section 6.5) 
• Serum IgG trough levels will be measured prior to each Infusion of IMP (Section 6.6) 
• Virology testing (Section 6.7), with a retention sample for future virology testing if 
necessary 
• Safety assessments, including general safety (hematology, blood chemistry, and 
urinalysis) (Section 6.8) 
• Hemolysis assessment, including urine hemosiderin, serum haptoglobin, plasma free 
hemoglobin, Coombs test (direct anti-globulin test) (Section 6.9). 
• For all subjects, a drop of ≥2.0 g/dL from the pre-infusion hemoglobin level or 
clinical signs of hemolysis between visits will lead to a full hemolysis work-up 
(Section 6.9). 
• Antibodies to β2GPI and β2GPI-DI (Section 6.10) and retention sample. 
Follow-up Phone Call at 8 weeks after last LTSF 
A follow-up phone call with the subject will take place approximately 8 weeks after the 
last LTSF performed for a review of laboratory assessments, including immunogenicity 
β2GPI and β2GPI-DI, adverse events and concomitant medication. 
 
8 
Administrative Considerations 
 
8.1 
Interim Analyses and Stopping Rules for Subjects on IMP 
The DSMB (see Section 8.7), Sponsor, or PI may elect to terminate the study early as 
defined by the clinical study agreement. 
The study may also be stopped, suspended, or terminated for subjects with specific 
characteristics or for all subjects at any or all sites for any of the reasons described below. 
As described in Section 3.1 and Section 12.5, two interim analyses will be performed, 
based on the following in Group 1 and Group 2: 
• 
Testing for antibodies to ß-2 glycoprotein I (ß2GPI) and to ß-2 glycoprotein I 
domain I (β2GPI-DI); 

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• 
General safety laboratory tests (hematology, chemistry, urinalysis) before 
Infusion and on Day 7 after Infusion; 
• 
Hemolysis laboratory test before Infusion and at Day 2 or 3 and Day 7 after 
Infusion; 
• 
Clinical hemolysis & thrombosis assessment 1 h, 24 h and 72 h after Infusion; 
• 
D-dimers & retention sample for proteins C & S 3-4 h after Infusion; 
• 
Adverse Event data. 
The algorithm for study-stopping rules shown in Figure 2 will be followed. 
• 
If ≥2 subjects showing either (a) treatment-emergent positive anti-ß2GPI and/or 
ß2GPI- DI antibody titers ≥ 40 U as defined in Section 8.1.1 or 
(b) treatment-emergent positive anti-ß2GPI and/or ß2GPI-DI antibody titers 
> 20 U but < 40 U in combination with a treatment-emergent thrombotic or 
thromboembolic event, or a combination of (a) and (b). 
• 
If ≥2 subjects present with confirmed thromboembolic events, as defined in 
Section 8.1.2, following full work-up for thrombosis. 
• 
If ≥2 subjects present with confirmed hemolytic events, as defined in Section 
8.1.3, following full work-up for hemolysis. 
In the event any of the above occurs, administration of IMP for all subjects will be on 
hold until the investigator, DSMB, and FDA have reviewed the safety data and agree to 
resume dosing with IMP. 

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Figure 2. 
Summary of Stopping Rules 
 

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8.1.1 
Immunogenic Reactions 
Diagnosis of an immunogenic reaction that may lead to a thrombotic event will be based 
on treatment-emergent positive anti-ß2GPI and β2GPI-DI antibody titers, defined as an 
antibody titer of ≥ 40 U found twice on tests that are at least 12 weeks apart and/or on 
treatment-emergent positive anti-ß2GPI and β2GPI-DI antibody titers > 20 U but < 40 U 
in combination with a treatment-emergent thrombotic or thromboembolic event (Unlu et 
al., 2015) by these definitions will be considered significant events. If any subject after 
receiving IMP seroconverts from negative to positive, with an elevated rising antibody 
titer at least 12 weeks apart, then all prior retention samples for ß2GPI and/or β2GPI-DI 
for all subjects should be analyzed. 
Subjects who develop treatment-emergent anti-ß2GPI and/or β2GPI-DI antibody titers 
> 20 U following exposure to IMP will be followed closely by the investigator for 
thrombotic and/or thromboembolic events. These subjects will have periodic (no more 
than 8 weeks apart) anti-β2GPI and β2GPI-DI antibody titer testing until they have 
completed 52 weeks of treatment with IMP or until immunogenicity titers have stabilized 
or are declining over 3 consecutive treatment cycles (21 or 28 day cycles), whichever is 
later. 
As shown in Figure 2: 
1. Any subject who has a significant event as defined above for anti-β2GPI and/or 
β2GPI-DI antibodies while being treated with IMP will permanently discontinue 
treatment with the IMP. The subject will remain in the study for safety assessments 
up to the time of the final follow-up phone call after LTSF (see Section 7.11). 
2. The occurrence of two such significant events as defined above for anti-β2GPI and/or 
β2GPI-DI antibodies will be referred to the DSMB for an urgent ad-hoc review to 
determine if this qualifies as a potential study-stopping event as defined above. 
3. If two or more subjects treated with IMP are confirmed to meet the criteria for a 
significant event, as defined above, all treatments with the IMP will be discontinued 
until the lead investigator, the DSMB, and the FDA have reviewed all the 
anti-β2GPI and ß2GPI-DI antibodies safety data for subjects enrolled. During this 
time, no new subjects will be enrolled. If a subject should require a scheduled 
infusion during this time, they will continue therapy with a commercially available 
preparation (CP). IMP infusions will be recommenced if approval to continue the 
study is given by the DSMB and FDA. 
4. Any subject who becomes positive for anti-β2GPI and/or ß2GPI-DI antibody titers, 
as defined above, while being treated with CP will be treated at the discretion of the 
Investigator in discussion with the sponsor. 

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The IRB/IEC and the US FDA/appropriate regulatory authority for trials outside the US 
will be immediately notified of any suspected ADRs involving immunogenic reactions. 
 
8.1.2 
Thrombotic Events 
As shown in Figure 2: 
• Investigator will examine subjects for clinical signs of thrombosis (Section 6.12.2). 
Positive assessments will lead to a full work-up for thrombosis, as appropriate, 
according to the facility’s standard of care. In the case that d-dimer results indicate 
potential thrombosis, protein C and protein S testing will be done based on 
Investigator evaluation (Section 6.11). 
• Any subject who is diagnosed with a thromboembolic event based on clinical and 
laboratory assessment while being treated with IMP will permanently discontinue 
treatment with the IMP and will receive standard medical care. The subject will 
remain in the study for safety assessments up to the time of the final follow-up phone 
call after LTSF (see Section 7.11). All such events will be referred to the DSMB for 
an urgent ad-hoc review to determine if this event qualifies as a potential study- 
stopping event as defined above. 
• Any subject who is diagnosed with a thrombotic or thromboembolic vascular event 
based on clinical and laboratory assessment while being treated with the commercial 
product will receive standard medical care and continuation in the study will be at the 
discretion of the Investigator. If the subject is terminated from the study, the PI will 
determine continued treatment for managing the disease, in consultation with the 
subject’s treating physician and per standards of care. The subject will remain in the 
study for safety assessments up to the time of the final follow-up phone call after 
LTSF (see Section 7.11). 
• If two or more subjects experience confirmed thrombotic or thromboembolic vascular 
events in the trial as a whole in subjects receiving IMP, the DSMB will put the study 
on temporary hold while an assessment is made. All treatments with the IMP will be 
discontinued until the investigator, the DSMB, and the FDA have reviewed safety 
data for subjects enrolled. During this time, no new subjects will be enrolled. If a 
subject should require a scheduled infusion during this time, they will continue 
therapy with a commercially available preparation (CP). IMP infusions will be 
recommenced if approval to continue the study is given by the DSMB and FDA. 
The IRB/IEC and the US FDA/appropriate regulatory authority for trials outside the US 
will be immediately notified of any suspected ADRs involving thromboembolic events. 

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8.1.3 
Hemolysis 
As shown in Figure 2: 
• Investigator will examine subjects for clinical signs of hemolysis (Section 6.12.2). 
Positive assessments will lead to a full work-up for hemolysis, as appropriate, 
according to the facility’s standard of care. 
• For all subjects, a drop of ≥2.0 g/dL from the pre-infusion hemoglobin level or 
clinical signs of hemolysis between visits will lead to a full hemolysis work-up 
(Section 6.9). 
• Any subject who is diagnosed for a hemolysis event based on clinical and laboratory 
assessment while being treated with IMP will permanently discontinue treatment with 
the IMP and will receive standard medical care. The subject will remain in the study 
for safety assessments up to the time of the final follow-up phone call after LTSF (see 
Section 7.11). Any such event will be referred to the DSMB for an urgent ad-hoc 
review to determine if this event qualifies as a potential study-stopping event as 
defined above. 
• Any subject who is diagnosed with hemolysis based on clinical and laboratory 
assessment while being treated with the commercial product will receive standard 
medical care and continuation in the study will be at the discretion of the Investigator. 
If the subject is terminated from the study, the PI will determine continued treatment 
for managing the disease, in consultation with the subject’s treating physician and per 
standards of care. The subject will remain in the study for safety assessments up to 
the time of the final follow-up phone call after LTSF (see Section 7.11). 
• If two or more subjects experience confirmed hemolysis events in the trial as a whole 
in subjects receiving IMP, the DSMB will put the study on temporary hold while an 
assessment is made. All treatments with the IMP will be discontinued until the 
investigator, the DSMB, and the FDA have reviewed safety data for subjects 
enrolled. During this time, no new subjects will be enrolled. If a subject should 
require a scheduled infusion during this time, they will continue therapy with a 
commercially available preparation (CP). IMP infusions will be recommenced if 
approval to continue the study is given by the DSMB and FDA. 
The IRB/IEC and the US FDA/appropriate regulatory authority for trials outside the US 
will be immediately notified of any suspected ADRs involving hemolysis. 
 
8.1.4 
Other Reasons for Termination 
• The safety data reviewed by the DSMB demonstrate or strongly suggest that the study 
treatment (or participation in the study) is unsafe. 

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• The protocol or conduct of the study is flawed such that the safety or rights of the 
study subjects may be adversely affected. 
• The IRB/IEC has withdrawn approval for the study and has denied reconsideration. 
• Relocation of the PI, reallocation of the PI’s responsibilities, or disqualification of the 
PI by order of the regulatory authority 
• Non-adherence to the protocol or unavailability/lack of supervision by the PI and/or 
inadequate resource to conduct the study. 
• Clinical hold imposed by the FDA/appropriate regulatory authority for trials outside 
the US. 
Any decision to voluntarily suspend or terminate a clinical study will be carefully 
reviewed and fully justified. The sponsor will notify the FDA/appropriate regulatory 
authority for trials outside the US and the IRB/IEC of any suspension or termination, 
along with justification for restarting or terminating the study as applicable. 
 
8.2 
Withdrawal Criteria and Replacement of Subjects 
Subjects will be withdrawn for any of the following reasons: 
• The subject withdraws consent (no justification is required); 
• The subject is pregnant; 
• The subject develops a condition that in the investigator’s opinion makes it medically 
necessary that the subject not continue in the study. 
After an investigator and sponsor discussion, subjects may be withdrawn for the 
following reasons: 
• An AE that in the Investigator’s or sponsor’s opinion requires the subject be 
withdrawn from the study; 
• Violation of eligibility criteria; 
• Major protocol violations or deviations from the treatment plan dictated by the 
protocol (e.g., incorrect IMP administration); 
• Lost to follow-up after all attempts at contacting the subject; and/or 
• Death. 
In all cases, the reasons for withdrawal will be recorded in the subject’s source 
documentation and in the eCRF. It is possible that some subjects may become lost to 
follow-up during the study. Every reasonable effort will be made to contact these 
subjects; all available efficacy and safety data collected for these subjects will be used, 
even if incomplete. 

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8.3 
Screen Failures 
Subjects who do not meet the entry criteria through Baseline will be ineligible for 
treatment and will be deemed screen failures. Subjects who fail screening will not receive 
the IMP; therefore, no efficacy, safety, or PK data will be collected for these subjects, 
and only demographic information will be collected on the eCRF. Subjects who fail 
screening will be considered screened but not enrolled. Only subjects who qualify for 
treatment with CP/IMP will be enrolled. 
 
8.4 
Subject Identification 
Subjects will be identified by a numerical code in the site master log or the site database. 
Prior to approaching a subject, the site must look at the general eligibility criteria of the 
subject as a pre-screen check to ensure that the cohort is not already fully enrolled across 
the study. The process will be an approval process via the CRO. Once approval has been 
given to enroll and in which group, the site will begin the screening process. All subjects 
who sign the ICF/assent will receive a Subject Identification Number according to the 
following format: XX-YYY (site number-subject number) to be defined in a Study- 
specific Operations Manual. The anonymity of subjects will be maintained insofar as is 
required by law in order to protect the subjects’ rights to privacy. Personal identifying 
information may only be obtained by the Investigator or their designee to complete the 
requirements of the protocol, and must be kept by the Investigator in strictest confidence 
and may not be released unless required by law. See Section 17 for additional 
information regarding confidentially. 
 
8.5 
Treatment Compliance 
IMP will be provided by the sponsor and delivered to participating sites by the Central 
Drug Repository selected for the study. All subjects will be infused under the supervision 
of the PI and will receive the IMP dose ordered by the PI, and these data will be recorded 
in the eCRF. Only subjects who have been enrolled into the study will receive IMP. For 
more information on IMP dispensing and accountability, please see Section 13. 
During the Waiting Period for IMP treatment, commercial product will be infused under 
the supervision of the PI according to standard care, and the data will be recorded in the 
eCRF. If a subject is enrolled directly from a clinical trial, the PI will make the 
determination which commercial product the subject will receive, in consultation their 
treating physician. 
 
8.6 
Protocol Deviations 
Every effort will be made to avoid deviations from the protocol during the conduct of the 
study. When protocol deviations do occur, the Investigator should promptly inform the 
Monitor, and the implications of each deviation must be reviewed and discussed. Any 
deviation must be documented, stating the reasons, date, actions taken, and the impact for 

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the subject and/or study for each deviation. This documentation must be kept in the 
Sponsor Files, Investigator Files, and recorded in the eCRF. In case of any major protocol 
deviations (i.e., violations), the PI and sponsor will decide on the further participation of 
the affected submitted to the IRB/IEC according to the requirements of each of these 
institutions. 
Unique scheduling windows are indicated throughout the protocol with the use the “±” or 
“+” symbols. Protocol-related activities that occur outside the scheduled time point but 
within the allotted “±” or “+” windows are allowed and are not considered deviations. 
 
8.7 
Data Safety Monitoring Board (DSMB) 
In addition to the Sponsor and PI’s responsibility for oversight, study oversight will be 
under the direction of an independent DSMB. The DSMB will be responsible for ongoing 
review of safety data. The PI will assess seriousness, causality, and intensity (severity) of 
an adverse event. 
The processes, composition, and intervals of meetings will be described in detail in a 
separate DSMB charter written in accordance with the FDA Guidance [March, 2006]. 
The DSMB will include members with expertise in immunology and experience in 
clinical trials with immunoglobulin product. The DSMB will at minimum meet after all 
subjects in Group 1 have received their first infusion of IMP and the immunogenicity 
results are available, prior to Infusion 2. They will meet again once a further 10 subjects 
have received their first infusion of IMP and immunogenicity results are available prior 
to Infusion 2. These subjects will continue on IMP during review of safety data, but no 
further subjects will receive IMP until DSMB and FDA provide safety evaluation. At any 
time a thrombotic or hemolytic event is suspected or reported the DSMB will review the 
data of individual subjects and if needed additional subjects to make a determination. 
All immunogenicity data except for the screening data, baseline and Infusion 2 (prior to 
infusion) will be batch tested. The DSMB can request that the retention samples for 
immunogenicity testing (anti-β2GPI and ß2GPI-DI antibodies) or Protein C and S can be 
tested at any time. Once Group 1 and Group 2 have been approved, a DSMB meeting will 
take place after 20 subjects in Group 3 receive at least 6 doses of IMP. In the event any 
safety concerns are raised in the periods between meetings by SAEs, the DSMB Chair 
will hold ad hoc meetings to ensure the safety of all subjects and determine whether the 
concern warrants applying the stopping rules. 
The DSMB will provide its analysis and conclusions to ProMetic BioTherapeutics, to the 
IRBs, and to the FDA. The DSMB Charter is a separate document detailing the 
composition, governance, meeting preparation and conduct, voting rules and stopping 
rules. 

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9 
Concomitant and Prohibited Medications 
 
9.1 
Commercial Product 
Subjects who prior to entering the study were receiving commercially available IGIV will 
continue to receive the same product. Subjects who prior to entry were receiving IGSC or 
who were receiving another investigational IGIV will receive the commercially available 
IGIV chosen by the Investigator in consultation with their treating physician. 
 
9.2 
Concomitant Medications 
The administration of concomitant medications, including topical steroids for skin 
conditions, steroid eye drops, chronic use of inhaled steroids for asthma, and intranasal 
steroids for rhinitis, is permitted during the study period in keeping with the standard of 
care for subjects with PIDD. A brief course of systemic steroids (i.e., a steroid burst) is 
allowed for treatment of a short-term condition such as an asthma exacerbation or poison 
ivy exposure. Any medications, including non-prescription medications, taken by the subject 
from 21 days (± 2 days) or 28 days (± 2 days) (depending on subjects’ dosing interval) 
before baseline (Infusion 1) through the end of the study and the reason for use will be 
recorded and captured in the eCRF. 
Hydration practices are allowed during the study. All fluids administered and the volumes 
used will be recorded and captured in the eCRF. 
The use of pre-medication for pain relief and/or diphenhydramine prior to an IMP infusion 
is only permitted if the subject is using these pre-medications as part of routine IGIV or 
IGSC treatment. 
 
9.3 
Prohibited Medications 
The following medications are prohibited in this study: 
• Other immune globulin therapy after Baseline IMP infusion 1. 
• Immunosuppressive drugs, e.g., chemotherapy drugs. 
• Oral or parenteral corticosteroid at a dose ≥ 0.15 mg/kg/day prednisone or equivalent, 
except a steroid burst as described in Section 9.2. 
• Continuous antibiotics intended for prophylaxis of bacterial infections. 
 
9.4 
Other Restrictions 
Medications from other research studies or clinical studies are not permitted. 

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10 
Reporting of Adverse Events 
 
10.1 
Definitions 
 
10.1.1 Adverse Event 
An AE is any untoward medical occurrence (whether or not considered to have a causal 
relationship to IMP) in a study subject administered an IMP. Therefore, an AE can be any 
unfavorable and unintended sign (including a clinically significant laboratory finding), 
symptom, or disease temporally associated with the use of an IMP, whether or not related 
to the IMP. For the purposes of this protocol, all AEs occurring during the study are 
considered treatment-emergent AEs (TEAEs) associated with the use of the immunoglobulin 
product (either IMP or CP), whether or not the AE is determined to be product related. 
 
10.1.2 Adverse Drug Reaction (ADR) 
According to the FDA Guidance for Industry Adverse Reactions Section of Labeling for 
Human Prescription Drug and Biological Products — Content and Format (January 
2006), an adverse reaction is an undesirable effect, reasonably associated with the use of 
a drug, that may occur as part of the pharmacological action of the drug or may be 
unpredictable in its occurrence. This definition does not include all adverse events 
observed during use of a drug, only those for which there is some basis to believe there is 
a causal relationship between the drug and the occurrence of the adverse event. Adverse 
reactions may include signs and symptoms, changes in laboratory parameters, and 
changes in other measures of critical body function, such as vital signs and ECG. 
 
10.1.3 Infusional and Temporally Associated Adverse Events 
AEs that occur during the infusion of the IMP or CP will be recorded as Infusional AEs. 
Temporally associated AEs are those that occur during the infusion or within 72 hours 
following the end of the infusion, regardless of other factors that may impact a possible 
causal association with IMP/CP administration. 
 
10.1.4 Serious Adverse Events (SAEs) 
All AEs must be evaluated as potential serious adverse events (SAEs). An SAE is any 
untoward medical occurrence that at any dose: 
• Results in death. 
• Is life-threatening (i.e., the subject was at immediate risk of death from the AE as it 
occurred. (This does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death). 
• Requires inpatient hospitalization or prolongation of existing hospitalization. 
• Results in persistent or significant disability/incapacity. 

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• Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) or 
• Is a medically important event or reaction: 
o Events that did not result in death or hospitalization but may, based on 
appropriate medical judgment, jeopardize the subject or require intervention, 
to prevent one of the outcomes in the definition of SAE listed above, should 
also be considered SAEs. 
 
10.1.5 Adverse Event Severity 
The Investigator will assess the severity of AEs according to the criteria below: 
• Mild: The AE is transient and does not interfere significantly with the subject’s 
normal functioning level. The AE resolves spontaneously or may require minimal 
therapeutic intervention. 
• Moderate: The AE produces limited functional impairment and may require 
therapeutic intervention. The AE produces no sequelae. 
• Severe: The AE results in significant impairment of function and may lead to 
temporary inability to resume the subject’s normal life pattern. The AE produces 
sequelae which require prolonged therapeutic intervention. 
 
10.1.6 Adverse Event Relationship to IMP or CP 
The following 4-point scale will be used by the Investigator to rate the relationship of the 
adverse event to the study product, and final determination of causality will be 
established by the Sponsor: 
• Definitely related: A clinical event (including laboratory test abnormality) occurring 
in a plausible time relationship to drug administration, and which cannot be explained 
by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
drug (de-challenge) should be clinically plausible. The event must be definitively 
associated pharmacologically, using a satisfactory re-challenge procedure, if 
necessary. 
• Probably related: A clinical event (including laboratory test abnormality) with a 
reasonable time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a clinically 
reasonable response on withdrawal (de-challenge). Re-challenge information is not 
required to fulfill this definition. 
• Possibly related: A clinical event (including laboratory test abnormality) with a 
reasonable time sequence to administration of the drug, but which could also be 

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explained by concurrent disease or other drugs or chemicals. Information on drug 
withdrawal may be lacking or unclear. 
• Not related: An event for which sufficient information exists to conclude that the 
etiology of the event is unrelated to the IMP. 
Causality will be assessed as follows: 
The Investigators will assign causality at their respective sites during the study, with final 
determination of causality established by the Sponsor. The DSMB will review the 
assigned causality for all AEs and SAEs prior to database lock. This assignment will be 
included in the study database and final study report. As noted in the FDA Guidance for 
Industry Adverse Reactions Section of Labeling for Human Prescription Drug and 
Biological Products — Content and Format, decisions on whether there is some basis to 
believe there is a causal relationship will be based on factors such as: (1) the frequency of 
reporting, (2) whether the adverse event rate for the drug exceeds the placebo rate, (3) the 
extent of dose-response, (4) the extent to which the adverse event is consistent with the 
pharmacology of the drug, (5) the timing of the event relative to the time of drug 
exposure, (6) existence of challenge and de-challenge experience, and (7) whether the 
adverse event is known to be caused by related drugs. 
 
10.2 
Handling and Reporting of Infusional and Temporally Related 
Adverse Events 
 
10.2.1 Common Temporally Associated AEs or ADRs 
Common temporally associated AEs or ADRs that may occur in approximately 5% of 
infusions or less include but are not limited to headache, fatigue, chills, dyspnea, pallor, 
backache, other body ache, leg cramps, light-headedness, fever, urticaria, flushing, 
elevation of blood pressure, nausea, vomiting, anaphylactic reactions, infusion site 
reactions, hypersensitivity reactions, oliguria, and anuria. 
On rare occasions, immunoglobulins may cause a sudden fall in blood pressure and, in 
isolated cases, anaphylactic shock, even when the subject has shown no hypersensitivity 
to previous administrations. Cases of reversible aseptic meningitis, isolated cases of 
reversible hemolytic anemia/hemolysis and rare cases of transient cutaneous reactions, 
have been observed with human normal immunoglobulin. Transfusion-related lung injury 
(TRALI) characterized by severe respiratory distress, pulmonary edema, fever, 
hypoxemia, and abnormal left ventricular function have also been reported, typically 
within 1 to 6 hours after the transfusion. Increases in serum creatinine levels and/or acute 
renal failure have been observed. Very rarely, thromboembolic reactions such as 
myocardial infarction, stroke, pulmonary embolism, and deep vein thrombosis may 
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10.2.2 Subject Monitoring 
The recommended infusion rates mandated by the protocol must be closely followed. 
Subjects must be closely monitored and carefully observed for any symptoms throughout 
the infusion period as per the protocol requirements. 
Certain severe ADRs may be related to the rate of infusion. 
Certain adverse reactions may occur more frequently: 
• in patients with hypo- or agammaglobulinemia with or without IgA deficiency 
• in case of high rate of infusion 
All subjects will be monitored for the first hour after each infusion, except for the first 
infusion where they will be monitored for 3-4 hours after the infusion. During this time, 
the subject will be observed in order to detect potential adverse signs and conduct the 
post-infusion 60-minute vital sign measurement and assessment for signs of hemolysis or 
thrombosis. Handling of Infusional and Temporally Associated AEs 
Infusional and temporally associated AEs will be closely monitored. For AEs that occur 
during infusions, the infusion rate in effect at the time of onset of the AE will be 
captured. 
IMP will be administered according to the infusion rate titration schedule in Section 13.6. 
Note: The dose and administration of CP for subjects on the Waiting Period will be per 
standard care, as determined by the Investigator in consultation with the treating 
physician. 
If an infusional AE occurs during the first treatment course, the study staff will initiate 
one of the following actions, which will be graded from 1 to 4 depending on the nature 
and/or severity of the event: 
1. Reduce the current infusion rate to one-half the rate of the infusion at which the 
AE was observed; or 
2. Reduce the rate of the infusion more than one-half the rate at which the AE was 
observed, as necessary to subside symptoms; or 
3. Reduce the rate of the infusion to one-half, or progressively reduces more than 
one-half, the rate at which the AE was observed and then stops the infusion, as 
necessary to subside symptoms; or 
4. Stop the infusion to subside symptoms. 
The study staff will evaluate the subject’s AE and then: 
• increase or resume the infusion at a rate tolerated by the subject once the symptoms 
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• stop the infusion and not resume it. 
If a subject has an infusional AE at the same infusion rate twice, then subsequent infusion 
rate escalation, if any, should be halted at the rate before the AE, depending on the 
severity of the AE. 
 
10.2.3 Reporting Infusional and Temporally Associated AEs 
Infusional and temporally associated AEs will be reported as the number occurring 
during the infusion and within 1 hour, 24 hours, and 72 hours after the end of the 
infusion, and the total number of AEs that occur during or within 72 hours of an infusion 
will be given in the Adverse Reactions section of the product’s draft package insert, along 
with the total number of infusions, and the mean number of such temporally associated 
AEs per infusion (see Section 12.3.4). 
 
10.3 
Eliciting and Reporting of Other Adverse Events 
AEs will be captured from signing of Informed Consent/Assent to until 21±4 days or 
28±4 days following the last infusion. AEs and ADRs will be elicited and reported as 
follows: 
The condition of the subject will be monitored throughout the study. At each visit, AEs 
will be elicited using a standard non-leading question such as “How have you been since 
the last visit / during the previous study period?” AEs will also be elicited through the 
use of Subject Diary cards, which the Investigator will review in detail with the subject at 
each visit, ensuring accuracy and completeness of entries recorded by the subject. 
The staff will also ask specific questions during phone calls to determine whether a work- 
up for hemolysis and/or thrombosis is necessary. During the phone calls, the staff will ask 
open-ended questions about the subject’s wellbeing and to ensure that AEs are being 
documented in the Subject Diary. The study staff will review these specific questions 
with the subject and ensure subject is completing the diary. (Section 6.12.3) 
Any AE or ADR occurring during the study will be noted in detail on the appropriate 
pages of the eCRF. If the subject reports several signs or symptoms, which represent a 
single syndrome or diagnosis, the latter should be recorded in the eCRF. The Investigator 
will grade the severity of all AEs or ADRs (mild, moderate, or severe), the seriousness 
(non-serious or serious) and relatedness, with final determination of causality established 
by the Sponsor, as defined in Section 10.1. 
In the event of abnormal laboratory findings considered clinically significant by the 
Investigator, the tests will be repeated and followed-up, as needed. Diseases, signs and 
symptoms, and/or laboratory abnormalities already existing before the first administration 
of IMP are not considered as AEs when observed at a later stage unless they represent a 
worsening. 

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The Investigator should always provide detailed information concerning any 
abnormalities and the nature of, and reasons for any necessary action(s), as well as any 
other observations or comments, which are useful for the interpretation and 
understanding of the subjects’ AEs or ADRs. 
 
10.4 
SAE Reporting 
All AEs assessed as serious must be reported beginning from the signing of Informed 
Consent/Assent to 21±4 days or 28±4 days following the last infusion. SAEs must be 
followed until the event resolves, the event or sequelae stabilize, or it is unlikely that 
additional information can be obtained after demonstration of due diligence with follow- 
up efforts (i.e., the subject or Investigator is unable to provide additional information or, 
the subject is lost to follow-up). 
 
10.4.1 SAE Reporting to Safety 
All SAEs will be reported within 24 hours of the Investigator becoming aware of the 
event and submit the Safety Report 24/7 to the Safety Department via the fax 
number/email below. 
Toll Free Fax: 1-866-246-1693. Toll Free Telephone: 1-888-784-2723 
Email: prometic_safety@integratedtsi.com 
Full details of SAE reporting to the Safety Department will be defined in the Safety 
Management Plan. 
It should be noted that reporting to the Safety Department within 24 hours of awareness 
is required for all SAEs regardless of their causal relationship with the IMP. 
The Safety Department, together with the sponsor’s medical monitor, will review all 
safety information/documentation and follow up with the investigative site to obtain any 
other required information. Follow-up information should be actively sought by the 
Investigator and reported to the Safety Department as it becomes available using the 
Safety Report. 
The sponsor and the appointed for the study are responsible for reporting SAEs to the 
FDA/appropriate regulatory authority for trials outside the US, as applicable. 
Serious adverse events that are unusual in the absence of drug therapy will be listed in the 
Adverse Reactions section of the draft package insert, even if there are only one or two 
reported events, unless it is clear that a causal relationship can be excluded. 
 
10.4.2 Institutional Review Board/Independent Ethics Committee 
A central IRB will be used for the majority of the sites in the US, and local IRBs/IECs for 
the remaining US sites and for the Russian sites. All AEs will be reported to the IRB/IEC 
according to the guidelines of the IRB/IEC. However, as a general guideline, IRBs need 

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to know about any AEs that are unknown or of a greater severity than what is reported in 
the Investigator’s Brochure. Reporting is always required for all SAEs. Any new safety 
data (or other finding) that might alter the assessment of an IRB/IEC regarding their risks 
versus benefits analysis should always be reported to the IRB/IEC. The sponsor and the 
clinical research associate (CRA) will assist the Investigator in determining which events 
require reporting and in what timeframes. 
 
10.4.3 Expedited Suspected Unexpected Serious Adverse Reaction 
(SUSAR) Reporting (Sponsor Responsibility) 
The Sponsor will submit a written IND Safety Report (i.e., completed FDA Form 3500A) 
within 15 calendar days of receipt to the responsible new drug review division of the 
FDA for any observed or volunteered AE that is determined to be: 
1. associated with the investigational drug or study treatment(s); 
2. serious; and 
3. unexpected. 
In addition, if the event is fatal or life-threatening and meets the above criteria, a 
telephone or facsimile notification will be sent to the FDA as soon as possible, but no 
later than 7 calendar days after the sponsor’s initial receipt, followed by a completed 
FDA Form 3500A within 15 calendar days after initial receipt. 
Each IND Safety Report will be prominently labeled “IND Safety Report,” and a copy 
will be provided to all participating site Investigators. 
For each written IND Safety Report, the Sponsor will identify all previously submitted 
IND Safety Reports that addressed a similar adverse event experience and will provide an 
analysis of the significance of the newly reported adverse event in light of the previous, 
similar report(s). 
If the results of the Sponsor’s follow-up investigation show that an adverse event that was 
initially determined to not require a written IND Safety Report does, in fact, meet the 
requirements for reporting, the Sponsor will submit a written IND Safety Report as soon 
as possible, but in no event later than 15 calendar days after the determination was made. 
Follow-up information to an IND Safety Report will be submitted to the applicable 
review division of the FDA as soon as the relevant information is available. 
For study sites outside of the United States, the corresponding reporting procedures will 
be followed according to local regulations. 
 
10.5 
Pregnancy 
Every effort will be made to avoid a pregnancy during the study. Contraceptives against 
pregnancy should be used (see Section 4.3.1), and the contraceptive techniques discussed 

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between the PI and subject at Screening should not be changed during the course of the 
study. A pregnancy test will be performed at all visits. 
In case a subject becomes pregnant during the study, she has to be withdrawn from the 
study. Pregnancies occurring during the study after exposure to the IMP must be 
reported. The pregnancy notification form has to be sent to the Safety Department. 
Follow-up information on the outcome of both mother and fetus must also be reported. 
 
10.6 
Procedure for Breaking the Blind 
As this is an open-label study, no subject or study personnel will be blinded. 
 
10.7 
Follow-up of Adverse Events 
The responsible Investigator will follow up each AE through the LTSV or LTSF (as 
applicable) until it is resolved or until the medical condition of the subject is stable. AEs 
that are not resolved or stable at the time of study completion will be recorded as 
ongoing. All relevant follow-up information will be reported to the sponsor. 
 
11 
Pharmacokinetic Analysis 
For all subjects in the PK sub-study, blood samples will be collected for the assessment 
of serum concentrations of total IgG. The serum concentrations will be determined as 
defined in a laboratory assay plan. All PK parameters will be estimated by both 
compartmental and non-compartmental analysis using Phoenix® WinNonlin 6.3 
(Pharsight) and summary statistics will be presented. For all subjects in the all treated 
population dataset, prior to each infusion, trough serum IgG concentrations will also be 
determined. The data will be baseline (predose) corrected for the PK analysis. 
The area under the concentration-time curve over 1 dosing interval (AUC0-t), the area 
under the concentration-time curve extrapolated to zero concentration (AUC0-inf) the 
maximum serum concentration (Cmax), the time to reach the maximum serum 
concentration (Tmax), the volume of distribution at steady-state (Vss), mean residence 
time (MRT), the total body clearance (Cl), and the terminal half-life (t1/2) will be 
determined from the total IgG serum concentrations measured at infusion of IMP at 
Infusion 6 (week 15 ± 2 days) for 21-day cycle subjects or Infusion 5 (week 16 ± 2 days) 
for 28-day cycle subjects (using the trough level immediately prior to this infusion as 
baseline). An additional sample will also be taken prior to the next infusion at Week 18 
(± 2 days), Infusion 7 for subjects on a 21-day cycle, or at Week 20 (± 2 days), and 
Infusion 6 for subjects on a 28-day cycle. 

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12 
Statistical Analysis 
 
12.1 
Analysis Populations 
The safety analysis set will consist of all subjects who are enrolled into the study and 
received study product. The all treated population analysis set will be will be the same as 
the safety set. A modified per-protocol population analysis set will be defined as all 
subjects in the full all treated population set who remain in the study for at least 6 
infusions. 
A per-protocol (PP) analysis set will consist of all subjects in the all treated population 
set who complete the whole 12-month study period and who do not have any major 
protocol violations as described in the Data Handling Plan. 
The analyses described below will be presented for all subjects in the all treated population, 
the modified PP population, and the PP population as follows: 
• Cohort 1 only; 
• Cohort 2 only; 
• Each of the 3 age groups within Cohort 2; 
• Cohorts 1 and 2 pooled. 
The primary efficacy analysis will be based on the all treated population analysis set, 
with separate analyses for Cohort 1 and Cohort 2. 
 
12.2 
Handling of Missing Data 
For the primary efficacy analysis, the method of maximum likelihood estimation will be 
used in conjunction with a negative binomial model to obtain a 99% one-sided upper 
confidence limit on the rate of serious bacterial infections. Since the resulting confidence 
interval leads to valid statistical inference assuming missing data are missing at random, 
no data imputation will be used in this analysis. With respect to safety and secondary 
endpoints, no data imputation will be used in the analysis of any other data from this 
study including the PK evaluations. Missing data will be omitted from summary 
statistics. 
 
12.3 
Statistical Analysis Plan 
 
12.3.1 Descriptive analyses 
Continuous variables will be summarized using a standard set of descriptive statistics, 
consisting of frequency count, mean, standard deviation, median, maximum, and 
minimum. Time to event endpoints will be presented using Kaplan-Meier plots. Binary 
endpoints and categorical data will be summarized by count and percentage. Count data 
will be summarized by total counts and rates per subject per infusion. 

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12.3.2 Primary Efficacy Endpoint 
The primary efficacy endpoint in this clinical study is the rate of acute serious bacterial 
infections (pneumonia, bacteremia and septicemia, osteomyelitis/septic arthritis, bacterial 
meningitis, visceral abscess) per subject during the 12-month study observation period 
while receiving IMP. Serious bacterial infections (SBIs) must be confirmed with the tests 
and outcomes as described in Section 21.1. 
The rate of occurrence of such infections will be calculated for each subject as 52n/w 
where n is the number of reported infections and w is the number of weeks on study. 
For the primary endpoint, a 99% one-sided (upper) confidence limit for the incidence rate 
of SBIs (scaled to represent 12 months exposure if necessary) will be derived, and the 
objective of demonstrating that the true infection rate is below 1 per subject per year will 
be considered established if this upper limit is less than 1. 
To calculate the confidence limit, a negative binomial regression model will be used. 
This model includes an over-dispersion parameter to account for possible intra-subject 
correlation as well as the actual time period each subject is on the study as an offset 
variable. The null hypothesis for this analysis is that the true SBI rate is at least 1 per 
subject per year, and the alternative hypothesis is that this rate is less than 1 per subject 
per year. Rejection of the null hypothesis is therefore equivalent to demonstration of the 
study objective to show that the true rate is less than 1 per subject per year. 
The proposed method of analysis makes appropriate allowance for any intra-subject 
correlation in the incidence of SBIs. Such correlation would occur whenever variability 
in the individual subject-specific SBI rates exceeds what would be expected in the 
presence of true Poisson variability. The proposed statistical test based on a negative 
binomial model includes an overdispersion parameter reflecting any such inflated 
variance. 
No formal statistical analyses will be done comparing the primary efficacy endpoint 
between the Waiting Period and the IMP Treatment Period. 
 
12.3.3 Secondary Efficacy Endpoints 
Secondary endpoints are: 
• Total serum IgG trough levels 
• Number of episodes of fever (≥ 100.4°F) 
• Number of days out of work/school/kindergarten/day care or unable to perform 
normal daily activities due to infection 
• Number of days of hospitalization due to infection 
• Number of days of antibiotic use for infection prophylaxis and/or treatment 

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• Number and duration of infections other than acute serious bacterial infections 
These endpoints will be analyzed descriptively, using frequency tables or the standard set 
of summary statistics as appropriate. 
No formal statistical analyses will be done comparing secondary efficacy endpoints 
between the Waiting Period and the IMP Treatment Period. However, any efficacy 
endpoints measured during both the Waiting Period on commercial product and IMP 
Treatment Period may be summarized side-by-side using the appropriate descriptive 
statistics. For the Waiting Period, the summary descriptive statistics will be aggregated 
over all commercially licensed products. 
 
12.3.4 Safety Endpoints 
Evaluation of safety includes the analyses of laboratory investigations, adverse events, 
and adverse reactions/suspected adverse reactions. No formal statistical analyses will be 
done comparing any of the safety endpoints between the Waiting Period on commercial 
product and the IMP treatment period. However, all safety endpoints measured during 
both the Waiting Period on commercial product and the IMP treatment period will be 
summarized side-by-side using the appropriate descriptive statistics. For the Waiting 
Period on commercial product, the summary descriptive statistics will be aggregated over 
all commercially licensed products. 
Laboratory Data: 
A summary by treatment period (Waiting period, IMP treatment period) will be produced 
for each of the laboratory parameters at each visit. These safety summaries will include 
descriptive summary tables and the data will be summarized in the form of frequency 
count, mean, standard deviation, median, minimum and maximum by treatment period 
and visit. 
Adverse Events: 
The seriousness, severity and relationship to the study drug of adverse events (AEs) will 
be observed and recorded on repeated administrations of the study drug using the 
MedDRA dictionary for the coding of AEs and serious adverse events (SAEs). 
The number and proportion of subjects who have one or more AEs will be tabulated by 
seriousness, severity, and relationship to treatment according to body system and 
treatment period. Temporally related AEs will be similarly summarized. Rates of AEs 
will be estimated on a per infusion per subject basis and tabulated by seriousness, 
severity, and relationship to treatment according to body system and treatment period. 
The following observations will be summarized, using the standard set of summary 
statistics (see 12.3.1). 
• The number of infusions administered 

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• The total number of AEs experienced (irrespective of causality) 
• The total number of AEs temporally associated with infusions 
• During the infusion 
• Within 1 hour after the infusion 
• Within 24 hours after the infusion 
• Within 72 hours after the infusion 
• The number and proportion of infusions with which one or more infusional AEs are 
associated 
• The number of infusional AEs per infusion 
• Rate-related AEs 
AEs will also be tabulated for the 30 subjects who received the highest doses of IMP and 
commercial product. 
The FDA recommends that for a novel IGIV formulation, a study should demonstrate that 
an upper 95% confidence limit on the rate of infusions having one or more temporally- 
associated AEs be less than 40 infusions per 100 patient infusions (0.40). An AE should 
be established as associated to the infusion of study drug by implicating temporal 
association (this includes all AEs regardless of relationship to product). 
For the purpose of this study, AEs are considered temporally associated with the study 
drug infusion, if they occur in the period from the start of the infusion until 72 hours after 
the end of the infusion. To meet the recommended target for this safety endpoint, the 
number of infusions having one or more temporally-associated AEs will be analyzed 
using a negative binomial regression model with an over-dispersion parameter to account 
for possible intra-patient correlation and the number of infusions per patient as an offset 
variable. To calculate the required upper 95% confidence limit, an intercept-only 
negative binomial regression model will be fit to the data in which the response for each 
subject is the number of affected infusions (i.e., the number of infusions with one or more 
temporally-associated AEs). A two-sided 90% confidence limit on the intercept will then 
be computed on the inverse link scale to achieve an upper one-sided 95% confidence 
limit on the expected mean number of infusions per 100 patient infusions having one or 
more temporally associated AEs. This upper limit should be below 40 in order to 
demonstrate safety with respect to the infusion process. 
Adverse Reaction/Suspected Adverse Reaction 
The operational definition of adverse reaction/suspected adverse reaction for analysis 
purposes will be all AEs meeting any of the following criteria: (a) the event began during 
or within 72 hours following the last IMP infusion; (b) the event was considered by the 

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investigator and/or the sponsor to be at least possibly related to the IMP administration; 
or (c) the causality assessment was missing or indeterminate. 
β2GPI and to β2GPI-DI Antibody Data 
Data on formation of antibodies to β2GPI and to β2GPI-DI will be tabulated and 
discussed individually in the text. 
Viral Safety Data 
Viral safety data will also be listed (not tabulated) and any seroconversions will be 
discussed individually in the text. 
Hemolysis Data 
Data on potential IGIV-associated hemolysis will be tabulated and discussed in the text. 
The operational definition of IGIV-associated hemolysis for this analysis is defined as 
any event meeting the following criteria occurring within 10 days following IGIV 
administration: (a) a fall of at least 1 g/dL in hemoglobin from the previous value; (b) a 
positive Coombs test (direct anti-globulin test); and (c) at least 2 of the following: 
increased reticulocyte count, increased LDH, low haptoglobin, increased bilirubin, 
increased plasma free hemoglobin, increased urine hemosiderin. 
 
12.3.5 Subgroup Analyses 
Subgroup analyses will be performed based on gender and region (USA and Russia). 
 
12.4 
Sample Size 
The power of this study to establish that the true infection rate is less than 1 per subject 
per year depends primarily on the unknown true infection rate. However, on the 
assumption that the number of serious bacterial infections (SBIs) per year follows a 
negative binomial distribution with mean μ and variance σ2 = μ(1+ϕμ) where μ is the 
population mean infection rate per year and ϕ is an overdispersion parameter reflecting 
possible variability in individual subject-specific rates, an estimate of the power can be 
made for a range of assumptions about the true infection rate. 
The following table shows the estimated power of a study with 40 subjects (Cohort 1) or 
20 subjects (Cohort 2) to achieve an upper 99% confidence limit below 1, for various true 
values of the population mean infection rate assuming a range of overdispersion from 
ϕ=0 (corresponding to a Poisson distribution with no overdispersion) to ϕ=2.0. These 
results were obtained using standard one-sample power calculations for testing the one- 
sided null hypothesis, H0: μ≥1, against the alternative hypothesis, H1: μ<1, where μ is the 
population mean number of SBI’s per subject per year. Specifically, the estimated power 
is given by Power = 1 – ß = Pr[m + Z1-ασ<1|H1] where m is the sample mean rate of 
infection, Z1-α = 2.326 is the standard normal quantile for an upper 99% confidence limit, 

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and σ2 = μ(1+ϕμ) is the true variance under the alternative hypothesis H1 for some 
specified value μ that is less than 1. 
Table 5. 
Calculations on Statistical Power 
 
True population infection rate per subject 
per year and possible overdispersion 
Chance of upper 99% one-sided 
confidence limit being below 1 
SBI rate μ 
Overdispersion 
parameter ϕ 
N=40 
(Cohort 1) 
N=20 
(Cohort 2) 
0.40 
0 (Poisson) 
2.0 
99.9% 
98.4% 
97.2% 
79.8% 
0.45 
0 (Poisson) 
2.0 
99.8% 
92.4% 
91.0% 
63.1% 
0.50 
0 (Poisson) 
2.0 
98.4% 
79.8% 
79.8% 
46.4% 
0.55 
0 (Poisson) 
2.0 
93.5% 
62.6% 
65.1% 
32.5% 
0.60 
0 (Poisson) 
2.0 
82.6% 
45.0% 
49.3% 
22.1% 
 
 
The study therefore has adequate power (80% or greater when rounded) provided that the 
true rate of serious bacterial infections in the study population is 0.50 per subject per year 
or below for adults, or 0.40 per subject per year or below for children, and if the 
assumption of a negative binomial distribution (or Poisson distribution when ϕ=0) is 
appropriate. 
 
12.5 
Interim Analysis 
Two interim safety analyses will be performed to allow the DSMB and FDA to evaluate 
safety data from the first 15 subjects (Section 3.1) before Group 3 begin receiving the 
IMP. 
No other interim analysis is planned. However, when all subjects in Cohort 1 have 
completed the LTSV, and all data have been fully reconciled, a database lock of Cohort 1 
will occur, and a Clinical Study Report will be prepared in support of a BLA for the adult 
population. All available safety data relating to Cohort 2, available at the time of the 
Cohort 1 database lock, will be included in this report. When all subjects in Cohort 2 
have completed the LTSV, this process will be repeated, and a separate Clinical Study 
Report will be prepared in support of a BLA for the pediatric population. This second 
report will also include the pooled analysis of the two cohorts. 

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13 
Management of Investigational Medicinal Product 
Detailed instructions are specified in the IMP Manual at each site. 
 
13.1 
Packaging and Labeling 
The IMP, ProMetic BioTherapeutics Immune Globulin Intravenous Solution 10%, is a 
sterile, 10% liquid preparation of highly purified immune globulin (IgG) derived from 
pools of human plasma of at least 1000 donors (21 CFR, §640.102) for IV administration 
under aseptic conditions. 
The IMP is filled in 50 mL (5 g) single-use, type-1 glass bottles seated with a rubber 
stopper and an aluminum seal with plastic flip-top cap. 
Vial labels will include information to comply with US regulations: 
• “Caution: New Drug - Limited by Federal (or United Sates) Law to Investigational 
Use Only” 
• The protocol number “2004C009G” 
• The product volume (50 mL) and 10% concentration 
• The lot number 
• The recommended storage conditions 
• The name of the Sponsor 
• Expiry date will not be included, as stability testing will be ongoing. Therefore, the 
documentation of the applicable expiry dates will be provided according to the lot 
number and stored in the IMP files at the site with the Investigator and/or Research 
Pharmacist, if applicable. 
• Labeling for the shelf cartons will also bear this information. 
Vial labels for non-US sites will include information to comply with local regulations. 
 
13.2 
Storage 
The IMP must be stored refrigerated at 2-8°C in a secured area until used. The 
temperature in the storage area should be monitored with properly calibrated instruments 
and monitored on a temperature log. 
 
13.3 
Accountability 
The PI or designee is responsible for maintaining accurate inventory records of IMP. The 
PI or designee will inventory all IMP shipments upon receipt, acknowledge possession by 
signing and returning all required documentation to the Sponsor or CRO. The PI must 

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ensure that all drug supplies are kept in a secure location at the site in accordance with 
recommended storage conditions. Inventory records for the IMP will include: 
• Protocol name, number, and sponsor. 
• Product name and description. 
• Study site and PI name. 
• Product lot number and Expiry Date(s)/Re-test date. 
• Number of vials, sizes received from the Central Drug Repository. 
• Number of vials dispensed, date and time of dispensing and study subject for whom 
product was dispensed. 
• Product balance. 
• Name and title of qualified individual dispensing product. 
These records will be reviewed by the Monitor, and may be reviewed by regulatory 
agencies. 
All correspondence with the sponsor regarding the stability and product release should be 
kept with the study specific documents at site and/or the pharmacy as applicable. 
 
13.4 
Shipment, Returns, and Destruction 
The IMP will be shipped from ProMetic BioTherapeutics to a selected Central Drug 
Repository and from the Central Drug Repository to the sites at a temperature of 2-8°C. 
During shipment, the temperature of the drug will be monitored to ensure the required 
temperature conditions are maintained. The PI or designee will be responsible for 
checking the number of vials and the condition of the vials received and entering this 
information into the drug accountability records, reporting the condition to ProMetic 
BioTherapeutics, the CRO and/ or the Central Drug Repository and return the data logger 
and all required documentation to the Central Drug Repository. At the end of the study, 
or upon request by the sponsor, all unused, partially used or empty vials will be returned 
to the sponsor or the Central Drug Repository or destroyed at the site after accountability 
has been completed by the Monitor. 
 
13.5 
Preparation 
The IMP should be inspected for particulate matter and discoloration prior to 
administration. The solution should be clear or slightly opalescent. Solutions that are 
cloudy or have particulates must not be used. Vials must not be shaken. 
The IMP can be infused directly from the vials or the IMP may be pooled and aseptically 
transferred into an empty sterile IV bag before administration as follows: 

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• The protective caps from the product vials must be removed. 
• The exposed central portion of the rubber stopper must be wiped with an isopropyl 
alcohol swab. 
• The dose will be calculated based on the prescription provided by the PI which will 
be based on the subjects’ weight and trough levels and calculated in a mg/kg dose. 
• IMP preparation will be made allowing for rounding up to the next 10mL. 
• IMP preparation can also be rounded down to the previous 10mL as long as the dose 
remains in the range mandated by the protocol (200mg-800mg/kg) 
• If the site pools the IMP into an infusion bag, then an appropriate volume of IMP will 
be drawn into a syringe, aseptically transferred into an appropriately sized sterile IV 
bag and labeled. The rounded dose will be pooled into the bag together with a 
predetermined extra volume per site for priming the tube, if applicable. Saline, DW5 
or IMP can be used to flush the tubing, per standard of care. 
• Flushing or priming the IV set with the IMP will be allowed, per the usual practices 
of the site. Any IMP used for this purpose will be included as part of the IMP dose. 
• Any other approved fluid (Saline, DW5) used to flush or prime IV tubing must be 
documented in the eCRF and not included as the IMP dose volume. 
• All vials empty and partial will be saved. 
Pooled infusions must be prepared by a pharmacist or appropriately qualified designee. 
In the event that a pharmacy will not be used, the IMP may be stored in an alternate 
location (e.g., a refrigerator monitored by site staff, etc.), as long as such location meets 
the requirements given in Section 13.2. In this case, the IMP should only be pooled if the 
aseptic technique described above can be ensured, and the person performing this task is 
appropriately qualified and working under the supervision of the Investigator. 
Empty and partially used study drug vials must be maintained for drug accountability. 
These supplies should be clearly marked by subject (e.g., empty and partially empty vials 
from a single infusion should be placed in a plastic bag that bears the subject number and 
initials and date) and must not be discarded until authorization has been provided by the 
CRA. The volume left behind in partially empty vials will be recorded as 
• <25% 
• 25%-50% 
• 50%-75% 
• 75%-100% 

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For any single infusion to a subject, the same lot must be used; no mixing of lots. 
However, over the 13 or 17 infusions for a subject, different lots can be used. Prior to 
infusion, the IMP should be brought to room temperature or body temperature, and once 
this process has occurred, unused IMP should not be returned to the refrigerator for future 
use. 
 
13.6 
Dose and Administration of IMP 
Note: The dose and administration of CP for subjects on the Waiting Period will be per 
standard care, as determined by the Investigator in consultation with the treating 
physician. This section only applies to IMP. 
 
13.6.1 IMP Dose 
The IMP dose should be consistent with previous IGIV or IGSC treatment. 
When subjects receiving IGIV enter the study, the IMP will be administered initially at a 
dose and schedule based on the subject’s previous IGIV dosing schedule (3- or 4-week 
interval). Subjects on a 21-day cycle when they enter the study will remain on a 21-day 
cycle, and subjects on a 28-day cycle will remain on a 28-day cycle. The study dose will 
be calculated by the Investigator using the subject’s body weight (200-800 mg/kg, 
allowing for ≤25% change). 
Subjects who are on IGSC when they enter the study must have previously tolerated 
IGIV use at either a 21-day or a 28-day cycle, and these subjects will be switched from 
IGSC to IGIV treatment at the same cycle as their previous IGIV treatment. However, 
because doses are adjusted in an ongoing manner for multiple reasons, including weight 
changes, the initial study dose may not be the same as the previous IGIV dose. Instead, 
the study IGIV dose may be based on the current IGSC dose and will be calculated by 
multiplying the weekly IGSC dose by 3 (for a 21-day cycle) or by 4 (for a 28-day cycle) 
and then dividing by the dose-adjustment coefficient as indicated by package insert. 
The PI may change the dose and/or dosing interval in order to maintain a trough level of 
≥ 5 mg/mL. For example, such changes may be necessary because of assessments of AEs 
or other safety assessments, or changes in the subject’s weight. If at any visit after the 
first infusion of IMP, a subject’s body weight has changed by 5% or more from the 
baseline value, the IMP dose will be adjusted accordingly. Any changes in the dose 
and/or dosing interval must be recorded on the subject’s CRF, along with the reason for 
the change. 
 
13.6.2 IMP Administration 
Subjects can have a central or peripheral line for infusion per the subject’s usual practice. 
The investigator will evaluate the subject’s history during the past 2 years for infections 
and compliance for port management. Subjects with a central port who have had infection 

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in the past 2 years may not be suitable for the study and should be evaluated on a case- 
by-case basis by the investigator in discussion with the sponsor. 
It is important to use separate vials, sterile syringe, and needle for each subject, to prevent 
transmission of infectious agents from one person to another. The IMP should be 
administered by IV infusion through a dedicated IV line. The IV line should be primed 
according to standard practice only with the IMP, Saline or DW5. No other medications 
should be injected into the IV line being used for IMP administration. Pre-medication is 
not allowed unless pre-medication is part of the subject’s routine IGIV therapy. 
Subjects will be hydrated prior to infusion of IMP per the site’s routine standard of care 
and any hydration fluids will be documented. 
Any bottle of the IMP that has been opened should be used promptly. Once vials are 
removed from the refrigerator they should not be replaced back into the refrigerator. 
Partially used bottles should be saved for drug accountability reconciliation by the 
Monitor before being discarded. 
The IMP is to be administered only under the direct supervision of the PI or a qualified 
sub-Investigator identified on the Statement of Investigator form (Form FDA 1572). 
Under no circumstances will the PI allow IMP to be used other than as specified in the 
protocol. 
 
13.6.2.1 
IMP Infusion Rate for Infusion 1 and Infusion 2 
The first two infusions will be administered according to the following algorithm: For the 
first 30 minutes, IMP will be initiated at an infusion rate of 0.01 mL/kg/min. If, in the 
Investigator’s opinion, the rate is well tolerated, the rate may be increased to 0.02 
mL/kg/min for the next 30 minutes. If the increase is well tolerated, the rate may be 
increased to 0.04 mL/kg/min for the next 30 minutes. If well tolerated, the remainder of 
the infusion may be administered at a maximum infusion rate of between 0.06 mL/kg/min 
and 0.08 mL/kg/min, depending on the subject’s body weight. The total volume infused 
per minute must not exceed a rate of 8.0 mL/min in any subject. If an AE occurs during 
the first dose, the infusion rate should be adjusted or halted in accordance with Section 
10.2.2. 
 
13.6.2.2 
IMP Infusion Rate for Infusion 3 Onward 
The rate for Infusion 3 onward will follow the same algorithm of infusion rate increase 
for the first two doses, but the increases can be implemented every 15 minutes instead of 
30 minutes. 
If an AE occurs, the infusion rate must be decreased to the rate of the previous step; 
in addition, the infusion should be stopped if deemed appropriate by the 
Investigator. 

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14 
Records Management 
 
14.1 
Direct Access to Source Data/Documents 
The Investigator will permit study-related monitoring, audits, IRB/IEC review, and 
regulatory inspection(s), providing direct access to source data and documents. 
The Investigator or designee must record study participation details including enrollment, 
safety, and efficacy information for each subject onto source documents. The Investigator 
is responsible for maintaining complete and adequate case histories in the source records 
of each subject. 
Source data must be preserved for the maximum period of time permitted by local 
regulations and made available by the Investigator in the cases described above. 
 
14.2 
Data Collection and Management 
Data generated as per protocol will be entered onto the eCRF in accordance with the 
International Conference on Harmonisation (ICH) Topic E6 (R1) Guidelines for Good 
Clinical Practice (GCP) (CPMP/ICH/135/95). When the eCRFs have been completed, a 
monitor, with the assistance of the study site coordinator, will verify the source 
documentation records and review the data. 
Subsequent electronic review of the data may result in queries being generated that will 
be forwarded simultaneously to the appropriate Investigator or designee and the CRO 
appointed for the study for prompt resolution. Resolutions will be sent back to Data 
Management in a timely fashion. All data modifications resulting from review or 
querying of the data will be electronically tracked. 
Any errors detected by either the Clinical Study Monitor or the Investigator after query 
resolution should be communicated via eCRF data change forms. In all cases, an 
Investigator or designee signature will be required. 
Coding of AEs and SAEs will be performed automatically by the Data Management 
using the MedDRA dictionary. Similarly, coding of all medications will occur using the 
WHO Drug Dictionary. 
The medical monitor or designee will perform a periodic medical review of the coding 
and of the AE profile. 
 
14.3 
Record Keeping 
The Investigator is responsible for maintaining all records pertaining to the clinical study 
and for ensuring complete and accurate documentation. 
The Investigator is responsible for maintaining a subject identification log. This 
confidential subject identification code provides the link between named subject source 
records in the subject file and anonymous eCRF data provided to the sponsor. 

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The Sponsor requires that each Investigator retain records (all regulatory documents such 
as the protocol, study approval letters, all eCRFs, drug dispensing and accountability 
logs, all original subject consent forms and all correspondence pertaining to the conduct 
of the study) for a period of no less than 7 years from the date of final regulatory approval 
or as per local regulations, whichever is longer. If the study is discontinued, or if no 
application/license is to be filed or if the application/license is not approved for such 
indication, records should be retained for 7 years after the investigation is discontinued or 
as per local regulations, whichever is longer. 
It is prohibited for study documents to be destroyed without prior written agreement 
between the Investigator and the sponsor. If the Investigator wishes to assign the study 
records to another party, or move them to another location, the sponsor must be notified 
in writing. 
 
15 
Quality Control and Quality Assurance 
 
15.1 
Quality Control by the Monitoring Team 
The CRAs will monitor the data collected throughout the study thus providing quality 
control (QC) of the study. Independent monitoring of the clinical study for protocol and 
GCP compliance will be conducted periodically at a minimum 5 selected sites by 
qualified quality assurance (QA) auditors. 
The Investigator must make himself or herself available for CRAs during their visits and 
ensure that CRAs have direct access to all documents that they require, including direct 
access to the subjects’ files. The Investigator agrees to cooperate with the CRAs to make 
certain that any problems detected in the course of monitoring visits are resolved. The 
Investigator will permit direct access to the source data and documents to the appropriate 
regulatory authorities to verify the accuracy of this data. 
The present study sponsored by ProMetic BioTherapeutics, will be conducted in 
accordance with ICH GCP. The clinical team at the CRO will systematically control the 
essential documents generated during this study. The study will be monitored by the 
clinical team and will be subject to internal audits by Quality Assurance. All clinical 
study monitoring visits and audits by QA will be followed by internal reports and 
corrective actions, if needed. Follow-up letters will be forwarded to sites after all visits 
and any findings should be addressed by the Investigator. The follow-up letters should be 
filed with the study correspondence and other essential documentation. 
 
15.2 
Quality Assurance by an Audit Team 
Any study site may be selected for audit at any moment by an audit team originating from 
the Sponsor or from an external organization acting on behalf of the Sponsor. 

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The Investigator agrees to cooperate with the auditor to ensure that any problems 
detected in the course of these audit visits are resolved. 
 
15.3 
Quality Assurance by Data Management 
An independent delegate from the CRO or Sponsor side will be responsible for QA and 
QC of the database and data management. 
 
16 
Ethics and Responsibility 
 
16.1 
Investigational Review Board 
The IRB/IEC must operate in compliance with local regulations (in the United States, 
FDA regulations 21 CFR 50 and 21 CFR 56), and in conformance with applicable ICH 
E6 Guidelines on GCP: Section 3 Institutional Review Board/Independent Ethics 
Committee (IRB)/(IEC). 
The Investigator-sponsor will obtain, from the IRB/IEC, prospective approval of the 
clinical protocol and corresponding informed consent/assent form(s); modifications to the 
clinical protocol and corresponding informed consent forms, advertisements (i.e., 
directed at potential research subjects) for study recruitment, and any other material 
presented to a subject. 
This board or committee, the makeup of which must conform to applicable regulations 
and guidelines, will approve all aspects of the study, including the current protocol, 
written Informed Consent Form/Assent Form, prior to initiation of the study. The 
Investigator will provide the Sponsor with a paper copy from the IRB/IEC to the 
Investigator indicating approval of the protocol and consent form/assent form. All 
amendments to the protocol must be reviewed and approved prior to implementation, 
except where necessary to eliminate apparent immediate hazards to human subjects. 
The Investigator will be responsible for obtaining annual IRB/IEC renewal and 
submitting SAE reports to the IRB/IEC for the duration of the study (as per IRB/IEC 
policies and procedures). Copies of the investigator’s report and/or copies of the IRB/IEC 
extension approval must be sent to the Sponsor. 
 
16.2 
Ethical Conduct of the Study 
The clinical study will be conducted in accordance with the current IRB/IEC-approved 
clinical protocol; ICH E6 Guidelines on GCP; and relevant policies, requirements, and 
regulations of the IRB/IEC and applicable federal agencies. Any violations by sites, 
CRO, or Sponsor will also be submitted to IRBs/IECs and relevant regulatory agencies. 
The IRB/IEC and the FDA/appropriate authority for sites outside the US will be notified 
promptly of discontinuation of the entire clinical study. Respective protocol 
modifications will be submitted prospectively to the IRB/IEC and to the FDA/ 

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appropriate authority for discontinuation or modification of parts of the clinical study. 
Enrolled subjects, Investigators, and sub-Investigators will be notified immediately of 
discontinuation of parts of the clinical study or if the study ends or the discontinuation of 
a subject is necessary. 
If there are changes to the protocol and a new informed consent has been approved, 
subjects should be informed of the changes and of any changes to the risks/benefits of 
participation. Subjects will need to go through the informed consent process and sign a 
new approved informed consent form to be eligible to continue on the study. 
If a subject decides she or he does not want to continue with the treatment portion of the 
study, a subject can give consent to be followed for safety only and can continue to allow 
access to Protected Health Information (PHI) even after withdrawal. However, the 
amended and approved ICF will need to be signed, and discontinuing treatment only 
should be clearly documented in a progress note in the subject’s source documents. A 
subject still retains the right to withdraw participation in the study at any time and to 
discontinue further access to PHI. However, all data collected to that point will be made 
available to the sponsor and the CRO. 
 
16.3 
Informed Consent and Assent 
Fully informed written consent will be obtained from the subject, or for subjects aged 
<18 years from the parent(s) or legal guardian in accordance with state and federal laws 
and the local IRB/IEC. The Investigator must explain to each subject, in language and 
terms they are able to understand, the nature of the study, the purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved, and any 
discomfort it may entail. The investigational product(s) should be identified as 
“experimental” and that its side effects are not completely known. Each subject or 
parent(s) or legal guardian must be informed that participation in the study is voluntary 
and that they may withdraw from the study at any time, and that withdrawal of consent 
will not affect their subsequent medical treatment or relationship with the treating 
physician. Adequate pregnancy protection must be listed in the ICF per the local IRB/IEC 
standards. 
The subject or parent(s) or legal guardian should be given sufficient time to read the 
informed consent form and the opportunity to ask questions and consider the statement 
before signing and dating it, and should be given a copy of the signed document. No 
subject can enter the study before informed consent or assent with parental consent has 
been obtained. 
During the study, subjects or parent(s) or legal guardian will be given any new 
information that may affect their decision to continue participation. 
The Sponsor or its designee will supply a model informed consent form that complies 
with regulatory requirements and is considered appropriate for the study. Any changes to 

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the sample consent form suggested by the Investigator must be agreed to by the Sponsor 
or its designee before submission to the IRB/IEC, and a copy of the approved version 
must be provided to the Sponsor or the designated Medical Monitor after IRB/IEC 
approval. 
Subjects under the age of 18 years will be given the same information at a level of 
understanding related to the age and comprehension of the subject. The subject will give 
assent to participate, with the parent or authorized representative giving consent, using 
the approved informed assent form and the informed consent form respectively, 
according to local state laws. 
 
16.4 
Changes in the Conduct of the Study 
The Investigator may change the protocol without IRB/IEC or Sponsor approval, 
provided that it is necessary in order to safeguard the safety or rights of the subjects. Any 
protocol amendment must be submitted for information or consideration to the applicable 
regulatory agencies. 
IRB/IEC approval will be requested for any change to this protocol that could affect the 
safety of subjects, the scope or design of the study. 
Minor procedural changes will be implemented by Study Notes to File, with supporting 
documentation at each site, if appropriate. 
A non-substantial amendment of a study protocol includes minor correction or 
clarification that have no significant impact on the way the clinical study is to be 
conducted and no effect on subject safety (i.e., administrative changes like change of 
telephone number(s), logistical changes, etc.). 
Any changes of the protocol (substantial amendments and non-substantial amendments) 
will be integrated into an updated study protocol, with a listing of all changes and 
reasoning for them. 
 
17 
Confidentiality 
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to investigate the efficacy, safety, quality, and 
utility of the investigational product(s) used in this study. 
The Investigator will ensure that the subjects’ anonymity will be maintained. The privacy 
rules of the US HIPAA will be followed to obtain authorization for most uses and 
disclosures of Protected Health Information. On eCRFs or other documents submitted to 
the Sponsor or its designee, subjects will not be identified by their names, but by an 
identification code, consisting of the combination of subject’s initials and study number. 
Documents not for submission to Sponsor or its designee (e.g., the site confidential 
subject enrollment log and original subjects’ consent forms) will be maintained by the 

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Investigator in strict confidence. Appropriate technical and organizational measures to 
protect the personal data against unauthorized disclosures or access, accidental or 
unlawful destruction, or accidental loss or alteration must be put in place. Sponsor 
personnel whose responsibilities require access to personal data agree to keep the identity 
of study subjects confidential. 
The informed consent obtained from the subject includes explicit consent for the 
processing of personal data and for the Investigator to allow direct access to his or her 
original medical records for study-related monitoring, audit, IRB, and regulatory 
inspection. This consent also addresses the transfer of the data to other entities and to 
other countries. 
The subject has the right to request through the Investigator access to his/her personal 
data and the right to request rectification of any data that are not correct or complete. 
Reasonable steps should be taken to respond to such a request, taking into consideration 
the nature of the request, the conditions of the study, and the applicable laws and 
regulations. 
 
18 
Publication Policy 
In collaboration with the sponsor, the CRO will prepare a draft study report after the 
completion of the study. The final draft study report will be submitted to the selected 
Investigators for information, review, and comments. 
Publication of data generated in the study is governed by the Investigator Clinical Study 
Agreement. 
 
19 
Liabilities and Insurance 
The sponsor will pay for all study-related costs. A separate financial agreement will be 
made (as appropriate) with the Investigator and/or Institutions. 
The sponsor also carries insurance coverage for incidents of damage or injury to study 
subjects while participating in the study or taking study medication. 

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20 
References 
Basta, M. (2014). Intravenous immunoglobulin-related thromboembolic events - an 
accusation that proves the opposite. British Society for Immunology, Clinical and 
Experimental Immunology, 178: 153–155. Poster Presentations. 
Doi.10.1111/cei.12551 
Bonilla, F. A. (2008). Population Prevalence of Diagnosed Primary Immunodeficiency 
Diseases in the United States. Pediatrics, 122(Supplement 4), S224-S225. doi: 
10.1542/peds.2008-2139FFFF 
Boyle, J. M., & Buckley, R. H. (2007). Population prevalence of diagnosed primary 
immunodeficiency diseases in the United States. J Clin Immunol, 27(5), 497-502. 
doi: 10.1007/s10875-007-9103-1 
Bruton, O. (1952). Agammaglobulinemia. Pediatrics, 9(6), 722-728. 
Conley, M., Notarangelo, L., & Etzioni, A. (1999). Diagnostic criteria for primary 
immunodeficiencies. Representing PAGID (Pan-American Group for 
Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin 
Immunol, 93(3), 190-197. doi: 10.1006/clim.1999.4799 
Conley, M., & Stiehm, E. (1996). Immunodeficiency disorders: General considerations. 
In E. Stiehm (Ed.), Immunologic Disorders in Infants and Children (4th ed., pp. 
201-252). Philadelphia: WB Saunders. 
Cunningham-Rundles, C., & Bodian, C. (1999). Common variable immunodeficiency: 
clinical and immunological features of 248 patients. Clin Immunol, 92(1), 34-48. 
doi: 10.1006/clim.1999.4725 
Eijkhout, H. W., van Der Meer, J. W., Kallenberg, C. G., Weening, R. S., van Dissel, J. 
T., Sanders, L. A., . . . Inter-University Working Party for the Study of Immune, 
D. (2001). The effect of two different dosages of intravenous immunoglobulin on 
the incidence of recurrent infections in patients with primary 
hypogammaglobulinemia. A randomized, double-blind, multicenter crossover 
trial. Ann Intern Med, 135(3), 165-174. 
Grimbacher, B., & ESID Registry Working Party. (2014). The European Society for 
Immunodeficiencies (ESID) registry 2014. Clin Exp Immunol, 178 Suppl 1, 18- 
20. doi: 10.1111/cei.12496 

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Immune Deficiency Foundation. (2015). Specific Disease Types. 
http://primaryimmune.org/about-primary-immunodeficiencies/specific-disease- 
types/ 
International Union of Immunological Societies. (1999). Primary immunodeficiency 
diseases. Report of an IUIS Scientific Committee. Clin Exp Immunol, 118 Suppl 
1, 1-28. 
Joshi, A. Y., Iyer, V. N., Hagan, J. B., St Sauver, J. L., & Boyce, T. G. (2009). Incidence 
and temporal trends of primary immunodeficiency: a population-based cohort 
study. Mayo Clin Proc, 84(1), 16-22. doi: 10.1016/S0025-6196(11)60802-1 
Reust, C. E. (2013). Evaluation of primary immunodeficiency disease in children. Am 
Fam Physician, 87(11), 773-778. 
Rizk, A., Gorson, Kenneth C., Kenney, L., & Weinstein, R. (2001). Transfusion-related 
acute lung injury after the infusion of IVIG. Transfusion, 41(2), 264-268. doi: 
10.1046/j.1537-2995.2001.41020264.x 
Roifman, C. M., & Gelfand, E. W. (1988). Replacement therapy with high dose 
intravenous gamma-globulin improves chronic sinopulmonary disease in patients 
with hypogammaglobulinemia. Pediatr Infect Dis J, 7(5 Suppl), S92-96. 
Schroeder, H. W., Jr. (2001). Primary antibody deficiencies. In R. R. Rich, T. A. Fleisher, 
W. T. Shearer, B. Kotzin, & H. W. Schroeder, Jr (Eds.), Clinical Immunology: 
Principles and Practice (2nd ed.). London New York: Mosby. 
Ünlü O, Zuily S, Erkan D. The clinical significance of antiphospholipid antibodies in 
systemic lupus erythematosus. Eur J Rheumatol. 2016 Jun;3(2):75-84. 
Wood, P. (2009). Primary antibody deficiency syndromes. Ann Clin Biochem, 46(Pt 2), 
99-108. doi: 10.1258/acb.2008.008175 

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21 
Appendices 
The primary endpoint of the study is the annual rate of validated acute serious bacterial 
infections per FDA Guidance for Industry: Safety, Efficacy, and Pharmacokinetic Studies 
to Support Marketing of Immune Globulin Intravenous (Human) as Replacement Therapy 
for Primary Humoral Immunodeficiency, 2008. The primary endpoint will be assessed 
based on the diagnostic criteria provided in this Guidance, as outlined below. 
 
21.1 
Diagnostic Criteria for Serious Infection Types (FDA Guidance, 
June 2008) 
 
Infection: Bacteremia/sepsisa 
Symptoms: chills, rigors 
Physical findings: fever, hypothermia, tachycardia, tachypnea, hypocarbia, hypotension 
(systolic blood pressure <90 mmHg or a reduction of >40 mmHg from baseline in the 
absence of other causes of hypotension), altered mental status, petechiae, purpura, 
oligouria, cutaneous vasodilation/vasoconstriction 
Laboratory tests: positive blood culture,b leukocytosis (white blood cell (WBC) count 
>12,000/mm3), differential WBC count demonstrating >10% immature (band) 
neutrophils, leukopenia, thrombocytopenia, coagulopathy, lactic acidosis 
Infection: Bacterial Meningitis 
Symptoms: headache, stiff neck, mental status changes, irritability, decreased feeding 
(infants), photophobia, nausea/vomiting, rigors, seizures 
Physical findings: Kernig’s sign, Brudzinski’s sign, meningococcal rash, fever of >38°C 
oral or >39°C rectal 
Laboratory tests: positive cerebrospinal fluid (CSF) Gram stain and/or culture and/or 
positive CSF bacterial antigen assay, positive blood culturec, CSF leukocytosis with 
neutrophil predominance, decrease in CSF glucose 
Infection: Osteomyelitis/Septic Arthritis 
Symptoms: pain, decreased range of motion, tenderness, edema, redness, warmth over the 
involved site (local inflammatory symptoms/signs may be lacking in adults.) 
Physical findings: evidence of soft tissue infection adjacent to the involved bone/joint, 
drainage from sinus tract from involved bone, fever of >38°C oral or >39°C rectal 
Laboratory tests: positive blood culture, positive probe to bone, positive bone aspirate 
culture, positive bone biopsy culture, positive bone histopathology, positive joint fluid 
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Imaging studies: positive X-ray, nuclear medicine bone scan, magnetic resonance imaging 
(MRI) scan, or computed tomography (CT) scan showing bony destruction with 
radiolucent areas; for chronic osteomyelitis: sequestra, involucra 
Infection: Bacterial Pneumoniad 
Symptoms: productive cough/change in character of sputum, dyspnea or tachypnea, chills, 
chest pain, rigors, headache, fatigue, sweats, anorexia, myalgias 
Physical findings: rales; pulmonary consolidation as reflected by: dullness on percussion, 
bronchial breath sounds, egophony; fever >38°C oral or >39°C rectal, or <36°C, 
hypothermia (temperature <36°C oral or <37°C rectal) 
Laboratory tests: leukocytosis, differential WBC count of >10% band neutrophils, 
leukopenia, hypoxemia (PaO2 <60 mmHg on room air), positive blood culture, Gram stain 
and culture of deep expectorated sputum,e positive culture with or without positive Gram 
stain of transtracheal aspirate, pleural fluid culture, lung biopsy, bronchoscopy with 
bronchoalveolar lavage (BAL) or protected brush sampling, 
Imaging studies: Pulmonary infiltrate with consolidation on chest X-Ray (CXR) (new in 
comparison with baseline CXR) 
Infection: Visceral Abscess 
Symptoms: abdominal pain, anorexia, weight loss, cough/pleuritic chest pain (hepatic 
abscess), rigors (seldom present) 
Physical findings: intermittent fevers (temperature >38°C oral or >39°C rectal), 
abdominal tenderness, palpable mass, hepatomegaly, jaundice 
Laboratory tests: positive Gram stain and/or culture from the infected site, with isolation 
of an appropriate pathogen, positive blood culture, leukocytosis with accompanying left 
shift, differential WBC count of >10% immature (band) neutrophils, elevated serum 
amylase concentration (pancreatic abscess), elevated alkaline phosphatase concentration 
(hepatic abscess) pyuria in renal abscess 
Imaging studies: typical findings on ultrasound, CT scan, MRI scan, or radionuclide scan 
Note: Items in bold are considered essential diagnostic features. 
a Two of the following should be present to make the diagnosis of sepsis in adults: 
temperature >38°C oral / >39°C rectal or <36°C oral or <37°C rectal; heart rate >90 
beats/min; respiratory rate >20 breaths/min, or PaCO2 <32 mm Hg; WBC count 
>12,000/mm3, <4,000/mm3, or >10% immature (band) forms (Levy et al. 2001). For 
pediatric subjects, we recommend you employ the definition of sepsis using age-specific 

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criteria as recommended by the International Consensus Conference on Pediatric Sepsis 
(International Consensus Conference on Pediatric Sepsis 2005). 
b Indwelling catheter- or vascular access device-related blood-borne infections are not 
included because evidence is lacking that these are preventable with IGIV replacement 
therapy. For subjects without indwelling catheters or vascular access devices, a single 
blood culture positive for a pathogenic organism will meet the diagnostic criteria for 
bacteremia. (Multiple blood cultures are typically obtained in cases of suspected 
bacteremia/sepsis, as per standard medical practice, and the finding of a single positive 
culture should prompt additional confirmatory cultures). Subjects meeting criteria for 
positive blood culture but without 2 or more of the sepsis criteria listed above will be 
classified as having bacteremia. 
c A blood culture positive for growth of Streptococcus pneumoniae, Neisseria 
meningitides, or Haemophilus influenzae, in combination with CSF leukocytosis and/or 
decrease in CSF glucose, can serve to confirm the diagnosis of acute bacterial meningitis 
(FDA Guidance, Acute Bacterial Meningitis July 1998). 
d For the diagnosis of pneumonia in adults, commonly at least 2 of the listed symptoms 
and/or signs should be present in conjunction with at least one laboratory and one imaging 
studies diagnostic element. However, for the purposes of counting serious infection 
episodes in a clinical trial of IGIV, the finding of a new pulmonary infiltrate with 
consolidation on CXR is considered sufficient. To establish the diagnosis of bacterial 
pneumonia for pediatric patients, most of the same diagnostic criteria listed may be used, 
with the following exceptions: Because pediatric patients may not produce a sputum 
specimen for culture, blood cultures or serology may be substituted to identify the 
etiologic bacterial pathogen. In infants age 3 to 24 months, who tend to have a higher 
baseline temperature, fever is defined as a rectal temperature >38.3°C (101°F). In children 
>2 years, fever is more commonly defined as a rectal temperature >38°C (100.4°F). In 
pediatric patients, elevations of WBC counts >15,000/mm3 are frequent but could be 
variable in patients with bacterial pneumonia, or leukopenia with WBC count <5000/mm3 
may be observed, usually associated with severe infection (FDA Guidance Community 
Acquired Pneumonia, July 1998). 
e We recommend a deep expectorated sputum gram stain to demonstrate the presence of 
microorganisms on examination of 10-20 oil immersion microscopic fields and <10 
squamous epithelial cells and >25 polymorphonuclear leukocytes at 10X low power 
magnification to determine suitability of sputum culture (FDA Guidance Community 
Acquired Pneumonia, July 1998). 

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21.2 
Declaration of Helsinki 
WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving 
Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and 
amended by the: 29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA 
General Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong 
Kong, September 1989 48th WMA General Assembly, Somerset West, Republic of 
South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 53rd WMA General 
Assembly, Washington DC, USA, October 2002 (Note of Clarification added) 55th 
WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 59th 
WMA General Assembly, Seoul, Republic of Korea, October 2008 64th WMA General 
Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. The World Medical Association (WMA) has developed the Declaration of Helsinki as 
a statement of ethical principles for medical research involving human subjects, 
including research on identifiable human material and data. 
The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should be applied with consideration of all other relevant paragraphs. 
2. Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research 
involving human subjects to adopt these principles. 
General Principles 
3. The Declaration of Geneva of the WMA binds the physician with the words, 
“The health of my patient will be my first consideration,” and the International Code 
of1/8“The health of my patient will be my first consideration,” and the International 
Code of Medical Ethics declares that, “A physician shall act in the patient's best 
interest when providing medical care.” 
4. It is the duty of the physician to promote and safeguard the health, wellbeing and 
rights of patients, including those who are involved in medical research. The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty. 
5. Medical progress is based on research that ultimately must include studies involving 
human subjects. 
6. The primary purpose of medical research involving human subjects is to understand 
the causes, development, and effects of diseases and improve preventive, diagnostic 
and therapeutic interventions (methods, procedures and treatments). Even the best 

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proven interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility, and quality. 
7. Medical research is subject to ethical standards that promote and ensure respect for all 
human subjects and protect their health and rights. 
8. While the primary purpose of medical research is to generate new knowledge, this 
goal can never take precedence over the rights and interests of individual research 
subjects. 
9. It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of 
personal information of research subjects. The responsibility for the protection of 
research subjects must always rest with the physician or other health care 
professionals and never with the research subjects, even though they have given 
consent. 
10. Physicians must consider the ethical, legal, and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal, or 
regulatory requirement should reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. 
11. Medical research should be conducted in a manner that minimizes possible harm to 
the environment. 
12. Medical research involving human subjects must be conducted only by individuals 
with the appropriate ethics and scientific education, training and individuals with the 
appropriate ethics and scientific education, training and qualifications. Research on 
patients or healthy volunteers requires the supervision of a competent and 
appropriately qualified physician or other health care professional. 
13. Groups that are underrepresented in medical research should be provided appropriate 
access to participation in research. 
14. Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic, or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients 
who serve as research subjects. 
15. Appropriate compensation and treatment for subjects who are harmed as a result of 
participating in research must be ensured. 

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Risks, Burdens and Benefits 
16. In medical practice and in medical research, most interventions involve risks and 
burdens. 
Medical research involving human subjects may only be conducted if the importance 
of the objective outweighs the risks and burdens to the research subjects. 
17. All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups involved in 
the research in comparison with foreseeable benefits to them and to other individuals 
or groups affected by the condition under investigation. 
Measures to minimize the risks must be implemented. The risks must be continuously 
monitored, assessed and documented by the researcher. 
18. Physicians may not be involved in a research study involving human subjects unless 
they are confident that the risks have been adequately assessed and can be 
satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is 
conclusive proof of definitive outcomes, physicians must assess whether to continue, 
modify or immediately stop the study. 
Vulnerable Groups and Individuals 
19. Some groups and individuals are particularly vulnerable and may have an increased 
likelihood of being wronged or of incurring additional harm. 
All vulnerable groups and individuals should receive specifically considered 
protection. 
20. Medical research with a vulnerable group is only justified if the research is responsive 
to the health needs or priorities of this group and the research cannot be carried out in 
a non-vulnerable group. In addition, this group should stand to benefit from the 
knowledge, practices or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, 
other relevant sources of information, and adequate laboratory and, as appropriate, 
animal experimentation. The welfare of animals used for research must be respected. 
22. The design and performance of each research study involving human subjects must be 
clearly described and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and 
should indicate how the principles in this Declaration have been addressed. The 
protocol should include information regarding funding, sponsors, institutional 

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affiliations, potential conflicts of interest, incentives for subjects and information 
regarding provisions for treating and/or compensating subjects who are harmed as a 
consequence of participation in the research study. 
In clinical studies, the protocol must also describe appropriate arrangements for post- 
study provisions. 
Research Ethics Committees 
23. The research protocol must be submitted for consideration, comment, guidance and 
approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the 
researcher, the sponsor and any other undue influence, and must be duly qualified. It 
must take into consideration the laws and regulations of the country or countries in 
which the research is to be performed as well as applicable international norms and 
standards but these must not be allowed to reduce or eliminate any of the protections 
standards but these must not be allowed to reduce or eliminate any of the protections 
for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must 
provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the 
researchers must submit a final report to the committee containing a summary of the 
study’s findings and conclusions. 
Privacy and Confidentiality 
24. Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
Informed Consent. 
25. Participation by individuals capable of giving informed consent as subjects in medical 
research must be voluntary. Although it may be appropriate to consult family 
members or community leaders, no individual capable of giving informed consent 
may be enrolled in a research study unless he or she freely agrees. 
26. In medical research involving human subjects capable of giving informed consent, 
each potential subject must be adequately informed of the aims, methods, sources of 
funding, any possible conflicts of interest, institutional affiliations of the researcher, 
the anticipated benefits and potential risks of the study and the discomfort it may 
entail, post-study provisions and any other relevant aspects of the study. The potential 
subject must be informed of the right to refuse to participate in the study or to 

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withdraw consent to participate at any time without reprisal. Special attention should 
be given to the specific information needs of individual potential subjects as well as 
to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician 
or another appropriately qualified individual must then seek the potential subject’s 
freely-given informed consent, preferably in writing. If the consent cannot be 
expressed in writing, the non-written consent must be formally documented and 
witnessed. 
All medical research subjects should be given the option of being informed about the 
general outcome and results of the study. 
27. When seeking informed consent for participation in a research study the physician 
must be particularly cautious if the potential subject is in a dependent relationship 
with the physician or may consent under duress. In such situations the informed 
consent must be sought by an appropriately qualified individual who is completely 
independent of this relationship. 
28. For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorized representative. 
These individuals must not be included in a research study that has no likelihood of 
benefit for them unless it is intended to promote the health of the group represented 
by the potential subject, the research cannot instead be performed with persons 
capable of providing informed consent, and the research entails only minimal risk and 
minimal burden. 
29. When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the 
physician must seek that assent in addition to the consent of the legally authorized 
representative. The potential subject’s dissent should be respected. 
30. Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or 
mental condition that prevents giving informed consent is a necessary characteristic 
of the research group. In such circumstances the physician must seek informed 
consent from the legally authorized representative. If no such representative is 
available and if the research cannot be delayed, the study may proceed without 
informed consent provided that the specific reasons for involving subjects with a 
condition that renders them unable to give informed consent have been stated in the 
research protocol and the study has been approved by a research ethics committee. 
Consent to remain in the research must be obtained as soon as possible from the 
subject or a legally authorized representative. 

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31. The physician must fully inform the patient which aspects of their care are related to 
the research. The refusal of a patient to participate in a study or the patient’s decision 
to withdraw from the study must never adversely affect the patient- physician 
relationship. 
32. For medical research using identifiable human material or data, such as research on 
material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage, and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such 
research. In such situations the research may be done only after for such research. In 
such situations the research may be done only after consideration and approval of a 
research ethics committee. 
Use of Placebo 
33. The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following 
circumstances: 
Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any 
intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention, and 
the patients who receive any intervention less effective than the best proven one, 
placebo, or no intervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Study Provisions 
34. In advance of a clinical study, sponsors, researchers, and host country governments 
should make provisions for post-study access for all participants who still need an 
intervention identified as beneficial in the study. This information must also be 
disclosed to participants during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 
36. Researchers, authors, sponsors, editors and publishers all have ethical obligations 
with regard to the publication and dissemination of the results of research. 
Researchers have a duty to make publicly available the results of their research on 

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human subjects and are accountable for the completeness and accuracy of their 
reports. All parties should adhere to accepted guidelines for ethical reporting. 
Negative and inconclusive as well as positive results must be published or otherwise 
made publicly available. Sources of funding, institutional affiliations, and conflicts of 
interest must be declared in the publication. Reports of research not in accordance 
with the principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert 
advice, with informed consent from the patient or a legally authorized representative, 
may use an unproven intervention if in the physician's judgment it offers hope of 
saving life, re-establishing health or alleviating suffering. This intervention should 
subsequently be made the object of research, designed to evaluate its safety and 
efficacy. In all cases, new information must be recorded and, where appropriate, 
made publicly available. 
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