A Phase III, Open-label, Prospective, Multicenter Study to Assess Efficacy, Safety and Pharmacokinetics of Kedrion Intravenous Immunoglobulin (IVIg) 10% in Primary Immunodeficiency Disease (PID) Patients
Phase: PHASE3
Conditions: Primary Immunodeficiency Disease
Sponsor: Kedrion S.p.A.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
Version 4, 30-November-2020 Amendment 2 to Version 2, 17-January-2019
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CLINICAL STUDY PROTOCOL KIG10_US3_PID01
Version 4, 30-November-2020
Amendment 2 to Version 2, 17-January-2019
A Phase III, Open-label, Prospective, Multicenter Study
to Assess Efficacy, Safety and Pharmacokinetics of 
Kedrion Intravenous Immunoglobulin (IVIg) 10% in 
Primary Immunodeficiency Disease (PID) Patients
Short Title: Clinical Assessment of phaRmacokinetics, Efficacy, and Safety of 10% IVIg in 
PID Patients (CARES10)
SPONSOR  
Kedrion S.p.A.
Loc. Ai Conti
55051 Castelvecchio Pascoli
Barga (Lucca) - Italy
STUDY CODE    
KIG10_US3_PID01
CONTRACT RESEARCH ORGANIZATION (CRO)
, MBA, PMP 
, 
Syneos Health
Headquarters
1030 Sync Street
Morrisville, NC 27560
Direct
Mobile
E-mail:
CENTRAL LABORATORY
Q2 Solutions - Valencia
27027 Tourney Road
Valencia, CA 91355
CRO STATISTICIAN
Syneos Health
Headquarters
1030 Sync Street
Morrisville, NC 27560
Tel: 
Email:
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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SPONSOR’S MEDICAL RESPONSIBLE
Kedrion S.p.A. 
Via Vittorio Veneto, 7
187 Roma Tel. 
E-mail: 
LEAD INVESTIGATOR
, MD
Tel. 
E-mail:
Confidentiality Statement
The information contained in this protocol is provided to you in confidence, for review by you, your 
staff and any applicable regulatory authority or Institutional Review Board/Independent Ethics 
Committee/Research Ethics Board. It is understood that this information may not be disclosed to 
any other party, in any form, without prior authorization from the Sponsor, except to the extent 
necessary to obtain informed consent from the persons to whom the drug may be administered.
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL KIG10_US3_PID01.............................................................. 1
CONFIDENTIALITY STATEMENT ............................................................................................ 2
TABLE OF CONTENTS............................................................................................................... 3
PROTOCOL SIGNATURE PAGE............................................................................................... 9
INVESTIGATOR STATEMENT.................................................................................................. 9
PROTOCOL SYNOPSIS ........................................................................................................... 11
TABLE 1.1:
TIME AND EVENTS TABLE FOR 28-DAY INFUSION SCHEDULE ......... 24
TABLE 1.2:
TIME AND EVENTS TABLE FOR 21-DAY INFUSION SCHEDULE ......... 27
1.
LIST OF ABBREVIATIONS ............................................................................................... 31
2.
BACKGROUND AND RATIONALE .................................................................................. 33
2.1
BACKGROUND .............................................................................................................. 33
2.2
RATIONALE.................................................................................................................... 35
2.3
BENEFITS AND RISKS ................................................................................................. 35
3.
OBJECTIVES...................................................................................................................... 39
3.1
PRIMARY OBJECTIVES ............................................................................................... 39
PRIMARY EFFICACY OBJECTIVE ........................................................................................ 39
SAFETY OBJECTIVE ............................................................................................................... 39
PHARMACOKINETIC OBJECTIVES...................................................................................... 39
3.2
SECONDARY OBJECTIVES ........................................................................................ 39
SECONDARY EFFICACY OBJECTIVES ............................................................................... 39
3.3
EXPLORATORY OBJECTIVES.................................................................................... 40
4.
STUDY DESIGN................................................................................................................. 41
4.1
OVERVIEW OF STUDY DESIGN................................................................................. 41
4.2
STUDY PERIOD............................................................................................................. 42
4.3
BLINDING AND RANDOMIZATION PROCEDURES................................................. 42
4.4
DATA COLLECTION...................................................................................................... 42
4.4.1
DATA COLLECTED FROM PATIENTS ................................................................... 42
4.4.2
TOOLS USED FOR DATA COLLECTION............................................................... 44

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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4.5
COLLECTION OF CLINICAL SPECIMENS................................................................. 47
4.6
STOPPING/PAUSING GUIDELINES ........................................................................... 48
4.7
DATA MONITORING COMMITTEE ............................................................................. 48
4.8
PREMATURE WITHDRAWAL FROM STUDY............................................................ 49
4.8.1
ADVERSE EVENT...................................................................................................... 50
4.8.2
DEATH......................................................................................................................... 50
4.8.3
WITHDRAWAL OF CONSENT ................................................................................. 50
4.8.4
LOST TO FOLLOW-UP.............................................................................................. 51
4.8.5
ADMINISTRATIVE REASON .................................................................................... 51
4.8.6
PROTOCOL COMPLIANCE...................................................................................... 51
4.9
END OF STUDY ............................................................................................................. 52
5.
SELECTION OF STUDY POPULATION.......................................................................... 52
5.1
INCLUSION CRITERIA.................................................................................................. 52
5.2
EXCLUSION CRITERIA................................................................................................. 53
6.
STUDY PROCEDURES..................................................................................................... 56
6.1
INFORMED CONSENT/ASSENT/ AUTHORIZATION TO ACCESS PERSONAL 
HEALTH INFORMATION .......................................................................................................... 56
6.2
SCREENING VISIT ........................................................................................................ 57
6.3
PATIENT IDENTIFICATION.......................................................................................... 58
6.4
ENROLLMENT................................................................................................................ 59
6.5
TREATMENT REGIMEN ............................................................................................... 59
6.6
BASELINE VISIT (DAY 1, WEEK 1)............................................................................. 60
6.7
TREATMENT VISITS ..................................................................................................... 60
6.8
REMINDER PHONE CALLS ......................................................................................... 62
6.9
UNSCHEDULED VISITS ............................................................................................... 62
6.10
STUDY TERMINATION VISIT....................................................................................... 62
6.11
EARLY TERMINATION VISIT....................................................................................... 63
7.
TREATMENT OF PATIENTS............................................................................................ 64
7.1
INVESTIGATIONAL MEDICINAL PRODUCT ............................................................. 64
7.1.1
METHOD OF ADMINISTRATION............................................................................. 64

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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7.1.2
SPECIAL WARNINGS AND PRECAUTIONS FOR USE ....................................... 65
7.1.3
CONTRAINDICATIONS............................................................................................. 70
7.1.4
INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS 
OF INTERACTIONS .................................................................................................................. 70
7.1.5
UNDESIRABLE EFFECTS ........................................................................................ 70
7.1.6
INSTRUCTIONS FOR USE....................................................................................... 71
7.1.7
EXPIRY AND STORAGE........................................................................................... 71
7.2
LABEL.............................................................................................................................. 72
7.3
INVESTIGATIONAL PRODUCT ACCOUNTABILITY AND DOCUMENTATION..... 74
7.4
DESTRUCTION OF USED (OR PARTIALLY USED) AND UNUSED STUDY DRUG
74
7.5
CONCOMITANT MEDICATIONS ................................................................................. 75
7.6
PROHIBITED MEDICATIONS....................................................................................... 75
7.7
MISUSE OF STUDY DRUG .......................................................................................... 76
8.
EFFICACY PHARMACOKINETIC, AND SAFETY VARIABLES.................................... 77
8.1
EFFICACY VARIABLES ................................................................................................ 77
8.1.1
SERIOUS BACTERIAL INFECTIONS...................................................................... 77
8.1.2
IGG LEVELS ............................................................................................................... 79
8.1.3
IGG SUBCLASSES/SPECIFIC ANTIBODIES LEVELS ......................................... 79
8.1.4
DAYS MISSED FROM WORK, SCHOOL, OTHER MAJOR ACTIVITIES DUE TO
INFECTIONS.............................................................................................................................. 80
8.1.5
INFECTIONS OTHER THAN SERIOUS ACUTE BACTERIAL INFECTIONS ..... 80
8.1.6
FEVER EPISODES .................................................................................................... 80
8.1.6.1
DAYS OF HOSPITALIZATIONS ............................................................................... 80
8.1.6.2
USE OF THERAPEUTIC ANTIBIOTICS .................................................................. 81
8.1.7
HEALTH CARE UTILIZATION .................................................................................. 81
8.1.8
QUALITY OF LIFE...................................................................................................... 81
8.1.8.1
PEDIATRIC QUALITY OF LIFE INVENTORY™..................................................... 81
8.2
SAFETY VARIABLES .................................................................................................... 81
CCI

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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8.2.1
VITAL SIGNS .............................................................................................................. 82
8.2.2
PHYSICAL EXAMINATION ....................................................................................... 82
8.2.3
CLINICAL LABORATORY ANALYSIS ..................................................................... 82
8.2.4
RETENTION OF SAMPLES FOR VIRAL SAFETY AND ANY FUTURE VIRAL 
TESTING..................................................................................................................................... 83
8.2.5
ADVERSE EVENT...................................................................................................... 83
8.3
DEMOGRAPHIC ASSESSMENT ................................................................................. 85
8.3.1
MEDICAL HISTORY AND DEMOGRAPHIC INFORMATION ............................... 85
8.3.2
CONCOMITANT MEDICATIONS.............................................................................. 85
8.3.3
CHEST X-RAY ............................................................................................................ 85
8.4
PHARMACOKINETIC ASSESSMENT (PK EVALUATION SET) .............................. 86
8.4.1
PK PARAMETERS OF TOTAL IGG ......................................................................... 86
8.4.2
IGG SUBCLASSES LEVELS..................................................................................... 87
8.4.3
PK PARAMETERS OF SPECIFIC IGG ANTIBODIES............................................ 87
9.
SAFETY REPORTING RULES......................................................................................... 88
9.1
DEFINITIONS ................................................................................................................. 88
9.1.1
ADVERSE EVENT/ADVERSE DRUG REACTION................................................. 88
9.1.2
SERIOUS ADVERSE EVENTS................................................................................. 88
9.1.3
UNEXPECTED ADVERSE DRUG REACTIONS .................................................... 89
9.1.4
CAUSALITY CORRELATION.................................................................................... 89
9.2
REPORTING METHODS............................................................................................... 90
9.2.1
SERIOUS ADVERSE EVENT/SERIOUS ADVERSE DRUG REACTIONS.......... 91
9.2.2
NON-SERIOUS ADVERSE EVENTS....................................................................... 91
9.2.3
ABNORMALITIES IN LABORATORY PARAMETERS........................................... 91
9.2.4
PRE-EXISTING AND CONCOMITANT DISEASES................................................ 92
9.2.5
PREGNANCIES.......................................................................................................... 92
9.2.6
INSTRUCTIONS FOR THE STUDY PERSONNEL REGARDING CLINICAL 
SIGNS AND SYMPTOMS ......................................................................................................... 92
10.
STATISTICAL CONSIDERATIONS.............................................................................. 94
10.1
ANALYSIS SETS............................................................................................................ 94

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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10.1.1
ALL PATIENTS ENROLLED SET............................................................................. 94
10.1.2
FULL ANALYSIS SET ................................................................................................ 94
10.1.3
SAFETY SET .............................................................................................................. 94
10.1.4
PER-PROTOCOL SET............................................................................................... 94
10.1.5
PHARMACOKINETIC EVALUATION SET............................................................... 94
10.2
DEMOGRAPHICS AND BASELINE CHARACTERISTICS........................................ 95
10.3
PRIMARY ENDPOINT ................................................................................................... 95
10.4
SECONDARY ENDPOINTS.......................................................................................... 96
10.4.1
SECONDARY EFFICACY ENDPOINTS.................................................................. 96
10.4.2
EXPLORATORY ENDPOINTS.................................................................................. 97
10.4.3
SAFETY ENDPOINTS ............................................................................................... 97
10.4.4
PHARMACOKINETIC ENDPOINTS......................................................................... 98
10.5
SCHEDULE OF ANALYSES ......................................................................................... 99
10.5.1
INTERIM PK ANALYSIS............................................................................................ 99
10.5.2
DSMB REVIEWS...................................................................................................... 100
10.6
SUBGROUPS ............................................................................................................... 100
10.6.1
AGE............................................................................................................................ 100
10.6.2
TREATMENT SCHEDULE ...................................................................................... 100
10.7
HANDLING OF MISSING DATA................................................................................. 100
10.8
PROTOCOL DEVIATIONS.......................................................................................... 100
10.9
SAMPLE SIZE............................................................................................................... 101
11
SOURCE DOCUMENTATION, STUDY MONITORING, AND AUDITING ............. 102
11.1
SOURCE DOCUMENTATION .................................................................................... 102
11.2
STUDY MONITORING, AUDITING, AND SOURCE DATA VERIFICATION ......... 103
11.3
QUALITY ASSURANCE PROCEDURES AND AUDITING...................................... 103
12
DATA MANAGEMENT................................................................................................. 105
12.1
DATA ENTRY AND MANAGEMENT.......................................................................... 105
12.2
DATA CLARIFICATION ............................................................................................... 105
12.3
DATA PROTECTION ................................................................................................... 105

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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13
RECORD RETENTION................................................................................................ 106
14
PROPERTY OF DATA AND PUBLICATION............................................................. 107
15
ETHICS.......................................................................................................................... 108
15.1
REGULATORY AND ETHICAL COMPLIANCE ........................................................ 108
15.2
INFORMED CONSENT PROCEDURES ................................................................... 108
15.3
RESPONSIBILITIES OF THE INVESTIGATOR AND IRB/IEC................................ 109
15.4
CONFIDENTIALITY...................................................................................................... 110
15.5
PROTOCOL AMENDMENTS...................................................................................... 111
16
REFERENCE LIST....................................................................................................... 112
17
APPENDIX A................................................................................................................. 115

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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PROTOCOL SIGNATURE PAGE
Protocol Number: KIG10_US3_PID01
VERSION 4, 30-November-2020
Amendment 2 to Version 2, 17-January-2019
INVESTIGATOR STATEMENT
By signing this statement, the Investigator declares receipt of a copy of protocol number 
KIG10_US3_PID01, entitled “A Phase III, Open-label, Prospective, Multicenter Study to Assess 
Efficacy, Safety and Pharmacokinetics of Kedrion Intravenous Immunoglobulin (IVIg) 10% in 
Primary Immunodeficiency Disease (PID) Patients” version 4 and dated 30-November-2020.
The Investigator declares that the clinical study will be carried out in compliance with the provisions 
of the protocol, with the Declaration of Helsinki, with the International Council for Harmonisation
(ICH) Good Clinical Practice (GCP) Guidelines and all applicable regulations and laws. 
The Investigator also declares the following:

To have the scientific qualifications and experience required to conduct clinical trials in the 
scientific area specified in the protocol; 

To have received all information needed to assess possible risks and adverse events (AEs) 
associated with the medical products to be used in the study, as described in the Investigator’s 
Brochure (IB), and that staff members will be properly informed; 

No changes shall be made to the protocol unless formally agreed upon with the Sponsor, 
except for emergency conditions that require the protection of safety, rights and welfare of the 
patients; 

All patients/parents/legal representatives will receive the Informed 
Consent/Assent/Authorization to access personal health information form(s); the Investigator
will collect patient’s/parent(s)’/legal representative’s signature on consent forms approved by 
the Sponsor and by the Independent Ethics Committee (IEC)/Institutional Review Board (IRB)
before patients will enter in the study;

Any clinical materials shall be used only in accordance with the protocol. The Investigator shall 
be responsible for the safety and documentation regarding the use of the trial drug supplies, 
devices supplies and any equipment provided on loan for use;

The electronic Case Report Forms (eCRF) shall be completed in a timely accurate manner. 
The “source documents” and the documents required for the study shall be archived as set 
forth by all applicable regulation; 

Monitoring visits will be permitted at a predetermined frequency or as needed; 

Inspections of the facilities and documents carried out by Competent Authorities (CAs) and 
representatives authorized by the Sponsor will be permitted, upon guarantee of confidential 
data protection; 

The Investigator is committed to send out all relative communications regarding the safety 
following the procedure described in the appropriate paragraph of the protocol; 

Any information obtained during the clinical trial must not be presented at scientific 
conferences or sent to scientific publications without prior authorization by the Sponsor. 

P P D
P P D
P P D
P P D

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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PROTOCOL SYNOPSIS
Sponsor Name: 
Kedrion S.p.A. - Loc. Ai Conti 55051 Castelvecchio Pascoli, Barga (Lucca) Italy
Product Name:
NA
Investigational Product:
Kedrion intravenous 
immunoglobulin (IVIg) 10%
Title of Study: 
A Phase III, Open-label, Prospective, Multicenter Study to Assess Efficacy, Safety and 
Pharmacokinetics of Kedrion Intravenous Immunoglobulin (IVIg) 10% in Primary Immunodeficiency 
Disease (PID) Patients.
Study Period:
Approximately 13 months, including a 21 or 28 days screening 
period, a 48 weeks treatment period, and 3 or 4 weeks follow-up 
(depending on treatment regimen)
Clinical Phase:
Phase III
Study Centers:
This study will be conducted at approximately 15 study centers in 2 countries, Canada and the 
United States.
Background and Rationale: 
Primary immunodeficiency diseases (PIDs) occur in individuals with a genetic defect in the immune 
system. As a consequence, patients are affected by recurrent protozoal, bacterial, fungal, and viral 
infections (Picard C, 2015). Antibody deficiencies, also referred to as B-cell or humoral 
immunodeficiencies, comprise the largest group of PIDs. This is a group of disorders characterized 
by an impaired ability to produce specific antibodies in response to antigen. Many of these 
disorders are caused by mutations in the immunoglobulin (Ig) genes or in genes involved in the 
regulation of B-cell growth and differentiation. Still, the molecular basis of most cases remains 
unknown.
The first antibody deficiency and best studied is X-linked agammaglobulinemia, which is caused by 
mutations in the Bruton tyrosine kinase (Bruton OC 1952; Bonilla FA, 2003). Loss-of-function 
mutations in this gene lead to a block in B-cell maturation, a near-total absence of B-cells in the 
periphery, and panagammaglobulinemia. Other autosomal recessive gene defects may lead to 
similar phenotype. Patients with agammaglobulinemia typically present with symptoms in early 
childhood but are usually well for the first 9 to 12 months of life because they are passively 
protected by transplacentally acquired IgG from their mothers. When symptoms present, they 
commonly appear as recurrent pyogenic infections such as otitis media, sinusitis, meningitis, 
conjunctivitis, pneumonia, and pyoderma mainly due to Haemophilus influenzae and 
Streptococcus pneumoniae (Rosen FS, 1995). Infrequently enteroviral infections with a chronic 
meningoencephalitis and a syndrome resembling dermatomyositis are present. Patients are also 
prone to mycoplasma pneumoniae infections.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Sponsor Name: 
Kedrion S.p.A. - Loc. Ai Conti 55051 Castelvecchio Pascoli, Barga (Lucca) Italy
Product Name:
NA
Investigational Product:
Kedrion intravenous 
immunoglobulin (IVIg) 10%
The largest group of patients with antibody deficiency is classified as common variable 
immunodeficiency (CVID), with an estimated prevalence of 1 in 50,000. Diagnosis of CVID is 
based on the exclusion of other known causes of humoral immune defects (Resnick ES, 2012). It 
is defined principally as low IgG (often with low IgA) together with a significant impairment of 
specific antibody production in response to bacterial vaccine or natural infectious challenge 
(Conley ME, 1999; Cunningham-Rundles C, 1999). Males and females are equally affected and 
presentation is most common at the ages of 20 to 40 with only about 20% of patients diagnosed in 
childhood. While some genetic defects have been shown to cause CVID, in most patients the 
molecular defect remains unknown. Signs and symptoms of CVID are generally that of recurrent 
pyogenic sino-pulmonary infections. The patients are also prone to infection with enteric 
pathogens, such as Giardia lamblia infection, and a variety of autoimmune disorders (Resnick ES, 
2012).
Polyclonal Ig preparations of human origin, including intravenous immunoglobulin (IVIg) products, 
have historically been used as replacement therapy to reduce the frequency of serious bacterial 
infections in patients with PID. Prior to the introduction of IVIg therapy, patients suffering from 
hypogammaglobulinemia and agammaglobulinemia due to PID experienced approximately 4 or 
more serious acute bacterial infections each year. However, maintenance of a trough serum level 
of ≥ 5g IgG/L controls most recurrent infections and their chronic complications, improving the 
patients’ quality of life (Roifman CM, 2008).
The study is being conducted to evaluate the efficacy, safety, and pharmacokinetics (PK) of 
Kedrion IVIg 10% (KIg10) in patients with PID, in accordance with the 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 (EMA) “Guideline on the 
clinical investigation of human normal immunoglobulin for intravenous administration (IVIg); 
EMA/CHMP/BPWP/94033/2007 rev. 3” and “Guideline on core SmPC for human normal 
immunoglobulin for intravenous administration (IVIg); EMA/CHMP/BPWP/94038/2007 Rev. 5.”

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Sponsor Name: 
Kedrion S.p.A. - Loc. Ai Conti 55051 Castelvecchio Pascoli, Barga (Lucca) Italy
Product Name:
NA
Investigational Product:
Kedrion intravenous 
immunoglobulin (IVIg) 10%
Study Objectives:
Primary Efficacy Objective
To assess the efficacy of KIg10 administered to patients with PID to demonstrate that the rate of 
acute serious bacterial infections (i.e., the mean number of acute serious bacterial infections per 
patient-year) is less than 1.0 to provide substantial evidence of efficacy from day 1 to week 51/52. 
Primary Safety Objective
To assess the safety of KIg10 in the overall study population from day 1 to week 51/52.
Pharmacokinetic Objectives
To assess distribution, metabolism, and elimination of KIg10 total IgG, IgG subclasses, and 
antigen specific IgGs at steady state in 20 adult PID patients with different dosing schedules.
To evaluate trough concentrations of total IgG and compare to IVIg trough concentrations prior to 
the study entry.
Study Design: 
This is a phase III, open-label, prospective, single arm, historically controlled, multicenter study to 
evaluate efficacy, safety, and PK of KIg10 in patients, aged 2 to 70 years at the time of screening, 
and affected by PID.
Enrollment of the 2 to 11 year-old pediatric patients will be delayed until acceptable safety and 
efficacy of KIg10 for the PID treatment of adolescents (12 to 17 years) or adults are demonstrated.
All patients will receive an intravenous infusion of KIg10 every 21 days or 28 days (depending on 
the treatment regimen determined by their attending physician) for a period of 48 weeks at the 
study site. The first infusion of KIg10 will mark the beginning of the investigation period and 
enrollment. Visits will be performed every 21 (±3) days or 28 (±4) days after each infusion until 
week 51, or 52 (i.e., study termination visit), depending on the patient’s treatment schedule (please 
refer to the table below).

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Sponsor Name: 
Kedrion S.p.A. - Loc. Ai Conti 55051 Castelvecchio Pascoli, Barga (Lucca) Italy
Product Name:
NA
Investigational Product:
Kedrion intravenous 
immunoglobulin (IVIg) 10%
Procedure
28-day regimen
(21-day regimen in parentheses)
Timing
Comments
Screening
Day -28 to day 0
(Day -21 to day 0)
up to 3/4 weeks prior to 
the first infusion
Infusion 1 
Week 1, Day 1
Baseline
Enrollment
Infusion 2-4 
(Infusion 2-4) 
Week 4 to 12
(Week 3 to 9)
PK Assessment 
Infusion 5, Week 16
(Infusion 7, Week 18)
For PK Evaluation Set
only
Infusion 6 to 13 
(Infusion 6 to 17) 
Week 20 to 48
(Week 15 to 48)
Study termination visit:
28 days after last infusion
(21 days after last infusion)
Week 52
(Week 51)
Up to 4 weeks after the 
last study infusion
After obtaining a signed informed consent form (ICF), assent form (as applicable), and 
authorization to access personal health information, the screening procedures will be performed. 
Screening will include documentation of diagnosis by the site Investigator.
A Patient Diary will be given to patients at each infusion visit to record adverse events (AEs), any 
medication taken including antibiotic treatment, infections of any type, fever episodes, days of 
hospitalizations, and days missed from major activities due to infections.
General (Pediatric Quality of Life Inventory [PedsQL™ Generic Core Scales]) and specific disease 
state
questionnaires will be administered to patients to evaluate the QoL. The PedsQL™ is a self-rated 
and proxy-rated questionnaire, and both versions include 23 items.
Based upon available data, health care utilization will be assessed also.
Patient satisfaction with participation and treatment during the study will be assessed.
Number of Patients Planned:
A sample size of at least 40 evaluable patients is considered a sufficient number to evaluate the 
primary study endpoint according to the relevant FDA and EMA guidelines. 
CCI
CCI

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Sponsor Name: 
Kedrion S.p.A. - Loc. Ai Conti 55051 Castelvecchio Pascoli, Barga (Lucca) Italy
Product Name:
NA
Investigational Product:
Kedrion intravenous 
immunoglobulin (IVIg) 10%
40 achieves 90% power to reject the null hypothesis of an acute serious bacterial infection 
incidence 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 0.49 per year (assuming a 
Poisson process). 
Approximately
adults of the
patients will have a PK profile analyzed before and after the 5th
study infusion for the 28-day infusion schedule and before and after the 7th infusion for the 21-day 
infusion schedule, to ensure data collection from at least 20 evaluable adult patients.  
Study Population and Patient Characteristics: 
Patients who have an acute infection at the time of screening (exclusion criterion #8) may be 
rescreened at the investigator’s discretion as long as the infection is not serious and is resolved by 
the time of rescreening.
Inclusion Criteria
Patients must meet the following inclusion criteria to be enrolled into the study.
1. Written informed consent/assent obtained from patients/patients’ 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.
2. Confirmed clinical diagnosis of a PID as defined by 2017 International Union of 
Immunological Societies (IUIS) Phenotypic Classification for Primary Immunodeficiencies 
(Bousfiha A, 2018) and requiring treatment with IVIg. Documented agammaglobulinemia
(defined as the total absence of one or more classes of antibodies) or 
hypogammaglobulinemia (defined as low levels of one or more classes [ie, at least 2 
standard deviations under the mean level per age]).
3. Male or female, ages 2 to 70 years at the time of screening.
4. Received 200 to 800 mg/kg of a commercially available IVIg therapy in the range of 21- or 
28-day intervals (±3 days or ±4 days, respectively) for at least 3 infusion cycles prior to 
screening.
(NOTE: Other IVIgs will be prohibited after ICF signature and until study end, week 51/52).
5. At least 2 documented IgG trough levels while receiving a IVIg, of ≥ 6 g/L obtained at 
2 infusion cycles within 12 months (1 must be within 6 months) prior to ICF signature.
CCI
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
Version 4, 30-November-2020 Amendment 2 to Version 2, 17-January-2019
Confidential
Sponsor Name: 
Kedrion S.p.A. - Loc. Ai Conti 55051 Castelvecchio Pascoli, Barga (Lucca) Italy
Product Name:
NA
Investigational Product:
Kedrion intravenous 
immunoglobulin (IVIg) 10%
6. Patient (and parent/guardian where applicable) is willing to comply with all requirements of 
the protocol.
7. Females of child-bearing potential with a negative urine pregnancy test and who agree to 
employ adequate birth control measures during the study.
8. Authorization to access personal health information.
9. Patients previously participating in a clinical trial with another experimental IVIg may be 
enrolled if they have received stable commercially available IVIg therapy for at least 
3 infusion cycles (21 or 28 days) prior to screening.
10. Patients currently on treatment with any subcutaneous immunoglobulin (SCIG) can be 
enrolled if they are switched to stable commercially available IVIg therapy for at least 
3 infusion cycles (21 or 28 days) prior to screening.
Exclusion Criteria
Patient must not meet any of the exclusion criteria to be enrolled into the study.
1. Newly diagnosed PID and naïve to IgG replacement therapy.
2. Dysgammaglobulinemia (defined as a deficiency in one or more classes of antibodies, but 
not severe enough to require substitutive therapy) or isolated IgG subclass deficiency, or 
profound primary T-cell deficiency (defined as the absence or severe reduction of T 
lymphocytes [CD3+ <300 cell/ mm3] and an absent or particularly low proliferative response
[10% of the lower normal range] to phytohaemagglutinin P [PHA]).
3. History of severe or serious reactions or hypersensitivity to IVIg or other injectable forms of 
IgG.
4. History of thrombotic events including deep vein thrombosis, cerebrovascular accident, 
pulmonary embolism, transient ischemic attacks, or myocardial infarction, as defined by at 
least 1 event in patient’s lifetime.
5. IgA deficiency with documented antibodies to IgA.
6. Received blood products that have not undergone viral inactivation measures within 
12 months prior to ICF signature.
7. Significant protein losing enteropathy, nephrotic syndrome, or lymphangiectasia.
8. An acute infection as documented by culture or diagnostic imaging and/or a body 
temperature ≥ 38°C (≥ 100.4°F) within 7 days prior to screening.
9. Acquired immunodeficiency syndrome (AIDS) and/or Hepatitis B/C active disease at ICF 
signature.
10. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 times of the 
upper limit of normal for the laboratory designated for the study.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
Version 4, 30-November-2020 Amendment 2 to Version 2, 17-January-2019
Confidential
Sponsor Name: 
Kedrion S.p.A. - Loc. Ai Conti 55051 Castelvecchio Pascoli, Barga (Lucca) Italy
Product Name:
NA
Investigational Product:
Kedrion intravenous 
immunoglobulin (IVIg) 10%
11. Using an implanted venous access device.
12. Profound anemia (hemoglobin < 10 g/dL) or persistent severe neutropenia 
(≤1000 neutrophils per mm3) or lymphopenia of less than 500 cells per microliter.
13. A severe chronic condition such as renal failure (creatinine concentration > 2.0 times the 
upper limit of normal*) with proteinuria, congestive heart failure (New York Heart 
Association III/IV), cardiomyopathy, cardiac arrhythmia associated with thromboembolic 
events (e.g., atrial fibrillation), unstable or advanced ischemic heart disease, hyperviscosity, 
or any other condition that the Investigator believes is likely to interfere with evaluation of 
the study drug or with satisfactory conduct of the trial.
* normal values for serum creatinine are the following: a) Female (18+ years): 45 - 84 
μmol/L or 0.51 - 0.95 mg/dl; b) Male (18+ years): 59 - 103 μmol/L or 0.67 - 1.17 mg/dl
14. History of a malignant disease other than properly treated carcinoma in situ of the cervix or 
basal cell or squamous cell carcinoma of the skin within 24 months prior to ICF signature.
15. History of pharmacoresistant epilepsy or multiple episodes of migraine (defined as at least 
1 episode within 6 months of ICF signature) not completely controlled by medication. 
16. Patient must not be receiving the following medication:
a) Steroids, oral or parenteral, at a daily dose of ≥ 0.15 mg/kg/day of prednisone or 
equivalent.
b) Other immunosuppressive drugs (including monoclonal antibodies) or chemotherapy.
17. Females who are pregnant, breast feeding, or planning a pregnancy during the course of 
the study. Women who become pregnant during the study will be withdrawn from the study.
18. Participated in another clinical study within 3 weeks prior to study ICF signature.
19. Active drug or alcohol abuse or history of drug or alcohol abuse within the 6 months before 
screening.
20. Employed or a direct relative of an employee of the Contract Research Organization, the 
study site, or the Sponsor.
21. Previously treated under this protocol.
22. Unable to provide informed consent or provide informed consent by a legally authorized 
representative.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
Version 4, 30-November-2020 Amendment 2 to Version 2, 17-January-2019
Confidential
Sponsor Name: 
Kedrion S.p.A. - Loc. Ai Conti 55051 Castelvecchio Pascoli, Barga (Lucca) Italy
Product Name:
NA
Investigational Product:
Kedrion intravenous 
immunoglobulin (IVIg) 10%
Study Procedures: 
At the screening visit, the signed ICF and authorization to access personal health information will 
be obtained from the patient or the patient’s parent(s)/legal guardian(s). The assent form will be 
also collected for children, as applicable according to local regulation.
Screening procedures will be performed up to 21 or 28 days (depending on the treatment regimen) 
prior to the first KIg10 infusion. During the screening, the diagnosis of PID will be confirmed by the 
site Investigator.
Each patient will be treated with the investigational product at a dose of 200 to 800 mg/kg body 
weight every 21 or 28 days for a period of 48 weeks (see protocol Time and Events table).
A blood sample will be obtained from all patients for evaluation IgG trough levels at screening, 
before each infusion, every 21 or 28 days during all study periods, and at the study termination 
visit.
Blood samples required for PK analysis will be taken before and after the 5th study infusion (for 
28-day infusion schedule) and the 7th study infusion (for 21-day infusion schedule) for those 
patients that consent to the PK portion of the study.
A pretreatment serum sample at the screening visit and a serum sample at the study termination 
visit will be collected and stored at ≤ -70°C for viral safety and possible future testing.
A Patient Diary will be given to the patient at each infusion visit. The patient and/or patient’s 
parent(s)/guardian(s) will be trained by the Investigator on how to complete the Patient Diary, starting 
after the first infusion. The Patient Diary will be collected at the following visit, data will be reviewed by 
the Investigator, and a new Patient Diary will be provided to the patient. 
The patient will be asked to complete QoL questionnaires (general and specific) at 3 visits as follows: 
at baseline (prior to first infusion of KIg10), at week 24 of treatment (infusion 7 for the 28-day schedule 
or infusion 9 for the 21-day schedule), and at the study termination visit. Patients who are unable to 
independently complete the questionnaires may enlist the assistance of a parent or caregiver.
During the study [at week 24 (infusion 7 for the 28-day schedule or infusion 9 for the 21-day 
schedule)] the patient will be asked to complete short assessment questionnaire (Appendix A to the 
protocol) about personal satisfaction with participation and treatment during the study.
Investigational Medicinal Product, Dosage Regimen and Route of Administration:
Immune Globulin Intravenous (Human) 10% solution. 
The product contains 100 mg human plasma protein per 1 mL solution, of which IgG represents at 
least 96%.
Dosage should be calculated so that the amount administered should match the patent’s 
previously individualized dosing regimen. 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
Version 4, 30-November-2020 Amendment 2 to Version 2, 17-January-2019
Confidential
Sponsor Name: 
Kedrion S.p.A. - Loc. Ai Conti 55051 Castelvecchio Pascoli, Barga (Lucca) Italy
Product Name:
NA
Investigational Product:
Kedrion intravenous 
immunoglobulin (IVIg) 10%
Modalities of Treatment Administration:

First infusion: infusion will proceed at an initial rate of 1 mg/kg/minute (0.01 mL/kg/min) for 
30 minutes. If well tolerated, the rate of administration may be increased to a maximum of 
8 mg/kg/minute (2 mg/kg/min – 0.02 mL/kg/min; 4 mg/kg/min – 0.04 mL/kg/min; 
6 mg/kg/min – 0.06 mL/kg/min; 8 mg/kg/min – 0.08 mL/kg/min) at 30 minute intervals.

Subsequent infusions: infusions will proceed at an initial rate of 2 mg/kg/minute 
(0.02 mL/kg/min) for 15 minutes. If well tolerated, the rate of administration may be 
increased to a maximum of 8 mg/kg/minute (4 mg/kg/min – 0.04mL/kg/min; 6 mg/kg/min –
0.06 mL/kg/min; 8 mg/kg/min – 0.08 mL/kg/min) at 15 minute intervals.
Efficacy Endpoints:
Primary Efficacy Endpoint
Incidence rate (i.e., the mean number of acute serious bacterial infections per patient-year) of 
acute serious bacterial infections [bacterial pneumonia, bacteremia/sepsis, bacterial meningitis, 
visceral abscess, osteomyelitis/septic arthritis] according to pre-specified criteria). 
Secondary Efficacy Endpoints

Serum IgG trough levels before each infusion of KIg10 and at the study termination visit 
(week 51/52).

IgG subclasses levels (IgG1, IgG2, IgG3, IgG4) before infusions 1, 5, 9, and 13 for the 
28-day infusion schedule and before infusions 1, 7, 11, and 17 for the 21-day infusion 
schedule.

Frequency of patients with total IgG below 6 g/L criteria.

Anti-tetanus toxoid antibody level (quantitative assay) before infusions 1, 5, 9, and 13 for 
the 28-day infusion schedule and before infusions 1, 7, 11, and 17 for the 21-day infusion 
schedule.

Anti-pneumococcal capsular polysaccharide antibody level (quantitative assay) before 
infusions 1, 5, 9, and 13 for the 28-day infusion schedule and before infusions 1, 7, 11, and 
17 for the 21-day infusion schedule.

Anti-measles antibody level (quantitative assay) before infusions 1, 5, 9, and 13 for the 
28-day infusion schedule and before infusions 1, 7, 11, and 17 for the 21-day infusion 
schedule.

Anti-Haemophilus influenza type b antibody level (quantitative assays), before infusions 1, 
5, 9, and 13 for the 28-day infusion schedule and before infusions 1, 7, 11, and 17 for the 
21-day infusion schedule.

Incidence rate (i.e., the mean number per patient-year) of any infection other than acute 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
Version 4, 30-November-2020 Amendment 2 to Version 2, 17-January-2019
Confidential
Sponsor Name: 
Kedrion S.p.A. - Loc. Ai Conti 55051 Castelvecchio Pascoli, Barga (Lucca) Italy
Product Name:
NA
Investigational Product:
Kedrion intravenous 
immunoglobulin (IVIg) 10%
serious bacterial infections from day 1 to week 51/52.

Duration of any infection other than acute serious bacterial infections day 1 to week 51/52.

Incidence rate (i.e., the mean number per patient-year) of fever episodes from day 1 to 
week 51/52.

Duration of fever episodes from day 1 to week 51/52.

Overall hospitalization days from day 1 to week 51/52.

Days of hospitalization due to infection from day 1 to week 51/52.

Incidence rate (i.e. the mean number per patient year) of patient on antibiotics for the 
treatment of any kind of infections from day 1 to week 51/52.

Duration of patient on antibiotics for the treatment of any kind of infections from day 1 to 
week 51/52.

Days of missed work/school/other major activities due to infections.

PedsQL™score at baseline, week 24, study termination visit.
Safety Endpoints:

Number of AEs (%) and proportion of patients experiencing at least 1 AE.

Number of serious AEs (SAEs) (%) and proportion of patients experiencing at least 1 SAE.

Number of related infusion AEs (%) occurring during infusion or within 1, 24, and 72 hours 
after the end of infusion, and proportion of patients experiencing at least 1 related infusion 
AE.

The proportion and number of KIg10 infusions for which the infusion rate is decreased due 
to AEs.

Number and proportion of infusions with 1 or more infusion (temporally) associated AE.

Changes in vital signs, physical examinations, and safety laboratory tests (hematology, 
CCI

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Page 21 of 115
Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
Version 4, 30-November-2020 Amendment 2 to Version 2, 17-January-2019
Confidential
Sponsor Name: 
Kedrion S.p.A. - Loc. Ai Conti 55051 Castelvecchio Pascoli, Barga (Lucca) Italy
Product Name:
NA
Investigational Product:
Kedrion intravenous 
immunoglobulin (IVIg) 10%
serum chemistry, and urinalysis).

The proportion and number of patients with a positive Coomb’s test following the 5th
infusion for the 28-day infusion schedule and the 7th infusion for the 21-day infusion 
schedule.

The proportion and number of patients with a positive urine hemosiderin test following the 
5th infusion for the 28-day infusion schedule and the 7th infusion for the 21-day infusion 
schedule.

Plasma-free hemoglobin level following the 5th infusion for the 28-day infusion schedule and 
the 7th infusion for the 21-day infusion schedule.

Serum haptoglobin level following the 5th infusion for the 28-day infusion schedule and the 
7th infusion for the 21-day infusion schedule.
Pharmacokinetics Endpoints (evaluated on approximately 24 adult patients in order to 
collect data on 20 evaluable patients):

Total IgG levels, IgG subclasses levels, and selected specific antibody levels before and 
after the 5th infusion for the 28-day infusion schedule and before and after the 7th infusion 
for the 21-day infusion schedule.

Pharmacokinetic parameters of total IgG and specific antibodies before and after the 5th
infusion for the 28-day infusion schedule and before and after the 7th infusion for the 21-day 
infusion schedule (i.e., concentration-time curve, half-life, area-under-the-curve [AUC 0-t; 
AUC0-in]), volume of distribution, concentration maximum [Cmax], Tmax, elimination rate 
constant).
Statistical Analyses:
A detailed statistical analysis plan (SAP) is provided with IND/CTA submission. Protocol deviations 
will be defined at the beginning, and data will be checked throughout the study on a regular basis 
(ICH E6 [R2] addendum). Protocol deviations will be described in the SAP.
The following populations are defined: The Full Analysis Set (FAS) comprises all patients who 
have received at least 1 dose of study medication. Safety Analysis Set (SAF) is coincident with 
FAS. Other populations will be defined. Efficacy end points will be analyzed on the FAS while 
safety endpoints will be analyzed on the SAF unless specified differently. The PK Evaluation Set 
will include all adult patients who consented to this part of the protocol and had PK analysis 
performed before and after the 5th infusion for the 28-day infusion schedule (or before and after the 
7th infusion for the 21-day infusion schedule).
Primary analysis of the primary endpoint will be performed on the FAS. Primary efficacy will be 
analyzed using a Poisson model using as offset the length of the observation period per patient in 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
Version 4, 30-November-2020 Amendment 2 to Version 2, 17-January-2019
Confidential
Sponsor Name: 
Kedrion S.p.A. - Loc. Ai Conti 55051 Castelvecchio Pascoli, Barga (Lucca) Italy
Product Name:
NA
Investigational Product:
Kedrion intravenous 
immunoglobulin (IVIg) 10%
years. The estimate and 1-sided 99% upper confidence limit will be reported. Efficacy will be 
claimed if this limit is less than 1.0. Supportive and sensitivity analyses will be performed as 
appropriate. Secondary and exploratory efficacy endpoints will be summarized using descriptive 
statistics.
Secondary safety endpoints will be summarized using descriptive statistics.
Additionally, a 1-sided 95% confidence interval (CI) will be produced for the proportion of infusions 
with 1 or more temporally-associated AEs (including AEs determined not to be product-related) 
using an exact binomial method. Due to the clustered nature of the data, a Design Effect will be 
applied to the CI. An analysis of variance method will be used to calculate the Intra Cluster 
Correlation Coefficient (Wu, 2012). For this analysis, safety will be declared if the upper 1-sided 
95% confidence is less than
 Other methods that take in account the clustered nature of the 
data could be performed (e.g., Generalized Estimating Equation).
Further details will be provided in the SAP.
Pharmacokinetic analysis of total IgG, IgG subclasses, and selected specific IgG antibody levels 
will be done by non-compartmental analysis. Pharmacokinetic parameters will be derived from 
serum IgG levels and summarized descriptively, taking into account doses of the drug. Trough 
levels for all patients will be summarized relative to dosing interval and age category. The 
frequency of patients with trough concentrations < 6 g/L will be estimated for each infusion 
number, dose level, and age category, as well as overall. All other data will be reported 
descriptively. Trough concentrations for total IgG at steady state achieved by the study drug will be 
compared to IVIg trough concentrations prior to the study entry using statistical model.
Interim PK analysis will be performed when approximately
adult patients (in order to have 
20 evaluable patients) complete intense PK sampling before and after infusion 5 for the 28-day
schedule and infusion 7 for the 21-day schedule.
Data Safety Monitoring Board:
A Data Safety Monitoring Board (DSMB) will be established for this study. The DSMB will be 
independent from Sponsor and Investigators. The primary responsibilities of the DSMB are to 
periodically monitor, review and evaluate the safety and infection data collected during study 
conduct.
The DSMB will be asked to review the full documentation for specific AEs and determine whether 
they meet the criteria for acute serious bacterial infections (as described in protocol Section 8.1.1, 
Serious Bacterial Infections), defining the study’s primary endpoint. Furthermore DSMB will be 
asked to review safety and efficacy data (in terms of IgG trough levels) on at least
adolescent or 
adult patients with 3 infusions (i.e., 3 months of exposure). After a positive evaluation, Kedrion
intends to continue studying the efficacy and safety of KIg10 in the young age group of PID patients 
(children < 
years of age).
CCI
CCI
CCI
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
Version 4, 30-November-2020 Amendment 2 to Version 2, 17-January-2019
Confidential
Sponsor Name: 
Kedrion S.p.A. - Loc. Ai Conti 55051 Castelvecchio Pascoli, Barga (Lucca) Italy
Product Name:
NA
Investigational Product:
Kedrion intravenous 
immunoglobulin (IVIg) 10%
DSMB will also review data that are indicative of intravascular hemolysis.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
Version 4, 30-November-2020 Amendment 2 to Version 2, 17-January-2019
Confidential
Table 1.1:
Time and Events Table for 28-day Infusion Schedule
Study Week
1 (Day 1)
4
8
12
16
20
24
28
32
36
40
44
48
52
Screening
Baseline
Visit 1
Treatment Visits
Study 
Termination 
Visit
Visit Number
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window (Days)
-28 to 0
n/a
+4
+4
+4
+4
+4
+4
+4
+4
+4
+4
+4
+4
+4
Infusion Number
1
2
3
4
5
6
7
8
9
10
11
12
13
STUDY EVENT
Study Treatment
IVIg infusion
X
X
X
X
X
X
X
X
X
X
X
X
X
Screening and safety
Informed Consent1
X
Medical History
X
Demography
X
Physical examination2
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Intravascular hemolysis testing 4
X
X
X
X
Chest X-ray5
X
Urinalysis 3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
X
Exclusion/Inclusion Criteria
X
Retention sample blood drawn6
X
X

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
Version 4, 30-November-2020 Amendment 2 to Version 2, 17-January-2019
Confidential
Study Week
1 (Day 1)
4
8
12
16
20
24
28
32
36
40
44
48
52
Screening
Baseline
Visit 1
Treatment Visits
Study 
Termination 
Visit
Visit Number
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window (Days)
-28 to 0
n/a
+4
+4
+4
+4
+4
+4
+4
+4
+4
+4
+4
+4
+4
Infusion Number
1
2
3
4
5
6
7
8
9
10
11
12
13
STUDY EVENT
Patient Diary reviewed and data 
collected7
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess any AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior and concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Efficacy
Assess serious bacterial 
infections
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fever episodes8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IgG levels3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IgG subclasses levels (Pre-
infusion)
X
X
X
X
Ab anti-measles and specific 
antibodies9 levels (Pre-infusion)
X
X
X
X
PK parameters of total IgG and 
specific antibodies (Pre and post 
infusion)9
X
Quality of life questionnaires10
X
X
X
Health care utilization
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
Version 4, 30-November-2020 Amendment 2 to Version 2, 17-January-2019
Confidential
Study Week
1 (Day 1)
4
8
12
16
20
24
28
32
36
40
44
48
52
Screening
Baseline
Visit 1
Treatment Visits
Study 
Termination 
Visit
Visit Number
2
3
4
5
6
7
8
9
10
11
12
13
Visit Window (Days)
-28 to 0
n/a
+4
+4
+4
+4
+4
+4
+4
+4
+4
+4
+4
+4
+4
Infusion Number
1
2
3
4
5
6
7
8
9
10
11
12
13
STUDY EVENT
Patient satisfaction 
questionnaire11
X
Study completion procedures
Study termination12
X
Abbreviations: Ab=antibody; AE=adverse events; IgG=immunoglobulin G; n/a = not applicable; 
; PedsQL™ = 
Pediatric Quality of Life Inventory; PK=pharmacokinetic(s).
1. Confirm consent and assent is obtained and the form(s) signed prior to any procedures.
2. Measure body weight at every visit for patients < 18 years of age. For adults (≥ 18 years of age), measure body weight at screening, baseline and weeks 12, 24, 36, 
and 48.
3. To be collected pre-infusion at all infusion visits.
4. Perform direct Coombs and tests for intravascular hemolysis (serum haptoglobin, plasma free hemoglobin, urine hemosiderin) post-infusion at all infusion visits.
5. If baseline X-ray within last 6 months is not available.
6. Two mL serum (approximately 4 mL of blood).
7. Reminder phone calls will be performed on day 2 or 3 after each scheduled infusion to remind the patient/parent(s)/legal guardian(s) about completion of the Patient 
Diary. The call follows the reminder telephone script provided to the site, and is not intended to be an interview for collection of safety data.
8. Fever will be defined as any temperature ≥38°C (≥100.4°F).
9. Specific antibodies refer to anti-tetanus toxoid, anti-pneumococcal polysaccharide and anti-haemophilus influenza.
10.Quality of life questionnaires will include PedsQL™, and 
.
11.The patient satisfaction questionnaire is provided in Appendix A to the protocol.
12.When a patient is withdrawn from treatment or withdraws from the study early, the Investigator will notify the Sponsor and, when possible, will perform the procedures 
as specified for the study termination visit.
CCI
CCI

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Page 27 of 115
Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
Version 4, 30-November-2020 Amendment 2 to Version 2, 17-January-2019
Confidential
Table 1.2:
Time and Events Table for 21-day Infusion Schedule
Study Week
1 (Day 1)
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
51
Treatment Visits
Visit Number
Screening
Baseline 
Visit 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Study 
Termination 
Visit
Visit Window (Days)
-21 to 0
n/a
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
Infusion Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
STUDY EVENT
Study Treatment
IVIg infusion
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Screening and safety
Informed Consent 1
X
Medical History
X
Demography
X
Physical Examination2
X
X 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood chemistry3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Intravascular hemolysis 
testing4
X
X
X
X
Chest X-ray5
X
Urinalysis3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy Test
X

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Study Week
1 (Day 1)
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
51
Treatment Visits
Visit Number
Screening
Baseline 
Visit 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Study 
Termination 
Visit
Visit Window (Days)
-21 to 0
n/a
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
Infusion Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
STUDY EVENT
Exclusion/Inclusion 
Criteria
X
Retention sample blood 
drawn6
X
X
Patient Diary reviewed 
and data collected7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess any AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior and concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Efficacy
Assess serious 
bacterial infections
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Fever episodes8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IgG levels3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
IgG subclasses (Pre-
infusion)
X
X
X
X

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Study Week
1 (Day 1)
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
51
Treatment Visits
Visit Number
Screening
Baseline 
Visit 1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Study 
Termination 
Visit
Visit Window (Days)
-21 to 0
n/a
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
+3
Infusion Number
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
STUDY EVENT
Ab anti-measles and 
specific antibodies (Pre-
infusion)9
X
X
X
X
PK parameters of total 
IgG and specific 
antibodies (Pre and 
post-infusion)9
X
Quality of life 
questionnaires10
X
X
X
Healthcare utilization
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient satisfaction 
questionnaire11
X
Study completion procedures
Study termination12
X
Abbreviations: Ab=antibody; AE=adverse events; IgG=immunoglobulin G; n/a = not applicable; 
; PedsQL™ = 
Pediatric Quality of Life Inventory; PK=pharmacokinetic(s).
1. Confirm consent and assent is obtained and the form(s) signed prior to any procedures.
2. Measure body weight at every visit for patients < 18 years of age. For adults (≥ 18 years of age), measure body weight at screening, baseline and weeks 12, 24, 36, 
and 48.
3. To be collected pre-infusion at all infusion visits.
4. Perform direct Coombs and tests for intravascular hemolysis (serum haptoglobin, plasma free hemoglobin, urine hemosiderin) post-infusion at all infusion visits. 
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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5. If baseline X-ray within last 6 months is not available.
6. Two mL serum (approximately 4 mL of blood).
7. Reminder phone calls will be performed on day 2 or 3 after each scheduled infusion to remind the patient/parent(s)/legal guardian(s) about completion of the Patient 
Diary. The call follows the reminder telephone script provided to the site, and is not intended to be an interview for collection of safety data.
8. Fever will be defined as any temperature ≥38°C (≥100.4°F).
9. Specific antibodies refer to anti-tetanus toxoid, anti-pneumococcal polysaccharide and anti-haemophilus influenza.
10.Quality of life questionnaires will include PedsQL™, and 
.
11.The patient satisfaction questionnaire is provided in Appendix A to the protocol.
12.When a patient is withdrawn from treatment or withdraws from the study early, the Investigator will notify the Sponsor and, when possible, will perform the procedures 
as specified for the study termination visit.
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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1.
LIST OF ABBREVIATIONS 
AE(s)/ADR(s)
Adverse event(s)/adverse drug reaction(s)
ALT 
Alanine aminotransferase
AMS
Aseptic meningitis syndrome
AST
Aspartate aminotransferase
AIDS
Acquired Immunodeficiency Syndrome
CFR
Code of Federal Regulations
eCRF(s)
Electronic case report form(s)
CSF
Cerebrospinal fluid
CVID
Common variable immunodeficiency
CRO
Clinical research organization
CT 
Computerized tomography
DSMB
Data Safety Monitoring Board
EDC
Electronic data capture
EMA
European Medicines Agency
IRB(s)/IEC(s)
Institutional Review Board(s)/Independent Ethics Committee(s)
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
ICH
International Council for Harmonization
ICF
Informed consent form
ID
Identification
Ig(s)
Immunoglobulin(s)
IMP
Investigational medicinal product
IUIS
International Union of Immunological Societies
IVIg
Intravenous immunoglobulin
Kg
Kilograms
KIg10
Kedrion intravenous immunoglobulin 10%
MedDRA
Medical Dictionary for Drug Regulatory Activities
mg
Milligram

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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ml
Milliliter
mm Hg
Millimeter of mercury
MRI
Magnetic resonance imaging
PedsQL™
Pediatric Quality of Life Inventory™
PID(s)
Primary immunodeficiency disease(s)
PK
Pharmacokinetic(s)
PPS
Per-Protocol Set
QoL
Quality of Life
RBC(s)
Red blood cell(s)
SAE(s)/SADR(s)
Serious adverse event(s)/serious adverse drug reaction(s)
SAF
Safety Set
SAP
Statistical analysis plan
SCIG
Subcutaneous immunoglobulin
SOPs
Standard operative procedures
TRALI
Transfusion-related acute lung injury
US
United States
WBC(s)
White blood cell(s)
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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2.
BACKGROUND AND RATIONALE
This study aims to evaluate the efficacy, safety, and pharmacokinetics (PK) of the Kedrion 
10% immunoglobulin preparation for intravenous administration (hereafter KIg10) in 
patients with primary immunodeficiency disease (PID), in accordance with Food and Drug 
Administration (FDA) guideline “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 (EMA) guidelines “Guideline on the clinical investigation of 
human normal immunoglobulin for intravenous administration (IVIg); 
EMA/CHMP/BPWP/94033/2007 rev. 3” and “Guideline on core SmPC for human normal 
immunoglobulin for intravenous administration (IVIg); EMA/CHMP/BPWP/94038/2007 
Rev. 5.”
KIg10 is a ready-to-use liquid normal immunoglobulin (Ig, 100 mg/mL) developed by 
Kedrion S.p.A. from source plasma obtained in the United States (US). The KIg10
manufacturing process includes 4 manufacturing steps, which are effective for viral 
removal/inactivation. The quality attributes, biological characteristics, and biological activity 
of the KIg10 product meet requirements of both US and European pharmacopoeias. In 
addition to the release testing, process intermediates, drug substance, and drug product
are further characterized by physicochemical standpoint.
2.1
BACKGROUND
Primary immunodeficiency disease occurs in individuals with a genetic defect in the immune 
system. As a consequence, patients are affected by recurrent protozoal, bacterial, fungal,
and viral infections (Picard C, 2015). Antibody deficiencies, also referred to as B-cell or 
humoral immunodeficiencies, comprise the largest group of PIDs. This is a group of 
disorders characterized by an impaired ability to produce specific antibodies in response to 
antigen. Many of these disorders are caused by mutations in the Ig genes or in genes 
involved in the regulation of B-cell growth and differentiation. Still, the molecular basis of 
most cases remains unknown.
The first antibody deficiency and best studied is X-linked agammaglobulinemia, which is 
caused by mutations in the Bruton tyrosine kinase (Bruton OC, 1952; Bonilla FA, 2003). 
Loss-of-function mutations in this gene lead to a block in B-cell maturation, a near-total 
absence of B-cells in the periphery, and panagammaglobulinemia. Other autosomal 
recessive gene defects may lead to similar phenotype. Patients with agammaglobulinemia 
typically present with symptoms in early childhood but are usually well for the first 9 to 
12 months of life because they are passively protected by transplacentally acquired IgG 
from their mothers. When symptoms present, they commonly appear as recurrent pyogenic 
infections such as otitis media, sinusitis, meningitis, conjunctivitis, pneumonia, and 
pyoderma mainly caused by Haemophilus influenzae and Streptococcus pneumoniae

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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(Rosen FS, 1995). Infrequently enteroviral infections with a chronic meningoencephalitis and 
a syndrome resembling dermatomyositis are present. Patients are also prone to 
Mycoplasma pneumoniae infections.
The largest group of patients with antibody deficiency are classified as common variable 
immunodeficiency (CVID) with an estimated prevalence of 1 in 50,000. Diagnosis of CVID is 
based on the exclusion of other known causes of humoral immune defects (Resnick ES, 
2012). It is defined principally as low IgG (often with low IgA) together with a significant 
impairment of specific antibody production in response to bacterial vaccine or natural 
infectious challenge (Conley ME, 1999; Cunningham-Rundles C, 1999). Males and females 
are equally affected, and presentation is most common at the ages of 20 to 40 with only 
about 20% of patients diagnosed in childhood. While some genetic defects have been 
shown to cause CVID, in most patients the molecular defect remains unknown. Signs and 
symptoms of CVID are generally that of recurrent pyogenic sino-pulmonary infections. The 
patients are also prone to infection with enteric pathogens, such as Giardia lamblia infection, 
and a variety of autoimmune disorders (Resnick ES, 2012). A number of studies have 
demonstrated the steadily decreasing incidence of infection with increasing frequency of 
IVIg administration in CVID patients. 
In PID diseases with primary antibody deficiency and bacterial infections, lifelong 
replacement therapy with IgG is required and necessary to reduce incidence (frequency)
and severity of infections and prevent long-term deterioration principally in pulmonary 
functions. Treatment recommendation is that patients with primary antibody deficiency 
should be treated with IVIg at a starting dose of 400-600 mg/kg every 3 to 4 weeks (Jolles S,
2015). Less frequent treatment, or use of lower doses, is not substantiated by clinical data.
Each patient may demonstrate his or her own individual response to therapy, and 
experience dramatic differences in the frequency and severity of infections with moderate 
changes in the dose of IVIg (Shapiro RS, 2017). Patients suffering from a serious acute 
infection often benefit from booster doses of IVIg. Ultimately, IVIg dosage must be 
individualized based upon the response of the patient (frequency of infection episodes)
and potential serious complication of the primary disease (e.g., bronchiectases).
Quality of Life
The direction of healthcare is moving toward patient satisfaction scores and perception of 
health. Quality of life (QoL) assessment is valued not only by patients, as they are able to 
directly contribute to the evolution of their care, but is also considered a measure of 
efficacy. Quality of life data are used to provide evidence to be used in making critical 
clinical decisions; it influences managed care, formulary, and purchasing decisions; and 
positively contributes to the body of scientific knowledge. Contemporary studies of IVIG in 
treatment of PID patients need to address QoL as an outcome measure to provide 
information to providers, patients, and payers (Routes J, 2016). The Pediatric Quality of Life 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Inventory™ (PedsQL™) is a self-rated and proxy-rated questionnaire, and both versions 
include 23 items (Varnj JW, 2005).
2.2
RATIONALE
Polyclonal Ig preparations of human origin, including IVIg products, have historically been 
used as replacement therapy to reduce the frequency and severity of serious bacterial 
infections in patients with PID. Prior to the introduction of IVIg therapy, patients suffering 
from hypogammaglobulinemia and agammaglobulinemia due to PID experienced 
approximately 4 or more serious acute bacterial infections each year. However, 
maintenance of a trough serum level of ≥ 5 g IgG/L controls most recurrent infections and 
their chronic complications, improving the patients’ quality of life (Roifman 2008).
With this clinical trial, Kedrion provides more treatment choice in the area of IgG therapy for 
PID patients and new insight regarding QoL prior to initiation of treatment compared to QoL 
following the initiation of KIg10. After performing the clinical trial and successive 
authorization of KIg10 in PID, Kedrion will take a part in stability for IVIg market’s supply and 
will confirm tolerability of IgG therapy as state of art treatment of these patients. Performing 
this clinical trial, Kedrion makes a higher scientific guarantee for using IgG in PID patients 
and at the same time provides the availability on various IgG production lines, allowing 
selection between different IgG products as to which is the most suitable (Feldmeyer L,
2010).
This study is being conducted to evaluate the efficacy, safety, and PK of KIg10 in PID 
patients. Furthermore this study will, for the first time, assess QoL and health care utilization 
data in PID patients.
The results obtained from this study will support the licensure of the product for the 
treatment of adult patients affected by PID.
2.3
BENEFITS AND RISKS
Replacement Ig therapy is standard practice for patients with PID. Most patients receive IVIg
infusions at intervals of 3 or 4 weeks. Reductions in hospitalization and infection rates have 
been well documented in patients receiving high dose (> 400 mg/kg every 3 weeks) IVIg, 
and maintaining trough levels of IVIg above 5 g/L is considered a reasonable standard of 
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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The main goal of replacement therapy in PID is to provide sufficient level of missing Ig to 
fight against common bacterial agents. To provide quantitative data about sufficient levels of 
IgG in PID patients during the clinical trial with KIg10, PK sampling will be performed. 
Determination of Ig levels through the PK parameters in PID patients is desirable for several 
important reasons. First, performing PK assessment in PID patients provides data about 
biological integrity of IVIg, measuring total IgG level. Assessment of PID PK parameters 
equips clinicians with the tools to rationally design IVIg therapeutic regimens (dosing) in 
order to maximize clinical benefits. Second, PK profile of specific immunoglobulins (Igs)
(e.g., antibodies against bacterial antigens (as H. influenzae and toxins), provides indirect 
proof that the IVIg administered in the study contains sufficient level of specific antibodies 
against the most common bacterial antigens which cause damage to the organs (primarily 
the lungs).
The expected adverse events (AEs) occurring with IVIg treatment have been described in 
the “Guideline on core SmPC for human normal immunoglobulin for intravenous 
administration (IVIg), EMA/CHMP/BPWP/94038/2007 Rev. 5”, in literature, and in clinical 
trials with PID patients (Schroeder HW, 2012). The incidence of AEs considered to be 
related to the study IVIg in earlier PID trials ranged from 5-27.6 % (Schroeder HW, 2012).
Safety monitoring during this trial will be managed through different levels of caution.
After all screening procedures have been conducted and reviewed by the site principal 
investigator, the patient’s eligibility assessment will be carried out by the CRO’s Medical 
Monitor, who will consult the study principal investigator for confirmation as needed, based 
on key protocol inclusion and exclusion criteria to promote appropriate patient enrollment 
and data quality. Sites should submit specific Screening information as soon as possible 
after the Screening Visit, but only when all required information is available, for review by the 
Medical Monitor prior to proceeding to the Baseline visit. Patients who are deemed eligible 
by the Medical Monitor will be allowed to proceed in the study.
Initially the trial will include adult PID patients and adolescents in whom data will be 
collected. The data of at least 10 patients with at least 3 infusions (i.e., 3 months of 
exposure) will be reviewed by a Data Safety Monitoring Board (DSMB), and after positive 
evaluation, Kedrion intends to continue studying the efficacy and safety of KIg10 in the 
young age group of PID patients (children < 12 years of age).
There is no risk to the patient in completing QoL questionnaires and self-reported health 
care utilization. Completion of questionnaires and reporting of data could be beneficial in 
determining the continuous utilization of IVIg in the treatment of PID.
The selected study centers are highly specialized centers with previous experience in the 
treatment of PID patients with IVIg as well as with experience in clinical trials. Patients will 
have diaries, and local medical staff will contact them to check on their well-being when they 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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are not at a regular site-scheduled visit. All patients will have the first infusion of IgG at a 
lower infusion speed which may be gradually increased based on individual experience and 
tolerance. Higher infusion speed might play an important role in determining the safety 
profile of the product (Cherin P, 2016). 
The following adverse reactions are known occasionally to be associated with IVIg products: 
chills, headache (which is the most frequent AE described in previous clinical trials with IVIg
in PID patients, range 22-52% of patients) (Schroeder HW, 2012), dizziness, fever, vomiting, 
allergic reactions, nausea, arthralgia, low blood pressure, and moderate low back pain.
Rarely, Ig therapy may cause a sudden fall in blood pressure and, in isolated cases, 
anaphylactic shock, even when the patient has shown no hypersensitivity to previous
administration.
Cases of reversible aseptic meningitis (Schroeder HW, 2012), and rare cases of transient 
cutaneous reactions (including cutaneous lupus erythematous – frequency unknown) have 
been observed with human normal Ig. Reversible hemolytic reactions have been observed 
in patients, especially those with blood groups A, B, and AB. Rarely, haemolytic anemia 
requiring transfusion may develop after high dose IVIg treatment. A specific test for early 
detection of hemolysis will be performed during this clinical trial (see Section 8.2.3, Clinical 
Laboratory Analysis). The appearance of Coombs positivity after infusion of the study IVIgs 
occurred in few clinical trials. The proportion of patients that became Coombs-positive after 
infusion varied from 8.5 to 47%. However, none of the patients in any of earlier trials 
developed evidence of hemolysis or anemia (Schroeder HW, 2012).
Increase in serum creatinine level and/or acute renal failure have been observed (in most 
patients with pretreatment known damage of kidney function). Very rarely, thromboembolic 
reactions such as myocardial infarction, stroke, pulmonary embolism and deep vein 
thrombosis have been observed. In previous clinical trials with PID patients only 1 serious 
AE (SAE) of thrombosis was reported (Moy JN, 2010). If thrombosis occurs, arterial 
thrombosis is present in about 80% of all patients after using IVIg, and venous thrombosis is 
seen in the remaining number of patients. There are different risk factors which could play 
an important role in developing this SAE after IVIg administration. Risk factors connected 
directly with patient characteristics are advanced age, pre-existing vascular risk factor in 
general, immobilization, or hereditary hypercoagulability conditions. Some co-medications
and risk factors directly related to IVIg product and method of administration for the first ever 
infusion of IVIg are large dose, high infusion rate, and presence of contaminants in IVIg
product such as activated factor XI, factor XII or pre-kallicrein activator (Cherin P, 2016). The 
careful monitoring of patients treated with IVIg for thrombosis is necessary, even if the risk 
for thrombosis is small, not only in the first few days after the infusion of IVIg, but also 
several weeks later (Sentinel Blood SCAN study, 2017). Very rarely, cases of Transfusion 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Related Acute Lung Injury (TRALI) have been reported in patients administered IVIg 
products.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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3.
OBJECTIVES
The purpose of this study is to evaluate the efficacy, safety, and PK of KIg10 in patients 
with PID in accordance both with FDA and EMA guidelines as specified previously.
3.1
PRIMARY OBJECTIVES
Primary Efficacy Objective
To assess the efficacy of KIg10 administered to patients with PID to demonstrate that 
the rate of acute serious bacterial infections (i.e., the mean number of acute serious 
bacterial infections per patient-year) is less than 1.0 to provide substantial evidence of 
efficacy from day 1 to week 51/52.
Safety Objective
To assess the safety of KIg10 in the overall study population from day 1 to week 51/52.
Pharmacokinetic Objectives
To assess the distribution, metabolism, and elimination of KIg10, total IgG, IgG 
subclasses, and antigen-specific IgGs at steady state in 20 adult PID patients with 
different dosing schedules.
To evaluate trough concentrations of total IgG and compare to IVIg trough 
concentrations prior to the study entry.
3.2
SECONDARY OBJECTIVES
Secondary Efficacy Objectives
To assess the efficacy of KIg10 administered to patients with PID as measured by:
1. IgG trough levels before each infusion and at the study termination visit 
(week 51/52).
2. IgG subclasses levels (IgG1, IgG2, IgG3, IgG4) before infusions 1, 5, 9, and 13 
for the 28-day infusion schedule and at infusions 1, 7, 11, and 17 for the 21-day
infusion schedule.
3. Anti-tetanus toxoid, anti-pneumococcal capsular polysaccharide, anti-
Haemophilus influenza, and anti-measles antibodies levels before infusions 1, 5, 
9, and 13 for the 28-day infusion schedule and before infusions 1, 7, 11, and 17 
for the 21-day infusion schedule.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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4. Occurrence and duration of any infection other than acute serious bacterial 
infections, from day 1 to week 51/52.
5. Occurrence and length of fever episodes, from day 1 to week 51/52.
6. Occurrence and duration of overall hospitalization, from day 1 to week 51/52.
7. Occurrence and duration of hospitalization due to infection, from day 1 to week 
51/52.
8. Occurrence and duration of patients on antibiotics for the treatment of any kind 
of infections, from day 1 to week 51/52.
9. The missed days of work/school/other major activities due to infections, from 
day 1 to week 51/52.
10.Quality of life using the PedsQL™questionnaires collected at baseline, at 
24 weeks (infusion 7 for the 28-day schedule and infusion 9 for the 21-day 
schedule), and at the study termination visit.
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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4.
STUDY DESIGN
4.1
OVERVIEW OF STUDY DESIGN
This is a phase III, open-label, prospective, single arm, historically controlled, 
multicenter study to evaluate efficacy, safety and PK of KIg10 in patients, aged
2 to 70 years at the time of screening and affected by PID.
However, enrollment of the 2 to 11 year-old pediatric patients will be delayed until 
acceptable safety and efficacy of KIg10 for the PID treatment of adolescents (age 
12 to 17) or adults are demonstrated.
All patients will receive an intravenous infusion of KIg10 every 21 or 28 days
(depending on the treatment regimen determined by their attending physician) for a 
period of 48 weeks at the study site. The first infusion of KIg10 will mark the beginning 
of the investigation period and enrollment, which is further described in Section 6.4. 
Visits will be performed every 21 (± 3) days or 28 (± 4) days after each infusion until 
week 51, or 52 (i.e., study termination visit), depending on the patient’s treatment 
schedule (please refer to the table below).
Procedure
28-day regimen
(21-day regimen in parentheses)
Timing
Comments
Screening
Day -28 to day 0
(Day -21 to day 0)
Up to 3 to 4 weeks prior to the 
first infusion
Infusion 1
Week 1, Day 1
Baseline
Enrollment 
Infusion 2 to 4
(Infusion 2 to 4)
Week 4 to 12
(Week 3 to 9)
PK assessment 
Infusion 5, Week 16 
(Infusion 7, Week 18)
For PK Evaluation Set only
Infusion 6 to 13
(Infusion 6 to 17)
Week 20 to 48
(Week 15 to 48)
Study termination visit:
28 days after last infusion
(21 days after last infusion)
Week 52
(Week 51)
Up to 3 to 4 weeks after the 
last study infusion

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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After obtaining a signed informed consent form (ICF), assent form (as applicable), and 
authorization to access personal health information, the screening procedures will be 
performed. Screening will include documentation of diagnosis by the site Investigator.
A Patient Diary will be given to patients at each infusion visit to record AEs, any
medication taken including antibiotic treatment, infections of any type, fever episodes,
days of hospitalizations, and days missed from major activities due to infections.
General and specific disease state questionnaires will be administered to patients to 
evaluate QoL.
Health care utilization data will also be collected during the study.
Patient personal satisfaction with participation and treatment during the study will be 
assessed.
The study design is in compliance with both FDA and EMA guidance as specified 
previously, except for the pediatric enrollment being lower than that required by FDA 
and EMA for market approval.
4.2
STUDY PERIOD
Each patient should expect to participate in the study for approximately 13 months
from the time of signing informed consent through the last study visit, including a 21-
or 28-day screening period, a 48-week treatment period, and 3- or 4-week study 
termination visit (depending on the treatment regimen).
4.3
BLINDING AND RANDOMIZATION PROCEDURES
This is an open-label study; no blinding and randomization procedures will be applied.
4.4
DATA COLLECTION
4.4.1
DATA COLLECTED FROM PATIENTS
The following data will be collected from each patient during their study 
participation:

Medical history, including infections history, tolerance of previous IgG 
treatment, antibody response to pneumococcal vaccination (when 
available), and documentation of the last 3 commercially available IVIg
infusions before the study entry.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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NOTE that any potential undesirable effect from screening to infusion 
1 will be reported as medical history. Those effects considered serious 
and related to prior IVIg, will also be notified to the marketing 
authorization holder.

Demographic information including date of birth, gender, and ethnicity.

Physical examination (evaluation of all body systems and body weight).

Vital signs (blood pressure, heart rate, and temperature).

Adverse events.

Relevant prior and concomitant medications, including antibiotic 
treatment.

Days missed from work/school/other major activities due to an infection.

Fever episodes.

Hospitalizations.

Chest X-ray obtained within 6 months prior to enrollment.

Laboratory analysis including hematology, blood chemistry, urinalysis,
and intravascular hemolysis testing.

Pregnancy test on urine (only for females of childbearing age).

IgG levels throughout the study, and 2 documented IgG levels within 
12 months (1 being within 6 months) prior to enrollment.

IgG subclasses levels (IgG1, IgG2, IgG3, IgG4).

Specific antibodies levels (anti-tetanus toxoid, anti-pneumococcal 
polysaccharide, anti-measles, and anti-haemophilus influenza).

PK parameters of total IgG and specific antibodies (anti-tetanus toxoid, 
anti-pneumococcal polysaccharide, and anti-haemophilus influenza) (PK 
Evaluation Set only).

QoL questionnaires (PedsQL™and 
).

Health care utilization data as measured by the need for any care in 
addition to the protocol-defined standard of care visits and items listed in 
the Schedule of Events (e.g., additional visits to health clinic, doctor 
office, urgent care center, hospital; additional prescription medications; 
additional therapies, etc).

Study-specific questionnaire to evaluate patient satisfaction with 
participation and treatment during the study (Appendix A).
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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4.4.2
TOOLS USED FOR DATA COLLECTION
Data will be recorded in medical records and Patient Diary, and collected on 
electronic case report form (eCRF).  
Patient Diary
Patients, and/or patient’s parent(s)/legal guardian(s), will be given a Patient 
Diary at each infusion visit. The Investigator will explain that the diary is a very 
important study document and that entries should be made daily in order to 
collect all safety and efficacy data. The Investigator will train the patient and/or 
patient’s parent(s)/legal guardian(s) on how to complete the Patient Diary, 
starting at the first infusion visit. The Patient Diary will be collected at the 
following visit, data will be reviewed by the Investigator, and a new Patient 
Diary provided to patients at every visit. The patient/patient’s parent(s)/legal 
guardian(s) will enter the following information in the diary:

All AEs that occurred since the previous study infusion with special 
emphasis on AEs during the first 24 and 72 hours after infusion, and 
infections of any type as diagnosed by a physician or other qualified 
personnel.
NOTE: Infusion AEs during the infusion and within 1 hour after the 
infusion will be collected at the site, not at home with the Patient Diary.

Any medication taken, prescription and non-prescription, including 
antibiotic treatment.

Days missed from work/school/other major activities due to an infection.

Fever episodes.

Days of hospitalization.
The Patient Diary will be collected and reviewed by the Investigator at the clinic 
visit. Any additional information will be recorded on the source document and 
collected in the eCRF.
The following additional rules apply to documentation of safety information 
collected in the Patient Diary:
1. No corrections or additions to the Patient Diary will be allowed after it is 
reviewed by the site study staff.
2. Any blank or illegible fields on the Patient Diary must be described as 
missing in the eCRF.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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3. Any corrections to the Patient Diary must be performed by the person 
completing the Patient Diary and should include a single strike through 
line through the incorrect value or text with a brief explanation for each 
change, the initials of that person, and date of correction.
Case Report Forms
This study utilizes eCRFs to collect study-related data from each patient. A 
qualified and trained site staff member(s) is required to enter patient data in the 
eCRFs based on the medical information available in each patient’s source 
record.
The following additional rules apply to documentation of Patient Diary 
information collected in the eCRFs:
1. The site must enter all readable entries in the Patient Diary into the 
eCRF.
2. Any illegible or implausible data (e.g., those values that may be 
biologically implausible - body temperature: 400°C) should be reviewed 
with the patient and parent(s)/legal guardian(s). If an AE is described 
upon review with the patient, this should be described in the source 
document and in the eCRF (e.g., if the patient above confirms body 
temperature of 40°C on the day in which body temperature: 400°C was 
written into his/her Patient Diary, this fever of 40°C should be recorded in 
the AE eCRF).
3. Any newly described safety information must not be written into the 
Patient Diary and must be described in the source document as a 
verbally reported AE. Any AE reported in this fashion must be entered on 
the eCRF.
4. Data should be entered into the eCRF within 72 hours following each 
patient’s clinic visit or study procedure. Each patient’s eCRF casebook 
will be compared with the patient’s source records by a Sponsor-
approved study monitor (or designee) over the duration of the study in 
order to ensure data collection accuracy.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Quality of Life Questionnaires
1. PedsQL™: The PedsQL™Measurement Model is a modular approach to 
measuring health-related QoL in healthy children and adolescents and those 
with acute and chronic health conditions. The 23-item PedsQL™Generic 
Core Scales were designed to measure the core dimension of health as 
delineated by the World Health Organization, as well as role (school) 
functioning (www.pedsql.org). This tool can be used across different 
countries and ages, including adults.
Scales
Summary Scores
Physical Functioning (8 items)
Total Scale Score (23 items)
Emotional Functioning (5 items)
Physical Health Summary Score 
(8 items)
Social Functioning (5 items)
Psychosocial Health Summary 
Score (15 items)
School Functioning (5 items)
CCI

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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4.5
COLLECTION OF CLINICAL SPECIMENS
Blood and urine clinical specimens will be collected from each patient. Processing of 
each specimen is to be completed by a qualified site member and in accordance with 
the study-specific Clinical Specimen Laboratory Manual. Testing of clinical specimens 
will be performed by a designated laboratory. 
Refer to the study-specific Clinical Specimen Laboratory Manual for additional details.
Blood Specimens
A total of approximately 25 to 35 mL of blood will be drawn from all patients at 
screening, baseline, Study Visits 11 and 17 (for 21-day infusion patients), Study Visits 
9 and 13 (for 28-day infusion patients, and at the study termination visit (Week 51/52).
At each PK time point (Visit 4 for 21-day infusion patients and Visit 7 for 28-day 
infusion patients, approximately 20 to 25 mL of blood will be drawn. At all other visits, 
approximately 10 mL of blood will be drawn. In addition, a pretreatment serum sample
at the screening visit and a serum sample at the study termination visit (retention 
samples) from each patient will be taken and stored at a temperature ≤ -70°C at the 
central laboratory for at least 2 years following study closure (last patient last visit), for 
viral safety and possible future viral testing. 
The blood samples collected from young/small children enrolled in this study will not 
exceed the recommended safety limits based on child’s size (Toronto Hospital for Sick 
Children Research Ethics Board) to avoid placing children at unreasonable risk of 
severe anemia and its complications (Howie SRC, 2011). Existing guidelines for blood 
sample volume limits (ranging from 1 to 5% of total blood volume within 24 hours and 
up to 10% of total blood volume over 8 weeks) are consistent with the limited evidence 
available on “minimal risk” to children. This specification is met if children are over 
12.2 kg and should be fulfilled for children ≥2 years of age.
Urine Specimens
Urine will be collected for pregnancy testing in females of child bearing potential at 
screening. In addition, urinalysis will be performed in all patients at each visit, 
including the screening visit and the study termination visit (week 51/52). 
NOTE: If clinical specimens other than those listed above are to be collected, specific 
purpose, date of collection and amount of sample, must be recorded in the source 
document and in the eCRF (as unscheduled visits).

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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4.6
STOPPING/PAUSING GUIDELINES
Investigational New Drug Safety Reports will be submitted to the FDA according to 
21 Code of Federal Regulations (CFR) 312.32 requirements and submitted to Health 
Canada.
If safety concerns arise during the study that indicate the study should be stopped, the 
Sponsor will terminate the study (21CFR 312.56[d]). 
Safety concerns that will be evaluated by the Sponsor and the DSMB will include the 
following:

Serious or life-threatening adverse drug experiences that are clearly related to 
the investigational product. 

Unexpected adverse drug experience related to treatment with the 
investigational product.

Suspected thrombotic events.
In addition, conditions that may warrant study termination at a particular site, include, 
but are not limited to, the following (21CFR 312.56[b]):

The discovery of unexpected and significant or unacceptable risks for the 
patients in the study, usually arising due to Good Clinical Practice (GCP)
violations.

A decision of the sponsor to suspend or terminate enrollment at a site due to 
low/no recruitment, noncompliance, or GCP issues.
If the trial is prematurely terminated or suspended, the Sponsor will inform the 
investigators, the Institutional Review Boards (IRBs) and the FDA promptly of the 
termination or suspension and the reason(s) for the termination or suspension.
Patients may be withdrawn from the study according to Investigator discretion as 
described in Section 4.8, Premature Withdrawal from Study.
4.7
DATA MONITORING COMMITTEE
The DSMB will be responsible for safeguarding the interests of trial participants, 
assessing the safety and efficacy of the interventions during the trial, and for 
monitoring the overall conduct of the clinical trial. The DSMB will provide 
recommendations about continuing or terminating the trial on ethical grounds.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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The DSMB will be advisory to the Sponsor clinical trial team. The sponsor clinical trial 
team will be responsible for promptly reviewing the DSMB recommendations, to 
decide whether to continue or terminate the trial and to determine whether 
amendments to the protocol or changes in study conduct are required.
The DSMB will be asked to review the full documentation for specific AEs and 
determine whether they meet the criteria for acute serious bacterial infections (as 
described in Section 8.1.1, Serious Bacterial Infections), defining the study’s primary 
endpoint. Furthermore, the DSMB will be asked to review safety and efficacy data (in 
terms of IgG trough levels) on at least 10 adolescent or adult patients with 3 infusions
(i.e., 3 months of exposure). After a positive evaluation, Kedrion intends to continue 
studying the efficacy and safety of KIg10 in the young age group of PID patients 
(children < 12 years of age).
DSMB will also review data that are indicative of intravascular hemolysis.
The DSMB will be independent from Sponsor and Investigators providing their 
expertise and recommendations. Functions and organization of DSMB are described 
in the DSMB Charter.
4.8
PREMATURE WITHDRAWAL FROM STUDY
Patients may withdraw or parent/legal guardian may withdraw a child at any time,
without any prejudice or negative impact on the patient’s further treatment. The patient
or parent should contact the Investigator immediately and notify him/her that they are 
leaving the study. If possible, the reason for withdrawal for all patients who do not 
complete the 12-month treatment period, including those who are withdrawn after 
screening but prior to their first infusion, will be recorded in the source documentation.
For details regarding withdrawals due to infusion AEs, refer to Section 7.1.1, Method 
of Administration.
The Investigator may withdraw a patient from the study in the following cases: 

For safety reasons, such as a severe AE or SAE, that does not justify 
continuation in the study in the opinion of the investigator.

For a protocol violation that jeopardizes performance of the study.

The patient does not comply with the protocol.

Continued participation will pose a risk to the patient.

Pregnancy.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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
Use of other IgG products.
In the event of patient withdrawal, site personnel should attempt to collect the patient 
study diary (completed through the day of withdrawal, if available).  
The Investigator or study coordinator must notify the Sponsor/clinical research 
organization (CRO) immediately when a patient has been withdrawn.
The circumstances above are referred to as premature withdrawal from the study, and 
the reason for premature withdrawal should be clearly documented and detailed in the 
source documentation. The Investigator should make every attempt to evaluate the 
patient’s safety, including resolution of ongoing AEs, at the time of premature 
withdrawal. If a patient wants to withdraw from the study before all doses are 
administered or prior to the last planned study visit, the patient will be asked to be 
followed for safety for the duration of the study. When a patient withdraws, or is 
withdrawn, from the study, the procedures described in this section should be 
completed if possible.
The reasons for premature withdrawal from the study include: AE, death, withdrawal of 
consent, lost to follow-up, administrative reason, and protocol deviation. These 
reasons are described in greater detail below.
4.8.1
ADVERSE EVENT
For any patient withdrawn from study participation prior to the planned Study 
Termination Visit, it is important to determine if an AE was associated with the 
reason for discontinuing the study. This AE must be identified on the AE eCRF 
page by indicating “Withdrawn from study due to AE.” Any ongoing AEs at the 
time of study withdrawal must be followed until resolution or stabilization. 
Patients who develop an SAE judged to be possibly or probably related to the 
study product should not receive subsequent treatment. 
4.8.2
DEATH
For any patient withdrawn from study participation due to death, this should be 
noted on the Study Termination eCRF page, and the associated SAE that led to 
the death must be reported.
4.8.3
WITHDRAWAL OF CONSENT
The patient and/or parent(s)/legal guardian(s) can withdraw consent for 
participation in the study at any time without penalty or loss of benefit to which 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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the patient is otherwise entitled. Reason for early termination should be deemed 
as “withdrawal of consent” if the patient withdraws from participation due to a 
non-medical reason (i.e., reason other than AE). 
4.8.4
LOST TO FOLLOW-UP
For patients who fail to show up for final clinic visits, or for 3 consecutive clinic 
visits, study staff are encouraged to make at least 3 documented attempts to 
contact the patient/patient’s parent(s)/legal guardian(s) by telephone and at 
least 1 documented written attempt to contact the patient/parent(s)/legal 
guardian(s) to encourage the completion of study termination procedures. 
These efforts to contact the patient should be recorded in the source document.
4.8.5
ADMINISTRATIVE REASON
Examples for patients withdrawn from the study due to administrative reason 
can include: Sponsor decision to terminate the study, patient meeting a pre-
specified withdrawal criterion, patient discontinuation for insurance issues, 
moving, no time, etc. This reason should be noted in the Study Termination 
eCRF page and any ongoing AEs at the time of study withdrawal must be 
followed until resolution/stabilization. 
If the clinical study is prematurely terminated by the Sponsor, the Investigator
has to promptly inform the study patients and local Independent Ethics 
Committee (IEC)/IRB and should assure appropriate therapy and follow up for 
the patients. All procedures and requirements pertaining to the archiving of 
study documents should be followed. All other study materials (study 
medication/devices, etc) must be returned to the Sponsor or its designee (See 
Section 7.4, Destruction of Used [or Partially Used] and Unused Study Drug).
4.8.6
PROTOCOL COMPLIANCE
Protocol compliance is the adherence to all the trial-related requirements, GCP,
and the applicable regulatory requirements. 
Investigators will apply due diligence to avoid protocol noncompliance. Under 
no circumstances should the Investigator contact the Sponsor or its designee, if 
any, monitoring the study to request approval of a protocol noncompliance, as 
no authorized deviations are permitted. If the Investigator feels a change to the 
protocol would improve the conduct of the study this must be considered a 
protocol amendment, and unless such an amendment is agreed upon by the 
Sponsor and approved by the IEC and health authorities it cannot be 
implemented (see Section 15.5, Protocol Amendments).

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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4.9
END OF STUDY
A patient is considered to have completed the study when he/she has:
1.
Received all intended doses of KIg10; and
2.
Completed the 3 or 4 weeks (according to the treatment regimen) safety study 
termination visit after the last dose of KIg10.
5.
SELECTION OF STUDY POPULATION
The study will entail the evaluation of approximately 50 patients selected in accordance 
with both the FDA and EMA guidelines stated previously, except for the pediatric 
enrollment being lower than that required by FDA and EMA for market approval.
Patients with a confirmed diagnosis of PID will be selected for the study. Confirmation 
of PID diagnosis will include a review of infections history, trough IgG serum 
concentration within 12 months (at least 2 documented IgG trough levels, 1 must be 
within 6 months), and previous IVIg treatment data (last 3 commercially available IVIg
infusions administered before study entry). 
Up to 12 pediatric patients (2 to 17 years old) may be enrolled among the 50 patients to 
gain primary data for the full pediatric study which is deferred after Biologic License 
Application approval of the PID adult population. In the meantime, enrollment of the 
2 to 11 year old pediatric patients in this study will be delayed until acceptable safety 
and efficacy of KIg10 for the PID treatment of adolescent or adult patients are 
demonstrated. 
Patients who have an acute infection at the time of screening (exclusion criterion #8) 
may be rescreened at the investigator’s discretion as long as the infection is not 
serious and is resolved by the time of rescreening.
5.1
INCLUSION CRITERIA
Patients must meet the following inclusion criteria to be enrolled into the study:
1. Written informed consent/assent obtained from patients/patients’ 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.
2. Confirmed clinical diagnosis of a PID as defined by 2017 International Union of 
Immunological Societies (IUIS) Phenotypic Classification for Primary 
Immunodeficiencies (Bousfiha A, 2018) and requiring treatment with IVIg.
Documented agammaglobulinemia (defined as the total absence of one or more 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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classes of antibodies) or hypogammaglobulinemia (defined as low levels of one 
or more classes [ie, at least 2 standard deviations under the mean level per 
age]).
3. Male or female, ages 2 to 70 years at screening.
4. Received 200 to 800 mg/kg of a commercially available IVIg therapy in a range 
of 21- or 28-day intervals (±3 days or ±4 days, respectively) for at least 3 
infusion cycles prior to screening.
(NOTE: Other IVIgs will be prohibited after ICF signature and until study end, 
week 51/52).
5. At least 2 documented IgG trough levels while receiving an IVIg, of ≥ 6 g/L 
obtained at 2 infusion cycles within 12 months (1 must be within 6 months) prior 
to ICF signature.
6. Patient (and parent/guardian where applicable) is willing to comply with all 
requirements of the protocol.
7. Females of child-bearing potential with a negative urine pregnancy test and who 
agree to employ adequate birth control measures during the study.
8. Authorization to access personal health information.
9. Patients previously participating in a clinical trial with another experimental IVIg
may be enrolled if they have received stable commercially available IVIg therapy 
for at least 3 infusion cycles (21 or 28 days) prior to screening.
10.Patients currently on treatment with any subcutaneous immunoglobulin (SCIG)
can be enrolled if they are switched to stable commercially available IVIg
therapy for at least 3 infusion cycles (21 or 28 days) prior to screening.
5.2
EXCLUSION CRITERIA
Patients must not meet any of the exclusion criteria to be enrolled into this study:
1. Newly diagnosed PID and naïve to IgG replacement therapy.
2. Dysgammaglobulinemia (defined as a deficiency in one or more classes of 
antibodies, but not severe enough to require substitutive therapy) or isolated IgG 
subclass deficiency, or profound primary T-cell deficiency (defined as the 
absence or severe reduction of T lymphocytes [CD3+ <300 cell/mm3] and an 
absent or particularly low proliferative response [10% of the lower normal range] 
to phytohaemagglutinin P [PHA]).
3. History of severe or serious reactions or hypersensitivity to IVIg or other 
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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4. History of thrombotic events including deep vein thrombosis, cerebrovascular 
accident, pulmonary embolism, transient ischemic attacks, or myocardial 
infarction, as defined by at least 1 event in patient’s lifetime.
5. IgA deficiency with documented antibodies to IgA.
6. Received blood products that have not undergone viral inactivation measures 
within 12 months prior to ICF signature.
7. Significant protein losing enteropathy, nephrotic syndrome, or lymphangiectasia.
8. An acute infection as documented by culture or diagnostic imaging and/or a 
body temperature ≥ 38°C (≥ 100.4°F) within 7 days prior to screening.
9. Acquired immunodeficiency syndrome (AIDS) and/or hepatitis B/C active 
disease at ICF signature.
10.Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 
> 2.5 times of the upper limit of normal for the laboratory designated for the 
study.
11.Using an implanted venous access device.
12.Profound anemia (hemoglobin < 10 g/dL) or persistent severe neutropenia 
(≤1000 neutrophils per mm3) or lymphopenia of less than 500 cells per 
microliter.
13.A severe chronic condition such as renal failure (creatinine concentration 
> 2.0 times the upper limit of normal*) with proteinuria, congestive heart failure 
(New York Heart Association III/IV), cardiomyopathy, cardiac arrhythmia 
associated with thromboembolic events (e.g., atrial fibrillation), unstable or 
advanced ischemic heart disease, hyperviscosity, or any other condition that the 
Investigator believes is likely to interfere with evaluation of the study drug or with 
satisfactory conduct of the trial.
* normal values for serum creatinine are the following: a) Female (18+ years): 45 
- 84 μmol/L or 0.51 - 0.95 mg/dl; b) Male (18+ years): 59 - 103 μmol/L or 0.67 -
1.17 mg/dl
14.History of a malignant disease other than properly treated carcinoma in situ of 
the cervix or basal cell or squamous cell carcinoma of the skin within 24 months 
prior to ICF signature.
15.History of pharmacoresistant epilepsy or multiple episodes of migraine (defined 
as at least 1 episode within 6 months of ICF signature) not completely controlled 
by medication.
16.Patient must not be receiving the following medication:

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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a) Steroids, oral or parenteral, at a daily dose of ≥ 0.15 mg/kg/day of prednisone 
or equivalent).
b) Other immunosuppressive drugs (including monoclonal antibodies) or 
chemotherapy.
17.Females who are pregnant, breast feeding or planning a pregnancy during the 
course of the study. Women who become pregnant during the study will be 
withdrawn from the study.
18.Participated in another clinical study within 3 weeks prior to study ICF signature.
19.Active drug or alcohol abuse or history of drug or alcohol abuse within the 
6 months before screening.
20.Employed or a direct relative of an employee of the CRO, the study site, or the 
Sponsor.
21.Previously treated under this protocol.
22.Unable to provide informed consent or provide informed consent by a legally 
authorized representative.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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6.
STUDY PROCEDURES
The sections below provide an overview of the procedures that are to be followed in 
enrolling, evaluating, and following up the patients who participate in this clinical study. 
The timing of study procedures is summarized in Table 1.1, Time and Events Table for 
28-day Infusion Schedule and Table 1.2, Time and Events Table for 21-day Infusion 
Schedule.
6.1
INFORMED CONSENT/ASSENT/ AUTHORIZATION TO ACCESS 
PERSONAL HEALTH INFORMATION
"Informed consent" is the voluntary agreement of an individual or his/her legal 
guardian(s) to participate in research. Consent must be given with free will of choice, 
and without undue inducement. The individual must have sufficient knowledge and 
understanding of the nature of the proposed research, the anticipated risks and 
potential benefits, and the requirements of the research to be able to make an 
informed decision.
"Assent" is a term used to express willingness to participate in research by persons 
who are by definition too young to give informed consent but who are old enough to 
understand the proposed research in general, its expected risks and possible benefits, 
and the activities expected of them as patients. Assent by itself is not sufficient, 
however. If assent is given, informed consent must still be obtained from the patient's 
parent(s) or legal guardian(s). Local laws define who constitutes a "child," and such 
definitions dictate whether or not a person can legally consent to participate in a 
protocol.
"Authorization to access personal health information" is the voluntary authorization of 
an individual or his/her legal guardian(s) to individual’s personal data (related to the 
clinical trial) processing by the Sponsor, the Investigator or their delegates.
"Processing" means any operation or set of operations, which is performed on 
personal data or on sets of personal data, whether or not by automated means, such 
as collection, recording, organization, structuring, storage, adaptation or alteration, 
retrieval, consultation, use, disclosure by transmission, dissemination or otherwise 
making available, alignment or combination, restriction, erasure or destruction.
Informed consent of the patient or of the parent(s)/legal guardian(s), assent of patient
and authorization to access personal health information (i.e. Health Insurance 
Portability and Accountability Act for US and Personal Information Protection and 
Electronic Documents Act for Canada) following local IRB/IEC guidance must be 
obtained before conducting any study-specific procedures (i.e., all of the procedures 
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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authorization to access personal health information should be documented in the 
patient source document.
The signed and dated informed consent, assent, and authorization to access personal 
health information (personally signed and dated by the patient/parent/legal guardian 
and by the Investigator) must be retained by the Investigator as part of the study 
records in the patient source document. A copy of the signed and dated informed 
consent, assent, and authorization to access personal health information will be given 
to the patient or patient’s legally authorized representative.
Additional specifics regarding the informed consent, assent, and authorization to 
access personal health information processes are located in Section 15.2, Informed 
Consent Procedures.
If the patient/parent(s)/legal guardian(s) is unable to read, an impartial witness should 
be present during the entire informed consent, assent, and authorization to access 
personal health information discussion. An impartial witness is defined as a person 
who is independent from study conduct, who cannot be unfairly influenced by those 
involved with the study, who attends the informed consent process if the patient or the 
patient's legally acceptable representative cannot read, and who reads the ICF and 
any other written information supplied to the patient. After the written ICF and any 
other written information to be provided to patients, is read and explained to the 
patient/parent(s)/legal guardian(s) and after the patient/parent(s)/legal guardian(s) has 
verbally consented to the patient’s participation in the study and, if capable of doing 
so, has signed and personally dated the ICF, the witness should sign and personally 
date the consent form. By signing the consent form, the witness attests that the 
information in the consent form and any other written information was accurately 
explained to, and apparently understood by, the patient/parent(s)/legal guardian(s) and 
that informed consent was freely given by patient/parent(s)/legal guardian(s).
6.2
SCREENING VISIT
Once the informed consent/assent form(s) and authorization to access personal health 
information have been signed and dated by the patient/parent/legal guardian and by 
the Investigator (Section 15.2, Informed Consent Procedures), for those patients who 
meet enrollment criteria, the following procedures will be performed at the screening 
visit.
1. Medical history including infections history, tolerance of previous IgG treatment, 
antibody response to pneumococcal vaccination (when available), documented 
last 3 commercially available IVIg infusions before the study entry.
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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3. Baseline IgG levels and 2 documented IgG trough levels within 12 months 
(1 being within 6 months) prior to screening.
4. Demography information including date of birth, gender, race, and ethnicity.
5. Physical examination (evaluation of all body systems and body weight) with an 
evaluation of vital signs (blood pressure, heart rate, and temperature).
6. Collection of blood samples for IgG levels, hematology, blood chemistry, and 
intravascular hemolysis testing (see Section 8.2.3, Clinical laboratory Analysis).
7. Collection of urine samples for urinalysis and pregnancy test (for patients of 
childbearing age).
8. Chest X-ray (if an X-ray performed within 6 months prior to ICF signature is not 
available).
9. Collection of blood for a retention serum sample, for viral safety and possible 
future testing.
All screening procedures should be performed within 3 or 4 weeks (depending on
treatment regimen) of the first KIg10 infusion.
6.3
PATIENT IDENTIFICATION
Patients who consent to participate in the study will be assigned a unique Patient
identification (ID) number. The Patient ID will be in the format xx-yy composed of the 
study center number (xx) and patient number (yy). The center number will be assigned 
by the Sponsor. The patient number will be assigned sequentially by the Investigator
beginning with 01 at each site.
The study center is responsible for recording all the different codes assigned to the 
patients in order to avoid errors such as missing subsequent numbers or assigning 
identical codes to different patients. The patient’s ID number must be included in all 
study documents (e.g., on the eCRF, on the sample containers, on the card where the 
administration of the medicinal product is recorded, etc.).
The Investigator is responsible for keeping the patient register up to date, in order to 
avoid the erroneous attribution of numbers (repetitions, skips). The ID number should 
be used to identify a given patient in all study documents (e.g., eCRFs, documents for 
submission of trial material, accounting records for the drug, etc.).

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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6.4
ENROLLMENT
Each patient who meets the following criteria will be enrolled in the study and will start 
the treatment:
1. Has a confirmed PID diagnosis as defined by IUIS Phenotypic Classification for 
Primary Immunodeficiencies (Bousfiha A, 2018);
2. Satisfies the inclusion and exclusion criteria;
3. Has supplied signed and dated informed consent, assent (as applicable) and 
authorization to access personal health information; and
4. Has completed all screening activities.
All patients in the study will be treated for a period of 48 weeks according to the dose 
and schedules reported in sections below.
Patient enrollment will be considered complete with the completion of the Study 
Eligibility Form in the eCRF.
6.5
TREATMENT REGIMEN
All patients will receive an intravenous infusion of KIg10 at the same dose and interval 
as used for their previous IVIg maintenance therapy. KIg10 will be administered every 
21 or 28 days for a period of 48 weeks (depending on the treatment regimen).
The dosage should be calculated so that the amount administered should match the 
patient’s previously individualized dosing regimen, to maintain a trough level of ≥6 g/L 
(200 to 800 mg/kg of body weight), in accordance with “Guideline on core SmPC for 
human normal immunoglobulin for intravenous administration (IVIg); 
EMA/CHMP/BPWP/94038/2007 Rev. 5.” The first infusion of KIg10 will be based on 
the patient’s baseline weight.
The patient’s weight will be measured and recorded at screening, baseline and before 
every infusion at clinic visit for pediatric patients, and at screening, baseline and weeks 
12, 24, 36, and 48 for adults, to determine if a dose adjustment is required. Variations 
in body weight of up to ± 10% will not require a dose adjustment. Variations in excess
of ± 10% may require a dose adjustment at the discretion of the Investigator, providing 
a rationale for his/her choice. In any case, dosage adjustment should be maintained 
within the standard dosage regimen, unless clinically required otherwise.
Patients will be treated at the site for each infusion (see Table 1.1, Time and Events 
Table for 28-day Infusion Schedule and Table 1.2, Time and Events Table for 21-day 
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Details regarding investigational product and treatment of patients are provided in 
Section 7, Treatment of Patients. Additional information about the investigational
product is provided in the Investigator’s Brochure.
6.6
BASELINE VISIT (Day 1, WEEK 1)
The day of the first KIg10 administration will be considered the baseline visit (day 1,
week 1).
Each patient will undergo the following tests and procedures:

A physical examination (evaluation of all body systems and body weight) with an 
evaluation of vital signs (blood pressure, heart rate, and temperature).

Collection of blood (pre-infusion) to measure IgG levels, IgG subclasses (IgG1, 
IgG2, IgG3, IgG4) and specific antibodies (anti-Haemophilus influenza type b, 
anti-Tetanus toxoid, anti-pneumococcal polysaccharide, and anti-measles)
levels.

Collection of blood samples (pre-infusion) for hematology and blood chemistry. 

Collection of urine samples (pre-infusion) for urinalysis.

Collection of blood and urine samples for intravascular hemolysis testing (post-
infusion).

Recording of all AEs and SAEs, including any infections, fever episodes, and 
hospitalization.

Recording of all prior and concomitant medication, including use of antibiotics for 
any kind of infection.

Training and dispensing of Patient Diary.

Recording of KIg10 administration information (batch number, dosage, amount of 
product infused, infusion start and end time, infusion rate).

Recording days off work/school/other major activities due to infections.

Completion of QoL questionnaires (PedsQL™and 
).

Other health care utilization information.
6.7
TREATMENT VISITS 
Patients will be required to return to the study site for each visit every 21 (± 3) days or 
every 28 (± 4) days depending on treatment regimen for a period of 48 weeks – see 
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Table 1.1, Time and Events Table for 28-day Infusion Schedule and Table 1.2, Time 
and Events Table for 21-day Infusion Schedule. 
Each patient will be treated with KIg10 as reported in the Section 6.5, Treatment 
Regimen, and undergo the following tests and procedures:

A physical examination (evaluation of all body systems) with an evaluation of vital 
signs (blood pressure, heart rate, and temperature); body weight will be collected 
at each visit for pediatric patients and at weeks 12, 24, 36, and 48 for adults.

Collection of blood (pre-infusion) to measure IgG levels

Collection of blood (pre-infusion) to measure IgG subclasses (IgG1, IgG2, IgG3 
and IgG4) and specific antibodies (anti-Haemophilus influenza type b, anti-Tetanus 
toxoid, anti-pneumococcal polysaccharide and anti-measles) at infusions 5, 9, and 
13 for the 28-day infusion schedule and at infusions 7, 11, and 17 for the 21-day 
infusion schedule.

Collection of blood samples (pre-infusion) for hematology and chemistry.

Collection of urine samples (pre-infusion) for urinalysis.

Collection of blood and urine samples for intravascular hemolysis testing (post-
infusion).(at infusion 5 for the 28-day infusion schedule or at infusion 7 for the 21-
day infusion schedule).

Recording of all AEs and SAEs, including any infections, fever episodes, and 
hospitalization.

Recording of all concomitant medication, including use of antibiotics for any kind of 
infection.

Review of Patient Diary (with data collection) and dispensing.

Record KIg10 administration information (batch number, dosage, amount of 
product infused, infusion start and end time, infusion rate).

Record days off work/school/other major activities due to infections.

At infusion 5 (28-day infusion schedule) or at infusion 7 (21-week infusion 
schedule), only for those patients that consent to the PK portion of the study (PK 
Evaluation Set), additional blood samples will be collected for evaluating total IgG 
levels, IgG subclasses, and specific antibodies, at the time points as described at 
Section 8.4 Pharmacokinetic (PK) Assessment (PK Evaluation Set):
o
Total IgG levels, IgG subclasses and selected specific antibody levels 
before (as for all patients) and after infusion 5 (28-day infusion schedule) or 
infusion 7 (21-day infusion schedule).

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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o
PK parameters1 of total IgG pre- and post-infusion 5 (28-day infusion 
schedule) or pre- and post-infusion 7 (21-day infusion schedule).
o
PK parameters1 of specific IgG antibodies pre- and post-infusion 5 (28-day
infusion schedule) or pre- and post-infusion 7 (21-day infusion schedule):
a. anti-Haemophilus influenza type b
b. anti-Tetanus toxoid 
c. anti-pneumococcal polysaccharide
1 Plasma concentration-time curve, half-life, area under the curve (AUC0-t; AUC0-inf), volume of 
distribution, concentration maximum (Cmax), Tmax, elimination rate constant.

At infusion 7 (for 28-day schedule) or at infusion 9 (for 21-day schedule) completion 
of QoL questionnaires (PedsQL™, and 
).

Collection of other health care utilization information.

Collection of study-specific questionnaire to evaluate patient satisfaction with 
participation and treatment during the study at week 24 (infusion 7 for the 28-day 
schedule or infusion 9 for the 21-day schedule).
6.8
REMINDER PHONE CALLS
Reminder calls will be performed on day 2 or 3 after each scheduled infusion. The 
purpose of this call is to remind the patient/parent(s)/legal guardian(s) about 
completion of the Patient Diary. The call follows the reminder telephone call script 
provided to the site, and it is not intended to be an interview for collection of safety 
data. If the patient/parent(s)/legal guardian(s) wishes to describe safety information, 
this information should only be collected by a healthcare professional at the site, and 
the safety data described must be written down in the patient’s source document. The 
patient/parent(s)/legal guardian(s) should be reminded to write the information down in 
the Patient Diary and to contact the site via the telephone number provided in the 
informed consent to discuss medical questions.
6.9
UNSCHEDULED VISITS
During all the study periods, an unscheduled visit (non-routine study visit triggered by 
a specific event or for repetition of tests, e.g. Direct Coombs) may occur at 
Investigator’s discretion and will be recorded in the source document and in eCRF.
6.10
STUDY TERMINATION VISIT
The study termination visit will occur at week 51/52 (depending on treatment 
regimen). The termination visit is a clinic visit. The date of termination is the date of 
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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the last contact in which the patients’ health status is assessed or, in case where the 
patient does not agree to any further follow up, it is the date the consent is withdrawn. 
This date should be recorded on the termination CRF page.
Each patient will undergo the following tests and procedures:
A physical examination (evaluation of all body systems and body weight) with an 
evaluation of vital signs (blood pressure, heart rate, and temperature).
Collection of blood to measure IgG levels.

Collection of blood samples for hematology. blood chemistry, and intravascular 
hemolysis testing.
Collection of urine sample for urinalysis and intravascular hemolysis testing (urine 
hemosiderin).
Collection of blood for a retention serum sample, for viral safety and possible future 
testing.
Recording of all AEs and SAEs, including any infections, fever episodes, and 
hospitalization.
Recording of concomitant medication, including use of antibiotics for any kind of 
infection.
Review Patient Diary (with data collection).
Record days off work/school/other major activities due to infections.
Completion of QoL questionnaires (PedsQL™, and 
).
Collection of other health care utilization information.
6.11
EARLY TERMINATION VISIT
When a patient is withdrawn from treatment or withdraws from the study (Section 4.8,
Premature Withdrawal From the Study), the Investigator will notify the Sponsor and, 
when possible, will perform the procedures listed in Section 6.10, Study Termination 
Visit. The reason(s) for the early termination will be included in the patient’s source 
documentation. If the Early Termination Visit is a telephone call, as much information as 
possible will be collected. 
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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7.
TREATMENT OF PATIENTS
The study drug used in this study must be stored separately from other drugs and 
medications in a secure location under appropriate storage conditions with temperature 
monitoring. All KIg10 vials must be checked for expiration date prior to use. Expired 
drug must not be administered to patients.
7.1
INVESTIGATIONAL MEDICINAL PRODUCT
Immune Globulin Intravenous (Human) 10% solution will be administered. 1 mL of 
solution for infusion contains:
Human plasma proteins mg 100 of which immunoglobulin G (IgG) at least 96%. 
For details on product composition please refer to the Investigator’s Brochure.
The solution is filled into 50 mL type II glass vials.
All study product shall be properly packaged for the clinical study and provided by 
the Sponsor in compliance with the arrangements made with the Investigator.
7.1.1
METHOD OF ADMINISTRATION
Before administration, the solution must be allowed to reach room temperature. 
The average time to reach room temperature after storage at
C is 
approximately
hours. Once a vial has been put outside the refrigerator must be 
used within the same day. Once opened the product must be used immediately.
The study drug will be administered intravenously. Prior to infusion of KIg10, the 
Investigator or his/her delegate must ensure that the patient is adequately 
hydrated.
The bottle should not be shaken because excessive shaking will cause foaming 
(existing foam does not prevent use as foam will stay in the bottle). The product 
should be visually inspected for particulate matter, turbidity and discoloration, 
prior to administration. Products which are not clear or have sediment must not 
be used. A slight yellow discoloration is not of concern.
CCI
CCI
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Infusion rate

First infusion: infusion will proceed at an initial rate of 1 mg/kg/minute
(0.01 mL/kg/min) for 30 minutes. If well tolerated, the rate of administration 
may be increased to a maximum of 8 mg/kg/minute (2 mg/kg/min –
0.02 mL/kg/min; 4 mg/kg/min – 0.04 mL/kg/min; 6 mg/kg/min – 0.06 
mL/kg/min; 8 mg/kg/min – 0.08 mL/kg/min) at 30 minute intervals.

Subsequent infusions: infusions will proceed at an initial rate of 
2 mg/kg/minute (0.02 mL/kg/min) for 15 minutes. If well tolerated, the rate of 
administration may be increased to a maximum of 8 mg/kg/minute
(4 mg/kg/min – 0.04 mL/kg/min; 6 mg/kg/min – 0.06 mL/kg/min; 
8 mg/kg/min – 0.08 mL/kg/min) at 15 minute intervals.
If an AE occurs, either the rate of administration must be reduced to the 
previous step or the infusion stopped. The treatment required depends on the 
nature and severity of the AE.
Patients should be monitored for pulmonary adverse reactions during the 
infusion since there have been reports of thrombotic events and non-cardiogenic 
pulmonary edema (Transfusion-Related Acute Lung Injury [TRALI]) in patients 
administered IVIg products. If TRALI is suspected, appropriate tests will be 
performed for the presence of anti-neutrophil antibodies in both the product and 
the patient serum.
Patients may be treated with different lots of KIg10 over the course of the 
48-week treatment period. Different lots may not be mixed for a single infusion.
7.1.2
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Specific information regarding warnings, precautions, contraindications, AEs, 
and other pertinent information on the investigational product that may impact 
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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patient participation is provided in the Investigator’s Brochure.
For intravenous application only.
Potential complications can often be avoided by ensuring that patients:

are not sensitive to human normal Ig by initially injecting the product slowly 
(with regards to the infusion rate, relevant section of the study protocol 
must be strictly followed);

are carefully monitored for any symptoms throughout the infusion period. In 
particular, patients naive to human normal Ig, patients switched from an 
alternative IVIg product or when there has been a long interval since the 
previous infusion should be monitored at the hospital during the first 
infusion and for the first hour after the first infusion, in order to detect 
potential adverse signs. All other patients should be observed for at least 
20 minutes after administration.
In all patients, IVIg administration requires:

adequate hydration prior to the initiation of the infusion of IVIg;

monitoring of urine output;

monitoring of serum creatinine levels;

avoidance of concomitant use of loop diuretics.
In case of adverse reaction, either the rate of administration must be reduced or 
the infusion stopped. The treatment required depends on the nature and severity 
of the adverse reaction.
Infusion reaction
Certain severe adverse drug reactions (ADRs) (e.g. headache, flushing, chills, 
myalgia, wheezing, tachycardia, lower back pain, nausea, and hypotension) may 
be related to the rate of infusion.
The recommended infusion rate given in the study protocols must be closely 
followed. Patients must be closely monitored and carefully observed for any 
symptoms throughout the infusion period.
Adverse reactions may occur more frequently:

in patients who receive human normal Ig for the first time or, in rare cases, 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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when the human normal Ig product is switched or when there has been a 
long interval since the previous infusion;

in patients with an untreated infection or underlying chronic inflammation.
Hypersensitivity
Hypersensitivity reactions are defined according to Gell and Coomb’s classification 
which categorizes hypersensitivity reactions into four subtypes (Uzzaman A, 2012).
Hypersensitivity reactions are rare.
Anaphylaxis can develop in patients who had tolerated previous treatment with 
human normal immunoglobulin.
In case of shock, standard medical treatment for shock should be implemented.
Thromboembolism
There is clinical evidence of an association between IVIg administration and 
thromboembolic events such as myocardial infarction, cerebral vascular accident 
(including stroke), pulmonary embolism, and deep vein thrombosis which is 
assumed to be related to a relative increase in blood viscosity through the high 
influx of Ig in at-risk patients. 
Acute myocardial infarction (MI) is defined as an acute myocardial injury with 
clinical evidence of acute myocardial ischemia and detection of a rise and/or fall of 
cTn values with at least 1 value above the 99th percentile upper reference limit and 
at least 1 of the following (Thygesen K, 2018):

Symptoms of myocardial ischemia

New ischemic ECG changes

Development of pathological Q waves

Imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality in a pattern consistent with an ischemic etiology

Identification of a coronary thrombus by angiography or autopsy (not for 
types 2 or 3 MIs)
Caution should be exercised in prescribing and infusing IVIg in obese patients and 
in patients with pre-existing risk factors for thrombotic events (such as advanced 
age, hypertension, diabetes mellitus and a history of vascular disease or 
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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patients with prolonged periods of immobilisation, severely hypovolemic patients, 
patients with diseases that increase blood viscosity).
In patients at risk for thromboembolic adverse reactions, IVIg products should be 
administered at the minimum rate of infusion and dose practicable.
Acute renal failure
Acute renal failure is defined according to AKIN/KDIGO criteria (Thomas ME, 
2015). Cases of acute renal failure have been reported in patients receiving IVIg
therapy. In most cases, risk factors have been identified, such as pre-existing 
renal insufficiency, diabetes mellitus, hypovolemia, overweight, concomitant 
nephrotoxic medicinal products or age over 65.
Renal parameters should be assessed prior to infusion of IVIg, particularly in 
patients judged to have a potential increased risk for developing acute renal 
failure, and again at appropriate intervals. In patients at risk for acute renal failure, 
IVIg products should be administered at the minimum rate of infusion and dose 
practicable. In case of renal impairment, IVIg discontinuation should be 
considered.
While reports of renal dysfunction and acute renal failure have been associated 
with the use of many of the licensed IVIg products containing various excipients 
such as sucrose, glucose and maltose, those containing sucrose as a stabiliser 
accounted for a disproportionate share of the total number. In patients at risk, the 
use of IVIg products that do not contain these excipients may be considered.
Aseptic meningitis syndrome
Aseptic meningitis syndrome (AMS) is defined as meningeal inflammation - i.e. 
cerebrospinal fluid (CSF) pleocytosis ≥5 cells/mm3 - not related to an infectious 
process (Tattevin P, 2019). Aseptic meningitis syndrome (AMS) has been reported 
to occur in association with IVIg treatment. The syndrome usually begins within 
several hours to 2 days following IVIg treatment. Cerebrospinal fluid studies are 
frequently positive with pleocytosis up to several thousand cells per mm3, 
predominantly from the granulocytic series, and elevated protein levels up to 
several hundred mg/dL.
AMS may occur more frequently in association with high-dose (2 g/kg) IVIg 
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Patients exhibiting such signs and symptoms should receive a thorough 
neurological examination, including CSF studies, to rule out other causes of 
meningitis.
Discontinuation of IVIg treatment has resulted in remission of AMS within several 
days without sequelae.
Haemolytic anaemia
IVIg products can contain blood group antibodies that may act as hemolysins and 
induce in vivo coating of red blood cells (RBCs) with Ig, causing a positive direct 
antiglobulin reaction (Coombs’ test) and, rarely, hemolysis. Hemolytic anaemia 
can develop subsequent to IVIg therapy due to enhanced RBC sequestration. IVIg 
recipients should be monitored for clinical signs and symptoms of hemolysis. 
Neutropenia
A transient decrease in neutrophil count and/or episodes of neutropenia, 
sometimes severe, have been reported after treatment with IVIgs. This typically 
occurs within hours or days after IVIg administration and resolves spontaneously 
within 7 to 14 days.
Transfusion related acute lung injury (TRALI)
In patients receiving IVIg, there have been some reports of acute non-cardiogenic 
pulmonary oedema TRALI. TRALI is characterised by severe hypoxia, dyspnoea,
tachypnoea, cyanosis, fever and hypotension. Symptoms of TRALI typically 
develop during or within 6 hours of a transfusion, often within 1-2 hours. 
Therefore, IVIg recipients must be monitored for and IVIg infusion must be 
immediately stopped in case of pulmonary adverse reactions. TRALI is a 
potentially life-threatening condition requiring immediate intensive-care-unit 
management.
Interference with serological testing
After the administration of Ig the transitory rise of the various passively transferred 
antibodies in the patient’s blood may result in misleading positive results in 
serological testing.
Passive transmission of antibodies to erythrocyte antigens, e.g., A, B, D may 
interfere with some serological tests for red cell antibodies for example the direct 
antiglobulin test (DAT, direct Coombs’ test).

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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7.1.3
CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients.
Hypersensitivity to human Igs, especially in patient with antibodies against IgA.
7.1.4
INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND 
OTHER FORMS OF INTERACTIONS
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 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 patients receiving measles vaccine should have their antibody 
status checked.
Loop diuretics
The use of loop diuretics should be avoided.
7.1.5
UNDESIRABLE EFFECTS
Adverse reactions caused by human normal Ig (in decreasing frequency) 
encompass:

chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, 
arthralgia, low blood pressure, and moderate low back pain;

reversible haemolytic reactions; especially in those patients with blood 
groups A, B, and AB and (rarely) haemolytic anaemia requiring 
transfusion;

(rarely) a sudden fall in blood pressure and, in isolated cases, 
anaphylactic shock, even when the patient has shown no 
hypersensitivity to previous administration;

(rarely) transient cutaneous reactions (including cutaneous lupus 
erythematosus – frequency unknown);

(very rarely) thromboembolic reactions such as myocardial infarction, 
stroke, pulmonary embolism, deep vein thrombosis;

cases of reversible aseptic meningitis;

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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
cases of increased serum creatinine level and/or acute renal failure;

cases of TRALI.
Frequencies have been evaluated according to the following convention: very 
common (1/10); common (1/100 to < 1/10); uncommon (1/1,000 to 
< 1/100); rare (1/10,000 to < 1/1,000); very rare (< 1/10,000); not known 
(cannot be estimated from the available data).
7.1.6
INSTRUCTIONS FOR USE
The product should be brought to room temperature before use.
The solution should be clear or slightly opalescent and colourless or pale 
yellow. Do not use solutions that are cloudy or have deposits.
Solution should be inspected visually for particulate matter and discoloration 
prior to administration. Any unused product or waste material should be 
disposed of in accordance with local requirements.
7.1.7
EXPIRY AND STORAGE
Data as collected from the stability studies support a shelf life of
when the drug product is stored at temperature of
The product 
must be stored at a temperature of 5°C ±3°C, away from the light. Do not 
freeze KIg10.
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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7.2
LABEL
KIg10 will be supplied open-label.
Vial Label text fac – simile (English and French)
Package Label Text  fac – simile
Number of treatment
Sponsor: Kedrion S.p.A.  Loc. ai Conti 55051 – Castelvecchio Pascoli - Barga (LU) Italy                                  
Study Code/ étude Clinique: KIG10_US3_PID01  
Center number n./Site n.: __ __       Patient/ Sujet n.: __ __  
Investigator/ Expérimentateur:_______________________________________
IMP: Immune Globulin Intravenous (Human) 10% solution ME: Immunoglobuline Intraveineuse (Humaine)
solution à 10 %
Dosage: See study protocol/ Voir l'étude clinique  Volume: 50 ml    Potency/ Puissance: 10 g/100 ml
Pharmaceutical form/ Forme pharmaceutique: solution for infusion/ solution pour perfusion              
Instruction for use/Des instructions pour l'utilisation: See study protocol/ Voir l'étude clinique     
Route of administration/ Procédé d'administration: intravenous/ intraveineuse
Storage condition/Préservation:
Caution: New drug - Limited by Federal law to investigational use by a qualified Investigator
Attention: Un nouveau médicament - Limité par la loi Fédérale à un usage expérimentalon par un 
chercheur qualifié
Batch n/Lot n:
XXXXX
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Sponsor: Kedrion S.p.A.  Loc. ai Conti 55051 – Castelvecchio Pascoli -
Barga (LU) Italy                                                                                              
Study Code: KIG10_US3_PID01    
Center number: __ __       Patient number: __ __    
Investigator: ____________________________
IMP: Immune Globulin Intravenous (Human) 10% solution
Volume: 50 ml          Potency: 10 g/100 ml     
Dosage: See study protocol                          
Pharmaceutical form: solution for infusion       
Instruction for use: See study protocol                  
Route of administration: intravenous
Storage condition: 
Caution: New drug - Limited by Federal law to investigational use by 
a qualified Investigator
Sponsor: Kedrion S.p.A.  Loc. ai Conti 55051 – Castelvecchio Pascoli -
Barga (LU) Italy                                                                                    
étude Clinique: KIG10_US3_PID01
Site n: __ __       Sujet n.: __ __    
Expérimentateur: ____________________________
ME: Immunoglobuline Intraveineuse (Humaine) solution à 10 %
Volume: 50 ml          Puissance: 10 g/100 ml     
Dosage: Voir l'étude clinique                         
Forme pharmaceutique: solution pour perfusion       
Des instructions pour l'utilisation: Voir l'étude clinique   
Procédé d'administration: intraveineuse 
Préservation: 
Attention: Un nouveau médicament - Limité par la loi Fédérale à un 
usage expérimentalon par un chercheur qualifié
C
C
I
C
C
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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7.3
INVESTIGATIONAL PRODUCT ACCOUNTABILITY AND 
DOCUMENTATION
The investigational product will be stored and administered at the investigational site by 
trained personnel. Each vial will have a lot number and a serial number. KIg10 vials will 
arrive from the distributor in boxes containing multiple vials. These boxes can be 
discarded confidentially or destroyed upon receipt and reconciliation of KIg10 vials 
contained within.
An Investigational Product Accountability Record for KIg10 used for this study must be 
kept current by the clinical site and must contain:
●
Dates, quantities, expiration date(s) and lot number(s) of all investigational 
product received;
●
Dates, quantities, serial number(s) and lot number(s) of investigational product 
dispensed for each infusion for each patient;
●
Patient ID;
●
Initials of the staff person dispensing the product.
The Investigator must account for all product and supplies used in the study. 
Investigators must complete and return the Investigational Product Form together with 
the unused vials of KIg10. At the end of the study, a final investigational product 
reconciliation statement must be completed by each site and provided to the Sponsor/
CRO representative.
Inventory records must be readily available for inspection by the trial monitor and/or 
auditor, and open to Regulatory Authority inspection or Sponsor/CRO inspection.
The Sponsor/CRO and the pharmacist (or otherwise dedicated person) must keep 
records regarding shipment, receipt, storage temperature logs, distribution, drug 
accountability and destruction of the study medication.
7.4
DESTRUCTION OF USED (OR PARTIALLY USED) AND UNUSED STUDY
DRUG
During the study, the used (or partially used) vials must not be destroyed until KIg10 
files have been checked by the monitor. After verification of KIg10 inventory 
documentation, the monitor will inform the pharmacist (or designated person) to 
destroy the used (or partially used) vials at the site. 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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At the end of the study:

any remaining used (or partially used) vials will be destroyed at site in 
accordance with local requirements;

the unused vials should return to the Investigational Product distribution vendor
for the destruction.
The Sponsor/CRO and the pharmacist (or designated person) must keep records 
regarding shipment, receipt, distribution, drug accountability and destruction of the 
study medication.
7.5
CONCOMITANT MEDICATIONS
Concomitant medications are those administered from the first KIg10 infusion until the 
study termination visit.
Patients who are prone to AEs associated with Ig infusions are frequently pre-
medicated with antihistamines, antipyretics, and/or steroids. Premedication intended to 
prevent AEs associated with infusion of KIg10 should be avoided in this study and may 
be used if considered necessary by the Investigator.
The rationale to initiate premedication to prevent re-occurrence of AEs will be 
recorded.
Any medication(s) (excluding biologics or chemotherapy agents) that is (are) not 
intended for the primary purpose of masking signs of adverse reactions to the 
infusions, and is (are) taken by the patient on a regular basis may be continued. In 
particular, daily low dose (≤ 100 mg) aspirin, non-steroidal anti-inflammatory drugs
medications, and salicylates for inflammatory bowel disease may be continued.
Concomitant medications (including over-the-counter medications) with start and 
stop dates must be recorded in the source documentation at the study site and 
collected in the eCRF. The indication for treatment must be recorded, including drug 
name, route, and duration of drug administration.
Concomitant medications will be recorded during all study periods.
7.6
PROHIBITED MEDICATIONS
The use of other polyclonal IgG (SCIG or IVIg) will be prohibited between the first 
infusion of KIg10 and the study termination visit. High dose steroids (oral and 
parenteral, daily ≥ 0.15 mg of prednisone equivalent/kg/day), and other 
immunosuppressive (including monoclonal antibodies)/cytotoxic drugs are prohibited 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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during the study period except when required for emergency use, and their use must 
be recorded.
After KIg10 administration, a time interval of at least 3 months must pass before use of 
a live attenuated virus vaccine.
7.7
MISUSE OF STUDY DRUG
Misuse is defined as administration of wrong dosage and any use not in accordance 
with IMP instructions. Any misuse must be reported to the Sponsor as such within 24 
hours.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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8.
EFFICACY PHARMACOKINETIC, AND SAFETY VARIABLES
8.1
EFFICACY VARIABLES
8.1.1
SERIOUS BACTERIAL INFECTIONS
If an acute serious bacterial infection is suspected, the patient must be 
evaluated for the infection according to the methods described in the FDA 
Guidance for Industry: “Safety, Efficacy and Pharmacokinetic Studies to 
Support Marketing of Immune Globulin Intravenous (Human) as Replacement 
Therapy for Primary Humoral Immunodeficiency; June 2008,” as defined 
below.
Items in bold are considered essential diagnostic features. 
The DSMB will be responsible for review the full documentation for specific AEs 
and determine whether they meet criteria for acute serious bacterial infections. 
The procedure to complete this activity will be detailed in the DSMB Charter.
All acute serious bacterial infections will be recorded in the eCRF.
Infection: Bacteremia/sepsisa

Symptoms: chills, rigors

Physical findings- fever, hypothermia, tachycardia, tachypnea, hypocarbia, hypotension 
(systolic blood pressure < 90 mm Hg or a reduction of ≥ 40 mm Hg from baseline in the 
absence of other causes of hypotension), altered mental status, petechiae, purpura, 
oligouria, cutaneous vasodilation/vasoconstriction

Laboratory tests: positive blood cultureb, leukocytosis (white blood cell count [WBC]
> 12,000/mm3), differential WBC count demonstrating > 10% immature (band) neutrophils, 
leukopenia (defined as ˂ 3000 WBC/μl), thrombocytopenia, coagulopathy, lactic acidosis
Infection: Bacterial meningitis

Symptoms: headache, stiff neck, mental status changes, irritability, decreased feeding 
(infants), photophobia, nausea/vomiting, rigors, seizures 

Physical findings: Kernig’s sign, Brudzinski’s sign, meningococcal rash, fever of > 38 ºC oral 
or > 39ºC rectal

Laboratory tests: positive cerebrospinal fluid (CSF) Gram stain and/or culture and/or 
positive CSF bacterial antigen assay, positive blood culturec, CSF leukocytosis with 
neutrophil predominance, decrease in CSF glucose

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Infection: Osteomyelitis/Septic arthritis

Symptoms: pain, decreased range of motion, tenderness, edema, redness, warmth over the 
involved site (Local inflammatory symptoms/signs may be lacking in adults.)

Physical findings: evidence of soft tissue infection adjacent to the involved bone/joint; 
drainage from sinus tract from involved bone; fever of > 38ºC oral or > 39ºC rectal

Laboratory tests: positive blood culture, positive probe to bone, positive bone aspirate 
culture, positive bone biopsy culture, positive bone histopathology, positive joint fluid Gram 
stain and culture

Imaging studies: positive X-ray, nuclear medicine bone scan, magnetic resonance 
imaging (MRI) scan, or computed tomography (CT) scan showing bony destruction 
with radiolucent areas; for chronic osteomyelitis: sequestra, involucra 
Infection: Bacterial pneumoniad

Symptoms: productive cough/change in character of sputum, dyspnea or tachypnea, chills, 
chest pain, rigors, headache, fatigue, sweats, anorexia, myalgias 

Physical findings: rales; pulmonary consolidation as reflected by: dullness on percussion, 
bronchial breath sounds, egophony; fever (> 38ºC oral or > 39ºC rectal), or < 36 ºC, or 
hypothermia (temperature < 36ºC oral or < 37ºC rectal) 

Laboratory tests: leukocytosis; differential WBC count of > 10% band neutrophils; 
leukopenia (defined as ˂ 3000 WBC/μl); hypoxemia (PaO2 < 60 mm Hg on room air); 
positive blood culture; Gram stain and culture of deep expectorated sputume, positive 
culture with or without positive Gram stain of transtracheal aspirate, pleural fluid culture, 
lung biopsy, bronchoscopy with bronchoalveolar or protected brush sampling, 

Imaging studies: Pulmonary infiltrate with consolidation on chest X-Ray (new in 
comparison with baseline chest X-Ray)
Infection: Visceral abscess

Symptoms: abdominal pain, anorexia, weight loss, cough/pleuritic chest pain (hepatic 
abscess), rigors (seldom present)

Physical findings: intermittent fevers (temperature > 38ºC oral or > 39ºC rectal); abdominal 
tenderness; palpable mass; hepatomegaly; jaundice

Laboratory tests: positive Gram stain and/or culture from the infected site, with 
isolation of an appropriate pathogen; positive blood culture; leukocytosis with 
accompanying left shift; differential WBC count of > 10% immature (band) neutrophils,
elevated serum amylase concentration (pancreatic abscess); elevated alkaline phosphatase 
concentration (hepatic abscess) pyuria in renal abscess

Imaging studies: typical findings on ultrasound, CT scan, MRI scan, or radionuclide 
scan
a Two of the following should be present to make the diagnosis of sepsis in adults: temperature > 38ºC oral/ > 39ºC 
rectal or < 36ºC oral or < 37ºC rectal; heart rate > 90 beats/minute; respiratory rate > 20 breaths/minute, or PaCO2
< 32 mm Hg; WBC count > 12,000/mm3, < 4,000/mm3, or > 10% immature (band) forms. For pediatric patients, 
the definition of sepsis using age-specific criteria is recommended by the International Consensus Conference on 
Pediatric Sepsis (Pediatric Crit Care Med 2005; 6(1):2-8). 
b Indwelling catheter or vascular access device-related blood-borne infections are not included because evidence is 
lacking that these are preventable with IVIg replacement therapy. For patients without indwelling catheters or 
vascular access devices, a single blood culture positive for a pathogenic organism will meet the diagnostic criteria 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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for bacteremia (multiple blood cultures are typically obtained in cases of suspected bacteremia/sepsis, as per 
standard medical practice, and the finding of a single positive culture should prompt additional confirmatory 
cultures). Patients meeting criteria for positive blood culture but without 2 or more of the sepsis criteria listed 
above will be classified as having bacteremia.
c A blood culture positive for growth of Streptococcus pneumoniae, Neisseria meningitides, or Haemophilus 
influenzae, in combination with CSF leukocytosis and/or glycorrhachia, can serve to confirm the diagnosis of 
acute bacterial meningitis.
d For the diagnosis of pneumonia in adults, commonly at least 2 of the listed symptoms and/or signs should be 
present in conjunction with at least one laboratory and one imaging studies diagnostic element. However, for the 
purposes of counting serious infection episodes in a clinical trial of IVIg, the finding of a new pulmonary infiltrate 
with consolidation on chest x-ray is considered sufficient. To establish the diagnosis of bacterial pneumonia for 
pediatric patients, most of the same diagnostic criteria listed may be used, with the following exceptions: Because 
pediatric patients may not produce a sputum specimen for culture, blood cultures or serology may be substituted 
to identify the etiologic bacterial pathogen. In infants age 3 to 24 months, fever is defined as a rectal temperature 
> 38.3ºC (101ºF). In children > 2 years, fever is more commonly defined as a rectal temperature > 38ºC (100.4ºF). 
In pediatric patients, elevations of WBC counts > 15,000/mm3 are frequent but could be variable in patients with 
bacterial pneumonia, or leukopenia with WBC count < 5000/mm3 may be observed, usually associated with 
severe infection.
e A deep expectorated sputum gram stain is recommended to demonstrate the presence of microorganisms on 
examination of 10-20 oil immersion microscopic fields and < 10 squamous epithelial cells and > 25 
polymorphonuclear leukocytes at 10X low power magnification to determine suitability of sputum culture.
8.1.2
IgG LEVELS
During the clinic visit the pre-infusion IgG levels will be evaluated.
During study treatment, a blood sample for the evaluation of IgG levels (pre-
infusion) will be taken before each infusion, every 21 or 28 days during all study 
period depending on the patient’s infusion schedule, and at the study 
termination visit.
Information about the IgG levels will be recorded in the source documentation at 
the study site and collected in eCRF.
8.1.3
IgG SUBCLASSES/SPECIFIC ANTIBODIES LEVELS
A blood sample for IgG subclasses (IgG1, IgG2, IgG3, IgG4) and the 
quantitative evaluation of the anti-Tetanus toxoid, anti-pneumococcal capsular 
polysaccharide, anti-Haemophilus influenza type B and anti-measles antibodies 
levels will be taken before the following infusions:

21-day infusion schedule: at infusions 1, 7, 11, and 17 

28-day infusion schedule: at infusions 1, 5, 9, and 13
Information about the above IgG subclasses and specific antibodies levels will
be recorded in the source documentation at the study site and collected in 
eCRF.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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8.1.4
DAYS MISSED FROM WORK, SCHOOL, OTHER MAJOR 
ACTIVITIES DUE TO INFECTIONS
The patient/patients’ parent(s)/legal guardian(s) will provide the following 
information in a Patient Diary that will be provided starting from the first infusion 
visit: days missed from work/school/other major activities due to infections.
The information entered in the diary since the previous visit will be reviewed at 
the following visit and collected in the visit specific eCRF pages.
8.1.5
INFECTIONS OTHER THAN SERIOUS ACUTE BACTERIAL 
INFECTIONS
All the information regarding infections (other than serious acute bacterial 
infections), including the number of days for resolution, collected by the 
patient/patient’s parent(s)/legal guardian(s) in the Patient Diary or during clinic 
visit will be recorded in the specific eCRF pages.
Information entered in the diary since the previous visit will be reviewed at every 
visit.
8.1.6
FEVER EPISODES
All the information regarding fever episodes, including the number of days for 
resolution, collected by the patient/patient’s parent(s)/legal guardian(s) in the 
Patient Diary or during clinic visit will be recorded in the specific eCRF pages. 
The definition of fever for all patients participating in the study will be defined as 
any temperature ≥38°C (≥100.4°F).
Information entered in the diary since the previous visit will be reviewed at every 
visit.
8.1.6.1
DAYS OF HOSPITALIZATIONS
The patient/patients’ parent(s)/legal guardian(s) will also provide the information 
regarding the overall hospitalization days and days of hospitalizations due to 
infection in the Patient Diary that will be provided starting from the first infusion 
visit.
Information entered in the diary since the previous visit will be reviewed at the 
following visit and collected in the specific eCRF page.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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8.1.6.2
USE OF THERAPEUTIC ANTIBIOTICS
The patient/patients’ parent(s)/legal guardian(s) will also provide the information 
regarding the use of therapeutic antibiotics, including the duration of patient on 
antibiotics, for the treatment of any kind of infections in the Patient Diary that will 
be provided starting from the first infusion visit.
Information entered in the diary since the previous visit will be reviewed at the 
following visit and collected in the specific eCRF page. 
Start dates and stop dates of antibiotic treatment will be collected to determine
the number of days on therapeutic antibiotics.
8.1.7
HEALTH CARE UTILIZATION
Health care utilization will be collected during the study as part of self-reported 
AEs and/or ADRs. These events may be collected from different sources by
study personnel assessment during routine study visits, patient diary, or by other 
notification such as an AE. The health economic data will include only additional
utilization of health care.
8.1.8
QUALITY OF LIFE
8.1.8.1
Pediatric Quality of Life Inventory™
The total score of PedsQL™, and scores in different domains will be computed 
at baseline, week 24, and at study termination visit, and will be collected in the 
specific eCRF page.
8.2
SAFETY VARIABLES
The safety assessment will be performed during all study periods.
Starting at the first infusion visit, a Patient Diary will be used to collect and document 
any AEs. The patient/patients parent(s)/guardian(s) will be trained to complete the 
Patient Diary.
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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8.2.1
VITAL SIGNS
The vital signs, including blood pressure, heart rate and temperature will be 
collected at each visit (including screening and study termination visit) and 
recorded in the eCRF.
Temperature method should be consistent throughout the study for any given 
patient.
All vital sign measurements will have an allowable window of ±5 minutes. For 
each infusion, vital signs will be measured at rest at the following time points:

10 to 15 min pre-infusion;

After start of infusion: 5 minutes before each increase of the infusion rate;

30 minutes after reaching the maximum infusion rate; every 60 minutes 
thereafter;

Immediately after completion of the infusion.
8.2.2
PHYSICAL EXAMINATION
A physical examination will be performed at screening, at each visit before the 
infusion, and at the study termination visit. The general physical examination 
will include an evaluation of all body systems, as per normal standard of care at 
each site. Body weight measurement will be collected at each visit for pediatric 
patients and at weeks 12, 24, 36, and 48 for adults.
Information about the physical examination will be recorded in the source 
documentation at the study site and in the eCRF.
8.2.3
CLINICAL LABORATORY ANALYSIS
The tests listed below will be performed at screening visit, at each visit before 
the infusion, and at the study termination visit (week 51/52):

Blood profile: hemoglobin, hematocrit, RBC count, WBC count with 
formula, number of platelets;

Blood chemistry profile: total bilirubin, creatinine, blood urea nitrogen,
ALT, AST, alkaline phosphatase, lactate dehydrogenase, glucose, 
sodium, potassium, chloride, and calcium;

Urinalysis (qualitative and quantitative/semi-quantitative): bilirubin, pH, 
protein, blood, nitrite, specific gravity, leukocyte esterase, RBCs, WBCs.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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The pregnancy test on urine (for patients of childbearing age) will be also 
performed at the screening visit.
Intravascular hemolysis testing will be performed at the screening visit, after the 
first study infusion, after the 5th infusion for the 28-day infusion schedule or the 
7th infusion for the 21-day infusion schedule, and at the study termination visit 
(week 51/52). Direct Coombs, serum haptoglobin, plasma-free hemoglobin, and 
urine hemosiderin tests will be performed.
If a Direct Coombs test is positive, the test and serum haptoglobin, plasma-free 
hemoglobin, and urine hemosiderin tests must be repeated immediately after the 
initial positive result.
Information about the clinical laboratory analysis will be recorded in the source 
documentation at the study site and in the eCRF.
Refer to the study-specific Clinical Specimen Laboratory Manual for additional 
details.
8.2.4
RETENTION OF SAMPLES FOR VIRAL SAFETY AND ANY 
FUTURE VIRAL TESTING
In compliance with the “Guideline on the clinical investigation of human normal 
immunoglobulin for intravenous administration (IVIg)” 
(EMA/CHMP/BPWP/94033/2007 rev.3), a serum sample before treatment at the 
screening visit and a serum sample at the study termination visit
must be drawn from each patient and stored 
for at least 2 years, following study closure (last patient last visit), at ≤-70°C 
temperature for viral safety and any future viral testing at the central laboratory. 
At the end of that period, the samples should be destroyed.
8.2.5
ADVERSE EVENT
All serious and non-serious AEs, will be collected for all study periods, evaluated 
with regard to the infusion rate, and recorded as indicated in the Section 9,
Safety Reporting Rules.
In particular, infusion AEs will be collected, defined as AEs occurring during or 
within 1 hour, 24 hours, and 72 hours following each infusion.
Severity and causality correlation to the therapy will be evaluated. Definition 
and reporting for event and collection of AEs are described in Section 9, Safety 
Reporting Rules.
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Note that any potential undesirable effect from screening to infusion 1 will be 
reported as medical history. Those effects considered serious and related to 
prior IVIg, will also be notified to the marketing authorization holder.
Medical Events of Interest
For this study, the following will be considered medical events of interest (see 
Section 7.1.2):

Thrombotic events

Hemolysis

Transfusion-related acute lung injury (see Section 7.1.1, Method of 
Administration)

Aseptic meningitis

Acute renal failure

Neutropenia 

Hypersensitivity reactions (including anaphylaxis)
Anaphylaxis, defined according to NIAID/FAAN clinical criteria (Shaker MS, 
2020), is highly likely when any one (1) of the following three (3) criteria are 
fulfilled:
1. Acute onset of an illness (minutes to several hours) with involvement of 
the skin, mucosal tissue, or both (eg generalized hives, pruritus or 
flushing, swollen lips-tongue-uvula)
AND AT LEAST 1 OF THE FOLLOWING:
a. Respiratory compromise (eg dyspnea, wheeze-bronchospasm, 
stridor, reduced peak expiratory flow (PEF), hypoxemia)
b. Reduced Blood Pressure (BP) or associated symptoms (eg 
hypotonia [collapse], syncope, incontinence)
2. Two or more of the following that occur rapidly after the exposure to a 
likely allergen for that patient (minutes to several hours):
a. Involvement of the skin-mucosal tissue (eg generalized hives, 
itch-flush, swollen lips-tongue-uvula)
b. Respiratory compromise (eg dyspnea, wheeze-bronchospasm, 
stridor, reduced peak expiratory flow (PEF), hypoxemia)
c. Reduced Blood Pressure (BP) or associated symptoms (eg 
hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg crampy abdominal pain, 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes 
to several hours):
a. Infants and children: low systolic BP (age specific) or greater than 
30% decrease in systolic BP
b.
Adults: systolic BP of less than 90 mm Hg or greater than 30% 
decrease from that person’s baseline
8.3
DEMOGRAPHIC ASSESSMENT
8.3.1
MEDICAL HISTORY AND DEMOGRAPHIC INFORMATION
The following demographic information, including date of birth, gender and 
ethnicity, and a complete medical history, will be collected at the screening visit 
and recorded directly in the eCRF:

infections history;

tolerance of previous IgG treatment;

antibody response to pneumococcal vaccination (when available);

documented last 3 commercially available IVIg infusions before the study 
entry;

baseline IgG levels;

2 documented IgG trough levels of ≥ 6 g/L within 12 months (1 being 
within 6 months) prior to enrollment.
In particular, history results relevant to the confirmation of PID diagnosis must 
be collected. Patients must have a documented history of stable commercially 
available IVIg therapy at approximately 21- or 28-day intervals for at least 
3 infusion cycles prior to receiving KIg10. There must also be documentation of 
at least 2 trough serum levels of ≥ 6 g/L during the previous 6 and 12 months.
8.3.2
CONCOMITANT MEDICATIONS
All medications, drugs and blood products taken or received by the patient
starting on the day of the first KIg10 infusion until the study termination visit are 
to be collected into the e-CRF (see Section 7.5, Concomitant Medications).
8.3.3
CHEST X-RAY
A chest x-ray will be performed at the screening visit if a chest x-ray is not 
available within last 6 months prior to the ICF signature.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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8.4
PHARMACOKINETIC ASSESSMENT (PK EVALUATION SET)
Pharmacokinetic assessments will be performed in approximately 24 adult patients in 
order to have 20 evaluable patients before and after the 5th study infusion (28-day
infusion schedule) or the 7th study infusion (21-day treatment schedule), when steady 
state is expected to be achieved (after 5 half-lives of regular infusion of the IMP).
Interim PK analysis will be performed when approximately 24 adult patients 
(20 evaluable patients) complete intense PK sampling before and after infusion 5 for 
the 28-day schedule or infusion 7 for 21-day schedule.
Blood samples (approximately 20 mL) will be obtained at the following time-points:
-
30 minutes to 10 minutes pre-infusion
-
30 minutes (± 5 minutes) post-infusion
-
2 hours (± 15 minutes) post-infusion
-
24 hours (± 2 hours) post-infusion
-
72 hours (± 2 hours) post-infusion
-
7 days (± 1 day) post-infusion
-
14 days (± 1 day) post-infusion
-
21 days (± 1 day) post-infusion
-
28 days (± 2 days) post-infusion (only for 28 days treatment schedule)
Information about the PK assessment will be recorded in the source documentation at 
the study site and in the eCRF.
8.4.1
PK PARAMETERS OF TOTAL IgG
Blood samples for the analysis of PK parameters for total IgG will be taken 
before and after infusion 5 for the 28-day infusion schedule or infusion 7 for the 
21-day infusion schedule, and at the time points indicated above in Section 8.4, 
Pharmacokinetic Assessment.
Total IgG levels and the following PK parameters will be evaluated. The PK 
parameters are also described in Section 10.4.4.
Plasma concentration-time curve, half-life, AUC0-t, AUC0-inf, volume of 
distribution, Cmax, Tmax, and elimination rate constant. AUC0-inf will be evaluated 
if data meet PK acceptance criteria to elimination parameters; AUC over dosing 
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Data about the above total IgG levels will be recorded in the source 
documentation at the study site and in the eCRF.
8.4.2
IgG SUBCLASSES LEVELS
Blood samples for the analysis of IgG subclasses levels (IgG1, IgG2, IgG3, 
IgG4) will be taken before (as for all patients) and after the infusion 5 (28-day
infusion schedule) or infusion 7 (21-day infusion schedule) at the time points 
indicated above in Section 8.4, Pharmacokinetic Assessment.
IgG subclasses levels will be recorded in the source documentation at the study 
site and in the eCRF.
8.4.3
PK PARAMETERS OF SPECIFIC IgG ANTIBODIES
Blood samples for the analysis of PK parameters for specific IgG antibodies 
(anti-Haemophilus influenza type b, anti-pneumococcal capsular 
polysaccharide, and anti-Tetanus toxoid) will be taken before and after the 
infusion 5 (28-day infusion schedule or infusion 7 (21-day infusion schedule) at 
the time-points indicated in Section 8.4, Pharmacokinetic Assessment.
Specific antibodies levels and the following PK parameters will be evaluated. 
The PK endpoints are also described in Section 10.4.4.
Plasma concentration-time curve, half-life, AUC0-t, volume of distribution, Cmax, 
Tmax, and elimination rate constant. AUC0-inf will be evaluated if data meet PK 
acceptance criteria to elimination parameters; AUC over dosing interval (21-day 
or 28-day) (AUCtau) and other parameters may be derived.
Data about the above specific IgG antibodies will be recorded in the source 
documentation at the study site and in the eCRF.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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9.
SAFETY REPORTING RULES
9.1
DEFINITIONS
9.1.1
ADVERSE EVENT/ADVERSE DRUG REACTION
An AE is “any untoward medical occurrence in a patient or clinical trial patient
administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment’’ Directive 2001/20/EC.
An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.
An ADR is “any untoward and unintended responses to an IMP related to any 
dose administered.” The definition of ADR covers also medication errors and 
uses outside what is foreseen in the protocol, including misuse and abuse of the 
product. The definition implies a reasonable possibility of a causal relationship 
between the event and KIg10. This means that there are facts (evidence) or 
arguments to suggest a causal relationship.
9.1.2
SERIOUS ADVERSE EVENTS
A SAE is “any AE that, at any dose:

results in death,

is life threatening,

requires hospitalization or prolongation of existing hospitalization,

results in persistent or significant disability or incapacity,

is a congenital anomaly or birth defect.”
These characteristics/consequences have to be considered at the time of the 
event. For example, regarding a life-threatening event, this refers to an event in 
which the patient 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 was more severe.
Some medical events may jeopardise the patient or may require an intervention 
to prevent one of the above characteristics/consequences. Such events 
(hereinafter referred to as ‘important medical events’) should also be considered 
as ‘serious’ in accordance with the definition.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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A non-serious AE is an AE that does not meet the above criteria.
9.1.3
UNEXPECTED ADVERSE DRUG REACTIONS
An unexpected adverse reaction is an “adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (e.g., 
Investigator’s brochure for an unauthorized investigational product or summary 
of product characteristics for an authorized product).’’
Reports which add significant information on the specificity, increase of 
occurrence, or severity of a known, already documented serious adverse 
reaction constitute unexpected events.
9.1.4
CAUSALITY CORRELATION 
The Investigator should evaluate the association between the AE and the 
on-going treatment using information found in the Investigator’s Brochure in 
conjunction with the patient’s pre-existing medical conditions and concomitant 
medications and the timing of the AE relative to the administration of KIg10. Any 
AE will be reported as “Related” or “Not Related” to KIg10 in accordance with 
the following definitions, elaborated from those of the World Health 
Organization:
Related: 
Any event which falls into one of the below definitions (certain, probable 
or possible), it should be considered as “Related” to study drug.
Certainly Related
A clinical event (including laboratory test abnormalities):

occurring in a plausible time relationship to drug administration;

which cannot be explained by concurrent disease or other drugs;

which response to withdrawal of the drug (de-challenge) is clinically 
plausible;

which must be definitively associated pharmacologically or 
phenomenologically, using a satisfactory “re-challenge” procedure, if 
necessary.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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Probably related:
A clinical event (including laboratory test abnormalities):

with reasonable time sequence to administration of the drug;

unlikely to be attributed to concurrent disease or other drugs or 
chemicals;

which follows a clinically reasonable response on withdrawal (de-
challenge);

“re-challenge” information is not required to fulfil this definition.
Possibly related:
A clinical event (including laboratory test abnormalities):

with a reasonable time sequence to administration of the drug;

which could also be explained by concurrent disease or other drugs or 
chemicals;

information on drug withdrawal may be lacking or unclear.
Not related:
An event for which sufficient information exists to conclude that the etiology of 
the event is unrelated to KIg10.
Please note that this definition is intended to be used when the exclusion of drug 
causality of a clinical event is supported by the existence of an alternative cause 
(e.g., concomitant medications, medical history, concomitant diseases, disease 
under study, or other) which should be clearly specified with additional details. 
If a possible correlation cannot be excluded, the definition to be used is 
“Related.”
9.2
REPORTING METHODS
Any serious and non-serious AE must be communicated to Kedrion or its designee. 
An eCRF will be used for this study. All serious AEs will be communicated to 
Kedrion/designee as noted in Section 9.2.1.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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9.2.1
SERIOUS ADVERSE EVENT/SERIOUS ADVERSE DRUG 
REACTIONS
All SAEs/serious adverse drug reactions (SADRs) must be reported by the 
Investigator to the Sponsor or its designee by entering all information relevant to 
the event in the appropriate "Serious Adverse Event(SAE)/Medical Event of 
Interest Report Form” immediately and, in any case, no later than 24 hours
following the receipt of this information. A detailed report (follow-up) on the 
case should be supplied by the Investigator within the subsequent 3 calendar 
days, using the same form.
In the case of a SAE with a fatal outcome, the Investigator must notify not only 
the Sponsor/designee but also the local IEC/IRB and must provide any 
additional required information.
9.2.2
NON-SERIOUS ADVERSE EVENTS
The Investigator is required to notify the Sponsor/designee of all non-serious 
AEs. This information should be reported by the Investigator to the 
Sponsor/designee by updating the eCRF "Adverse Event Report Form” 
following the receipt of this information.
9.2.3
ABNORMALITIES IN LABORATORY PARAMETERS
The Investigator must evaluate the clinical significance of all abnormal 
laboratory values based on standard laboratory reference values. Any clinically 
significant abnormality must be fully investigated. The term "clinically significant" 
refers to any abnormal value that, according to the Investigator, represents an 
important clinical problem that requires the intervention of a physician or that 
otherwise may fall within the definition of a "serious" AE. When clinical
significance is indicated, further analysis or other assessments must be 
obtained in order to determine the significance or cause of an abnormal result, 
or to monitor the course of an AE. Any persistently abnormal value must be 
monitored at the Investigator’s discretion. Clinically significant abnormal results 
shall be documented in the appropriate eCRF.
Pregnancy test will be performed locally at each site. Hematology, chemistry, 
urinalysis, IgG levels, subclasses, specific antibodies, and intravascular 
hemolysis testing will be analyzed centrally. Direct Coombs and urine 
hemosiderin can be tested either centrally or at site level. For centralized tests, 
Investigators will receive the results and the reference normal ranges for patient 
monitoring.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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9.2.4
PRE-EXISTING AND CONCOMITANT DISEASES
Pre-existing diseases that are present prior to the study entry before the ICF 
signature up to the first KIg10 infusion must be reported in the appropriate 
eCRF (Medical History). Please note that signs/symptoms of a pre-existing 
disease that occur with the same severity, frequency or duration after the 
administration of KIg10 will be considered as Medical History.
Concomitant diseases that occur following the first KIg10 infusion until the study 
termination visit or cases that show an increase in the severity or the duration of 
a pre-existing disease must be reported as AEs.
9.2.5
PREGNANCIES
To ensure patients’ safety, each pregnancy in a patient after study drug 
administration must be reported to the Sponsor within 24 hours of the site 
learning of its occurrence. If the patient agrees to submit this information, the 
pregnancy must be followed to determine outcome, including spontaneous or 
voluntary termination, details of the birth, and the presence or absence of any 
birth defects, congenital abnormalities, or maternal and/or newborn 
complications. This follow-up should occur even if intended duration of safety 
follow-up for the study has ended.
Pregnancy data must be recorded on a Pregnancy and Breastfeeding Exposure 
Report form and reported to the Sponsor/designee. Follow-up reports will be 
submitted on the same form. Instructions and contact details for submitting the 
Pregnancy and Breastfeeding Exposure Report will be provided to the 
Investigator.
9.2.6
INSTRUCTIONS FOR THE STUDY PERSONNEL REGARDING 
CLINICAL SIGNS AND SYMPTOMS 
Patients/patient’s parent(s)/legal guardian(s) will be instructed to call specified 
study personnel if any clinical sign or symptom appears after treatment. 
Patients who develop severe systemic events should be examined, if possible, 
at the treating facility at the time of the maximal symptoms and clinically 
monitored until their resolution.
Any event causing the withdrawal of the patient from the study shall be reported 
in the appropriate eCRF section. All AEs shall be followed until recovery and/or 
diagnosis. If an AE is not resolved by the end of the study, the Investigator shall 
determine whether to authorize a follow-up. All drugs administered during the 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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study to treat either AEs or previously diagnosed conditions shall be recorded in 
the appropriate eCRF.
Where a diagnosis is possible, it is preferable to report this rather than a series 
of terms relating to the diagnosis itself. When a syndrome is reported, the 
associated signs and symptoms must be documented as part of the syndrome 
and not as separate events.
Any patient reporting an AE shall be examined by a physician as soon as 
possible. The physician must do whatever is necessary for the safety and 
welfare of the patient. All these events shall be monitored until recovery or 
clinical stabilization.
The AE shall be described in the eCRF using standard terminology (MedDRA) 
to avoid the use of vague, ambiguous, or colloquial expressions. The 
Investigator shall evaluate the severity of all AEs and their correlation with the 
study drug and shall report the result of the analysis and the necessary actions 
to be taken.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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10.
STATISTICAL CONSIDERATIONS
A detailed statistical analysis plan (SAP) is provided with IND/CTA submission. Protocol 
deviations will be defined at the beginning and data will be checked throughout the study 
on a regular basis (International Council for Harmonization [ICH] E6 [R2] addendum).
Protocol deviations will be described in the SAP.
10.1
ANALYSIS SETS
The efficacy and safety analyses will be based, respectively on the Full Analysis Set 
(FAS) and the Safety Set (SAF) unless stated otherwise. All PK analyses will be done 
on the PK Evaluation Set.
The following analysis sets will be defined:
10.1.1
ALL PATIENTS ENROLLED SET
The All Patients Enrolled Set includes all patients who have given informed 
consent/assent to this study.
10.1.2
FULL ANALYSIS SET
The FAS comprises all patients who have received at least 1 dose of study 
medication.
10.1.3
SAFETY SET
The SAF comprises all patients who have received at least 1 dose of study 
medication. In this study, the SAF and FAS are coincident as no randomization 
occurred.
10.1.4
PER-PROTOCOL SET
The Per-protocol Set (PPS) includes all patients who are compliant with the 
study protocol without any major protocol deviations that could affect efficacy.
Any analysis based on the PPS will be performed for the primary efficacy 
endpoint as an additional supportive analysis.
10.1.5
PHARMACOKINETIC EVALUATION SET
The PK Evaluation Set includes all adult patients that consent to this part of the 
protocol and who have PK analysis performed at the 5th infusion (28-day 
infusion schedule) or the 7th infusion (21-day infusion schedule). The population
includes all patients following the principles of the SAF for whom at least 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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1 concentration of total IgGs, IgG subclasses 1-4, or IgG specific antibody 
levels (anti-pneumococcal capsular polysaccharide, anti-haemophilus 
influenzae type B, anti-tetanus toxoid), measured in the dense sampling period 
(i.e., before and after the 5th infusion of the 28-day infusion schedule and before
and after the 7th infusion for the 21-day infusion schedule).
10.2
DEMOGRAPHICS AND BASELINE CHARACTERISTICS
Demographic and other baseline characteristics will be summarized on the FAS using 
descriptive statistics.
10.3
PRIMARY ENDPOINT
Definition
Incidence rate (i.e., the mean number of acute serious bacterial infections per patient-year) 
of acute serious bacterial infections (bacterial pneumonia, bacteremia/sepsis, bacterial 
meningitis, visceral abscess, osteomyelitis/septic arthritis) according to pre-specified 
criteria).
Main Analysis
Primary analysis of the primary endpoint will be performed on the FAS. Primary efficacy 
will be analyzed using a Poisson model using as offset the length of the observation period 
per patient. The estimate and 1-sided 99% upper confidence limit will be reported. Efficacy 
will be claimed if this limit is less than 1.0.
CCI

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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10.4
SECONDARY ENDPOINTS
10.4.1 SECONDARY EFFICACY ENDPOINTS
Definitions
1. Serum IgG trough levels before each infusion of KIg10 and at the study termination
visit (week 51/52).
2. IgG subclasses levels (IgG1, IgG2, IgG3, IgG4) before infusions 1, 5, 9, and 13 for 
the 28-day infusion schedule, and before infusions 1, 7, 11, and 17 for the 21-day
infusion schedule.
3. Frequency of patients with total IgG below 6 g/L criteria.
4. Anti-tetanus toxoid antibody level (quantitative assay) before infusions 1, 5, 9, and 
13 for the 28-day infusion schedule and before infusions 1, 7, 11 and 17 for the 
21-day infusion schedule.
5. Anti-pneumococcal capsular polysaccharide antibody level (quantitative assay) 
before infusions 1, 5, 9, and 13 for the 28-day infusion schedule and before
infusions 1, 7, 11, and 17 for the 21-day infusion schedule.
6. Anti-measles antibody level (quantitative assay) before infusions 1, 5, 9, and 13 for 
the 28-day infusion schedule and before infusions 1, 7, 11, and 17 for the 21-day
infusion schedule.
7. Anti-Haemophilus influenza type b antibody level (quantitative assay) before
infusions 1, 5, 9, and 13 for the 28-day infusion schedule and before infusions 1, 7, 
11, and 17 for the 21-day infusion schedule.
8. Incidence rate (i.e., the mean number per patient-year) of any infection other than 
acute serious bacterial infections from day 1 to week 51/52.
9. Duration of any infection other than acute serious bacterial infections from day 1 to 
week 51/52.
10.Incidence rate (i.e. the mean number per patient-year) of fever episodes, from 
day 1 to week 51/52.
11.Duration of fever episodes, from day 1 to week 51/52.
12.Overall hospitalization days from day 1 to week 51/52.
CCI

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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13.Days of hospitalizations due to infection from day 1 to week 51/52.
14.Incidence rate (i.e. the mean number per patient-year) of patient on antibiotics for 
the treatment of any kind of infection from day 1 to week 51/52.
15.Duration of patients on antibiotics for the treatment of any kind of infection from day 
1 to week 51/52.
16.Days of missed work/school/other major activities due to infections from day 1 to 
week 51/52.
17.PedsQL™score at baseline, week 24, and study termination visit.
Analysis
Secondary efficacy endpoints will be summarized using descriptive statistics. Further 
details will be provided in the SAP.
10.4.3 SAFETY ENDPOINTS
Definition
1. Number of AEs (%) and proportion of patients experiencing at least 1 AE.
2. Number of SAEs (%) and proportion of patients experiencing at least 1 SAE.
3. Number of related infusion AEs (%) occurring during infusion or within 1, 24, and 
72 hours after the end of infusion and proportion of patients experiencing at least 
1 of such related infusion AE.
CCI

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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4. The proportion and number of KIg10 infusions for which the infusion rate is 
decreased due to AEs.
5. Number and proportion of infusions with 1 or more infusion (temporally-associated) 
AE.
6. Changes in vital signs, physical examinations, and safety laboratory tests 
(hematology, serum chemistry, and urinalysis).
7. The proportion and number of patients with a positive Coomb’s test following the 5th
infusion for the 28-day infusion schedule and the 7th infusion for the 21-day infusion
schedule.
8. The proportion and number of patients with a positive urine hemosiderin test 
following the 5th infusion for the 28-day infusion schedule and the 7th infusion for the 
21-day infusion schedule.
9. Plasma-free hemoglobin level following the 5th infusion for the 28-day infusion 
schedule and the 7th infusion for the 21-day infusion schedule.
10.Serum haptoglobin level following the 5th infusion for the 28-day infusion schedule 
and the 7th infusion for the 21-day infusion schedule.
Analysis
Secondary safety endpoints will be summarized using descriptive statistics. Additionally, a 
1-sided 95% CI will be produced for the proportion of infusions with 1 or more 
temporally-associated AEs (including AEs determined not to be product-related) using an 
exact binomial method. Due to the clustered nature of the data, a Design Effect will be 
applied to the confidence interval. An analysis of variance method will be used to calculate 
the Intra Cluster Correlation Coefficient (Wu, 2012). For this analysis, safety will be 
declared if the upper 1-sided 95% confidence is less than 0.4. Other methods that take in 
account the clustered nature of the data could be performed (e.g., Generalized Estimating 
Equation). Additionally, a 2-way table will summarize the frequency and proportion of 
infusion related AE by speed of infusion category. This table will be produced overall and 
by the number of infusional related AE experienced per patient (e.g., 1 event experienced, 
2 events experienced, 3+ events experienced).
Further details will be provided in the SAP.
10.4.4
PHARMACOKINETIC ENDPOINTS
The following PK endpoints will be derived for the PK Evaluation Set only.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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1.
Serum total IgG levels, IgG subclasses levels and selected specific 
antibody levels before and after the 5th infusion (28-day infusion 
schedule) or 7th infusion (21-day infusion schedule).
2.
PK parameters of total IgG before and after the 5th infusion (28-day
infusion schedule) or 7th infusion (21-day infusion schedule).
3.
PK parameters of specific IgG antibodies before and after the 5th infusion
(28-day infusion schedule) or 7th infusion (21-day infusion schedule).
a. anti-haemophilus influenza type b
b. Anti-tetanus toxoid
c. Anti-pneumococcal capsular polysaccharide
4.
Plasma concentration-time curve, Cmax, Tmax, AUC0-t, other parameters 
such as steady state parameters AUCtau, average concentration of drug 
over the dosing interval (Cave), and steady state clearance (CLss) may 
also be derived. Elimination parameters such as elimination rate 
constant, elimination half-life. AUC0-inf, volume of distribution will be 
derived if data allow based on PK acceptance criteria. 
5.
Exploratory correlation analysis between health outcomes and PK 
parameters or trough concentrations may be included in the analysis. 
The details will be further described in the SAP.
10.5
SCHEDULE OF ANALYSES
10.5.1 INTERIM PK ANALYSIS
Interim PK analysis is planned after at least 20 patients will complete intense PK 
sampling before and after infusion 5 for 28 days schedule or infusion 7 for 21 days 
schedule. The data for total IgG, IgG subclasses and specific IgGs will be received 
from the bioanalytical laboratory for PK analysis and reconciled by data management
to format interim PK datasets. Planned and additional PK parameters as data allow 
will be derived by the PK scientist using professional PK software and formatted as 
interim PK analysis TLFs in SAS. Interim PK report will be produced by the study PK 
scientist.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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10.5.2 DSMB ReviewsSafety and efficacy data recorded during the study 
period will be reviewed by an independent DSMB at specific intervals. The timing of 
the DSMB reviews will be described in the DSMB charter.
10.6
SUBGROUPS
Subgroup analyses are planned to be performed for the primary and secondary 
efficacy endpoints and for safety endpoints, including AEs (infusional AEs and 
treatment-emergent AEs).
10.6.1
AGE
The age categories for the subgroup analyses will be children (2 to 11 years, 
inclusive), adolescents (12 to 17 years, inclusive), and adults (18 to 70 years, 
inclusive). The age categories will be consistent for all subgroup analyses with 
the exception of PK, where blood samples will only be taken from adults.
Age will be the age recorded at screening (initial visit). The same age will be 
used per patient during the entire study (i.e., if a patient’s age changes from 
17 to 18 years during the study, the patient will remain in the age category of 
12 through 17 years during the entire study).
10.6.2
TREATMENT SCHEDULE
The treatment categories for the subgroup analyses will be 21 days and 
28 days.
10.7
HANDLING OF MISSING DATA
Missing data will not be an issue on primary efficacy analysis as, in the worst case 
scenario, a patient will contribute with no person year to analysis. For other data, 
further details will be provided in the SAP.
10.8
PROTOCOL DEVIATIONS
Deviations from the protocol will be defined in advance and documented on an 
ongoing 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. Patients with major protocol deviations that affect efficacy will 
be excluded from the PPS under the assumption that the deviation may have an 
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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The investigator should not implement any deviation from, or changes of the protocol, 
without agreement by the sponsor and prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment, except where 
necessary to eliminate an immediate hazard(s) to study patients. The investigator, or 
person designated by the investigator, should document and explain any deviation 
from the approved protocol.
10.9
SAMPLE SIZE
A sample size of at least 40 evaluable patients is considered a sufficient number to 
evaluate the primary study endpoint according to the relevant FDA and EMA 
guidelines. A sample size of 40 achieves 90% power to reject the null hypothesis of an 
acute serious bacterial infection incidence 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 0.49 per year (assuming a Poisson process). CCI

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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11
SOURCE DOCUMENTATION, STUDY MONITORING, AND AUDITING
In order to ensure consistency across sites, study monitoring and auditing will be 
standardized and performed in accordance with the Sponsor’s or delegated CRO standard 
operating procedures (SOPs) and applicable regulatory requirements (e.g., FDA, EMA, 
and ICH guidelines).
Prior to enrollment of the first study patient, the Sponsor or its delegate will train 
Investigators and/or their study staff on the study protocol, all applicable study procedures, 
documentation practices and all electronic systems. eCRFs supplied by the Sponsor must 
be completed for each enrolled patient. All patients’ documentation, including screened but 
not enrolled patients, must be maintained at the site and made available for review by the 
site monitor. Data and documents will be checked by the Sponsor and/or monitor.
11.1
SOURCE DOCUMENTATION
Prior to the start of the study, the site staff participating in the study conduct will be 
instructed on what documents will be required for review as source documents. The 
list of documents that will serve as source documents will be agreed between Sponsor 
(or its designee) and Investigator and study staff prior to patient enrollment.
In addition, source documentation must include all of the following: patient ID number, 
eligibility and participation, proper informed consent procedures, dates of visits, 
adherence to protocol procedures, adequate reporting and follow-up of AEs, 
documentation of prior/concomitant medication/drugs, study drug 
receipt/dispensing/return records, study drug administration information, any data 
collected during the visits and by a telephone conversation with the patient and/or
parent(s)/legal guardian(s), and date of completion and reason.
The patient and/or parent(s)/legal guardian(s) must also allow access to the patient’s 
medical records. Each patient and/or the parent(s)/legal guardian(s) must be informed 
of this prior to the start of the study and consent for access to medical records may be 
required in accordance with local regulations.
All safety data reported by patients must be collected down in source documents prior 
to entry of the data into eCRFs. If there are multiple sources of information (e.g., 
verbal report of the patient, telephone contact details) supporting the diagnosis of an 
AE, these sources must be identified in the source documents, discrepancies between 
sources clarified, the ultimate diagnosis must be justified and written in the source 
documents, and this diagnosis must be captured in eCRF. The eCRF must also 
capture which source(s) of information were used to determine the AE (e.g., patient
recall, medical chart, Patient Diary).

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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11.2
STUDY MONITORING, AUDITING, AND SOURCE DATA VERIFICATION
Study progress will be monitored by the Sponsor or its designee as frequently as 
necessary to ensure:

that the rights, safety and well-being of human patients are protected;

the reported study data are accurate, complete, and verifiable from the source 
documents; and

the conduct of the study is in compliance with the current approved 
protocol/amendment(s), GCP and applicable regulatory requirements.
Contact details for the Sponsor or its designee involved in study monitoring will be 
provided to the Investigator. Study data recorded on eCRFs will be verified by checking 
the CRF entries against source documents in order to ensure data completeness and 
accuracy as required by study protocol.
Additional documents such as the Investigator site file, pharmacy records, and 
informed consent documentation must also be available for review if requested. 
Arrangements for monitoring visits will be made in advance in accordance with the 
monitoring plan, except in case of emergency.
The Investigator and/or site staff must make source documents of patients enrolled in 
this study available for inspection by Sponsor or its representative at the time of each 
monitoring visit and Sponsor audits, when applicable. These documents must also be 
available for inspection, verification and copying, as required by regulations, by officials 
of the regulatory health authorities (e.g., FDA, EMA, and others) and/or IECs. The 
Investigator and study site staff must comply with applicable privacy, data protection,
and medical confidentiality laws for use and disclosure of information related to the 
study and enrolled patients.
11.3
QUALITY ASSURANCE PROCEDURES AND AUDITING
The competent authorities or the Sponsor, may decide to audit the study in order to 
ensure its compliance with the Protocol, with SOPs, GCP and all applicable 
regulations. The Investigator shall ensure that the inspectors/auditors have access to 
the patients’ medical records and to all study documents. The Investigator and his/her 
staff shall also be available to discuss any issues that may arise with the inspectors.
Sponsor and/or its designee, in particular, may carry out periodic audits at the trial 
centers, laboratories and CROs/other vendors involved in the study.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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The patient or the patient’s parents or legally acceptable representative(s) must also 
allow access to the patient’s medical records. Each patient, or the patient’s parent(s) or 
legally acceptable representative(s), should be informed of this prior to the start of the 
study.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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DATA MANAGEMENT
12.1
DATA ENTRY AND MANAGEMENT
All clinical data will be entered onto eCRFs in 72 hours by the Investigator and/or the 
Investigator’s dedicated site staff. The data collected on this secure website are 
assimilated into an electronic data capture (EDC) system. The data system includes 
password protection and internal quality checks. The Investigator or designated 
delegate must review data entered and electronically sign the eCRFs to verify their 
accuracy.
Access to the EDC for data entry or review will require training and distinct individual 
access code assignments to those site staff members who will be entering study data 
and those involved in study oversight who may review study data. Data are collected 
within the EDC system, to which the Sponsor and site monitors have exclusively “read 
only” access.
12.2
DATA CLARIFICATION
The Investigator must review and electronically sign the eCRFs to verify their 
accuracy. Correction to data on eCRFs will be tracked via an audit trail within the web 
based EDC system. Each correction will be identified by the person making the 
change and will include time, date, and reason for change. If corrections are made to a 
previously and electronically signed eCRF, the Investigator must confirm and endorse 
the changes.
As part of the conduct of the trial, the Sponsor may have questions about the data 
entered by the site, referred to as queries. All corrections and clarifications will be 
entered into the EDC system and will be identified by the person entering the 
information, the reason for the change, as well as the time of the changes made. If 
changes are made to a previously and electronically signed eCRF, the Investigator
must confirm and endorse the changes.
12.3
DATA PROTECTION
Sponsor and its designee respect the patients’ rights to privacy and will ensure the 
confidentiality of their medical information in accordance with all applicable laws and 
regulations.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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13
RECORD RETENTION
The Investigator is responsible for maintaining all records pertaining to the clinical trial and 
for ensuring complete and accurate documentation.
The Investigator is responsible for maintaining a patient ID log. This confidential patient ID
code provides the link between named patient source records in the patient file and 
anonymous CRF data provided to Sponsor.
The Sponsor requires that each Investigator retain all study related documents for a 
minimum of 25 years after the study completion (last patient last visit) in alignment with the 
current applicable guidelines. If the study is discontinued, or if no application/license is to 
be filed or if the application/license is not approved for such indication, records should be 
retained for 25 years after the investigation is discontinued or as per local regulations, 
whichever is longer.
The Investigator could be relieved of this responsibility by transferring the documentation 
custody to another person who is a member of the trial center and who will accept the 
conservation responsibility. In this case the Sponsor should be informed about the custody 
transfer, preferably within 10 days from the date of transfer.
It is prohibited for study documents to be destroyed without prior written agreement 
between the Investigator and the Sponsor. Should the Investigator wish to assign the 
study records to another party, or move them to another location, the Sponsor must be 
notified in writing.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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14
PROPERTY OF DATA AND PUBLICATION
The Investigator is informed that the information produced in such study will be used by 
the Sponsor in relationship with the product development and, therefore, may be 
widespread to the governmental agencies in various countries. To enable the use of data, 
the Investigator should supply the Sponsor with the complete results of the tests, all the 
study data and the access to all study documents.
As the exclusive owner of the results obtained, the Sponsor acknowledges the importance 
of the diffusion of medical data and, therefore, encourages their publication on reputed 
scientific journals and the diffusion during seminars and conferences.
The Investigator may publish the trial results only following the relative authorization from 
the Sponsor. The eventual absence of the Sponsor authorization should be adequately 
motivated.
Any results of the medical research on Kedrion’s products and/or the publication/oral 
diffusion/relevant manuscripts will be examined and discussed by the Investigator and 
Kedrion representative 60 days before the submission for the publication or presentation 
during a conference. The due diligence should be offered to the Sponsor’s legitimate 
interests, or the paternity of the manuscript, obtaining an excellent patent protection, 
coordinating and keeping the exclusive nature of the submission to the health authorities, 
coordinating with other studies on-going in the same area, and protecting the confidential 
data and information. 
The Sponsor should receive the copy of each publication proposed. Kedrion’s comments 
should be issued without any exceeding delay and not beyond 60 days. In case of 
publication or presentation of the material of multicentre clinical trials, Kedrion should act 
as a coordinator and referee. The individual Investigators of a multicentre trial cannot 
publish or submit data which are considered to be common to such a study without the 
consent of the other Investigators and the previous review of Kedrion.
In the case of a disagreement between the participants in the multicentre trial, Kedrion will 
be the final arbiter. Kedrion’s comments should be issued with no extra delays. Whenever 
they are not accepted, the senior author of the manuscript and the Kedrion’s 
representatives should meet to discuss and find a common position for the final written text 
and/or the character of the publication. The above mentioned procedure also applies to 
data pertaining to prematurely discontinued or not completed studies.
The results of the Investigators can be divulged to third parties from the trial team only with 
the paper version and only after Kedrion’s approval. Kedrion will not mention the data of 
Investigators’ publications in its scientific information and/or promotional material without 
the complete acknowledgment of the sources (namely author and references). 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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15
ETHICS
15.1
REGULATORY AND ETHICAL COMPLIANCE
International Council for Harmonization E6 GCP Guidelines require that Independent 
IRB/IEC oversees all investigational drug studies. This committee, the makeup of 
which must conform to applicable regulations and guidelines, will approve all aspects 
of the study, including said protocol, written ICF, and any patient information sheets to 
be used, prior to initiation of the study. The Investigator will provide the Sponsor with a 
copy of the communication from the committee to the Investigator indicating approval 
of the protocol and consent form/information sheets. All amendments to the protocol 
must be reviewed and approved prior to implementation, except where necessary to 
eliminate apparent immediate hazards to human patients.
The Investigator will be responsible for obtaining annual IRB/IEC renewal and 
submitting SAE reports to the IRB/IEC for the duration of the study (as per IRB/IEC 
policies and procedures). Copies of the Investigator’s report and/or copies of the 
IRB/IEC extension approval must be sent to the Sponsor.
Protocol deviations and violations will be submitted to IRB/IEC according to the 
requirements of each of these institutions.
15.2
INFORMED CONSENT PROCEDURES
Eligible patients may only be included in the study after providing written ICF, assent
and authorization to Access Personal Health Information, in compliance with the GCP 
and local regulation, as described in Section 6.1, Informed 
Consent/Assent/Authorization to Access Personal Health Information. Before the start 
of the study, the Investigator will have the informed consent, assent, authorization to 
access personal health information and any other materials that will be provided to the 
patients and parent(s)/legal guardian(s) reviewed and approved by the IRB/IEC. This 
review and approval will be documented and archived with other study documents.
The Investigator or designee must fully inform the patient and parent(s)/legal guardian 
of all pertinent aspects of the study. A copy of the written ICF, assent and 
authorization to access personal health information will be given to the patient or the 
designee. The patient/designee must be allowed ample time to ask about the details of 
the study and to make a decision as to whether or not to participate in the study. The 
patient and/or legal guardian(s) must sign the consent form indicating their agreement 
to participate in the study before any study-related procedures are conducted. If the 
patient and/or legal guardian(s) is unable to read and write, a witness must be present 
during the informed consent discussion and at the time of ICF signature. Adult patients 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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who lack the capacity to provide consent will not be allowed to enroll in the protocol 
through the use of a legally authorized representative.
Women of childbearing potential should be informed that taking the study medication 
may involve unknown risks to the fetus if pregnancy were to occur during the study 
and agree that in order to participate in the study they must adhere to the 
contraception requirements indicated in the protocol for the duration of the study. If 
case of doubts on the ability of a patient to adhere to these requirements, that patient
should not be allowed in the study.
In addition, the Investigator or designee should explain pertinent aspects of the study 
in an age appropriate manner to pediatric patients who are eligible for informed assent 
in accordance with local policies. 
15.3
RESPONSIBILITIES OF THE INVESTIGATOR AND IRB/IEC
The protocol and the proposed informed consent/assent/authorization to access 
personal health information forms must be reviewed and approved by a properly 
constituted IRB/IEC before study start. Properly constituted IEC is defined in ICH 
Guideline for GCP E6 (R1), Section 3 (ICH, 1997). A signed and dated statement that 
the protocol and informed consent have been approved by the IRB/IEC must be given 
to the Sponsor before study initiation. Prior to study start and at any time the protocol 
is amended during study conduct, the Investigator is required to sign a protocol 
signature page confirming his/her agreement to conduct the study in accordance with 
these documents and all of the instructions and procedures found in this protocol and 
to give access to all relevant data and records to the Sponsor’s monitors, auditors, and
Clinical Quality Assurance representatives, designated agents of the Sponsor, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the Investigator must inform the Sponsor
immediately that this request has been made.
The Investigator is also responsible for the following:

Maintaining a list of appropriately qualified persons to whom the Investigator has 
delegated significant study-related duties.

Demonstrating the capability of recruiting the required number of suitable patients 
within the recruitment period.

Demonstrating sufficient time and staffing to properly conduct and complete the 
study within the agreed study period.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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
Ensuring that all persons assisting with the study are adequately informed about 
the protocol, the investigational product(s), and their study-related duties and 
functions.

Ensuring that appropriately trained health care professionals are responsible for 
all study-related medical decisions and for ensuring appropriate medical care of 
patients experiencing any AE related to the study.

If permission to do so is given by the patient and parent(s)/legal guardian(s), 
ensuring that the patient’s primary healthcare provider is informed of the patient’s 
participation in the study.
The Investigator should not implement any deviation from, or changes of the protocol 
without agreement by the Sponsor and prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment, except where 
necessary to eliminate an immediate hazard(s) to study patients. In addition, the 
Investigator, or person designated by the Investigator, should document and explain 
any deviation from the approved protocol.
The Investigator may implement a deviation from, or a change of the protocol to 
eliminate an immediate hazard(s) to study patients without prior IRB/IEC 
approval/favorable opinion. As soon as possible, the implemented deviation or change, 
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should be 
submitted:
(a) to the IRB/EC for review and approval/favorable opinion;
(b) to the Sponsor for agreement and, if required;
(c) to the regulatory authority(ies).
Liabilities and Insurance
The study sponsor, Kedrion S.p.A. will pay for all study-related costs. A separate 
financial agreement will be made (as appropriate) with the Investigator and/or 
institutions.
In case of any damage or injury occurring to a patient in association with the
investigational product or participation in the study, the manufacturer of KIg10 has a 
policy with an insurance company.
15.4
CONFIDENTIALITY
The Investigator will ensure that the patients’ confidentiality will be maintained on the 
eCRF or other documents submitted to the Sponsor or its designee. Patients will not be 

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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identified by their names, but by a unique Patient ID number, (see Section 6.3, Patient 
Identification). Documents not for submission to the Sponsor or its designee (e.g., the 
site confidential patient enrollment log, original ICF, assent form, and authorization to 
access personal health information), will be maintained by the Investigator in strict 
confidence.
15.5
PROTOCOL AMENDMENTS
An amendment is a written description of change(s) to or formal clarification of a study 
protocol, which may impact on the conduct of the clinical study, potential benefit of the 
clinical study, or may affect patient safety, including changes of study objectives, study 
design, patient population, sample sizes, study procedures, or significant administrative 
aspects. 
The changes to the protocol may be performed only after consultation and agreement 
with the Sponsor and the Investigator. The only exception is when the Investigator
deems that the patients’ safety may be impaired without an immediate action. In these 
cases, the immediate approval of the IRB/IEC should be required and the Investigator
should inform the Sponsor and the Competent Authority within 5 working days after the 
occurrence of the emergence. All the changes that have an impact on the risk of the 
patients or on the objectives of the study or require a change of the Informed Consent 
should receive the approval of the IRB/IEC before their implementation.
An administrative change of a study protocol is a minor correction or clarification that 
has no significant impact on the way the clinical study is to be conducted and no effect 
on patient safety (e.g., change of telephone number(s), logistical changes). Protocol 
amendments must be approved by the Sponsor, health authorities where required, and 
the IRB/IEC.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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16
REFERENCE LIST
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Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9:722-728.
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Cherin P, Marie I, Michallet M, et al. Management of adverse events in the treatment of 
patients with immunoglobulin therapy: A review of evidence. Autoimmun Rev. 2016 
Jan; 15(1):71-81.
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Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary 
immunodeficiencies. Representing PAGID (Pan-American Group for 
Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin 
Immunol, 1999;93(3):190-197.
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Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and
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Directive 2001/20/EC of the European parliament and of the council of 4 April 2001 on 
the approximation of the laws, regulations and administrative provisions of the Member 
States relating to the implementation of good clinical practice in the conduct of clinical 
trials on medicinal products for human use.
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European Medicines Agency (EMA) - Committee for Medicinal Products for Human 
Use (CHMP): Guideline on the clinical investigation of human normal immunoglobulin 
for intravenous administration (IVIg). EMA/CHMP/BPWP/94033/2007 rev. 3; 28 June
2018.
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European Medicines Agency (EMA) - Committee for Medicinal Products for Human 
Use (CHMP): Guideline on core SmPC for human normal immunoglobulin for 
intravenous administration (IVIg). EMA/CHMP/BPWP/94038/2007 Rev. 5; 28 June 
2018.
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FDA/CBER. Guidance for industry: safety, efficacy, and pharmacokinetic studies to 
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primary humoral immunodeficiency, 2008.
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Feldmeyer L, Benden C, Haile SR, et al. Not all intravenous immunoglobulin 
preparations are equally well tolerated. Acta Derm Venereol. 2010 Sep;90(5):494-497.

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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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
Goldstein B, Giroir B, Randolph A. International pediatric consensus conference: 
definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med. 2005 
Jan;6(1):2-8.
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Howie SRC. Blood sample volumes in child health research: review of safe limits. Bull 
World Health Organ 2011; 89:46–53.
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ICH Guidance E6 – Guidelines for Good Clinical Practice: Consolidated Guideline. ICH 
Harmonised Tripartite Guideline, ICH Secretariat, May 1996.
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Jolles S, Orange JS, Gardulf A, et al. Current treatment options with immunoglobulin G 
for the individualization of care in patients with primary immunodeficiency disease. 
Clinical Exp Immunol 2015; 179: 146–160.
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Moy JN, Scharenberg AM, Stein MR, et al. Efficacy and safety of a new 
immunoglobulin G product, Gammaplex®, in primary immunodeficiency diseases. Clin 
Exp Immunol. 2010 Dec;162(3):510-515.
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Picard C, Al-Herz W, Bousfiha A, et al. Primary Immunodeficiency Diseases: an 
Update on the Classification from the International Union of Immunological Societies 
Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015 
Nov;35(8):696-726.
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Resnick ES, Cunningham-Rundles C. The many faces of the clinical picture of common 
variable immune deficiency. Curr Opin Allergy Clin Immunol. 2012 Dec; 12(6):595-601.
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Roifman CM, Berger M, Notarangelo LD. Management of primary antibody deficiency 
with replacement therapy: summary of guidelines. Immunol Allergy Clin North Am. 
2008 Nov; 28(4):875-876.
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Rosen FS, Cooper MD, Wedgwood RJ. The primary immunodeficiencies. N Engl J 
Med, 1995. 333(7): p. 431-440.
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Routes J, Tavares Costa-Carvalho B, Grimbacher B, et al. Health related quality of life
and health resource utilization in patients with primary immunodeficiency disease prior 
to and following 12 months of immunoglobulin G treatment. J Clin Immunol 2016; 
36:450–461.
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Schroeder HW Jr, Dougherty CJ. Review of intravenous immunoglobulin replacement 
therapy trials for primary humoral immunodeficiency patients. Infection. 2012 Dec;
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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
Sentinel Blood SCAN study, 2017 
(https://www.sentinelinitiative.org/sites/default/files/PRISM/Sentinel_Product_Assessmen
t_Evaluation_of_the_Risk_of_TEE_after_IG_Administration_Report_20170713.pdf).
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Shapiro RS, Wasserman RL, Bonagura V, et al. Emerging Paradigm of Primary 
Immunodeficiency Disease: Individualizing Immunoglobulin Dose and Delivery to 
Enhance Outcomes. Clin Immunol. 2017 Feb;37(2):190-196. doi: 10.1007/s10875-014-
9990-x. Epub 2014 Jan 30.
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al. Anaphylaxis-a 2020 practice parameter update, systematic review, and Grading of 
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Allergy Clin Immunol. 2020 Jan 28. pii: S0091-6749(20)30105-6. doi: 
10.1016/j.jaci.2020.01.017 .
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meningitis. Rev Neurol (Paris). 2019 Sep - Oct;175(7-8):475-480. doi: 
10.1016/j.neurol.2019.07.005 .
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10.1038/ki.2014.328 .
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Varni JW, Burwinkle TM, Seid M. The PedsQL as a pediatric patient-reported outcome: 
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Kedrion S.p.A.                                                                                         Protocol Code KIG10_US3_PID01 
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17
APPENDIX A
STUDY-SPECIFIC QUESTIONNAIRE
Additional questions for PID patients
in the context of the Kedrion IVIG clinical study
1.
How satisfied you were with your previous IVIG treatment before entering in this clinical 
study?
unsatisfied
rather 
unsatisfied 
neither 
unsatisfied nor 
satisfied 
rather 
satisfied 
satisfied
2.
How satisfied you are with your current IVIG treatment during this clinical study?
unsatisfied
rather 
unsatisfied 
neither 
unsatisfied nor 
satisfied 
rather 
satisfied 
satisfied
3.
Is there something that disturbs or bothers you with your current IVIG treatment during
this clinical study?
_________________________________________________________________________
_________________________________________________________________________
______________________________________________________________________
_________________
4.
What was your motivation to participate in this clinical study?
_________________________________________________________________________
______________________________________________________________________
______________________________________________________________________
___________________________
5.
Based on your experience during this clinical study with KEDRION IVIG, would you 
recommend a friend with primary immunodeficiency (PID) to use this IVIG treatment?
0
        100
|
          |
      not at all
     completely