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

BAXALTA CONFIDENTIAL – RESTRICTED: DO NOT DISTRIBUTE WITHOUT PRIOR APPROVAL
PROTOCOL: 471101
TITLE:
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
SHORT TITLE:
Ph 3/4 GLASSIA Safety, Immunogenicity, and Bronchoalveolar 
Lavage Study
STUDY PHASE:
Phase 3/4
DRUG:
GLASSIA
NCT NUMBER:
NCT02525861
IND NUMBER:
14774
SPONSOR:
Baxalta US Inc.*, 
300 Shire Way, Lexington, MA 02421, USA
AND
Baxalta Innovations GmbH*, 
Industriestrasse 67, A-1221 Vienna, Austria
* Baxalta is now part of Shire
PROTOCOL 
HISTORY:
AMENDMENT 6: 2018 AUG 27
Replaces: Amendment 5: 2017 NOV 21
ALL VERSIONS: 
Amendment 6: 2018 AUG 27
Amendment 5: 2017 NOV 21
Amendment 4: 2016 JAN 15
Amendment 3: 2015 AUG 26
Amendment 2: 2015 MAY 07
Amendment 1: 2015 JAN 19
Original: 2011 JUL 05
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1. STUDY PERSONNEL
1.1 Authorized Representative (Signatory)/Responsible Party
, MD
 
Global Clinical Development Operations
Baxalta Innovations GmbH.
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, INCLUDING SUSARs, ARE TO BE REPORTED ON THE ADVERSE 
EVENT ELECTRONIC CASE REPORT FORM (ECRF) WITHIN 24 HOURS 
AFTER BECOMING AWARE OF THE EVENT. IF THE ECRF IS NOT 
AVAILABLE THEN THE SAE MUST BE REPORTED ON THE SERIOUS 
ADVERSE EVENT REPORT (SAER) FORM AND TRANSMITTED TO THE 
SPONSOR TO MEET THE 24 HOUR TIMELINE REQUIREMENT.
Drug Safety contact information: see SAE Report Form.
Refer to SAE Protocol Sections and the study team roster for further information.
For definitions and information on the assessment of these events, refer to the following:

AE, Section 12.1

SAE, Section 12.1.1.1

SUSARs, Section 12.1.1.2

Assessment of AEs, Section 12.1.2
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3. SYNOPSIS
INVESTIGATIONAL PRODUCT
Name of Investigational Product (IP)
GLASSIA 
Name of Active Ingredient
Alpha1-Proteinase Inhibitor (Human)
CLINICAL CONDITION(S)/INDICATION(S)
GLASSIA is indicated for chronic augmentation and maintenance therapy in adults with clinically evident 
emphysema due to severe congenital deficiency of alpha1-proteinase inhibitor (A1PI) (also known as 
alpha1-antitrypsin [AAT] deficiency).
PROTOCOL ID
471101
PROTOCOL TITLE
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
Short Title
Ph 3/4 GLASSIA Safety, Immunogenicity, and Bronchoalveolar 
Lavage Study
STUDY PHASE
Ph 3/4
PLANNED STUDY PERIOD
Initiation
Q4 2015
Primary Completion
Q2 2020
Study Completion
Q4 2020
Duration
Approximately 5 years
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of the study is 2-fold: (1) to further evaluate the safety and potential immunogenicity of 
GLASSIA following intravenous (IV) administration via in-line filtration; and, (2) to assess the effects of 
GLASSIA augmentation therapy on the levels of A1PI and 
 in the epithelial lining fluid 
(ELF) following IV administration at a dosage of 60 mg/kg body weight (BW)/week active A1PI protein
for 25 weeks in subjects with emphysema due to congenital A1PI deficiency.
Primary Objectives
1.
To evaluate the effectiveness of the use of 5-micron in-line filter on the safety and potential 
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.
Secondary Objective
1.
To collect additional safety information for GLASSIA.
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Exploratory Objective
 
 
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 is a Phase 3/4, 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 a dosage of 60 mg/kg BW/week 
active A1PI protein (the dosing regimen that is currently approved by the 
Food and Drug Administration [FDA]) 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. A subject will be considered evaluable only if acceptable BAL samples 
(see Section 10.3.4 for definitions) are obtained at both baseline and on-
treatment BAL visits.
Once the target of 15 to 18 evaluable subjects has been reached, the 
remaining subjects to be enrolled will not be required to undergo baseline and 
on-treatment bronchoscopy/BAL procedures. Subjects with confirmed 
medical history (IC #1a, #9a, #9b, ExC #20, #21, #22, #23, and #24) known 
not to meet eligibility criteria to undergo bronchoscopy/BAL procedures, 
may be screened and randomized with sponsor approval before the target 
enrollment of BAL evaluable subjects is reached. 
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 
last A1PI treatment) during screening. Screening A1PI measurement may be 
taken at any time during the screening period for treatment-naïve subjects. 
For subjects who have previously received alpha-1 augmentation therapy 
however, screening A1PI measurement should be taken after the washout 
period. During the washout period, subjects will be allowed to undergo other 
screening procedures for eligibility determination.
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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 approved 
labeled dosage of 60 mg/kg BW/week active A1PI protein 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 1 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).
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 active A1PI protein 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 7, Week 13, Week 19, and Week 
25, must be administered at the study site to facilitate monitoring and 
reporting of potential adverse events (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. 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 AEs
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 BW 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 in ELF. 
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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 evident) plus an additional minimum period of 
4 weeks after the end of exacerbation.
Planned Duration of 
Subject Participation
The duration of each subject’s participation will 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 after the last 
infusion.
Primary Outcome Measures
Safety
1.
Number (proportion) of AEs considered potentially related to the presence of protein aggregates
(particle load) in the GLASSIA solution
2.
Incidence of treatment-emergent adverse reactions (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 anti-neutrophil elastase capacity [ANEC]) levels in ELF
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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
following GLASSIA administration
3.
Number (proportion) of subjects with treatment-emergent seroconversion or positive nucleic acid 
test (NAT) for parvovirus B19 (B19V)
Exploratory Outcome Measures
 
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
GLASSIA
Dose: 60 mg/kg BW active A1PI protein 
Dosage form: Injection, solution
Dosage frequency: Weekly
Mode of Administration: Intravenous
SUBJECT SELECTION
Targeted Accrual
Enrollment will be closed when both conditions are met: 
(a) 15 to 18 evaluable subjects with acceptable BAL samples 
collected from both the baseline and on-treatment BAL visits
(b) A minimum of 36 randomized subjects.
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 subjects meeting the following age criteria:
(a) For subjects who will undergo bronchoscopy/BAL procedures: 18 to 75 years of age at the 
time of screening. 
(b) For subjects who will be waived from undergoing bronchoscopy/BAL procedures -: 18 years 
of age or older at the time of screening.
2.
Documented A1PI genotype of Pi*Z/Z, Pi*Z/Null, Pi*Malton/Z, Pi*Null/Null, or other “at-risk”
allelic combinations such as SZ (excluding MS and MZ without the presence of another allowable 
at-risk genotype) and an endogenous A1PI plasma levels of ≤11 µM (≤0.572 mg/mL).
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3.
Screening levels of endogenous plasma (antigenic) A1PI of ≤11 µM at any time during the 
screening period for treatment-naïve subjects, or following a 4-week minimum washout from 
previous augmentation therapy in treatment-experienced subjects.
4.
Subjects must have at least one of the following: clinical diagnosis of emphysema, evidence of 
emphysema on chest X-ray or computerized tomography (CT) scan of the chest, and/or evidence 
of airway obstruction which is not completely reversed with bronchodilator treatment at the time 
of screening.
5.
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.
6.
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. Subjects with a positive cotinine test due to nicotine 
replacement therapy (eg, patches, chewing gum), vapor cigarettes, or snuff are eligible.
7.
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.
8.
The subject is willing and able to comply with the requirements of the protocol.
9.
The subject must have pulmonary function at the time of screening which meets both of the 
following:
(a) Post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥50% of predicted
(b) If FEV1 is >80% predicted, then FEV1/forced vital capacity (FVC) must be <0.7.
Note: Inclusion criterion #1a, #9a, and #9b are not applicable to subjects who are not required to 
undergo the bronchoscopy/BAL procedures.
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, chronic bronchitis, mild bronchiectasis, and stable asthma).
2.
The subject is experiencing or has a history of chronic severe cor pulmonale (resting mean 
pulmonary artery pressure ≥40 mm Hg).
3.
The subject routinely produces more than 1 tablespoon of sputum per day.
4.
The subject has a history of frequent pulmonary exacerbations (greater than 2 moderate or severe 
exacerbations within 52 weeks prior to screening; see Section 10.4 for the definition of moderate 
and severe exacerbations).
5.
The subject is experiencing a pulmonary exacerbation at the time of screening (subject may be 
rescreened 4 weeks after the clinical resolution of an exacerbation).
6.
The subject has clinically significant abnormalities (other than emphysema, chronic bronchitis, or 
mild bronchiectasis) detected on chest X-ray or CT scan at the time of screening. (Past records
obtained within 52 weeks prior to screening may be used, if available).
7.
The subject has clinically significant abnormalities detected on a 12-lead electrocardiogram (ECG) 
performed at the time of screening (Past records obtained within 26 weeks prior to screening may 
be used, if available).
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8.
The subject has clinically significant congestive heart failure with New York Heart Association 
(NYHA) Class III/IV symptoms.
9.
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.
10.
The subject has a history of lung or other organ transplant, is currently on a transplant list, or has 
undergone major lung surgery.
11.
The subject is receiving long-term around-the-clock oxygen (O2) supplementation. (the following 
are allowed: short-term use of O2 supplementation [eg, for the management of acute COPD 
exacerbation], O2 supplementation required during night time only, and supplemental O2 with 
continuous positive airway pressure [CPAP] or bi-level positive airway pressure [BiPAP]).
12.
Known history of hypersensitivity following infusions of human blood or blood components.
13.
Immunoglobulin A (IgA) deficiency (<8 mg/dL at screening).
14.
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
15.
Ongoing active infection with hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus 
(HCV), or human immunodeficiency virus (HIV) Type 1/2 at the time of screening.
16.
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.
17.
The subject has participated in another clinical study involving an IP or investigational device
within 30 days prior to enrollment or is scheduled to participate in another clinical study involving 
an IP or device during the course of this study.
18.
The subject is a family member or employee of the investigator.
19.
If female, the subject is nursing at the time of screening.
Note: Exclusion criteria #20, #21, #22, #23, and #24 are not applicable to subjects who are not required to 
undergo the bronchoscopy/BAL procedures.
20.
The subject has contraindication(s) to bronchoscopy such as recent myocardial infarction, unstable 
angina, other cardiopulmonary instability, tracheal obstruction or stenosis, moderate to severe 
hypoxemia or any degree of hypercapnia, unstable asthma, Stage 4 or 5 chronic kidney disease, 
pulmonary hypertension, severe hemorrhagic diathesis, and cervical C1/C2 arthritis.
21.
The subject has had lung surgery which may interfere with bronchoscopy.
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22.
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.
23.
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.
24.
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 a previous clinical study (Clinical
Protocol 460502; Baxter Healthcare Corporation) for the evaluation of the effects of A1PI augmentation 
therapy with ARALAST NP on the levels of A1PI and other analytes in the ELF. 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 1-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 1-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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Changes from baseline in ELF and plasma antigenic and functional A1PI levels will be summarized in the 
following subgroups: by sex, age (≤65; >65), race, and ethnicity.
 
 
The safety outcome measures, including AEs of interest that may be immune-mediated, treatment-emergent 
ARs plus suspected ARs (see Section 12.1.1.3 for definitions), and treatment-emergent incidence of 
immunogenicity and seroconversion, will be summarized descriptively with 95% confidence intervals (CIs) 
as appropriate. 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. In the event of treatment-emergent immunogenicity, any potential temporal relationship 
of anti-A1PI antibody formation with the occurrence of potentially immune-mediated AEs will be 
examined.
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.
Safety parameters will be summarized descriptively by sex, age (≤65; >65), race, and ethnicity. No 
hypothesis tests are planned; however, 
 
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4. TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE................................................................................. 2
Sponsor’s (Shire) Approval.......................................................................................... 2
Investigator’s Acknowledgement ................................................................................ 3
1. STUDY PERSONNEL ................................................................................................. 4
1.1 Authorized Representative (Signatory)/Responsible Party................................ 4
1.2 Study Organization................................................................................................. 4
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 5
3. SYNOPSIS..................................................................................................................... 6
4. TABLE OF CONTENTS ........................................................................................... 15
5. LIST OF ABBREVIATIONS .................................................................................... 20
6. BACKGROUND INFORMATION .......................................................................... 23
6.1 Description of Investigational Product ............................................................... 26
6.1.1 Rationale for the Selection of Dosing Regimen........................................... 26
6.1.2 Rationale for the Selection of Route of Administration and Infusion Rate
......................................................................................................................... 26
6.2 Clinical Condition/Indication .............................................................................. 27
6.3 Population To Be Studied..................................................................................... 27
6.4 Findings From Nonclinical and Clinical Studies ............................................... 27
6.4.1 Summary of Nonclinical Data....................................................................... 27
6.4.2 Summary of Clinical Data............................................................................. 27
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 28
6.6 Compliance Statement.......................................................................................... 28
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 29
7.1 Study Purpose ....................................................................................................... 29
7.2 Primary Objectives............................................................................................... 29
7.3 Secondary Objective............................................................................................. 29
7.4 Exploratory Objective.......................................................................................... 29
8. STUDY DESIGN......................................................................................................... 30
8.1 Brief Summary...................................................................................................... 30
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8.2 Study Design.......................................................................................................... 30
8.3 Duration of Study Period(s) and Subject Participation .................................... 32
8.4 Outcome Measures ............................................................................................... 32
8.4.1 Primary Outcome Measures......................................................................... 32
8.4.2 Secondary Outcome Measures ..................................................................... 33
8.4.3 Exploratory Outcome Measures .................................................................. 33
8.5 Randomization and Blinding............................................................................... 33
8.5.1 Unblinding Procedures at Study Sites ......................................................... 34
8.6 Study Stopping Rules............................................................................................ 34
8.7 Investigational Product(s).................................................................................... 34
8.7.1 Packaging, Labeling, and Storage................................................................ 34
8.7.2 Preparation of Infusion Solution.................................................................. 34
8.7.3 Administration ............................................................................................... 35
8.7.4 Description of Treatment.............................................................................. 35
8.7.5 Investigational Product Accountability ....................................................... 35
8.8 Source Data ........................................................................................................... 36
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 37
9.1 Inclusion Criteria.................................................................................................. 37
9.2 Exclusion Criteria................................................................................................. 38
9.3 Withdrawal and Discontinuation ........................................................................ 40
10. STUDY PROCEDURES .......................................................................................... 42
10.1 Informed Consent and Enrollment ................................................................... 42
10.2 Subject Identification Code................................................................................ 42
10.3 Screening and Study Visits................................................................................. 42
10.3.1 Screening Visit ............................................................................................. 42
10.3.1.1 Confirmation of Severe Congenital A1PI Deficiency........................ 43
10.3.1.2 Pulmonary Function Tests................................................................... 43
10.3.1.3 Rescreening ........................................................................................... 44
10.3.2 Infusion Visits............................................................................................... 44
10.3.2.1 IP Administration................................................................................. 44
10.3.2.2 Management of Treatment-Emergent (S)AEs................................... 46
10.3.2.3 Pre-Medications.................................................................................... 47
10.3.2.4 Post-Infusion Follow-Up ...................................................................... 47
10.3.3 Clinical Assessment Visits........................................................................... 47
10.3.4 BAL Visits..................................................................................................... 48
10.4 COPD Exacerbation and Lower Respiratory Tract Infection ....................... 49
10.5 Medications and Non-Drug Therapies.............................................................. 51
10.6 Subject Completion/Discontinuation ................................................................ 52
10.7 Procedures for Monitoring Subject Compliance............................................. 53
11. ASSESSMENT OF EFFICACY.............................................................................. 54
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11.1 ELF Antigenic and Functional A1PI Levels..................................................... 54
11.2
.................................................................................... 54
12. ASSESSMENT OF SAFETY................................................................................... 55
12.1 Adverse Events.................................................................................................... 55
12.1.1 Definitions..................................................................................................... 55
12.1.1.1 Serious Adverse Event.......................................................................... 55
12.1.1.2 Non-Serious Adverse Event ................................................................. 56
12.1.1.3 Adverse Reactions Plus Suspected Adverse Reactions ..................... 56
12.1.1.4 Unexpected Adverse Events................................................................. 56
12.1.1.5 Adverse Events Potentially Associated with Protein Aggregates..... 57
12.1.1.6 Preexisting Diseases.............................................................................. 57
12.1.2 Assessment of Adverse Events.................................................................... 57
12.1.2.1 Severity .................................................................................................. 58
12.1.2.2 Causality................................................................................................ 59
12.1.2.3 Safety Reporting ................................................................................... 60
12.2 Urgent Safety Measures ..................................................................................... 61
12.3 Untoward Medical Occurrences........................................................................ 62
12.4 Non-Medical Complaints ................................................................................... 62
12.5 Medical, Medication, and Non-Drug Therapy History................................... 63
12.6 Physical Examinations........................................................................................ 63
12.7 Clinical Laboratory Parameters........................................................................ 63
12.7.1 Hematology and Clinical Chemistry.......................................................... 63
12.7.1.1 Other Analysis....................................................................................... 64
12.7.2 Complement Activation and Immune Complex Panel............................. 64
12.7.3 Viral Serology and Nucleic Acid Tests....................................................... 65
12.7.4 Urine Tests.................................................................................................... 65
12.7.5 Assessment of Clinical Laboratory Values................................................ 66
12.7.5.1 Assessment of Abnormal Laboratory Values..................................... 66
12.7.6 Biobanking.................................................................................................... 66
12.8 Plasma Antigenic and Functional A1PI Levels................................................ 67
12.9 Immunogenicity .................................................................................................. 68
12.10 Vital Signs.......................................................................................................... 68
13. STATISTICS............................................................................................................. 70
13.1 Sample Size and Power Calculations ................................................................ 70
13.2 Datasets and Analysis Cohorts .......................................................................... 70
13.2.1 Full Analysis Set........................................................................................... 70
13.2.2 Per-Protocol Analysis Set............................................................................ 70
13.2.3 BAL Analysis Set ......................................................................................... 71
13.2.4 Safety Analysis Set....................................................................................... 71
13.3 Handling of Missing, Unused, and Spurious Data........................................... 71
13.4 Methods of Analysis............................................................................................ 71
13.4.1 Efficacy Outcome Measures ....................................................................... 71
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13.4.2 Exposure....................................................................................................... 72
13.4.3 Safety Outcome Measures........................................................................... 73
13.5 Planned Interim Analysis of the Study ............................................................. 74
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 74
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 75
15.1 Investigator’s Responsibility.............................................................................. 75
15.1.1 Final Clinical Study Report........................................................................ 75
15.2 Training ............................................................................................................... 75
15.3 Monitoring........................................................................................................... 75
15.3.1 Safety Monitoring ........................................................................................ 75
15.4 Auditing ............................................................................................................... 76
15.5 Non-Compliance with the Protocol ................................................................... 76
15.6 Laboratory and Reader Standardization ......................................................... 76
16. ETHICS ..................................................................................................................... 77
16.1 Subject Privacy ................................................................................................... 77
16.2 Ethics Committee and Regulatory Authorities................................................ 77
16.3 Informed Consent ............................................................................................... 77
16.4 Data Monitoring Committee.............................................................................. 78
17. DATA HANDLING AND RECORD KEEPING................................................... 79
17.1 Confidentiality Policy ......................................................................................... 79
17.2 Study Documents and Case Report Forms....................................................... 79
17.3 Document and Data Retention........................................................................... 79
18. FINANCING AND INSURANCE........................................................................... 80
19. PUBLICATION POLICY........................................................................................ 80
20. SUPPLEMENTS....................................................................................................... 81
20.1 Study Flow Chart................................................................................................ 81
20.2 Schedule of Study Procedures and Assessments.............................................. 82
20.3 Schedule of Clinical Laboratory Assessments.................................................. 85
20.4 Thresholds for Clinically Significant Laboratory Abnormalities .................. 88
21. REFERENCE LIST.................................................................................................. 90
22. SUMMARY OF CHANGES.................................................................................... 93
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Tables
Table 3-1 Treatment Assignments...................................................................................... 8
Table 8-1 Treatment Assignments.................................................................................... 31
Table 20.2-1 Schedule of Study Procedures and Assessments......................................... 82
Table 20.3-1 Clinical Laboratory Assessments ................................................................ 85
Figures
Figure 10-1 Exacerbation of COPD.................................................................................. 50
Figure 20-1 Study Flow Chart for Baxalta Clinical Study 471101 .................................. 81
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5. LIST OF ABBREVIATIONS
Abbreviation
Definition
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
ANOVA
Analysis of Variance
APE
Acute pulmonary exacerbation
AR/ARs
Adverse reaction/adverse reactions
AST
Aspartate aminotransferase
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
COPD
Chronic obstructive pulmonary disease
CPAP
Continuous positive airway pressure
CPK
Creatine phosphokinase
CRF(s)
Case report form(s)
CT
Computerized tomography
DMC
Data Monitoring Committee
EC
Ethics Committee
ECG
Electrocardiogram
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Abbreviation
Definition
eCRF
Electronic case report form
EDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
ELF
Epithelial lining fluid
EP
European Pharmacopeia
ExC
Exclusion criterion
FAS
Full analysis set
FDA
United States Food and Drug Administration
FEV1
Forced expiratory volume in 1 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
IC
Inclusion criterion
ICF
Informed consent form
ICH
International Council for Harmonisation
IgA
Immunoglobulin A
IP
Investigational product
IRT
Interactive response technology
IV
Intravenous
IWRS
Interactive Web Response System
LDH
Lactic dehydrogenase
LRT
Lower respiratory tract
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Abbreviation
Definition
LRTI
Lower respiratory tract infection
MDI
Metered dose inhaler
MedDRA
Medical Dictionary for Regulatory Activities
NAT
Nucleic acid test
NE
Neutrophil elastase
NMC
Non-medical complaint
NYHA
New York Heart Association 
O2
Oxygen
PCR
Polymerase chain reaction
PP
Per-protocol
RBC
Red blood cell
RSI
Reference safety information
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, the 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.6,8,11,13,14,15,16,17,18 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.6,11 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.11
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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 1 dose-escalation and a Phase 2/3 pivotal 
clinical trial in a total of 65 individual subjects with severe A1PI deficiency.
The clinical lots used in the GLASSIA Phase 2/3 trial contained small amounts of visible 
protein particulates which were aggregates of A1PI. GLASSIA A1PI functional activity 
is independent of the particulate load of the solution for infusion. Protein aggregation is a 
known phenomenon with protein therapeutics and has been shown to be present in the 
active comparator used in the Phase 2/3 trial, as well as in other commercially available 
A1PI products upon reconstitution of the lyophilized powder. During the Phase 2/3 
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 other 
licensed A1PI products. Potential immunogenicity following repeated administration of 
GLASSIA was evaluated in the Phase 2/3 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 1 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 insert and/or investigator's brochure [IB]).
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The effectiveness of the in-line filtration procedure in removing visible and subvisible 
particles in GLASSIA was examined in a recent in vitro study. GLASSIA lots with at 
least a factor of 2-fold differential were 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 raised about protein
aggregates in a therapeutic product regarding the potential safety risks to humans. To 
address these concerns, a key goal of this study is to evaluate the clinical safety profile of 
GLASSIA with a 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 and/or IB.
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.
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In the pivotal Phase 2/3 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 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 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 and/or IB.
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 through 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 and/or IB).
6.1.2 Rationale for the Selection of Route of Administration and Infusion Rate
The route of administration (IV 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 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 2 single dose general toxicology studies in Sprague-Dawley 
rats and New Zealand White rabbits, and 2 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 BW, clinical chemistry, hematology and gross pathology that could be 
attributed to GLASSIA administration.
In a repeated dose study, New Zealand White rabbits received GLASSIA (300 mg/kg) 
once daily for 5 consecutive days. Animals were monitored for changes in clinical signs, 
BW, 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 and/or IB.
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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 2 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 Council
for Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP E6(R2),
November 2016), Title 21 of the US Code of Federal Regulations (US CFR), the (EU 
Directives 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 2-fold: (1) to further evaluate the safety and potential 
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 
potential 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
 
 
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8. STUDY DESIGN
8.1 Brief Summary
This Phase 3/4, 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 
a dosage of 60 mg/kg BW/week (the dosing regimen that is currently approved by the 
FDA) 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 
of last A1PI treatment) during screening. Screening A1PI measurement may be taken at 
any time during the screening period for treatment-naïve subjects. For subjects who have 
previously received alpha-1 augmentation therapy, screening A1PI measurement should 
be taken at the end of the washout period. 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 has been reached, the remaining subjects to 
be enrolled will not be required to undergo baseline and on-treatment bronchoscopy/BAL 
procedures. Subjects with confirmed medical history (IC #1a, #9a, #9b, ExC #20, #21,
#22, #23, and #24) known not to meet eligibility criteria to undergo bronchoscopy/BAL 
procedures, may be screened and randomized with sponsor approval before the target 
enrollment of BAL evaluable subjects is reached. 
Enrollment will be closed when both conditions are met: 
(a) 15 to 18 evaluable subjects with acceptable BAL samples collected from both the 
baseline and on-treatment BAL visits.
(b) A minimum of 36 randomized subjects.
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If for any reasons the target of 15 to 18 evaluable subjects have not been achieved with 
initial 36 randomized subjects, additional subjects will be enrolled to meet 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 1 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
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 7, Week 13, 
Week 19, 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 BW measurements, as well as physical examination, vital sign 
measurements, and blood draws 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 and 
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.
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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 5 years from study initiation (ie, 
first subject enrolled) to study completion (ie, last subject last visit).
The recruitment period is expected to be approximately 43 months. The duration of each 
subject’s participation from enrollment to subject completion (ie, last study visit) is 
anticipated to be approximately 8 months (unless the subject withdraws or is prematurely 
discontinued from the study), 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 after the last infusion.
8.4 Outcome Measures
8.4.1 Primary Outcome Measures
Safety
1.
Number (proportion) of AEs considered potentially related to the presence of
particle load 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.
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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 following GLASSIA administration.
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
 
 
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 and Section 9.2) 
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 15 to 18 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 biostatistician.
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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 (in the US) with a demonstrated record of safety at the approved
dosage of 60 mg/kg BW/week which is to be employed in this study. This study will 
include a Data Monitoring Committee (DMC) to monitor the study for any safety or medical 
concerns, and may recommend stopping the study based on the criteria defined in the DMC 
charter (see Section 16.4).
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 BW at screening and at each 
subsequent study visit. Dose adjustments based on BW changes from screening or 
previous visit will be made if the subject’s BW changes by >5%. Only BW
measurements taken using standardized procedures during study visits (Weeks 1, 7, 13, 
19, or 25) will be used for dose calculations.
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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 and/or IB.
8.7.3 Administration
GLASSIA is for IV 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.)
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.
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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.
No data will be entered directly onto the case report form (CRF).
For additional information on study documentation and CRFs, see Section 17.2.
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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 subjects meeting the following age criteria:
(a) For subjects who will undergo bronchoscopy/BAL procedures: 18 to 75 years 
of age at the time of screening.
(b) For subjects who will be waived from undergoing bronchoscopy/BAL 
procedures: 18 years of age or older at the time of screening.
2.
Documented A1PI genotype of Pi*Z/Z, Pi*Z/Null, Pi*Malton/Z, Pi*Null/Null, or 
other “at-risk” allelic combinations such as SZ (excluding MS and MZ without 
the presence of another allowable at-risk genotype) and an endogenous A1PI 
plasma levels of ≤11 µM (≤0.572 mg/mL).
3.
Screening levels of endogenous plasma (antigenic) A1PI of ≤11 µM may be 
collected at any time during the screening period for treatment-naïve subjects, or 
following a 4 week minimum washout from previous augmentation therapy in 
treatment-experienced subjects.
4.
Subjects must have at least one of the following: clinical diagnosis of emphysema, 
evidence of emphysema on computerized tomography (CT) scan of the chest, 
and/or evidence of airway obstruction which is not completely reversed with 
bronchodilator treatment at the time of screening.
5.
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.
6.
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. Subjects with a positive cotinine test due to nicotine replacement therapy 
(eg, patches, chewing gum), vapor cigarettes, or snuff are eligible.
7.
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.
8.
The subject is willing and able to comply with the requirements of the protocol.
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9.
The subject must have pulmonary function at the time of screening meeting both 
of the following:
(a) Post-bronchodilator forced expiratory volume in 1 second (FEV1) ≥50% of 
predicted.
(b) If FEV1 is >80% predicted, then FEV1/forced vital capacity (FVC) must 
be <0.7.
Note: Inclusion criterion #1a, #9a, and #9b are not applicable to subjects who are not 
required to undergo the bronchoscopy/BAL procedures.
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, chronic bronchitis, mild bronchiectasis, 
and stable asthma).
2.
The subject is experiencing or has a history of chronic severe cor pulmonale
(resting mean pulmonary artery pressure ≥40 mm Hg).
3.
The subject routinely produces more than 1 tablespoon of sputum per day.
4.
The subject has a history of frequent pulmonary exacerbations (greater than 
2 moderate or severe exacerbations within 52 weeks prior to screening; see 
Section 10.4 for the definition of moderate and severe exacerbations).
5.
The subject is experiencing a pulmonary exacerbation at the time of screening 
(subject may be rescreened 4 weeks after the clinical resolution of an 
exacerbation).
6.
The subject has clinically significant abnormalities (other than emphysema, 
chronic bronchitis, or mild bronchiectasis) detected on chest X-ray or CT scan at 
the time of screening (Past records obtained within 52 weeks prior to screening 
may be used, if available).
7.
The subject has clinically significant abnormalities detected on a 12-lead 
electrocardiogram (ECG) performed at the time of screening (Past records
obtained within 26 weeks prior to screening may be used, if available).
8.
The subject has clinically significant congestive heart failure with New York 
Heart Association (NYHA) Class III/IV symptoms.
9.
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.
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10. The subject has a history of lung or other organ transplant, is currently on a 
transplant list, or has undergone major lung surgery.
11. The subject is receiving long-term around-the-clock oxygen (O2) 
supplementation. (The following are allowed: short-term use of O2
supplementation [eg, for the management of acute COPD exacerbation], O2
supplementation required during night time only, and supplemental O2 with 
continuous positive airway pressure [CPAP] or bi-level positive airway pressure 
[BiPAP]).
12. Known history of hypersensitivity following infusions of human blood or blood 
components.
13. Immunoglobulin A (IgA) deficiency (<8 mg/dL at screening).
14. 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
15. Ongoing active infection with HAV, HBV, hepatitis C virus (HCV), or HIV Type 
1/2 infection at the time of screening.
16. 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.
17. The subject has participated in another clinical study involving an IP or 
investigational device within 30 days prior to enrollment or is scheduled to 
participate in another clinical study involving an IP or device during the course of 
this study.
18. The subject is a family member or employee of the investigator.
19. If female, the subject is nursing at the time of screening.
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Note: Exclusion criteria #20, #21, #22, #23, and #24 are not applicable to subjects 
who are not required to undergo the bronchoscopy/BAL procedures.
20. The subject has contraindication(s) to bronchoscopy such as recent myocardial 
infarction, unstable angina, other cardiopulmonary instability, tracheal obstruction 
or stenosis, moderate to severe hypoxemia or any degree of hypercapnia, unstable 
asthma, Stage 4 or 5 chronic kidney disease, pulmonary hypertension, severe 
hemorrhagic diathesis, and cervical C1/C2 arthritis.
21. The subject has had lung surgery which may interfere with bronchoscopy.
22. 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.
23. 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.
24. 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.
9.3 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.
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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.
•
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 IP/device 
other than IP.
5.
If a subject experiences >1 moderate or severe COPD exacerbation and/or lower 
respiratory tract infection (LRTI) during the screening period (Rescreening may 
be permitted as defined in Section 10.3.1.3).
6.
The sponsor terminates the study.
For subjects undergoing BAL procedures, if no acceptable BAL samples can be obtained 
from any of the 3 lobes attempted during the baseline BAL visit, the subject will not be 
screen failed and then rescreened based solely on this reason. The subject may be 
randomized to the immunogenicity portion of the study without the need to rescreen, with 
sponsor approval, provided they are within the screening window and meet all applicable 
criteria. If acceptable BAL samples can be obtained during the baseline BAL visit but not 
from 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.
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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 SIC: protocol identifier (eg, 471101) 
to be provided by the sponsor, 3-digit number study site number (eg, 002) to be provided
by the sponsor, and 3-digit subject number (eg, 003) reflecting the order of enrollment 
(ie, signing the ICF). For example, the third subject who signed an ICF at study site 002
will be identified as Subject 471101-002003. 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, in 
compliance with laws governing data privacy.
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) and screening 
assessments (see Section 20.2 and Section 20.3 for detailed list of study 
procedures/laboratory assessments including serum IgA, ECG, and Chest X-ray/CT).
Randomization is to take place after the subject has met all eligibility criteria and, as
applicable, the subject has 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 who provided informed consent. 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. If a subject is rescreened, the End of Study CRF should 
be completed, and a new ICF, new SIC and new CRF are required for that subject.
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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 by measurement of 
endogenous plasma A1PI levels. The plasma level must be ≤11 µM, and the plasma 
sample can be collected any time during screening for treatment-naïve A1PI deficient 
subjects, but only following a washout from previous A1PI augmentation therapy in 
treatment-experienced subjects. The presence of exogenously-administered A1PI may 
interfere with the verification of endogenous plasma A1PI levels in treatment-
experienced subjects; therefore, they will be required to have their pre-study A1PI 
therapy withdrawn for a minimum of 4 weeks to allow A1PI levels to return to the 
subject’s pre-augmentation levels. Screening A1PI measurement may be repeated in the 
event of suspected inadequate washout resulting in initial screening A1PI level of 
>11 µM.
Subjects must have a diagnosis of A1PI deficiency (ie, genotype of Pi*Z/Z, Pi*Z/Null, 
Pi*Malton/Z, or Pi*Null/Null, or other “at-risk” allelic combinations such as SZ 
[excluding MS and MZ without the presence of another allowable at-risk genotype])
AND plasma antigenic A1PI level of ≤11 µM in order to meet eligibility criteria. Results
of these screening tests will be used to establish the subject’s eligibility for participation 
in the study.
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.19,20 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 × 200 µg or 4 × 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.
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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 ≥11 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 
rescreened 4 weeks after the clinical resolution of an exacerbation).
4.
Ineligibility due to failure to meet protocol pre-specified time intervals 
(eg, inclusion criteria #5 and #6, and exclusion criteria #5 and #17).
5.
For additional reasons after discussion with the medical monitor and sponsor 
approval.
Subjects who were discontinued early from the study due to failure to yield adequate 
baseline BAL samples or failure to meet the eligibility criteria required to undergo the 
bronchoscopy/BAL procedure will be allowed to be rescreened before the target 
enrollment of BAL evaluable subjects is completed.
If a subject is to be rescreened, 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.
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). If a weekly infusion is more than 
+5 days from the expected date, the infusion should be skipped and the next regularly 
scheduled infusion should take place.
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 
in Section 8.7.
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The first infusion (Week 1), as well as infusions during Week 7, Week 13, Week 19, 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 
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 at 30 (±15) 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°C (101°F) 
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)
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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.
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 and report the SAE as described in Section 2.
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.

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 
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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 rechallenge 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 9.3.
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, telephone follow-up will be conducted by the 
investigator/designee at 72 hours (+1 business day) to document AEs, and/or 
administration of concomitant medications or non-drug therapies, which may have 
occurred within 72 hours after the completion of an infusion.
10.3.3 Clinical Assessment Visits
Following Week 1 visit, subjects will be asked to return to the study site during Week 13 
and Week 25 for on-treatment clinical and safety laboratory assessments, as well as 
plasma A1PI measurements. Additional blood samples will be drawn for the monitoring 
of plasma A1PI levels during Week 7 and Week 19, which will take place at study site 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.
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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 bronchoscopy/BAL procedures. 
Bronchoscopy/BAL procedure will be waived for subjects who are enrolled after 15 to 
18 BAL evaluable subjects have been obtained. An evaluable subject is defined as a 
subject who has successfully completed both the baseline and the on-treatment BAL 
visits, and has acceptable BAL sample (defined as a total recovery of ≥20% of the 
instilled volume of saline, no blood by visual inspection in any individual aliquot, overall 
number of acceptable aliquots no less than 3 per lobe, at least 1 acceptable BAL sample 
obtained from any of the 3 lobes) collected from each visit.
Subjects will be asked to undergo the bronchoscopy/BAL procedures on 2 occasions: at 
baseline (prior to randomization) and following initiation of GLASSIA treatment for 
12 to 14 weeks.
The baseline BAL visit must be conducted after verification of deficient plasma 
(antigenic) A1PI levels (≤11 M) has been obtained. Subjects who have been receiving
A1PI augmentation therapy prior to study entry must have plasma samples collected 
within 10 days prior to the baseline BAL visit for the measurement of plasma (antigenic) 
A1PI levels to verify the adequacy of the washout from A1PI therapy prior to performing 
BAL. The baseline bronchoscopy/BAL visit must be completed prior to randomization 
and within 48 hours prior to the first IP administration. In order for a subject to be 
randomized and remain in the study, the subject must have acceptable BAL sample (total 
recovery of ≥20% of the total original instilled volume of saline, no blood by visual 
inspection in any individual aliquot, overall number of acceptable aliquots no less than 
3 per lobe). If no acceptable BAL samples can be obtained from any of the 3 lobes 
attempted during the baseline BAL visit, the subject will not be screen failed and then 
rescreened based solely on this reason. The subject may be randomized to the 
immunogenicity portion of the study without the need to rescreen, with sponsor approval, 
provided they are within the screening window and meet all applicable criteria.
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 7 (±1) days following the last IP 
infusion, but must be completed prior to the next IP infusion. Whenever possible, it is 
recommended that sufficient time (typically 24 to 48 hours) is allowed for the subject to 
recover from the bronchoscopy/BAL procedures prior to IP administration. 
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Subjects who have successfully completed the on-treatment BAL visit and have
acceptable BAL samples will be considered as an 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 completion visit (Week 26). These subjects, however, would not 
be considered as a BAL evaluable subject. New subjects may be enrolled to achieve the 
target of 15 to 18 evaluable subjects, as necessary.
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 and/or IB). 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 
timing of the rescheduled BAL visit will follow the same requirements as described 
above for the on-treatment BAL visit.
10.4 COPD Exacerbation and Lower Respiratory Tract Infection
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 IV) corticosteroids. The end of an exacerbation is defined as the 
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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 usual clinical 
state) for at least 2 consecutive days. As depicted in Figure 10-1, the total length of the 
episode includes any delay in treatment (time taken for treatment to be initiated after the 
onset of exacerbation) and time to resolution of signs and symptoms.21,22
Figure 10-1
Exacerbation of COPD
Onset of 
Exacerbation
Initiation of 
Treatment
End of 
Exacerbation
Delay in 
Treatment
Resolution of Exacerbation Signs and 
Symptoms Since Commencement of 
Treatment
Additional 4 weeks during 
which subjects remain 
clinically stable 
Bronchoscopy/BAL Visit
(As Applicable for Subjects Undergoing 
Bronchoscopy/BAL Procedure) 
If a subject experiences a moderate or severe COPD exacerbation and/or LRTI during the 
screening period, the 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.
The severity of a COPD exacerbation and/or LRTI will be categorized as mild, moderate,
or severe according to the following definitions:

Mild – treated at home without seeing a health care provider.

Moderate – visit with health care provider (eg, home visit, visit to an outpatient 
facility or an emergency department, but not requiring admission to hospital).

Severe – hospitalization (an emergency department stay >24 hours is considered a 
hospitalization).
Any occurrences of COPD exacerbation and/or LRTI are to be recorded on the AE CRF.
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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.
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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).
Reasons for completion/discontinuation will be reported on the 
Completion/Discontinuation CRF, including: completed, screen failure, (S)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.
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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.
Trough antigenic and functional A1PI levels in plasma would be determined as a check 
on subject’s compliance/adherence to treatment.
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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.
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 
An SAE is defined as an untoward medical occurrence that at any dose meets 1 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.

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 B19V.
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12.1.1.1.1 Uncomplicated Pregnancies 
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 AE which met any of the following criteria: 
(a) an AE that began during infusion or within 72 hours following the end of IP 
infusion, or
(b) an AE considered by either the investigator and/or the sponsor to be possibly or 
probably related to IP administration, or 
(c) an AE 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 AE that began during infusion or within 24 hours following the end of IP
infusion, or
(b) an AE considered by either the investigator and/or the sponsor to be possibly or 
probably related to IP administration, or 
(c) an AE 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 (RSI) (eg, IB, package insert). “Unexpected” also refers to the AEs that are 
mentioned in the RSI 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. The expectedness of AEs will be determined 
by the sponsor using the IB and/or prescribing information as the RSI. This determination 
will include considerations such as the number of AEs previously observed, but not on 
the basis of what might be anticipated form the pharmacological properties of a product.
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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
Report Form within 24 hours of awareness and followed-up at estimated date of delivery 
and 1 year post-delivery, if feasible. (S)AEs associated with these events must be 
reported on the appropriate (S)AE forms, and follow the guidance on timing of the report 
provided in Section 12.1.2.3.
If an investigator becomes aware of an SAE occurring in a subject after study 
completion, the SAE must be reported on the provided SAE Report 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: 
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o
Reappearance of a similar reaction upon re-administration (positive 
rechallenge).
o
Positive results in a drug sensitivity test (skin test, etc.).
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.
12.1.2.3 Safety Reporting
Adverse events/SAEs will be assessed at all study visits (from first IP exposure) as 
outlined in the Schedule of Study Procedures and Assessments (see Table 20.2-1) and 
Section 12.1 above.
Adverse Events/SAEs are to be recorded on the AE page of the eCRF. Each event should 
be recorded separately.
Any SAE, including death due to any cause, which occurs during this study, whether or 
not related to the IP, must be reported immediately (within 24 hours of the study center’s 
first knowledge of the event). All SAEs must be reported via the Electronic Data Capture 
(EDC) system by completing the relevant electronic CRF (eCRF) page(s) in English.
Once the SAE has been recorded in the EDC system, the sponsor and other designated 
recipients will be informed of the event automatically. For instances in which the EDC 
may become unavailable, SAEs must be reported using the backup paper SAE Report 
Form to meet the 24-hour timeline requirement (contacts and instructions to be provided 
in separate documentation). Once the EDC becomes available, the site must enter all SAE 
data as reported on the backup paper SAE Report Form on the applicable eCRF pages.
The initial SAE information reported on the applicable eCRF pages (or backup SAE 
Report Form, if applicable) must at least include the following:

Protocol Number

Subject identification number and demographics (gender, age at onset of event 
and/or date of birth)

IP exposure
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
Medical Term for Event (Diagnosis preferably) 

Description of the (S)AE, including:

Date of onset

(S)AE treatment (drug, dose, route of administration)

Causal relationship by the investigator

Measures taken (ie, action taken regarding IP in direct relationship to the AE)

Seriousness criteria (ie, death, life-threatening, or other criterion)

Cause of death

Autopsy findings (if available)

Name, address, fax number, email, and telephone number of the reporting 
investigator (for paper SAE Report Forms) 
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 (EC) and relevant competent authority(s) are 
notified of the urgent safety measures taken in such cases according to local regulations.
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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 AE CRF (and SAE Report Form if eCRF is not available). 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 
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.
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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 
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: 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.
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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. 
Whole blood will be collected for the assessment of hematology and serum for 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.
12.7.1.1 Other Analysis
Serum samples will be collected for serum cotinine concentrations for nonsmoking 
assessments (levels within normal range of a nonsmoker).
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 assay for 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.
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Complement activation and immune complex assessments will be performed at a central 
laboratory.
12.7.3 Viral Serology and Nucleic Acid Tests
At screening, subjects would be tested for HAV, Hep B, HCV and HIV1/HIV2 by 
serology for antigenemia or antibodies or by PCR based NAT, towards 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, nitrite, leukocyte esterase, and microscopic examination (RBC, 
WBC, bacteria, casts). Urinalysis will be performed 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. 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.
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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.
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 (1 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 (1 of the 2 aliquots 
will serve as backup sample):

Anti-A1PI antibodies for binding antibody (screening and confirmatory)
assays
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
Anti-A1PI antibodies for neutralizing antibody assay

BAL samples collected for the determination of the following analytes will each 
be split into 2 or more aliquots of approximately equal volume (at least 1 of the 
aliquots will serve as backup sample; see Laboratory Manual for further details):

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 plasma 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.
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.
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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 AEs. 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 
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 (mm Hg). 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).
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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 at 30 (±15) 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 ≥38.2ºC (101ºF).
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 
clinically indicated. Any abnormal value that persists should be followed at the discretion 
of the investigator.
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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 
a previous clinical study (Clinical Protocol 460502; Baxter Healthcare Corporation) for 
the evaluation of the effects of A1PI augmentation therapy with ARALAST NP on the 
levels of A1PI and other analytes in the ELF. 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 1-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 1 IP infusion 
and have at least 1 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 2 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 1 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 
1 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.
Since an increase from baseline in the mean ELF levels of antigenic A1PI is expected, 
a 1-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: 
H0: Mean change in antigenic A1PI in the ELF from baseline to the on-treatment 
measurement will be less than or equal to zero.
H0: μd ≤0
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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.
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.
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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.
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.
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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.
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 
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.
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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. 
15.3.1 Safety Monitoring
The safety of the subjects in this study shall be monitored by an external Data 
Monitoring Committee (DMC). The DMC is a group of individuals with pertinent 
expertise that reviews on a regular basis accumulating data from an ongoing clinical 
study. For this study, the DMC will be composed of recognized experts in the field of 
pulmonary clinical care and research who are not recruiting subjects for this study. 
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The DMC will recommend to the sponsor whether to continue or stop the trial or to
continue the study after proper amendment to the protocol.
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 (Baxalta) will also ensure the responsible EC 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.
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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.
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.
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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
This study will be monitored by Data Monitoring Committee (DMC). The DMC is a 
group of individuals with pertinent expertise that reviews on a regular basis accumulating 
data from an ongoing clinical study. For this study, the DMC will be composed of 
recognized experts in the field of A1PI deficiency and COPD clinical care and research 
who are not recruiting subjects for this study.
The DMC will be responsible for monitoring the safety of the study participants including 
periodic review of SAEs, AEs, and any relevant information that may have an impact on the 
safety of the participants or the ethics of the trial. Based on data review, the DMC may make 
a recommendation to continue the study as is, temporarily suspend the study, or terminate the 
study based on pre-defined criteria such as unacceptable toxicities or lack of treatment 
benefits. The membership, responsibilities, interactions, and operations of the DMC in 
providing oversight of the study, as well as criteria for DMC recommendations, are detailed 
in the DMC charter.
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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.
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 Baxalta Clinical Study 471101
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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 (Max 
48 hours after 
Baseline BAL)
Week 7
(±2 Days)
On-Treatment 
BAL (Week 
12-14)b
Week 13
(±2 Days)
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
Xg
Xg
Xg
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
Xg
Xg
Xg
Xg
Xg
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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 (Max 
48 hours after 
Baseline BAL)
Week 7
(±2 Days)
On-Treatment 
BAL (Week 
12-14)b
Week 13
(±2 Days)
Week 19
(±2 Days)
Week 25
(±2 Days)
Study Completion 
(Week 26±3 Days)/
Early Terminationc
Anti-A1PI 
Antibodiesm,n
Xg
Xg
Xg
X
Weekly GLASSIA 
Infusionso
X
Adverse Event
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
Abbreviations: BAL = Bronchoalveolar lavage; ECG = Electrocardiogram; A1PI = Alpha1-Proteinase Inhibitor.
a
For subjects who undergo bronchoscopy/BAL procedures (see Section 10.3.4 for more details). 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 (see Section 10.3.4 for more details). The on-treatment 
bronchoscopy/BAL visit will be postponed once if a subject experiences a moderate or severe COPD exacerbation and/or LRTI (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.
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Continued
d
Written informed consent must be obtained prior to performance of any study procedures including screening/rescreening 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). Bronchoscopy/BAL visit with evaluable BAL samples collected must be completed prior to randomization and within 
48 hours prior to the first IP administration.
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. Dose adjustment based on body weight changes during the course of the study may be made if the changes are clinically significant 
(eg, >5%).
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 at 30 (±15) 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]) to be performed in 
triplicate, which is to be taken 30±5 minutes after administration of a short-acting inhaled β2 agonist bronchodilator (eg, 400 μg of salbutamol, or its 
equivalent).
l
For laboratory assessments, see Table 20.3-1.
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 AEs, 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 accompanied 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 7, Week 13, Week 19, 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
Following each infusion visit, telephone follow-up will be conducted by the investigator/designee at 72 hours (+1 business day) to document AEs, 
and/or administration of concomitant medications or non-drug therapies, which may have occurred within 72 hours after the completion of an infusion. 
Any AEs that occur and/or concomitant medications/non-drug therapies that the subject takes after the post-infusion telephone follow-up will be 
collected during the subsequent weekly infusion visit.
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  
(Max 48 hours 
after Baseline 
BAL)
Week 7
(±2 Days)
On-Treatment 
BAL
(Week 12-14)b
Week 13
(±2 Days)
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, HBV, HCV, and 
HIV1/HIV2 by serology 
for antigenemia or 
antibodies or by PCR 
based NAT
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
Se
S
S
Screening (Antigenic) 
A1PIk,l
P
On-Treatment Trough 
Plasma Antigenic A1PIl
Pe
Pe
Pe
Pe
Pe
P
On-Treatment Trough 
Plasma Functional 
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  
(Max 48 hours 
after Baseline 
BAL)
Week 7
(±2 Days)
On-Treatment 
BAL
(Week 12-14)b
Week 13
(±2 Days)
Week 19
(±2 Days)
Week 25
(±2 Days)
Study Completion 
(Week 26±3 Days)/
Early Terminationc
Pe
Pe
Pe
Pe
Pe
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
L
L
Abbreviations: BAL = Bronchoalveolar lavage; W = Whole blood; S = Serum; HAV = Hepatitis A Virus; HBV = Hepatitis B virus; 
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; 
.
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Continued
a
For subjects undergoing bronchoscopy/BAL procedures (see Section 10.3.4 for more details). 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 (see Section 10.3.4 for more details). The on-treatment 
bronchoscopy/BAL visit will be postponed once if a subject experiences a moderate or severe COPD exacerbation and/or LRTI (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
Hematology panel will consist of complete blood count: 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, 50% hemolytic complement activity of serum (CH50), C1q binding 
assay (circulating immune complexes).
h
Viral testing will consist of viral serology for 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. 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.
i
Urinalysis will consist of color, specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrite, 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 (≥11 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
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
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Laboratory Test
Lowest Alert 
Limit
Highest Alert 
Limit
Comment
Complement Activation and Immune Complex
Serum C3
<70 mg/dL
---
Serum C4
<14 mg/dL
---
Total complement (CH50)
<30 U/ml
---
C1q binding/CICs
<12 mg/dL
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.
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21. REFERENCE LIST
1.
a1-antitrypsin deficiency: memorandum from a WHO meeting. Bull World Health 
Organ,. 1997;75(5):397-415.
2.
de Serres FJ, Blanco I. Prevalence of a1-antitrypsin deficiency alleles PI*S and 
PI*Z worldwide and effective screening for each of the five phenotypic classes 
PI*MS, PI*MZ, PI*SS, PI*SZ, and PI*ZZ: A comprehensive review. Ther Adv 
Respir Dis. 2012;6(5):277-295.
3.
de Serres FJ, Blanco I, Fernández-Bustillo E. Ethnic differences in alpha-1 
antitrypsin deficiency in the United States of America. Ther Adv Respir Dis. 
2010;4(2):63-70.
4.
Brantly M, Nukiwa T, Crystal RG. Molecular basis of alpha-1-antitrypsin 
deficiency. Am J Med. 1988;84(6A):13-31.
5.
Hutchison DC. Natural history of alpha-1-protease inhibitor deficiency. Am J Med. 
1988;84(6A):3-12.
6.
Hubbard RC, Crystal RG. Alpha-1-antitrypsin augmentation therapy for alpha-1-
antitrypsin deficiency. Am J Med. 1988;84(6A):52-62.
7.
Ogushi F, Fells GA, Hubbard RC, Straus SD, Crystal RG. Z-type a1-antitrypsin is 
less competent than M1-type a1- antitrypsin as an inhibitor of neutrophil elastase. J 
Clin Invest. 1987;80(5):1366-1374.
8.
Buist AS, Burrows B, Cohen A, et al. Guidelines for the approach to the patient 
with severe hereditary alpha- 1-antitrypsin deficiency. American Thoracic Society. 
Am Rev Respir Dis. 1989;140(5):1494-1497.
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9.
Stoller JK. Clinical features and natural history of severe a1- antitrypsin deficiency. 
Roger S. Mitchell Lecture. Chest. 1997;111(6 Suppl):123S-128S.
10.
Crystal RG, Brantly ML, Hubbard RC, Curiel DT, States DJ, Holmes MD. The 
alpha 1-antitrypsin gene and its mutations. Clinical consequences and strategies for 
therapy. Chest. 1989;95(1):196-208.
11.
Wewers MD, Casolaro MA, Sellers SE, et al. Replacement therapy for alpha 1-
antitrypsin deficiency associated with emphysema. N Engl J Med. 
1987;316(17):1055-1062.
12.
Casolaro MA, Fells G, Wewers M, et al. Augmentation of lung antineutrophil 
elastase capacity with recombinant human a-1-antitrypsin. J Appl Physiol. 
1987;63(5):2015-2023.
13.
Crystal RG. a1-antitrypsin deficiency: pathogenesis and treatment. Hosp Pract (Off 
Ed). 1991;26(2):81-89, 93-94.
14.
Crystal RG. a 1-antitrypsin deficiency, emphysema, and liver disease. Genetic basis 
and strategies for therapy. J Clin Invest. 1990;85(5):1343-1352.
15.
Hubbard RC, Sellers S, Czerski D, Stephens L, Crystal RG. Biochemical efficacy 
and safety of monthly augmentation therapy for a-1-antitrypsin deficiency. JAMA. 
1988;260(9):1259-1264.
16.
Hubbard RC, Crystal RG. Augmentation therapy of a 1-antitrypsin deficiency. Eur 
Respir J Suppl. 1990;9:44s-52s.
17.
Stoller JK. a 1-antitrypsin deficiency and augmentation therapy in emphysema. 
Cleve Clin J Med. 1989;56(7):683-689.
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18.
Wewers MD, Casolaro MA, Crystal RG. Comparison of alpha-1-antitrypsin levels 
and antineutrophil elastase capacity of blood and lung in a patient with the alpha-1-
antitrypsin phenotype null-null before and during alpha-1-antitrypsin augmentation 
therapy. Am Rev Respir Dis. 1987;135(3):539-543.
19.
Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur 
Respir J. 2005;26(2):319-338.
20.
Miller MR, Crapo R, Hankinson J, et al. General considerations for lung function 
testing. Eur Respir J. 2005;26(1):153-161.
21.
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(15):1543-1554.
22.
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.
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22. SUMMARY OF CHANGES
Protocol Amendment 6: 2018 AUG 27
Replaces: Protocol Amendment 5: 2017 NOV 21
In this section, changes from the previous version of the Protocol Amendment 5, dated 
2017 NOV 21, 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 text have been made to align with the current 
version of the sponsor’s protocol template. Changes in the numbering of 
sections/lists 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.
Cover Page
Description of Change: The Company address is changed to “Baxalta US Inc., 
300 Shire Way, Lexington, MA 02421 USA AND Baxalta Innovations GmbH* 
Industriestrasse 67, A-1221 Vienna, Baxalta is now part of Shire”. Older entry was 
‘Baxalta US Inc., One Baxter Way, Westlake Village, CA 91362’.
Purpose for Change: To maintain consistency with document requirement.
3.
Synopsis (Planned Study Period), Section 8.3
Description of Change: The primary completion is updated to Q2 2020 and Study 
completion is updated to Q4 2020. The overall duration of the study will be 
approximately 5 years from study initiation. The recruitment period is expected to 
be approximately 43 months.
Purpose for Change: The study duration and timelines is updated.
4.
Synopsis (Study Design), Section 8.2
Description of Change: IC #9b is added to the list of criteria for subjects with 
confirmed medical history and now reads as “. Subjects with confirmed medical 
history (IC #1a, #9a, #9b, EC #20, #21, #22, #23, and #24)---”.
Purpose for Change: Changed for better clarity.
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5.
Synopsis (Study Design), Section 8.2
Description of Change: Text modified to read as ‘Subjects may be screened and 
randomized with sponsor approval before the target enrollment of BAL evaluable 
subjects is reached.’
Purpose for Change: Updated as per requirement for better understanding.
6.
Synopsis (Study Design), Section 8.2, Section 10.3.2.1, 
Section 20.2 (footnote ‘o’)
Description of Change: Infusion of GLASSIA treatment during Week 7 and 
Week 19 visit (along with already mentioned Week 13 and Week 25 visits) must be 
administered at the study site.
Purpose for Change: To facilitate monitoring and reporting of potential AEs 
associated with GLASSIA infusions.
7.
Synopsis (Inclusion Criteria), Section 9.1, Section 10.3.1.1
Description of Change: Inclusion criterion 2 is modified from “Documented A1PI 
genotype of Pi*Z/Z, Pi*Z/Null, Pi*Malton/Z, Pi*Null/Null, or other “at-risk” allelic 
combinations such as SZ (excluding MS and MZ) and an endogenous A1PI plasma 
levels of ≤11 µM” to read as “Documented A1PI genotype of Pi*Z/Z, Pi*Z/Null, 
Pi*Malton/Z, Pi*Null/Null, or other “at-risk” allelic combinations such as SZ 
(excluding MS and MZ without the presence of another allowable at-risk 
genotype) and an endogenous A1PI plasma levels of ≤11 µM”.
Purpose for Change: Changed for better clarity.
8.
Synopsis (Inclusion Criteria), Section 9.1
Description of Change: In the inclusion criterion number 2, the value and unit of 
“an endogenous A1PI plasma levels of ≤11 µM” is updated to read as “an 
endogenous A1PI plasma levels of ≤11 µM (≤0.572 mg/mL)”.
Purpose for Change: Changed for better clarity.
9.
Synopsis (Inclusion Criteria, Note), Section 9.1
Description of Change: Note below inclusion criteria is modified to include #9b in 
the text and now reads as “Inclusion criterion #1a, #9a, and #9b are not applicable
to subjects who are not required to undergo the bronchoscopy/BAL procedures”.
Purpose for Change: Changed for better clarity.
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10. Synopsis (Exclusion Criteria, Note), Section 9.2
Description of Change: Note below exclusion criteria list is moved to location after 
criterion no.19 and prior to criterion no.20.
Purpose for Change: Changed for better readability.
11. Synopsis (Planned Statistical Analysis)
Description of change: The following text related to safety outcome measure is 
deleted “Additionally, 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”.
Purpose for Change: The text was redundant, so deleted.
12. Section 6.6
Description of change: The ‘ICH GCP April 1996’ has been modified to ‘ICH GCP 
E6(R2), November 2016. 
Purpose for Change: To reflect the revised GCP E6 guidelines in the document.
13. Section 8.6, Section 15.3.1, Section 16.4
Description of Change: Text about Data Monitoring Committee (DMC) is added in 
the protocol at various instances.
Purpose for Change: A DMC will monitor the safety and medical concerns of the 
study, to decide whether to continue or stop the study or to continue the study after 
proper amendment to the protocol.
14. Section 9.3, Section 10.3.4
Description of Change: Text for subjects undergoing BAL procedures is modified 
to read as “For subjects undergoing BAL procedures, if no acceptable BAL samples 
can be obtained from any of the 3 lobes attempted during the baseline BAL visit, 
the subject will not be screen failed and then rescreened based solely on this 
reason. The subject may be randomized to the immunogenicity portion of the 
study without the need to rescreen, with sponsor approval, provided they are 
within the screening window and meet all applicable criteria” and only in 
Section 9.3, the following sentence is deleted “---randomized and will not be 
discontinued from the study. These subjects may be rescreened after the target 
enrollment of BAL evaluable subjects is completed”.
Purpose for Change: The text modified to be consistent with current requirements.
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15. Section 10.2
Description of Change:
(1) The SIC code numbers are modified to restrict to 3-digits for site number and 
subject number, and example SIC number is updated to reflect same.
(2) Details of personal identification of a subject are modified from “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” to read as “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, in compliance with laws governing data 
privacy.”
Purpose for Change:
(1) To reflect actuality of study, as 3-digits for site and subject numbers is used.
(2) Clarity to allow for differences between countries.
16. Section 10.3.1
Description of Change: The screening visit details are updated to read as “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) and screening assessments (see Section 20.2 and Section 20.3 for 
detailed list of study procedures/laboratory assessments including serum IgA, 
ECG, and Chest X-ray/CT).”
Purpose for Change: Changed for consistency and better clarity.
17. Section 10.3.1.3
Description of Change: Criterion no. 5 added in subject rescreening conditions, as 
“5. For additional reasons after discussion with the medical monitor and sponsor 
approval”.
Purpose for Change: Changed for better clarity.
18. Section 10.3.2
Description of Change: A clarification sentence added to infusion visits as “If a 
weekly infusion is more than +5 days from the expected date, the infusion should 
be skipped and the next regularly scheduled infusion should take place”.
Purpose for Change: Changed for better clarity.
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19. Section 10.3.3
Description of Change: Blood samples drawn at Week 7 and Week 19 are added as 
mandatory site visits.
Purpose for Change: Blood samples (Plasma Functional A1PI, Plasma Antigenic 
A1PI, 
) are drawn at 
Week 7 and Week 19. All samples need to be centrifuged and some are frozen at 
−80°C. This is not possible at the subject’s home.
20. Section 12.1.2.3
Description of Change: AE reporting period is modified to read as “Adverse 
events/SAEs will be assessed at all study visits (from first IP exposure)---”.
Purpose for Change: Changed for better clarity.
21. Section 12.7.1
Description of Change: The text is revised from “Blood will be collected for the
assessment of hematology and clinical chemistry parameters during each of the 
following visits” to read as “Whole blood will be collected for the assessment of 
hematology and serum for clinical chemistry parameters during each of the 
following visits”.
Purpose for Change: Changed for better clarity.
22. Section 20.1, Section 20.2, Section 20.3
Description of Change: Time window for Week 1 visit was updated to “Week 1 
(Max 48 hours after Baseline BAL)”.
Purpose for Change: Corrected in study flow chart and table headers to be 
consistent with protocol text.
23. Section 20.2
Description of Change: In the table row for “Adverse Event”, the “X” mark under 
the “Screening (Max 6 Weeks)” column is removed.
Purpose for Change: Corrected in study flow chart to be consistent with protocol 
text.
24. Section 20.2 (footnote ‘k’)
Description of Change:
(1) Changed pulmonary function tests include spirometry need to be taken ‘30±5 
minutes’ instead of ‘30±15 minutes’.
(2) Regarding pulmonary function text footnote, the detail like “to be performed in 
triplicate” is added.
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Purpose for Change:
(1) Modified in Schedule of study procedure and assessment table footnote to be 
consistent with protocol text.
(2) To be consistent with protocol text.
25. Section 20.3 (footnote ‘h’)
Description of Change: The wordings “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.” are 
added to the footnote h.
Purpose for Change: Modified in Schedule of clinical laboratory assessment table 
footnote to be consistent with protocol text.
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