A Phase 3/4 Study to Evaluate the Safety, Immunogenicity, and Effects on the Alpha1-Proteinase Inhibitor (A1PI) Levels in Epithelial Lining Fluid Following Glassia Therapy in A1PI-Deficient Subjects
Phase: PHASE3
Conditions: Alpha1-antitrypsin Deficiency
Sponsor: Baxalta now part of Shire

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CLINICAL STUDY PROTOCOL
PRODUCT: GLASSIA
STUDY TITLE: A Phase 4 Study to Evaluate the Safety, Immunogenicity, and 
Effects on the Alpha1-Proteinase Inhibitor (A1PI) Levels in Epithelial Lining Fluid 
Following GLASSIA Therapy in A1PI-Deficient Subjects
STUDY SHORT TITLE: Ph 4 GLASSIA Safety, Immunogenicity, and 
Bronchoalveolar Lavage Study
PROTOCOL IDENTIFIER: 471101
CLINICAL TRIAL PHASE 4
AMENDMENT 1: 2015 JAN 19
Replaces Original: 2011 JUL 05
ALL VERSIONS: 
Amendment 1: 2015 JAN 19
Original: 2011 JUL 05
OTHER ID(s)
NCT Number: Not Available
EudraCT Number: Not Available
IND NUMBER: 14774
Study Sponsor(s): 
Baxter Healthcare Corporation
One Baxter Way
Westlake Village, CA 91362
Baxter Innovations GmbH
Industriestrasse 67
A-1221 Vienna, AUSTRIA
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory) / Responsible Party
, MD
, Clinical Development
Baxter Healthcare Corporation
1.2 Study Organization
The name and contact information of the responsible party and individuals involved with 
the study (eg, investigator(s), sponsor’s medical expert and study monitor, sponsor’s 
representative(s), laboratories, steering committees, and oversight committees [including 
ethics committees (ECs)], as applicable) will be maintained by the sponsor and provided 
to the investigator.
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2. SERIOUS ADVERSE EVENT REPORTING
The investigator will comply with applicable laws/requirements for reporting serious 
adverse events (SAEs) to the ECs.
ALL SAEs ARE TO BE REPORTED ON THE 
SERIOUS ADVERSE EVENT REPORT (SAER) FORM AND 
TRANSMITTED TO THE SPONSOR 
WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT
See SAER form for contact information. 
Further details are also available in the study team roster.
For definitions and information on the assessment of these events, refer to the following:

AE, Section 12.1

SAE, Section 12.1.1.1

Assessment of AEs, Section 12.1.2
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STUDY DESIGN
Study Type/ 
Classification/ 
Discipline
Safety, Immunogenicity, Efficacy
Control Type
Concurrent (active)
Study Indication Type
Treatment
Intervention Model
Parallel
Blinding/Masking
Double-blind
Study Design
This Phase 4, prospective, 2-arm, double-blind, randomized, controlled, 
multicenter study will assess the safety, immunogenicity, and effects on the 
antigenic and functional A1PI levels in the ELF following GLASSIA 
administration via a 5-micron in-line filter at the labeled dosage of 60 mg/kg 
BW/week for 25 weeks in approximately 36 A1PI-deficient subjects. Subjects 
will be required to undergo bronchoscopy/bronchoalveolar lavage (BAL) 
procedures at baseline and during augmentation therapy for the evaluation of 
the effects of GLASSIA augmentation therapy on the levels of A1PI and 
 in the ELF. Once the target of 15 to 18 evaluable subjects is 
reached, the remaining subjects to be enrolled will be waived from undergoing
the baseline and on-treatment bronchoscopy/BAL procedures. A subject will be 
considered evaluable only if acceptable BAL samples are obtained at both 
baseline and on-treatment BAL visits (see Section 20.5 and Figure 20-2 for 
BAL sample acceptability criteria and definition of evaluable subjects).
A1PI-deficient subjects, who are A1PI treatment naïve or have been treated 
with A1PI augmentation therapy prior to study entry, will be enrolled. Subjects 
who are receiving or have recently been exposed to A1PI augmentation therapy 
at the time of study enrollment will be required to undergo an adequate washout 
period (minimum of 4 weeks from the time of prior A1PI treatment 
withdrawal) during screening. Screening A1PI measurement may be repeated 
due to suspected inadequate washout. During the washout period, subjects will 
be allowed to undergo other screening procedures for eligibility determination.
Subjects meeting eligibility criteria will be required to undergo 
bronchoscopy/BAL procedures at baseline to collect BAL samples for the 
evaluation of the effects of GLASSIA augmentation therapy at the labeled 
dosage of 60 mg/kg BW/week on the levels of A1PI and 
 in 
the ELF. Subjects who have completed the baseline bronchoscopy/BAL visit 
and have acceptable BAL samples will be randomized in a 1:1 ratio to one of 
the 2 treatment arms as shown in Table 3-1. Subjects who are waived from the 
bronchoscopy/BAL procedures will be randomized after completing screening 
procedures and confirmation of eligibility (note that BAL-related eligibility 
criteria are not applicable for these subjects).
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Table 3-1
Treatment Assignments
Treatment 
Arm
No. of Subjects 
per arm
Treatment
1
18
GLASSIA lot with particle loads 
representing the high end within the 
normal range observed in GLASSIA lots 
manufactured
2
18
GLASSIA lot with particle loads 
representing the low end within the 
normal range observed in GLASSIA lots 
manufactured
During the treatment period, all subjects will receive weekly IV infusions of 
GLASSIA at 60 mg/kg BW administered at a rate of 0.2 mL/kg/min for 25 
weeks (ie, 25 planned infusions) via an IV administration set that includes a 5-
micron in-line filter. The first infusion (Week 1), as well as infusions during 
Week 13 and Week 25, must be administered at the study site to facilitate 
monitoring and reporting of potential adverse events associated with GLASSIA 
infusions. At the investigator’s discretion, subsequent infusions may be 
administered at the study site or at another suitable location (eg, the subject’s 
home) by a qualified healthcare professional, as acceptable per local regulations 
and standard practices of the study site. The infusion rate may be decreased or 
the infusion may be interrupted or discontinued in an individual subject in the 
event of intolerable moderate to severe infusion-related adverse events and/or at 
the discretion of the investigator.
Subjects will be asked to return to the study site every 6 weeks (ie, during 
Weeks 1, 7, 13, 19, and 25) for body weight measurements, as well as physical 
examination, vital sign measurements, and blood draw for plasma A1PI and 
safety laboratory sample collection, as applicable (see Table 20.2-1 and 
Table 20.3-1 for detailed list of study procedures/laboratory assessments). The 
on-treatment BAL visit will be conducted between Week 12 and Week 14 
following initiation of GLASSIA augmentation therapy for the determination of 
antigenic and functional A1PI levels, as well as 
, 
in ELF. After completing the on-treatment BAL visit, subjects will continue to 
receive weekly GLASSIA infusions until Week 25 (the last infusion visit), 
followed by the study completion visit (Week 26) at 7 (±3) days post-last 
infusion.
If a subject experiences a moderate or severe chronic obstructive pulmonary 
disease (COPD) exacerbation and/or lower respiratory tract infection (LRTI)
during the screening period, baseline BAL visit will be postponed once in order 
for the subject to recover from the exacerbation (ie, any signs and symptoms of 
the COPD exacerbation and/or LRTI are no longer clinically evident) and 
remain stable for at least 4 weeks after the end of exacerbation. If a moderate or 
severe episode of COPD exacerbation and/or LRTI occurs during the treatment 
phase, the subject should continue with the planned study visits and to receive 
weekly infusions of GLASSIA as planned, unless deemed medically 
inappropriate by the investigator. However, the on-treatment BAL visit will be 
postponed until clinical resolution of the exacerbation (ie, any signs and 
symptoms of the COPD exacerbation and/or LRTI are no longer clinically 
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SUBJECT SELECTION
Targeted Accrual
Enrollment will be closed when both conditions are met: 
(a) At least 15 evaluable subjects with acceptable BAL samples 
collected from both the baseline and on-treatment BAL visits 
have been achieved
(b) A minimum of 36 subjects have been randomized.
Number of Groups/Arms/Cohorts
2
Inclusion Criteria
A subject must meet ALL of the following criteria to be eligible for inclusion in this study:
1.
Male or female 18 years of age or older at the time of screening.
2.
A1PI genotype of Pi*Z/Z, Pi*Z/Null, Pi*Malton/Z, or Pi*Null/Null.
3.
Endogenous circulating A1PI level of <8 µM (A1PI measurement may be repeated for subjects 
with an initial screening A1PI level of 8 µM or above that is suspected to be due to inadequate 
washout of prior A1PI therapy).
4.
Subject must have at least one of the following: clinical diagnosis of emphysema, evidence of 
emphysema on computerized tomography (CT) scan of the chest within 52 weeks of screening, 
and/or evidence of airway obstruction which is not completely reversed with bronchodilator 
treatment at the time of screening.
5.
No clinically significant abnormalities detected on a 12-lead electrocardiogram (ECG) performed 
at the time of screening (ECG obtained within 26 weeks prior to screening may be used, if 
available).
6.
No clinically significant abnormalities (other than emphysema and chronic bronchitis) detected on 
chest X-ray at the time of screening (chest X-ray or CT scan obtained within 52 weeks prior to 
screening may be used, if available).
7.
If the subject is being treated with any respiratory medications including inhaled bronchodilators, 
inhaled anticholinergics, inhaled corticosteroids, or low-dose systemic corticosteroids (prednisone 
≤10 mg/day or its equivalent), the doses of the subject’s medications have remained unchanged 
for at least 14 days prior to screening.
8.
The subject is a nonsmoker or has ceased smoking for a minimum of 13 weeks prior to screening
(serum cotinine level at screening within normal range of a nonsmoker) and agrees to refrain from 
smoking throughout the course of the study.
9.
If female of childbearing potential, the subject presents with a negative pregnancy test at 
screening and agrees to employ adequate birth control measures for the duration of the study.
10. The subject is willing and able to comply with the requirements of the protocol.
Exclusion Criteria
A subject who meets ANY of the following criteria is NOT eligible for this study:
1.
The subject is experiencing or has a history of clinically significant pulmonary disease other than 
COPD/emphysema and/or chronic bronchitis.
2.
The subject is experiencing or has a history of cor pulmonale.
3.
The subject has moderate or severe bronchiectasis, defined as total daily sputum production of 
>10 mL.
4.
The subject has a history of frequent pulmonary exacerbations (greater than 2 moderate or severe 
exacerbations within 52 weeks prior to screening).
5.
The subject is experiencing a pulmonary exacerbation at the time of screening (subject may be re-
screened 4 weeks after the clinical resolution of an exacerbation).
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6.
The subject has clinically significant congestive heart failure, with New York Heart Association 
(NYHA) Class III/IV symptoms.
7.
The subject is experiencing an active malignancy or has a history of malignancy within 5 years 
prior to screening, with the exception of the following: adequately treated basal cell or squamous 
cell carcinoma of the skin, carcinoma in situ of the cervix, or stable prostate cancer not requiring 
treatment.
8.
The subject has a history of lung or any other organ transplant, is currently on a transplant list, or 
has undergone major lung surgery.
9.
The subject is receiving long-term oxygen supplementation (other than on a short-term basis for 
acute COPD exacerbation, or supplemental O2 with continuous positive airway pressure [CPAP], 
or bi-level positive airway pressure [BiPAP]).
10. Known history of hypersensitivity following infusions of human blood or blood components.
11. Immunoglobulin A (IgA) deficiency (<8 mg/dL at screening).
12. Abnormal clinical laboratory results obtained at the time of screening meeting any of the 
following criteria:
a.
Serum alanine aminotransferase (ALT) >3.0 times upper limit of normal (ULN)
b.
Serum total bilirubin >2.0 times ULN
c.
>2+ proteinuria on urine dipstick analysis
d.
Serum creatinine >2.0 times ULN
e.
Absolute neutrophil count (ANC) <1500 cells/mm3
f.
Hemoglobin (Hgb) <9.0 g/dL
g.
Platelet count <100,000/mm3
13. Known history of OR positive serological evidence at the time of screening for hepatitis A virus 
(HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus 
(HIV) Type 1/2 infection.
14. The subject has any clinically significant medical, psychiatric, or cognitive illness, or any other 
uncontrolled medical condition (eg, unstable angina, transient ischemic attack) that, in the opinion 
of the investigator, would impede the subject’s ability to comply with the study procedures, pose 
increased risk to the subject’s safety, or confound the interpretation of study results.
15. The subject has participated in another clinical study involving an investigational product (other 
than A1PI) or investigational device within 30 days prior to enrollment or is scheduled to 
participate in another clinical study involving an investigational product or device during the 
course of this study.
16. The subject is a family member or employee of the investigator.
17. If female, the subject is nursing at the time of screening.
Additional Inclusion Criterion for Subjects Who Are to Undergo Bronchoscopy/BAL Procedures
1.
The subject must have pulmonary functions at screening meeting both of the following:
a.
Post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥50% 
b.
If FEV1 is >80% predicted, then FEV1/forced vital capacity (FVC) must be <0.7 and/or DLCO
must be ≥30% and ≤65% predicted.
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Additional Exclusion Criteria for Subjects Who Are to Undergo Bronchoscopy/BAL Procedures
1.
The subject has contraindication(s) to bronchoscopy or high risk factors, such as recent 
myocardial infarction, active myocardial ischemia, other cardiopulmonary instability, tracheal 
obstruction or stenosis, moderate to severe hypoxemia or any degree of hypercapnia, unstable 
asthma, uremia, pulmonary hypertension, severe hemorrhagic diathesis, and cervical C1/C2 
arthritis.
2.
The subject has had lung surgery which may interfere with bronchoscopy.
3.
Known history of allergic/hypersensitivity reactions to medications used during and for 
perioperative care associated with the bronchoscopy/BAL procedures, such as local anesthetics, 
sedatives, pain control medications.
4.
The subject is receiving and requires long-term (>4 weeks) immunosuppressive therapy, such as 
systemic corticosteroids at doses greater than 10 mg/day of prednisone (or its equivalent), 
mycophenolate mofetil, azathioprine, cyclophosphamide, and rituximab.
5.
If a subject is receiving anticoagulant or anti-platelet therapy (such as warfarin and clopidogrel), 
the subject is unwilling to or unable to safely discontinue anticoagulant or anti-platelet therapy 
within 7 days prior to until at least 24 hours after the BAL procedures. An exception is low-dose 
aspirin alone which is allowed.
STATISTICAL ANALYSIS
Sample Size Calculation
The sample size calculation for the BAL component of the study was based on the natural log transformed 
primary endpoint data, ELF antigenic A1PI level (nM), generated during Baxter’s Clinical Study 460502. 
In Clinical Study 460502, a mean difference from pre- to post-treatment in ELF antigenic A1PI of 1.32 
with standard deviation of 0.96 on natural log scale was observed. Using this variance estimate, a sample 
size of 15 evaluable subjects should be sufficient to detect a mean difference in the natural log transformed 
ELF antigenic A1PI of approximately 0.87 with 90% power, using a paired t-test and a one-sided 
significance level of 0.025. 
A sample size of 15 evaluable subjects will also be sufficient to detect a mean difference in the natural log 
transformed ELF functional A1PI (ANEC) of approximately 1.04, with 90% power, assuming a standard 
deviation in the differences between pre- and post-treatment ANEC values to be 20% higher than that for 
antigenic A1PI.
Based on the experience from Clinical Study 460502, it is estimated that approximately 26 to 32 subjects 
will be needed in order to achieve 15 to 18 BAL evaluable subjects, respectively. Thus, an overall study 
enrollment target of 36 subjects should be adequate to meet the target sample size for the BAL component 
of the study.
Planned Statistical Analysis
ELF antigenic and functional A1PI levels, as well as changes from baseline, will be summarized 
descriptively and displayed graphically (data permitting) based on data pooled across both treatment arms. 
These changes will be analyzed in one-sided paired t-tests at an alpha level of 0.025.
Plasma trough antigenic and functional A1PI levels, as well as changes from baseline, will be summarized 
descriptively and displayed graphically (data permitting) based on data pooled across both treatment arms.
Plasma antigenic and functional A1PI levels obtained at the baseline and on-treatment BAL visits will be 
summarized separately and, data permitting, to be correlated with the corresponding values in the ELF.
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4. TABLE OF CONTENTS
1. STUDY PERSONNEL ................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 12
5. LIST OF ABBREVIATIONS .................................................................................... 17
6. BACKGROUND INFORMATION .......................................................................... 20
6.1 Description of Investigational Product ............................................................... 23
6.1.1 Rationale for the Selection of Dosing Regimen........................................... 23
6.1.2 Rationale for the Selection of Route of Administration and Infusion 
Rate................................................................................................................. 23
6.2 Clinical Condition/Indication .............................................................................. 24
6.3 Population To Be Studied..................................................................................... 24
6.4 Findings From Nonclinical and Clinical Studies ............................................... 24
6.4.1 Summary of Nonclinical Data....................................................................... 24
6.4.2 Summary of Clinical Data............................................................................. 24
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 25
6.6 Compliance Statement.......................................................................................... 25
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 26
7.1 Study Purpose ....................................................................................................... 26
7.2 Primary Objectives............................................................................................... 26
7.3 Secondary Objective............................................................................................. 26
7.4 Exploratory Objective.......................................................................................... 26
8. STUDY DESIGN......................................................................................................... 26
8.1 Brief Summary...................................................................................................... 26
8.2 Study Design.......................................................................................................... 26
8.3 Duration of Study Period(s) and Subject Participation .................................... 28
8.4 Outcome Measures ............................................................................................... 29
8.4.1 Primary Outcome Measures......................................................................... 29
8.4.2 Secondary Outcome Measures ..................................................................... 29
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8.4.3 Exploratory Outcome Measures .................................................................. 29
8.5 Randomization and Blinding............................................................................... 30
8.5.1 Unblinding Procedures at Study Sites ......................................................... 30
8.6 Study Stopping Rules............................................................................................ 30
8.7 Investigational Product(s).................................................................................... 31
8.7.1 Packaging, Labeling, and Storage................................................................ 31
8.7.2 Preparation of Infusion Solution.................................................................. 31
8.7.3 Administration ............................................................................................... 31
8.7.4 Description of Treatment.............................................................................. 32
8.7.5 Investigational Product Accountability ....................................................... 32
8.8 Source Data ........................................................................................................... 32
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 33
9.1 Inclusion Criteria.................................................................................................. 33
9.2 Exclusion Criteria................................................................................................. 34
9.3 Additional Inclusion Criterion for Subjects Who Are to Undergo 
Bronchoscopy/BAL Procedures........................................................................... 35
9.4 Additional Exclusion Criteria for Subjects Who Are to Undergo 
Bronchoscopy/BAL Procedures........................................................................... 35
9.5 Withdrawal and Discontinuation ........................................................................ 36
10. STUDY PROCEDURES .......................................................................................... 37
10.1 Informed Consent and Enrollment ................................................................... 37
10.2 Subject Identification Code................................................................................ 37
10.3 Screening and Study Visits................................................................................. 38
10.3.1 Screening Visit ............................................................................................. 38
10.3.1.1 Confirmation of Severe Congenital A1PI Deficiency........................ 38
10.3.1.2 Pulmonary Function Tests................................................................... 39
10.3.1.3 Rescreening ........................................................................................... 40
10.3.2 Infusion Visits............................................................................................... 40
10.3.2.1 IP Administration................................................................................. 40
10.3.2.2 Management of Treatment-Emergent (S)AEs................................... 41
10.3.2.3 Pre-Medications.................................................................................... 43
10.3.2.4 Post-Infusion Follow-Up ...................................................................... 43
10.3.3 Clinical Assessment Visits........................................................................... 43
10.3.4 BAL Visits..................................................................................................... 44
10.4 COPD Exacerbation and Lower Respiratory Tract Infection (LRTI).......... 45
10.5 Medications and Non-Drug Therapies.............................................................. 47
10.6 Subject Completion/Discontinuation ................................................................ 47
10.7 Procedures for Monitoring Subject Compliance............................................. 48
11. ASSESSMENT OF EFFICACY.............................................................................. 49
11.1 ELF Antigenic and Functional A1PI Levels..................................................... 49
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11.2 
.................................................................................... 49
12. ASSESSMENT OF SAFETY................................................................................... 50
12.1 Adverse Events.................................................................................................... 50
12.1.1 Definitions..................................................................................................... 50
12.1.1.1 Serious Adverse Event.......................................................................... 50
12.1.1.2 Non-Serious Adverse Event ................................................................. 51
12.1.1.3 Adverse Reactions Plus Suspected Adverse Reactions ..................... 51
12.1.1.4 Unexpected Adverse Events................................................................. 51
12.1.1.5 Adverse Events Potentially Associated with Protein Aggregates..... 52
12.1.1.6 Preexisting Diseases.............................................................................. 52
12.1.2 Assessment of Adverse Events.................................................................... 52
12.1.2.1 Severity .................................................................................................. 53
12.1.2.2 Causality................................................................................................ 54
12.2 Urgent Safety Measures ..................................................................................... 55
12.3 Untoward Medical Occurrences........................................................................ 55
12.4 Non-Medical Complaints ................................................................................... 56
12.5 Medical, Medication, and Non-Drug Therapy History................................... 56
12.6 Physical Examinations........................................................................................ 56
12.7 Clinical Laboratory Parameters........................................................................ 57
12.7.1 Hematology and Clinical Chemistry.......................................................... 57
12.7.2 Complement Activation and Immune Complex Panel............................. 58
12.7.3 Viral Serology and Nucleic Acid Tests....................................................... 58
12.7.4 Urine Tests.................................................................................................... 58
12.7.5 Assessment of Clinical Laboratory Values................................................ 59
12.7.5.1 Assessment of Abnormal Laboratory Values..................................... 59
12.7.6 Biobanking.................................................................................................... 60
12.8 Plasma Antigenic and Functional A1PI Levels................................................ 60
12.9 Immunogenicity .................................................................................................. 61
12.10 Vital Signs.......................................................................................................... 62
13. STATISTICS............................................................................................................. 63
13.1 Sample Size and Power Calculations ................................................................ 63
13.2 Datasets and Analysis Cohorts .......................................................................... 63
13.2.1 Full Analysis Set........................................................................................... 63
13.2.2 Per-Protocol Analysis Set............................................................................ 63
13.2.3 BAL Analysis Set ......................................................................................... 64
13.2.4 Safety Analysis Set....................................................................................... 64
13.3 Handling of Missing, Unused, and Spurious Data........................................... 64
13.4 Methods of Analysis............................................................................................ 64
13.4.1 Efficacy Outcome Measures ....................................................................... 64
13.4.2 Exposure....................................................................................................... 65
13.4.3 Safety Outcome Measures........................................................................... 66
13.5 Planned Interim Analysis of the Study ............................................................. 67
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14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 67
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 68
15.1 Investigator’s Responsibility.............................................................................. 68
15.1.1 Final Clinical Study Report........................................................................ 68
15.2 Training ............................................................................................................... 68
15.3 Monitoring........................................................................................................... 68
15.4 Auditing ............................................................................................................... 69
15.5 Non-Compliance with the Protocol ................................................................... 69
15.6 Laboratory and Reader Standardization ......................................................... 69
16. ETHICS ..................................................................................................................... 69
16.1 Subject Privacy ................................................................................................... 69
16.2 Ethics Committee and Regulatory Authorities................................................ 69
16.3 Informed Consent ............................................................................................... 70
16.4 Data Monitoring Committee.............................................................................. 70
17. DATA HANDLING AND RECORD KEEPING................................................... 70
17.1 Confidentiality Policy ......................................................................................... 70
17.2 Study Documents and Case Report Forms....................................................... 71
17.3 Document and Data Retention........................................................................... 71
18. FINANCING AND INSURANCE........................................................................... 72
19. PUBLICATION POLICY........................................................................................ 72
20. SUPPLEMENTS....................................................................................................... 73
20.1 Study Flow Chart................................................................................................ 73
20.2 Schedule of Study Procedures and Assessments.............................................. 74
20.3 Schedule of Clinical Laboratory Assessments.................................................. 78
20.4 Thresholds for Clinically Significant Laboratory Abnormalities .................. 82
20.5 Bronchoscopy/Bronchoalveolar Lavage Procedure ........................................ 83
21. REFERENCE LIST.................................................................................................. 87
22. SUMMARY OF CHANGES.................................................................................... 90
Tables
Table 3-1 Treatment Assignments..................................................................................... 6
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Table 8-1 Treatment Assignments................................................................................... 27
Table 20.2-1 Schedule of Study Procedures and Assessments........................................ 74
Table 20.3-1 Clinical Laboratory Assessments ............................................................... 78
Figures
Figure 10-1 Exacerbation of COPD................................................................................. 46
Figure 20-1 Study Flow Chart for Baxter Clinical Study 471101................................... 73
Figure 20-2 BAL Procedural Flow Chart ........................................................................ 86
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
˚C
Degree Celsius
˚F
Degree Fahrenheit
A1PI
Alpha1-Proteinase Inhibitor
AAT
Alpha1-antitrypsin
AE/AEs
Adverse event/adverse events
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ANEC
Anti-neutrophil elastase capacity
APE
Acute pulmonary exacerbation
AR/ARs
Adverse reaction/adverse reactions
AST
Aspartate aminotransferase
ATS
American Thoracic Society
BAL
Bronchoalveolar lavage
B19V
Parvovirus B19
BiPAP
Bi-level positive airway pressure
BUN
Blood urea nitrogen
BW
Body weight
C3
Complement component 3
C4
Complement component 4
CFR
Code of Federal Regulations
CH50
50% hemolytic complement activity of serum
CIs
Confidence intervals
cm
Centimeter(s)
COPD
Chronic obstructive pulmonary disease
CPAP
Continuous positive airway pressure
CPK
Creatine phosphokinase
CRF(s)
Case Report Form(s)
CT
Computerized tomography
dL
Deciliter(s)
DLCO
Diffusing Capacity of Carbon Monoxide
DMC
Data Monitoring Committee
EC
Ethics Committee
ECG
Electrocardiogram
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Abbreviation
Definition
EDTA
Ethylenediaminetetraacetic acid
ELF
Epithelial lining fluid
EP
European Pharmacopeia
ERS
European Respiratory Society
FAS
Full analysis set
FDA
United States Food and Drug Administration
FEV1
Forced expiratory volume in one second
FVC
Forced vital capacity
GCP
Good Clinical Practice
GGT
Gamma-glutamyl-transferase
HAV
Hepatitis A virus
HBV
Hepatitis B virus
Hct
Hematocrit
HCV
Hepatitis C virus
HEV
Hepatitis E virus
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
hpf
High power field
ICF
Informed consent form
ICH
International Conference on Harmonization
IgA
Immunoglobulin A
in
Inch(es)
IP
Investigational product
IRT
Interactive response technology
IV
Intravenous
IWRS
Interactive Web Response System
kD
Kilodalton(s)
kg
Kilogram(s)
lb
Pound(s)
LDH
Lactic dehydrogenase
LRT
Lower respiratory tract
LRTI
Lower respiratory tract infection
μM
Micromolar
MDI
Metered dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
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Abbreviation
Definition
mg
Milligram(s)
min
Minute (s)
mL
Milliliter(s)
mm3
Cubic millimeter
mm Hg
Millimeter(s) of mercury
NAT
Nucleic acid test
NE
Neutrophil elastase
nM
Nanomolar(s)
NMC
Non-medical complaint
NYHA
New York Heart Association 
O2
Oxygen
PCR
Polymerase chain reaction
PP
Per protocol
ppm
Parts per million
RBC
Red blood cell
SAE
Serious adverse event
SAER
Serious adverse event report
S/D
Solvent/detergent
SIC
Subject identification code
ULN
Upper limit of normal
US
United States
USP
United States Pharmacopeia
WBC
White blood cell
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6. BACKGROUND INFORMATION
Alpha1-Proteinase Inhibitor (A1PI), also known as alpha1-antitrypsin (AAT), is a serum 
glycoprotein of molecular mass 52 kD. The protein is synthesized in the liver and is 
reported to be present in the serum at levels between 20 and 53 μM (104 to 275.6 
mg/dL).1
Severe A1PI deficiency (also known as AAT deficiency) is an autosomal recessive 
hereditary disorder affecting an estimated 34,395 to 48,904 individuals in the United 
States (US), with 91.6% being Caucasian Americans, 7.8% Hispanic Americans, and 
0.5% African Americans.2; 3 Individuals with a severe deficiency are defined as those 
with serum A1PI levels less than 35% of the average normal level,4; 5 or less than 
11 μM.6; 7; 8 Severely affected individuals may have no detectable A1PI protein in their 
serum. In addition, genetic variants associated with reduced A1PI levels also produce an 
altered form of A1PI, the capacity of which to inhibit neutrophil elastase (NE) is 
reduced.9 In clinical practice, majority (96%) of A1PI deficiency related diseases are 
linked to Pi*ZZ genotype, with the remaining 4% to Pi*SZ and other rare or null 
genotypes.
Individuals with Pi*ZZ show a significant intracellular polymerization of their A1PI in 
the liver, often resulting in liver damage with a variable clinical presentation. In addition, 
the profound suppression of A1PI secretion into the systemic circulation significantly 
increases the risk of developing panacinar emphysema.10 The threshold level of A1PI in 
the lower respiratory tract (LRT) needed to provide clinical benefit is not known;
however, emphysema in A1PI-deficient subjects has been thought to develop because the 
level of A1PI in the LRT is insufficient to inhibit serine proteases. Serine proteases, such 
as NE, are present in the LRT in higher than normal concentrations as a result of 
inflammation or infection.11 If left unchecked, due to insufficient A1PI, the proteolytic 
activity of these proteases can destroy the connective tissue framework of the lung 
parenchyma.12; 13
Therapy for A1PI-deficient subjects is directed towards replacement or augmentation of 
serum A1PI levels.14; 15; 16; 17; 18; 19; 20; 21; 22 This therapy is based on the concept that an 
increase in the serum level of A1PI will lead to higher A1PI concentrations in the lung 
parenchyma, which in turn, may mitigate the A1PI protease imbalance, thereby 
preventing or slowing the destruction of lung tissue and thus the clinical course of the 
disease.23; 24 Wewers et al. showed that, at steady-state, augmentation therapy with once a 
week dosing of A1PI (60 mg/kg body weight [BW]/week) resulted in trough circulating 
A1PI levels to >11 µM in subjects with A1PI deficiency of Pi*Z/Z genotype.25
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Historically, it was believed that 11 µM is the protective threshold level, based on the 
assumption that subjects with Pi*Z/Z, Pi*Null/Null, or Pi*Z/Null genotypes had severe 
A1PI deficiency (circulating A1PI levels below 11 µM) and emphysema; whereas
subjects with Pi*S/Z genotype, who at that time were considered to have an average 
A1PI level of 11 µM, were protected from emphysema. 
GLASSIA is the only sterile, ready-to-use, liquid preparation of purified human A1PI 
indicated for chronic augmentation and maintenance therapy in adults with clinically 
evident emphysema due to severe congenital deficiency of A1PI. The product was 
approved by the US Food and Drug Administration (FDA) in 2010, on the basis of safety 
and biochemical demonstration in a Phase I dose-escalation and a Phase II/III pivotal 
clinical trial in a total of 65 individual subjects with severe A1PI deficiency.
The clinical lots used in the GLASSIA Phase II/III trial contained small amounts of 
visible protein particulates which were aggregates of the A1PI. Protein aggregation is a 
known phenomenon with protein therapeutics and has been shown to be present in active 
comparator used in the Phase II/III trial, as well as other commercially available A1PI 
products upon reconstitution of the lyophilized powder. During the Phase II/III clinical 
trial, no safety signals of concern were reported. The most common adverse reactions
(ARs) (>0.5% of infusions) reported were headache and upper respiratory tract infection. 
These adverse events (AEs) were consistent with those reported for the other licensed 
A1PI products. Potential immunogenicity following repeated administration of 
GLASSIA was evaluated in the Ph II/III trial, where 50 subjects received weekly 
infusions of either GLASSIA or PROLASTIN (active comparator) from Week 1 to Week 
12 and then weekly infusions of GLASSIA (all subjects) from Week 13 to Week 24.
Immunogenicity was monitored at baseline, Week 12, and Week 24. All samples were 
negative for the presence of anti-A1PI antibodies, with the exception of a single sample 
(Week 12) with a low titer of 2 in one subject. The Week 24 sample from this subject was 
negative, suggesting a low level, transient immunogenic response. Nevertheless, as an 
added precautionary measure, it is recommended that GLASSIA be filtered twice before 
product administration: through a 5 micron filter needle during product pooling and then 
through a 5 micron in-line filter during product administration (see GLASSIA package 
inserti).
The effectiveness of the in-line filtration procedure in removing visible and subvisible 
particles in GLASSIA was examined in a recent in vitro study. Four GLASSIA lots were 
                                                
i Baxter Healthcare Corporation. Product label: GLASSIA [Alpha1-Proteinase Inhibitor (Human)]. 
March 2014.
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chosen to represent the high and low ends of the range of particle counts normally 
observed for GLASSIA manufactured. (Note that all GLASSIA lots must meet the 
requirements for visible and subvisible particulates set forth by the United States 
Pharmacopeia [USP] and the European Pharmacopeia [EP] prior to release for use in 
humans). The use of a 5-micron in-line filter has been shown to effectively remove 
visible particles (from several to >10 particles in unfiltered solution to no more than 
2 particles per 50-mL vial after filtration) and subvisible particles (by 12- to 76-fold for 
particles across all particle size categories ranging from 2 to >100 micron) (data on file). 
In fact, the 5-micron in-line filter is also effective in reducing the number of particles that 
are smaller (2 to 5-micron in diameter) than the nominal 5-micron pore-size of the filter 
from an average of 23227 to 489 particles per 50-mL vial, representing a 49-fold 
reduction. The filtration process did not alter the A1PI potency, as demonstrated by a lack 
of difference in the elastase inhibitory activity measurements in unfiltered and filtered 
GLASSIA solution.
Nevertheless, given a lack of clear understanding and the paucity of direct clinical 
evidence correlating parenteral administration of protein aggregates to clinical AEs and 
risk of immunogenicity, there have been theoretical concerns about protein aggregates in 
a therapeutic product on the safety risks to humans. To address these concerns, a key goal 
of this study is to evaluate the clinical safety profile of GLASSIA with focus on AEs of 
interest that have been suggested to be potentially associated with protein aggregates and 
visible/subvisible particles, such as pulmonary embolism particularly of non-thrombotic
or microvascular origin, unexplained chest pain, dyspnea, or cardiopulmonary arrest of 
non-cardiac etiology, interstitial pneumonitis, injection site reactions, granuloma, 
hypersensitivity or anaphylactic reactions, and immunogenicity incidence. GLASSIA lots 
containing particles of ≥2 micron in diameter representative of the high and low ends of 
the range normally observed in GLASSIA manufacturing will be selected for evaluation 
in this study. All GLASSIA administrations will follow the 2-step filtration process 
(through a 5 micron filter needle during product pooling and then through a 5 micron in-
line filter during product administration) as outlined in the GLASSIA package insert.
The second goal of this study is to obtain additional safety data, and to evaluate the 
effects of GLASSIA augmentation therapy on the levels of A1PI and 
 in 
the ELF following weekly intravenous (IV) augmentation therapy with GLASSIA in 
subjects with emphysema due to congenital A1PI deficiency. In the pivotal Ph II/III 
study, there were fewer subjects (7 subjects in the GLASSIA group and 2 subjects in the 
active comparator group) than planned (15 subjects) having ELF analyte results available 
for evaluation. Additionally, effect of GLASSIA augmentation therapy on ELF functional 
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A1PI (ie, anti-neutrophil elastase capacity [ANEC]) could not be examined due to 
missing data. Thus, this study is designed to include bronchoscopy/bronchoalveolar 
lavage (BAL) visits to collect data for the assessments of change from baseline in the 
antigenic and functional A1PI levels, as well as 
, in the ELF 
following 13 weeks of weekly IV administration of GLASSIA at the approved dose of 60 
mg/kg BW.
6.1 Description of Investigational Product
GLASSIA is a sterile, ready-to-use, liquid preparation of purified human A1PI. The 
solution contains 2% active A1PI in a phosphate-buffered saline solution. The specific 
activity of GLASSIA is at least 0.7 mg functional A1PI per mg of total protein (the 
specific activity of a particular lot will be provided in the certificate of analysis). The 
product is clear and colorless to yellow-green and may contain a few particles (ie, protein 
filaments). 
GLASSIA supplied in the US is prepared from human plasma obtained from US-licensed 
plasma collection centers by a modified version of the cold ethanol fractionation process 
and the A1PI is then purified using chromatographic methods. GLASSIA does not 
contain stabilizers or any other added substances (such as sucrose, albumin or mannitol). 
GLASSIA contains no preservatives and no latex. 
Further information can be found in the GLASSIA package insert.
6.1.1 Rationale for the Selection of Dosing Regimen
The dosing regimen of GLASSIA chosen for this study, 60 mg/kg given intravenously 
once per week, is the standard FDA-approved dosing regimen for GLASSIA, as well as 
all other plasma-derived A1PI products in the same class. At this dosage, GLASSIA has 
been demonstrated to be safe and well tolerated in a total of 65 subjects with congenital 
A1PI-deficiency, and was shown to increase and maintain circulating trough antigenic 
and functional A1PI levels to 14.7 µM (median; range: 11.6-18.5 µM) and 11.9 µM
(median; range: 8.2-16.9 µM), respectively (see GLASSIA package insert).
6.1.2 Rationale for the Selection of Route of Administration and Infusion Rate
The route of administration (intravenous infusion), as well as the infusion rate (0.2 mL/kg 
BW/min), selected for this study are in accordance with the FDA-approved package 
insert.
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6.2 Clinical Condition/Indication
GLASSIA is indicated for chronic augmentation and maintenance therapy in adults with 
clinically evident emphysema due to severe congenital deficiency of A1PI (AAT 
deficiency).
6.3 Population To Be Studied
Subjects with severe congenital A1PI-deficiency (endogenous A1PI level <8 µM with 
genotype of Pi*Z/Z, Pi*Z/Null, Pi*Malton/Z, or Pi*Null/Null) and emphysema are 
planned for enrollment into this study. 
6.4 Findings From Nonclinical and Clinical Studies
6.4.1 Summary of Nonclinical Data
GLASSIA was evaluated in two single dose general toxicology studies in Sprague-
Dawley rats and New Zealand White rabbits, and one repeated dose study in New 
Zealand White rabbits. 
In single dose studies, a single dose of 0, 60 and 600 mg/kg (rabbits) or 640 mg/kg (rats) 
was administered intravenously and the animals were observed for 14 days. There were 
no changes in body weight, clinical chemistry, hematology and gross pathology that 
could be attributed to GLASSIA administration. 
In the repeated dose study, New Zealand White rabbits received GLASSIA (300 mg/kg) 
once daily for five consecutive days. Animals were monitored for changes in clinical 
signs, body weight, clinical chemistry, hematology, necropsy and histopathology on 
Day 1 or 14 after the last administration. A minor increase in group mean neutrophils was 
measured on Day 1 after the last GLASSIA administration. Recovery was observed after 
14 days. 
Long-term studies in animals to evaluate carcinogenesis, mutagenesis or impairment of 
fertility have not been conducted. 
Animal reproduction studies have not been conducted with GLASSIA. 
No toxicological effects due to the solvent/detergent reagents, tri-(n)-butyl phosphate, 
and polysorbate 80 (Tween 80), used in the virus inactivation procedure are expected 
since the residual levels are less than 5 and 20 ppm, respectively.
6.4.2 Summary of Clinical Data
Findings from clinical studies are provided in the GLASSIA package insert.
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6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
Transmission of blood-borne diseases is a theoretical risk since GLASSIA is derived 
from pooled human plasma. To decrease the potential contamination with blood-borne 
viruses, stringent procedures have been employed in the manufacture of this product from 
the screening of plasma donors through plasma collection and preparation. To further 
reduce the risk of viral transmission, the manufacturing process includes two steps of 
viral removal or inactivation: (1) treatment with a solvent/detergent (S/D) mixture of tri-
n-butyl phosphate and polysorbate 80 (Tween 80) which inactivates enveloped viral 
agents such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and 
hepatitis C virus (HCV); and, (2) a nanofiltration step through a 15 nm filter which can 
remove both enveloped and non-enveloped viral agents (such as hepatitis A virus 
[HAV]). In vitro virus clearance studies demonstrated a virus log reduction factor of 4 or 
greater. To date, no seroconversion for hepatitis B or C (HBV or HCV) or human 
immunodeficiency virus (HIV) or any other known infectious agent have been reported 
with the use of GLASSIA during the clinical studies.
GLASSIA is contraindicated in subjects with a history of anaphylactic or severe 
hypersensitivity reactions to human A1PI preparations.
GLASSIA may contain trace amounts of immunoglobulin A (IgA). GLASSIA is 
contraindicated in subjects with known antibodies to IgA, and in subjects with selective 
or severe IgA deficiency who may develop anti-IgA antibodies that can result in severe 
hypersensitivity and anaphylactic reactions. IF ANAPHYLACTIC OR SEVERE 
ANAPHYLACTOID REACTIONS OCCUR, THE INFUSION MUST BE 
DISCONTINUED IMMEDIATELY. Epinephrine, antihistamines, and other appropriate 
supportive therapy should be available for the treatment of any acute anaphylactic or 
anaphylactoid reactions.
6.6 Compliance Statement
This study will be conducted in accordance with this protocol, the International 
Conference on Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, 
April 1996), Title 21 of the US Code of Federal Regulations (US CFR), the European 
Clinical Trial Directive (2001/20/EC and 2005/28/EC), and applicable national and local 
regulatory requirements.
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7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of the study is two-fold: (1) to evaluate the safety and immunogenicity of 
GLASSIA following IV administration via in-line filtration; and, (2) to assess the effects 
of GLASSIA augmentation therapy on the levels of A1PI and 
in the 
ELF following IV administration at a dosage of 60 mg/kg BW/week for 25 weeks in 
subjects with emphysema due to congenital A1PI deficiency.
7.2 Primary Objectives
1. To evaluate the effectiveness of the use of 5-micron in-line filter on the safety and 
immunogenicity of GLASSIA.
2. To determine the effects of weekly IV augmentation therapy with GLASSIA at a 
dosage of 60 mg/kg BW on antigenic and functional A1PI levels in ELF in 
subjects with congenital A1PI deficiency.
7.3 Secondary Objective

To collect additional safety information for GLASSIA.
7.4 Exploratory Objective
 
 
8. STUDY DESIGN
8.1 Brief Summary
This Phase 4, prospective, 2-arm, double-blind, randomized, controlled, multicenter study 
will assess the safety, immunogenicity, and effects on the antigenic and functional A1PI 
levels in the ELF following GLASSIA administration via a 5-micron in-line filter at the 
labeled dosage of 60 mg/kg BW/week for 25 weeks in A1PI-deficient subjects who are 
A1PI-treatment naïve, who are currently receiving A1PI treatment at the time of 
enrollment, or who have previously received A1PI treatment.
8.2 Study Design
A1PI-deficient subjects, who are A1PI treatment naïve or have previously been treated 
with A1PI augmentation therapy, will be enrolled. Subjects who are receiving or have 
recently been exposed to A1PI augmentation therapy at the time of study enrollment will 
be required to undergo an adequate washout period (minimum of 4 weeks from the time 
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of prior A1PI treatment withdrawal) during screening. Screening A1PI measurement may 
be repeated due to suspected inadequate washout. During the washout period, subjects 
will be allowed to undergo other screening procedures for eligibility determination.
Subjects meeting eligibility criteria will be required to undergo bronchoscopy/BAL 
procedures at baseline and following IP treatment for the evaluation of the effects of 
GLASSIA augmentation therapy at the labeled dosage of 60 mg/kg BW/week on the 
levels of A1PI and 
 in the ELF. Once the target of 15 to 18 evaluable 
subjects is reached, the remaining subjects to be enrolled will be waived from undergoing 
the baseline and on-treatment bronchoscopy/BAL procedures. A subject will be 
considered evaluable only if acceptable BAL samples are obtained at both baseline and 
on-treatment BAL visits (see Section 20.5 and Figure 20-2 for BAL sample acceptability 
criteria and definition of evaluable subjects).
Enrollment will be closed when both conditions are met: 
(a) At least 15 evaluable subjects with acceptable BAL samples collected from both 
the baseline and on-treatment BAL visits
(b) At a minimum of an overall 36 randomized subjects.
If for any reasons the target of at least 15 evaluable subjects have not been attained with 
initial 36 randomized subjects, additional subjects will be enrolled to achieve the BAL 
enrollment target.
Subjects who have completed the baseline bronchoscopy/BAL visit and have acceptable 
BAL samples will be randomized in a 1:1 ratio to one of the 2 treatment arms as shown in 
Table 8-1. Subjects who are waived from the bronchoscopy/BAL procedures will be 
randomized after completing screening procedures and confirmation of eligibility (note 
that BAL-related eligibility criteria are not applicable for these subjects).
Table 8-1
Treatment Assignments
Treatment 
Arm
No. of Subjects Per 
Arm
Treatment
1
18
GLASSIA lot with particle loads representing the high 
end within the normal range observed in GLASSIA 
lots manufactured
2
18
GLASSIA lot with particle loads representing the low 
end within the normal range observed in GLASSIA 
lots manufactured
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During the treatment period, subjects in both treatment arms will receive weekly IV 
infusions of GLASSIA at 60 mg/kg BW administered at a rate of 0.2 mL/kg/min for 25 
weeks (ie, 25 planned infusions) via an IV administration set that includes a 5-micron in-
line filter. The first infusion (Week 1), as well as infusions during Week 13 and Week 25, 
must be administered at the study site to facilitate monitoring and reporting of potential 
AEs associated with GLASSIA infusions. At the investigator’s discretion, subsequent 
infusions may be administered at the study site or at another suitable location (eg, the 
subject’s home) by a qualified healthcare professional, as acceptable per local regulations 
and standard practices of the study site. 
Subjects will be asked to return to the study site every 6 weeks (ie, during Weeks 1, 7, 13, 
19, and 25) for body weight measurements, as well as physical examination, vital sign 
measurements, and blood draw for plasma A1PI and safety laboratory sample collection, 
as applicable (see Table 20.2-1 and Table 20.3-1 for detailed list of study 
procedures/laboratory assessments). The on-treatment BAL visit will be conducted 
between Week 12 and Week 14 following initiation of GLASSIA augmentation therapy 
for the determination of antigenic and functional A1PI levels, as well as 
 
 in ELF. After completing the on-treatment BAL visit, subjects will continue 
to receive weekly GLASSIA infusions until Week 25 (the last infusion visit), followed by 
the study completion visit (Week 26) at 7 (±3) days post-last infusion.
The overall study design is illustrated in Figure 20-1 (Supplement 20.1).
8.3 Duration of Study Period(s) and Subject Participation
The overall duration of the study will be approximately 2 years from study initiation (ie, 
first subject enrolled) to study completion (ie, last subject last visit). The recruitment 
period is expected to be approximately 16 months.

The duration of each subject’s participation from enrollment to subject 
completion (ie, last study visit) is anticipated to be approximately 8 months 
(including a screening period of up to 6 weeks, a baseline period of up to 2 weeks 
[for subjects undergoing baseline BAL procedure], a treatment period of 25 
weeks, and a post-treatment safety follow-up period of 7 [±3] days of after the last
infusion), unless the subject withdraws or is prematurely discontinued from the 
study.
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8.4 Outcome Measures
8.4.1 Primary Outcome Measures
Safety
1. Number (proportion) of AEs considered potentially related to the presence of protein 
aggregates in the GLASSIA solution
2. Incidence of treatment-emergent ARs plus suspected ARs
3. Number (proportion) of infusions that are discontinued, slowed, or interrupted due to 
an AE
4. Number (proportion) of subjects who develop binding and/or neutralizing anti-A1PI 
antibodies
Efficacy
1. Antigenic A1PI levels in ELF
2. Functional A1PI (also known as ANEC) levels in ELF
8.4.2 Secondary Outcome Measures
Safety
1. Incidence of treatment-emergent AEs
2. Number (proportion) of subjects who experienced a shift from normal or clinically 
insignificant abnormal laboratory values at baseline to clinically significant abnormal 
laboratory values
3. Number (proportion) of subjects with treatment-emergent seroconversion or positive 
viral nucleic acid test (NAT) for parvovirus B19 (B19V)
8.4.3 Exploratory Outcome Measures
 
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8.5 Randomization and Blinding
This is a 2-arm, double-blind, randomized, controlled clinical study. In order to 
minimize/avoid bias, subjects meeting all eligibility criteria (Section 9.1 through 
Section 9.4) will be randomly assigned to 1 of 2 treatment arms at a ratio of 1:1. Note that 
randomization is to take place only after the subject has successfully completed the 
baseline BAL visit with verification of having evaluable BAL samples collected. For 
those subjects to be enrolled after the target of at least 15 evaluable BAL subjects have 
been achieved and thus exempted from BAL procedures, randomization will take place 
upon confirmation of the main study eligibility criteria (Section 9.1 and Section 9.2) 
being met. 
Randomization codes will be generated and maintained by an Interactive Response 
Technology (IRT) via an Interactive Web Response System (IWRS). Treatment 
assignment will not be revealed to the subject, investigators, study site personnel or the 
sponsor, except for unblinded study personnel such as the unblinded pharmacist directly
involved in the preparation of infusion solutions, the unblinded study monitor(s), and the 
unblinded biostatistician. The pharmacist preparing the infusion solution will be able to 
access the randomization codes and will be responsible for maintaining any unblinded 
pharmacy records in a secure, access-controlled location.
8.5.1 Unblinding Procedures at Study Sites
The randomization assignment is not to be revealed before the study is terminated, except 
in emergency cases when unblinding is necessary for the clinical management of an SAE. 
In such events, every attempt must be made to inform the sponsor before breaking the 
blind or immediately when unblinding has been performed. The investigator may request 
for the treatment assignment of the specific individual subject involved in the emergency 
event via the centralized randomization service or the unblinded biostatistician.
8.6 Study Stopping Rules
The study may be terminated by the sponsor in the event of unexpected safety or medical 
concerns. Specific stopping rules will not be established for this study, as GLASSIA is an 
approved product with a demonstrated record of safety at the approved dosage of 
60 mg/kg BW/week which is to be employed in this study.
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8.7 Investigational Product(s)
8.7.1 Packaging, Labeling, and Storage
Packaging: GLASSIA will be supplied as a sterile, non-pyrogenic, ready-to-use solution 
in single use vials containing 1 gram of functional A1PI in 50 mL of solution.
Dosage Form: Injection, solution
Labeling: The product will be labeled according to the valid regulatory requirements for 
clinical studies.
Storage: GLASSIA must be stored at 2-8 ˚C (36 to 46 ˚F). Do not freeze the product. Do 
not use past the expiration date.
8.7.2 Preparation of Infusion Solution
The dose (in mg) will be calculated based on the subject’s individual body weight at 
screening. The same dose (in mg) is to be administered to an individual subject 
throughout the course of treatment. Adjustment based on body weight changes during the 
course of the study is not planned; however, dose (in mg) may be adjusted if deemed 
medically necessary at the discretion of the investigator (eg, body weight change by 
>10%). Only body weight measurements taken using standardized procedures during 
study visits (Weeks 1, 7, 13, 19, or 25) will be used for dose calculations.
The volume of infusion solution (in mL) will be calculated based on the content of 
functional A1PI (potency) in GLASSIA vials, as specified in the certificate of analysis to 
be provided with a particular GLASSIA lot and as printed on the product carton and vial.
For instructions for the preparation and administration of GLASSIA infusion solution, 
please refer to the GLASSIA package insert.
8.7.3 Administration
GLASSIA is for intravenous use only.
Route of administration: IV infusion via a 5-micron in-line filter
Rate of administration: 0.2 mL/kg BW/min
(The rate of infusion will be regulated by an ambulatory infusion pump.)
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8.7.4 Description of Treatment
Treatment: GLASSIA [Alpha1-Proteinase Inhibitor (Human)]
Dose: 60 mg/kg BW/week
Dosage frequency: Once every week (± 2 days)
Treatment period: 25 weeks (ie, 25 planned infusions), to be followed by a 7 (± 3 days)
post-treatment safety follow-up period
8.7.5 Investigational Product Accountability
The investigator will ensure that the IP(s) is stored as specified in the protocol and that 
the storage area is secured, with access limited to authorized study personnel. The 
investigator will maintain records that the IP(s) was received, including the date received,
drug identity code, date of manufacture or expiration date, amount received and 
disposition. IP(s) must be dispensed only at the study site or other suitable location 
(eg, infusion center; home, as applicable per study design). Records will be maintained 
that include the subject identification code (SIC), dispensation date, and amount 
dispensed. All remaining partially used and/or unused IP(s) will be returned to the 
sponsor or sponsor’s representative after study completion/termination, or destroyed with 
the permission of the sponsor in accordance with applicable laws and study site 
procedures. If IP(s) is to be destroyed, the investigator will provide documentation in 
accordance with sponsor’s specifications.
8.8 Source Data
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations, or other activities in a clinical 
trial that are necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents (original records or certified copies), which may be in 
paper and/or electronic format. Source data for this study comprise the following: 
hospital records, medical records, clinical and office charts, laboratory notes, 
memoranda, evaluation checklists, outcomes reported by subjects, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate copies, microfiches, photographic negatives, microfilm or 
magnetic media, x-rays, subject files, records entered into web and/or phone IRT system
and/or any direct data capture system, and records kept at the pharmacy, at the 
laboratories and at medico-technical departments involved in the clinical study.
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For additional information on study documentation and case report forms (CRFs), see 
Section 17.2.
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
A subject must meet ALL of the following criteria to be eligible for inclusion in this 
study:
1. Male or female 18 years of age or older at the time of screening.
2. A1PI genotype of Pi*Z/Z, Pi*Z/Null, Pi*Malton/Z, Pi*Null/Null.
3. Endogenous circulating A1PI level of <8 µM (A1PI measurement may be repeated 
for subjects with an initial screening A1PI level of 8 µM or above that is suspected to 
be due to inadequate washout of prior A1PI therapy).
4. Subject must have at least one of the following: clinical diagnosis of emphysema, 
evidence of emphysema on computerized tomography (CT) scan of the chest within 
52 weeks of screening, and/or evidence of airway obstruction which is not completely 
reversed with bronchodilator treatment at the time of screening.
5. No clinically significant abnormalities detected on a 12-lead electrocardiogram 
(ECG) performed at the time of screening (ECG obtained within 26 weeks prior to 
screening may be used, if available).
6. No clinically significant abnormalities (other than emphysema and chronic 
bronchitis) detected on chest X-ray at the time of screening (chest X-ray or CT scan 
obtained within 52 weeks prior to screening may be used, if available).
7. If the subject is being treated with any respiratory medications including inhaled 
bronchodilators, inhaled anticholinergics, inhaled corticosteroids, or low-dose 
systemic corticosteroids (prednisone ≤10 mg/day or its equivalent), the doses of the 
subject’s medications have remained unchanged for at least 14 days prior to 
screening.
8. The subject is a nonsmoker or has ceased smoking for a minimum of 13 weeks prior 
to screening (serum cotinine level at screening within normal range of a nonsmoker) 
and agrees to refrain from smoking throughout the course of the study.
9. If female of childbearing potential, the subject presents with a negative pregnancy test 
at screening and agrees to employ adequate birth control measures for the duration of 
the study.
10. The subject is willing and able to comply with the requirements of the protocol.
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9.2 Exclusion Criteria
A subject who meets ANY of the following criteria is NOT eligible for this study:
1. The subject is experiencing or has a history of clinically significant pulmonary 
disease other than COPD/emphysema and/or chronic bronchitis.
2. The subject is experiencing or has a history of cor pulmonale.
3. The subject has moderate or severe bronchiectasis, defined as total daily sputum 
production of >10 mL.
4. The subject has a history of frequent pulmonary exacerbations (greater than 2 
moderate or severe exacerbations within 52 weeks prior to screening).
5. The subject is experiencing a pulmonary exacerbation at the time of screening 
(subject may be re-screened 4 weeks after the clinical resolution of an exacerbation).
6. The subject has clinically significant congestive heart failure, with New York Heart 
Association (NYHA) Class III/IV symptoms.
7. The subject is experiencing an active malignancy or has a history of malignancy 
within 5 years prior to screening, with the exception of the following: adequately 
treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the 
cervix, or stable prostate cancer not requiring treatment.
8. The subject has a history of lung or any other organ transplant, is currently on a 
transplant list, or has undergone major lung surgery.
9. The subject is receiving long-term oxygen supplementation (other than on a short-
term basis for acute COPD exacerbation, or supplemental O2 with continuous positive 
airway pressure [CPAP], or bi-level positive airway pressure [BiPAP]).
10. Known history of hypersensitivity following infusions of human blood or blood 
components.
11. Immunoglobulin A (IgA) deficiency (<8 mg/dL at screening).
12. Abnormal clinical laboratory results obtained at the time of screening meeting any of 
the following criteria:
a.
Serum alanine aminotransferase (ALT) >3.0 times upper limit of normal 
(ULN)
b.
Serum total bilirubin >2.0 times ULN
c.
>2+ proteinuria on urine dipstick analysis
d.
Serum creatinine >2.0 times ULN
e.
Absolute neutrophil count (ANC) <1500 cells/mm3
f.
Hemoglobin (Hgb) <9.0 g/dL
g.
Platelet count <100,000/mm3
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13. Known history of OR positive serological evidence at the time of screening for 
hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), or human 
immunodeficiency virus (HIV) Type 1/2 infection.
14. The subject has any clinically significant medical, psychiatric, or cognitive illness, or 
any other uncontrolled medical condition (eg, unstable angina, transient ischemic 
attack) that, in the opinion of the investigator, would impede the subject’s ability to 
comply with the study procedures, pose increased risk to the subject’s safety, or 
confound the interpretation of study results.
15. The subject has participated in another clinical study involving an investigational 
product (other than A1PI) or investigational device within 30 days prior to enrollment 
or is scheduled to participate in another clinical study involving an investigational 
product or device during the course of this study.
16. The subject is a family member or employee of the investigator.
17. If female, the subject is nursing at the time of screening.
9.3 Additional Inclusion Criterion for Subjects Who Are to Undergo 
Bronchoscopy/BAL Procedures
1. The subject must have pulmonary functions at screening meeting both of the 
following:
a. Post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥50% 
b. If FEV1 is >80% predicted, then FEV1/forced vital capacity (FVC) must be 
<0.7 and/or DLCO must be ≥30% and ≤65% predicted.
9.4 Additional Exclusion Criteria for Subjects Who Are to Undergo 
Bronchoscopy/BAL Procedures
1. The subject has contraindication(s) to bronchoscopy or high risk factors, such as 
recent myocardial infarction, active myocardial ischemia, other cardiopulmonary 
instability, tracheal obstruction or stenosis, moderate to severe hypoxemia or any 
degree of hypercapnia, unstable asthma, uremia, pulmonary hypertension, severe 
hemorrhagic diathesis, and cervical C1/C2 arthritis.
2. The subject has had lung surgery which may interfere with bronchoscopy.
3. Known history of allergic/hypersensitivity reactions to medications used during and 
for perioperative care associated with the bronchoscopy/BAL procedures, such as 
local anesthetics, sedatives, pain control medications.
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4. The subject is receiving or requires long-term (>4 weeks) immunosuppressive 
therapy, such as systemic corticosteroids at doses greater than 10 mg/day of 
prednisone (or its equivalent), mycophenolate mofetil, azathioprine, 
cyclophosphamide, and rituximab.
5. If a subject is receiving anticoagulant or anti-platelet therapy (such as warfarin and 
clopidogrel), the subject is unwilling to or unable to safely discontinue anticoagulant 
or anti-platelet therapy within 7 days prior to until at least 24 hours after the BAL 
procedures. An exception is low-dose aspirin alone which is allowed.
9.5 Withdrawal and Discontinuation 
Any subject may voluntarily withdraw (ie, reduce the degree of participation in the study) 
consent for continued participation and data collection. The reason for withdrawal will be 
recorded on the appropriate CRF. Assessments to be performed at the termination visit 
(including in cases of withdraw or discontinuation) are described in Section 10.6, 
Section 20.2, and Section 20.3.
Discontinuation (ie, complete withdrawal from study participation) may be due to 
dropout (ie, active discontinuation by subject) or loss to follow-up (ie, discontinuation by 
subject without notice or action). Additionally, the investigator and sponsor have the 
discretion to discontinue any subject from the study if, in their judgment, continued 
participation would pose an unacceptable risk for the subject.
Subjects also will be withdrawn from treatment or discontinued from further study 
participation for the following reasons:
1. The subject becomes pregnant. IP exposure will be discontinued. Attempts will be 
made to follow the subject through completion of the pregnancy and up to 1 year 
post-delivery, if feasible. The investigator will record a narrative description of 
the course of the pregnancy and its outcome.
2. The subject begins nursing. IP exposure will be discontinued. The investigator 
will record a narrative description of the course of the baby’s development.
3. The subject develops a serious AE, which, based on the medical judgment of the 
investigator, prevents completion of participation in the study.
4. The subject fails to comply with protocol requirements or procedures that may 
include, but are not limited to:
The subject frequently misses scheduled administration of the IP, defined as 
missing a total of >20% (ie, >5) of planned infusions, or 4 or more 
consecutive weekly infusions.
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The subject is treated with any A1PI product (including commercially 
available GLASSIA) other than IP.
The subject participates in another clinical study and/or receives an 
investigational product/device other than IP.
5. The sponsor terminates the study.
For subjects undergoing BAL procedures, if no evaluable BAL samples can be obtained 
from any of the 3 lobes attempted during the baseline BAL visit, the subject will not be 
randomized and will be discontinued from the study. If acceptable BAL samples can be 
obtained during the baseline BAL visit but not from any of the 3 lobes attempted during 
the on-treatment BAL visit (between Week 12 to Week 14), the subject will continue to 
complete the remaining infusion visits and the study completion visit. These subjects
would not be considered as a BAL evaluable subject. Acceptability criteria of BAL 
samples and definition of evaluable subjects are provided in Section 20.5 and 
Figure 20-2.
10. STUDY PROCEDURES
The overall study flow chart is illustrated in Figure 20-1 (Supplement 20.1). Details on 
the procedures to be performed at each study visit, including screening, can be found in 
Supplement 20.2 Schedule of Study Procedures and Assessments and Supplement 20.3
Schedule of Clinical Laboratory Assessments.
10.1 Informed Consent and Enrollment
Any patient who provides informed consent (ie, signs and dates the informed consent 
form [ICF]) is considered enrolled in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the subject identification code (SIC): 
protocol identifier (eg, 471101) to be provided by the sponsor, 2- or 3-digit number study 
site number (eg, 02) to be provided by the sponsor, and 3- or 4-digit subject number 
(eg, 0003) reflecting the order of enrollment (ie, signing the ICF). For example, the third 
subject who signed an ICF at study site 02 will be identified as Subject 471101-020003. 
All study documents (eg, CRFs, clinical documentation, sample containers, drug 
accountability logs, etc.) will be identified with the SIC. Additionally, a uniquely coded 
SIC(s) is permitted as long as it does not contain a combination of information that 
allows personal identification of a subject (eg, collection of a subject’s initials and birth 
date would not be permitted), in compliance with laws governing data privacy.
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10.3 Screening and Study Visits
10.3.1 Screening Visit
After informed consent has been obtained from the subject and/or their legally authorized 
representative, subjects will be screened on-site for eligibility based on the Inclusion and 
Exclusion Criteria defined in Section 9.1 and Section 9.2, respectively. Additionally, for 
subjects who are to undergo BAL assessments in the study, randomization is to take place 
after the subject has met all eligibility criteria (including those listed in Section 9.3 and 
Section 9.4) and successfully undergone the baseline BAL visit with evaluable BAL 
samples collected.
The study site is responsible for maintaining an enrollment/screening log that includes all 
subjects enrolled. The log also will serve to document the reason for screening failure. 
All screening data will be collected and reported in CRFs, regardless of screening 
outcome.
10.3.1.1 Confirmation of Severe Congenital A1PI Deficiency
To establish eligibility for participation in the study, the subject’s diagnosis of severe 
congenital A1PI deficiency must be confirmed during screening that includes 2 tests:

A1PI genotype

Measurement of endogenous circulating A1PI level
Subjects must have A1PI genotype of Pi*Z/Z, Pi*Z/Null, Pi*Malton/Z, or Pi*Null/Null,
AND circulating antigenic A1PI level of <8 µM in order to meet eligibility criteria. A 
subject’s past (pre-study) records, if available, may be used as an initial assessment (eg, a 
subject will be considered ineligible based on past record of Pi*SZ genotype). However, 
for confirmation of congenital A1PI deficiency, all otherwise potentially eligible subjects 
will be required to undergo A1PI genotype and circulating A1PI tests during screening. 
Results of these screening tests will be used to establish the subject’s eligibility for
participation in the study.
For those subjects who are receiving or have recently been exposed to A1PI 
augmentation therapy at the time of study enrollment, the presence of exogenously 
administered A1PI may interfere with the verification of endogenous circulating A1PI 
levels. Therefore, these subjects will be required to have their pre-study A1PI therapy 
withdrawn for a minimum of 4 weeks to allow A1PI to return to the subject’s 
unaugmented levels. The 4-week washout period should be adequate, based on an
average A1PI half-life of 4.6 daysi and that typically 4 to 5 half-lives would be required 
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(ie, 18 to 23 days). However, in light of inter-subject variability in A1PI half-life, some 
subjects may require a longer washout period. Therefore, screening A1PI measurement 
may be repeated in the event of suspected inadequate washout resulting in initial 
screening A1PI level of >8 µM.
During the washout period, these subjects will be allowed to undergo other screening 
procedures (Supplement 20.2 and Supplement 20.3).
10.3.1.2 Pulmonary Function Tests
10.3.1.2.1 Spirometry
Spirometry tests are to be conducted according to standard guidelines published by the 
American Thoracic Society and European Respiratory Society.26; 27 Whenever possible, 
all measurements should be performed with the same equipment around the same time of 
the day (± 2 hours) during site visits to minimize equipment and diurnal variability. All 
spirometric measurements (FEV1 and FVC) are to be measured 30 ± 5 minutes following 
administration of a short-acting β-2 agonist bronchodilator (eg, a total of 400 µg of 
salbutamol [2 x 200 µg or 4 x 100 µg] or its equivalent). Spirometric measurements 
(FEV1 and FVC) are to be performed in triplicate, and the highest value at each time 
point for each variable is to be used for analyses. The spirometry equipment is to be 
calibrated according to the manufacturer’s recommendation and documented in a 
maintenance log. The same method for the calculation of predicted normal values will be 
applied for all subjects and assessment time points to maintain standardization.
10.3.1.2.2 Single-Breath Determination of Carbon Monoxide Uptake in the Lung 
(DLCO)
DLCO will be measured using the single-breath technique, which involves the 
measurement of carbon monoxide uptake from the lung over a single breath-holding 
period. In order to minimize test variability, all determinations will be conducted in 
accordance with recommendations for the standardization of testing published by the 
American Thoracic Society (ATS) and European Respiratory Society (ERS)28; 29 and 
general guidelines for lung function testing.20 Gas volumes are reported with body 
temperature and pressure saturated corrections and results are expressed in absolute 
values and as percentage of predicted values.
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10.3.1.3 Rescreening
Subjects may be rescreened once for study eligibility. Subjects who have failed screening 
for any of the following reasons may be rescreened:
1. Circulating antigenic A1PI level of ≥8 µM that is suspected to be due to inadequate 
washout of the prior A1PI therapy
2. Erroneous screening results
3. Pulmonary exacerbation at the time of initial screening (Note: subjects may be re-
screened 4 weeks after the clinical resolution of an exacerbation)
4. Ineligibility due to failure to meet protocol pre-specified time intervals (eg, inclusion 
criteria #7 and 8, and exclusion criteria #7 and 15)
If a subject is to be re-screened, the study completion/termination CRF should be 
completed. The subject or his/her legally authorized representative must sign a new ICF
prior to rescreening procedures. A new SIC will be assigned, and new CRFs will be used 
for the subject upon re-enrollment. All screening procedures, with the exception of A1PI 
genotype (unless repeat is necessary, eg, the test was not performed or erroneous result 
was obtained during initial screening), will be performed during rescreening.
10.3.2 Infusion Visits
GLASSIA will be administered as IV infusions at 60 mg/kg BW every week (± 2 days) 
for a total of 25 infusions. Scheduling of all infusion or study visits will be based on the 
date of the first IP infusion visit (Week 1, Day 1).
10.3.2.1 IP Administration
Description of GLASSIA treatment including treatment period, dose and dosing 
frequency, mode of administration, as well as preparation of infusion solution are detailed 
provided in Section 8.7.
The first infusion (Week 1), as well as infusions during Week 13 and Week 25, must be 
administered at the study site to facilitate monitoring and reporting of potential AEs 
associated with GLASSIA infusions. At the investigator’s discretion, all other infusions 
may be administered at the study site or at another suitable location (eg, the subject’s 
home) by a qualified healthcare professional, as acceptable per local regulations and 
standard practices of the study site.
During Weeks 1, 7, 13, 19, and 25 infusion visits, vital signs (ie, body temperature, 
respiratory rate, pulse rate, and systolic and diastolic blood pressure; see Section 12.10
and Table 20.3-1 for additional details) are to be taken on the day of infusion at any time 
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prior to the start of an infusion, at each rate reduction due to AE(s) and/or infusion 
interruption/discontinuation due to AE(s), and within 90 minutes after the completion of 
an infusion. The investigator should be contacted to determine appropriate action to be 
taken, as necessary, if vital signs meet any of the following criteria:

Systolic blood pressure ≤80 mm Hg or ≥180 mm Hg and/or diastolic blood 
pressure: ≤50 mm Hg or ≥110 mm Hg

Pulse rate ≤48 beats/min or ≥110 beats/min

Respiratory rate ≤8 breaths/min or ≥24 breaths/min

Body temperature ≥38.2 ºC (101 ºF) 
For each infusion, the following IP administration information will be recorded in the 
appropriate CRF(s):

Date, start and end time of the infusion

Planned infusion volume

Actual volume infused

Infusion rate, including each infusion rate change (if any) and reason

Infusion interruptions or early discontinuation (if any), including the time of 
infusion interruption (or early stop) and restart 

AE(s)

Concomitant use of any medications and any non-drug therapies, including those 
used to treat AE(s)
10.3.2.2 Management of Treatment-Emergent (S)AEs
Mild-to-moderate non-serious AEs or other constitutional symptoms that developed 
during an infusion may be treated by standard-of-care medical interventions appropriate 
for the AE at the investigator’s discretion. In the event that the AE continues or increase 
in severity despite interventions, the infusion rate may be decreased by 0.04 mL/kg 
BW/min or the infusion may be temporarily interrupted at the investigator’s discretion. If 
the AE is not resolving, the infusion rate may be further decreased in a stepwise manner 
by 0.04 mL/kg BW/min or discontinued. Once an AE resolves, the infusion may be 
resumed or continued at an infusion rate as tolerated by the subject (but not to exceed 
0.2 mL/kg BW/min) at the discretion of the investigator.
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If a severe, non-serious AE or SAE occurs during an infusion, the infusion should be 
interrupted pending assessment by the investigator, and appropriate action is to be taken 
to treat the AE. The infusion may be restarted if the AE resolves in response to 
interventions and/or reduction in infusion rate and if it’s deemed safe by the investigator.
In the event of a life-threatening SAE, study personnel should take immediate steps to 
preserve the subject’s well-being and call for emergency assistance, as well as contact the 
investigator. All SAEs must be reported on the SAER form and transmitted to the 
sponsor within 24 hours after becoming aware of the event. 
For moderate-to-severe hypersensitivity reactions (ie, urticaria, low blood pressure,
angioedema, or wheezing), the infusion should be stopped immediately and the subject
should be treated according to the standard of care at the discretion of the investigator. 
Prior to further IP administrations, the investigator should consult the sponsor’s Medical 
Monitor.
In the event a subject develops a rash at any time during the study, the nature, severity, 
extent of the eruption, its temporal relationship to the last IP administration, and the 
likely cause(s) should be examined prior to the next scheduled infusion. Management of 
rashes includes, but is not limited to, the following:

Minor rashes are those involving 10% of body surface or less without bleeding or
signs of secondary infection. Minor rashes may be treated as indicated with 
topical medications, including anti-pruritic and corticosteroid creams. Infusions 
can be continued if the rash is confirmed to be minor and/or deemed unrelated to 
IP.
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
Major rashes are those that involve more than 10% of the body surface, are 
progressive, are associated with hemorrhage and/or secondary infection, or 
require systemic corticosteroid treatment. These should be treated appropriately 
and infusions should be discontinued immediately until the condition has resolved 
completely or is judged to be not clinically significant. Procedures (eg, biopsy of 
the lesion) may be performed to investigate the pathophysiology of the rash. At 
the discretion of the investigator, IP treatment may be resumed only after the rash 
has resolved and the subject’s condition is deemed medically safe and 
appropriate. Pre-medications such as oral or topical corticosteroid treatment may 
be administered for the subsequent 2 infusions, as applicable, at the discretion of 
the investigator in accordance with the standard of care at the investigative site. 
Subjects with recurrent major rashes, rashes that recur upon re-challenge of IP 
despite (pre-)medication(s), or rashes that do not resolve within 6 weeks will be 
discontinued from further IP administration and will be followed as outlined in 
Section 9.5.
Any rate reductions, interruptions or discontinuation of an infusion and, if applicable, any
medications and/or non-drug therapies used to treat AE(s), must be recorded in the
appropriate CRF(s).
10.3.2.3 Pre-Medications
If the same type of mild-to-moderate, non-serious AE expected to be related to IP 
infusion (eg, headache, chills, fever, flushing, and malaise) or other constitutional 
symptoms recurs for 2 or more infusions, the subject may be pre-medicated for 
subsequent infusion(s) at the discretion of the investigator in accordance with the 
standard of care at the investigative site. The use of any pre-medications must be 
recorded in the appropriate CRF(s).
10.3.2.4 Post-Infusion Follow-Up
Following each infusion visit, the investigator/designee will contact the subject to 
document AEs and concomitant medications, as well as non-drug therapies, which may 
have occurred within 24 and 72 hours after the completion of an infusion visit. Follow-up 
should be conducted within 1 business day after 72 hours following the completion of the 
infusion.
10.3.3 Clinical Assessment Visits
During the treatment period, subjects will be asked to return to the study site during 
Week 13 and Week 25 for clinical and safety laboratory assessments, as well as plasma 
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A1PI measurements. Additional blood samples will be drawn for the monitoring of 
plasma A1PI levels during Week 7 and Week 19, which may take place at study site or at 
another suitable location (eg, the subject’s home) by a qualified healthcare professional. 
Following the last infusion (Week 25), subjects will return to the study site 7 ±3 days 
post-infusion for study completion assessments.
A detailed list of assessments to be performed at each clinical assessment visit is 
provided in Supplement 20.2 and Supplement 20.3.
10.3.4 BAL Visits
This section applies to subjects who are to undergo BAL procedures. Bronchoscopy/BAL 
procedure will be waived for subjects who are enrolled after at least 15 BAL evaluable 
subjects have been obtained.
Subjects who have met all eligibility criteria (including the additional eligibility criteria 
for undergoing the BAL procedure outlined in Section 9.3 and Section 9.4) will undergo 
bronchoscopy/BAL procedure on 2 occasions: at baseline (prior to randomization) and 
following initiation of GLASSIA treatment for 12 to 14 weeks.
For subjects who have received A1PI augmentation therapy prior to study entry, plasma 
samples for baseline antigenic A1PI levels will be collected within 10 days prior to the 
baseline BAL visit to verify the adequacy of the washout from A1PI therapy prior to 
performing BAL.
In order for a subject to be randomized and remain in the study, the subject must have at 
least one lobe with an acceptable BAL sample collected at the baseline BAL visit. 
Following the baseline BAL procedure, subjects will be allowed to recover for a 
minimum of 2 days prior to the first IP infusion. If no acceptable BAL samples can be 
obtained from any of the 3 lobes attempted during the baseline BAL visit, the subject will 
undergo early termination visit and be discontinued from the study. 
During GLASSIA augmentation therapy, the subject will be asked to undergo the on-
treatment BAL visit between Week 12 and Week 14. The on-treatment 
bronchoscopy/BAL procedure will be conducted at least 3 days after the last IP infusion 
but with a minimum of 2 days prior to the next IP infusion to allow subjects to recover 
from the BAL procedure. Subjects with acceptable BAL samples obtained from at least 
one lobe will be considered as evaluable subject. If acceptable BAL samples cannot be 
obtained from any of the 3 lobes attempted during the on-treatment BAL visit, the subject 
will continue to complete the remaining infusion visits through Week 25 and the study 
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completion visit (Week 26). These subjects, however, would not be considered as a BAL 
evaluable subject. See Section 20.5 and Figure 20-2 for more detailed BAL sample 
acceptability criteria and definition of evaluable subjects. New subjects may be enrolled 
to achieve the target of 15 to 18 evaluable subjects.
During the BAL visits, plasma samples will be collected within 2 hours prior to the BAL 
procedure for the measurement of plasma urea, as well as plasma antigenic and functional 
A1PI levels. Vital signs will be measured within 2 hours prior to each BAL procedure 
and within 1 hour after the completion of the BAL procedure. Pre-BAL vital signs are to 
be assessed prior to bronchodilator and local anesthesia administration. The subject 
should be monitored for ECG, blood pressure, respiratory rate, and pulse oximetry during 
the procedure in accordance with standard practice at the local institution. The subject 
will remain in the hospital/clinic until, in the investigator’s medical judgment, it is safe to 
discharge the subject. Subjects will be followed for post-BAL safety monitoring (ie, AEs 
and concomitant medications/non-drug therapies) at the study site or by telephone within 
2 weeks after each BAL procedure.
In order to assess the effects of GLASSIA maintenance treatment on the ELF A1PI 
levels, it is important for the on-treatment BAL procedure be performed after stable 
dosing of GLASSIA has been maintained for at least 4 half-lives of A1PI (ie, average 
half-life ~4.6 days, see GLASSIA package insert). Thus, should a subject miss 1 or more 
consecutive GLASSIA infusion(s) within 4 week(s) immediately prior to the scheduled 
on-treatment BAL visit, the BAL procedure will be rescheduled to occur after the subject 
has received at least 4 consecutive weekly GLASSIA administrations. The rescheduled 
BAL procedure will be performed at least 3 days after the last IP infusion and at least 
2 days prior to the next IP infusion.
Detailed bronchoscopy/BAL procedures are provided in Supplement 20.5.
10.4 COPD Exacerbation and Lower Respiratory Tract Infection (LRTI)
An exacerbation of COPD is defined as an acute event characterized by a worsening of 
the patient’s respiratory symptoms that is beyond normal day-to-day variations and lead 
to a change in medication. The onset of an exacerbation is defined as the first day of an 
increase in or new onset of more than one of the respiratory symptoms (cough, sputum, 
sputum purulence, wheezing, or dyspnea), compared to the subject’s usual clinical state, 
for at least 2 consecutive days and requiring treatment with antibiotics and/or systemic 
(oral, intramuscular or intravenous) corticosteroids. The end of an exacerbation is defined 
as the first day that any signs and symptoms of COPD exacerbation and/or LRTI 
symptoms are no longer clinically evident (ie, the first day that a subject returns to his/her 
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10.5 Medications and Non-Drug Therapies
The following medications are not permitted at any time during the course of the study:

Any A1PI augmentation therapy other than IP in this study; commercially 
available GLASSIA is also not permitted

Any investigational drug, biologic, or device other than IP in this study
A subject who has taken any of the above medications will be discontinued from further 
treatment and/or from the study. 
The following medications are not permitted within a pre-specified time interval prior to 
each BAL procedure:

Immunosuppressive therapies (such as systemic corticosteroids at doses greater 
than 10 mg/day of prednisone or its equivalent, mycophenolate mofetil, 
azathioprine, and cyclophosphamide) within 4 weeks prior to and during the BAL 
procedures
Rituximab at any time during the study

Anticoagulant or anti-platelet therapy (such as warfarin and clopidogrel) within 7 
days prior to and during the BAL procedures, with the exception of low-dose 
aspirin which is allowed
The following medications are permitted during the course of the study provided that the 
dosage remains stable throughout the course of the study:
1. Any respiratory medications including inhaled bronchodilators, inhaled 
anticholinergics, inhaled corticosteroids, or low-dose systemic corticosteroids 
(prednisone ≤10 mg/day or its equivalent)
2. Theophylline
3. Other medications that a subject is taking for a pre-existing medical condition except 
for those listed under prohibited medications above
Dosages of permitted concomitant medications are to remain stable throughout the course 
of the study, unless otherwise medically indicated.
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study because the subject has, or is presumed to have, completed all 
study procedures according with the protocol (with or without protocol deviations).
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Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, AE (eg, death), 
discontinuation by subject (eg, lost to follow-up [defined as 3 documented unsuccessful 
attempts to contact the subject], dropout), physician decision (eg, pregnancy, progressive 
disease, non-compliance with IP/protocol violation(s), recovery), study terminated by 
sponsor, or other (reason to be specified by the investigator, eg, technical problems). 
Regardless of the reason, all data available for the subject up to the time of 
completion/discontinuation should be recorded on the appropriate CRF. 
Every effort will be made to have discontinued subjects complete the study 
completion/termination visit. Subjects who are discontinued early from the study prior to 
receiving any IP administration will not need to undergo early termination procedures, 
except for those subjects who have undergone the baseline BAL procedure in which case 
subjects will be followed for potential post-BAL complications for a period of time in 
accordance with local institutional standard practice but not to exceed 30 days.
If the completion/termination visit is done as an additional, unscheduled visit, the 
assessment results shall be recorded with the completion/termination visit. If a subject 
terminates participation in the study and does not return for the completion/termination 
visit, their last recorded assessments shall remain recorded with their last visit. The 
reason for discontinuation will be recorded, and the data collected up to the time of 
discontinuation will be used in the analysis and included in the clinical study report. If 
additional assessments are required, the assessments shall be recorded separately. 
Assessments to be performed at the termination visit (including in cases of withdraw or 
discontinuation) can be found in Supplement 20.2 Schedule of Study Procedures and 
Assessments and Supplement 20.3 Schedule of Clinical Laboratory Assessments.
In the event of subject discontinuation due to an (S)AE, clinical and/or laboratory 
investigations that are beyond the scope of the required study observations/assessments 
may be performed as part of the evaluation of the event. These investigations will take 
place under the direction of the investigator in consultation with the sponsor, and the 
details of the outcome may be reported to the appropriate regulatory authorities by the 
sponsor.
10.7 Procedures for Monitoring Subject Compliance
All study procedures are to be performed under the direct supervision of the 
investigator/a qualified healthcare professional at the study site or at another suitable 
location (eg, the subject’s home or infusion center), and thus, no separate procedures will 
be used to monitor subject compliance.
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Trough antigenic and functional A1-PI levels in plasma would be determined as a check 
on subject’s compliance/adherence to treatment.
11. ASSESSMENT OF EFFICACY
11.1 ELF Antigenic and Functional A1PI Levels
This study will evaluate the effects of GLASSIA weekly augmentation therapy on the 
A1PI levels in the ELF.
BAL samples will be analyzed for the determination of the following in the BAL fluid
using validated bioanalytical assays at a qualified laboratory:
1.
Antigenic A1PI level
2.
Functional A1PI (ANEC) level
3.
Urea level
ELF antigenic and functional A1PI levels will be estimated based on the respective 
values measured in the BAL fluid using the plasma-to-BAL urea correction method. This 
approach is based on the fact that urea is freely diffusible through most body 
compartments, including the alveolar wall. A dilution factor, k, will be determined with 
the following formula: dilution factor k = UP (concentration of urea in plasma)/UBAL
(concentration of urea in BAL fluid). Using this dilution factor, quantitative 
measurements of ELF A1PI and 
will be corrected accordingly.
Detailed information for the BAL visits and bronchoscopy/BAL procedures can be found 
in Section 10.3.4 and Supplement 20.5.
11.2
 
 
 
 
 
 
 
 
 
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12. ASSESSMENT OF SAFETY
12.1 Adverse Events
12.1.1 Definitions
An AE is defined as any untoward medical occurrence in a subject administered an IP 
that does not necessarily have a causal relationship with the treatment. An AE can 
therefore be any unfavorable and unintended sign (eg, an abnormal laboratory finding), 
symptom (eg, rash, pain, discomfort, fever, dizziness, etc.), disease (eg, peritonitis, 
bacteremia, etc.), or outcome of death temporally associated with the use of the IP, 
whether or not considered causally related to the IP.
12.1.1.1 Serious Adverse Event 
A serious adverse event (SAE) is defined as an untoward medical occurrence that at any 
dose meets one or more of the following criteria:

Outcome is fatal/results in death (including fetal death)

Is life-threatening – defined as an event in which the subject was, in the judgment 
of the investigator, at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death had it been more severe.

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission,
regardless of length of stay.

Results in persistent or significant disability/incapacity (ie, a substantial 
disruption of a person’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Is a medically important event – a medical event that may not be immediately 
life-threatening or result in death or require hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definitions above. Examples of such events are: 
Intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse 
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Reviewed and confirmed seroconversion for human immunodeficiency virus 
(HIV), hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus 
(HCV), hepatitis E virus (HEV), or parvovirus B19 (B19V)
Uncomplicated pregnancies, following maternal or paternal exposure to the IP are not 
considered an (S)AE; however, any pregnancy complication or pregnancy termination by 
therapeutic, elective, or spontaneous abortion shall be considered an SAE.
12.1.1.2 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.1.1.3 Adverse Reactions Plus Suspected Adverse Reactions
An AR plus suspected AR is any adverse event which met any of the following criteria: 
(a) an adverse event that began during infusion or within 72 hours following the end 
of IP infusion, or
(b) an adverse event considered by either the investigator and/or the sponsor to be 
possibly or probably related to IP administration, or 
(c) an adverse event for which causality assessment was missing or indeterminate.
In addition, safety data will also be analyzed for any ARs plus suspected ARs which met 
any of the following criteria:
(a) an adverse event that began during infusion or within 24 hours following the end 
of IP infusion, or
(b) an adverse event considered by either the investigator and/or the sponsor to be 
possibly or probably related to IP administration, or 
(c) an adverse event for which causality assessment was missing or indeterminate.
12.1.1.4 Unexpected Adverse Events
An unexpected adverse event is an AE whose nature, severity, specificity, or outcome is 
not consistent with the term, representation, or description used in the Reference Safety 
Information (eg, GLASSIA package insert). “Unexpected” also refers to the AEs that are 
mentioned in the Reference Safety Information as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically 
mentioned as occurring with the particular drug under investigation.
Any AEs (expected and unexpected) will be recorded on the AE CRF.
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12.1.1.5 Adverse Events Potentially Associated with Protein Aggregates
The safety database will be reviewed and assessed for AEs that may potentially be 
associated with protein aggregates in GLASSIA solution.
12.1.1.6 Preexisting Diseases
Preexisting diseases that are present before entry into the study are described in the 
medical history, and those that manifest with the same severity, frequency, or duration 
after IP exposure, will not be recorded as AEs. However, when there is an increase in the 
severity, duration, or frequency of a preexisting disease, the event must be described on 
the AE CRF.
Any occurrences of COPD exacerbation and/or LRTI are to be recorded on the AE CRF 
(see Section 10.4).
12.1.2 Assessment of Adverse Events
Each AE from the first IP exposure until study completion/early discontinuation from the 
study will be described on the AE CRF using the medical diagnosis (preferred), or, if no 
diagnosis could be established at the time of reporting the AE, a symptom, or sign, in 
standard medical terminology in order to avoid the use of vague, ambiguous, or 
colloquial expressions (see definition in Section 12.1). Each AE will be evaluated by the 
investigator for:

Seriousness as defined in Section 12.1.1.1

Severity as defined in Section 12.1.2.1

Causal relationship to IP exposure or study procedure as defined in 
Section 12.1.2.2
For each AE, the outcome (ie, recovering/resolving, recovered/resolved, 
recovered/resolved with sequelae, not recovered/not resolved, fatal, unknown) and if 
applicable action taken (ie, dose increased, dose not changed, dose reduced, drug 
interrupted, drug withdrawn, not applicable, or unknown) will also be recorded on the AE 
CRF. Recovering/resolving AEs will be followed until resolution, medically stabilized, or 
30 days after the study completion/termination visit, whichever comes first. AE and other 
CRF(s), as applicable, will be updated if additional follow-up information is 
collected/reported prior to study completion (no additional reporting on CRF(s) is 
necessary after study completion).
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If the severity rating for an ongoing AE changes before the event resolves, the original 
AE report will be revised (ie, the event will not be reported as separate AE). During the 
course of any AE, the highest severity rating will be reported.
Deviations from the protocol-specified dosage (including overdosing [by >50%], 
underdosing [by >50%], abuse, and withdrawal), treatment errors (including incorrect 
route of administration, use of an incorrect product, and deviations from the protocol-
defined dosing schedule), failures of expected pharmacological actions, and unexpected 
therapeutic or clinical benefits will be followed with regard to occurrence of AEs, lack of 
efficacy, and/or other observations because these events may be reportable to regulatory 
authorities.
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Form and followed-up at 1 year post-delivery, if feasible.
If an investigator becomes aware of an SAE occurring in a subject after study 
completion, the SAE must be reported on the SAE Form within 24 hours after awareness; 
no additional reporting on CRFs is necessary.
For the purposes of this study, each AE (expected and unexpected) experienced by a 
subject undergoing bronchoscopy/BAL procedure will be recorded on the AE CRF.
12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the most appropriate description below:

Mild
The AE is a transient discomfort and does not interfere in a significant 
manner with the subject’s normal functioning level.
The AE resolves spontaneously or may require minimal therapeutic 
intervention.

Moderate
The AE produces limited impairment of function and may require therapeutic 
intervention.
The AE produces no sequela/sequelae.
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
Severe
The AE results in a marked impairment of function and may lead to 
temporary inability to resume usual life pattern.
The AE produces sequela/sequelae, which require (prolonged) therapeutic 
intervention.
These severity definitions will also be used to assess the severity of an AE with a study-
related procedure(s), if necessary.
12.1.2.2 Causality
Causality is a determination of whether there is a reasonable possibility that the IP is 
etiologically related to/associated with the AE. Causality assessment includes, eg, 
assessment of temporal relationships, dechallenge/rechallenge information, association 
(or lack of association) with underlying disease, presence (or absence) of a more likely 
cause, and physiological plausibility. For each AE, the investigator will assess the causal 
relationship between the IP and the AE using his/her clinical expertise and judgment 
according to the following most appropriate algorithm for the circumstances of the AE:

Not related (both circumstances must be met)
Is due to underlying or concurrent illness, complications, concurrent 
treatments, or effects of concurrent drugs
Is not associated with the IP (ie, does not follow a reasonable temporal 
relationship to the administration of IP or has a much more likely alternative 
etiology). 

Unlikely related (either 1 or both circumstances are met)
Has little or no temporal relationship to the IP 
A more likely alternative etiology exists

Possibly related (both circumstances must be met)
Follows a reasonable temporal relationship to the administration of IP
An alternative etiology is equally or less likely compared to the potential 
relationship to the IP

Probably related (both circumstances must be met)
Follows a strong temporal relationship to the administration of IP, which may 
include but is not limited to the following: 
o
Reappearance of a similar reaction upon re-administration (positive 
rechallenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
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o
Toxic level of the IP as evidenced by measurement of the IP 
concentrations in the blood or other bodily fluid
Another etiology is unlikely or significantly less likely
For events assessed as not related or unlikely related and occurring within 72 hours 
following completion of each IP administration, the investigator shall provide the 
alternative etiology. These causality definitions will also be used to assess the 
relationship of an AE with a study-related procedure(s), if necessary.
12.2 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the 
protocol, in order to protect subjects participating in a clinical trial from immediate harm. 
Urgent safety measures may be taken by the sponsor or clinical investigator, and may 
include any of the following: 

Immediate change in study design or study procedures

Temporary or permanent halt of a given clinical trial or trials

Any other immediate action taken in order to protect clinical trial participants 
from immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. In the 
event(s) of an apparent immediate hazard to the subject, the investigator will notify the 
sponsor immediately by phone and confirm notification to the sponsor in writing as soon 
as possible, but within 1 calendar day after the change is implemented. The sponsor will 
also ensure the responsible ethics committee is notified of the urgent measures taken in 
such cases according to local regulations.
12.3 Untoward Medical Occurrences
Untoward medical occurrences occurring before the first exposure to IP are not 
considered AEs (according to the definition of AE, see Section 12.1). However, each 
serious untoward medical occurrence experienced before the first IP exposure (ie, from 
the time of signed informed consent up to but not including the first IP exposure) will be 
described on the SAE Report. These events will not be considered as SAEs and will not 
be included in the analysis of SAEs.
For the purposes of this study, each non-serious untoward medical occurrence 
experienced by a subject undergoing study-related procedure(s) (eg, washout of a 
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subject’s pre-study A1PI augmentation therapy, bronchoscopy/BAL procedures) will be 
recorded on the AE CRF. These events, if occurred before the first IP exposure, will not
be considered as AEs and will not be included in the analysis of AEs. On the other hand, 
these events, if occurred after initiation of IP treatment, will be considered as AEs and 
will be included in the analysis of AEs.
12.4 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety and performance of the product but did not
result in an AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or 
design function, eg reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (eg, potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication, and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems including severity (as defined in Section 12.1.2.1) or surgery and start and end 
dates, if known: eyes, ears, nose, and throat; respiratory; cardiovascular; gastrointestinal; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary.
All medications taken and non-drug therapies received from enrollment until 
completion/termination will be recorded on the concomitant medications and non-drug 
therapies CRFs.
12.6 Physical Examinations
At screening and subsequent study visits (as described in Table 20.2-1), a physical 
examination will be performed on the following body systems: general appearance, head 
and neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen, extremities and 
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joints, lymph nodes, skin, and neurological. At screening, if an abnormal condition is 
detected, the condition will be described on the medical history CRF. At study visits, if a 
new abnormal or worsened abnormal pre-existing condition is detected, the condition will 
be described on the AE CRF. If the abnormal value was not deemed an AE because it 
was due to an error, due to a preexisting disease (described in Section 12.1.1.6), not 
clinically significant, a symptom of a new/worsened condition already recorded as an AE, 
or due to another issue that will be specified, the investigator will record the justification 
on the source record.
12.7 Clinical Laboratory Parameters
The schedule of sample collection for clinical laboratory assessments is provided in 
Table 20.3-1 Clinical Laboratory Assessments. Detailed requirements for sample 
collection and handling can be found in the Laboratory Manual.
12.7.1 Hematology and Clinical Chemistry
The hematology panel will consist of complete blood count (hemoglobin [Hgb], 
hematocrit [Hct], erythrocytes [ie, red blood cell (RBC)] count, leukocytes [ie, white 
blood cell (WBC)] count with differential (ie, basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils), absolute neutrophil count (ANC), absolute lymphocyte 
count, reticulocyte count, and platelet count.
The clinical chemistry panel will consist of sodium, potassium, calcium, chloride, 
bicarbonate, total protein, albumin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), lactic dehydrogenase (LDH), 
gamma-glutamyl-transferase (GGT), bilirubin (direct and total), blood urea nitrogen 
(BUN), uric acid, creatinine, creatine phosphokinase (CPK), and glucose. 
Blood will be collected for the assessment of hematology and clinical chemistry 
parameters during each of the following visits: screening, Week 1 (prior to the first IP 
infusion; this will serve as baseline value), Week 13, Week 25, and at study completion 
(Week 26) visit. Samples to be collected on the day of IP administration (ie, Week 1, 
Week 13, and Week 25) must be collected prior to the start of IP infusion. Subjects who 
are discontinued early from the study will be asked to undergo hematology and clinical 
chemistry assessments at the Early Termination visit, only if these subjects have been 
exposed to IP.
Hematology and clinical chemistry assessments will be performed on 
ethylenediaminetetraacetic acid (EDTA)-anticoagulated whole blood and serum samples, 
respectively, at a central laboratory.
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12.7.2 Complement Activation and Immune Complex Panel
Complement activation and immune complex panel will consist of serum complement 
component 3 (C3), complement component 4 (C4), total complement (50% hemolytic 
complement activity of serum; CH50), C1q binding, and circulating immune complexes.
Blood will be collected to obtain serum samples for the assessment of complement 
activation and circulating immune complexes during each of the following visits: Week 1 
(prior to the first IP infusion; this will serve as baseline value), Week 13, Week 25, and at 
study completion (Week 26) visit. Samples to be collected on the day of IP 
administration (ie, Week 1, Week 13, and Week 25) must be collected prior to the start of 
IP infusion. Subjects who are discontinued early from the study will be asked to undergo 
complement activation and immune complex evaluation at the Early Termination visit, 
only if these subjects have been exposed to IP.
Complement activation and immune complex assessments will be performed at a central 
laboratory.
12.7.3 Viral Serology and Nucleic Acid Tests
Viral serology tests for HAV antibody, hepatitis B virus surface antigen (HBsAg), HCV 
antibody, and HIV-1/HIV-2 antibody will be performed at screening for subject 
eligibility determination.
Viral testing for B19V will consist of B19V antibody serology test and NAT, based on 
real-time polymerase chain reaction (PCR) detection of B19V DNA. Serum samples will 
be collected prior to the first IP infusion during Week 1 (which serves as the baseline 
value) and at the last infusion visit (Week 25). If a subject’s Week 1 pre-dose sample is 
tested positive, then no further testing (eg, Week 25) is required. Any evidence of
seroconversion (eg, change from a negative test result at baseline [Week 1 prior to the 
first IP infusion] to a positive result at a post-baseline assessment) for B19V should be re-
tested. Subjects who are discontinued early from the study will be asked to undergo viral 
serology and NAT testing at the Early Termination visit, only if these subjects have been 
exposed to IP.
Serology testing and NAT will be performed at a central laboratory.
12.7.4 Urine Tests
Urinalysis will consist of color, specific gravity, pH, protein, glucose, ketones, bilirubin, 
urobilinogen, blood, nitrate, leukocyte esterase, and microscopic examination (RBC, 
WBC, bacteria, casts). Urinalysis will be performed during each of the following visits: 
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screening, Week 1 (prior to the first IP infusion; this will serve as baseline value), Week 
13, Week 25, and at study completion (Week 26) visit. Samples to be collected on the 
day of IP administration (ie, Week 1, Week 13, and Week 25) must be collected prior to
the start of IP infusion. Urinalysis will be performed at a central laboratory.
Pregnancy test will be performed for females of childbearing potential at screening and at 
study completion (Week 26) visit. Subjects who are discontinued early from the study 
will be asked to undergo urinalysis and urine/serum pregnancy test (for females of 
childbearing potential only) at the Early Termination visit, only if these subjects have 
been exposed to IP. Urine pregnancy test will be performed, unless serum pregnancy test 
is mandatory as specified by local regulatory/institutional requirements.
12.7.5 Assessment of Clinical Laboratory Values
12.7.5.1 Assessment of Abnormal Laboratory Values
The investigator’s assessment of each safety-related laboratory value will be recorded on 
the laboratory form. For each abnormal laboratory value, the investigator will determine 
whether the value is considered clinically significant or not. For clinically significant 
values, the investigator will indicate if the value constitutes an new AE (see definition in 
Section 12.1, and record the sign, symptom, or medical diagnosis on the AE CRF), is a 
symptom or related to a previously recorded AE, is due to a pre-existing disease 
(described in Section 12.1.1.6), or is due to another issue that will be specified. If the 
abnormal value was not clinically significant, the investigator will indicate the reason, ie 
because it is due to a preexisting disease, due to a lab error, or due to another issue that 
will be specified. Additional tests and other evaluations required to establish the 
significance or etiology of an abnormal value, or to monitor the course of an AE should 
be obtained when clinically indicated. Any seroconversion result for B19V should be re-
tested. Any abnormal value that persists should be followed at the discretion of the 
investigator.
In addition to investigator’s assessment of the clinical significance of laboratory 
abnormalities, clinical laboratory abnormalities with values that meet the criteria listed in 
Section 20.4 will be separately analyzed and reported.
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12.7.6 Biobanking
Backup samples should be taken and stored appropriately for additional analysis, if 
necessary. These samples may be used for re-testing, further evaluation of an AE, or 
follow-up of other test results. The following samples are planned:

Plasma samples collected for the determination of the following analytes will 
each be split into duplicate aliquots of approximately equal volume (one of the 2 
aliquots will serve as the backup sample):
Plasma antigenic A1PI
Plasma functional A1PI (ie, ANEC)
Plasma urea

Serum samples collected for the determination of the following analytes will 
each be split into duplicate aliquots of approximately equal volume (one of the 2 
aliquots will serve as backup sample):
Anti-A1PI antibodies for screening and confirmatory assays
Anti-A1PI antibodies for neutralizing antibody assay

BAL samples collected for the determination of the following analytes will each 
be split into duplicate aliquots of approximately equal volume (one of the 2 
aliquots will serve as backup sample):
BAL antigenic A1PI
BAL functional A1PI (ie, ANEC)
BAL urea
Backup samples that remain after study testing is done may be stored and used for 
additional testing (eg, further evaluation of an abnormal test or an AE. Samples will be 
stored in a coded form for up to 2 years after the final study report has been completed, 
unless otherwise notified by the sponsor, and then the samples will subsequently be 
destroyed.
12.8 Plasma Antigenic and Functional A1PI Levels
Throughout the treatment period, plasma trough A1PI levels will be assessed to monitor 
the increase in and maintenance of circulating A1PI levels at target of 11 µM or greater. 
Plasma samples for the determination of trough antigenic A1PI and functional A1PI (also 
known as ANEC) levels will be collected prior to the first IP infusion during Week 1, on 
the day of IP administration (must be collected prior to the start of IP infusion) during
Week 7, Week 13, Week 19, and Week 25, and at the study completion (Week 26) visit.
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For subjects who are to undergo BAL assessments, plasma samples for baseline antigenic 
A1PI level will be collected within 10 days prior to the baseline BAL visit to verify the 
adequacy of the washout from A1PI therapy prior to performing the baseline BAL visit. 
Then, on the day of the baseline BAL visit, plasma samples for the measurement of 
antigenic and functional A1PI levels will be collected simultaneously with plasma 
samples for urea measurements within 2 hours prior to the BAL procedure. These values 
will be used for the calculation of the corresponding A1PI levels in ELF using plasma-to-
BAL urea correction method. Sample collection for plasma antigenic and functional A1PI 
and urea will be repeated on the day of the on-treatment BAL visit within 2 hours prior to 
the BAL procedure (see Section 10.3.4).
Subjects who are discontinued early from the study after having been exposed to IP 
administration will be asked to have a plasma sample collected for A1PI determination. 
The early termination plasma sample will be analyzed to support analysis/interpretation 
of the early termination anti-A1PI antibody assessment. 
Sample analysis for the determination of plasma antigenic and functional A1PI levels will 
be performed using validated bioanalytical assays at a qualified laboratory.
12.9 Immunogenicity
Blood will be collected to obtain serum samples for monitoring the appearance/presence 
of anti-A1PI antibodies prior to the first IP infusion during Week 1, on the day of IP 
administration (must be collected prior to the start of IP infusion) during Week 13 and 
Week 25, and at study completion (Week 26) visit. Subjects who are discontinued early 
from the study after having been exposed to IP administration will be asked to have a 
serum sample collected for immunogenicity assessment at the Early Termination visit.
Unscheduled samples for the detection of circulating anti-A1PI antibodies may be 
collected as necessary and upon consultation with or notification by the sponsor, to 
support investigation of suspected immune-related adverse events. At any scheduled or 
unscheduled time points, plasma samples for the determination of circulating A1PI levels 
will be collected concurrently to assess potential interference with the assay. 
Each sample is to be stored as duplicate aliquots each with sufficient volume needed for 
sample analysis. Detailed sample handling and storage instructions will be provided in 
the laboratory manual.
Anti-A1PI antibodies will be detected using validated binding and neutralizing anti-A1PI 
antibody assays at a qualified immunoassay laboratory. The presence of anti-A1PI 
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antibodies in a sample will be detected using a screening assay and confirmed using a 
confirmatory assay. Only those samples with confirmed positive results will be further 
analyzed for the examination for the presence of neutralizing antibodies.
12.10 Vital Signs
Body height (in or cm) will be collected at screening only. Body weight (lb or kg) will be 
measured at screening and at study visits during Weeks 1, 7, 13, 19, and 25.
Vital signs will include body temperature (°C or °F), respiratory rate (breaths/min), pulse 
rate (beats/min), and systolic and diastolic blood pressure (mmHg). Blood pressure 
measurements will be taken when subjects are in either the sitting or supine position; the 
same position should preferably be maintained each time a blood pressure is measured. 
These vital signs will be measured at screening, during treatment period (Weeks 1, 7, 13, 
19, and 25), and at study completion (Week 26)/early termination visit (see also 
Section 10.3.2.1 and Table 20.3-1).
For each of the IP infusion visits where vital signs are to be taken, vital signs will be 
recorded at any time prior to the start of an infusion, at each rate reduction due to AE(s) 
and/or infusion interruption/discontinuation due to AE(s), and within 90 minutes after the 
completion of an infusion. The investigator should be contacted to determine appropriate 
action to be taken, as necessary, if vital signs meet any of the following criteria:

Systolic blood pressure ≤80 mm Hg or ≥180 mm Hg and/or diastolic blood 
pressure: ≤50 mm Hg or ≥110 mm Hg

Pulse rate ≤48 beats/min or ≥110 beats/min

Respiratory rate ≤8 breaths/min or ≥24 breaths/min

Body temperature ≥38.2 ºC (101 ºF)
For subjects undergoing BAL procedures, vital signs will be measured within 2 hours 
prior to each BAL procedure and within 1 hour after the completion of the BAL 
procedure. Pre-BAL vital signs are to be performed prior to the administration of 
bronchodilator and local anesthesia.
Vital sign values are to be recorded on the CRF. For each abnormal vital sign value, the 
investigator will determine whether or not to report an AE (see definition in Section 12.1
and record the medical diagnosis (preferably), symptom, or sign on the AE CRF). 
Additional tests and other evaluations required to establish the significance or etiology of 
an abnormal vital sign value or to monitor the course of an AE should be obtained when 
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clinically indicated. Any abnormal value that persists should be followed at the discretion 
of the investigator.
13. STATISTICS
13.1 Sample Size and Power Calculations
The sample size calculation for the BAL component of the study was based on the natural 
log transformed primary endpoint data, ELF antigenic A1PI level (nM), generated during 
Baxter’s Clinical Study 460502. In Clinical Study 460502, a mean difference from pre- to 
post-treatment in ELF antigenic A1PI of 1.32 with standard deviation of 0.96 on natural 
log scale was observed. Using this variance estimate, a sample size of 15 evaluable 
subjects should be sufficient to detect a mean difference in the natural log transformed 
ELF antigenic A1PI of approximately 0.87 with 90% power, using a paired t-test and a 
one-sided significance level of 0.025.
A sample size of 15 evaluable subjects will also be sufficient to detect a mean difference 
in the natural log transformed ELF functional A1PI (ANEC) of approximately 1.04, with 
90% power, assuming a standard deviation in the differences between pre- and post-
treatment ANEC values to be 20% higher than that for antigenic A1PI.
Based on the experience from Clinical Study 460502, it is estimated that approximately 
26 to 32 subjects will be needed in order to achieve 15 to 18 BAL evaluable subjects, 
respectively. Thus, an overall study enrollment target of 36 subjects should be adequate 
to meet the target sample size for the BAL component of the study.
13.2 Datasets and Analysis Cohorts
13.2.1 Full Analysis Set
The full analysis set (FAS) will include all subjects who received at least one IP infusion 
and have at least one available A1PI measurement during the treatment period.
13.2.2 Per-Protocol Analysis Set
The per-protocol (PP) analysis set will include a subset of the full analysis set, 
comprising subjects with no major protocol deviations. For the purpose of statistical 
analysis, major deviations include, but are not limited to, the following: failure to comply 
with the washout period for pre-study A1PI augmentation therapy, missing two or more 
consecutive weekly infusions and/or >15% of planned infusions, and use of an A1PI 
product (including commercially available GLASSIA) other than IP during the study 
treatment period.
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13.2.3 BAL Analysis Set
The BAL analysis set will include a subset of the FAS analysis set, comprising subjects 
who meet all of the following criteria:

Subjects who have met all study inclusion and exclusion criteria, including 
additional BAL-related eligibility criteria

Subjects have successfully completed both the baseline and the on-treatment BAL 
visits and have a minimum of one evaluable sample per BAL visit with no 
missing infusion(s) within 4 weeks immediately preceding the on-treatment BAL 
procedure

Subjects must have available ELF data for both the baseline and the on-treatment
BAL visits in order to be included in the efficacy analyses for the assessment of 
ELF analyte levels following GLASSIA augmentation therapy.
13.2.4 Safety Analysis Set
The safety analysis set will include all subjects enrolled in the study who received at least 
one IP infusion.
13.3 Handling of Missing, Unused, and Spurious Data
No missing data imputation will be performed.
13.4 Methods of Analysis
13.4.1 Efficacy Outcome Measures
Antigenic and functional A1PI levels in the ELF will be estimated based on the 
corresponding BAL measurements at each time point using plasma-to-BAL urea 
correction method. ELF antigenic and functional A1PI levels, as well as changes from 
baseline, will be summarized descriptively and displayed graphically (data permitting)
based on data pooled across both treatment arms. For a given subject, if BAL 
measurements are obtained from more than 1 lung lobe, then the urea-corrected values 
will be averaged at the corresponding time point prior to being summarized.
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Since an increase from baseline in the mean ELF levels of antigenic A1PI is expected, a 
one-sided paired t-test will be conducted at an α-level of 0.025 with the following null 
and alternative hypotheses where the mean change in antigenic A1PI from baseline to the 
on-treatment BAL measurement is μd: 
Ho: Mean change in antigenic A1PI in the ELF from baseline to the on-treatment 
measurement will be less than or equal to zero.
Ho: μd ≤ 0
H1: Mean change in antigenic A1PI in the ELF from baseline to the on-treatment
measurement will be greater than zero.
H1: μd > 0
The mean change in functional A1PI (ANEC) from baseline to on-treatment 
measurement will be analyzed in a similar fashion, if data permit. The natural logarithm 
transformation may be applied to the ELF antigenic or functional A1PI values prior to 
analysis if the distributions are highly skewed. This analysis will be conducted with the 
BAL analysis set.
 
 
 
Changes from baseline in ELF and plasma antigenic and functional A1PI levels, as well 
as 
, will be summarized in the following subgroups: by sex, 
age (≤65, >65), race, and ethnicity. 
 
.
13.4.2 Exposure
Plasma trough antigenic and functional A1PI levels, as well as changes from baseline, 
will be summarized descriptively and displayed graphically (data permitting) based on 
data pooled across both treatment arms. Plasma antigenic and functional A1PI levels 
obtained at the baseline and on-treatment BAL visits will be summarized separately and, 
data permitting, to be correlated with the corresponding values in the ELF. Plasma A1PI 
levels obtained at the study completion (Week 26) or early termination visit will not be 
part of this analysis. These analyses will be conducted with both the FAS and the PP 
analysis sets.
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In the event of anti-A1PI antibody formation is detected, the individual antigenic and 
functional A1PI levels may be evaluated in conjunction with binding and neutralizing 
anti-A1PI antibody titers, as applicable.
13.4.3 Safety Outcome Measures
The safety analysis set will be used for the following analyses, unless otherwise stated:
AEs that are considered potentially related to the presence of protein aggregates or 
immune-mediated will be summarized descriptively with 95% confidence intervals (CIs) 
as appropriate for each AE of interest by each treatment arm and, if appropriate, pooled 
across both treatment arms. In the event of any clinically significant trends in treatment-
emergent AE(s) of interest, further analysis including potential correlation with the 
presence of particulates in the GLASSIA solution will be performed.
ARs plus suspected ARs, using a time frame for AE onset of (a) during and within 24
hours and (b) during and within 72 hours of completion of an infusion, will be tabulated 
separately and presented according to seriousness, severity, and causality, as well as by 
MedDRA preferred term. Similar tabulation of data will be conducted for AEs and SAEs.
The number (proportion) of subjects experiencing SAEs, AEs, related AEs, and/or ARs 
plus suspected ARs will be summarized by each treatment arm and, if appropriate, pooled 
across both treatment arms with their point estimates and exact 95% CIs.
The number (proportion) of infusions (defined as percentage of the total number of 
infusions administered) temporally associated with AEs or SAEs (defined as during or 
within (a) 24 hours and (b) 72 hours of completion of infusion) will be computed for each 
subject. The median (95% CI), minimum, and maximum of these numbers (or 
percentages, respectively) will be tabulated.
The number (proportion) of infusions (defined as percentage of the total number of 
infusions administered) causally associated with AEs or SAEs will be computed for each 
subject. The median (95% CI), minimum, and maximum of these numbers (or 
percentages, respectively) will be tabulated.
The number (proportion) of infusions (defined as percentage of the total number of 
infusions administered) associated with ARs will be computed for each subject. The 
median (95% CI), minimum, and maximum of these numbers (or percentages, 
respectively) will be tabulated.
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The number (proportion) of infusions that are discontinued, slowed, or interrupted due to 
an AE will be summarized. The rates of AEs and ARs expressed as the number of events 
that occurred in total number of infusions administered will be provided by MedDRA 
term.
The proportion of subjects who develop binding and/or neutralizing anti-A1PI antibodies 
will be summarized with their point estimates and exact 95% CIs. Treatment-emergent 
anti-A1PI antibody data will be listed along with the corresponding plasma antigenic and 
functional A1PI levels in the individual subject. Additionally, temporal relationship of 
anti-A1PI antibody formation with potentially immune-related AEs, if any, will be 
examined.
The number (proportion) of subjects who experienced a shift from normal or clinically 
non-significant abnormal laboratory values at baseline to clinically significant abnormal 
laboratory values will be summarized with their point estimates and exact 95% CIs. Any 
clinically significant laboratory values that are considered as clinically significant by the 
investigator (ie, reported as AEs), as well as in accordance with the thresholds provided 
in Section 20.4, will be analyzed and reported, including shift tables.
Changes in vital signs obtained pre- and post-infusions, as well as pre- and post-BAL
procedures as applicable, will be provided in a listing.
The proportion of subjects with confirmed treatment-emergent seroconversion by viral 
serology or nucleic acid test for B19V during or following treatment with GLASSIA will 
be summarized with exact 95% CIs.
Safety parameters will be summarized descriptively by sex, age (≤65, >65), race, and 
ethnicity. No hypothesis tests are planned; however, 
 
AEs that occur before treatment will be listed separately.
13.5 Planned Interim Analysis of the Study
Not applicable; no interim analyses are planned for this study.
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the EC, and inspections by applicable 
regulatory authorities, as described in the Clinical Study Agreement. If contacted by an 
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applicable regulatory authority, the investigator will notify the sponsor of contact, 
cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses, as described in 
the Clinical Study Agreement.
15. QUALITY CONTROL AND QUALITY ASSURANCE
15.1 Investigator’s Responsibility
The investigator will comply with the protocol (which has been approved/given favorable 
opinion by the EC), ICH GCP, and applicable regulatory requirements as described in the 
Clinical Study Agreement. The investigator is ultimately responsible for the conduct of 
all aspects of the study at the study site and verifies by signature the integrity of all data 
transmitted to the sponsor. The term “investigator” as used in this protocol as well as in 
other study documents, refers to the investigator or authorized study personnel that the 
investigator has designated to perform certain duties. Sub-investigators or other 
authorized study personnel are eligible to sign for the investigator, except where the 
investigator’s signature is specifically required.
15.1.1 Final Clinical Study Report 
The investigator, or coordinating investigator(s) for multicenter studies, will sign the 
clinical study report. The coordinating investigator will be selected before study start.
15.2 Training
The study monitor will ensure that the investigator and study site personnel understand 
all requirements of the protocol, the investigational status of the IP, and his/her regulatory 
responsibilities as an investigator. Training may be provided at an investigator’s meeting, 
at the study site, and/or by instruction manuals. In addition, the study monitor will be 
available for consultation with the investigator and will serve as the liaison between the 
study site and the sponsor.
15.3 Monitoring
The study monitor is responsible for ensuring and verifying that each study site conducts 
the study according to the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable regulatory guidelines/requirements. 
The investigator will permit the study monitor to visit the study site at appropriate 
intervals, as described in the Clinical Study Agreement. Monitoring processes specific to 
the study will be described in the clinical monitoring plan. 
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15.4 Auditing
The sponsor and/or sponsor’s representatives may conduct audits to evaluate study 
conduct and compliance with the protocol, standard operating procedures, other written 
instructions/agreements, ICH GCP, and applicable regulatory guidelines/requirements. 
The investigator will permit auditors to visit the study site, as described in the Clinical 
Study Agreement. Auditing processes specific to the study will be described in the 
auditing plan.
15.5 Non-Compliance with the Protocol
The investigator may deviate from the protocol only to eliminate an apparent immediate 
hazard to the subject. In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification to the 
sponsor in writing as soon as possible, but within 1 calendar day after the change is 
implemented. The sponsor (Baxter) will also ensure the responsible ethics committee is 
notified of the urgent measures taken in such cases according to local regulations.
If monitoring and/or auditing identify serious and/or persistent non-compliance with the 
protocol, the sponsor may terminate the investigator’s participation. The sponsor will 
notify the EC and applicable regulatory authorities of any investigator termination.
15.6 Laboratory and Reader Standardization
Not applicable; each type of assay is planned to be conducted at a single laboratory
facility for consistency and standardization.
16. ETHICS 
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the Clinical Study Agreement.
16.2 Ethics Committee and Regulatory Authorities
Before enrollment of patients into this study, the protocol, ICF, any promotional 
material/advertisements, and any other written information to be provided will be 
reviewed and approved/given favorable opinion by the EC and applicable regulatory 
authorities. The EC’s composition or a statement that the EC’s composition meets 
applicable regulatory criteria will be documented. The study will commence only upon 
the sponsor’s receipt of approval/favorable opinion from the EC and, if required, upon 
the sponsor’s notification of applicable regulatory authority(ies) approval, as described in 
the Clinical Study Agreement.
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If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the EC and 
applicable regulatory authorities, where applicable. The protocol amendment will only be 
implemented upon the sponsor’s receipt of approval and, if required, upon the sponsor’s 
notification of applicable regulatory authority(ies) approval.
16.3 Informed Consent
Investigators will choose patients for enrollment considering the study eligibility criteria. 
The investigator will exercise no selectivity so that no bias is introduced from this source. 
All patients and/or their legally authorized representative must sign an ICF before 
entering into the study according to applicable regulatory requirements and ICH GCP. 
Before use, the ICF will be reviewed by the sponsor and approved by the EC and 
regulatory authority(ies), where applicable, (see Section 16.2). The ICF will include a 
comprehensive explanation of the proposed treatment without any exculpatory 
statements, in accordance with the elements required by ICH GCP and applicable 
regulatory requirements. Patients or their legally authorized representative(s) will be 
allowed sufficient time to consider participation in the study. By signing the ICF, patients 
or their legally authorized representative(s) agree that they will complete all evaluations 
required by the study, unless they withdraw voluntarily or are terminated from the study 
for any reason.
The sponsor will provide to the investigator in written form any new information that 
significantly bears on the subjects’ risks associated with IP exposure. The informed 
consent will be updated, if necessary. This new information and/or revised ICF that have 
been approved by the applicable EC and regulatory authorities, where applicable, will be 
provided by the investigator to the subjects who consented to participate in the study (see 
Section 16.3).
16.4 Data Monitoring Committee
A Data Monitoring Committee (DMC) will not be used for this study, since the IP is 
already a licensed product and the dosing regimen being evaluated is already approved 
for chronic treatment in the patient population to be enrolled in this study.
17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the Clinical 
Study Agreement. 
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17.2 Study Documents and Case Report Forms
The investigator will maintain complete and accurate paper format study documentation 
in a separate file. Study documentation may include information defined as “source data” 
(see Section 8.8), records detailing the progress of the study for each subject, signed 
ICFs, correspondence with the EC and the study monitor/sponsor, enrollment and 
screening information, CRFs, SAE reports (SAERs), laboratory reports (if applicable), 
and data clarifications requested by the sponsor. 
The investigator will comply with the procedures for data recording and reporting. Any 
corrections to paper study documentation must be performed as follows: 1) the first entry 
will be crossed out entirely, remaining legible; and 2) each correction must be dated and 
initialed by the person correcting the entry; the use of correction fluid and erasing are 
prohibited.
The investigator is responsible for the procurement of data and for the quality of data 
recorded on the CRFs. CRFs will be provided in electronic form. 
If electronic format CRFs are provided by the sponsor, only authorized study site 
personnel will record or change data on the CRFs. If data is not entered on the CRFs 
during the study visit, the data will be recorded on paper, and this documentation will be 
considered source documentation. Changes to a CRF will require documentation of the 
reason for each change. An identical (electronic/paper) version of the complete set of 
CRFs for each subject will remain in the investigator file at the study site in accordance 
with the data retention policy (see Section 17.3).
The handling of data by the sponsor, including data quality assurance, will comply with 
regulatory guidelines (eg, ICH GCP) and the standard operating procedures of the 
sponsor. Data management and control processes specific to the study will be described 
in the data management plan.
17.3 Document and Data Retention 
The investigator will retain study documentation and data (paper and electronic forms) in 
accordance with applicable regulatory requirements and the document and data retention 
policy, as described in the Clinical Study Agreement.
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18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance, 
and subject compensation policies, if applicable, as described in the Clinical Study 
Agreement.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the Clinical 
Study Agreement. 
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20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 20-1
Study Flow Chart for Baxter Clinical Study 471101
Informed Consent
GLASSIA Infusions
(60 mg/kg BW every week)
Week 13 (± 2 days)
This visit must take place at the study site.
Study Completion (Week 26 [± 3 days])
Week 7 (± 2 days)
Infusion may occur at study site or at a suitable location at the discretion of the investigator.
Screening for Eligibility (Max 6 weeks)
Any prior A1PI therapy will be withdrawn for at least 4 weeks prior to the assessment of endogenous 
circulating A1PI level.
Week 1
First infusion must take place at the study site after completion of all baseline assessments.
Week 25 (± 2 days)
This visit must take place at the study site.
Week 19 (± 2 days)
Infusion may occur at study site or at a suitable location at the discretion of the investigator.
Baseline BAL Visit (Max 2 weeks)
This visit must take place at the study site. BALvisit may not be applicable for subjects enrolled after the 
target of at least 15 BAL evaluable subjects have been reached.
On-treatment BAL Visit (Between Week 12 and Week 14)
This visit must take place at the study site. BALvisit may not be applicable for subjects enrolled 
after the target of at least 15 BAL evaluable subjects have been reached.
Randomization
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20.2 Schedule of Study Procedures and Assessments
Table 20.2-1
Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening
(Max 6 
Weeks)
Baseline BALa
(Max 2 Weeks)
Week 
1
Week 7
(± 2
Days)
Week 13
(± 2
Days)
On-Treatment BAL 
(Week 12-14)b
Week 19
(± 2 Days)
Week 25
(± 2 Days)
Study Completion 
(Week 26 ± 3 Days) / 
Early Terminationc
Informed Consentd
X
Eligibility Criteria
X
Randomization
Xe
Demographics
X
Medical and 
Medication History
X
Height
X
Body Weightf
X
X
X
X
X
X
Physical Exam
X
Xg
Xg
X
Vital Signs
X
Xh
Xh
Xh
Xh
Xh
ECGi
X
Chest X-ray/CTj
X
Pulmonary Function 
Testsk
X
Screening/Safety 
Laboratory Testsl
X
Xg
Xg
Xg
X
Screening/On-
Treatment Trough 
A1PIm
X
Xg
Xg
Xg
Xg
Xg
X
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Table 20.2-1
Schedule of Study Procedures and Assessments
Procedures/
Assessments
Screening
(Max 6 
Weeks)
Baseline BALa
(Max 2 Weeks)
Week 
1
Week 7
(± 2
Days)
Week 13
(± 2
Days)
On-Treatment BAL 
(Week 12-14)b
Week 19
(± 2 Days)
Week 25
(± 2 Days)
Study Completion 
(Week 26 ± 3 Days) / 
Early Terminationc
Xg
Xg
Xg
Xg
Xg
X
Anti-A1PI 
Antibodiesm,n
Xg
Xg
Xg
X
Weekly GLASSIA 
Infusionso
X
Adverse Event
X
X
X
X
Concomitant 
Medications and 
Non-drug Therapies
X
X
X
X
Telephone Follow-
upp
X
Additional Procedures for Subjects Undergoing BAL Procedures
BAL Procedure
X
X
Vital Signs
Xq
Xq
BAL and Plasma 
Urea and A1PIm
X
X
X
X
Abbreviations: BAL = Bronchoalveolar lavage; ECG = Electrocardiogram; A1PI = Alpha1-Proteinase Inhibitor.
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Continued
a.
For subjects who undergo bronchoscopy/BAL procedures. The baseline bronchoscopy/BAL visit will be postponed once if a subject experiences a 
moderate or severe COPD exacerbation and/or LRTI during the screening period (see Section 10.4 for more details).
b.
The on-treatment BAL procedure will be performed between Week 12 and Week 14 at least 3 days after the preceding IP infusion but with a 
minimum of 2 days prior to the next IP infusion. Should a subject miss 1 or more consecutive GLASSIA infusion(s) within 4 week(s) immediately 
prior to the scheduled on-treatment BAL visit, the BAL procedure will be rescheduled to occur after the subject has received at least 4 consecutive 
weekly GLASSIA administrations. Additionally, the on-treatment bronchoscopy/BAL visit will be postponed once if a subject experiences a 
moderate or severe COPD exacerbation and/or LRTI during the screening period (see Section 10.4 for more details).
c.
Subjects who are being discontinued from the study early and having been exposed to IP will be asked to return to the study site 7 ±3 days after the 
last infusion for early termination assessments. Subjects who are discontinued early from the study prior to receiving any IP administration will not 
need to undergo early termination procedures, except for those subjects who have undergone the baseline BAL procedure in which case subjects 
will be followed for potential post-BAL complications for a period of time in accordance with local institutional standard practice but not to exceed 
30 days.
d.
Written informed consent must be obtained prior to performance of any study procedures including screening/re-screening procedures.
e.
Randomization is to take place after verification of subject’s meeting all the main eligibility criteria, as well as additional bronchoscopy/BAL-
related eligibility criteria (as applicable). For those undergoing bronchoscopy/BAL procedures, randomization is to take place only after the subject 
has successfully completed the baseline BAL visit with evaluable BAL samples collected.
f.
Body weight will be taken at screening (for the calculation of the initial IP infusion dose [in mg] / volume [in mL]). Body weight will be monitored 
at 6-week intervals (ie, during Weeks 1, 7, 13, 19, and 25) throughout the study. All body weight measurements must be taken using standardized 
procedures. Adjustment based on body weight changes during the course of the study is not planned; however, dose (in mg) may be adjusted if 
deemed medically necessary at the discretion of the investigator (eg, clinically significant body weight changes).
g.
To be performed prior to dosing on the day of the IP administration. Measurements taken prior to the first IP infusion (Week 1) will serve as the 
baseline values.
h.
During treatment period, vital signs (body temperature, respiratory rate, pulse rate, and systolic and diastolic blood pressure) are to be taken on the 
day of IP infusion during Weeks 1, 7, 13, 19, and 25 infusion visits at any time prior to the infusion, at each rate reduction due to AE(s) and/or 
infusion interruption/discontinuation due to AE(s), and within 90 minutes after the completion of an infusion.
i.
ECG obtained within 26 weeks prior to screening may be used, if available.
j.
Chest X-ray or CT scan obtained within 52 weeks prior to screening may be used, if available.
k.
Pulmonary function tests include spirometry (forced expiratory volume in 1 second [FEV1] and forced vital capacity [FVC]) and single-breath 
diffusing capacity of carbon monoxide [DLCO]). Spirometry is to be taken 30 ± 15 minutes after administration of a short-acting inhaled β2 agonist 
bronchodilator (eg, 400 μg of salbutamol, or its equivalent). Measurement of DLCO is to be performed prior to bronchodilator administration and 
spirometry.
l.
For laboratory assessments, see Table 20.3-1.
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m. Samples will each be split into duplicate aliquots of approximate equal volume. One of the 2 aliquots will serve as the backup sample and stored 
appropriately until notified by the sponsor.
n.
In the event of suspected immune-related adverse events, unscheduled anti-A1PI antibody samples may be collected as necessary and upon 
consultation with or notification by the sponsor to support AE investigation. The unscheduled anti-A1PI antibody samples must be accompanies by 
plasma sample collection for the determination of antigenic and functional A1PI levels.
o.
The first infusion (Week 1), as well as infusions at Week 13 and Week 25, must be administered at the study site. Other weekly infusions may be 
administered at the study site or at another suitable location (eg, the subject’s home) by a qualified healthcare professional, as acceptable per local 
regulations and standard practices of the study site.
p.
The investigator/designee will contact the subject within 1 business day following 72 hours after the completion of each infusion to document AEs 
and concomitant medications, as well as non-drug therapies, which may have occurred within 24 and 72 hours after the completion of an infusion.
q.
Vital signs will be measured within 2 hours prior to each BAL procedure and within 1 hour after the completion of the BAL procedure. Pre-BAL 
vital signs are to be performed prior to the administration of bronchodilator and local anesthesia.
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20.3 Schedule of Clinical Laboratory Assessments
Table 20.3-1
Clinical Laboratory Assessments
Assessments
Screening
(Max 6 
Weeks)
Baseline BALa
(Max 2 Weeks)
Week 
1
Week 7
(± 2 Days)
Week 13
(± 2 Days)
On-Treatment 
BAL
(Week 12-14)b
Week 19
(± 2 Days)
Week 25
(± 2 Days)
Study Completion 
(Week 26 ± 3 Days) / 
Early Terminationc
Hematologyd
W
We
We
We
W
Clinical Chemistryf
S
Se
Se
Se
S
Complement 
Activation and 
Immune Complex 
Panelg
Se
Se
Se
S
HAV Antibody, 
HBsAg, HCV 
Antibody, and HIV-
1/HIV-2 Antibody
S
B19V Serology and 
NATh
Se
Se
S
Urinalysisi
U
Ue
Ue
Ue
U
Pregnancy Testj
S/U
S/U
Serum IgA
S
Serum Cotinine
S
S
S
A1PI Genotype
S
Screening
(Antigenic) A1PIk,l
P
On-Treatment 
Trough Plasma 
Antigenic A1PIl
Pe
Pe
Pe
Pe
Pe
P
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Table 20.3-1
Clinical Laboratory Assessments
Assessments
Screening
(Max 6 
Weeks)
Baseline BALa
(Max 2 Weeks)
Week 
1
Week 7
(± 2 Days)
Week 13
(± 2 Days)
On-Treatment 
BAL
(Week 12-14)b
Week 19
(± 2 Days)
Week 25
(± 2 Days)
Study Completion 
(Week 26 ± 3 Days) / 
Early Terminationc
On-Treatment 
Trough Plasma 
Functional A1PIl
Pe
Pe
Pe
Pe
Pe
P
Pe
Pe
Pe
Pe
Pe
P
Serum Anti-A1PI 
Antibodiesl
Se
Se
Se
S
Additional Procedures for Subjects Undergoing BAL Procedures
Plasma Ureal
Pm
Pm
Plasma Antigenic 
A1PIl
Pm,n
Pm
Plasma Functional 
A1PIl
Pm
Pm
Pm
Pm
BAL Ureal
L
L
BAL Antigenic 
A1PIl
L
L
BAL Functional 
A1PI (ANEC)l
L
L
L
L
L
L
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Table 20.3-1
Clinical Laboratory Assessments
Assessments
Screening
(Max 6 
Weeks)
Baseline BALa
(Max 2 Weeks)
Week 
1
Week 7
(± 2 Days)
Week 13
(± 2 Days)
On-Treatment 
BAL
(Week 12-14)b
Week 19
(± 2 Days)
Week 25
(± 2 Days)
Study Completion 
(Week 26 ± 3 Days) / 
Early Terminationc
L
L
L
L
Abbreviations: BAL = Bronchoalveolar lavage; W = Whole blood; S = Serum; HAV = Hepatitis A Virus; HBsAg = Hepatitis B virus surface antigen; 
HCV = Hepatitis C virus; HIV = Human immunodeficiency virus; NAT = Nucleic acid test; B19V = Parvovirus B19; U = Urine; IgA = 
Immunoglobulin A; A1PI = Alpha1-Proteinase Inhibitor; P = Plasma; L = Bronchoalveolar lavage fluid; ANEC = Anti-neutrophil elastase capacity; 
 
a.
For subjects undergoing bronchoscopy/BAL procedures.
b.
The on-treatment BAL procedure will be performed between Week 12 and Week 14 at least 3 days after the preceding IP infusion but with a 
minimum of 2 days prior to the next IP infusion. Should a subject miss 1 or more consecutive GLASSIA infusion(s) within 4 week(s) immediately 
prior to the scheduled on-treatment BAL visit, the BAL procedure will be rescheduled to occur after the subject has received at least 4 consecutive 
weekly GLASSIA administrations.
c.
Subjects who are being discontinued from the study early and having been exposed to IP will be asked to return to the study site 7 ±3 days after the 
last infusion for early termination assessments. Subjects who are discontinued early from the study prior to receiving any IP administration will not 
need to undergo early termination procedures, except for those subjects who have undergone the baseline BAL procedure in which case subjects 
will be followed for potential post-BAL complications for a period of time in accordance with local institutional standard practice but not to exceed 
30 days.
d.
Hematology panel will consist of complete blood count (hemoglobin [Hgb], hematocrit [Hct], erythrocytes [ie, red blood cell (RBC)] count, 
leukocytes [ie, white blood cell (WBC)] count with differential (ie, basophils, eosinophils, lymphocytes, monocytes, and neutrophils), absolute 
neutrophil count (ANC), absolute lymphocyte count, reticulocyte count, and platelet count.
e.
Samples must be collected prior to GLASSIA administration.
f.
Clinical chemistry panel will consist of sodium, potassium, calcium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase (ALP), lactic dehydrogenase (LDH), gamma-glutamyl-transferase (GGT), bilirubin (direct 
and total), blood urea nitrogen (BUN), uric acid, creatine, creatine phosphokinase (CPK), and glucose.
g.
Complement activation and immune complex panel will consist of serum C3, C4, total complement (CH50), C1q binding, and circulating immune 
complexes.
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Continued
h.
Viral testing will consist of viral serology for parvovirus B19 (PVB19) antibody and NAT (PVB19 PCR). If a subject’s Week 1 pre-dose sample is 
tested positive, then no further testing (eg, Week 25) is required.
i.
Urinalysis will consist of color, specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrate, leukocyte esterase, and 
microscopic examination (RBC, WBC, bacteria, casts).
j.
For females of childbearing potential only. Urine pregnancy test will be performed, unless serum pregnancy test is mandatory as specified by local 
regulatory/institutional requirements.
k.
For those subjects who are receiving or have recently been exposed to A1PI therapy at the time of study enrollment, pre-study A1PI therapy must 
be discontinued and sample for the determination of endogenous circulating A1PI level is to be taken after completion of an adequate washout 
period (approximately 4 half-lives; average half-life ~4.6 days). The screening A1PI measurement may be repeated if an exclusionary level (≥8 
µM) is obtained that is suspected to be due to inadequate washout of the prior A1PI therapy.
l.
Samples will each be split into duplicate aliquots of approximate equal volume. One of the 2 aliquots will serve as the backup sample and stored 
appropriately until notified by the sponsor.
m. Samples must be collected within 2 hours prior to BAL procedure.
n.
For subjects who have received A1PI augmentation therapy prior to study entry, plasma sample for baseline antigenic A1PI level will be collected 
within 10 days prior to the baseline BAL visit to verify the adequacy of the washout from A1PI therapy prior to performing BAL.
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20.4 Thresholds for Clinically Significant Laboratory Abnormalities
Each abnormal laboratory test result will be assessed for clinical significance by the 
investigator based on the medical judgment of the investigator. Independently, abnormal 
clinical laboratory values that meet the following criteria will be analyzed and reported.
Laboratory Test
Lowest Alert 
Limit
Highest Alert 
Limit
Comment
Hematology
Hemoglobin (Hgb)
(M) 10.0 g/dL
(F) 9.0 g/dL
----
----
Serial Hgb values allow assessment 
of the rate of decline over time
Leukocytes
2800/mm3
16,000/mm3
To be interpreted in the context of 
clinical symptoms
Absolute neutrophil count
<1000 /mm3
---
Reticulocyte count
<0.5%
>10%
To be interpreted in relation to 
changes in Hgb and other evidence 
of bone marrow suppression or 
hemolysis 
Platelet count
<50,000/mm3
>750,000/mm3
Clinical Chemistry
Sodium 
<125 mmol/L
>160 mmol/L
Serial values allow assessment of 
rate of change
Potassium
<3 mmol/L
>6 mmol/L
To be interpreted in conjunction with 
possible changes in ECG 
ALT
---
>3x ULN
AST
---
>3x ULN
ALP
---
>3x ULN
LDH
---
>3x ULN
GGT
---
>3x ULN
Bilirubin (total and 
indirect)
---
>3x ULN
Serum creatinine
---
(M) >2.0 mg/dL
(F) >1.6 mg/dL
CPK
---
>5x ULN
Glucose
<30 mg/dL
>200 mg/dL
Hyperglycemia should be interpreted 
in the context of known diabetes as a 
comorbidity
Serum albumin
<3.0 g/dL
----
May indicate protein loss, 
inflammation or malnutrition
Complement Activation and Immune Complex
Serum C3
<70 mg/dL
---
Serum C4
<14 mg/dL
---
Total complement 
(CH50)
<30 U/ml
---
C1q binding
<12 mg/dL
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Laboratory Test
Lowest Alert 
Limit
Highest Alert 
Limit
Comment
Urinalysis
Protein
---
>3+
Must be interpreted in relation to 
urinary concentration. Only valid 
when urine specific gravity is ≥1.010
RBC
---
>15/hpf or gross 
hematuria
Abbreviations:  M = Male; F = Female; Hgb = Hemoglobin; ALT = Alanine aminotransferase; ULN = 
Upper limit of normal; AST = Aspartate aminotransferase; ALP = Alkaline phosphatase; LDH = Lactic 
dehydrogenase; GGT = Gamma-glutamyl-transferase; CPK = creatine phosphokinase; C3 = Complement 
component 3; C4 = Complement component 4; CH50 = 50% hemolytic complement activity of serum; 
RBC = Red blood cell; hpf = High power field.
20.5 Bronchoscopy/Bronchoalveolar Lavage Procedure
Pre-Bronchoscopy:

Use of anticoagulants such as warfarin or heparin is to be avoided within 7 days 
prior to and during the BAL procedures.

It is critical that plasma samples for the measurement of urea, antigenic and 
functional A1PI levels be collected at the time of the lavage (or shortly before the 
procedure, not to exceed 2 hours). Plasma urea concentration, assumed to be 
equivalent to the corresponding urea concentration in the ELF, will be used to 
estimate the dilution factor in the urea-correction method for the calculation of the 
ELF analyte levels from the corresponding BAL levels.
Materials:

Continuous suction

50 to 100 mL specimen traps 

50 mL conical tubes 

Sterile normal saline solution

Bronchoscope

Sterile cotton gauze

Centrifuge

30 mL syringes for instilling of lavage fluid (5 per lobe)

10 to 30 mL syringes for aspirating lavage fluid from specimen traps, as necessary
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Procedures: 
1.
Use local anesthesia, sedation, and pre-medication per standard practice at the 
local institution. Note: Subject must not have a known history of 
allergic/hypersensitivity reactions to medications used during and for 
perioperative care associated with the BAL procedures, such as local anesthetics, 
sedatives, or pain control medications. Intravenous medication and access to the 
venous system is typically required for most conscious sedation protocols. The 
subject should be monitored for ECG, blood pressure, respiratory rate, and pulse 
oximetry during the procedure. During and after the procedure, the patient 
should have nasal O2 at a flow rate sufficient to achieve adequate arterial O2
saturation. Always bronchodilate the subject prior to local anesthesia. 
2.
Supine position for bronchoscopy is preferable.
3.
Transoral or transnasal intubation, depending on subject’s anatomy and comfort, 
may be required.
4.
The right upper lobe anterior segment, right middle lobe medial or lateral 
segments, and left superior lobe superior or inferior lingular segments generally 
yield the best lavage returns and are preferred. Avoid bronchiectatic segments. 
Whenever possible, BAL fluid should be sampled from the same lobes and 
segments of an individual for both the baseline and the on-treatment BAL 
procedures.
5.
Note any erythema, edema, friability, or secretions. Advance the bronchoscope 
until the distal lumen fills the airway to a wedge position. (This may be 
confirmed by gentle suction that causes the collapse of the airway. Take care not 
to suck too hard to prevent damage to the mucosa.)
6.
After adequate administration of conscious sedation and analgesia, the study 
subject will undergo a fiberoptic bronchoscopy with a BAL in the supine 
position. Total lavage amount should not exceed 300 mL. The bronchoscope will 
be wedged initially into 2 lobes (right upper lobe anterior segment, right middle 
lobe medial or lateral segments, and left superior lobe superior or inferior 
lingular segments are preferred). 
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7.
Each lobe should be lavaged with 5 sequential 20-mL aliquots for a total of 
100 mL per lobe (each syringe should have 5 to 10 mL of air plus saline). The 
saline should be infused quickly with no dwell time between aspiration and 
infusion. Control the suction to generate a partial but not complete collapse of 
the airway; a manual suction or a pump-suction pressure of -80 to 100 cm H2O is 
recommended. On the last aliquot, as the return from lobe begins to significantly 
decrease, have the patient take a deep breath and exhale slowly to collect the 
remaining return.
8.
Process individual BAL aliquots from each lobe separately and immediately after 
lavage:
a. Remove mucus from each sample by pouring the lavage fluid through 2 
layers of unfolded sterilized cotton gauze into a 50-mL conical tubes that 
are placed on ice.
b. Spin down the BAL aliquots at approximately 850 x g for 15 minutes to 
remove cells.
c. Harvest the supernatant from each aliquot and discard the pellet.
d. For each aliquot, the volume instilled (eg, 20 mL), the volume returned, 
and the percentage of the original volume that was recovered for each 
aliquot will be recorded. Returns of less than 20% (ie, <4 mL) or the 
presence of blood by visual inspection in any individual aliquot will be 
considered non-evaluable, and the aliquot(s) will be discarded. 
e. Combine all of the remaining acceptable aliquots (blood-free aliquots with 
≥20% [ie, ≥4 mL] recovery each) for each lobe.
f.
Calculate and record the overall percentage recovery for each lobe.
g. Divide the supernatant in duplicate samples of approximately equal volume 
and store the samples in a freezer at -70 °C or below until shipment to the 
central laboratory and until sample analysis.
9.
If the overall percent recovery is less than 20% (ie, <20 mL per lobe) or the 
overall number of acceptable aliquots (blood-free aliquots with ≥20% [ie, ≥4 
mL] recovery each) is less than 3 per lobe for one or both of the lobes, then a 
third lobe lavage should be attempted (see Figure 20-2). (In general, for A1PI
patients, overall returns are usually 20-50% of total instilled saline.)
10. After a subject completes the study, ship the BAL samples (in duplicates) on dry 
ice by overnight delivery to the central laboratory. Only evaluable BAL samples 
will be shipped for sample analyses.
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21. REFERENCE LIST
1. Alpha 1-antitrypsin deficiency: memorandum from a WHO meeting. Bull.World 
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11. Wewers MD, Casolaro MA, Sellers SE et al. Replacement therapy for alpha 1-
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22. Wewers MD, Casolaro MA, Crystal RG. Comparison of alpha-1-antitrypsin levels 
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30. Tashkin DP, Celli B, Senn S et al. A 4-year trial of tiotropium in chronic 
obstructive pulmonary disease. N.Engl.J.Med. 2008;359: 1543-1554.
31. Vijayasaratha K, Stockley RA. Relationship between frequency, length, and 
treatment outcome of exacerbations to baseline lung function and lung density in 
alpha-1 antitrypsin-deficient COPD. Int.J.Chron.Obstruct.Pulmon.Dis. 2012;7: 789-
796. Link to Publisher's Site: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3514009/pdf/copd-7-789.pdf
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22. SUMMARY OF CHANGES
Protocol Amendment 1: 2015 JAN 19
Replaces: Original: 2011 JUL 05
In this section, changes from the original version of the protocol, dated 2011 JUL 05, are 
described and their rationale is given.
1. Throughout the document
Description of Change: Editorial/grammatical and/or administrative changes that 
do not substantively affect the study conduct or patient safety have been made.
Rearrangement/modifications of sections and text have been made to align with 
the current version of the sponsor’s protocol template. Changes in the numbering 
of sections without substantial/major changes in the content will not be listed 
individually in the list of changes below.
Purpose for Change: To comply with current protocol standards and regulatory 
requirements, to improve the readability and/or clarity of the protocol, to 
minimize redundancy, to correct typos and inconsistencies, and to reflect minor 
administrative/operational changes.
2. Throughout the document
Description of Change: The study design has been revised from a single-arm, 
open-label study to reflect a 2-arm, double-blind, randomized, controlled study 
comparing GLASSIA lots with no. of particles of ≥2 micron in diameter 
representing the high end (Treatment Arm 1, 18 planned subjects) vs the low end
(Treatment Arm 2, 18 planned subjects) of the range normally observed in 
GLASSIA lots manufactured.
Purpose for Change: To comply with FDA’s request to conduct this post-
marketing commitment study as a controlled study.
3. Section 3 Synopsis, Section 6.3 Population To Be Studied, Section 9.1 Inclusion 
Criteria, Section 9.2 Exclusion Criteria, Section 9.3 Additional Section 9.3 
Additional Inclusion Criteria for Subjects Who Are to Undergo 
Bronchoscopy/BAL Procedures, and Section 9.4 Additional Exclusion Criteria for 
Subjects Who Are to Undergo Bronchoscopy/BAL Procedures
Description of Change: The target study population of subjects with severe 
congenital A1PI deficiency defined on the basis of non-augmented circulating 
A1PI level and phenotype in the original version of the protocol has been
modified to subjects with severe congenital A1PI deficiency defined on the basis 
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of endogenous A1PI level <8 µM and A1PI genotype. Additionally, subjects must 
have at least one of the following: clinical diagnosis of emphysema, evidence of 
emphysema on computerized tomography (CT) scan of the chest within 52 weeks 
of screening, and/or evidence of airway obstruction which is not completely 
reversed with bronchodilator treatment at the time of screening (see inclusion 
criterion #4). Unless being exempted from the bronchoscopy/BAL procedures, 
subjects must have post-bronchodilator forced expiratory volume in one second 
(FEV1) ≥50%; and, if subject’s FEV1 is >80% of predicted, then subject must 
have FEV1/forced vital capacity (FVC) <0.7 and/or DLCO between 30% and 65% 
predicted at screening. Additional exclusion criteria pertinent to 
bronchoscopy/BAL procedures have also been included (see item 11 below for 
detailed descriptions).
Purpose for Change: The subject eligibility criteria have been revised to reflect 
the intended patient population for which GLASSIA is indicated (ie, subjects with 
emphysema due to severe congenital deficiency of A1PI), in order to more 
appropriately evaluate the effects of GLASSIA augmentation therapy on A1PI 
levels in the target (lung) tissue. In addition, given that bronchoalveolar lavage 
return tends to be poorer in subjects with severe emphysema, the pulmonary 
function criterion has been revised to exclude subjects with severe emphysema 
but to enroll only subjects with mild to moderate emphysema.
4. Section 3 Synopsis, Section 7 Study Purpose and Objectives, Section 8.4 
Outcome Measures, Section 13.4 Methods of Analysis, and Section 20.3 Schedule 
of Clinical Laboratory Assessments
Description of Change: The study objective and outcome measure sections have 
been re-arranged into primary, secondary, and exploratory categories. The safety 
outcome measures have been streamlined and re-ordered, such that the primary 
endpoints would focus on pertinent safety endpoints that are perceived to be 
associated with protein aggregates or visible/subvisible particles in therapeutic 
protein products. The immunogenicity endpoint has been revised to “Number 
(proportion) of subjects who develop binding and/or neutralizing anti-A1PI”. The 
other safety endpoints, such as treatment-emergent AEs, clinically significant 
shift in laboratory test abnormalities, and B19V seroconversion, are moved to 
secondary outcome measures. ELF antigenic A1PI level and now with the 
addition of ELF functional A1PI level serve as primary “efficacy” endpoints of 
the study, whereas plasma trough antigenic and functional A1PI levels are 
removed as study endpoints.
 
 
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Purpose for Change: (i) To re-classify study objectives and outcome measures as 
primary, secondary, and exploratory in alignment with the sponsor’s protocol 
template. (ii) To consolidate safety outcome measures with improved 
clarity/readability, and to reflect the hierarchical order of study endpoints by their 
relevance in accordance with FDA’s recommendations. (iii) To specify AEs of 
interest for the evaluation of possible association of GLASSIA’s safety profile to 
protein aggregates present in GLASSIA solution. (iv) To explicitly state that both 
binding and inhibitory (neutralizing) anti-A1PI antibodies will be monitored as a 
safety endpoint of the study. (v) To remove plasma antigenic and functional A1PI 
levels as study endpoints. (vi) 
5. Section 3 Synopsis, and Section 8 Study Design
Description of Change: Text has been revised to reflect an increase in target BAL 
evaluable subjects from 12 to at least 15-18, and that “(s)ubjects will be required 
to undergo bronchoscopy/bronchoalveolar lavage (BAL) procedures at baseline 
and during augmentation therapy to collect BAL samples for the evaluation of the 
effects of GLASSIA augmentation therapy on the levels of A1PI and 
 
 in the ELF. Once the target of 15 to 18 evaluable subjects is reached, 
the remaining subjects to be enrolled will be waived from the baseline and 
on-treatment bronchoscopy/BAL procedures. … Enrollment will be closed when 
both conditions are met: 
(a) At least 15 evaluable subjects with acceptable BAL samples collected 
     from both the baseline and on-treatment BAL visits have been achieved
(b) A minimum of 36 subjects have been randomized.”
Purpose for Change: The target number of BAL evaluable subjects is increased 
from 12 to at least 15-18 per FDA’s request. The increase in the BAL sample size 
should in theory increase the power to detect the effect of GLASSIA 
augmentation therapy in elevating antigenic and functional A1PI levels in the 
ELF. Based on the past experience from a similar study, it is estimated that 
approximately 26 to 32 subjects will be needed in order to achieve 15 to 18 BAL 
evaluable subjects, respectively. Thus, an overall study enrollment target of 36 
subjects remains unchanged as this should be adequate to meet the target number
of BAL evaluable subjects. If for any reasons the target of at least 15 evaluable 
subjects have not been attained with the initial 36 randomized subjects, additional 
subjects will be enrolled to achieve the BAL enrollment target. Text has been 
added to reflect that both conditions must be met in order for enrollment to be 
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considered completed. Additionally, in order to ensure that the BAL enrollment 
target will be met and given that the majority of the study subjects are expected to 
be needed, the BAL component of the study has been revised to become an 
integral part of the study (rather than as an optional sub-study) and that all 
subjects will be required to undergo bronchoscopy/BAL procedures (unless 
waived by the sponsor once the target of at least 15 BAL evaluable subjects has 
been reached).
6. Section 3 Synopsis, Section 8.2 Study Design, Section 8.3 Duration of Study 
Period(s) and Subject Participation, Section 20.2 Schedule of Study Procedures 
and Assessments, and Section 20.3 Schedule of Clinical Laboratory Assessments
Description of Change: A separate baseline visit (prior to randomization, with a 
minimum of 2 days for recovery from bronchoscopy/BAL procedure prior to the 
first IP infusion) has been specified for subjects undergoing bronchoscopy/BAL 
procedures. The post-treatment safety follow-up period has been changed from 4 
weeks to 1 week, thus the study completion visit is planned to take place during 
Week 26 (± 3 days).
Purpose for Change: To allow adequate time interval for subjects to recover from 
the BAL procedure prior to the first IP infusion, and to shorten the in-study post-
treatment safety follow-up period to 1 week which is adequate and which allows 
the subjects to be maintained on their own A1PI therapy without much 
interruption after completing the study. 
7. Section 3 Synopsis, Section 8.2 Study Design, Section 10.3.2.1 Preparation and 
Storage of Pooled IP Solutions, and Section 20.2 Schedule of Study Procedures 
and Assessments
Description of Change: Revisions have been made to stipulate that subject’s body 
weight is to be measured at 6-weeks intervals (ie, during Weeks 1, 7, 13, 19, and 
25. Dose (mg) adjustments due to changes in body weight are not planned, 
however, dose (mg) may be adjusted if deemed medically necessary at the 
discretion of the investigator (e.g., clinically significant body weight changes).
Purpose for Change: To add provision for dose (mg) adjustment if deemed 
medically necessary.
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8. Section 3 Synopsis, Section 8.2 Study Design, Section 10.3.2.2 IP Administration, 
and Section 20.2 Schedule of Study Procedures and Assessments
Description of Change: Revisions have been made to stipulate that GLASSIA 
infusion is to be administered at the study site during the Week 13 and Week 25 
visits.
Purpose for Change: To provide additional safety monitoring and to facilitate 
prompt AE reporting by requiring additional on-site study product infusions.
9. Section 3 Synopsis, Section 9.1 Inclusion Criteria, Section 9.2 Exclusion Criteria, 
Section 9.3 Additional Inclusion Criteria for Subjects Who Are to Undergo 
Bronchoscopy/BAL Procedures, and Section 9.4 Additional Exclusion Criteria for 
Subjects Who Are to Undergo Bronchoscopy/BAL Procedures
Description of Change: 
Original Protocol
Protocol Amendment 1
Reason for Change
9.1 Inclusion Criteria
1. Signed and dated informed 
consent
Deleted
Not applicable; informed 
consent should have been 
obtained prior to screening 
for eligibility.
4. Phenotype Pi Z (which includes 
Pi*Z/Z, Pi*Z/Null, or 
Pi*Malton/Z), or Pi*Null/Null
2. A1PI genotype of Pi*Z/Z, 
Pi*Z/Null, Pi*Malton/Z, or 
Pi*Null/Null.
To ensure the target A1PI-
deficient patients are 
enrolled.
--
4. Subject must have at least one of 
the following: clinical diagnosis 
of emphysema, evidence of 
emphysema on computerized 
tomography (CT) scan of the 
chest within 52 weeks of 
screening, and/or evidence of 
airway obstruction which is not 
completely reversed with 
bronchodilator treatment at the 
time of screening.
The subject eligibility 
criteria has been revised to 
reflect the intended patient 
population that GLASSIA 
is indicated for (ie, subjects 
with emphysema due to 
severe congenital 
deficiency of A1PI) in order 
to more appropriately 
evaluate the effects of 
GLASSIA augmentation 
therapy on A1PI levels in 
the target (lung) tissue.
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Original Protocol
Protocol Amendment 1
Reason for Change
6. No clinically significant 
abnormalities (other than 
emphysema, bronchitis or 
bronchiectasis) detected on chest 
X-ray (CXR) at the time of 
screening (CXR previously 
obtained within the past 6 months 
may be used, if available).
6. No clinically significant 
abnormalities (other than 
emphysema, and chronic 
bronchitis) detected on chest X-
ray (CXR) at the time of 
screening (chest X-ray or CT 
scan obtained within 52 weeks
prior to screening may be used, 
if available).
To clarify that a patient 
with bronchiectasis will not 
be eligible.
To allow the use of past CT 
scan of the chest be used for 
eligibility determination.
To increase the time period 
allowable for the past 
records of chest x-ray or CT 
scan from 6 to 12 months.
8. If the subject is treated with any 
respiratory medications including 
inhaled bronchodilators, inhaled 
corticosteroids, or systemic 
corticosteroids (prednisone ≤ 
10mg/day or its equivalent), the 
doses of the subject’s medications 
are unchanged for at least 14 days 
prior to screening.
7. If the subject is being treated 
with any respiratory medications 
including inhaled 
bronchodilators, inhaled 
anticholinergics, inhaled 
corticosteroids, or low-dose 
systemic corticosteroids 
(prednisone ≤10 mg/day or its 
equivalent), the doses of the 
subject’s medications have 
remained unchanged for at least 
14 days prior to screening
To add inhaled 
anticholinergics.
7. Laboratory results obtained at the 
screening visit, meeting the 
following criteria:
a) Serum alanine 
aminotransferase (ALT) ≤ 3 times 
upper limit of normal (ULN)
b) Serum total bilirubin ≤ 2 
times ULN
c) ≤ +2 proteinuria on dipstick 
analysis
d) Serum creatinine ≤ 2.0 times 
ULN
e) Absolute neutrophil count 
(ANC) > 1500 cells/µL
f)
Hemoglobin (Hgb) ≥ 9.0 g/dL
g) Platelet count ≥ 100,000/µL
Under Exclusion Criteria:
12. Abnormal clinical laboratory 
results obtained at the time of 
screening meeting the 
following criteria:
a. Serum alanine 
aminotransferase (ALT) >3.0 
times upper limit of normal 
(ULN)
b. Serum total bilirubin >2.0 
times ULN
c. >2+ proteinuria on urine
dipstick analysis
d. Serum creatinine >2.0 times 
ULN
e. Absolute neutrophil count 
(ANC) <1500 cells/mm3
f. Hemoglobin (Hgb) <9.0 
g/dL
g. Platelet count 
<100,000/mm3
This eligibility criterion is 
moved to Section 9.2
Exclusion Criteria (#12), 
and to specify proteinuria is 
to be tested with urine 
dipstick method.
--
9. The subject is willing and able to 
comply with the requirements of 
the protocol.
New criterion added to 
comply with current 
protocol standards.
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Original Protocol
Protocol Amendment 1
Reason for Change
Section 9.2 Exclusion Criteria
--
1. The subject is experiencing or 
has a history of clinically 
significant pulmonary 
impairment other than chronic 
obstructive pulmonary disease 
(COPD)/emphysema and/or 
chronic bronchitis.
New exclusion criteria (#1, 
#2, #6, #7, #9, #10) added 
to better define target 
patient population for 
participation in this study –
to exclude conditions that 
may pose increased risk to 
the subject’s safety, impede 
the subject’s ability to 
comply with the study 
procedures (eg, BAL), or 
confound the interpretation 
of study results. 
--
2. The subject is experiencing or 
has a history of cor pulmonale.
--
6. The subject has clinically 
significant congestive heart 
failure, with New York Heart 
Association (NYHA) Class 
III/IV symptoms.
--
7. The subject is experiencing an 
active malignancy or has a 
history of malignancy within 5 
years prior to screening, with the 
exception of the following: 
adequately treated basal cell or 
squamous cell carcinoma of the 
skin, carcinoma in situ of the 
cervix, or stable prostate cancer 
not requiring treatment.
--
9. The subject is receiving long-
term oxygen supplementation 
(other than on a short-term basis
for acute COPD exacerbation, or 
supplemental O2 with 
continuous positive airway 
pressure [CPAP], or bi-level 
positive airway pressure 
[BiPAP]).
--
10. Known history of 
hypersensitivity following 
infusions of human blood or 
blood components.
--
16. The subject is a family member 
or employee of the investigator.
New criterion added to 
comply with current 
protocol standards.
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Original Protocol
Protocol Amendment 1
Reason for Change
Under additional eligibility criteria 
for the BAL component of the study:
3. History of frequent exacerbations 
(greater than 2 moderate or severe 
exacerbations in the 12 months 
preceding the signing of the 
informed consent
Under exclusion criteria:
4. The subject has a history of 
frequent pulmonary 
exacerbations (greater than 2 
moderate or severe 
exacerbations within 52 weeks
prior to screening).
Original additional 
exclusion criteria #2 and #3 
for BAL sub-study were 
moved to Section 9.2 as 
Exclusion criteria #4 and 
#5. Original additional 
exclusion criteria #5 for 
BAL sub-study were moved 
to Section 9.2 and 
consolidated with original 
Exclusion Criterion #5 as 
the new Exclusion criterion 
#8, given that these criteria 
apply to all subjects being 
screened for study 
eligibility, not only for 
BAL sub-study.
2. Presence of clinical symptoms of 
any lower respiratory tract 
infection (LRTI) or acute 
pulmonary exacerbation (APE) 
within 4 weeks prior to screening
5. The subject is experiencing a 
pulmonary exacerbation at the 
time of screening (subject may 
be re-screened 4 weeks after the 
clinical resolution of an 
exacerbation).
5. History of lung transplant/lung 
resection
8. The subject has a history of lung 
or any other organ transplant, is 
currently on a transplant list, or 
has undergone major lung 
surgery.
Section 9.3 Additional Inclusion Criterion for Subjects Who Are to Undergo Bronchoscopy/BAL
Procedures
Under exclusion criteria:
Subjects who meet ANY of the 
following criteria are not eligible for 
the BAL component of the study:
1. FEV1 < 40% predicted (post 
bronchodilator)
1. The subject must have 
pulmonary functions at 
screening meeting both of the 
following:
a. Post-bronchodilator forced 
expiratory volume in 1 second 
(FEV1) ≥50%
b. If FEV1 is >80% predicted, 
then FEV1/forced vital 
capacity (FVC) must be <0.7 
and/or DLCO must be ≥30% 
and ≤65% predicted.
Given that bronchoalveolar 
lavage return tends to be 
poorer in subjects with 
severe emphysema, the 
qualifying lung functions 
have been modified to 
exclude subjects with 
severe emphysema but to 
enroll subjects with mild to 
moderate emphysema.
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Original Protocol
Protocol Amendment 1
Reason for Change
Section 9.4 Additional Exclusion Criteria for Subjects Who Are to Undergo Bronchoscopy/BAL 
Procedures
Under exclusion criteria:
Subjects who meet ANY of the 
following criteria are not eligible for 
the BAL component of the study:
4. Inability to undergo bronchoscopy 
(prior history of adverse reaction 
to local anesthetics, sedatives, 
pain control medications, and 
other medications employed at the 
study site for perioperative care 
associated with the BAL 
procedure)
1. The subject has 
contraindication(s) to 
bronchoscopy or high risk 
factors, such as recent 
myocardial infarction, active 
myocardial ischemia, other 
cardiopulmonary instability, 
tracheal obstruction or stenosis, 
moderate to severe hypoxemia 
or any degree of hypercapnia, 
unstable asthma, uremia, 
pulmonary hypertension, severe 
hemorrhagic diathesis, and 
cervical C1/C2 arthritis.
To add/clarify exclusionary 
conditions that are 
contraindications to 
bronchoscopy and/or may 
pose increased risk to the 
subject’s safety.
--
3. Known history of 
allergic/hypersensitivity 
reactions to medications used 
during and for perioperative 
care associated with the BAL 
procedures, such as local 
anesthetics, sedatives, pain 
control medications
--
4. If the subject is receiving or 
requires long-term (>4 weeks) 
immunosuppressive therapy, 
such as systemic corticosteroids 
at doses greater than 10 mg/day 
of prednisone (or its equivalent), 
mycophenolate mofetil, 
azathioprine, 
cyclophosphamide, and 
rituximab.
Purpose for Change: See column “Reason for change” in the table above.
10. Section 3 Synopsis and Section 10.4 COPD Exacerbation and Lower Respiratory 
Tract Infection (LRTI)
Description of Change: The following text has been modified from “A moderate 
or severe acute pulmonary exacerbation (APE)* or lower respiratory tract 
infection (LRTI) occurring within 4 weeks of any of the scheduled BAL visits will 
result in postponement of the respective visit until any pulmonary exacerbation 
and/or LRTI symptoms are no longer clinically evident for a minimum of 4 weeks. 
A moderate or severe acute pulmonary exacerbation or lower respiratory tract 
infection will not affect the study start or visit schedule of subjects who are not 
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enrolled in the BAL substudy.” to “If a subject experiences a moderate or severe 
COPD exacerbation and/or LRTI during the screening period, baseline BAL visit 
will be postponed once in order for the subject to recover from the exacerbation 
(ie, any signs and symptoms of the COPD exacerbation and/or LRTI are no 
longer clinically evident) and remain stable for at least 4 weeks after the end of 
exacerbation. If a moderate or severe episode of COPD exacerbation and/or 
LRTI occurs during the treatment phase, the subject should continue with the 
planned study visits and to receive weekly infusions of GLASSIA as planned, 
unless deemed medically inappropriate by the investigator. However, the on-
treatment BAL visit will be postponed until clinical resolution of the exacerbation 
(ie, any signs and symptoms of the COPD exacerbation and/or LRTI are no 
longer clinically evident) plus an additional minimum period of 4 weeks after the 
end of exacerbation.” In addition, definitions of onset and end of COPD 
exacerbation, as well as a diagrammatic presentation illustrating the duration of an 
episode of COPD exacerbation, are provided in Section 10.4.
Purpose for Change: To clarify that planned study and infusion visits are to be 
conducted as scheduled during an episode of moderate or severe COPD 
exacerbation and/or LRTI. The only study procedure that will be postponed due to 
occurrence of COPD exacerbation is the bronchoscopy/BAL procedure. In this 
event, subjects must have recovered from the COPD exacerbation and/or LRTI 
(ie, any signs and symptoms of the COPD exacerbation and/or LRTI are no longer 
clinically evident) and remained stable (no recurrence of COPD exacerbation 
and/or LRTI) for at least 4 weeks after the end of the exacerbation.
11. Section 6 Background Information
Description of Change: (i) New paragraphs (5th, 6th, 7th, and 8th) have been added 
to provide more detailed explanation why this study is being conducted. (ii) The 
paragraph beginning with “The primary purpose of this clinical study…” in the 
original version of the protocol is revised to align with the primary and secondary 
goals of this study. (iii) The last paragraph in the original version of the protocol 
has been deleted, as the information related to the infusion rate of 0.2 mL/kg/min 
is now available in the GLASSIA package insert (March 2014 version). (iv) New 
sub-sections have been added: Section 6.1.1 Rationale for the Selection of Dosing 
Regimen and Section 6.1.2 Rationale for the Selection of Route of Administration 
and Infusion Rate. (v) Added clinical immunogenicity data from the pivotal Ph 
II/III study that recently become available.
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Purpose for Change: (i) Added new paragraphs to provide more detailed 
background information explaining why this study is being conducted. (ii) Made 
editorial changes to align with the addition of the new paragraphs and to improve 
readability. (iii) Deleted paragraph to remove outdated information and replace
with the appropriate reference. (iv) Added sub-sections to provide the rationale 
underlying the selected dosing regimen, route of administration, and infusion rate.
(v) To provide new safety (immunogenicity) information.
12. Section 6.4 Findings from Nonclinical and Clinical Studies
Description of Change: A new section (Section 6.4 Summary of Nonclinical Data) 
has been added and all references to IB have been deleted throughout the 
protocol.
Purpose for Change: Given that the study population is an approved indication for 
GLASSIA and there is no new clinical and human safety information in 
GLASSIA IB that is not presented in the package insert (Mar 2014), it is decided 
that GLASSIA package insert with supplementary information being provided 
within the study protocol (eg, findings from nonclinical studies) should suffice.
13. Section 8.5 Randomization and Blinding
Description of Change: The text “This is an open-label, active treatment clinical 
study.” is replaced with “This is a 2-arm, double-blind, randomized, controlled 
clinical study. In order to minimize/avoid bias, subjects meeting eligibility criteria 
will be randomly assigned to 1 of 2 treatment arms at a ratio of 1:1 (for those 
undergoing bronchoscopy/BAL procedures, randomization is to take place only 
after the subject has successfully completed the baseline BAL visit with evaluable 
BAL samples collected). Randomization codes will be maintained by an 
Interactive Response Technology (IRT) via an Interactive Web Response System 
(IWRS).”
A new section (Section 8.5.1 Unblinding Procedures at Study Sites) is added.
Purpose for Change: To update the description of the measures taken to 
avoid/minimize bias, the methods for maintaining randomization codes, and the 
unblinding procedures.
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14. Section 8.7.3 Description of Treatment, Section 10.3.2 Infusion Visits, 
Section 20.2 Schedule of Study Procedures and Assessments, and Section 20.3 
Schedule of Clinical Laboratory Assessments
Description of Change: Infusion visit window has been revised from ± 1 week to 
± 2 days. Accordingly, clinic visit window (Weeks 7, 13, 19, 20, and 25) has also 
been updated to ± 2 days.
Purpose for Change: To ensure that sufficient time is allowed in between two 
consecutive infusions (ie, no overlapping infusions on the same day or within 
close temporal proximity).
15. Section 8.8 Source Data
Description of Change: A new section has been added to clearly define Source 
Data in clinical study protocols.
Purpose for Change: To comply with current protocol standards and ICH GCP 
requirements.
16. Section 9.5 Withdrawal and Discontinuation
Description of Change: The reasons for withdrawal from study treatment or 
discontinuation from the study have been updated: 
(i) To add further details that include actions to be taken for those events 
involving subjects who become pregnant or who begin nursing during the study. 
(ii) To consolidate and provide additional examples of major protocol deviations 
that will result in discontinuation from further study treatment or participation.
(iii) To clarify that subjects who do not meet BAL evaluable criteria at the 
baseline BAL visit will not be randomized and will be discontinued from the 
study. Subjects who had successfully completed the baseline BAL visit but do not 
meet BAL evaluable criteria during the on-treatment BAL visit will continue to 
complete the remaining infusion visits (to collect safety and immunogenicity data) 
through study completion visit. These subjects will not be counted toward the 
target of 15 to 18 evaluable subjects, thus additional subjects will need to be 
enrolled.
Purpose for Change: To improve clarity and to improve the integrity of the study.
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17. Section 10.3 Screening and Study Visits
Description of Change: Previous by-study visit sections (Sections 10.3.1 through 
10.3.8 in the original version of the protocol) have been deleted and reorganized 
as follows: 
Section 10.3.1 Screening Visit, with sub-sections:
Section 10.3.1.1 Confirmation of Severe Congenital A1PI Deficiency
Section 10.3.1.2 Pulmonary Function Tests
Section 10.3.1.3 Rescreening
Section 10.3.2 Infusion Visits, with sub-sections:
Section 10.3.2.1 IP Administration
Section 10.3.2.3 Management of Treatment-Emergent (S)AEs
Section 10.3.2.4 Pre-Medications
Section 10.3.2.5 Post-Infusion Follow-Up
Section 10.3.3 Clinical Assessment Visits
Section 10.3.4 BAL Visits
Purpose for Change: Section 10.3 has been reorganized to minimize redundancy, 
since study procedures, study visits, and the timing of assessments have already
been provided in tabular form in Section 20.2 Schedule of Study Procedures and 
Assessments, and Section 20.3 Schedule of Clinical Laboratory Assessments. 
New sections have been added to highlight important aspects of the study conduct 
and to provide supplemental information.
18. Section 10.3.1 Screening Visit
Description of Change: Text has been added as follows:
“Additionally, for subjects who are to undergo BAL assessments in the study, 
randomization is to take place after the subject has met all eligibility criteria 
(including those listed in Section 9.3 and Section 9.4) and successfully undergone 
the baseline BAL visit with evaluable BAL samples collected.”
Purpose for Change: To improve clarity regarding the timing of randomization.
19. Section 10.3.2.1 IP Administration
Description of Change: Text has been added to specify alert values for vital signs
to be collected during each IP infusion visit that, when met, the investigator 
should be contacted to determine appropriate action to be taken, as necessary (eg, 
if prior to infusion, whether the infusion should be administered).
Purpose for Change: To increase the level of safety monitoring by the 
investigator, given that an infusion may be taken place at a location outside of the 
study site.
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20. Section 10.3.2.2 Management of Treatment-Emergent (S)AEs
Description of Change: The section has been expanded to include measures to be 
taken, including medical interventions as applicable, reduction of infusion rate 
and/or interruption/discontinuation of study drug infusions, should the following 
develop during investigational product administration:
- Severe non-serious AEs or SAEs
- Life-threatening SAEs
- Moderate-to-severe hypersensitivity reactions
- Minor/major rashes 
Purpose for Change: To provide specific guidelines for handling infusion 
associated (S)AEs.
21. Section 10.3.2.4 Post-Infusion Follow-Up, and Section 20.2 Schedule of Study 
Procedures and Assessments
Description of Change: New study procedure added that requires the 
investigator/designee to contact the subject at or after 72 hours following each 
infusion visit via a telephone call.
Purpose for Change: To facilitate the monitoring and recording of adverse events, 
as well as any changes to the use of concomitant medications and/or non-drug 
therapies, that occur within 72 hours following each study product administration.
22. Section 10.3.4 BAL Visits, Section 20.2 Schedule of Study Procedures and 
Assessments, and Section 20.3 Schedule of Clinical Laboratory Assessments
Description of Change: The timing and windows of the baseline and on-treatment 
BAL procedures have been revised, as follows:
- Baseline bronchoscopy/BAL procedure: A minimum of 2 days prior to the 
  first IP infusion
- On-treatment BAL procedure: between Week 12 to Week 14 with at least 3 
   days after the last IP infusion but with a minimum of 2 days prior to the 
   next IP infusion
Purpose for Change: To allow subjects sufficient time to recover from the 
bronchoscopy/BAL procedures prior to the first/next IP infusion.
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23. Section 10.3.4 BAL Visits, Section 12.8 Plasma Antigenic and Functional A1PI 
Levels, and Section 20.3 Schedule of Clinical Laboratory Assessments
Description of Change: The following text has been added:
“For subjects who have received A1PI augmentation therapy prior to study entry, 
plasma sample for baseline antigenic A1PI level will be collected within 10 days 
prior to the baseline BAL visit to verify the adequacy of the washout from A1PI 
therapy prior to performing BAL.”
Purpose for Change: To add repeat measurement of baseline antigenic A1PI level 
in plasma prior to the baseline BAL visit per FDA request.
24. Section 10.4 COPD Exacerbation and Lower Respiratory Tract Infection (LRTI)
Description of Change: Added the definitions of onset and end of COPD 
exacerbation, as well as a diagrammatic presentation illustrating the duration of an 
episode of COPD exacerbation (Figure 10-1).
Purpose for Change: To improve clarity.
25. Section 10.5 Medications and Non-Drug Therapies
Description of Change: (i) In addition to any A1PI augmentation therapy other 
than IP, the list of prohibited medications has been updated to include: 
commercially available GLASSIA, and any investigational drug, biologic, or 
device other than IP that are not permitted at any time during the study. (ii) 
Immunosuppressive therapies and anticoagulants have been added as medications 
that are not permitted within 4 weeks and 7 days, respectively, prior to and during 
the BAL procedures. An exception will be rituximab which is not permitted at any 
time throughout the study, given the long pharmacokinetic and pharmacodynamic 
half-life of the biologic. (iii) Text has been added to indicate certain medications 
(eg, inhaled bronchodilators/anticholinergics/corticosteroids, low-dose systemic 
corticosteroids, and theophylline) that a subject is taking for a pre-existing 
medical condition are permitted during the study, provided that stable dosages are 
to be maintained throughout the study.
Purpose for Change: To provide more detailed information on prohibited and 
allowed medications.
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26. Section 10.6 Subject Completion/Discontinuation, Section 12.7 Clinical 
Laboratory Parameters, Section 20.2 Schedule of Study Procedures and 
Assessments, and Section 20.3 Schedule of Clinical Laboratory Assessments
Description of Change: Text has been added to specify that subjects who are 
discontinued early from the study prior to receiving any IP administration will not 
need to undergo early termination procedures, except for those subjects who have 
undergone baseline bronchoscopy/BAL procedure (in which case subjects will be 
followed for potential post-BAL complications for a period of time in accordance 
with local institutional standard practice but not to exceed 30 days).
Purpose for Change: To improve clarity related to early termination procedures.
27. Section 10.7 Procedures for Monitoring Subject Compliance
Description of Change: Added trough antigenic and functional A1PI in plasma as 
a measure of subject’s compliance/adherence to treatment.
Purpose for Change: To state the purpose behind sample collection and analysis 
for plasma A1PI levels.
28. Section 11 Assessments of Efficacy
Description of Change: Section 11.1 Plasma Antigenic and Functional A1PI 
Levels in the original version of the protocol has been deleted.
Purpose for Change: To be consistent with the removal of plasma antigenic and 
functional A1PI levels as efficacy outcome measures.
29. Section 11 Assessments of Efficacy
Description of Change: Detailed BAL procedures outlined in Section 11.2 
Antigenic and Functional A1PI in the ELF, including the BAL Procedural Flow 
Chart, in the original version of the protocol has been moved to Section 20.5 
Bronchoscopy/Bronchoalveolar Lavage Procedure.
Purpose for Change: To improve readability.
30. Section 11.2 
Description of Change: Added new section.
Purpose for Change: Section inadvertently omitted in the previous version of the 
protocol.
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31. Section 12.1.1.1 Serious Adverse Event
Description of Change: The following text has been added:
“Uncomplicated pregnancies, following maternal or paternal exposure to the IP 
are not considered an (S)AE; however, any pregnancy complication or pregnancy 
termination by therapeutic, elective, or spontaneous abortion shall be considered 
an SAE.”
Purpose for Change: To comply with current protocol standards.
32. Section 12.1.1.3 Adverse Reactions Plus Suspected Adverse Reactions
Description of Change: A new section has been added to provide definition of 
adverse reactions, as follows: 
“An AR plus suspected AR is any adverse event which met any of the following 
criteria:
(a) an adverse event that began during infusion or within 72 hours following 
the end of IP infusion, or
(b) an adverse event considered by either the investigator and/or the sponsor 
to be possibly or probably related to IP administration, or 
(c) an adverse event for which causality assessment was missing or 
indeterminate.
In addition, safety data will also be analyzed for any ARs plus suspected ARs 
which met any of the following criteria:
(a) an adverse event that began during infusion or within 24 hours following 
the end of IP infusion, or
(b) an adverse event considered by either the investigator and/or the sponsor 
to be possibly or probably related to IP administration, or 
(c) an adverse event for which causality assessment was missing or 
indeterminate.”
Purpose for Change: To provide definition of adverse reactions for safety analysis 
in accordance with FDA’s request.
33. Section 12.1.1.4 Unexpected Adverse Events
Description of Change: The following text has been added:
“Any AEs (expected and unexpected) will be recorded on the AE CRF.”
Purpose for Change: To improve clarity.
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34. Section 12.1.1.5 Adverse Events Potentially Associated with Protein Aggregates
Description of Change: New section added to indicate that the safety data 
collected in this study will be reviewed and assessed for potential association with 
protein aggregates in the GLASSIA solution. Listing of AEs of interest by 
treatment arm will be provided in the clinical study report. Examples of potential 
AEs of interest were removed from safety endpoint section.
Purpose for Change: To improve readability.
35. Section 12.2 Urgent Safety Measures
Description of Change: A new section has been added.
Purpose for Change: To explicitly define and provide examples of urgent safety 
measures that should be taken immediately with or without prior authorization 
from the sponsor in order to protect subjects against immediate hazard to their 
health or safety.
36. Section 12.3 Untoward Medical Occurrences
Description of Change: The following text has been added:
“For the purposes of this study, each non-serious untoward medical occurrence 
experienced by a subject undergoing study-related procedure(s) (eg, washout of a 
subject’s pre-study A1PI augmentation therapy, bronchoscopy/BAL procedures) 
will be recorded on the AE CRF. These events, if occurred before the first IP 
exposure, will not be considered as AEs and will not be included in the analysis of 
AEs. On the other hand, these events, if occurred after initiation of IP treatment, 
will be considered as AEs and will be included in the analysis of AEs.”
Purpose for Change: To make a revision such that procedure-related untoward 
medical occurrences, whether expected or unexpected, will all be captured and 
analyzed as AEs if occurring after IP exposure.
37. Section 12.4 Non-Medical Complaints
Description of Change: A new section has been added.
Purpose for Change: To comply with current protocol standards, and to specify a 
requirement for the site to report any non-medical complaints.
38. Section 12.7.1 Hematology and Clinical Chemistry, Section 12.7.2 Complement 
Activation and Immune Complex Panel, Section 12.7.3 Viral Serology and 
Nucleic Acid Tests, Section `12.7.4 Urine Tests, Section 12.8 Plasma Antigenic 
and Functional A1PI Levels, Section 12.9 Immunogenicity, Section 20.2 
Schedule of Study Procedures and Assessment, and Section 20.3 Schedule of 
Clinical Laboratory Assessments
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Description of Change: The following time points have been modified to clinical 
laboratory assessments:
For all subjects:
(a) Hematology, Clinical Chemistry, Urinalysis – Added to Week 26 (study 
completion visit)
(b) Complement Activation and Immune Complex Panel – Deleted from 
screening visit (as this is not part of eligibility determination), and added to 
Week 26 (study completion visit).
(c) Viral testing for HAV, HBV, HCV, and HIV-1/2 - Only serology testing will 
be performed and only at screening to support eligibility determination; NAT at 
baseline and study completion/early termination are no longer required per FDA’s 
communication.
(d) Viral testing for B19V – Both viral serology and NAT will be performed.
Instead of screening, baseline B19V viral testing will be performed prior to the 
first IP infusion during Week 1, prior to the last infusion during Week 25, and at 
study completion/early termination.
(e) Serum anti-A1PI antibodies– Added to the Week 13 and Week 25 visits
(f) Pregnancy test – Clarified that, while urine pregnancy test will be the default 
test to be performed, serum pregnancy test may be performed if specified by local 
regulatory/institutional requirements.
For those subjects undergoing bronchoscopy/BAL procedures:
(a) Plasma antigenic and functional A1PI – Added to baseline and on-treatment 
BAL visits to be collected at the same time as plasma urea samples
(b)
 
Purpose for Change: To enhance the ability to detect and/or evaluate treatment-
emergent incidences of immunogenicity, hypersensitivity reactions, or other 
potentially immune-mediated AEs, if any, that may be associated with residual 
protein aggregates present in GLASSIA infusion solution despite the use of a 5-
micron inline filter, and to better characterize the time course of such events by 
stipulating clinical laboratory assessments at baseline, at 3-month intervals during 
treatment, and after a 1-week post-treatment safety follow-up period.
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39. Section 12.7.6 Biobanking
Description of Change: A new section has been added to explicitly state that 
plasma samples for A1PI and urea, serum samples for anti-A1PI antibodies, and 
BAL samples for antigenic and functional A1PI, urea as well as other 
 
should be divided and stored as duplicate aliquots, such that one 
of the aliquots will serve as back up samples.
Purpose for Change: To ensure back up aliquots will be collected.
40. Section 12.10 Vital Signs
Description of Change: The frequency of infusion visit vital sign measurements 
has been adjusted from “…at screening and within 30 minutes before and after … 
each administration of IP and at each study visit.” to “ at screening, during 
treatment period (Weeks 1, 7, 13, 19, and 25), and at study completion (Week 
26)/early termination visit. … For each of the IP infusion visits where vital signs 
are to be taken, vital signs will be recorded at any time prior to the start of an 
infusion, at each rate reduction due to AE(s) and/or infusion 
interruption/discontinuation due to AE(s), and within 90 minutes after the 
completion of an infusion.”
Purpose for Change: To reduce the burden on site, infusion nurse, and subject, 
given that GLASSIA is safe and well tolerated even at the higher infusion rate of 
0.2 mL/kg/min. 
41. Section 3 Synopsis, and Section 13.1 Sample Size and Power Calculations
Description of Change: Text has been revised to the following: 
“Using this variance estimate, a sample size of 15 evaluable subjects should be 
sufficient to detect a mean difference in the natural log transformed ELF antigenic 
A1PI of approximately 0.87 with 90% power, using a paired t-test and a one-sided 
significance level of 0.025.”
Additionally, similar sample size and power calculations have been performed 
based on functional A1PI levels in ELF, as follows: 
“A sample size of 15 evaluable subjects will also be sufficient to detect a mean 
difference in the natural log transformed ELF functional A1PI (ANEC) of 
approximately 1.04, with 90% power, assuming a standard deviation in the 
differences between pre- and post-treatment ANEC values to be 20% higher than 
that for antigenic A1PI.”
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Purpose for Change: (i) To update power calculations on the basis of change from 
baseline in ELF antigenic A1PI levels, in light of the increase in BAL target from 
12 to 15 evaluable subjects. This increase in the number of BAL evaluable 
subjects should have 90% power to detect a smaller treatment effect (a mean 
treatment difference from approximately 1.0 to 0.87). (ii) To add power 
calculations for ELF functional A1PI level, which is considered to be a key ELF 
analyte.
42. Section 13.2 Datasets and Analysis Cohorts
Description of Change: Definition of full analysis set has been revised to replace 
“… have at least one available measurement for at least one efficacy variable” to 
“…have at least one available A1PI measurement during the treatment period” 
(Section 13.2.1). Definition of per-protocol analysis set has been modified to add 
a total of >15 missed planned infusions will be considered as a major protocol 
deviation for the purpose of statistical analysis and the subject will be excluded 
from the per-protocol analysis (Section 13.2.2). Definition of BAL analysis set 
has been revised to reflect that subjects who missed 1 or more infusions within 4
weeks immediately preceding the scheduled on-treatment bronchoscopy/BAL 
procedure would be excluded from BAL analysis dataset.
Purpose for Change: To update statistical analysis dataset definitions.
43. Section 13.4 Methods of Analysis
Description of Change: Editorial changes have been made to Section 13.4.1 
Efficacy Outcome Measures and Section 13.4.3 Safety Outcome Measures. A 
new section (Section 13.4.2 Exposure) is added. Analysis of adverse reactions has 
been added. In addition, the following text has been added:
“AEs that are considered potentially related to the presence of protein aggregates 
or immune-mediated will be summarized descriptively with 95% confidence 
intervals (CIs) as appropriate for each AE of interest by each treatment arm and, 
if appropriate, pooled across both treatment arms. In the event of any clinically 
significant trends in treatment-emergent AE(s) of interest, further analysis 
including potential correlation with the presence of particulates in the GLASSIA 
solution will be performed.”
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“The proportion of subjects who develop binding and/or neutralizing anti-A1PI 
antibodies will be summarized with their point estimates and exact 95% CIs. 
Treatment-emergent anti-A1PI antibody data will be listed along with the 
corresponding plasma antigenic and functional A1PI levels in the individual 
subject. Additionally, temporal relationship of anti-A1PI antibody formation with 
potentially immune-related AEs, if any, will be examined.”
Purpose for Change: To improve clarity, to add safety analysis for adverse 
reactions, to add provision for analyzing the possible relationship between 
specific types of AEs and the potential presence of particulates in GLASSIA, and 
to add provision for analyzing the temporal association of the appearance and 
presence of treatment-emergent serum antibodies against A1-PI with occurrence 
of adverse events which may be immune-mediated.
44. Section 3 Synopsis, and Section 13.4.1 Efficacy Outcome Measures
Description of Change: The following text has been added:
 
 
 
 
 
Changes from baseline in ELF and plasma antigenic and functional A1PI levels, 
as well as 
, will be summarized in the following 
subgroups: by sex, age (≤65, >65), race, and ethnicity. 
 
 
Purpose of Change: 
 
45. Section 3 Synopsis, and Section 13.4.3 Safety Outcome Measures
Description of Change: The following text has been added:
“Safety parameters will be summarized descriptively by sex, age (≤65, >65), 
race, and ethnicity. No hypothesis tests are planned, however, 
 
 
Purpose of Change: To add descriptive analysis of safety data by subgroups per 
FDA’s request. 
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46. Section 15.1.1 Investigator Report and Final Clinical Study Report (in the 
original version of the protocol)
Description of Change: This section has been deleted.
Purpose for Change: This section is not applicable, as the study is not planned to 
be conducted in the European Union.
47. Section 15.5 Non-Compliance with the Protocol
Description of Change: The following text has been modified (Strikethrough text 
denotes deleted text, and underlined text denotes added text):
“The investigator may deviate from the protocol only to eliminate an apparent 
immediate hazard to the subject or when the change(s) involves only logistical or 
administrative aspects of the study (eg, change of study monitor, change of phone 
number). In the event(s) of an apparent immediate hazard to the subject, the 
investigator will notify the sponsor immediately by phone and confirm notification 
to the sponsor in writing as soon as possible, but within 5 working days 1 
calendar day after the change is implemented. The investigator sponsor will also 
notify the EC of the emergency change ensure the responsible ethics committee is 
notified of the urgent measures taken in such cases according to local 
regulations.”
Purpose for Change: To comply with current protocol standards and regulatory 
requirements.
48. Section 16.3 Informed Consent
Description of Change: The sentence “An assent form may be provided and 
should be signed by patients less than 18 years of age.” has been deleted.
Purpose for Change: Not applicable, since this study will enroll only adult 
subjects with A1PI deficiency and emphysema.
49. Section 20.4 Thresholds for Clinically Significant Laboratory Abnormalities
Description of Change: A new section added to provide a table of relevant clinical 
laboratory test threshold values which are considered significant, independent of 
the medical assessment made by the investigator, for reporting and safety 
analysis.
Purpose for Change: Per FDA’s request.
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INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: GLASSIA
STUDY TITLE: A Phase 4 Study to Evaluate the Safety, Immunogenicity, and 
Effects on the Alpha1-Proteinase Inhibitor (A1PI) Levels in Epithelial Lining Fluid 
Following GLASSIA Therapy in A1PI-Deficient Subjects
PROTOCOL IDENTIFIER: 471101
CLINICAL TRIAL PHASE 4
AMENDMENT 1: 2015 JAN 19
Replaces Original: 2011 JUL 05
ALL VERSIONS: 
Amendment 1: 2015 JAN 19
Original: 2011 JUL 05
OTHER ID(s)
NCT Number: Not Available
EudraCT Number: Not Available
IND NUMBER: 14774
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, clinical 
study agreement, ICH GCP guidelines, and all applicable regulatory requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator
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INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: GLASSIA
STUDY TITLE: A Phase 4 Study to Evaluate the Safety, Immunogenicity, and 
Effects on the Alpha1-Proteinase Inhibitor (A1PI) Levels in Epithelial Lining Fluid 
Following GLASSIA Therapy in A1PI-Deficient Subjects
PROTOCOL IDENTIFIER: 471101
CLINICAL TRIAL PHASE 4
AMENDMENT 1: 2015 JAN 19
Replaces Original: 2011 JUL 05
ALL VERSIONS: 
Amendment 1: 2015 JAN 19
Original: 2011 JUL 05
OTHER ID(s)
NCT Number: Not Available
EudraCT Number: Not Available
IND NUMBER: 14774
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and provides assurance that this study will be conducted according to all 
requirements as defined in this protocol, clinical study agreement, ICH GCP guidelines, 
and all applicable regulatory requirements.
Signature of Coordinating Investigator
Date
Print Name and Title of Coordinating Investigator
Signature of Sponsor Representative
Date
, MD
, Clinical Development
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