An Open-label, Prospective, Multicenter Study Investigating Clinical Efficacy, Safety, and Pharmacokinetic Properties of the Human Normal Immunoglobulin for Intravenous Administration BT595 as Replacement Therapy in Patients With Primary Immunodeficiency Disease (PID)
Phase: PHASE3
Conditions: Primary Immunodeficiency Disease
Sponsor: Biotest

 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 1 of 82 
 
 
Clinical Study Protocol 
 
Title: 
An open-label, prospective, multicenter study investigating 
clinical efficacy, safety, and pharmacokinetic properties of the 
human normal immunoglobulin for intravenous administration 
BT595 as replacement therapy in patients with primary 
immunodeficiency disease (PID) 
 
 
Clinical phase: 
III Pivotal 
 
Version incl. date: 
Final 4.0 of 21-MAR-2018 
 
EudraCT number/ 
IND number: 
2015-003652-52/ 
17046 
 
Study no.: 
991 
 
 
 
 
Sponsor 
Biotest AG 
Department of Corporate Clinical Research & 
Development 
Landsteinerstraße 5, 
63303 Dreieich, Germany 
 
 
Head Corporate Clinical Research & Development 
 
 
 
 
 
Associate Director Corporate Clinical Research & 
Development 
 
 
 
 
Coordinating Investigator 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This protocol is property of Biotest AG, and may not be circulated, reproduced or published – either in 
whole or in part – without the company’s written permission. 
 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 2 of 82 
Overview of amendments integrated in the protocol text of version 1.0 of 14-MAR-2016: 
Protocol # 
Global/Local 
amendment 
Date 
Sections concerned 
Rationale 
2.0 
global 
21 Oct 2016 
Flow chart, 9.2.1.4, 
9.4 
Additional blood sampling for Coombs test 
and serum haptoglobin for the first 10 
patients and the first 2 infusions. 
3.0 
global 
02 Jun 2017 
Study synopsis, 7.1, 
9.5.2 
Allowance of homecare service for the 
pharmacokinetic sampling of pediatric 
subjects. 
3.0 
global 
02 Jun 2017 
Flowchart of study, 
7.1 
Further specification regarding vital sign 
assessments. In any case where the 
change in infusion rate is sooner than a 
15 minutes interval, vital signs should be 
measured prior to the change. 
3.0 
global 
02 Jun 2017 
Study synopsis, 6.2 
Clarification that every infusion should start 
at an initial rate of 0.3 mL/kg/h. 
4.0 
global 
21 Mar 2018 
Title, Header 
Correction of IND Number from 128413 to 
17046 
4.0 
global 
21 Mar 2018 
Synopsis, 3, 4.1, 10.9 Increase of study subjects from 
approximately 60 to approximately 70 for 
ensuring to have a sufficient number of 
paediatric subjects and to fullfil the 
requirements of the respective guidelines 
(Food and Drug Administration (FDA) 
Guidance for Industry: Safety, efficacy, and 
pharmacokinetic studies to support 
marketing of immune globulin intravenous 
(human) as replacement therapy for 
primary humoral immunodeficiency, June 
2008 and European Medicines Agency 
Guideline on the clinical investigation of 
human normal immunoglobulin for 
intravenous administration (IVIg). 
EMA/CHMP/BPWP/94033/2007 rev. 2; 22 
July 2010.) 
4.0 
global 
21 Mar 2018 
Synopsis, 7.2 
Change of last patient last visit from 
February 2018 to November 2019 due to 
shifted timelines 

-
Study No.: 991
Final Version 4.0
EudraCT No.: 2015·003652-52f
IND No.: 17046
Clinical Study Protocol
21·MAR·2018
I.
SIGNATURE PAGE
Date, signature
This clinical study 15 carried out in accordance with the international guidelines on
Good GUnical Practice (ICH GCP) and
in compliance with appllcable Regulatory
Authority requirements. It is confirmed that the clinical study will be carried out and
documented in a<;cordance wlth this study protocol.
Coordlnatlng Investigator
Head Corporate Gllnlcal
Research & Development
"Le>,
-"';;"F~--"--"-
Date, signature
Blostatlstlclan,
Date, signature
·SOP-CCR-007-T0013.0
CONFIDENTIAL
Page 30[82

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 4 of 82 
I.I 
Signature Page for Investigators 
 
Declaration of the Principal Investigator 
 
I have read and understood this clinical study protocol and agree to the following: 
• To adhere to the ethical and scientific principles of Good Clinical Practice, and 
the principles of the Declaration of Helsinki, the local laws and regulations, and 
the applicable regulatory requirements. 
• To conduct the clinical study as set out in the protocol. 
This includes: 
• 
To wait until I have received approval from the appropriate Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) before enrolling any subject in 
this study. 
• 
To obtain informed consent for all subjects prior to any study-related measure 
performed. 
• 
To permit study-related monitoring, audits, IEC/IRB review, and Regulatory 
Authority inspections. 
• 
To provide direct access to all study-related records, source documents, and 
subject files for the monitor, auditor, IEC/IRB, or Regulatory Authority upon 
request. 
• 
To use the investigational medicinal product (IMP) and all study materials only 
within the framework of this clinical study protocol. 
• 
To understand that changes to the clinical study protocol must be made in the 
form of an amendment that has the prior written approval of Biotest and, as 
applicable, of the appropriate IEC/IRB and Regulatory Authority. 
• 
To comply with the reporting obligations for all Adverse Events. 
 
I understand that all documentation that has not been previously published will be kept 
in the strictest confidence. This documentation includes the clinical study protocol, 
Investigator’s Brochure, case report forms, and other scientific data. 
 
Principal Investigator 
Name 
 
 
Date, signature 
 
 
Investigator stamp: 
 
 
 
 
 
 
 
Please insert stamp of investigational site 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 5 of 82 
II. 
STUDY SYNOPSIS 
Title 
An open-label, prospective, multicenter study investigating 
clinical efficacy, safety, and pharmacokinetic properties of 
the 
human 
normal 
immunoglobulin 
for 
intravenous 
administration BT595 as replacement therapy in patients 
with primary immunodeficiency disease (PID) 
Clinical Phase 
III Pivotal 
Coordinating Investigator 
 
Study Objectives 
The primary objective of this study is to demonstrate that the 
rate of acute serious bacterial infections (i.e., the mean 
number 
of 
acute 
serious 
bacterial 
infections 
per 
subject-year) is less than 1.0 to provide substantial evidence 
of efficacy. The secondary objectives of this study, in 
addition to further efficacy assessments, are to evaluate the 
safety and pharmacokinetic characteristics of BT595. 
Study Design 
Open-label, prospective, multicenter, multinational. 
Study Population 
Male or female subjects (age: 2-75 years, inclusive) with 
PID. For those countries where local regulations permit 
enrolment of adult subjects only, subject recruitment will be 
restricted to those who are 18 through 75 years. 
Inclusion Criteria 
a) Written 
informed 
consent/assent 
obtained 
from 
subjects/subjects’ 
parent(s) 
or 
legally 
acceptable 
representative indicating that they understand the 
purpose of and procedures required for the study and 
are willing to participate in it. 
b) Male or female, aged 2 through 75 years. 
c) Diagnosis of PID with impaired antibody production, i.e.: 
- Diagnosis of common variable immunodeficiency 
(CVID) as defined by the European Society for 
Immunodeficiencies (ESID)/Pan American Group for 
Immunodeficiency (PAGID) diagnostic criteria. 
Or 
- X-linked agammaglobulinemia (XLA) as defined by 
ESID/PAGID diagnostic criteria. 
d) Established replacement therapy with any intravenous 
immunoglobulin (IVIg) reference preparation during the 
previous 
6 months, 
including 
documentation 
of 
immunoglobulin G (IgG) trough levels. 
e) Established replacement therapy with a single IVIg 
reference preparation for at least 3 months prior to 
treatment start with BT595 at a 3- or 4-week schedule 
with a constant IVIg dose that did not change by ±20% of 
the mean dose, regular dosage intervals, and at least 
1 IgG trough level of ≥5 g/L during the previous 
3 months. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 6 of 82 
Exclusion Criteria 
a) Pregnancy or unreliable contraceptive measures or 
lactation period (females only). 
b) Known intolerance to immunoglobulins or comparable 
substances (e.g., vaccination reaction). 
c) Known intolerance to proteins of human origin or known 
allergic reactions to components of the study product. 
d) Participation in another clinical study within 30 days 
before entering the study or during the study and/or 
previous participation in this study. 
e) Employee or direct relative of an employee of the 
Contract Research Organization, the study site, or 
Biotest. 
f) Acquired medical conditions known to cause secondary 
immune deficiency, such as chronic lymphatic leukemia, 
lymphoma, multiple myeloma, as well as protein losing 
enteropathies and hypoalbuminemia. 
g) Other medical condition, laboratory finding, or physical 
examination finding that precludes participation. 
h) Recent 
febrile 
illness 
that 
precludes 
or 
delays 
participation. 
i) Active infection and receiving antibiotic therapy for the 
treatment of this infection at the time of screening. Note: 
if the subject is deemed to be a screen failure due to a 
nonserious active infection requiring antibiotic therapy, 
the subject may be rescreened after the initial screening. 
j) Therapy 
with 
systemic 
steroids 
or 
other 
immunosuppressant drugs at the time of enrollment 
(current 
daily 
use 
of 
corticosteroids, 
i.e., >10 mg 
prednisone equivalent/day for >30 days. Intermittent 
corticosteroid use during the study is allowable, if 
medically necessary). 
k) History of thrombotic events (including myocardial 
infarction, cerebral vascular accident [including stroke], 
pulmonary embolism, and deep vein thrombosis) within 
the 6 months before treatment start with BT595 or the 
presence of significant risk factors for thrombotic events. 
l) Therapy with live-attenuated virus vaccines within 
3 months before start of the study. 
m) Selective, absolute immunoglobulin A (IgA) deficiency or 
known antibodies to IgA. 
n) Positive diagnosis of hepatitis B or hepatitis C. 
o) Positive HIV test. 
p) History of drug or alcohol abuse within the 12 months 
before treatment start with BT595. 
q) Inability or lacking motivation to participate in the study. 
Number of Subjects 
At least 50 evaluable subjects. At least 20 subjects should 
be pediatric subjects (i.e., children [2-11 years, inclusive] or 
adolescents 
[12-17 years, 
inclusive]) 
with 
the 
age 
distribution representative of the PID patient population. At 
least 20 subjects should be adult subjects.  
Before any pediatric subjects begin the study, at least 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 7 of 82 
10 adult subjects will receive at least 2 BT595 infusions with 
no safety concerns (as reviewed by the Data and Safety 
Monitoring Board). 
About 70 subjects will have to be enrolled to account for 
drop-outs. 
Countries/Number of 
Study Sites 
About 25 sites in Europe and the United States. 
Investigational Medicinal 
Product (IMP) 
BT595: 
human 
normal 
IVIg 
for 
intravenous 
(iv) 
administration (10 g/100 mL). 
Dosage and Mode of 
Administration 
Dosage: Planned doses in a range of 0.2 to 0.8 g/kg body 
weight (bw) (2 to 8 mL/kg bw) as an iv infusion at 3- or 
4-week intervals for a treatment period of approximately 
12 months. 
The initial dose and dosage interval must be consistent with 
the subject’s prestudy IVIg treatment and the initial dose and 
dosage interval will only be changed if medically indicated. 
This change will be at the investigator’s discretion. 
Infusion rate: BT595 should be infused intravenously at an 
initial rate of 0.3 mL/kg/h for 30 minutes, to be increased to 
1.4 mL/kg/h for a further 30 minutes. If well tolerated, the 
rate of administration may then be gradually increased to a 
maximum of 2.0 mL/kg/h for the remainder of the first 
infusion. From the second infusion, in subjects who have 
tolerated the infusion rate of 2.0 mL/kg/h well, the rate may 
be gradually increased to 4 mL/kg/h and, if still tolerated 
well, it may be further increased gradually to 6 mL/kg/h, and 
to a maximum of 8 mL/kg/h. 
In general, subjects’ infusion rates will be individually 
tailored at the discretion of the investigator, but must always 
start again at an initial rate of 0.3 mL/kg/h. 
Duration of Treatment 
Approximately 12 months per subject. 
Criteria for Evaluation 
 
- Efficacy Primary Endpoint: 
Rate of acute serious bacterial infections 
(i.e., the mean number of acute serious bacterial infections 
per subject-year). 
Acute serious bacterial infections include: 
• 
Bacteremia or sepsis 
• 
Bacterial meningitis 
• 
Osteomyelitis/septic arthritis 
• 
Bacterial pneumonia 
• 
Visceral abscess 
Specific diagnostic criteria for these infection types as given 
in the Food and Drug Administration (FDA) guidance will be 
used. 
Secondary Endpoints: 
• 
IgG trough levels (total IgG) before each infusion  
• 
Rate of any infections (number per year) 
• 
Rate of nonserious infections (number per year) 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 8 of 82 
• 
Time to resolution of infections 
• 
Antibiotic treatment (number of days antibiotic treatment 
received per month) 
• 
Rate of time lost from school/work due to infections 
(number of days per month) and their treatment (number 
of days treatment per month) 
• 
Hospitalization (number of days per month overall and 
due to infection) 
• 
Fever episodes (number of days per year) 
• 
Changes 
in 
health-related 
quality-of-life: 
Pediatric 
subjects (2-17 years, inclusive) 
will complete the 
Pediatric Quality of Life (Peds QL™) Measurement 
Model (child self-report and/or parent proxy-report). 
Additionally, all adult subjects will complete the EuroQol 
Five Dimension (EQ-5D-3L™) Health Questionnaire and 
pediatric subjects (4-17 years, inclusive) will complete 
the youth version of the EQ-5D™ (EQ-5D-Y™) Health 
Questionnaire (child self-report or proxy-report). 
 
- Safety Tolerability and safety of BT595: 
• 
Adverse events: 
- 
Number, severity, causality, and seriousness of 
adverse events (AEs) (including nonproduct related) 
temporally associated with the infusion (occurring 
during infusion or within 1, 24, and 72 hours after the 
end of infusion), defined as “infusional AEs”. 
Infusional AEs will be evaluated with regard to 
infusion rate and at which infusion (1st, 2nd, etc) they 
occurred. 
- 
Number of related infusional AEs occurring during 
infusion or within 1, 24, and 72 hours after the end of 
infusion. 
- 
Number and percentage of infusions temporally 
(within 72 hours) associated with 1 or more AEs. 
- 
Number, severity, causality, and seriousness of all 
AEs. 
- 
Number, severity, causality, and seriousness of all 
treatment-emergent AEs. 
- Number of noninfusional AEs (occurring more than 
72 hours after the end of infusion). 
• 
Changes in safety laboratory parameters (including 
standard clinical chemistry, hematology, coagulation, 
urinalysis; 
outside 
reference 
range 
and 
clinically 
relevant). 
• 
Number of positive intravascular hemolysis test results 
(direct 
Coombs’ 
test, 
and 
other 
tests 
for 
detection/evaluation of intravascular hemolysis). 
• 
Changes in vital sign parameters (body temperature, 
blood pressure, pulse rate, respiratory rate). 
• 
Changes in physical examination parameters. 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 9 of 82 
- Pharmacokinetics Pharmacokinetic (PK) endpoints: 
• 
IgG trough levels (total IgG) before each administration. 
• 
IgG trough levels (subclasses 1-4) at baseline and 
before 
the 
7th/5th infusion 
of 
the 
3-week/4-week 
schedule, respectively (with the exception of pediatric 
subjects aged 2-5 years, inclusive). 
• 
IgG trough 
levels 
of 
specific 
antibody 
levels 
(anti-pneumococcal 
capsular 
polysaccharide, 
anti-hemophilus 
influenzae 
type B, 
anti-measles, 
anti-tetanus, 
anti-cytomegalovirus, 
and 
anti-HBs/hepatitis B) 
at 
baseline 
and 
before 
the 
7th/5th infusion 
of 
the 
3-week/4-week 
schedule, 
respectively (with the exception of pediatric subjects 
aged 2-11 years, inclusive). 
 
A homecare service is allowed for the PK sampling of 
pediatric subjects (2-17 years, inclusive). 
Subjects will complete serial blood sampling according to 
their age category. For adult subjects (18-75 years, 
inclusive) and pediatric subjects (6-17 years, inclusive), 
samples will be taken at a fixed series of time points after 
the 7th/5th infusion (according to treatment schedule). For 
pediatric subjects (2-5 years, inclusive), sparse sampling at 
flexible time points within specified time windows after the 
end of this infusion may be performed (note: these samples 
are optional). Evaluable data from at least 20 adult subjects 
and all available pediatric data will be included in the PK 
analysis. Analysis of the concentration-time profiles will be 
used 
to 
derive 
key 
PK 
parameters 
for 
total IgG, 
IgG subclasses 1-4, 
and 
IgG specific 
antibody 
levels 
following simple noncompartmental analysis or a more 
appropriate approach including population analysis. For 
pediatric subjects, analysis for total IgG will be from pediatric 
subjects 
aged 
2 through 
17 years, 
analysis 
for 
IgG subclasses 1-4 will be from pediatric subjects aged 
6 through 17 years, and analysis for IgG specific antibody 
levels will be from pediatric subjects aged 12 through 
17 years only. 
The following key PK parameters will be derived from the 
analysis: maximum concentration (Cmax), time to reach 
maximum concentration (tmax), trough concentration (Ctrough), 
area under the concentration-time curve (AUC) calculated 
from time zero to time t of the last measured concentration 
(AUC(0-t)), 
area 
under 
the 
concentration-time 
curve 
calculated from start to end of the dosing interval (AUCtau), 
steady-state clearance (CLss), volume of distribution at 
steady-state (Vss), %Fluctuation, and if data permit, terminal 
elimination half-life (t1/2), area under the concentration-time 
curve calculated from time zero extrapolated to infinity 
(AUC(0-inf)), mean residence time (MRT), and terminal 
elimination rate constant (λz). 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 10 of 82 
The efficacy, safety, and PK results of this study will be 
compared to historical data from previous PID studies with 
Intratect and Bivigam (already marketed 10% IVIgs), as well 
as to available data from literature. 
Biostatistical Concept 
A sample size of at least 50 evaluable subjects is 
considered a sufficient number to evaluate the primary study 
endpoint according to the relevant FDA and EMA guidelines. 
A sample size of at least 50 subjects will ensure a power of 
at least 80% to reject the null hypothesis of an acute serious 
bacterial infection rate greater or equal to 1.0 by means of a 
1-sided test and a Type 1 error of 0.01 assuming a true 
underlying rate of acute serious bacterial infections of 
0.5 per year. 
The primary endpoint is the rate of acute serious bacterial 
infections (i.e., the mean number of acute serious bacterial 
infections per subject-year). The null hypothesis of 1 or 
more acute serious bacterial infections per subject-year will 
be tested against the 1-sided alternative hypothesis of less 
than 1 acute serious bacterial infection per subject-year at 
the 1% level of statistical significance. This 1-sided 
hypothesis test will utilize a Poisson model as used for the 
calculation of the upper confidence limit. Rejection of the 
null hypothesis of 1 or more acute serious bacterial infection 
per subject-year will result in the acceptance of the alternate 
hypothesis of less than 1 acute serious bacterial infection 
per subject-year. 
Secondary efficacy endpoints and safety endpoints will be 
analyzed descriptively. Exploratory 2-sided 90% confidence 
intervals will be calculated for the total incidence of AEs and 
of temporally associated AEs. Exploratory upper 1-sided 
95% confidence limits will be calculated for the proportion of 
infusions temporally associated with 1 or more AE. 
Analyses of the IgG trough levels and PK parameters will be 
done descriptively and presented graphically, including a 
comparison of the IgG trough levels by analyte (total IgG, 
IgG subclasses, and IgG specific antibody levels), treatment 
schedule (3-week and 4-week schedule), and age category. 
Evaluation of total IgG trough levels will include the 
calculation of the proportion of subjects who failed to meet 
the target level (≥5 g/L) prior to dose adjustment, and an 
intra-individual comparison to trough levels of the former 
IVIg product (i.e., using prestudy data). No formal statistical 
test will be performed for these variables. 
First Subject In (planned) 
June 2016 
Last Subject Last Visit 
(planned) 
November 2019 
 
Confidentiality Statement 
This protocol is the property of Biotest AG, and may not be circulated, reproduced, or published – either 
in whole or in part – without the company’s written permission.  

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 11 of 82 
III. 
FLOWCHART OF STUDY 
3-Week and 4-Week Schedule 
Study Schedule 
Visit 
3-week 
4-week 
V1 
V2 BL 
 
V 3-19 
V 3-15  
 
V 20 
V 16 
Week 
3-week 
4-week 
W -4 to W 0 
W 0 
 
W 3-51 
W 4-52 
 
Up to W 54 
Up to W 56 
Day 
3-week 
4-week 
D -28 through 
D 0 
D 1 
Approx 
D 22-358 
D 29-365 
Approx  
Up to D 379 
Up to D 393 
Assessments 
Periods 
Screening 
Treatmenta 
Closing 
(Follow-up)a 
Informed consent/assent 
• 
 
 
 
Demographic data (incl. gender, date of birth, ethnic origin, height) 
• 
 
 
 
Medical and surgical history (incl. drug history, previous medication, 
disease history) 
• 
• 
 
 
Eligibility criteria (inclusion/exclusion) 
• 
• 
 
 
Physical examinationb 
• 
• 
• 
• 
Vital signs (pulse, blood pressure, temperature, respiratory rate) 
• 
•c 
•c 
• 
Body weight 
• 
• 
• 
 
Pregnancy testd 
• 
• 
• 
• 
Safety laboratory (hematology, coagulation, clinical chemistry, urinalysis) 
• 
•e 
• 
• 
Intravascular hemolysis parameters (incl. Coombs test, haptoglobin, 
hemoglobin, hemosiderin) 
• 
 
•i 
• 
Viral safety (retention samples) 
• 
 
 
• 
Virus serology (hepatitis B, hepatitis C, HIV) 
• 
 
 
 
Infusion of BT595 
 
• 
• 
 
Immunoglobulin G trough levels (total IgG) 
• 
•e 
• 
• 
Immunoglobulin G trough levels (subclasses 1-4) 
 
•f 
•f 
 
Specific antibody trough levels 
 
•g 
•g 
 
Subject diary (paper) dispensed 
 
• 
• 
 
Collection and review of subject diary (paper)  
 
 
• 
• 
Health-related quality-of-life assessment 
 
• 
• 
• 
Concomitant medications 
• 
• 
Adverse events 
 
• 
Pharmacokinetic parameters for total IgG, IgG subclasses, and 
IgG specific antibody levels 
 
 
•h 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 12 of 82 
Approx = approximately; BL = baseline; D = day; incl = including; V = visit; W = week. 
a A time window of ±2 days will be allowed for the treatment period visits and the closing (follow-up) visit; however, this time window will not apply 
for the PK assessments. Pharmacokinetic assessments will follow time point specific time windows. 
b The physical examination will be followed-up with a verbal exchange (face-to-face) between the subject and the investigator 1 hour after the end 
of each infusion, and a verbal exchange (by telephone) 24 and 72 hours after the end of each infusion. 
c Vital signs (pulse, blood pressure, respiratory rate) will be assessed within 30 minutes before each infusion, 15 to 30 minutes after the start of 
each infusion, 15 to 30 minutes after the end of each infusion, and 15 to 30 minutes after the start of any change in the infusion rate. In any case 
where the change in infusion rate is sooner than a 15 minute interval, vital signs should be measured prior to the change. The vital sign, 
temperature, will be recorded within 30 minutes before each infusion only. 
d A pregnancy human chorionic gonadotropin test in serum will be taken for all female subjects ≥12 years of age or with presence of menstruation 
at screening. Urine pregnancy dipstick tests will be performed at all other study visits. 
e Additional samples for safety laboratory assessments and total IgG will be taken at the end of the first BT595 infusion. 
f Samples will be taken from subjects (6-75 years, inclusive) at baseline and before the 7th/5th infusion of the 3-week/4-week schedule, 
respectively (i.e., this sample is the same sample as the predose sample for PK analysis). 
g Samples will be taken from subjects (12-75 years, inclusive) at baseline and before the 7th/5th infusion of the 3-week/4-week schedule, 
respectively (i.e., this sample is the same sample as the predose sample for PK analysis). 
h At the 7th infusion (Week 18 [3-week schedule]) or 5th infusion (Week 16 [4-week schedule]), serum samples for the PK analysis of total IgG, 
IgG subclasses 1-4, and IgG specific antibody levels (anti-pneumococcal capsular polysaccharide, anti-hemophilus influenzae type B, 
anti-measles, anti-tetanus, anti-cytomegalovirus, and anti-HBs/hepatitis B) will be drawn from subjects (6-75 years, inclusive for total IgG and 
IgG subclasses 1-4; 12-75 years inclusive for IgG specific antibody levels) at the following time points: predose (i.e., 10 to 30 minutes before the 
infusion), 10 to 30 minutes postinfusion (end of infusion), 4 and 24 hours postinfusion; and 4, 7, 14, 21 days (for the 3-week and the 4-week 
treatment schedule), and 28 days postinfusion (4-week schedule only). For pediatric subjects (2-5 years, inclusive), sparse sampling for PK 
analysis of total IgG only may be performed at flexible time points within specified time windows after the end of the infusion (note: these samples 
are optional). 
I For detecting any hemolytic outcome the first two infusions (V2, V3) should be followed up on the following visit (V3, V4) for the first 10 patients by 
analyzing Coombs test and test of haptoglobin. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 13 of 82 
IV. 
TABLE OF CONTENTS 
I. 
SIGNATURE PAGE ............................................................................................ 3 
I.I 
Signature Page for Investigators ..................................................................... 4 
II. 
STUDY SYNOPSIS ............................................................................................ 5 
III. 
FLOWCHART OF STUDY ................................................................................ 11 
IV. 
TABLE OF CONTENTS ................................................................................... 13 
V. 
LIST OF ABBREVIATIONS ............................................................................. 17 
1 
INTRODUCTION .............................................................................................. 19 
2 
STUDY OBJECTIVES ...................................................................................... 20 
3 
STUDY DESIGN ............................................................................................... 21 
4 
STUDY POPULATION ..................................................................................... 22 
4.1 
Study Population, Diagnosis, and Number of Subjects .............................. 22 
4.1.1 
Gender Distribution .................................................................................................. 22 
4.2 
Inclusion Criteria ............................................................................................. 23 
4.3 
Exclusion Criteria ........................................................................................... 23 
4.4 
Subjects Withdrawal Criteria and Replacements ......................................... 24 
4.5 
Subjects’ Information ..................................................................................... 25 
4.6 
Declaration of Informed Consent/Assent ..................................................... 26 
5 
INVESTIGATIONAL MEDICINAL PRODUCT .................................................. 26 
5.1 
Investigational Medicinal Product BT595 ..................................................... 26 
5.1.1 
Description of Investigational Medicinal Product BT595 ....................................... 26 
5.1.2 
Formulation, Packaging, and Labelling .................................................................. 27 
5.1.3 
Storage Conditions and Stability ............................................................................. 27 
5.1.4 
Preparation for Use .................................................................................................. 27 
6 
STUDY TREATMENT ....................................................................................... 27 
6.1 
Dosage Regimen ............................................................................................. 27 
6.2 
Dosage and Administration ........................................................................... 27 
6.2.1 
Dose Changes during the Study .............................................................................. 28 
6.3 
Compliance with Dosage Regimens ............................................................. 28 
6.4 
Dose Justification ........................................................................................... 28 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 14 of 82 
6.5 
Treatment of Overdose ................................................................................... 29 
6.6 
Randomization Code ...................................................................................... 30 
6.7 
Procedures for Emergency Unblinding ........................................................ 30 
6.8 
Drug Accountability ........................................................................................ 30 
6.9 
Previous and Concomitant Medication or Treatment .................................. 30 
6.9.1 
Previous Medication or Treatment .......................................................................... 30 
6.9.2 
Concomitant Medication or Treatment .................................................................... 31 
6.10 
Prohibited Medication or Treatment .............................................................. 31 
6.11 
Warnings and Precautions ............................................................................. 31 
7 
COURSE OF THE CLINICAL STUDY .............................................................. 32 
7.1 
Visit Schedule ................................................................................................. 32 
7.2 
Duration of the Clinical Study ........................................................................ 36 
7.2.1 
End of Study ............................................................................................................. 37 
7.3 
Criteria for Premature Termination ............................................................... 37 
7.3.1 
Premature Termination of the Entire Clinical Study ............................................... 37 
7.3.2 
Premature Termination of an Individual Study Site ............................................... 37 
7.4 
Treatment and Care after the End of the Study ............................................ 37 
8 
BENEFIT-RISK EVALUATION......................................................................... 37 
8.1 
Benefit .............................................................................................................. 37 
8.2 
Foreseeable Risk and Discomfort Related to BT595 ................................... 38 
8.3 
Other Sources of Possible Risk and Discomfort ......................................... 38 
8.4 
Summary of Possible Risk and Discomfort .................................................. 39 
9 
ASSESSMENT OF OBJECTIVES/CRITERIA FOR EVALUATION ................. 41 
9.1 
Efficacy ............................................................................................................ 41 
9.1.1 
Specification of Efficacy Parameters ...................................................................... 41 
9.1.1.1 Primary Efficacy .......................................................................................................... 41 
9.1.1.2 Secondary Efficacy ..................................................................................................... 41 
9.1.2 
Methods for Assessing and Recording Efficacy Parameters ................................ 41 
9.1.2.1 Primary Efficacy Parameter ........................................................................................ 41 
9.1.2.2 Secondary Efficacy Parameters .................................................................................. 42 
9.1.3 
Specification of Efficacy Endpoints ........................................................................ 44 
9.1.3.1 Primary Efficacy .......................................................................................................... 44 
9.1.3.2 Secondary Efficacy ..................................................................................................... 44 
9.2 
Safety ............................................................................................................... 44 
9.2.1 
Specification of Safety Parameters ......................................................................... 44 
9.2.1.1 Adverse Events .......................................................................................................... 45 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 15 of 82 
9.2.1.2 Physical Examination .................................................................................................. 45 
9.2.1.3 Vital Signs .................................................................................................................. 45 
9.2.1.4 Laboratory Parameters ............................................................................................... 46 
9.2.1.5 Viral Safety (Retention Samples) ................................................................................ 48 
9.2.2 
Methods for Assessing and Recording Safety Parameters ................................... 48 
9.2.3 
Safety Endpoints ...................................................................................................... 48 
9.3 
Adverse Events ............................................................................................... 49 
9.3.1 
Definitions (also refer to Appendix 1) ..................................................................... 49 
9.3.2 
Recording Adverse Events ...................................................................................... 51 
9.3.3 
Period of Observation .............................................................................................. 52 
9.3.4 
Assessment of Adverse Events ............................................................................... 52 
9.3.5 
Immediate Reporting by Investigator to Sponsor .................................................. 54 
9.3.6 
Use of Investigational Medicinal Product Outside the Specifications of the 
Clinical Study Protocol ............................................................................................. 54 
9.3.7 
Investigational Medicinal Product Complaints ....................................................... 54 
9.3.8 
Special Situations Requiring Immediate Reporting ............................................... 54 
9.3.8.1 Pregnancy .................................................................................................................. 55 
9.4 
Data and Safety Monitoring Board ................................................................ 55 
9.5 
Pharmacokinetics ........................................................................................... 55 
9.5.1 
Specification of Pharmacokinetic Parameters........................................................ 55 
9.5.2 
Methods for Assessing and Recording Pharmacokinetic Parameters ................. 56 
9.5.3 
Pharmacokinetic Endpoints ..................................................................................... 57 
10 
STATISTICS ..................................................................................................... 57 
10.1 
Analysis Sets................................................................................................... 57 
10.2 
Protocol Deviations ........................................................................................ 58 
10.3 
General Considerations ................................................................................. 59 
10.4 
Efficacy Analyses ........................................................................................... 60 
10.5 
Primary Efficacy Analysis .............................................................................. 60 
10.6 
Secondary Efficacy Analyses ........................................................................ 60 
10.7 
Safety Analysis ............................................................................................... 62 
10.8 
Interim Analyses ............................................................................................. 64 
10.9 
Determination of Sample Size........................................................................ 64 
10.10 
Pharmacokinetic Analyses ............................................................................ 64 
11 
DATA MANAGEMENT ..................................................................................... 65 
11.1 
Data Collection ................................................................................................ 65 
11.2 
Correction of Data ........................................................................................... 66 
11.3 
Data Handling .................................................................................................. 66 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 16 of 82 
12 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................... 66 
12.1 
Study Initiation Activities ............................................................................... 66 
12.2 
Training of Site Staff ....................................................................................... 67 
12.3 
Documentation and Filing .............................................................................. 67 
12.4 
Monitoring ....................................................................................................... 68 
12.5 
Audits and Inspections .................................................................................. 68 
12.6 
Archiving ......................................................................................................... 68 
13 
GENERAL REGULATIONS, AGREEMENTS, AND ORGANIZATIONAL 
PROCEDURES................................................................................................. 68 
13.1 
Study Administrative Structure ..................................................................... 68 
13.2 
Ethical and Regulatory Considerations ........................................................ 68 
13.3 
Committees/Monitoring Boards..................................................................... 69 
13.4 
Written Agreements ........................................................................................ 69 
13.5 
Insurance/Liability .......................................................................................... 69 
13.6 
Investigator’s Brochure .................................................................................. 69 
13.7 
Amendments to the Protocol ......................................................................... 69 
13.8 
Confidentiality ................................................................................................. 70 
13.9 
Final Report and Publication ......................................................................... 70 
14 
LIST OF REFERENCES ................................................................................... 71 
15 
APPENDICES................................................................................................... 73 
Appendix 1: "Safety Definitions" 
Appendix 2: "Reporting Procedures" 
Appendix 3: “Diagnostic Criteria for Serious Infection Types” 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 17 of 82 
V. 
LIST OF ABBREVIATIONS 
ADR 
adverse drug reaction 
AE 
adverse event 
AESI 
adverse event of special interest 
anti-HBc 
hepatitis B core antibody 
anti-HBs 
hepatitis B surface antibody 
AUC 
area under the concentration-time curve 
AUC(0-∞) 
area under the concentration-time curve from time zero 
extrapolated to infinity 
AUC(0-t) 
area under the concentration-time curve from time zero to time 
t of the last measured concentration 
AUCtau 
area under the concentration-time curve calculated from start 
to end of the dosing interval 
bw 
body weight 
CLss 
steady-state clearance 
Cmax 
maximum concentration 
CRO 
contract research organization 
Ctrough 
trough concentration 
CVID 
common variable immunodeficiency 
DEVP (Form) 
Drug Exposure Via Parent Report (Form) 
DRM 
Data Review Meeting 
DSMB 
Data and Safety Monitoring Board 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
EQ-5D™ 
EuroQol Five Dimension 
EQ-5D-3L™ 
EuroQol Five Dimension (3 levels) 
EQ-5D-Y™ 
EuroQol Five Dimension (youth version) 
EQ VAS 
EuroQol Visual Analog Scale 
ESID 
European Society for Immunodeficiencies 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
ICH 
The International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
IEC 
Independent Ethics Committee 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRAE 
immediately reportable adverse event 
ITP 
idiopathic thrombocytopenic purpura 
iv 
intravenous 
IVIg/IGIV 
intravenous immunoglobulin 
Λz (lambda z) 
terminal elimination rate constant 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 18 of 82 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MRT 
mean residence time 
n 
number of observations 
no. 
number 
PAGID 
Pan American Group for Immunodeficiency 
Peds QL™ 
Pediatric Quality of Life 
PHI 
protected health information 
PID 
primary immunodeficiency disease 
PK 
pharmacokinetic 
PPS  
Per-protocol Set 
PRO 
patient reported outcome 
SAE 
serious adverse event 
SAF 
Safety Set 
SAP 
statistical analysis plan 
SmPC 
Summary of Product Characteristics 
TEAE 
treatment-emergent adverse event 
t1/2 
terminal elimination half-life 
tmax 
time to reach maximum concentration 
TMF 
Trial Master File 
TRALI 
transfusion-related acute lung injury 
Vss 
volume of distribution at steady-state 
WHO-DD 
World Health Organization Drug Dictionary 
XLA 
X-linked agammaglobulinemia 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 19 of 82 
1 INTRODUCTION 
Primary immunodeficiency diseases (PIDs) are a class of disorders in which there is an 
intrinsic defect in the human immune system. Since the original description of X-linked 
agammaglobulinemia (XLAs) in 1952, the number of independent PIDs has expanded 
to more than 100 entities. 
 
Intravenous administration of immunoglobulins is a well-established therapy in patients 
with primary or secondary immune deficiencies and recurrent infections. The primary 
aim of therapy is to prevent infections by substituting missing antibodies. Moreover, 
immunoglobulins have a modulating effect on the immune system and may therefore 
also be helpful in the treatment of recurrent infections and autoimmune diseases 
(Björkander et al, 2006; Chapel et al, 2014; Imbach et al, 2010; Schwab and 
Nimmerjahn, 2013; Lünemann et al, 2015). 
 
Immunoglobulin G Next Generation (BT595) is a normal immunoglobulin preparation 
manufactured from human plasma. BT595 is a sterile, highly purified solution of human 
normal 
immunoglobulin 
for 
intravenous 
administration 
(IVIg) 
containing, 
in 
concentrated form, all the immunoglobulin G (IgG) antibodies that regularly occur in the 
donor population. BT595 contains 100 mg human plasma protein per mL of solution 
(i.e., 10% ready-for-use solution). 
 
Fundamental knowledge on the manufacturing conditions of the licensed IVIg products 
at Biotest AG formed the basis for the development of BT595. To optimize the 
production process, Biotest has established a new process aiming to produce an 
intravenously tolerated IgG preparation with a low content of polymers and high purity. 
The manufacturing process of BT595 ensures the required viral safety and provides a 
reproducible quality.  
 
Further details on the manufacturing process are provided in the Investigator’s 
Brochure. 
 
To date, no clinical studies have previously been conducted with BT595 but 
pharmacokinetic (PK) properties and the efficacy and safety profile are expected to be 
comparable with other currently licensed immunoglobulin products, including Bivigam 
(Biotest's intravenous immunoglobulin [IGIV] 100 g/L; licensed in the United States) 
and Intratect, the IVIg preparation available in 2 strengths (50 g/L and 100 g/L) and 
marketed by Biotest in the EU and other international markets as a replacement 
therapy for patients with PID as well as for other antibody-deficiency/autoimmune 
diseases.  
 
With Bivigam, 1 clinical study has been performed in 63 subjects with PID (Wasserman 
et al, 2012). These subjects received a total of 746 infusions over approximately 
12 months. Forty subjects were reported with adverse events (AEs) that were related 
to the study product. The majority of the AEs were mild to moderate. The reported AEs 
were in the expected profile for IGIVs. 
 
With Intratect (50 g/L), 3 clinical studies have been performed: 2 in subjects with PID 
(Study 941 [2002] and Study 957 [Kreuz et al, 2010]) and 1 in subjects with idiopathic 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 20 of 82 
thrombocytopenic purpura (ITP; Study 942 [Colovic et al, 2003]). In the 2 PID studies, 
overall 68 subjects were treated over a period of 6 and 12 months, respectively. 
 
With Intratect (100 g/L), 1 clinical study (Study 981 [Krivan et al, 2015]) has been 
performed over 3 to 6 months in 30 subjects with PID. These 30 subjects received a 
total of 165 infusions, where a total of 19 infusions (11.5%) were associated with 
adverse drug reactions (ADRs). The majority of these ADRs were mild to moderate 
and self-limiting. No serious ADR was observed during this study. The reported ADRs 
were consistent with the expected profile for IVIgs.  
 
Study 981 demonstrated that the PK and safety profile of Intratect (100 g/L) is 
consistent with those of Intratect (50 g/L) and other IVIg products. Moreover, the data 
demonstrated that the escalation of infusion rates of Intratect (100 g/L) can lead to the 
identification of an individual’s maximum tolerated infusion rate, which is well-tolerated 
and safe when administered at subsequent infusions. 
 
The goal of the current clinical development plan is the parallel development of BT595 
in European and United States’ regulatory regions. Three studies are planned for the 
clinical development of BT595 which consider both European Medicines Agency 
(EMA/CHMP/BPWP/94033/2007 rev. 2, 2010) and Food and Drug Administration 
(FDA, 2008) guidelines for the PID and ITP indications, as well as recently-published 
and ongoing studies in the chronic inflammatory demyelinating polyneuropathy 
indication. The plan is to begin with a PID study in Europe and the United States to 
obtain PK data for BT595, as well as safety and efficacy data of long-term replacement 
therapy in this target indication in adult and pediatric subjects. 
 
In the present study, subjects will receive intravenous infusions of BT595 at a dose and 
dosage interval consistent with their prestudy IVIg treatment. The planned schedule for 
the gradual increase of the infusion rate is based on the results of Clinical Study 981 
(Krivan et al, 2015) which showed a good tolerability of Intratect (100 g/L); however, 
the infusion rate will be individualized for each subject.  
 
In conclusion, due to comparable quality/biologic characteristics of BT595 and based 
on the clinical experience with the already-marketed Intratect, it is predicted that BT595 
will have an acceptable safety profile, even at the scheduled increased infusion rate. 
The principal benefit for the participating PID subjects will be to receive their required 
immunoglobulin replacement therapy that will have the antiinfective effect already 
demonstrated for Intratect. Balancing the risk of a limited increase in frequency of 
maximally mild to moderate adverse reactions with the expected benefit for subjects 
and resource savings for the health care system, the expected benefits of the study 
clearly exceed the expected risks. Thus, the benefit-risk ratio of BT595 is considered 
favorable and the use of BT595 in this clinical study is justified. 
2 STUDY OBJECTIVES 
The main purpose of this study is to assess the efficacy, safety, and pharmacokinetics 
of BT595 in subjects with PID. The primary objective of this study is to demonstrate 
that the rate of acute serious bacterial infections (i.e., the mean number of acute 
serious bacterial infections per subject year) is less than 1.0 to provide substantial 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 21 of 82 
evidence of efficacy. The secondary objectives of this study, in addition to further 
efficacy assessments, are to evaluate the safety and PK characteristics of BT595. 
3 STUDY DESIGN 
This is an open-label, prospective, uncontrolled, multicenter Phase III Pivotal study to 
evaluate the efficacy, safety, and pharmacokinetics of the human normal 
immunoglobulin for intravenous administration BT595 in subjects with PID. 
 
The rate of acute serious bacterial infection – the primary efficacy endpoint - will also 
be compared to historical data from previous PID studies with Intratect and Bivigam 
(already marketed 10% IVIgs) as well as to available data from literature. These data 
will be provided by Biotest by the time of the analyses. 
 
About 70 subjects will be enrolled to ensure data are available for at least 50 evaluable 
subjects. At least 20 subjects should be adult subjects (18-75 years, inclusive). At least 
20 subjects should be pediatric subjects (i.e., children [2-11 years, inclusive] or 
adolescents [12-17 years, inclusive]), with the age distribution representative of the PID 
patient population. Age will be the age recorded at screening (initial visit). The same 
age will be used per subject during the entire study (i.e., if a subject’s age changes 
from 17 years to 18 years during the study, the subject will remain in the age category 
of 12 through 17 years during the entire study). 
 
A Data and Safety Monitoring Board (DSMB) will be used to monitor the safety data of 
at least 10 adult subjects (18-75 years, inclusive) (Section 9.4) before any pediatric 
subjects are enrolled to the study. The DSMB will review these data and provide 
recommendations on the suitability of the enrolment of pediatric subjects in the study. 
The final decision to enroll/not enroll pediatric subjects will be the responsibility of the 
sponsor. 
 
Efficacy and safety will be assessed from baseline (Week 0) to the closing (follow-up) 
visit (Week 54 [3-week schedule]/Week 56 [4-week schedule]). For the baseline visit 
and the treatment period visits, subjects will remain at the site for at least 1 hour 
following the end of infusion and any new AEs will be reported to the investigator at the 
site. All changes in concomitant medications and any AEs following subject discharge 
from the site must be reported continuously (by subject diary) between site visits. The 
duration of treatment will be approximately 12 months per subject. In addition, all 
subjects will attend a closing (follow-up) visit up to 3 or 4 weeks (depending on the 
subject’s treatment schedule) following the final treatment visit. 
 
Serum samples for detailed PK analysis will be taken at a fixed series of time points 
after the 7th/5th infusion of the 3-week/4-week schedule, respectively, from at least 
20 adult subjects (18-75 years, inclusive) and from pediatric subjects (6-17 years, 
inclusive). For pediatric subjects (2-5 years, inclusive), sparse sampling at flexible time 
points within specified time windows after the end of the infusion may be performed 
(note: these samples are optional). Evaluable data from at least 20 adult subjects and 
all available pediatric data will be included in the PK analysis. Analysis of the 
concentration-time profiles will be used to derive key PK parameters for total IgG, IgG 
subclasses 1-4, and IgG specific antibody levels (anti-pneumococcal capsular 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 22 of 82 
polysaccharide, 
anti-hemophilus 
influenzae 
type B, 
anti-measles, 
anti-tetanus, 
anti-cytomegalovirus, and anti-HBs/hepatitis B). 
 
Further details on the assessment schedule that will be used for the assessment of the 
efficacy, safety, and PK parameters in this study are presented in a flowchart in 
Section III. 
 
The design of this study follows the EMA guidelines (“Guideline on the Clinical 
Investigation of Human Normal Immunoglobulin for Intravenous Administration [IVIg]”; 
EMA/CHMP/BPWP/94033/2007 rev. 2, 2010) and the FDA guidelines (“Guidance for 
Industry - Safety, Efficacy, and Pharmacokinetic Studies to Support Marketing of 
Immune Globulin Intravenous [Human] as Replacement Therapy for Primary Humoral 
Immunodeficiency”; FDA, 2008) applicable to the PID study type. 
 
As the current regulatory goal is to receive marketing authorization in both the United 
States and European regions, this clinical study will be carried out in parallel in sites in 
the United States and Europe; thus, taking into account guidelines from both regions 
that provide specific recommendations on the general principles for the design of a 
clinical investigation of human normal immunoglobulin products for intravenous 
administration as replacement therapy in patients with PID. These guidelines also 
provide recommendations on the primary efficacy endpoint, secondary efficacy 
endpoints, and safety endpoints to be assessed in a study of this type. The present 
study will follow these guidelines to demonstrate clinical evidence of the efficacy and 
safety of BT595, and as such, the efficacy and safety endpoints used in this study are 
consistent with the recommendations made by both the EMA and the FDA. All safety 
signals, including short-term tolerance, will be closely monitored in this study. In 
addition, all PK parameters recommended by the EMA and FDA guidelines will be 
calculated to support the pharmacological activity and efficacy of BT595. 
4 STUDY POPULATION 
4.1 Study Population, Diagnosis, and Number of Subjects 
It is planned to enroll about 70 male or female subjects (2-75 years, inclusive) with PID 
and established replacement therapy in approximately 25 sites in Europe and the 
United States, with about 2-3 subjects per site. For those countries where local 
regulations permit enrolment of adult subjects only, subject recruitment will be 
restricted to those who are 18 through 75 years. The goal is to have at least 
50 evaluable subjects in this study. At least 20 of the evaluable subjects should be 
pediatric subjects (i.e., children [2-11 years, inclusive] or adolescents [12-17 years, 
inclusive]), with the age distribution representative of the PID patient population. At 
least 20 of the evaluable subjects should be adult subjects. Age will be the age 
recorded at screening (initial visit). The same age will be used per subject during the 
entire study. At least 10 adult subjects will receive at least 2 BT595 infusions with no 
safety concerns (as reviewed by the DSMB; Section 9.4) before any pediatric subjects 
begin the study. 
4.1.1 Gender Distribution 
The number of male and female subjects will not be predefined by the protocol. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 23 of 82 
4.2 Inclusion Criteria 
Only subjects meeting all of the following inclusion criteria will be considered for study 
inclusion: 
 
Inclusion Criteria 
Rationale 
Screening 
Baseline 
a) Written informed consent/assent obtained from 
subjects/subjects’ parent(s) or legally acceptable 
representative indicating that they understand the 
purpose of and procedures required for the study 
and are willing to participate in it 
Administrative 
X 
 
b) Male or female, aged 2 through 75 years 
Administrative 
X 
 
c) Diagnosis 
of 
PID 
with 
impaired 
antibody 
production, i.e.: 
- Diagnosis 
of 
common 
variable 
immunodeficiency (CVID) as defined by the 
European 
Society 
for 
Immunodeficiencies 
(ESID)a/Pan 
American 
Group 
for 
Immunodeficiency (PAGID)b diagnostic criteria 
Or 
- X-linked agammaglobulinemia (XLA) as defined 
by ESID/PAGID diagnostic criteria 
Disease 
requirement 
X 
 
d) Established replacement therapy with any IVIg 
reference 
preparation 
during 
the 
previous 
6 months, including documentation of IgG trough 
levels 
Pretreatment 
requirement 
X 
 
e) Established replacement therapy with a single 
IVIg reference preparation for at least 3 months 
prior to treatment start with BT595 at a 3- or 
4-week schedule with a constant IVIg dose that 
did not change by ±20% of the mean dose, 
regular dosage intervals, and at least 1 IgG 
trough level of ≥5 g/L during the previous 
3 months 
Pretreatment 
requirement 
X 
X 
a ESID diagnostic criteria (European Society for Immunodeficiencies, 2006). 
b PAGID diagnostic criteria (Conley et al, 1999). 
4.3 Exclusion Criteria 
Subjects having any of the following criteria, either at screening and/or baseline, will 
not be included in the study: 
 
Exclusion Criteria 
Rationale 
Screening 
Baseline 
a) Pregnancy or unreliable contraceptive measures 
or lactation period (females only) 
Lack of suitability 
for study due to 
safety reasons 
X 
X 
b) Known 
intolerance 
to 
immunoglobulins 
or 
comparable 
substances 
(e.g., vaccination 
reaction) 
Lack of suitability 
for study due to 
safety reasons 
X 
X 
c) Known intolerance to proteins of human origin or 
known allergic reactions to components of the 
study product 
Lack of suitability 
for study due to 
safety reasons 
X 
X 
d) Participation in another clinical study within 
30 days before entering the study or during the 
study and/or previous participation in this study 
Lack of suitability 
for study 
X 
X 
e) Employee or direct relative of an employee of the 
Contract Research Organization (CRO), the study 
site, or Biotest 
Administrative 
X 
X 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 24 of 82 
Exclusion Criteria 
Rationale 
Screening 
Baseline 
f) Acquired medical conditions known to cause 
secondary immune deficiency, such as chronic 
lymphatic 
leukemia, 
lymphoma, 
multiple 
myeloma, as well as protein losing enteropathies 
and hypoalbuminemia 
Lack of suitability 
for study 
X 
X 
g) Other medical condition, laboratory finding, or 
physical examination finding that precludes 
participation 
Lack of suitability 
for study 
X 
X 
h) Recent febrile illness that precludes or delays 
participation 
Lack of suitability 
for study due to 
safety reasons 
X 
X 
i) Active infection and receiving antibiotic therapy 
for the treatment of this infection at the time of 
screening. Note: if the subject is deemed to be a 
screen failure due to a nonserious active infection 
requiring antibiotic therapy, the subject may be 
rescreened after the initial screening 
Lack of suitability 
for study 
X 
X 
j) Therapy 
with 
systemic 
steroids 
or 
other 
immunosuppressant 
drugs 
at 
the 
time 
of 
enrollment (current daily use of corticosteroids, 
i.e., >10 mg 
prednisone 
equivalent/day 
for 
>30 days. Intermittent corticosteroid use during 
the study is allowable, if medically necessary) 
Interference with 
study outcomes 
X 
 
k) History of thrombotic events (including myocardial 
infarction, cerebral vascular accident [including 
stroke], pulmonary embolism, and deep vein 
thrombosis) within the 6 months before treatment 
start with BT595 or the presence of significant 
risk factors for thrombotic events 
Lack of suitability 
for study due to 
safety reasons 
X 
X 
l) Therapy with live-attenuated virus vaccines within 
3 months before start of the study 
Interference of 
IVIg with 
live-attenuated 
virus vaccines 
X 
 
m) Selective, 
absolute 
immunoglobulin A (IgA) 
deficiency or known antibodies to IgA 
Lack of suitability 
for study due to 
safety reasons 
X 
X 
n) Positive diagnosis of hepatitis B or hepatitis C 
Lack of suitability 
for study 
X 
X 
o) Positive HIV test 
Lack of suitability 
for study 
X 
X 
p) History of drug or alcohol abuse within the 
12 months before treatment start with BT595 
Subject 
compliance 
X 
X 
q) Inability or lacking motivation to participate in the 
study 
Subject 
compliance 
X 
X 
4.4 Subjects Withdrawal Criteria and Replacements 
The participation of an individual subject may be terminated prematurely for reasons 
such as: 
a. Withdrawal of written informed consent/assent 
b. Study discontinuation due to subject's own request (e.g., personal reasons) 
c. Required treatment with any medication known or suspected to interfere with the 
investigational medicinal product (IMP) 
d. Any AE, laboratory abnormality, or other medical condition or situation occurs 
suggesting that continued participation in the study would not be in the best 
interest of the subject. 
e. Protocol deviation requiring discontinuation of study treatment 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 25 of 82 
f.  Evidence of exclusion criteria 
g.  Lack of study compliance 
h. Any of the following AEs occur: thromboembolic events (such as stroke, 
myocardial infarction, lung embolism) or hemolysis [Section 9.3.1 for further 
details]). 
 
A subject and/or his/her parent(s) or legally acceptable representative is/are entitled to 
discontinue participation in the clinical study at their own request at any time without 
stating a reason. 
 
The investigator can terminate a subject's participation in the study at any time if 
continuation could lead to disadvantages for the subject which cannot be justified by 
the investigator. 
 
The participation of subjects may be stopped following guidance from the DSMB 
(Section 9.4). 
 
The reason for withdrawal of the subject must be documented by the investigator 
together with all data collected until the day of premature study termination, including 
laboratory results and assessment of AEs. All examinations foreseen for the subject’s 
last study visit (e.g., closing [follow-up] visit) should be performed. 
 
In case a subject withdraws due to an AE or serious adverse event (SAE), please 
follow the instructions given in Appendix 2 of this protocol. 
 
Withdrawn subjects will not be replaced. 
4.5 Subjects’ Information 
The subject and/or - if applicable – his/her legally acceptable representative will be 
informed about the clinical study according to the requirements of Good Clinical 
Practice (GCP) and the legal requirements of the country in which the subject is 
recruited.  
 
The clinical study, its objectives, possible benefits and risks, and its consequences will 
be verbally explained to the subject and/or his/her legally acceptable representative. 
Moreover, the subject and/or his/her legally acceptable representative is/are provided 
with written information about the clinical study. Sufficient time will be allowed for the 
information to be read and for questions to be asked. Attention should be paid to any 
signs of undue distress in pediatric subjects who are unable to clearly indicate their 
distress (ICH Harmonised Tripartite Guideline; E11 Step 4, 2000). The subject and/or 
his/her legally acceptable representative must be told that refusal to participate in the 
clinical study does not cause any disadvantages to their treatment; similarly, 
withdrawal of written informed consent/assent is possible at any time, without stating a 
reason, and without prejudice to further medical management. 
 
Subjects and/or his/her legally acceptable representative should be informed and 
should agree that medical data may be reviewed by authorized persons during 
monitoring and during an audit or an inspection by the appointed Regulatory Authority 
or Ethics Committee, but that personal data will be treated with absolute confidentiality. 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 26 of 82 
Upon request, the subject and/or his/her legally acceptable representative must be 
granted access to the insurance terms and conditions. 
 
Any new and relevant information that evolves during the course of the clinical study 
concerning the IMP, alternative treatments, or the benefit/risk ratio will be 
communicated to the subject and/or his/her legally acceptable representative. 
4.6 Declaration of Informed Consent/Assent 
The subject and/or - if applicable – his/her legally acceptable representative must have 
given written consent/assent to participate in the clinical study by signing and 
personally dating the informed consent form. For pediatric subjects who can only be 
enrolled in the study with consent of their parent(s) or legally acceptable 
representative, the subject will be informed about the study to the extent compatible 
with their understanding and, if capable, the subject will assent, write their name when 
applicable, sign, and personally date the written informed consent. Separate assent 
and consent forms will be provided for pediatric subjects and their parent(s) or legally 
acceptable representative. Informed consent/assent to the proposed data handling and 
to data inspection must also be documented in written form. Written informed 
consent/assent must be obtained from each subject or legally acceptable 
representative before any study-related procedures are performed. The subject’s 
and/or his/her legally acceptable representative’s written informed consent/assent will 
be filed at the investigator’s site. 
 
A duplicate of the signed and dated written informed consent/assent form must be 
handed over to the subject and/or – if applicable – his/her legally acceptable 
representative. 
5 INVESTIGATIONAL MEDICINAL PRODUCT 
5.1 Investigational Medicinal Product BT595 
5.1.1 Description of Investigational Medicinal Product BT595 
Substance code: 
BT595 
Active ingredients: 
 
Composition: 
 
 
 
Excipients: 
 
pH:  
 
Dosage form: 
Solution of 10 g human plasma protein per 100 mL for 
intravenous administration 
Concentration: 
100 mg/mL (10%) human plasma protein 
Container: 
Glass bottle (100 mL) 
Manufacturer: 
Biotest AG, 63303 Dreieich 
 
Batch number(s) and expiry date(s) are given in the applicable certificates of analysis. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 27 of 82 
5.1.2 Formulation, Packaging, and Labelling 
The dosage form of BT595 is a solution of 10 g human plasma proteins per 100 mL for 
intravenous administration in a 100 mL infusion bottle (glass). 
 
The labelling of BT595 will be performed according to local requirements. A sample 
label will be contained in the Trial Master File (TMF). 
 
Batch number(s) and bottle number(s) must be documented in the electronic case 
report form (eCRF) and the drug accountability log. 
5.1.3 Storage Conditions and Stability 
BT595 is to be stored in a cabinet or other enclosure which is security locked. 
Generally, access should be restricted to the investigator and authorized personnel. 
 
BT595 is to be stored and transported at a temperature between 2°C to 8°C and 
documented on a temperature log. BT595 will have the following instructions: Please 
keep in original packaging carton and Do not freeze. 
The expiry date for each batch will be given on the bottle label/outer carton and the 
Certificate of Analysis. 
5.1.4 Preparation for Use 
The product should be brought to room or body temperature before use (may take 
approximately 15 minutes). The solution should be administered immediately after 
opening the receptacle. The solution should be clear to slightly opalescent. Solutions 
that are cloudy or have deposits are not to be used. Bottles are for single use only. 
BT595 should not be mixed with any other product. 
6 STUDY TREATMENT 
6.1 Dosage Regimen 
BT595 will be administered at 3- or 4-week intervals for a treatment period of 
approximately 12 months. The initial dose and dosage intervals must be consistent 
with the subject’s prestudy IVIg treatment and the initial dose and dosage interval will 
only be changed if medically indicated. This change will be at the investigator’s 
discretion. 
6.2 Dosage and Administration 
The planned dose of BT595 is 0.2 to 0.8 g/kg body weight (bw; 2 to 8 mL/kg) 
administered as intravenous infusions at 3- or 4-week intervals for a treatment period 
of approximately 12 months. 
 
Infusion rate: BT595 should be infused intravenously at an initial rate of 0.3 mL/kg/h 
for 30 minutes, to be increased to 1.4 mL/kg/h for a further 30 minutes. If well tolerated, 
the rate of administration may then be gradually increased to a maximum of 
2.0 mL/kg/h for the remainder of the first infusion. Every infusion must start again at an 
initial rate of 0.3 mL/kg/h. From the second infusion, in subjects who have tolerated the 
infusion rate of 2.0 mL/kg/h well, the rate may be gradually increased to 4 mL/kg/h, and 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 28 of 82 
if still tolerated well, it may be further increased gradually to 6 mL/kg/h, and to a 
maximum of 8 mL/kg/h.  
 
From the second infusion, subjects’ infusion rates may be individually tailored (i.e., a 
certain infusion rate for a certain time period) at the discretion of the investigator, but 
must start again at an initial infusion rate of 0.3 mL/kg/h. This means that the 30 minute 
interval may be shortened to less than 30 minutes if deemed appropriate for the 
subject. Changes in infusion rates (increases and/or decreases) and the respective 
time of day must be documented.  
 
In case of a decrease in infusion rate or an interruption of infusion as a consequence of 
an AE, all AE details must be recorded in the eCRF. 
6.2.1 Dose Changes during the Study 
The subject’s total IgG trough levels from the previous infusion will be assessed at the 
local laboratory to allow dose adjustment at the next infusion if a subject’s trough level 
was below 5 g/L. Serum trough levels of IgG ≥5 g/L must be met throughout the study. 
If a subject’s IgG level changes to <5 g/L, the subject’s dose must be adjusted to meet 
the target trough levels. Dose changes will be made at the investigator’s discretion and 
must follow the dosage regimen detailed in Section 6.2 (i.e., 0.2 to 0.8 g/kg bw [2 to 
8 mL/kg] administered as intravenous infusions at 3- or 4-week intervals). 
 
Body weight will be assessed before each study infusion in order to calculate an 
accurate dose for each subject’s dose infusion. The investigator will calculate the 
percentage change in the subject’s body weight since the last assessment. If a 
subject’s body weight changes by <5% from the weight used for the current dose, the 
total dose will remain the same as the current dose. If a subject’s body weight changes 
by ≥5% from the weight used for the current dose, the total dose (g), but not the dose 
per weight (g/kg), will be adjusted accordingly to maintain a constant dose in 
g/kg/infusion during the study. 
 
Any changes in dose and the reason for the change in dose will be recorded in the 
eCRF. 
6.3 Compliance with Dosage Regimens 
BT595 will be administered intravenously by the instructed study staff. If a subject’s 
treatment deviates from the dosage regimen (e.g., a dosing interruption occurs due to 
the occurrence of an AE), this will be recorded in the eCRF (Section 6.2). 
 
If a subject fails to comply with the dosage regimen (i.e., misses ≥1 dose[s] of BT595), 
the subject will be considered to be noncompliant and may be terminated prematurely 
from the study. The decision to terminate a subject from the study prematurely will be 
at the investigator’s discretion after consultation with the sponsor. Details of any 
deviations from the dosage regimen will be recorded in the eCRF. 
6.4 Dose Justification 
The planned monthly dose of BT595 is in the range of 200 to 800 mg/kg bw (2 to 
8 mL/kg bw) in 3- or 4-week intervals for a treatment period of approximately 
12 months. This schedule follows the recommendation in the EU-Core Summary of 
Product Characteristics (SmPC) for human normal immunoglobulin for intravenous 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 29 of 82 
administration 
as 
replacement 
therapy 
in 
subjects 
with 
PID 
(EMA/CHMP/BPWP/94038/2007 rev. 4, 2012). 
 
Accordingly, the dose and dosage interval must be consistent with the subjects’ 
prestudy standard IVIg treatment and only changed if medically indicated. The dose 
needs to be individualized for each subject depending on the subject’s total IgG trough 
levels (the dose may need to be adjusted to meet target subject trough levels 
[measured before the next infusion] of ≥5 g/L). 
 
The infusion rate is planned to be escalated from 0.3 mL/kg/h to a maximum of 
8 mL/kg/h, initially at 30 minute intervals. Although no clinical studies have previously 
been conducted with BT595, it is expected from previous experience with Intratect that 
a relevant proportion of subjects will tolerate this escalation procedure up to an 
individually determined maximum tolerated infusion rate. The use of premedications to 
prevent AEs should be avoided in this study, if possible (Section 6.10). 
 
In the clinical study conducted with Intratect at 100 g/L (Study 981; Krivan et al, 2015), 
subjects with PID received Intratect at the established dose and dosing interval of their 
previous reference IVIg therapy. The study was designed to gradually escalate infusion 
rates from 0.3 to 1.4 mL/kg/h to 2.0 mL/kg/h (in Part A; 30 subjects) to 0.3 to 
1.4 mL/kg/h to 4.0 mL/kg/h to a maximum of 8.0 mL/kg/h (in Part B; 25 subjects). Of 
the 25 subjects treated in Part B, 16 subjects (64.0%) achieved an individual maximum 
tolerated infusion rate of 6.0 or 8.0 mL/kg/h at their 4th infusion and only 4 subjects 
(16%) had individual maximum tolerated rates of <4.0 mL/kg/h. The 30 subjects in the 
study (Part A and Part B) received a total of 165 infusions of Intratect, where a total of 
19 infusions (11.5%) were associated with ADRs. Overall, 5 subjects (20%) in Part B 
experienced AEs limiting the infusion rate (all were nonserious). Three subjects 
reported SAEs in the study, but none were related to treatment with Intratect. 
 
This study demonstrated that escalation of infusion rates leads to the identification of 
an individual’s maximum tolerated infusion rate, which is well-tolerated and safe when 
administered at subsequent infusions. The identification of an individual’s maximum 
tolerated infusion rate allows PID patients and their physicians to choose an infusion 
rate that shortens the duration of infusion (higher infusion rates reduce the time 
required for infusions). Shorter infusion times reduce the time PID patients spend 
receiving their IVIg treatment, reducing the burden of this condition on these chronically 
ill patients, and lowering the demand for healthcare resources. 
 
Infusion rates of up to approximately 8.0 mL/kg/h have been shown to be tolerated for 
other 10% IVIgs: Bivigam (Wasserman et al, 2012), Gamunex (Gelfand and Hanna, 
2006), Kiovig (Björkander et al, 2006), and Privigen (Stein et al, 2009).  
 
Thus, the administration of BT595 at infusion rates currently recommended for Intratect 
is expected to demonstrate an acceptable tolerability compared to similar marketed 
IVIgs.  
6.5 Treatment of Overdose 
Based on the dosage recommendations in the EU-Core SmPC for human normal 
immunoglobulin 
for 
intravenous 
administration 
(EMA/CHMP/BPWP/94038/2007 
rev. 4, 2012), an IVIg dose of more than 2 g/kg is considered to be an overdose in this 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 30 of 82 
indication. However, within this PID study design, where doses of 0.2 to 0.8 g/kg are 
recommended for this indication, any dose ≥0.9 g/kg will be reported as an overdose. 
 
BT595 will be administered intravenously by the instructed study staff; however, in the 
case of accidental overdose, subjects should be monitored closely for signs of adverse 
reactions. Overdose may lead to fluid overload and hyperviscosity, particularly in 
subjects at risk, including elderly subjects or subjects with renal impairment. 
 
Any overdose event will be reported as an AE that must be reported to the sponsor 
within 24 hours of the study site being aware of the AE (i.e., overdose is an 
immediately reportable adverse event [IRAE]; Appendix 2). 
6.6 Randomization Code 
This is a nonrandomized, open-label clinical study; therefore, no randomization code is 
required. 
6.7 Procedures for Emergency Unblinding 
This is a nonrandomized, open-label clinical study; therefore, no procedure for 
unblinding is required. 
6.8 Drug Accountability 
The IMP will be supplied to the investigator at the time of site initiation under the 
assumption that all required regulatory documents are in place. The investigator or 
his/her designee should maintain records that document adequately that the subjects 
were provided the doses specified in the protocol and reconcile all IMPs received for 
the clinical study. The investigator has to ensure that consignments of IMPs are 
received correctly by a dedicated person (e.g., pharmacy) and that the IMP is safely 
and appropriately handled and stored. 
 
The investigator or designee is obliged to keep sufficient documentation of the delivery, 
use, and destruction or return of unused, used, or partially used packages of IMP. The 
investigator must allow the monitor to perform drug reconciliation before any IMP is 
returned or destroyed. The documentation must include dates, quantities, subject 
numbers, batch numbers or other identification numbers, and expiry dates. 
 
The entries in the eCRF as well as the documentation kept in the Investigator Site File 
will be compared with the returned and residual IMPs, with clarification of any 
discrepancies or inconsistencies. 
6.9 Previous and Concomitant Medication or Treatment 
6.9.1 Previous Medication or Treatment 
Previous Established Replacement Therapy 
Before the subject enters the study, the subject must have been on an established 
replacement therapy with any IVIg reference preparation for at least the previous 
6 months. Before treatment starts with BT595 in a 3- or 4-week schedule, the subject 
must have been on an established replacement therapy with a single IVIg reference 
preparation for at least 3 months. The single IVIg reference preparation must have 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 31 of 82 
been at a constant dose that did not change by ±20% of the mean dose, at regular 
dosage intervals. This information will be assessed at the initial visit and at the baseline 
visit (Day 1) to ensure the subject meets criteria for study entry and this information will 
be documented in the eCRF. 
 
Other Previous Medications or Treatments 
In case of blood-derived medications (i.e., administration of blood or blood products), 
documentation will be required for a period of 3 months before inclusion in the study. 
 
Administration of all medication in the 4 weeks before enrollment will be documented in 
the eCRF. 
6.9.2 Concomitant Medication or Treatment 
Concomitant medication (other than immunoglobulins) may be taken as required. All 
routine concomitant medication should be given after information of/consultation with 
the investigator (i.e., the subject will be instructed to inform the investigator before 
taking any concomitant medications). In case of concomitant medication given for 
emergency reasons, the investigator should be informed as soon as possible. 
 
Full details of any concomitant medication given during the study, including the time of 
its discontinuation, if applicable, will be documented in the eCRF. Changes of therapy 
(including changes in regimen) during the study will be recorded in the eCRF and in the 
subject’s medical record. 
 
For any concomitant medication (including any change in dose) given as treatment for 
a new or worsened condition after the first infusion of study treatment, the investigator 
will record the condition as an AE in the eCRF. 
6.10 Prohibited Medication or Treatment 
If not required by an emergency situation, passive or active immunizations, 
administration of plasma preparations, or administration of other immunoglobulins is 
not allowed during the study. In such instances, the subject will be withdrawn from the 
study. 
 
Subjects who are prone to AEs occurring in conjunction with the infusion of IVIg 
products are often premedicated with antihistamines, antipyretics, and/or steroids. In 
this study, however, the use of premedications should be avoided (if possible), except 
in cases where such premedication is important to the safety of the study subject. The 
use of any premedication must be approved by the principal investigator before use 
and recorded in the concomitant medication record in the eCRF. 
6.11 Warnings and Precautions 
The safety profile of BT595 is expected to be comparable to Intratect (100 g/L; a 10% 
IVIg marketed in the EU and international markets), Bivigam (a 10% IGIV marketed in 
the United States), and other 10% IVIgs on the market. For further details, see the 
Investigator’s Brochure.  
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 32 of 82 
Safety With Respect to Transmissible Agents 
Standard measures to prevent infections resulting from the use of medicinal products 
prepared from human blood or plasma will include selection of donors, screening of 
individual donations and plasma pools for specific markers of infection, and the 
inclusion of effective manufacturing steps for the inactivation/removal of viruses. 
Despite this, when medicinal products prepared from human blood or plasma are 
administered, the possibility of transmitting infective agents cannot be totally excluded. 
This also applies to unknown or emerging viruses and other pathogens. 
 
The measures taken are considered effective for enveloped viruses such as HIV, 
hepatitis B virus, and hepatitis C virus (HCV). The measures taken may be of limited 
value against nonenveloped viruses such as hepatitis A virus and parvovirus B19. 
 
There is reassuring clinical experience regarding the lack of hepatitis A or 
parvovirus B19 transmission with immunoglobulins and it is also assumed that the 
antibody 
content 
makes 
an 
important 
contribution 
to 
the 
viral 
safety 
(EMA/CHMP/BPWP/94033/2007 rev. 2, 2010). 
7 COURSE OF THE CLINICAL STUDY 
7.1 Visit Schedule 
Screening Visit (Visit 1, Week -4 to 0, Day -28 through Day 0) 
All subjects will attend a screening visit up to 4 weeks before the first BT595 infusion, 
where the following procedures will be performed: 
 
• Written informed consent/assent will be obtained. 
• Demographic data (including gender, date of birth [for calculation of age; 
note: age will be the age recorded at screening], ethnic origin, height, and 
body weight) will be recorded. 
• Medical and surgical history with regard to the subjects’ drug history, 
previous medication, disease (i.e., PID) history, and other medical and 
surgical history will be recorded. Previous medication data up to 4 weeks 
before enrollment will be recorded, with the exception of data on the 
subject’s established replacement therapy (at least 6 months before study 
enrollment) and data on blood-derived medication (i.e., administration of 
blood or blood products; at least 3 months before study enrollment). The type 
of previous medication, dose schedule, duration, and the indication the 
previous medication was given for will be documented. An x-ray may be 
performed at any time throughout the study to evaluate new observations 
against baseline findings, if medically indicated, and to confirm diagnostic 
criteria for acute serious bacterial infections. This is not applicable for 
Germany. (Note: if the subject has recently had an x-ray taken [i.e., within 
the last 3 months before study start], this result may be considered as 
baseline data). 
• Eligibility to take part in the study will be assessed against the inclusion and 
exclusion criteria. 
• A physical examination will be performed. 
• Vital signs (pulse, blood pressure, temperature, respiratory rate) will be 
recorded. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 33 of 82 
• A serum pregnancy test (human chorionic gonadotropin) will be performed 
for all female subjects of child-bearing potential (≥12 years of age or 
presence of menstruation at screening). 
• Samples for routine safety laboratory parameters (hematology, coagulation, 
clinical chemistry, urinalysis) will be taken. 
• Samples for intravascular hemolysis laboratory parameters (including 
Coombs’ test, haptoglobin, hemoglobin, hemosiderin) will be taken. 
• Retention samples for viral safety laboratory parameters will be taken. 
• Samples for virus serology laboratory parameters (hepatitis B, hepatitis C, 
HIV) will be taken. 
• Samples for IgG trough levels (total IgG) will be taken. 
 
Baseline Visit (Visit 2, Week 0, Day 1) 
All subjects will attend a baseline visit on Day 1, where the following assessments will 
be performed 3 or 4 weeks (depending on the subject’s treatment schedule) after the 
last infusion of the subject’s previous IVIg replacement therapy and before the 
subject’s first BT595 infusion (unless indicated): 
 
• Any changes in medical and surgical history with regard to the subjects’ drug 
history, previous medications, disease (i.e., PID) history, and other medical and 
surgical history since the screening visit will be recorded. The type of previous 
medication, dose schedule, duration, and the indication the previous medication 
was given for will be documented. (Note: if the subject has recently had an x-ray 
taken [i.e., within the last 3 months before study start], this result may be 
considered as baseline data). 
• Eligibility to take part in the study will be confirmed against the inclusion and 
exclusion criteria, as appropriate (i.e., diagnostic tests will be repeated at the 
investigator’s discretion). 
• A physical examination will be performed. 
• Vital signs (pulse, blood pressure, respiratory rate) will be recorded within 
30 minutes before the infusion, 15-30 minutes after the start of infusion, 
15-30 minutes after the end of infusion, and 15-30 minutes after the start of any 
change in the infusion rate. Temperature will only be recorded within 30 minutes 
before the infusion. 
• Body weight will be recorded (to calculate subject dose). 
• A urine pregnancy test (dipstick) will be performed for all female subjects of 
child-bearing potential (≥12 years of age or presence of menstruation at 
screening). 
• Samples for routine safety laboratory parameters (hematology, coagulation, 
clinical chemistry, urinalysis) will be taken.  
• An additional sample for routine safety laboratory parameters (hematology, 
coagulation, clinical chemistry, urinalysis) will be taken at the end of the first 
BT595 infusion. 
• Samples for IgG trough levels (total IgG) will be taken.  
• An additional sample for total IgG will be taken at the end of the first BT595 
infusion. 
• Samples for IgG trough levels (IgG subclasses 1-4) will be taken (with the 
exception of pediatric subjects [2-5 years, inclusive]). 
• Samples for IgG trough levels (specific antibody levels) will be taken (with the 
exception of pediatric subjects [2-11 years, inclusive]). 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 34 of 82 
• A subject diary (paper) will be dispensed. Full instructions on how to complete 
the paper diary (including information on how to identify and document AEs) will 
be given. Subject diaries will include a record of the following: occurrence of 
AEs (including infections), concomitant medication use (including antibiotic 
treatment), days lost from school/work due to infections and their treatment, any 
hospitalization, and the number of days in hospital. 
• Health-related quality-of-life assessment will be performed. 
• BT595 will be infused intravenously. 
• Concomitant medications (including prohibited treatments) will be recorded. The 
type of concomitant medication, dose/schedule, duration, and the indication the 
concomitant medication was given for will be documented. 
• Adverse events will be recorded. 
 
Treatment Period Visits (Visit 3 through Visit 19, Week 3 through Week 51 
[3-Week Schedule] or Visit 3 through Visit 15, Week 4 through Week 52 [4-Week 
Schedule]) 
Subjects will attend the study site for a further 17 visits (3-week schedule) or 13 visits 
(4-week schedule). All assessments will be carried out before BT595 infusion, unless 
indicated. The following procedures will be performed at each study site visit: 
 
• A physical examination will be performed. 
• Vital signs (pulse, blood pressure, respiratory rate) will be recorded within 
30 minutes before each infusion, 15-30 minutes after the start of each infusion, 
15-30 minutes after the end of each infusion, and 15-30 minutes after the start 
of any change in the infusion rate. In any case where the change in infusion rate 
is sooner than a 15 minute interval, vital signs should be measured prior to the 
change. 
• The vital sign, temperature, will be recorded within 30 minutes before each 
infusion only. 
• Body weight will be recorded (to calculate subject dose). 
• A urine pregnancy test (dipstick) will be performed for all female subjects of 
child-bearing potential (≥12 years of age or presence of menstruation at 
screening). 
• Samples for routine safety laboratory parameters (hematology, coagulation, 
clinical chemistry, urinalysis) will be taken.  
• Samples for IgG trough levels (total IgG) will be taken. The subject‘s total IgG 
trough level result from the previous infusion will be made available before the 
infusion of BT595 to allow dose adjustment if a subject’s trough level was below 
5 g/L. 
• A subject diary (paper) will be collected and reviewed. 
• A subject diary (paper) will be dispensed. 
• Health-related quality-of-life assessment will be performed. 
• Concomitant medications (including prohibited treatments) will be recorded. The 
content of the subjects’ diaries will be reviewed and the type of concomitant 
medication, dose/schedule, duration, and the indication the concomitant 
medication was given for will be documented. 
• Adverse events will be recorded. The content of the subjects’ diaries will be 
reviewed and AEs will be documented. 
• BT595 will be infused intravenously. 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 35 of 82 
Pharmacokinetic Sampling (From Week 18 [3-Week Schedule] or From Week 16 
[4-Week Schedule]) 
Serial sampling for PK analysis of total IgGs, IgG subclasses 1-4, and IgG specific 
antibody 
levels 
(anti-pneumococcal 
capsular 
polysaccharide, 
anti-hemophilus 
influenzae 
type B, 
anti-measles, 
anti-tetanus, 
anti-cytomegalovirus, 
and 
anti-HBs/hepatitis B) will be made at estimated steady-state after the 7th infusion of the 
3-week schedule (Week 18) or after the 5th infusion of the 4-week schedule 
(Week 16). The number of blood draws (and the amount of blood per sample) will be 
dependent on the subject’s age category.  
 
For adult subjects (18-75 years, inclusive) and pediatric subjects (6-17 years, 
inclusive), samples will be taken at a fixed series of time points. Note: samples for 
IgG specific antibody levels will be taken from pediatric subjects aged 12 through 
17 years only. Samples for all analytes will be taken as 1 aliquot. Subjects (6-75 years, 
inclusive) will have 8 or 9 PK blood samples taken (according to treatment schedule): 
 
• 10 to 30 minutes before the infusion (note: this sample is the same sample as 
that taken for the trough levels of IgG subclasses 1-4 and IgG specific antibody 
levels before the 7th/5th infusion of the 3-week/4 week-schedule, respectively.) 
• 10 to 30 minutes postinfusion (end of infusion sample) 
• 4 hours (±1 hour) postinfusion 
• 24 hours (±1 hour) postinfusion 
• 4 days (±1 day) postinfusion 
• 7 days (±1 day) postinfusion 
• 14 days (±1 day) postinfusion 
• 21 days (±1 day) postinfusion for trough IgG levels for all subjects (6-75 years, 
inclusive) both, in the 3-week treatment schedule and in the 4-week treatment 
schedule. This sample must be taken before the next infusion of BT595 for 
subjects in the 3-week treatment schedule. 
• 28 days (±1 day) postinfusion for trough IgG levels for all subjects (6-75 years, 
inclusive) in the 4-week treatment schedule only. This sample must be taken 
before the next infusion of BT595. 
 
For pediatric subjects (2-5 years, inclusive), sparse sampling for total IgG only may be 
performed at flexible time points within specified time windows after the end of this 
infusion. Pediatric subjects (2-5 years, inclusive) will have up to 5 PK blood samples 
taken (note: these samples are optional): 
 
• 10 to 30 minutes before the infusion 
• 10 to 30 minutes postinfusion (end of infusion sample) 
• 6 hours (±1 hour) postinfusion or 24 hours (±1 hour) postinfusion 
• 7 days (±1 day) postinfusion or 14 days (±1 day) postinfusion 
• 21 days (±1 day) postinfusion for trough IgG levels for subjects in the 3-week 
treatment schedule only. This sample must be taken before the next infusion of 
BT595. 
• 28 days (±1 day) postinfusion for trough IgG levels for subjects in the 4-week 
treatment schedule only. This sample must be taken before the next infusion of 
BT595. 
 
A homecare service is allowed for the PK sampling of pediatric subjects (2-17 years, 
inclusive). 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 36 of 82 
Closing (Follow-up) Visit (Visit 20, Week 54 [3-Week Schedule] or Visit 16, 
Week 56 [4-Week Schedule]) 
A closing (follow-up) visit will be performed 3 or 4 weeks after the last infusion, 
according to the subject’s treatment schedule, and the following procedures will be 
performed: 
 
• A physical examination will be performed. 
• Vital signs (pulse, blood pressure, temperature, respiratory rate) will be 
recorded. 
• A urine pregnancy test (dipstick) will be performed for all female subjects of 
child-bearing potential (≥12 years of age or presence of menstruation at 
screening). 
• Samples for routine safety laboratory parameters (hematology, coagulation, 
clinical chemistry, urinalysis) will be taken. 
• Samples for intravascular hemolysis laboratory parameters (including Coombs’ 
test, haptoglobin, hemoglobin, hemosiderin) will be taken. 
• Retention samples for viral safety laboratory parameters will be taken. 
• Samples for IgG trough levels (total IgG) will be taken. 
• A subject diary (paper) will be collected and reviewed. 
• Health-related quality-of-life assessment will be performed. 
• Concomitant medications (including prohibited treatments) will be recorded. The 
content of the subjects’ diaries will be reviewed and the type of concomitant 
medication, dose/schedule, duration, and the indication the concomitant 
medication was given for will be documented. 
• Adverse events will be recorded. The content of the subjects’ diaries will be 
reviewed and AEs will be documented. 
 
Further details on the visit schedule that will be used for the assessment of the 
efficacy, safety, and PK parameters in this study are presented in Section III, Flowchart 
of Study. A time window of ±2 days will be allowed for the treatment period visits and 
the closing (follow-up) visit; however, this time window will not apply for the PK 
assessments. Pharmacokinetic assessments will follow the time point specific time 
windows. 
7.2 Duration of the Clinical Study 
First Subject in (planned) 
June 2016 
Last Subject Last Visit (planned) 
November 2019 
 
Individual Subject 
Each subject will be administered BT595 at 3- or 4-week intervals for a treatment 
period of approximately 12 months. In addition, each subject will attend a closing 
(follow-up) visit 3 or 4 weeks after the last BT595 infusion, according to the subject’s 
treatment schedule. 
 
A subject is considered to have completed the study when he/she is presumed to have 
followed the protocol (i.e., completed visits up to the end of Week 51 [3-week schedule] 
or up to the end of Week 52 [4-week schedule]). If for any reason, a subject 
discontinues involvement in the study early, every effort should be made to ensure the 
subject attends a closing (follow-up) visit (Section 4.4). 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 37 of 82 
7.2.1 End of Study 
The end of the clinical study will be defined as the Last Visit of the Last Subject. 
7.3 Criteria for Premature Termination 
7.3.1 Premature Termination of the Entire Clinical Study 
The clinical study as a whole may be stopped by Biotest after consultation with the 
coordinating investigator if there are reasons for which continuation of the clinical study 
is no longer justified, such as: 
a) Unacceptable delay of study completion 
b) Low recruitment rate 
c) A large number of subjects with premature termination 
d) Changed benefit-risk ratio according to the efficacy and/or safety results from this or 
parallel studies 
e) Lack of efficacy 
f) Recently emerged information suggest that the study population can be offered a 
more advantageous study design 
 
For sites in Europe, in case of premature termination of the entire clinical study, the 
sponsor has to notify the appropriate Regulatory Authorities within 15 days. 
 
For sites in the US, in case of premature termination of the entire clinical study, the 
investigator has to notify the appropriate Regulatory Authorities promptly. 
7.3.2 Premature Termination of an Individual Study Site 
The clinical study may be stopped at an individual study site for reasons such as: 
a) Determination of unexpected, significant, or unacceptable risk to subjects 
b) Low recruitment rate 
c) Lack of cooperation 
d) Severe deviations from study protocol 
e) Manipulation of study data 
f) Violation of other ethical or legal principles 
 
The participation of subjects may be stopped following guidance from the DSMB 
(Section 9.4). The DSMB Charter will include a description of stopping rules for the 
participation of subjects. 
7.4 Treatment and Care after the End of the Study 
For subjects who have finished the clinical study and for all subjects who drop out 
prematurely, it is the responsibility of the investigator to choose adequate therapeutic 
measurements. 
8 BENEFIT-RISK EVALUATION 
8.1 Benefit 
The principal benefit for the participating PID subjects will be to receive the required 
immunoglobulin replacement therapy and thereby the antiinfective effect of BT595, 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 38 of 82 
i.e. to prevent infections by substituting missing antibodies. Moreover, the participating 
PID subjects’ quality of life will improve via the smaller infusion volume and shorter 
infusion duration feasible with BT595 (compared to a 5% IVIg), which will allow 
subjects to potentially experience a shorter stay in hospital or other health care facility. 
 
Based on the extensive clinical experience with Intratect (50 g/L and 100 g/L) and the 
expected comparability of the safety profile between Intratect (100 g/L) and BT595, it is 
estimated that BT595 will show an acceptable safety profile even at the scheduled 
increased infusion rates. 
8.2 Foreseeable Risk and Discomfort Related to BT595 
Adverse Drug Reactions to be Expected with BT595 
The identified risks for BT595 have been derived from the well-established safety 
profiles of Bivigam (licensed in the United States) and Intratect (50 g/L and 100 g/L; 
licensed in the EU and international markets); the EU-Core SmPC for IVIgs 
(EMA/CHMP/BPWP/94038/2007 
rev. 4, 2012); 
and 
EMA 
guidance 
(EMA/CHMP/BPWP/94033/2007 rev. 2, 2010). 
 
The following identified risks are considered to be expected ADRs for BT595 during the 
clinical study program: 
 
• Thromboembolic events, including myocardial infarction, stroke, pulmonary 
embolism, and deep vein thrombosis; 
• Hypersensitivity 
reactions 
(anaphylactoid 
and 
anaphylactic, 
including 
anaphylactic shock, chills, headache, dizziness, fever, vomiting, allergic 
reactions, nausea, arthralgia, low blood pressure, and moderate low back pain; 
and transient cutaneous reactions); 
• Aseptic meningitis; 
• Hemolysis; 
• Acute renal failure, increased serum creatinine; 
• Leukopenia/neutropenia. 
 
Foreseeable discomfort may result from blood samples taken from each subject during 
the course of the study for the assessment of exclusion criteria, laboratory parameters, 
viral safety (retention samples), immunoglobulin G trough levels, specific antibody 
trough levels, and PK parameters. The puncture of a vein and/or placement of 
indwelling catheters for blood withdrawal may cause pain and occasionally result in 
thrombosis or thrombophlebitis. Discomfort may also be caused by intravenous 
infusion of BT595. 
8.3 Other Sources of Possible Risk and Discomfort 
The following additional possible risks for BT595 have also been derived from the 
well-established safety profiles of Intratect (50 g/L and 100 g/L; licensed in the EU and 
international markets) and Bivigam (licensed in the United States); the EU-Core SmPC 
for 
IVIgs 
(EMA/CHMP/BPWP/94038/2007 
rev. 4, 2012); 
and 
EMA 
guidance 
(EMA/CHMP/BPWP/94033/2007 rev. 2, 2010). 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 39 of 82 
The following possible risks are considered relevant, but unexpected, for BT595 during 
this clinical study program: 
 
• Suspected transmission of pathogen infection (infective agents) 
• Interference of IVIg (interaction) with live-attenuated virus vaccines 
• Transfusion-related acute lung injury (TRALI) 
• Interference with serological testing by passively-transferred antibodies of IVIg. 
 
To minimize the potential risk of transmission of infective agents, standard 
measures are established to prevent infections resulting from the use of medicinal 
products prepared from human blood or plasma. These include the selection of donors, 
screening of individual donations and plasma pools for specific markers of infection, 
and the inclusion of effective manufacturing steps for the inactivation/removal of 
viruses. Despite this, when medicinal products prepared from human blood or plasma 
are administered, the possibility of transmitting infective agents cannot be totally 
excluded. This also applies to unknown or emerging viruses and other pathogens. 
 
Interference 
(interaction) 
of 
IVIgs 
with 
live-attenuated 
virus 
vaccines: 
Immunoglobulin administration may impair, for a period of at least 6 weeks and up to 
3 months, the efficacy of live-attenuated virus vaccines (such as measles, rubella, 
mumps, and varicella). After administration of this medicinal product, an interval of 
3 months should elapse before vaccination with live-attenuated virus vaccines. In the 
case of measles, this impairment may persist for up to 1 year. Therefore, subjects 
receiving measles vaccine should have their antibody status checked. The foreign 
antibodies administered with IVIg could suppress a sufficient antibody induction by the 
live-attenuated virus vaccine in the subject. 
 
Consequently, the above mentioned live-attenuated virus vaccines must not be 
administered during the respective time period. 
 
Transfusion-related acute lung injury (TRALI) is a very rare and serious blood 
transfusion complication characterized by the acute onset of noncardiogenic pulmonary 
edema following transfusion of blood products. Transfusion-related acute lung injury is 
typically associated with products from SINGLE donors, such as fresh frozen plasma, 
or of packed red blood cells due to the residual plasma present in the unit. The 
American Association of Blood Banks recommended on 03 NOV 2006 (in Association 
Bulletin #06-07) that blood banks use high plasma volume components from female 
donors for further manufacturing instead of transfusion due to the higher risk of TRALI. 
In the company’s opinion at present, no risk is seen for polyvalent immunoglobulins 
with manufacturing pool sized of more than 2000 donors. The reason for keeping it in 
this section is a class-label established in the United States. 
 
Regarding the interference with serological testing by passively-transferred 
antibodies of IVIg, this risk can be considered in many cases as mild to moderate, and 
is spontaneously resolving. 
8.4 Summary of Possible Risk and Discomfort 
A single dose toxicity study is being performed in rats. The results are not yet available. 
 
Of the possible risks associated with the administration of IVIgs in humans 
(Section 8.3), the risk of transmission of infective agents is considered to be controlled 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 40 of 82 
by the manufacturing process, which includes several process-steps for the removal of 
bacteria, viruses, and other infective agents 
 
The possible risk of interference (interaction) of IVIgs with live-attenuated virus 
vaccines will be prevented by the respective exclusion criterion (Section 4.3). 
 
At present, there is considered to be no risk of TRALI in subjects with PID who are on a 
long-term low dose treatment regimen if the IVIg is manufactured from a sufficiently 
sized donor pool. 
 
The possible risk of interference with serological testing by passively transferred 
antibodies of IVIg, if relevant, will be assessed by virus serology control. 
 
No clinical studies in humans have previously been performed with BT595. However, 
BT595 as a 10% IVIg is expected to have a comparable safety profile to Intratect 
(100 g/L) and Bivigam, where favorable benefit-risk profiles have been established. In 
addition, the subjects eligible for this study will have been treated with an established 
replacement IVIg therapy for at least 6 months before inclusion in this study. So it is 
also predicted that similar ADRs will be observed under treatment with BT595 as with 
their previously established IVIg replacement therapy before study start. 
 
This study will assess infusion rates ranging from 0.3 mL/kg/h to 8 mL/kg/h for BT595. 
As this is the same infusion rate range that is currently recommended for Intratect at 
100 g/L, it is expected that BT595 at infusion rates up to 8 mL/kg/h will result in similar 
ADR frequencies and severities of ADRs as those observed with Intratect at 100 g/L. It 
is well known that the risk of hypersensitivity reactions, such as chills, headache, 
dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure, 
back pain, and transient cutaneous reactions increases with increased infusion rates 
(EMA/CHMP/BPWP/94033/2007 rev. 2, 2012), and as such, these types of 
anaphylactoid ADRs are expected in this study. 
 
No change of the risk profile under treatment with BT595 is expected for subjects 
already being treated with other approved 10% polyvalent immunoglobulins at higher 
infusion rates. The occurrence of AEs which interfere significantly with the subjects’ 
physical wellbeing or social activity during or after the testing period is not expected; 
however, cannot be excluded as a possibility. 
 
The frequency, type, and severity of ADRs in the pediatric population are expected to 
be the same as in adults. A DSMB will be used to review the safety data of at least 
10 adult subjects (18-75 years, inclusive) who have received at least 2 infusions with 
no safety concerns (Section 9.4), and will provide recommendations on the suitability of 
the enrollment of pediatric subjects into the study. 
 
Although risks in general cannot be excluded entirely, the potential to occur can be 
minimized by the careful selection of subjects and by their close surveillance by 
experienced investigators who recognize safety issues early by carefully surveying 
warning signs and taking appropriate corrective action in case of AEs. 
 
The potential risks and discomfort to the individual subject are reasonably balanced by 
the relevance of the study. Under the conditions of the study as described in the 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 41 of 82 
present protocol, the coordinating investigator and the sponsor consider the benefit-risk 
ratio to be favorable. 
9 ASSESSMENT OF OBJECTIVES/CRITERIA FOR EVALUATION 
9.1 Efficacy 
9.1.1 Specification of Efficacy Parameters 
9.1.1.1 Primary Efficacy 
The primary efficacy parameter is determined from the rate of acute serious bacterial 
infections per subject-year. 
 
Data will be compared to historical data from previous PID studies with Intratect and 
Bivigam, as well as to available data from literature. 
9.1.1.2 Secondary Efficacy 
Secondary efficacy will be determined using the following: 
• Immunoglobulin G trough levels (total IgG) before each infusion 
• Infections (serious and nonserious, time to resolution of infections, antibiotic 
treatment for infections, and days lost from school/work due to infections and 
their treatment) 
• Hospitalization 
• Fever episodes 
• Health-related quality-of-life 
9.1.2 Methods for Assessing and Recording Efficacy Parameters 
9.1.2.1 Primary Efficacy Parameter 
The number and type of acute serious bacterial infections will be determined through 
review of data collected on infections. Infections will be reported as AEs which will be 
obtained by the investigator through observation of the subject (including examinations 
and investigations), from any information volunteered by the subject, and through 
active questioning. Subject diaries will be reviewed to check for instances where the 
AE occurs and the subject is not on a site visit. Subjects will receive instructions from 
the investigator on how to record this information in their subject diary (paper) in ‘real 
time’ from the time they leave their current site visit until the next site visit, what steps 
to take if an AE occurs, and the action to be taken if an infection is suspected. If a 
subject suspects they have an infection between visits, the subject must inform the 
investigator as soon as possible. If the investigator confirms/suspects the subject has 
an infection, the subject must attend the site to be examined by the investigator. 
Subjects will be instructed to bring their subject diary to each study visit. During each 
scheduled visit, subjects will be asked about AEs occurring since their last visit and 
subject diaries will be collected and reviewed for any signs of AEs (infections) 
occurring between visits before IMP administration. Specific diagnostic criteria, as 
recommended by the FDA guidance (Appendix 3), will be used by the investigator to 
define each type of serious infection included in the primary efficacy analysis. 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 42 of 82 
Acute serious bacterial infections will include: 
 
• Bacteremia or sepsis 
• Bacterial meningitis 
• Osteomyelitis/septic arthritis 
• Bacterial pneumonia 
• Visceral abscess 
 
Essential diagnostic features are defined in the diagnostic criteria for acute serious 
bacterial infections recommended by the FDA guidance (Appendix 3). The infections 
must be documented by objective findings. If possible, blood for measurement of acute 
phase reactants should be obtained, but this is not an absolute requirement. If imaging 
procedures (i.e., x-rays) are taken to confirm diagnostic criteria for acute serious 
bacterial infections, data will be recorded in the eCRF. 
 
The investigator will confirm the date of onset of an episode of acute serious bacterial 
infection and record this in the eCRF. 
 
Details of all AEs defined as acute serious bacterial infections will be recorded in the 
subject’s eCRF. 
9.1.2.2 Secondary Efficacy Parameters 
Immunoglobulin G Trough Levels (Total IgG) 
Blood samples (approximately 7.5 mL) for the assessment of total IgG trough levels will 
be taken at the time points detailed in Section III, Flowchart of Study. Note: the 
approximate blood sample volumes are estimated, and as the samples will be tested 
by local laboratories, may differ from the approximate blood volumes detailed. 
 
Before each infusion of BT595, blood samples will be taken for the assessment of 
total IgG trough levels. Samples will be analyzed at the local laboratory using standard 
assay methods. During the treatment period, the subject’s total IgG trough level result 
from the previous infusion will be made available to the investigator before the next 
infusion of BT595. This is to allow dose adjustments to be made if the subject’s trough 
level fell below the specified level of 5 g/L. 
 
Infections and Infection-Related Events 
All infections and episodes of fever will be reviewed and recorded as described in 
Section 9.1.2.1. 
 
Infections (serious and nonserious) will be assigned using the most current version of 
the Medical Dictionary for Regulatory Activities (MedDRA®) and using the coding levels 
of system organ class and preferred term. The investigator will confirm the date of 
onset of infection and record this in the eCRF. The time to resolution of infection will be 
recorded by the subject in the subject diary and verified by the investigator. 
 
For each episode of infection, the subject must be examined by his/her investigator 
before initiation of antibiotic therapy. A record of antibiotic treatments will be reported in 
the subject’s diary. If a subject’s antibiotic treatment includes antipyretic treatment, the 
subject must also have their body temperature (before the antipyretic is taken) 
recorded in the subject diary. 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 43 of 82 
A record of the number of days a subject is not able to attend school or work due to the 
infection and the treatment of the infection will be reported in the subject’s diary. A 
record of any admission to hospital and the number of days in hospital will also be 
reported in the subject diaries. This record will include the hospitalization type 
(i.e., hospital admission or emergency room), the dates of the visit/admission, and the 
reason for the visit/admission. 
 
Fever is defined as a body temperature ≥38°C (≥100.4°F). Fever which recurs after 
≥3 days without fever will be counted as a new fever episode. The number of days of 
fever for a given fever episode is defined as the number of days from the first day of a 
body temperature ≥38°C (≥100.4°F) to the last day with a body temperature ≥38°C 
(≥100.4°F). 
 
Details of all AEs defined as infections or episodes of fever will be recorded in the 
subject’s eCRF. 
 
Health-Related Quality-of-Life 
The subjects’ health-related quality-of-life will be assessed using 2 subject 
questionnaires (Peds QL™ [PedsQL™ Measurement Model] and EQ-5D™ [EuroQol 
Five Dimension Health Questionnaire, 2015]) collected as patient reported outcomes 
(PROs) while the subject attends the investigator site for a visit. For pediatric subjects, 
the PROs may be completed by proxy (i.e., by the subjects’ parent[s] or legally 
acceptable representative). 
 
All pediatric subjects (2-17 years, inclusive) will complete the 23-Item Pediatric Quality 
of Life (Peds QL™) Measurement Model (Version 4.0). The Peds QL™ Measurement 
Model consists of developmentally appropriate forms for children aged 2 through 
4 years, 5 through 7 years, 8 through 12 years, and 13 through 18 years, and must 
include both child self-reports and parent proxy-reports, with the exception of children 
aged 2 through 4 years where only the parent proxy-report is required. The 
developmentally appropriate form will be selected based on the subject’s age recorded 
at screening (initial visit). The same age will be used per subject during the entire study 
and the same developmentally appropriate form will be used per subject during the 
entire study, even if the subject’s age indicates a change in form is required (i.e., if a 
subject’s age changes from 7 to 8 years during the study, they must complete the form 
for children aged 5 through 7 years during the entire study). The person completing the 
parent proxy-report should be constant for the duration of the subject’s study 
participation. The Peds QL™ Core Scales encompass the essential core domains for 
pediatric health-related quality-of-life measurement: physical functioning (8 items), 
emotional functioning (5 items), social functioning (5 items), and school functioning 
(5 items). In each domain, the person completing the form will be provided with a list of 
things which might be a problem for the subject and asked to respond with ‘how much 
of a problem’ each one is (i.e., 0 if it is never a problem, 1 if it is almost never a 
problem, 2 if it is sometimes a problem, 3 if it is often a problem, and 4 if it is almost 
always a problem). 
 
All adult subjects will rate their quality of life by self-completing the EQ-5D™ Health 
Questionnaire (Version 1.0). The EQ-5D™ essentially consists of 2 pages: the 
EQ-5D™ descriptive system page and the EQ visual analog scale (EQ VAS) page. The 
EQ-5D™ descriptive system comprises the following 5 dimensions: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each EQ-5D™ dimension has 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 44 of 82 
3 levels (EQ-5D-3L™): no problems, some problems, extreme problems. The EQ-5D™ 
EQ VAS records the respondent’s self-rated health on a vertical, visual analog scale 
where the endpoints are labelled ‘Best imaginable health state’ and ‘Worst imaginable 
health state’. 
 
In addition to the Peds QL™ Measurement Model, pediatric subjects (4-17 years, 
inclusive) will rate their quality of life by completing the youth version of the EQ-5D™ 
(EQ-5D-Y™; child self-report or proxy-report). The EQ-5D-Y™ consists of the same 
2 pages: the EQ-5D-Y™ descriptive system page and the EQ VAS page. The 
descriptive system comprises the same dimensions as the EQ-5D-3L™, but using 
child-friendly wording (mobility; looking after myself; doing usual activities; having pain 
or discomfort; and feeling worried, sad, or unhappy) and has 3 levels: no problems, 
some problems, and a lot of problems. The EQ VAS endpoints are labelled ‘The best 
health you can imagine’ and ‘The worst health you can imagine’. A proxy version of the 
form will be used for children aged 4 through 7 years. All other pediatric subjects 
(8-17 years, inclusive) will self-complete the EQ-5D-Y™. 
9.1.3 Specification of Efficacy Endpoints 
9.1.3.1 Primary Efficacy 
• Rate of acute serious bacterial infections (i.e., the mean number of acute serious 
bacterial infections per subject-year) 
9.1.3.2 Secondary Efficacy 
• IgG trough levels (total IgG) before each infusion 
• Rate of any infections (number per year) 
• Rate of nonserious infections (number per year) 
• Time to resolution of infections 
• Antibiotic treatment (number of days antibiotic treatment received per month) 
• Rate of time lost from school/work due to infections (number of days per month) and 
their treatment (number of days treatment per month) 
• Hospitalization (number of days per month overall and due to infection) 
• Fever episodes (number of days per year) 
• Changes in health-related quality-of-life parameters 
9.2 Safety 
9.2.1 Specification of Safety Parameters 
Safety and tolerability in this clinical study will be addressed by the following safety 
parameters: AEs, laboratory parameters (routine and intravascular hemolysis), vital 
signs, and physical examination. 
 
For the timing of individual safety parameters refer to Section III, Flowchart of Study. 
Any abnormal observation or finding detected during the screening procedures after 
subject's informed consent/assent that is considered clinically relevant must be 
documented as concomitant disease (ongoing medical history) or as past medical 
history. All medications other than the study medications should also be documented. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 45 of 82 
9.2.1.1 Adverse Events 
Adverse event data are obtained by the investigator through observation of the subject 
(including examinations and investigations), from any information volunteered by the 
subject, and through active questioning. At each visit after informed consent/assent 
has been signed, subjects will be asked about AEs that occurred since the last visit, by 
questioning them with regard to their well-being by ‘nonleading’ questions. This 
includes AEs occurring during the administration of the study medication, as well as 
changes in concomitant diseases (i.e., ongoing medical history). The subject’s diary 
(paper) is a source of collection of AE data that will be transcribed to the eCRF. 
Subject diaries will be reviewed for any signs of AEs occurring between visits.  
 
Occurrence, frequency, nature, severity, causality, and seriousness of AEs will be 
recorded. This includes observations or abnormalities in physical examination, vital 
signs, laboratory, or other investigations reported as AEs. Any treatments for AEs will 
also be recorded. For further details regarding AEs including definitions and reporting 
procedures refer to Appendix 1 and Appendix 2. 
9.2.1.2 Physical Examination 
For each subject, a complete physical examination will be performed at the time points 
specified in Section III, Flowchart of Study. Physical examination includes inspection of 
general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, heart, 
lungs, abdomen, lymph nodes, vascular system, extremities, musculo-skeletal system, 
and nervous system. Clinical findings and existing diseases at screening are to be 
documented as medical history. A new appearance of an abnormal finding or 
worsening of a concomitant disease that is considered clinically significant and occurs 
after signature of informed consent/assent must be documented as an AE. 
 
• Body weight is measured in kilograms (kg). 
• Body height is measured in cm once at the screening visit for the purpose of 
calculation of body mass index. 
 
The physical examination will be followed-up with a verbal exchange (face-to-face) 
between the subject and the investigator 1 hour after the end of each infusion, and a 
verbal exchange (by telephone) 24 and 72 hours after the end of each infusion. At 
each exchange, the subject will report any changes since the physical examination 
performed before the BT595 infusion. Any new physical examination finding will be 
documented as an AE.  
9.2.1.3 Vital Signs 
Vital signs are measured with the following methods/units: 
 
• Blood pressure is measured in mmHg according to the Riva Rocci method while 
the subject has been resting in supine position for at least 15 minutes. The 
same arm should be used for blood pressure measurements throughout the 
study. The size of the cuff has to be chosen appropriately in relation to the 
subject’s arm circumference. 
• Pulse rate is measured in beats per minute either electronically and/or by 
palpation for 1 minute while the subject is supine and has been resting for at 
least 15 minutes. When pulse rate is of concern, cardiac monitors are used to 
determine not only rate, but also rhythm. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 46 of 82 
• Respiratory rate is measured in breaths per minute while the subject has been 
resting for at least 15 minutes. 
• Body temperature is measured in degrees Centigrade or Fahrenheit using axillar 
measurements. 
 
Measurements outside the normal range (according to the age and gender of the 
subject) or even values within the normal range showing a trend have to be assessed 
for clinical relevance by the investigator, and reported as AEs if considered to 
represent a clinically significant change as compared to screening values. 
9.2.1.4 Laboratory Parameters 
Routine Laboratory Parameters 
All routine laboratory results have to be evaluated in the eCRF (by the investigator) 
according to the following pattern: 
a) Within reference range (normal range) 
b) Outside reference range but not clinically relevant (e.g., marginal deviation only, 
due to underlying diseases in the study population) 
c) Outside reference range and clinically relevant 
Laboratory values occurring (by date of blood sampling) after signature of informed 
consent/assent, which are outside the reference range and assessed as clinically 
relevant (as determined by investigator), have to be documented as AEs. 
An abnormal laboratory value that is a sign of an AE (e.g., increased leukocytes due to 
bacterial infection) that has already been reported during the present clinical study, has 
to be stated but the respective abnormal laboratory value (e.g., increased leukocytes) 
does not constitute a separate AE. 
For the routine laboratory parameters, the total volume of blood that will be drawn from 
a subject per visit will be approximately 13.5 mL. 
The laboratory safety parameters to be assessed are summarized in Table 1. 
Table 1: Laboratory Safety Parameters 
Clinical Chemistry (Approximately 7.5 mL) 
• 
Alanine aminotransferase 
• 
Aspartate aminotransferase 
• 
Gamma-glutamyltransferase 
• 
Alkaline phosphatase 
• 
Lactate dehydrogenase 
• 
Bilirubin (direct and indirect if total bilirubin is elevated) 
• 
Glucose 
• 
Total protein 
• 
Albumin 
• 
Creatinine 
• 
Blood urea nitrogen 
• 
Sodium 
• 
Chloride 
• 
Potassium 
• 
Calcium 
Hematology (Approximately 3 mL) 
• 
Hematocrit 
• 
Hemoglobin 
• 
Red blood cells 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 47 of 82 
• 
White blood cells 
• 
Differential white blood cells 
• 
Platelets 
• 
Erythrocyte sedimentation rate  
• 
C-reactive protein  
Coagulation (Approximately 3 mL) 
• 
Fibrinogen 
• 
Prothrombin time, international normalized ratio  
• 
Partial prothrombin time 
Urinalysis 
• 
pH 
• 
Qualitative for blood 
• 
Leukocytes 
• 
Protein 
• 
Glucose 
• 
Ketone bodies 
• 
Bilirubin 
• 
Urobilinogen 
• 
Nitrites 
• 
Osmolality 
• 
Urine sediment microscopy 
 
Note: the approximate blood sample volumes are estimated, and as the samples will 
be tested by local laboratories, volumes may differ from the approximate blood 
volumes detailed. 
 
In addition, the following specific safety laboratory parameters will be assessed at the 
time points specified in Section III, Flowchart of Study: 
Intravascular Hemolysis 
The intravascular hemolysis tests will be performed at screening (initial visit) and the 
closing (follow-up) visit only, unless further tests are required. Tests for the detection of 
intravascular hemolysis will consist of a direct antiglobulin test (Coombs’ test; 
approximately 7 mL blood sample) and the measurement of serum haptoglobin, 
plasma-free hemoglobin, and urine hemosiderin. If the Coombs’ test result is positive, 
the test will be repeated and red blood cell count, hematocrit, hemoglobin, serum 
haptoglobin, bilirubin (total, direct, and indirect), lactate dehydrogenase, and urine 
hemosiderin tests will be performed within 2 to 5 days. If the hemoglobin level has 
dropped by ≥2.0 g/dL from the screening level, in conjunction with both a drop in serum 
haptoglobin to below the lower limit of normal and a rise in serum lactate 
dehydrogenase from the screening level, this will suggest intravascular hemolysis, and 
a repeat urine dipstick, micro-urinalysis, and assessment of hemoglobin levels will be 
obtained within 72 hours of being informed of the drop in hemoglobin levels. 
 
For the first 10 patients and their first 2 infusions (V2 and V3) the results of the direct 
antiglobulin test (Coombs test) and the test of serum haptoglobin at the time points V3 
and V4 are required as a prerequisite for the decision of the Data and Safety 
Monitoring Board. For those 10 patients approximately 7 mL of additional blood will be 
taken for each of the two visits (V3 + V4). 
 
Note: the approximate blood sample volumes are estimated, and as the samples will 
be tested by local laboratories, volumes may differ from the approximate blood 
volumes detailed. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 48 of 82 
Virus Serology 
The immunological status of viral infections will be assessed at screening (initial visit) 
for: 
 
• HIV (anti-HIV1 and anti-HIV2) 
• hepatitis B (total hepatitis B core antibody [anti-HBc], hepatitis B surface 
antibody [anti-HBs], hepatitis B surface antigen [HBsAg]) 
• hepatitis C (anti-HCV) 
 
Pregnancy Test 
In females of child-bearing potential (i.e., female subjects ≥12 years or with presence 
of menstruation at screening), a pregnancy human chorionic gonadotropin test in 
serum will be performed at screening (initial visit). Urine pregnancy dipstick tests will be 
performed at other time points in the clinical study as specified in Section III, Flowchart 
of Study. 
 
The serum sample will be analyzed by the local laboratory using standard assay 
methods and the urine dipstick test will be analyzed at the study site. 
9.2.1.5 Viral Safety (Retention Samples) 
In order to respond rapidly to any reports on additional viral infections, a screening 
blood sample (5 mL) from each subject included in the study must be taken at the start 
of the study (screening [initial visit]) and stored at -70°C for possible future serum 
testing.  
 
At the closing (follow-up) visit, an additional blood sample (5 mL) must be taken and 
stored up to 6 months after study end. 
9.2.2 Methods for Assessing and Recording Safety Parameters 
The following safety parameters are recorded in the eCRF: AEs (Section 9.3 for further 
details), physical examination findings, laboratory values (routine and intravascular 
hemolysis), virus serology, and vital signs. 
 
All laboratory analyses will be performed by the local laboratory using standard assay 
methods and will be transcribed to the eCRF by the investigator in a timely manner. 
9.2.3 Safety Endpoints 
For each subject and for the study as a whole: 
• Number, severity, causality, and seriousness of infusional AEs (including 
nonproduct related) temporally associated with the infusion (occurring during 
infusion or within 1, 24, and 72 hours after the end of infusion) 
• Number of related infusional AEs (occurring during infusion or within 1, 24, and 
72 hours after the end of infusion) 
• Number and percentage of infusions temporally (within 72 hours) associated 
with 1 or more AEs 
• Number, severity, causality, and seriousness of all AEs 
• Number, severity, causality, and seriousness of all treatment-emergent AEs 
(TEAEs) 
• Number of noninfusional AEs (occurring more than 72 hours after the end of 
infusion) 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 49 of 82 
• Changes in safety laboratory parameters (outside reference range and clinically 
relevant) 
• Number of positive intravascular hemolysis test results 
• Changes in vital sign parameters 
• Changes in physical examination parameters 
 
For AEs that occur during an infusion, the following should be reported and analyzed: 
(1) the infusion rate in effect at the time of onset of the AE; (2) the time of onset of the 
AE; and (3) the time at which the AE changed materially in intensity and/or resolved. 
Listings of SAEs; AEs by severity; AEs by body system; and a determination of which 
AEs were product-related, and which were not, will be provided. 
 
The mean number of AEs temporally associated with infusions per infusion will be 
calculated by (a)/(b) where: (a) equals the total number of AEs that occur during or 
within 72 hours of an infusion, and (b) equals the total number of infusions. 
 
The proportion of infusions administered to subjects for which “infusional” AEs have 
been reported will be provided. 
 
The proportion of subjects who experience 1 or more AEs at any time during the 
course of the study will be provided. 
 
For each AE, it will be indicated which infusion of investigational product this occurred 
with or followed (i.e., 1st infusion, 2nd infusion, etc). The AE listings will include 
separate reports of all AEs and of AEs judged by investigators to be associated with 
the infusion of the product, even if the sponsor determines the AE not to be 
product-related. 
 
Where appropriate, analyses of AEs should take into account the observed 
intra-subject correlation of the same type or any type of AE, as such within-subject 
events may not be independent. Methodology for these analyses will be described in 
the Statistical Analysis Plan (SAP). 
9.3 Adverse Events 
9.3.1 Definitions (also refer to Appendix 1) 
• Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical study subject 
administered an investigational medicinal product (IMP) and which does not 
necessarily have a causal relationship with this treatment. An AE may be any 
aggravation or new unfavorable and unintended sign (including abnormal 
laboratory findings), symptom, or disease temporally associated with the use of 
an IMP, whether or not considered related to the IMP. 
Adverse Reaction (ADR) of an Investigational Medicinal Product: 
All untoward and unintended responses to an IMP related to any dose 
administered. All AEs judged by either the reporting investigator or the sponsor 
as having a reasonable causal relationship to a medicinal product qualify as 
ADRs (= related AEs). The expression reasonable causal relationship means to 
convey in general that there is evidence or argument to suggest a causal 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 50 of 82 
relationship. This definition also covers medication errors and uses outside what 
is foreseen in the protocol, including misuse and abuse of the IMP 
(Section 9.3.6). 
• Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence or effect that at any dose*: 
• results in death 
• is life-threatening 
• requires hospitalization or prolongation of existing hospitalization 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is another important medical event 
* “At any dose” does not necessarily imply that the subject is receiving the study drug at the time 
of the event. 
Reporting requirements are detailed in Appendix 2. 
• Adverse Event of Special Interest (AESI) 
An AESI (serious or nonserious) is one of scientific and medical concern specific 
to the sponsor’s IMP or development program, for which ongoing monitoring and 
immediate communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to 
characterize and understand them. Reporting requirements are detailed in 
Appendix 2. 
The following AEs have been defined as AESIs for this study: 
• Thromboembolic events (such as stroke, myocardial infarction, lung 
embolism) 
• Hemolysis 
• Immediately Reportable Adverse Event (IRAE) 
An AE that must be reported to the sponsor within 24 hours of the study site 
being aware of the AE. Reporting requirements are detailed in Appendix 2. 
For this clinical study, IRAEs include: 
• All SAEs 
• All AESIs 
• All AEs that result in a subject’s withdrawal from the study 
• Overdose 
• Pregnancy 
• Adverse Events Leading to Subject’s Withdrawal from the Clinical Study 
An AE, serious or nonserious, resulting in a subject’s withdrawal from the clinical 
study, i.e. permanent treatment discontinuation. Reporting requirements by the 
investigator are detailed in Appendix 2. 
Mandatory Adverse Event Stopping Rules 
Subjects have to be withdrawn if any of the following AEs occur: 
• Thromboembolic events (such as stroke, myocardial infarction, lung 
embolism) 
• Hemolysis 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 51 of 82 
9.3.2 Recording Adverse Events 
All AEs, serious and nonserious, that occur during the period of observation defined for 
the clinical study (Section III, Flowchart of Study) have to be fully documented in the 
eCRF according to the provisions given in this section of the study protocol and CRF 
completion guidelines, as well as in the subject’s source data. This applies also to AEs 
in subjects who signed the informed consent/assent but never received the study drug. 
In addition, for a subset of AEs (SAEs, AESIs, AEs leading to withdrawal, overdose, 
and pregnancy), immediate reporting from the investigator to sponsor is required 
(IRAEs). This is further detailed in Appendix 2. The following information is necessary: 
• Diagnosis vs. Signs/Symptoms 
The investigator should provide a diagnosis rather than individual signs and 
symptoms, wherever possible and appropriate. However, if there is not enough 
information to provide a diagnosis, individual signs and symptoms are to be 
recorded. If a diagnosis is accompanied by unusual symptoms, the diagnosis 
itself and the unusual symptoms have to be reported separately. For SAEs and 
other IRAEs, the investigator shall provide any other supporting information that 
may be required for the assessment of the events. 
A complication of an AE constitutes another AE. For example, in diarrhea 
leading to dehydration, diarrhea and dehydration would be captured as separate 
AEs. 
The eCRF provides for a number of items to be completed for each AE. This 
includes the onset date; end date; intensity/severity; seriousness; action taken 
with study medication; treatment for the AE; outcome; and causal relationship of 
the AE with the study medication, other drugs, or study procedures 
(Appendix 1). 
Severe vs. Serious: The severity is used to describe the intensity of an event. 
This is not the same as seriousness, which is based on subject/event outcome 
or action criteria usually associated with events that pose a threat to subject’s 
life or functioning. Seriousness, not severity, serves as the guide for defining 
regulatory reporting obligations. 
• Causal Relationship of the Adverse Event 
The causal relationship with the study medication has to be reported for each 
AE. It refers to the presence or absence of a reasonable possibility of a causal 
relationship between the study medication and the AE. 
The investigator is asked to use medical judgment and take into account the 
nature of the AE; the subject’s medical history; temporal relation; response to 
withdrawal or interruption of study drug (dechallenge); response to 
reintroduction of study drug (rechallenge); and any alternative explanations such 
as underlying or concomitant diseases, concomitant drugs, or study procedures. 
 
The following categories are used: 
• Related: There is a reasonable possibility of a causal relationship 
between the study medication and the AE. 
• Not related: There is no reasonable possibility of a causal relationship 
between the study medication and the AE. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 52 of 82 
For SAEs and other IRAEs, the investigator is asked to specify if there are 
alternative and/or additional explanations for the occurrence of the event 
(e.g., concomitant drugs, study procedures, or concomitant/underlying disease) 
and should provide this information already with the initial case report. 
9.3.3 Period of Observation 
The period of observation for collection of AEs extends from the time the subject signs 
the informed consent/assent form until the last study visit (closing [follow-up] visit), 
which is scheduled 3 or 4 weeks after the last dose of study medication (depending on 
the subject’s treatment schedule). 
Abnormal, clinically relevant findings or observations made prior to signature of 
informed consent/assent are to be recorded as medical history/concomitant disease, 
but not as AEs. 
Adverse events occurring in the pretreatment period between signature of informed 
consent/assent until first administration of study medication are nontreatment emergent 
AEs. 
Adverse events occurring from the first administration of study medication until the 
subject’s last study visit are TEAEs. 
If an SAE occurs in a subject after the period of observation, i.e., after the last study 
visit, which is considered by the investigator to be related to the study medication, this 
should be recorded as an SAE and should follow the immediate reporting process for 
SAEs as described in Appendix 2. If the eCRF has been closed for the subject, the 
investigator should contact the sponsor to determine how to report the SAE. 
9.3.4 Assessment of Adverse Events 
• Responsibilities of Investigator 
Adverse events are assessed by the investigator in a standardized manner 
including, but not limited to seriousness, severity, outcome, and causality. This 
has to be performed in line with the definitions and provisions given in 
Appendix 1. 
Laboratory values outside the reference range have to be assessed for clinical 
relevance taking into account the pretreatment values. For reporting of abnormal 
laboratory values as AEs, refer to Section 9.2.1.4. 
If an AE meets the definition of any of the mandatory AE related stopping rules 
(Section 9.3.1), the investigator must withdraw the subject and report the AE as 
an IRAE according to Appendix 2. 
For all AEs, the causality assessment has to be provided in the eCRF, even if 
based on preliminary data. Once more information is available, the investigator 
may change a preliminary causality assessment. 
During and after participation of a subject in a clinical study, the 
investigator/institution has to ensure that adequate medical care is provided to 
the subject for any ongoing AEs, including clinically significant abnormal 
laboratory values. The investigator has to inform the subject when medical care 
is needed for any intercurrent disease of which the investigator becomes aware. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 53 of 82 
• Responsibilities of Sponsor 
Adverse events are reviewed and assessed by the sponsor during ongoing 
safety monitoring activities throughout the study, as well as medical evaluation 
and regulatory assessment for reportability of SAEs and IRAEs. For the purpose 
of regulatory reporting, the causality assessment given by the investigator will 
not been downgraded by the sponsor. If the sponsor disagrees with the 
investigator’s causality assessment, both the opinion of the investigator and the 
sponsor will be recorded. 
Regulatory assessment of an AE by the sponsor comprises the assessment of 
expectedness, which is based on Section 7 of the Investigator’s Brochure for 
BT595. 
• Follow-up of Adverse Events 
Adverse events should be followed up to determine the outcome. 
Adverse events that are serious or severe or considered related to the study 
medication or study procedures must be followed-up by the investigator until the 
AE is resolved or resolved with sequelae, and until all queries related to the AE 
have been clarified. If the subject had an AE with fatal outcome, an autopsy 
report should be provided, if possible. 
If AEs that are serious or severe or considered related to study medication or 
study procedures are ongoing at the time of the subject’s last study visit, or if the 
subject has clinically relevant laboratory parameter abnormalities at the last 
study visit, one or more safety follow-up visit should be scheduled for those 
subjects. The investigator should set the interval to the additional Safety 
follow-up visit according to his/her medical judgment. Follow-up activities should 
be continued until the investigator considers it medically justifiable to stop further 
follow-up. 
All other AEs must be followed up by the investigator until the AE is resolved or 
resolved with sequelae or the end of the period of observation (i.e., last study 
visit), whichever comes first. 
The investigator should respond to any queries raised by the sponsor in relation 
to AEs, including provision of supporting documentation for SAEs or other 
IRAEs (e.g., electrocardiogram [ECG] data, laboratory results, hospital 
summary, autopsy report) within the requested timeline. In case of fatal or 
life-threatening SAEs, the sponsor may request urgent clarification within 
1 calendar day. In general, if for AEs requiring immediate reporting from the 
investigator to sponsor (IRAEs/SAEs), follow-up information becomes available, 
this must be reported to the sponsor within 24 hours of becoming aware of this 
information (i.e., the same timeframe as for initial IRAE/SAE reports). Any 
supporting documents have to be identified by the subject identification, and 
personal data (e.g., subject name, address, or phone number) obliterated prior 
to sending to the sponsor. For details on reporting IRAEs/SAEs, see 
Appendix 2. 
Adverse event data in the eCRF must be updated accordingly when follow-up 
information is received. 
All efforts to collect follow-up information must be documented in the subject’s 
source data. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 54 of 82 
Subjects who were treated with the study medication but did not complete the 
study as per protocol, should receive all the examinations and investigations 
scheduled for the last study visit. The investigator should make all efforts to 
contact subjects lost to follow-up and document the attempts in the subject’s 
source data. 
9.3.5 Immediate Reporting by Investigator to Sponsor 
The reporting processes are outlined in detail in Appendix 2. 
9.3.6 Use of Investigational Medicinal Product Outside the Specifications of the 
Clinical Study Protocol 
Situations may occur where the IMP is used outside the specifications of the protocol, 
which may or may not be associated with an AE. These special situations comprise: 
• Medication errors (including overdose) 
• Abuse/misuse of the IMP 
Such situations, whether or not associated with an AE, are documented in the eCRF 
on dedicated pages. Any AE that occurred in association with such a special situation 
has to be cross-referenced on the dedicated eCRF page. An IRAE/SAE occurring in 
conjunction with a medication error or abuse/misuse of the IMP has to follow the 
immediate reporting process for IRAE/SAE as described in Appendix 2 in addition to its 
documentation in the eCRF (also refer to Sections 9.3.1, 9.3.8, and 10.2). 
9.3.7 Investigational Medicinal Product Complaints 
Investigational medicinal product complaints must be recorded in the eCRF and in 
addition reported to the sponsor on the “Investigational Medicinal Product Complaint 
Report Form” within 24 hours of the investigator becoming aware of the IMP 
complaint. If the IMP complaint is associated with an AE, the AE must be entered in the 
eCRF also. 
Any complaint samples should be provided to the sponsor upon request. 
9.3.8 Special Situations Requiring Immediate Reporting 
Special situations may occur that may or may not be associated with AEs. For these 
situations, special reporting provisions apply. 
Special situations comprise: 
• Pregnancy in a female study subject or the partner of a male study subject 
• Investigational medicinal product complaint 
• Use of IMP outside the specifications of the Clinical Study Protocol 
(e.g., medication errors, overdose, misuse and abuse; also refer to Section 9.3.6 
and Section 10.2) 
• Protocol deviations (refer to Section 10.2) 
If such a situation occurs, the investigator should contact the sponsor immediately. A 
special paper report form has to always be completed in these situations and sent to 
the sponsor immediately, but not later than 24 hours after the investigator becoming 
aware of the situation. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 55 of 82 
9.3.8.1 Pregnancy 
Pregnant women are excluded from the study, and female study subjects of 
child-bearing potential (≥12 years or presence of menstruation at screening) undergo 
pregnancy testing at screening and regularly during the study (Section III, Flowchart of 
Study). If pregnancy is suspected in a study subject during treatment with the IMP, the 
IMP must be immediately withheld until the result of a confirmatory test is available. If 
confirmed, the subject must be withdrawn from the study. Furthermore, the reason and 
the contraception methods may need to be reviewed and documented as a 
preventative measure for other participants. 
Although not an AE per se, pregnancy in a female study subject or the partner of a 
male study subject must be recorded if it occurs during the period of observation of the 
study (see definition in Section 9.3.3). The investigator must contact the sponsor 
immediately in such a situation. 
The pregnancy must be documented on a “Drug Exposure Via Parent Report Form” 
(DEVP Form) and reported to the sponsor within 24 hours of the investigator 
becoming aware of the pregnancy. If an AE occurs in relation to the pregnancy, it has 
to be noted on the DEVP Form and recorded in the eCRF. If an IRAE/SAE occurs in 
relation to the pregnancy, it has to be noted on the DEVP Form and recorded in the 
eCRF and follow the immediate reporting process for IRAE/SAE as described in 
Appendix 2. 
The investigator must make all reasonable efforts to follow up the pregnancy until its 
end and will report all outcomes associated with the pregnancy to the sponsor. In the 
situation of pregnancy of the female partner of a male study subject, consent for the 
release of medical data should be obtained from the female partner to allow collection 
of information on the outcome of the pregnancy. 
9.4 Data and Safety Monitoring Board 
To monitor the safety data from adult subjects and provide advice and 
recommendations on the enrollment of pediatric subjects, a DSMB consisting of 
independent experts will be convened. The DSMB will review the safety data of at least 
10 adult subjects (18-75 years, inclusive) who have received at least 2 BT595 infusions 
with no safety concerns and provide recommendations on the suitability of the 
enrollment of pediatric (2-17 years, inclusive) subjects into the study. In addition to the 
laboratory values already described and as a requirement from the DSMB the direct 
antiglobulin test (Coombs' test) and the test for serum haptoglobin for these 10 adult 
patients and their first two visits have to be performed on V3 and V4. The final decision 
to enroll/not enroll pediatric subjects will be the responsibility of the sponsor. 
 
The specific responsibilities and composition of the DSMB are outlined in a separate 
document, the DSMB Charter, which will include a description of stopping rules for the 
participation of subjects. The DSMB Charter will also include details on the frequency 
of DSMB meetings and details of the information to be provided for the DSMB review. 
9.5 Pharmacokinetics 
9.5.1 Specification of Pharmacokinetic Parameters 
Serial blood samples (approximately 7.5 mL) for the establishment of the PK 
characteristics of BT595 and the determination of PK parameters at steady-state for 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 56 of 82 
total IgG, IgG subclasses 1-4, and IgG specific antibody levels (anti-pneumococcal 
capsular polysaccharide, anti-hemophilus influenzae type B, anti-measles, anti-tetanus, 
anti-cytomegalovirus, and anti-HBs/hepatitis B) will be obtained from at least 20 adult 
subjects (18-75 years, inclusive) and from pediatric subjects (6-17 years, inclusive). 
Note: samples for IgG specific antibody levels will be taken from pediatric subjects 
aged 12 through 17 years only.  
 
Sufficient samples will be obtained to reconstruct a concentration-time curve and to 
derive key PK parameters for total IgG, IgG subclasses 1-4, and IgG specific antibody 
levels. The samples will be taken as 1 aliquot for all analytes. 
 
Unused PK serum samples may be used to measure additional specific antibody 
levels/immunological variables of medical relevance as optional analytical variables 
which may be of importance with regard to efficacy of an IVIg in PID. 
 
For pediatric subjects (2-5 years, inclusive), sparse sampling at flexible time points 
within specified time windows after the end of the infusion may be performed (note: 
these samples are optional; see Section 7.1). For pediatric subjects (2-5 years, 
inclusive), only total IgG kinetics at steady-state will be established; no samples for 
IgG trough levels of subclasses 1-4 and IgG trough levels of specific antibody levels 
will be taken. 
9.5.2 Methods for Assessing and Recording Pharmacokinetic Parameters 
Blood samples will be collected by health care professionals, with procedures adapted 
for each age category (i.e., pediatric tubes and plasma micro-sampling). A homecare 
service is allowed for the PK sampling of pediatric subjects (2-17 years, inclusive). 
Blood sampling will be performed with a very thin gauge needle to reduce discomfort 
as much as possible. Blood collection immediately and up to 6 hours after the infusion 
must not be performed from the subject’s arm to which the infusion of study medication 
was administered; instead the contralateral arm must be used. 
 
Blood samples will be taken at estimated steady-state after the 7th infusion of the 
3-week schedule or after the 5th infusion of the 4-week schedule. Subjects will 
complete serial blood sampling according to their age category; therefore, the number 
of blood draws will depend on the subject’s age category. For adult subjects 
(18-75 years, inclusive) and pediatric subjects (6-17 years, inclusive), samples will be 
taken at a fixed series of time points. For pediatric patients (2-5 years, inclusive), 
sparse sampling at flexible time points within specified time windows after the end of 
this infusion may be performed (note: these samples are optional). 
 
The samples will be taken at the time points detailed in Section III, Flowchart of Study, 
and Section 7.1. 
 
In total, 8 or 9 PK blood samples will be taken from adult subjects (18-75 years, 
inclusive) and pediatric subjects (6-17 years, inclusive) over a period of 3 or 4 weeks 
(according to the treatment schedule). The samples will be taken as 1 aliquot for all 
analytes. For pediatric subjects (2-5 years), up to 5 PK blood samples may be taken 
over a period of 3 or 4 weeks (according to the treatment schedule). 
 
The blood samples taken for PK analysis will be analyzed by the central laboratory 
using standard assay methods, including the predose samples (trough levels) collected 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 57 of 82 
for this purpose. An aliquot of each sample will be stored at -20ºC until the end of the 
study and centrally measured. 
 
Pharmacokinetic data (including total IgG trough levels) will also be compared to 
historical data from previous PID studies with Intratect and Bivigam, as well as to 
available data from literature. 
 
The statistical analysis of the PK data will be performed by 
. 
9.5.3 Pharmacokinetic Endpoints 
• 
IgG trough levels (total IgG) before each administration 
• 
IgG trough levels (subclasses 1-4) at baseline and before the 7th/5th infusion of the 
3-week/4-week schedule, respectively (with the exception of pediatric subjects aged 
2-5 years, inclusive) 
• 
IgG trough levels of specific antibody levels (anti-pneumococcal capsular 
polysaccharide, anti-hemophilus influenzae type B, anti-measles, anti-tetanus, 
anti-cytomegalovirus, and anti-HBs/hepatitis B) at baseline and before the 
7th/5th infusion of the 3-week/4-week schedule, respectively (with the exception of 
pediatric subjects aged 2-11 years, inclusive) 
• 
Pharmacokinetic parameters at steady-state: maximum concentration (Cmax), time 
to reach maximum concentration (tmax), trough concentration (Ctrough), area under 
the concentration-time curve calculated from start to end of the dosing interval 
(AUCtau), steady-state clearance (CLss), %Fluctuation, and if possible, terminal 
elimination half-life (t1/2), terminal elimination rate constant (λz), as well as other 
parameters described in greater detail in Section 10.10. 
10 STATISTICS 
The statistical planning and evaluation of the clinical study will be carried out by a 
qualified biostatistician in accordance with the ICH-guidelines and adequate 
biostatistical standard operating procedures. A SAP, providing details about the 
statistical methods for the analyses, will be finalized before the inclusion of the first 
subject in the study to avoid any data driven bias. This ensures that the integrity of the 
analyses is maintained. 
Any deviations from the planned analyses will be described and justified in the clinical 
study report. 
10.1 Analysis Sets 
The following analysis sets will be defined: 
All Subjects Enrolled Set: 
The All Subjects Enrolled Set includes all subjects who have given informed 
consent/assent to this study. 
Safety Set (SAF): 
The SAF comprises all subjects who have received at least 1 dose of study medication. 
Subjects will be analyzed according to the treatment received. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 58 of 82 
Full Analysis Set (FAS): 
The FAS includes all subjects following the principle of intention-to-treat. The FAS 
comprises all subjects who received at least 1 dose of study medication (i.e., there is 
no difference between the FAS and the SAF in this study). 
Per-protocol Set (PPS): 
The PPS includes all subjects who are compliant with the study protocol without any 
major protocol deviations. Classification of protocol deviations as major or minor will be 
agreed upon at the Data Review Meeting (DRM) prior to database lock. The decision to 
carry out any analysis based on the PPS will be evaluated at the DRM. Any analysis 
based on the PPS will be performed for the primary efficacy endpoint as an additional 
analysis. 
Pharmacokinetic Trough Set: 
The PK Trough Set includes all subjects following the principles of the SAF for whom at 
least 1 trough concentration of total IgG and/or subclass/specific IgG was available. 
Dense Pharmacokinetic Subset: 
The Dense PK Subset includes all subjects following the principles of the SAF for 
whom at least 1 concentration of total IgGs, IgG subclasses 1-4, or IgG specific 
antibody 
levels 
(anti-pneumococcal 
capsular 
polysaccharide, 
anti-hemophilus 
influenzae 
type B, 
anti-measles, 
anti-tetanus, 
anti-cytomegalovirus, 
and 
anti-HBs/hepatitis B), measured in the dense sampling period (i.e., after/at the 
7th infusion of the 3-week schedule or after/at the 5th infusion of the 4-week schedule 
[depending on dosing schedule]) was available. 
The FAS will be used for efficacy analyses. The safety analyses will be based on the 
SAF. All PK analyses involving trough concentrations will be conducted using the PK 
Trough Set. Pharmacokinetic parameter derivation will be done using the Dense PK 
Subset. 
10.2 Protocol Deviations 
Deviations from the protocol will be documented on an on-going basis during conduct 
of the clinical study based on monitoring reports (e.g., failure of eligibility criteria), data 
management checks, and statistical programming (e.g., prohibited medications based 
on drug codes) and stored in the clinical study database. Protocol deviations will be 
collected and agreed in the DRM to find protocol deviations with major impact on 
subject safety or the validity of the study data. Subjects with major protocol deviations 
will be excluded from the PPS under the assumption that the deviation may have an 
impact on the efficacy analysis. 
The investigator should not implement any deviation from, or changes of the protocol, 
without 
agreement 
by 
the 
sponsor 
and 
prior 
review 
and 
documented 
approval/favorable opinion from the Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) of an amendment, except where necessary to eliminate an 
immediate hazard(s) to study subjects. The investigator, or person designated by the 
investigator, should document and explain any deviation from the approved protocol. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 59 of 82 
10.3 General Considerations 
Quantitative (continuous) data - absolute values and differences from baseline, where 
appropriate - will be summarized with number of observations (n), arithmetic mean, 
standard deviation, median, minimum, and maximum. Confidence intervals (95%, 
2-sided) will be added where applicable. 
Qualitative (categorical) data will be summarized using number of observations (n), 
and frequency and percentages of subjects. Unless stated otherwise, the calculation of 
percentages will be based on the total number of subjects in the population of interest. 
Thus counts of missing observations will be included in the denominator and presented 
as a separate category. Confidence intervals (95%, 2-sided) will be added, where 
applicable. 
Definition of Baseline 
In general, the last nonmissing valid observation before the first infusion will serve as 
the baseline measurement and may be measured at an unscheduled visit. 
Missing Data Conventions 
All available data will be included in the analyses and will be summarized as far as 
possible. Unless otherwise specified, there will be no substitution of missing data, 
i.e., missing data will not be replaced; missing data will be handled as ‘missing’ in the 
statistical evaluation. 
A more detailed description of the handling of missing data will be provided in the SAP. 
Pooling of Centers 
As it is expected that the number of subjects within each center will be very small, 
summaries of data by center would be unlikely to be informative; data from all centers 
will be pooled. 
Subgroups 
Besides the analyses sets as described in Section 10.1, and the planned subgroup 
analyses for the PK parameters (see Section 10.10), subgroup analyses by age 
category are planned to be performed for the primary efficacy endpoints and for AEs 
(infusional AEs and TEAEs). 
The age categories for the subgroup analyses will be children (2-11 years, inclusive), 
adolescents (12-17 years, inclusive), and adults (18-75 years, inclusive). The age 
categories will be consistent for all subgroup analyses, with the exception of PK where 
blood samples will be taken from all pediatric subjects aged 6 through 17 years and 
where PK blood samples are optional for pediatric subjects aged 2 through 5 years. 
Age will be the age recorded at screening (initial visit). The same age will be used per 
subject during the entire study (i.e., if a subject’s age changes from 17 to 18 years 
during the study, the subject will remain in the age category of 12 through 17 years 
during the entire study). 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 60 of 82 
10.4 Efficacy Analyses 
Analyses of the efficacy parameters will be based on the FAS and PPS as determined 
during the DRM. The analysis based on the FAS will be performed for the primary 
efficacy endpoint and the secondary efficacy endpoints, while the possible analysis 
based on the PPS will be carried out as an additional analysis for the primary efficacy 
endpoint only (see Section 10.1). 
10.5 Primary Efficacy Analysis 
The primary efficacy endpoint is the acute serious bacterial infection rate (i.e. the mean 
number of acute serious bacterial infections per subject-year). 
The primary endpoint will be analyzed using the upper 1-sided 99% confidence limit for 
the acute serious bacterial infection rate, which will be calculated using a Poisson 
model accounting for the length of the observation period per subject. 
A generalized linear model assuming the Poisson distribution for the number of acute 
serious bacterial infections with the logarithm as link function will be used. The Poisson 
model will include the natural logarithm of the length of the observation period in years 
as an offset to account for the (possibly) different lengths of the observation periods 
per subject. 
To assess the primary outcome for efficacy, the null hypothesis of 1 or more acute 
serious bacterial infections per subject-year will be tested against the 1-sided 
alternative hypothesis of less than 1 acute serious bacterial infection per subject-year 
at the 1% level of statistical significance. This 1-sided hypothesis test will utilize the 
same Poisson model as used for the calculation of the upper confidence limit. 
Rejection of the null hypothesis if 1 or more acute serious bacterial infection per 
subject-year will result in the acceptance of the alternate hypothesis of less than 
1 acute serious bacterial infection per subject-year. 
If sensitivity analyses is to be carried out (the decision will be made during the DRM), 
this will be performed with the PPS. 
10.6 Secondary Efficacy Analyses 
The following secondary endpoints will be summarized descriptively: 
• IgG trough levels (total IgG) before each infusion will be presented in tabulated 
statistical summaries of the raw data and absolute changes from baseline 
values by infusion schedule and overall (evaluation of IgG trough levels will 
include the calculation of the proportion of subjects who failed to meet the target 
level of ≥5 g/L). 
• Rate of any infections: The annual rate of infection will be calculated as the 
mean number of all infections (serious plus nonserious) per subject-year. The 
point estimate will be the total number of infections in all subjects divided by the 
total duration expressed in years of the observation period of all subjects. 
• Rate of nonserious infections: The annual rate of nonserious infection will be 
calculated as the mean number of nonserious infections per subject-year. The 
point estimate will be the total number of nonserious infections in all subjects 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 61 of 82 
divided by the total duration expressed in years of the observation period of all 
subjects. 
• Time to resolution of infections will be calculated as infection stop date – 
infection start date + 1. The presentation will be done by infusion schedule and 
overall and will include the frequencies of number of days until the resolution of 
infection. Kaplan-Meier plots will be generated for time to resolution of infection 
by infusion schedule and overall. 
• Antibiotic treatment information will be collected via the subject diary: Monthly 
rates of days on antibiotic treatment will be calculated per subject-month. The 
point estimates will be the total number of days on antibiotics in all subjects 
divided by the total duration expressed in months (of 30 days) of the observation 
period of all subjects. 
• Rate of time lost from school/work due to infections and their treatment: Monthly 
rates of the number of days not able to attend school/work due to infections and 
their treatment will be calculated per subject-month. The point estimates will be 
the total number of days off school/work due to infections and their treatment in 
all subjects divided by the total duration expressed in months (of 30 days) of the 
observation period of all subjects. 
• Hospitalization: Monthly rates of the number of days of hospitalization (any 
hospitalization) will be calculated per subject-month. The point estimates will be 
the total number of days in hospital in all subjects divided by the total duration 
expressed in months (of 30 days) of the observation period of all subjects. 
• Hospitalization due to infection: Monthly rates of the number of days of 
hospitalization due to infection will be calculated per subject-month. The point 
estimates will be divided by the total number of days in hospital due to infection 
in all subjects divided by the total duration expressed in months (of 30 days) of 
the observation period of all subjects. 
• Fever episodes: The number of days with episodes of fever will be calculated as 
the mean number of fever episodes per subject-year. The point estimate will be 
the total number of days with episodes of fever in all subjects divided by the total 
duration expressed in years of the observation period of all subjects. 
• The Peds QL™ questionnaire consists of 23 items. Scoring and handling of 
missing values will be done as recommended in the user manual. Three scores 
will be calculated: the Total Scale Score (all 23 items), the Physical Health 
Summary (8 items), and the Psychosocial Health Summary (15 items). The 
descriptive summary statistics for the total score and the single dimension 
scores will be provided by visit. In addition, changes from the baseline (Week 0) 
assessment to the posttreatment assessment will be determined. 
• The EQ-5D™ questionnaire and the youth version of the EQ-5D™ (EQ-5D-Y™) 
questionnaire are 5 dimension instruments assessing quality of life. Scoring and 
handling of missing values will be done as recommended in the user manual. 
Descriptive summary statistics for the total score and the single dimension 
scores will be provided by visit. In addition, changes from baseline (Week 0) 
assessments to each posttreatment assessment will be determined. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 62 of 82 
10.7 Safety Analysis 
The safety endpoints will be summarized descriptively. 
 
Adverse events temporally associated with the infusion are AEs occurring during 
infusion or within 1, 24, and 72 hours after the end of infusion and will be defined as 
infusional AEs. Summaries of AEs will be based on TEAEs, defined as those events 
with onset date/time at or after the first infusion date/time. All AEs will be attributed to 
the most recently received infusion rate at the time of onset. Presentation for TEAEs 
will be done overall. The safety analysis has to consider the severity, causality, and 
seriousness of AEs. 
 
Safety issues will mainly be addressed by measuring: 
 
• 
The number of infusional AEs (including nonproduct related; occurring during 
infusion or within 1, 24, and 72 hours after the end of infusion). 
• 
The number of related infusional AEs (occurring during infusion or within 1, 24, 
and 72 hours after the end of infusion). 
• 
The number of infusional AEs (occurring during infusion or within 1, 24, and 
72 hours after end of infusion) by infusion (e.g., 1st infusion, 2nd infusion, etc). 
• 
The number of serious infusional AEs (occurring during infusion or within 1, 24, 
and 72 hours after the end of infusion). 
• 
The number of nonserious infusional AEs (occurring during infusion or within 1, 
24, or 72 hours after the end of infusion). 
• 
The number of infusions temporally (within 72 hours) associated with 1 or more 
infusional AEs. 
• 
The number of all AEs. 
• 
The mean number of AEs temporally associated with infusions per infusion. 
• 
The number of TEAEs (infusional and noninfusional). 
• 
The number of TEAEs (noninfusional). 
• 
The number of serious TEAEs (infusional and noninfusional). 
• 
The number of serious TEAEs (infusional). 
• 
The number of serious TEAEs (noninfusional). 
• 
The number of related TEAEs (non infusional). 
• 
The number of serious related TEAEs (noninfusional). 
• 
The number of TEAEs by maximum severity (noninfusional). 
• 
The number of TEAEs leading to study drug infusion interruption and/or study 
drug infusion stop. 
• 
The number of TEAEs leading to premature withdrawals. 
• 
The number of TEAEs of special interest. 
• 
The number of ADRs. 
• 
The number of expected/unexpected TEAEs or ADRs. 
• 
Changes in safety laboratory parameters (outside reference range and clinically 
relevant). 
• 
Results of intravascular hemolysis parameters (number of positive hemolysis 
test results). 
• 
Changes in vital sign parameters. 
• 
Changes in physical examination parameters. 
 
Adverse events will be coded using the most current version of MedDRA. The version 
used will be defined in the SAP. Incidence rates (i.e., number and percentage of 
affected subjects) will be calculated for the coding levels system organ class and 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 63 of 82 
preferred term. Further analyses of AEs will focus on seriousness, intensity, causal 
relationship to study medication, and outcome. Immediately reportable AEs (including 
SAEs etc) will be displayed in detail. Where appropriate, analyses of AEs will consider 
the observed intra-subject correlation of the same type or any type of AE, and as such 
within-subject events may not be independent. Methodology for these analyses is 
described in the SAP. 
 
An exploratory 2-sided 90% confidence limit interval will be calculated for the total 
number of subjects with TEAEs and for the number of subjects with infusional AEs 
(i.e., AEs within 72 hours after the end of infusion). 
 
An exploratory upper 1-sided 95% confidence limit will be calculated for the proportion 
of the infusions with 1 or more temporally-associated AE (including nonproduct 
related). The proportion will be calculated as the total number of infusions with 
infusional AEs (AEs occurring during or within 1, 24, and 72 hours after the end of an 
infusion) divided by the total number of infusions. 
 
All AEs will be captured and registered (listed) and will include separate reports of all 
AEs and of all AEs judged by the investigator to be associated with the BT595 infusion, 
even if the sponsor determines the AE not to be product-related. 
 
Safety laboratory assessments will be categorized with respect to the laboratory 
specific reference ranges as normal/abnormal. Abnormal values will be further 
classified with respect to clinical relevance. Changes over time will be described by 
means of “shift-tables”. The raw data will be listed. Values below or above the 
reference values in the data listings will be flagged. All laboratory values will be 
converted into common units for presentation reasons. 
 
Intravascular hemolysis laboratory assessments will be summarized by the number 
and percentage of subjects and infusions with the given results at each visit. In case of 
positive Coombs’ test results, further evaluations and/or time points will be included in 
the summaries. 
 
For the viral safety parameters (retention samples), the presentation of the data will be 
detailed in the SAP. 
 
For vital sign parameters, absolute values and changes from baseline will be presented 
for each study visit using summary descriptive statistics. 
 
Physical examination data will be summarized at each visit. 
 
Safety analyses will be based on the SAF. 
 
Data and Safety Monitoring Board 
To monitor the safety data from adult subjects and provide advice and 
recommendations on the enrollment of pediatric subjects, a DSMB consisting of 
independent experts will be convened (see Section 9.4 for further details). 
 
The DSMB Charter will include details of the outputs provided for the DSMB review. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 64 of 82 
10.8 Interim Analyses 
No interim analysis is planned during the study. 
10.9 Determination of Sample Size 
A sample size of at least 50 subjects will ensure a power of at least 80% to reject the 
null hypothesis of an acute serious bacterial infection rate greater or equal to 1.0 by 
means of a 1-sided test and a Type 1 error of 0.01 assuming a true underlying rate of 
acute serious bacterial infections of 0.5 per year. Thus, about 70 subjects will be 
enrolled to account for drop-outs. 
The sample size will be at least 50 evaluable male or female subjects (2-75 years, 
inclusive), including at least 20 pediatric subjects (i.e., children [2-11 years, inclusive] 
or adolescents [12-17 years, inclusive]). Pharmacokinetic investigations will be carried 
out in at least 20 adult subjects and in pediatric subjects (6-17 years, inclusive). 
The above sample size number (to obtain at least 50 subject–years) and inclusion of at 
least 20 pediatric (i.e., children [2-11 years, inclusive] or adolescent [12-17 years, 
inclusive]) subjects with the age distribution representative of the patient population 
follows 
the 
advice 
provided 
by 
both 
the 
EMA 
guidelines 
(EMA/CHMP/BPWP/94033/2007 rev. 2, 2010) and the FDA guidelines (FDA, 2008). 
10.10 
Pharmacokinetic Analyses 
All PK data (IgG trough levels and PK parameters; as defined in Section 9.5.1) will be 
summarized by descriptive statistics by analyte (total IgG, IgG subclasses 1-4, and 
IgG specific 
antibody 
levels 
[anti-pneumococcal 
capsular 
polysaccharide, 
anti-hemophilus influenzae type B, anti-measles, anti-tetanus, anti-cytomegalovirus, 
and anti-HBs/hepatitis B]) for the study population as a whole, for each age category, 
for both treatment schedules (3-week and 4-week schedule) together, and treatment 
schedules separately. Similarly, data on dose levels and infusion rates will be 
summarized. Data from the different age categories will be compared descriptively. 
However, no formal statistical analysis will be performed.  
 
Pharmacokinetic serum samples will be optionally analyzed to identify additional 
specific antibody levels/immunological variables of medical relevance which may be of 
importance with regard to efficacy of an IVIg in PID. 
 
Graphical presentations will be provided for the IgG trough levels as well as for the PK 
time profiles for individual subjects and summarized by analyte (for subjects 
6-75 years, inclusive), by schedule, and by age category (adult [18-75 years, inclusive] 
vs pediatric [6-17 years, inclusive for total IgG and IgG subclasses 1-4], [12-17 years, 
inclusive for IgG specific antibody levels], and [2-5 years, inclusive]). 
 
The time-course of total IgG, IgG subclasses 1-4, and IgG specific antibody levels in 
adult subjects (18-75 years, inclusive) and pediatric subjects (6-17 years, inclusive for 
total IgG and IgG subclasses 1-4; 12-17 years inclusive for IgG specific antibody 
levels) will be analyzed by noncompartmental analysis. Key PK parameters will be 
derived from this analysis: maximum concentration (Cmax), time to reach maximum 
concentration (tmax), trough concentration (Ctrough), area under the concentration-time 
curve (AUC) calculated from time zero to time t of the last measured concentration 
(AUC(0-t)), area under the concentration-time curve calculated from start to the end of 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 65 of 82 
dosing interval (AUCtau), steady-state clearance (CLss), volume of distribution at 
steady-state (Vss), %Fluctuation, and if data permit, terminal elimination half-life (t1/2), 
area under the concentration-time curve calculated from time zero extrapolated to 
infinity (AUC(0-inf)), mean residence time (MRT), and terminal elimination rate constant 
(λz). 
 
A similar analytical approach might not be possible for pediatric subjects (2-5 years, 
inclusive) where only sparse sampling (total IgG only) is planned. Therefore, a 
population modelling approach will be proposed. First, a preliminary model based on 
prior PK data obtained with BT595 in adult subjects (18-75 years, inclusive) and 
pediatric subjects (6-17 years, inclusive) will be established. This model will be updated 
and used to reconstruct dense individual concentration-time profiles for all subjects, 
including the youngest pediatric subjects (2-5 years, inclusive), and to derive the 
different key PK parameters. 
 
Finally, all data will be summarized by descriptive statistics for the study population as 
a whole, and for each age category. Data from the different age categories will be 
compared descriptively. However, no formal statistical analysis will be performed.  
 
Evaluation of the total IgG trough levels will include the calculation of the proportion of 
subjects who failed to meet the target level (≥5 g/L) prior to dose adjustment. In 
addition, an intra-individual comparison to currently licensed IVIg products in the same 
subjects (i.e., using prestudy data) will be performed by suitable methods. No formal 
statistical test will be performed for these variables. 
 
Pharmacokinetic data (including total IgG trough levels) will also be compared to 
historical data from previous PID studies with Intratect and Bivigam (already marketed 
10% IVIgs) and to available data from literature. 
11 DATA MANAGEMENT 
11.1 Data Collection 
Electronic Case Report Form (eCRF)  
The eCRF is the primary data collection instrument for the clinical study. All data to be 
recorded according to this clinical study protocol must be documented. Entries in the 
eCRF must only be made by the investigator or persons authorized by the investigator. 
A list of all persons who are allowed to make entries in the eCRF must be available in 
each study site. Electronic case report form completion guidelines including 
e.g. handling of data corrections will be described in the Data Management Plan. 
 
Clinical study data will be directly entered via the eCRF into the study database on a 
central server by the authorized investigator and/or study personnel. 
 
According to the ICH GCP Guideline (Section 5.5), it is ensured that the electronic data 
capture system is built up with the following requirements: validated system, 
functionality of different user roles and access administration, password protection, 
given traceability, record keeping, and availability of audit trail functionality, and as well 
that appropriate standard operation procedures are maintained. 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 66 of 82 
The investigator and/or assigned study personnel at each site will enter data from 
source documents corresponding to a subject’s visit into the protocol-specific eCRF. 
Subjects will be identified by a unique study specific number and/or code in any 
database. The subject's name and any other identifying detail will not be included in 
any study data-electronic file. 
Laboratory samples (e.g., for IgG trough levels, specific antibody trough levels, safety 
laboratory levels, intravascular hemolysis levels, viral safety [retention samples], virus 
serology, PK, and any other study specific laboratory data) will be collected at each 
site. 
Outcome measure data (e.g., the health-related quality-of-life questionnaire responses) 
will be collected by the investigator or assigned study personnel at each site to be 
further processed into the eCRF. 
The complete data management activities (data capture, data entry, data validation, 
query handling, data editing after entry, coding, database closure, etc) will be defined 
in advance within a Data Management Plan together with a description of the 
personnel responsible for data entry/correction performance and controlling as well as 
specific data handling procedures. 
MedDRA dictionary will be used for coding of AEs, concomitant diseases, and medical 
history. Concomitant medications will be coded of the A(natomical) T(herapeutical 
C(hemical)-code, level 2, using the Word Health Organization Drug Dictionary 
(WHO-DD). 
11.2 Correction of Data 
After data have been entered into the clinical study database, a system of 
computerized data validation checks will be implemented and applied to the database 
on a regular basis. 
Queries are entered, tracked, and resolved through the electronic data capture system 
directly. If a correction is required for the eCRF, the time and date stamps tracking 
function creates an electronic audit trail for the person entering/updating the eCRF 
data. 
11.3 Data Handling 
The data will be entered into a validated database via the eCRF. The Data 
Management personnel will be responsible for data processing, in accordance with 
procedural documentation. Database lock will occur once quality assurance 
procedures have been completed. 
All procedures for the handling and analysis of data will be conducted according to 
available ICH-GCP guidelines for the handling and analysis of data for clinical studies. 
12 QUALITY CONTROL AND QUALITY ASSURANCE 
12.1 Study Initiation Activities 
The investigators are informed about objectives and methods of the study, the 
inclusion and exclusion criteria, the time-schedule, and the applied procedures by 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 67 of 82 
means of a Prestudy Visit by the monitor (if necessary), an investigators’ meeting prior 
to start of the study, and during the Site Initiation Visit by the monitor. 
12.2 Training of Site Staff 
The principal investigator needs to ensure that all persons assisting with the clinical 
study are adequately informed about the protocol, the investigational product, and their 
study-related duties and functions. Furthermore, the principal investigator is requested 
to maintain a list of appropriately qualified persons to whom the investigator has 
delegated significant study-related duties. 
12.3 Documentation and Filing 
List of Subjects (Subject Identification Log) 
The investigator is asked to keep a confidential list of names of all subjects 
participating in the study, giving reference to the subjects’ records. 
 
With the help of this list it must be possible to identify the subjects and their medical 
records. In addition, the investigator is asked to keep a list of all subjects screened on 
a screening log to document identification of subjects who entered prestudy screening. 
In case of noneligibility, a reason is to be provided. 
 
Source Data 
Source data are all the information in the original records and certified copies of 
original records of clinical findings, observations, or other activities in a clinical study 
necessary for the reconstruction and evaluation of the study. Source data are 
contained in source documents which comprise clinical documentation, data, and 
records (e.g., hospital records; clinical and office charts; laboratory notes; memoranda; 
subjects’ diaries or evaluation checklists; pharmacy dispensing records; recorded data 
from automated instruments; copies or transcriptions certified after verification as being 
accurate copies; microfiches; photographic negatives; microfilm or magnetic media; 
x-rays; subject files; and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical study). In this study, no data will 
be recorded directly on the eCRF and be considered as source data. 
 
Investigator Site File/Regulatory Binder 
Before site initiation, the CRO will provide an Investigator Site File/Regulatory Binder to 
each study site. The Investigator Site File will include essential documents as defined 
by the ICH-GCP guideline and applicable local requirements. 
 
The investigator will be responsible for the continual update and maintenance of the 
Investigator Site File, which will be periodically reviewed by the monitor(s). In case of 
an audit by the sponsor or an inspection by the Regulatory Authorities, these 
documents will be reviewed. 
 
All study-related documents are to be archived and stored according to legal 
requirements, but at least for 15 years after completion of the study. 
 
Prior to destruction the investigator will contact Biotest AG for approval and 
conformation of such. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 68 of 82 
12.4 Monitoring 
The monitor is responsible for checking the quality of data and adherence to the study 
protocol and to legal and ethical requirements according to local laws and GCP. 
 
The interval between monitoring visits will be dependent on the recruitment rate and 
the complexity of the study. 
 
Source data verification is an essential part of the monitoring process and the 
investigator must grant direct access to the subjects' source data. 
 
The extent and nature of monitoring will be described in detail within the monitoring 
plan. 
12.5 Audits and Inspections 
Audits will be performed according to the corresponding audit program, including the 
possibility that a member of the sponsor’s quality assurance function may arrange to 
visit the investigator in order to audit the performance of the study at the study site, as 
well as all study documents originating there. Audits may also be performed by 
contract auditors. In this case, the sponsor’s quality assurance function will agree with 
the contract auditor regarding the timing and extent of the audit(s). In case of audits at 
the investigational site, the monitor, Project Manager CRO, or Clinical Manager, Biotest 
will usually accompany the auditor(s). 
 
Inspections by Regulatory Authority representatives and IECs/IRBs are possible at any 
time, even after the end of study. The investigator has to notify the sponsor 
immediately of any such inspection. The investigator and institution will permit and 
support study-related monitoring, audits, reviews by the IEC/IRB and/or Regulatory 
Authorities, and will allow direct access to source data and source documents for 
monitoring, audits, and inspections. The principal investigator shall personally 
participate in all audits and inspections. 
12.6 Archiving 
After evaluation and reporting of the study data, all documents relating to the clinical 
study will be kept in the archives of the sponsor or of a contracted service provider and 
the study site(s) according to applicable regulatory requirements. 
13 GENERAL REGULATIONS, AGREEMENTS, AND 
ORGANIZATIONAL PROCEDURES 
13.1 Study Administrative Structure 
Details for the study administrative structure are kept as a separate list filed in the 
TMF. 
13.2 Ethical and Regulatory Considerations 
This clinical study protocol and any amendments will be submitted to a properly 
constituted IEC/IRB and/or Regulatory Authorities, in agreement with applicable 
regulatory requirements, for formal approval of the study conduct. A copy of these 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 69 of 82 
approvals must be submitted to Biotest before initiation of the clinical study and each 
site needs to keep a copy of these documents. 
 
The clinical study will be performed according to the applicable regulatory requirements 
taking into account the principles of GCP and the latest version of the Declaration of 
Helsinki. 
13.3 Committees/Monitoring Boards 
Safety data from the clinical study (adult subjects only) will be evaluated by a DSMB at 
predetermined points in time, to ensure that the continuation of the study is appropriate 
and to make recommendations to the sponsor on the suitability of further conduct of 
the study in pediatric subjects. The DSMB will consist of permanent members who are 
not associated with the sponsor or with the operative conduct of the study. A 
description of the scope of work and operating procedures for the DSMB is provided in 
the DSMB Charter. The composition of the DSMB will also be outlined in the DSMB 
Charter. 
13.4 Written Agreements 
A written agreement will be set up between Biotest and each investigator setting out 
any arrangements on delegation and distribution of tasks and obligations and, if 
appropriate, on financial matters. 
13.5 Insurance/Liability 
In accordance with the relevant national regulations, the sponsor has taken out a 
subject liability insurance for all subjects who have given their consent to the clinical 
study. The subjects are insured against injury caused by study medication or 
participation. The subjects will be informed about the insurance and their own 
responsibilities and duties. 
 
The insurance of this study will be outlined in a separate agreement between 
 
 and Biotest. 
13.6 Investigator’s Brochure 
The investigator will be informed about current knowledge concerning the study 
medication through an Investigator’s Brochure. All investigators will be informed 
immediately about relevant new information available. 
13.7 Amendments to the Protocol 
Changes to the clinical study protocol must be made in the form of a clinical study 
protocol amendment that has the prior written approval of Biotest. Substantial changes 
to the protocol need to be notified to/approved by IRB/IEC and/or Regulatory 
Authorities prior to implementation, as required by applicable regulations. 
 
Amendments required in order to eliminate immediate hazard to subjects may be 
implemented before the approval of the IEC/IRB and/or Regulatory Authorities after 
consultation with Biotest. 
 
In the event that a significant deviation from the protocol is anticipated based on the 
subjects’ status, or occurs due to an accident or mistake, the investigator or his/her 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 70 of 82 
designee must contact the CRO and then escalation will be made to Biotest, as 
appropriate, at the earliest possible time. This will allow an early joint decision to be 
made as to whether or not the subject should continue in the study. This decision will 
be documented by both the investigator and the CRO. 
13.8 Confidentiality 
The objectives and contents of this clinical study as well as its results are to be treated 
as confidential and may not be made accessible to third parties. 
 
Information about study subjects will be kept confidential and managed according to 
the requirements of the Health Insurance Portability and Accountability Act of 1996. 
These regulations require a signed subject authorization informing the subject of the 
following: 
• What protected health information (PHI) will be collected from subjects in this 
study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization. For subjects that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status 
(i.e., that the subject is alive) at the end of their scheduled study period. 
13.9 Final Report and Publication 
For each study, an integrated final report according to ICH-requirements will be 
produced. At the end of the study, the sponsor will provide the Competent Authority 
and IEC/IRB with a summary of the clinical study report within 6 months after the end 
of the study (where required) or as agreed with the Competent Authorities. 
 
It is generally recommended that the results of clinical studies be presented at 
congresses and symposia and/or published in scientific journals. Prior to their 
publication, all results of medical tests with the sponsor’s products, and/or publications 
or lecture manuscripts concerning such results, are to be reviewed and discussed by 
the coordinating investigator and the sponsor by mutual agreement. 
 
Each investigator is obligated to keep data pertaining to the study secret. He/she must 
consult with the sponsor before any study data are published. 
 
The legitimate interests of the sponsor, such as acquiring optimum patent protection, 
coordinating submissions to the health authorities or coordination with other studies in 
the same field that are underway, protection of confidential data and information, etc. 
will be given due consideration by all partners involved. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 71 of 82 
14 LIST OF REFERENCES 
1. Björkander J, Nikoskelainen J, Leibl H et al (2006). Prospective open-label study of 
pharmacokinetics, efficacy and safety of a new 10% liquid intravenous 
immunoglobulin in patients with hypo- or agammaglobulinemia. Vox Sang; 
90(4):286-93. 
2. Chapel H, Prevot J, Gaspar HB et al (2014). Primary immune deficiencies – 
principles of care. Front Immunol; 5(627): 1-12. 
3. Imbach P, Lazarus AH, Kühne T (2010). Intravenous immunoglobulins induce 
potentially synergistic immunomodulations in autoimmune disorders. Vox Sang.; 
98(3 Pt 2): 385-94. 
4. Schwab I and Nimmerjahn F (2013). Intravenous immunoglobulin therapy: how 
does IgG modulate the immune system? Nat Rev Immunol; 13(3): 176-88. 
5. Lünemann JD, Nimmerjahn F, Dalakas MC (2015). Intravenous immunoglobulin in 
neurology – mode of action and clinical efficacy. Nat Rev Neurol; 11(2): 80-9. 
6. Wasserman RL, Church JA, Stein M et al (2012). Safety, efficacy and 
pharmacokinetics of a new 10% liquid intravenous immunoglobulin (IVIG) in 
patients with primary immunodeficiency. J Clin Immunol; 32:663-9. 
7. Clinical Study Report 941 (2002). A multicentre, open, prospective study 
investigating clinical efficacy, safety, and pharmacokinetic properties of the human 
normal immunoglobulin for intravenous administration BT681 with intraindividual 
comparisons 
to 
previous 
standard 
treatment 
in 
patients 
with 
primary 
immunodeficiency disease (PID). 
8. Kreuz W, Erdos M, Rossi P et al (2010). A multi-centre study of efficacy and safety 
of Intratect®, a novel intravenous immunoglobulin preparation. Clin Exp Immunol; 
161(3):512-7; DOI: 10.1111/ j.1365-2249.2010.04187.x. 
9. Colovic M, Dimitrijevic M, Sonnenburg C et al (2003). Clinical efficacy and safety of 
a novel intravenous immunoglobulin preparation in adult chronic ITP. Hematol J; 
4(5):358-62. 
10. Krivan G, Konigs Ch, Bernatowska E et al. An open, prospective trial investigating 
the pharmacokinetics and safety, and the tolerability of escalating infusion rates of a 
10% human normal immunoglobulin for intravenous infusion (IVIg), BT090, in 
patients with primary immunodeficiency disease. Vox Sang 109(3):248-56, DOI: 
10.1111/Vox. 12275, Article first published online: 07 May 2015. 
11. European Medicines Agency Guideline on the clinical investigation of human 
normal 
immunoglobulin 
for 
intravenous 
administration 
(IVIg). 
EMA/CHMP/BPWP/94033/2007 
rev. 
2; 
22 
July 
2010. 
Available 
from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/
10/WC500004766.pdf. 
12. Food and Drug Administration (FDA) Guidance for Industry: Safety, efficacy, and 
pharmacokinetic studies to support marketing of immune globulin intravenous 
(human) as replacement therapy for primary humoral immunodeficiency. June 
2008. 
Available 
from: 
http://www.fda.gov/downloads/BiologicsBloodVaccines/ 
GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm078526.pdf. 
13. European Society for Immunodeficiencies [Internet]. [Place unknown], [Publisher 
unknown]; 
10 May 2006. 
Available 
from: 
http://esid.org/Working-
Parties/Clinical/Resources/Diagnostic-criteria-for-PID2#tophttp://esid. 
14. Conley ME, Notarangelo LD, Etzioni A (1999). Diagnostic criteria for primary 
immunodeficiencies. Clin Immunol., 93(3):190-7. 
15. International 
Conference 
on 
Harmonisation 
of 
Technical 
Requirements 
for Registration of Pharmaceuticals for Human Use Tripartite Guideline on 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 72 of 82 
clinical investigation 
of 
medicinal 
products 
in 
the 
pediatric 
population. E11 Step 4; 20 July 2000. 
Available 
from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E1
1/Step4/E11_Guideline.pdf. 
16. European Medicines Agency Guideline on core SmPC for human normal 
immunoglobulin 
for 
intravenous 
administration 
(IVIg). 
EMA/CHMP/BPWP/94038/2007 
rev. 4; 
13 December 2012. 
Available 
from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/
12/WC500136433.pdf. 
17. Gelfand EW, Hanna K (2006). IGIV-C Increased Maximum Infusion Rate Study 
Group. Safety and tolerability of increased rate of infusion of intravenous 
immunoglobulin G, 10% in antibody deficient patients. J Clin Immunol; 
26(3):284-90. 
18. Stein MR, Nelson RP, Church JA et al (2009). IgPro10 in PID study group. Safety 
and efficacy of Privigen, a novel 10% liquid immunoglobulin preparation for 
intravenous use, in patients with primary immunodeficiencies. J Clin Immunol; 
29(1):37-44. 
19. The PedsQL™ Measurement Model for the Pediatric Quality of Life Inventory™ 
[Internet]. [Place unknown], [Publisher unknown]; [Date Unknown]. Available from: 
http://www.pedsql.org/index.html. 
20. EuroQol Five Dimension Health (EQ5D™) Questionnaire [Internet]. [Place 
unknown], 
[EuroQol 
Research 
Foundation]; 
[2015]. 
Available 
from: 
http://www.euroqol.org/. 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 73 of 82 
15 APPENDICES 
 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 74 of 82 
Appendix 1: "Safety Definitions" 
• Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical study subject 
administered an IMP and which does not necessarily have a causal relationship 
with this treatment. An AE may be any aggravation or new unfavorable and 
unintended sign, symptom, or disease temporally associated with the use of an 
IMP, whether or not considered related to the IMP. 
This includes abnormal laboratory and other investigation results which are 
considered clinically relevant by the investigator (unless already pre-existing at 
baseline). However, if an abnormal laboratory value is a sign of an already 
reported AE (e.g., infection), the respective abnormal laboratory value does not 
constitute a separate AE. 
A surgical or invasive procedure is not an AE in itself. Instead, the condition for 
which the surgical or invasive procedure is performed may be an AE. Planned or 
elective surgery or procedures (i.e., planned prior to signature of informed 
consent/assent) for a pre-existing condition and the pre-existing condition leading 
to surgery or procedure are not AEs. However, if the pre-existing condition 
worsened after signature of informed consent/assent, the worsening of the 
condition constitutes an AE. 
Worsening of the disease under study (underlying disease): This will be captured 
by efficacy parameters and should not usually be recorded as an AE, unless 1 or 
more of the following criteria are met: 
 The worsening of the disease under study constitutes a SAE 
 A deterioration exceeding the usual fluctuations of the disease under 
study has occurred in the opinion of the investigator 
 The worsening leads to discontinuation of the study medication 
 Additional treatment is required for the worsening, e.g., concomitant 
medication is added or changed. 
No causal relationship with the investigational drug, or comparator drug, or study 
procedures is implied by the use of the term “Adverse Event”. 
• Adverse Reaction (ADR) of an Investigational Medicinal Product: 
All untoward and unintended responses to an IMP related to any dose 
administered. All AEs judged by either the reporting investigator or the sponsor 
as having a reasonable causal relationship to a medicinal product qualify as 
ADRs (= related AEs). The expression reasonable causal relationship means to 
convey in general that there are facts, evidence, or arguments to suggest a 
causal relationship. This definition also covers medication errors and uses 
outside what is foreseen in the protocol, including misuse and abuse of the IMP 
• Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence or effect that at any dose*: 
 results in death 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 75 of 82 
- 
Death is an outcome of an AE and not an AE in itself. All 
deaths, regardless of cause or relationship must be reported 
for study subjects. 
 is life-threatening 
- 
“Life-threatening” refers to an event in which the subject was 
at risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it 
were more severe. 
 requires hospitalization or prolongation of existing hospitalization 
- 
In-subject hospitalization means that the subject has been 
formally admitted to a hospital for medical reasons, for any 
length of time, which may or may not be overnight. It does 
not include presentation and care within an emergency 
department. 
- 
A complication that occurs during hospitalization and 
prolongs 
the 
existing 
hospitalization 
is 
an 
SAE. 
Complications that occur during hospitalization but do not 
prolong the existing hospitalization and do not meet any 
other seriousness criteria are nonserious AEs. 
- 
Elective or preplanned (prior to signature of informed 
consent/assent) hospitalization for investigations, medical or 
surgical treatment does not meet this seriousness criterion. 
However, if the underlying condition for which hospital 
treatment or surgery had been planned worsened during the 
study, the worsening of the condition is to be reported as an 
SAE. 
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 is another important medical event 
- 
Adverse events that may not be immediately life-threatening 
or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to 
prevent one of the other outcomes listed above, should be 
reported as serious. Medical and scientific judgment must be 
exercised in deciding whether an event is serious. 
* “At any dose” does not necessarily imply that the subject is receiving the study 
drug at the time of the event. 
• Diagnosis vs Signs/Symptoms 
The investigator should provide a diagnosis rather than individual signs and 
symptoms, wherever possible and appropriate. However, if there is not enough 
information to provide a diagnosis, individual signs and symptoms are to be 
recorded. If a diagnosis is accompanied by unusual symptoms, the diagnosis 
itself and the unusual symptoms have to be reported separately. For SAEs and 
other IRAEs, the investigator shall provide any other supporting information that 
may be required for the assessment of the events, specifically in the free text 
narrative description of the case. This is of particular importance in situations 
where a diagnosis cannot (yet) be made. Any subject identifying data on 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 76 of 82 
supporting documents (e.g., name, address, phone number) have to be 
obliterated prior to sending them to the sponsor. 
A complication of an AE constitutes another AE. For example in diarrhea leading 
to dehydration, diarrhea and dehydration would be captured as separate AEs. 
The eCRF provides for a number of items to be completed for each AE. This 
includes the onset date, end date, intensity/severity, seriousness, action taken 
with study medication, treatment for the AE, outcome, and causal relationship of 
the AE with the study medication, other drugs, or study procedures. 
• Onset Date, End Date 
If an AE started during the study but did not end before the final closing 
(follow-up) visit, the investigator must make a reasonable effort to establish the 
outcome and the end date. If this is not possible, e.g., because the AE is still 
ongoing, or the subject is lost to follow-up, there will be no end date for the AE. 
For all AEs that resolve, resolve with sequelae, or have a fatal outcome, an end 
date must be provided. 
If an AE stops and restarts later, all occurrences have to be recorded separately. 
If an AE starts as a nonserious AE and becomes serious at a later point in time, 
the following applies in regard to onset and end dates: 
• Intensity/Severity 
Refers to the extent to which an AE affects the subject’s daily activities. Severity 
will be categorized according to the following criteria: 
Table: Adverse Event Severity 
Mild 
The AE does not interfere with the subject’s routine 
activities. 
Moderate 
The AE interferes with the subject’s daily routine, but usual 
routine activities can still be carried out. 
Severe 
The AE results in inability to perform routine activities. 
Severe vs Serious: The severity is used to describe the intensity of an event. 
This is not the same as seriousness, which is based on subject/event outcome or 
action criteria usually associated with events that pose a threat to subject’s life or 
functioning. Seriousness, not severity, serves as the guide for defining regulatory 
reporting obligations. 
Example: While an event may be of “severe” intensity, it may be of relatively 
minor medical significance, such as severe headache. On the other hand, a 
myocardial infarction would be usually regarded as serious, even if its intensity is 
“mild”. 
Adverse events with changes in severity: If an AE changes in severity, this 
will be captured as 1 AE, with the highest severity grade recorded. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 77 of 82 
• Seriousness 
For definition of seriousness criteria refer to Section 9.3.1 For an SAE, all 
seriousness criteria that apply have to be reported. Reporting requirements by 
the investigator are detailed in Appendix 2. 
• Action Taken With Study Medication 
The action taken with study medication as a result of the AE has to be 
documented. In the situation that the AE leads to permanent discontinuation of 
the study medication, this meets the definition of an AE leading to subject’s 
withdrawal from the study, which is an IRAE. Reporting requirements by the 
investigator are detailed in Appendix 2. 
• Treatment for the Adverse Event 
It has to be specified in the eCRF if counteractive treatment was given for the 
AE. Any treatment for an AE, whether pharmacological or other (e.g., surgical) 
treatment, has to be recorded in the eCRF. 
• Outcome 
The following categories are used: 
 Resolved 
- 
Indicates that the event has fully resolved. 
 Resolving 
- 
Indicates that the event is in the process of recovery but has not 
yet fully resolved. 
 Not resolved 
- 
Indicates that the event is ongoing and there has been no recovery. 
 Resolved with sequelae 
- 
Indicates that there is a residual, possibly permanent consequence 
of the event (e.g., residual hemiparesis subsequent to stroke). 
 Fatal 
- 
Indicates that the subject died due to the event. The outcome “fatal” 
applies only to the event(s) that were the cause(s) of death. For 
other AEs that were ongoing at the time of death, the outcome 
must not be “fatal” but “not resolved”. 
• Causal Relationship of Adverse Events 
The causal relationship with the study medication has to be reported for each 
AE. It refers to the presence or absence of a reasonable possibility of a causal 
relationship between the study medication and the AE. The investigator is asked 
to use medical judgment and take into account the nature of the AE; subject’s 
medical history; temporal relation; response to withdrawal or interruption of study 
drug (dechallenge); response to reintroduction of study drug (rechallenge); and 
any alternative explanations such as underlying or concomitant diseases, 
concomitant drugs, or study procedures. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 78 of 82 
The following categories are used: 
 Related: There is a reasonable possibility of a causal relationship between 
the study medication and the AE. 
 Not related: There is no reasonable possibility of a causal relationship 
between the study medication and the AE. 
For SAEs and other IRAEs, the investigator is asked to specify if there are 
alternative and/or additional explanations for the occurrence of the event, 
e.g., concomitant drugs, study procedures, or concomitant/underlying disease, 
and should provide this information already with the initial case report. 
 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 79 of 82 
Appendix 2: "Reporting Procedures" 
Reporting Procedure: 
All IRAE/SAEs have to be recorded in the eCRF immediately, but not later than 
24 hours, after the investigational site becoming aware of the IRAE/SAE. In addition to 
the AE pages, the following eCRF pages have to be updated or completed at the same 
time as necessary: Subject accountability, study drug accountability, subject 
demographics, 
medical 
history, 
concomitant 
medication, 
and 
study 
completion/termination (in case of an AE leading to withdrawal). 
The investigator must report the IRAE/SAE by means of a paper IRAE/SAE form within 
24 hours of becoming aware of the event via fax or email to the following contact: 
Biotest Corporate Drug Safety 
Email  
 
Biotest Corporate Drug Safety 
Fax Number  
 
 Email 
 Fax Number 
 
For questions regarding IRAE/SAEs or to notify the sponsor of an IRAE/SAE in the 
event of technical failure of the email or fax system, the investigator should contact 
Biotest CDS by phone under 
 
Once the eCRF is available again, the investigator has to record the IRAE/SAE and all 
additional information as required immediately (within a maximum of 24 hours). 
Whenever follow-up information becomes available to a previously recorded IRAE/SAE, 
this has to be entered into the eCRF by the investigator immediately but not later than 
24 hours after becoming aware of the follow-up information. In addition, any supporting 
documents (e.g., medical records, autopsy report, ECG, or laboratory reports) as part of 
the follow-up information to an IRAE/SAE must be sent accompanied by a cover page 
and provided via fax or email within a maximum of 24 hours of the investigator 
becoming aware of the information to the reporting contact above. 
The investigator has to undertake active follow-up for subjects with IRAE/SAEs. The 
investigator shall respond to queries raised by the sponsor with regard to IRAE/SAEs 
within the timelines stipulated in the query, and provide all necessary information as 
requested. In case of a fatal or life-threatening SAE, the sponsor will contact the 
investigator urgently to obtain required additional information within 1 business day. If 
supporting documents are requested by the sponsor (e.g., copies of medical records, 
laboratory reports, ECG tracings, autopsy report), the investigator must ensure that 
subject identifying data are obliterated prior to sending to the sponsor. The supporting 
documents should carry the subject ID for identification. 
If required the investigator is responsible to inform local IECs/IRBs of safety reports in 
compliance with applicable regulatory requirements. Copies of all correspondence 
relating to reporting of safety reports to IECs/IRBs should be maintained in the 
Investigator Site File/Regulatory Binder. 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 80 of 82 
The sponsor is responsible for fulfilling all obligations regarding notification of 
Regulatory Authorities, ethics committees according to applicable regulatory 
requirements, in regard to expedited reporting (e.g., serious unexpected suspected 
adverse reactions) and periodic reporting (e.g., Development Safety Update Report). In 
addition, the sponsor is responsible for information of investigators according to the 
current legislation. 
 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 81 of 82 
Appendix 3: “Diagnostic Criteria for Serious Infection Types” 
 

Study No.: 991 
Final Version 4.0 
Clinical Study Protocol 
EudraCT No.: 2015-003652-52/ 
IND No.: 17046 
 
21-MAR-2018 
 
SOP-CCR-007-T001_2.0 
CONFIDENTIAL 
 Page 82 of 82 
 
Source: Food and Drug Administration Guidance for Industry: Safety, efficacy, and pharmacokinetic 
studies to support marketing of immune globulin intravenous (human) as replacement therapy for primary 
humoral 
immunodeficiency. 
June 
2008. 
Available 
from: 
http://www.fda.gov/downloads/ 
BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm078526.pdf.