Clinical trial NCT02956122
Conditions: Graft Versus Host Disease
Sponsor: Baxalta now part of Shire
Start date: 2017-04-26; Completion date: 2018-05-03
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate the safety and efficacy of GLASSIA as an add-on biopharmacotherapy to standard-of-care steroid treatment as the first-line treatment in participants with acute GvHD with lower GI involvement.

Detailed description:

Arms: arm 1: Participants to receive GLASSIA (intravenously) and methylprednisolone or equivalent steroid (either IV or oral per investigator discretion) arm 2: Participants to receive GLASSIA (intravenously) and methylprednisolone or equivalent steroid (either IV or oral per investigator discretion) arm 3: Participants to receive control (intravenously) and methylprednisolone or equivalent steroid (either IV or oral per investigator discretion)
Interventions: intervention 1: GLASSIA intervention 2: methylprednisolone or equivalent steroid intervention 3: Albumin
Intervention descriptions: intervention 1: GLASSIA \[Alpha1-Proteinase Inhibitor (Human)\] intervention 2: The conventional steroid treatment (methylprednisolone or equivalent steroid) will be supplied by the investigators per their institutional practice. intervention 3: The control vials contain human albumin 20% in 50 mL normal saline solution in glass vials (for non-United States (US) Countries), or Flexbumin 25% in 50 mL in normal saline solution in plastic IV bags (for US).

Protocol documents:
Prot_000.pdf: 
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
CLINICAL STUDY PROTOCOL
PRODUCT: GLASSIA
STUDY TITLE: A Two-Part, Multi-Center, Prospective, Phase 2/3 Clinical Study to 
Evaluate the Safety and Efficacy of GLASSIA as an Add-On Biopharmacotherapy 
to Conventional Steroid Treatment in Subjects with Acute Graft-Versus-Host 
Disease with Lower Gastrointestinal Involvement
STUDY SHORT TITLE: A Phase 2/3 Study of GLASSIA for the Treatment of 
Acute GvHD
PROTOCOL IDENTIFIER: CT2/3-GVHD-IV-Multi-Center-KAM/BAX; 471501
CLINICAL TRIAL PHASE 2/3
AMENDMENT 1: 2017 APR 19
Replaces: ORIGINAL: 2016 APR 19
ALL VERSIONS: 
AMENDMENT 1: 2017 APR 19
ORIGINAL: 2016 APR 19
OTHER ID(s)
NCT Number: NCT02956122
EudraCT Number: To be determined
IND NUMBER: 017014
Study Sponsor(s):
Baxalta US Inc.
One Baxter Way
Westlake Village, CA 91362
UNITED STATES
Baxalta Innovations GmbH
Industriestrasse 67
A-1221 Vienna
AUSTRIA
Co-Sponsor:
Kamada Ltd.
7 Sapir St.
Kiryat Weizmann Science Park
Ness Ziona 74140
ISRAEL


Al p ha- 1 Pr otei nase I n hi bit or/ G L A S SI A
Pa ge 2 of 1 0 1
Cli nical St u d y Pr ot oc ol I de ntifier: 4 7 1 5 0 1
2 0 1 7 A P R 1 9
B A X A L T A C o nfi de ntial – Restricte d: D o N O T distri b ute wit h o ut pri or a p pr o val.
1. S T U D Y P E R S O N N E L
1. 1 A ut h orize d Re prese nt ati ve ( Si g n at or y) / Res p o nsi ble P art y
J u dit K ora n yi, M D
Gl o bal Cli nical De vel o p me nt O perati o ns
Ba xalta U S I nc. / Ba xalta I n n o vati o ns G m b H
1. 2 St u d y Or g a niz ati o n
P P D
T h e na me a n d c o ntact i nf or mati o n of t he res p o nsi ble party a n d i n di vi d uals i n v ol ve d wit h 
t he st u d y (e g, i n vesti gat or(s), s p o ns or’s me dical e x pert a n d st u d y m o nit or, s p o ns or’s 
re prese ntati ve(s), lab orat ories, steeri n g c o m mittees a n d o versi g ht c o m mittees [i ncl u di n g 
et hics c o m mittees ( E Cs) ], as a p plica ble) will be mai ntai ne d b y t he s p o ns or a n d pr o vi de d 
t o t he i n vesti gat or.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 3 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
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 SUSPECTED UNEXPECTED SERIOUS ADVERSE 
REACTIONS (SUSARS), ARE TO BE REPORTED ON THE 
SERIOUS ADVERSE EVENT REPORT (SAER) FORM AND 
TRANSMITTED TO THE SPONSOR 
WITHIN 24 HOURS AFTER BECOMING AWARE OF THE EVENT
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:

Adverse event (AE), Section 12.1

SAE, Section 12.1.1.1

SUSARs, Section 12.1.1.2

Assessment of AEs, Section 12.1.2


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 4 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
3. SYNOPSIS 
INVESTIGATIONAL PRODUCT
Name of Investigational 
Product (IP)
GLASSIA
Name(s) of Active 
Ingredient(s)
Alpha-1 Proteinase Inhibitor
CLINICAL CONDITION(S)/INDICATION(S)
Treatment of acute graft-versus-host disease (GvHD) with lower gastrointestinal (GI) involvement resulting 
from allogeneic hematopoietic stem cell transplant (HSCT)
PROTOCOL ID
CT2/3-GVHD-IV-Multi-Center-KAM/BAX; 471501
PROTOCOL TITLE
A Two-Part, Multi-Center, Prospective, Phase 2/3 Clinical Study to Evaluate 
the Safety and Efficacy of GLASSIA as an Add-On Biopharmacotherapy to 
Conventional Steroid Treatment in Subjects with Acute Graft-Versus-Host 
Disease with Lower Gastrointestinal Involvement
Short Title
A Phase 2/3 Study of GLASSIA for the Treatment of Acute GvHD
STUDY PHASE
Ph2/3
PLANNED STUDY PERIOD
Initiation
2016 OCT
Primary Completion
2018 SEP (all subjects complete Day 56 in Part 2 or discontinue study treatment)
Study Completion
2019 JUL
Duration
Approximately 3 years
STUDY OBJECTIVES AND PURPOSE
Study Purpose
The purpose of the study is to evaluate the safety and efficacy of GLASSIA as an add-on 
biopharmacotherapy to standard-of-care steroid treatment as the first-line treatment in subjects with acute 
GvHD with lower GI involvement.
Primary Objective
This study has 2 study parts:
Part 1:
To confirm the safety and efficacy of GLASSIA administered at a dose of 90 mg/kg (Day 0) followed 
by 30 mg/kg every other day (Days 2 to 12), then followed by 120 mg/kg weekly (Days 14 to 49), when 
added to conventional steroid therapy, in subjects with acute GvHD with Stage 1 to 4 lower GI 
involvement, as assessed by treatment response at Day 28, and to determine whether continuation to
Part 2 is warranted.
Part 2:
To confirm the safety and efficacy of the GLASSIA dose regimen studied in Part 1 versus albumin 
(control), when added to conventional steroid therapy, in subjects with acute GvHD with Stage 1 to 4 
lower GI involvement, as assessed by treatment response at Day 28.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 5 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Secondary Objective(s)
Efficacy
Part 1:
To evaluate the treatment effects of GLASSIA, when added to conventional steroid therapy, on other 
clinical outcomes, such as rate, duration and magnitude of response; all-cause, transplant-related, 
infection-related and GvHD-related mortality; overall survival; GvHD-free survival; treatment 
failure-free survival and incidence of chronic GvHD.
Part 2:
To determine the efficacy of GLASSIA versus albumin (control), when added to conventional steroid 
therapy, on other clinical outcomes, such as rate, duration and magnitude of response; all-cause, 
transplant-related, infection-related and GvHD-related mortality; overall survival; GvHD-free survival; 
treatment failure-free survival and incidence of chronic GvHD.
Safety (Parts 1 and 2):
1. To evaluate the safety and tolerability of GLASSIA in addition to conventional steroid therapy 
(Part 1) and compared with conventional steroid treatment alone (Part 2)
2. To assess the incidence of recurrence of primary malignancies 
3. To assess the incidence and type of infection
Pharmacokinetics (Part 1 Only): 
1. To characterize the pharmacokinetic (PK) profile of GLASSIA, when added to conventional steroid 
treatment, using noncompartmental analysis methodology
Exploratory (Parts 1 and 2):
1. To assess alpha-1 proteinase inhibitor (A1PI) plasma and stool concentrations and clearance in stool
2. To characterize the PK profile of GLASSIA, when added to conventional steroid treatment, using a 
population PK approach
3. To assess biomarkers in plasma (ie, inflammatory cytokines interleukin [IL]-2, IL-6, IL-8, and IL-
10; IL-1 receptor antagonist [IL-1RA] and T cell subpopulations, including CD4+ CD25+ CD127+
FoxP3+ regulatory T cells [Tregs]) and stool (ie, calprotectin concentrations)
4. To assess quality-of-life (QoL), GvHD symptoms and healthcare resource utilization for GLASSIA 
treatment as a first-line add-on therapy
Exploratory (Part 2 Only):
1. To assess the following additional biomarkers in plasma on Day 0 and Day 28: Reg3α, ST2, and 
TNFR1


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 6 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
STUDY DESIGN
Study Type/ 
Classification/ Discipline
Efficacy, PK, Pharmacodynamic, Safety, Tolerability
Control Type
Part 1: No control
Part 2: Concurrent control (albumin control)
Study Indication Type
Treatment
Intervention model
Part 1: Single group
Part 2: Parallel groups
Blinding/Masking
Part 1: Open-label
Part 2: Double-blind
Study Design
This is a 2-part Phase 2/3, prospective, controlled, randomized, multicenter 
study in subjects with acute GvHD with Stage 1 to 4 lower GI involvement. 
Part 1 will evaluate the safety, efficacy, and PK of GLASSIA in approximately 
20 evaluable subjects. Part 2 will compare the safety and efficacy of GLASSIA 
versus albumin (control) in a total of approximately 148 randomized subjects 
(74 subjects/group).
All eligible subjects in Parts 1 and 2 will be given 2 mg/kg/day of 
methylprednisolone or equivalent steroid and intravenous (IV) study treatment 
(defined as GLASSIA in Part 1; GLASSIA or control in Part 2). Steroids will 
be tapered as appropriate, according to institutional practice and guidance 
provided in the protocol.
Results from Part 1 will be used to determine whether continuation to Part 2 is 
warranted. All efficacy data will be adjudicated by an Adjudication 
Committee.
All subjects will be treated with study treatment in combination with 
conventional steroid treatment through Day 49, or until treatment failure, 
withdrawal from treatment or withdrawal from the study, whichever comes 
first. Thereafter, subjects will be treated with standard-of-care for the 
remainder of their participation in the study based on the investigator’s 
discretion. Subjects who are withdrawn from study treatment will continue to 
be followed through at least Day 28, unless the subject withdraws consent. 


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 7 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Part 1
Part 1 of this study is a nonrandomized, open-label, active treatment, 
multicenter study evaluating GLASSIA in combination with conventional 
steroid treatment.
Cohort 1 (20 evaluable subjects): GLASSIA loading dose of 90 mg/kg 
(Baseline/Day 0) followed by GLASSIA 30 mg/kg every other day (Days 2 to
12), then followed by 120 mg/kg weekly (Days 14 to 49), in combination with 
2 mg/kg/day methylprednisolone or equivalent steroid. Steroids will be tapered 
as appropriate, according to institutional practice and guidance provided in the 
protocol.
For Part 1, subjects who are treated but subsequently found to have a lower GI 
biopsy inconsistent with GvHD will be replaced to ensure a total of 
20 evaluable subjects.
Interim Analysis
An analysis will take place when the last subject in Part 1 has completed the 
GvHD response assessment at Day 28, to determine whether continuation from 
Part 1 to Part 2 is warranted.
Part 2
Criteria for Initiation of Part 2
The following decision criteria will be followed for the initiation of Part 2 of 
the study:

The study may be terminated by the sponsor for toxicities or adverse 
safety findings observed in Part 1 of the study

The study may proceed to Part 2 if an overall response rate of ≥55% is 
observed at Day 28 in Part 1, as determined by the sponsor

The study may be stopped for futility if the overall response rate is 
<55% at Day 28

The sponsor will be the final arbiter of the decision to move into Part 2. 
The decision will be based on the totality of cumulative data available 
(eg, rate of GvHD complete response [CR], partial response [PR] and 
very good partial response [VGPR]; rate of GI CR and PR, including 
response at Days 28 and 56; duration of any overall and any GI 
response; and GvHD-free survival)


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 8 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Study Design for Part 2
Part 2 of this study is a randomized, parallel-group, double-blind, placebo
(albumin)-controlled, clinical study comparing GLASSIA in combination with
conventional steroid treatment versus albumin (control) in combination with
conventional steroid treatment. Part 2 of the study is planned to enroll 
approximately 148 randomized subjects (74 subjects/group) in order to obtain 
134 evaluable subjects, provided that the study does not stop early for futility. 
Eligible subjects will be randomized 1:1 in a double-blind fashion to 1 of the 
following groups:
Group 2a: GLASSIA loading dose of 90 mg/kg (Baseline/Day 0) followed 
by GLASSIA 30 mg/kg every other day (Days 2 to 12), then followed by 
120 mg/kg weekly (Days 14 to 49), in combination with 2 mg/kg/day 
methylprednisolone or equivalent steroid. Steroids will be tapered as 
appropriate, according to institutional practice and guidance provided in the 
protocol.
Group 2b: Albumin (control), in combination with 2 mg/kg/day 
methylprednisolone or equivalent steroid. Steroids will be tapered as 
appropriate, according to institutional practice and guidance provided in the 
protocol.
Randomization will be stratified, using a single stratification factor: lower GI 
involvement severity (2 strata). Subjects who are randomized to treatment in 
Part 2 and subsequently discontinue treatment or withdraw from the study will 
not be replaced.
Interim Analysis
An interim analysis will take place when approximately 50% of the primary 
endpoint data in Part 2 has been collected. The study will be analyzed for 
futility based on the primary endpoint. A Data Monitoring Committee (DMC) 
will provide recommendations to the Sponsor based on the interim analysis. 
However, the sponsor may decide to stop the trial even if statistical criteria for 
futility are not observed.
Planned Duration of 
Subject Participation
Approximately 52 weeks from enrollment to study completion, including the 
follow-up period
Primary Outcome Measure (Parts 1 and 2)
1. Proportion of subjects achieving overall response at Day 28. Overall response is defined as GvHD CR 
+ PR, which are defined as follows:

GvHD CR is complete resolution of all signs and symptoms of acute GvHD in all organs without 
intervening salvage

GvHD PR is improvement of 1 stage in 1 or more organs involved in GvHD without progression 
in other organs


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 9 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Secondary Outcome Measures
Key Secondary Efficacy Outcome Measure (Parts 1 and 2)
1. Proportion of subjects achieving GI response at Day 28. Gastrointestinal response is defined as GI 
CR + PR, as defined below:

GI CR is defined as
a) Able to eat; not requiring parenteral nutrition, and
b) Passing primarily formed stools

GI PR is defined as
a) Decrease in need for parenteral nutrition to ≤50% of required calories; and
b) Reduction of stool volume by ≥50%, without ileus 
Other Secondary Efficacy Outcome Measures (Parts 1 and 2)
1. Proportion of subjects achieving overall response at Day 56
2. Change from baseline in acute GvHD grading at Days 28, 56 and 180
3. Incidence of chronic GvHD at Days 100, 180 and 365
4. Duration of any overall response
5. Duration of any GI response
6. Overall survival through Days 100, 180 and 365
7. Transplant-related mortality at Days 28, 56, 100 and 180
8. Failure-free survival at Days 100 and 180 
9. GvHD-free survival at Days 28, 56, 100 and 180
10. Infection-related mortality at Days 28, 56, 100 and 180
11. GvHD-related mortality at Days 28, 56, 100 and 180
12. All-cause mortality at Days 28, 56, 100 and 180
Safety Outcome Measures (Parts 1 and 2)
1.
The incidence and severity of all AEs, related AEs, all serious adverse events (SAEs), related SAEs 
and temporally-associated AEs
2.
Change from baseline in clinical laboratory safety parameters and vital signs
3.
Incidence of recurrence of primary malignancies through Days 180 and 365
4.
Incidence and type of infection (eg, bacterial, fungal, viral, etc) at Days 28, 56, 180 and 365
Pharmacokinetic Outcome Measures (Part 1 only)
The following noncompartmental analysis PK parameters by day and/or dosing frequency, as applicable, 
will be assessed:
1.
Area under the plasma concentration curve (AUC) from time zero to the last quantifiable activity
2.
AUC from time zero to time “t”
3.
Systemic clearance at steady state
4.
Maximum plasma concentration at steady state


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 10 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
5.
AUC from time zero to infinity 
6.
Apparent volume of distribution at steady state
7.
The terminal half-life
8.
Mean residence time
9.
Trough plasma A1PI levels at steady state
Exploratory Outcome Measures
Efficacy (Parts 1 and 2)
1.
Proportion of subjects achieving GvHD VGPR at Day 28. A GvHD VGPR is defined as follows:

Skin: no rash, or residual erythematous rash involving <25% of the body surface, without bullae 
(residual faint erythema and hyperpigmentation do not count) 

Liver: total serum bilirubin concentration <2 mg/dL or <25% of baseline at enrollment

Gut: tolerating food or enteral feeding, predominantly formed stools, no overt GI bleeding or 
abdominal cramping and no more than occasional nausea or vomiting
2.
Cumulative steroid dose at Days 28, 56, 100 and 180
3.
Steroid dose at Days 28, 56 and 100
4.
Proportion of subjects achieving GI CR and GI PR at Days 28, 56 and 180 at each baseline GvHD 
severity grade (B, C and D)
Pharmacokinetics (Parts 1 and 2)
An exploratory, mixed-effects population PK model will be developed from the Part 1 and Part 2 data. 
Potential exploratory outcome measures include, but are not limited to, the following:
1.
Systemic clearance at steady state
2.
Maximum plasma concentration at steady state
3.
Apparent volume of distribution at steady state
4.
The terminal half-life
5.
Trough plasma A1PI levels at steady state
Pharmacodynamics (Parts 1 and 2)
1.
Change from baseline in plasma and stool concentrations of A1PI
2.
A1PI clearance in stool
3.
Change from baseline in plasma biomarkers (eg, cytokines IL-2, IL-6, IL-8, and IL-10; and IL-1RA)
and stool calprotectin concentrations
4.
T cell subpopulations from serum, including CD4+ CD25+ CD127+ FoxP3+ Tregs 
Pharmacodynamics (Part 2 Only)
1. Change from baseline in additional plasma biomarkers on Day 0 and Day 28 (Reg3α, ST2, and 
TNFR1)


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 11 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Health Outcomes (Parts 1 and 2)
1.
Change from baseline in QoL as measured by the Functional Assessment of Cancer Therapy-Bone 
Marrow Transplant subscale version 4.0 instrument (FACT-BMT)
2.
Change from baseline in acute GvHD symptoms as measured by the Chronic GvHD Symptom Scale
3.
Change from baseline in health utility as measured by European Quality of 
Life-5 Dimensions-5 Level (EQ-5D-5L)
4.
Healthcare resource utilization:

Type of admission (Hospital, Intensive Care Unit and/or transplant unit)

Length of stay

Number of unscheduled physician office visits

Number of emergency room visits
5.
Medication:

Days on steroids
INVESTIGATIONAL PRODUCT(S), DOSE AND MODE OF ADMINISTRATION
Active Product
GLASSIA (human A1PI). Subjects will receive a loading dose of 90 mg/kg 
Baseline/Day0) followed by 30 mg/kg every other day (Days 2 to 12), then 
followed by 120 mg/kg weekly (Days 14 to 49). 
Dosage form: injection, solution
Dosage frequency: every other day (Days 0 to 12), then weekly (Days 14 to 49) 
Mode of Administration: IV
In combination with assigned therapy, all subjects in Parts 1 and 2 will receive 
2 mg/kg/day of methylprednisolone or equivalent steroid (either oral or IV per 
investigator’s discretion). Steroids will be tapered as appropriate, according to 
institutional practice and guidance provided in the protocol.
Control
(Part 2 only)
Human albumin in normal saline solution (see Pharmacy Manual for details)
Dosage form: injection, solution
Dosage frequency: every other day (Days 0 to 12), then weekly (Days 14 to 49)
Mode of Administration: IV
In combination with assigned therapy, all subjects will receive 2 mg/kg/day of 
methylprednisolone or equivalent steroid (either oral or IV per investigator’s 
discretion). Steroids will be tapered as appropriate, according to institutional 
practice and guidance provided in the protocol.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 12 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
SUBJECT SELECTION
Targeted Accrual
Part 1: approximately 20 evaluable subjects
Part 2: approximately 148 randomized subjects
Number of 
Groups/Arms/Cohorts
Part 1: 1 cohort
Part 2: 2 groups (GLASSIA or control) of 74 randomized subjects per group
Inclusion Criteria
1. Male or female subjects aged ≥18 years at the time of screening
2. Recipient of an HSCT
3. The disease indication for which the subject required HSCT must be in remission
4. Newly diagnosed acute GvHD, including lower GI involvement (modified International Bone Marrow 
Transplant Registry [IBMTR] Severity Stage 1 to 4 [>500 mL diarrhea/day]), with or without other 
organ system involvement. 
5. Willing to undergo or must have had a lower GI biopsy within 7 days of informed consent to confirm 
GI GvHD. Biopsy results are not needed to initiate treatment; however, if biopsy results are not 
consistent with aGvHD, treatment with GLASSIA will be discontinued. 
6. Subjects must be receiving systemic corticosteroids. Treatment with methylprednisolone/systemic 
steroids must have been initiated within 72 hours prior to the first dose of study treatment after 
enrollment.
7. Evidence of myeloid engraftment (absolute neutrophil count ≥0.5 x 109/L)
8. Lower GI GvHD manifested by diarrhea must have other causes of diarrhea ruled out (eg, negative for 
Clostridium difficile or cytomegalovirus [CMV] infection or oral magnesium administration)
9. Karnofsky Performance Score ≥50%
10. If female of childbearing potential, subject presents with a negative blood pregnancy test 
11. Females of childbearing potential with a fertile male sexual partner must agree to employ adequate 
contraception for the duration of the study. Adequate contraception is defined as using hormonal 
contraceptives or an intrauterine device combined with at least 1 of the following forms of 
contraception: a diaphragm, cervical cap or a condom
12. Males must use adequate contraception and must not donate sperm for the duration of the study. 
Adequate contraception for the male subject and his female partner is defined as using hormonal 
contraceptives or an intrauterine device combined with at least 1 of the following forms of 
contraception: a diaphragm, cervical cap or a condom
13. Subject is willing and able to comply with the requirements of the protocol


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 13 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Exclusion Criteria
1. Subject with manifestations of chronic GvHD
2. Subject with acute/chronic GvHD overlap syndrome
3. Subject whose GvHD developed after donor lymphocyte infusion
4. Subject with myocardial infarction within 6 months prior to enrollment or New York Heart 
Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular 
arrhythmias or electrocardiographic evidence of acute ischemia or active conduction system 
abnormalities. Prior to the first dose of study treatment, any electrocardiogram (ECG) abnormality at 
screening must be documented by the investigator as not medically relevant
5. Subject with evidence of recurrent malignancy
6. Subject with veno-occlusive disease (ie, sinusoidal obstruction syndrome)
7. Subject receiving GvHD treatment other than continued prophylaxis (eg, cyclosporine and/or
mycophenolate mofetil, etc) or corticosteroid therapy. In addition, a subject who received the first 
dose of corticosteroid therapy for acute GvHD with lower GI involvement more than 72 hours before 
the first dose of study treatment is not eligible for the study
8. Subject with severe sepsis involving at least 1 organ failure
9. Subject who is seropositive or positive in the nucleic acid test for human immunodeficiency virus
(HIV)
10. Subject with active hepatitis B or C
11. 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 
investigational device during the course of this study
12. If female, subject is pregnant or lactating at the time of enrollment, or has plans to become pregnant 
during the study
13. Subject with a serious medical or psychiatric illness likely to interfere with participation in the study
14. Subject is a family member or employee of the investigator
STATISTICAL ANALYSIS
Sample Size Calculation
The sample size for Part 1 was determined from an operational perspective and was not based on statistical 
power considerations. With 20 evaluable subjects and an assumed true response rate of 65%, the 
probability of observing an overall response rate of at least 55% is 87.8%. If the true response rate is 40%, 
the probability of observing an overall response rate of 55% or higher is less than 13%.
The sample size for Part 2 is based on the assumptions of a control group overall response rate of 40%
across strata; GLASSIA group overall response rate of 65% across strata; randomization ratio 1:1; 1-sided 
family wise Type I error rate of 0.025; Type II error rate of 0.20; and a group sequential design with 
1 interim look. Based on the sample size calculations, using a Cochran-Mantel-Haenszel chi-squared test, 
controlling the stratification factor, to detect the difference between the 2 groups, the primary analysis will 
require 67 evaluable subjects per group. Assuming a 10% early withdrawal rate, the target number of 
subjects will include 74 randomized subjects per group for a total of 148 randomized subjects.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 14 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Planned Statistical Analysis
For Part 1, all endpoints will be summarized with descriptive statistics. 
For Part 2, all statistical tests will be conducted at a 1-sided significance level of 2.5% unless otherwise 
specified. For Part 2, the primary endpoint of overall response rate at Day 28 will be analyzed using the 
Cochran-Mantel-Haenszel chi-squared test, controlling the stratification factor (lower GI involvement 
severity), to test the null hypothesis that the odds ratio is equal to 1 for Part 2 of the study. An unstratified 
comparison of the overall response rate at Day 28 will be conducted as a sensitivity analysis. The binary 
types of secondary efficacy endpoints, such as GI response rate, will be analyzed similarly to the primary 
endpoint. The time-to-event type of secondary endpoints, including overall survival and failure-free 
survival rate; all-cause, transplant-related, infection-related and GvHD-related mortality; and durations of 
any overall and any GI response will be analyzed using the Cox proportional hazard model. The change 
from baseline in acute GvHD grading will be analyzed with a shift table. All other secondary endpoints will 
be summarized with descriptive statistics.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 15 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
4. TABLE OF CONTENTS
1. STUDY PERSONNEL ................................................................................................. 2
1.1 Authorized Representative (Signatory) / Responsible Party .............................. 2
1.2 Study Organization................................................................................................. 2
2. SERIOUS ADVERSE EVENT REPORTING........................................................... 3
3. SYNOPSIS..................................................................................................................... 4
4. TABLE OF CONTENTS ........................................................................................... 15
5. LIST OF ABBREVIATIONS .................................................................................... 20
6. BACKGROUND INFORMATION .......................................................................... 22
6.1 Description of Investigational Product ............................................................... 22
6.1.1 GLASSIA........................................................................................................ 22
6.1.2 Control............................................................................................................ 23
6.2 Clinical Condition/Indication .............................................................................. 24
6.3 Population to be Studied ...................................................................................... 24
6.4 Findings from Nonclinical and Clinical Studies................................................. 25
6.4.1 Nonclinical Studies......................................................................................... 25
6.4.2 Clinical Studies............................................................................................... 25
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) 
to Human Subjects................................................................................................ 26
6.6 Compliance Statement.......................................................................................... 27
7. STUDY PURPOSE AND OBJECTIVES ................................................................. 28
7.1 Study Purpose ....................................................................................................... 28
7.2 Primary Objective................................................................................................. 28
7.3 Secondary Objectives ........................................................................................... 28
7.3.1 Efficacy ........................................................................................................... 28
7.3.2 Safety (Parts 1 and 2) .................................................................................... 29
7.3.3 Pharmacokinetics (Part 1 Only)................................................................... 29
7.4 Exploratory Objectives (Parts 1 and 2) .............................................................. 29
7.5 Exploratory Objectives (Part 2 Only)................................................................. 29
8. STUDY DESIGN......................................................................................................... 30
8.1 Brief Summary...................................................................................................... 30
8.2 Overall Study Design............................................................................................ 30
8.2.1 Part 1 Study Design ....................................................................................... 32


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 16 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
8.2.2 Part 2 Study Design ....................................................................................... 32
8.3 Duration of Study Period(s) and Subject Participation .................................... 34
8.4 Outcome Measures ............................................................................................... 34
8.4.1 Primary Outcome Measure (Parts 1 and 2) ................................................ 34
8.4.2 Secondary Outcome Measures ..................................................................... 34
8.4.2.1 Efficacy (Parts 1 and 2).......................................................................... 34
8.4.2.2 Safety Outcome Measures (Parts 1 and 2) ........................................... 35
8.4.2.3 Pharmacokinetic Outcome Measures (Part 1 Only)............................ 35
8.4.3 Exploratory Outcome Measures .................................................................. 36
8.4.4 Rationale for Endpoints ................................................................................ 37
8.5 Randomization and Blinding............................................................................... 38
8.5.1 Randomization ............................................................................................... 38
8.5.2 Blinding........................................................................................................... 39
8.5.3 Unblinding...................................................................................................... 39
8.6 Study Stopping Rules............................................................................................ 39
8.7 Investigational Product(s).................................................................................... 40
8.7.1 Packaging, Labeling, and Storage................................................................ 40
8.7.1.1 GLASSIA and Control........................................................................... 40
8.7.1.2 Conventional Steroid Treatment........................................................... 40
8.7.1.3 Anti-infective Prophylaxis ..................................................................... 40
8.7.2 Administration ............................................................................................... 40
8.7.3 Description of Treatment.............................................................................. 41
8.7.4 Investigational Product Accountability ....................................................... 41
8.8 Source Data ........................................................................................................... 42
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION .......... 43
9.1 Inclusion Criteria.................................................................................................. 43
9.2 Exclusion Criteria................................................................................................. 44
9.3 Withdrawal from Study Participation and Discontinuation of Study 
Treatment .............................................................................................................. 45
10. STUDY PROCEDURES .......................................................................................... 46
10.1 Informed Consent ............................................................................................... 46
10.2 Subject Identification Code................................................................................ 46
10.3 Screening and Study Visits................................................................................. 46
10.4 Medications and Non-Drug Therapies.............................................................. 46
10.5 Subject Diary....................................................................................................... 48
10.6 Subject Completion/Discontinuation ................................................................ 48
10.7 Procedures for Monitoring Subject Compliance............................................. 50
11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS........................ 50
11.1 Demographics and Baseline Characteristics.................................................... 50
11.2 CMV and HIV Testing ....................................................................................... 50


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 17 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
11.3 Lower GI Biopsy................................................................................................. 50
11.4 GvHD Staging/Assessment................................................................................. 51
11.5 Overall Response, GI Response, and GvHD VGPR........................................ 52
11.6 Chronic GvHD Assessment................................................................................ 52
11.7 Pharmacokinetic, Biomarker and Stool Sample Collection............................ 52
11.8 Functional Assessment of Cancer Therapy – Bone Marrow Transplant...... 53
11.9 Chronic GvHD Symptom Scale......................................................................... 54
11.10 European Quality of Life – 5 Dimensions – 5 Level ...................................... 54
11.11 Healthcare Resource Utilization...................................................................... 55
11.12 Mortality and Survival Assessments............................................................... 55
11.13 Adjudication Committee.................................................................................. 56
12. ASSESSMENT OF SAFETY................................................................................... 57
12.1 Adverse Events.................................................................................................... 57
12.1.1 Definitions..................................................................................................... 57
12.1.1.1 Serious Adverse Event.......................................................................... 57
12.1.1.2 Suspected Unexpected Serious Adverse Reaction (SUSAR)............. 58
12.1.1.3 Non-Serious Adverse Event ................................................................. 58
12.1.1.4 Unexpected Adverse Events................................................................. 58
12.1.1.5 Preexisting Diseases.............................................................................. 58
12.1.2 Assessment of Adverse Events.................................................................... 59
12.1.2.1 Severity .................................................................................................. 60
12.1.2.2 Causality................................................................................................ 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.................................... 62
12.6 Physical Examinations........................................................................................ 63
12.7 Clinical Laboratory Parameters........................................................................ 63
12.7.1 Hematology and Clinical Chemistry.......................................................... 63
12.7.2 Urinalysis...................................................................................................... 64
12.7.3 Assessment of Laboratory Values .............................................................. 64
12.7.3.1 Toxicity Grading Scale......................................................................... 64
12.7.3.2 Assessment of Abnormal Laboratory Values..................................... 64
12.7.4 Backup Samples and Biobanking............................................................... 65
12.8 Vital Signs............................................................................................................ 65
12.9 Electrocardiogram.............................................................................................. 65
12.10 Pregnancy Test.................................................................................................. 66
12.11 Recurrent Malignancy...................................................................................... 66
13. STATISTICS............................................................................................................. 67
13.1 Sample Size and Power Calculations ................................................................ 67
13.2 Analysis Sets........................................................................................................ 68
13.3 Handling of Missing, Unused, and Spurious Data........................................... 69


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 18 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
13.4 Methods of Analysis............................................................................................ 69
13.4.1 Primary Outcome Measure......................................................................... 70
13.4.2 Secondary Outcome Measures ................................................................... 70
13.4.3 Exploratory Outcome Measures ................................................................ 71
13.5 Planned Interim Analysis of the Study ............................................................. 72
14. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................... 73
15. QUALITY CONTROL AND QUALITY ASSURANCE...................................... 73
15.1 Investigator’s Responsibility.............................................................................. 73
15.1.1 Final Clinical Study Report........................................................................ 73
15.2 Training ............................................................................................................... 73
15.3 Monitoring........................................................................................................... 74
15.4 Safety Monitoring ............................................................................................... 74
15.5 Auditing ............................................................................................................... 74
15.6 Non-Compliance with the Protocol ................................................................... 75
15.7 Laboratory and Reader Standardization ......................................................... 75
16. ETHICS ..................................................................................................................... 76
16.1 Subject Privacy ................................................................................................... 76
16.2 Ethics Committee and Regulatory Authorities................................................ 76
16.3 Informed Consent ............................................................................................... 76
17. DATA HANDLING AND RECORD KEEPING................................................... 77
17.1 Confidentiality Policy ......................................................................................... 77
17.2 Study Documentation and Case Report Forms ............................................... 77
17.3 Document and Data Retention........................................................................... 78
18. FINANCING AND INSURANCE........................................................................... 78
19. PUBLICATION POLICY........................................................................................ 78
20. SUPPLEMENTS....................................................................................................... 79
20.1 Study Flow Chart................................................................................................ 79
20.2 Schedule of Study Procedures and Assessments.............................................. 81
20.3 Clinical Laboratory Assessments ...................................................................... 84
20.4 Toxicity Grading Scale for AEs......................................................................... 86
21. REFERENCES.......................................................................................................... 87
22. SUMMARY OF CHANGES.................................................................................... 92


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 19 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
INVESTIGATOR ACKNOWLEDGEMENT............................................................ 100
Tables
Table 1 Schedule of Study Procedures and Assessments (Parts 1 and 2)........................ 81
Table 2 Clinical Laboratory Assessments........................................................................ 84
Table 3 Mapping Conventions for AE Severity  (For AEs Not Described Within 
NCI CTCAE version 4.03) ....................................................................................... 86
Figures
Figure 1 Study Design for Baxalta Clinical Study 471501 Part 1................................... 79
Figure 2 Study Design for Baxalta Clinical Study 471501 Part 2................................... 80


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 20 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
5. LIST OF ABBREVIATIONS
Abbreviation
Definition
A1PI
alpha-1 proteinase inhibitor, also known as alpha-1 antitrypsin
AE
adverse event
AUC
area under the plasma concentration curve
CMV
Cytomegalovirus
CR
complete response
CRF
case report form
CTA
Clinical Trial Agreement
DMC
Data Monitoring Committee
EC
ethics committee
ECG
Electrocardiogram
eCRF
electronic case report form
EDTA
ethylenediaminetetraacetic acid
EMA
European Medicines Agency
EQ-5D-5L
European Quality of Life-5 Dimensions-5 Level
FACT-BMT
Functional Assessment of Cancer Therapy-Bone Marrow Transplant subscale 
version 4.0 instrument
FA set
Full Analysis set
FDA
Food and Drug Administration
GI
Gastrointestinal
GI CR/PR
Complete/partial gastrointestinal response
Gastrointestinal response is defined as GI CR + PR
GvHD
graft-versus-host disease
GvHD CR/PR/VGPR
Complete/partial/very good partial graft-versus-host disease response
Overall response is defined as GvHD CR + PR
HIV
human immunodeficiency virus
HSCT
hematopoietic stem cell transplantation
IB
investigator's brochure
IBMTR
International Bone Marrow Transplant Registry
ICH GCP
International Council for Harmonisation Guideline for Good Clinical Practice
IgA
immunoglobulin A
IL
Interleukin
IL-1RA
interleukin-1 receptor antagonist
INR
international normalized ratio


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 21 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Abbreviation
Definition
IP
investigational product
IRT
Interactive Response Technology
IV
intravenous(ly)
LOCF
last-observation-carried-forward
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NMC 
Non-medical complaint
PK
pharmacokinetic(s)
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
QoL
quality-of-life
Reg3α
regenerating islet-derived protein 3α
SAE
serious adverse event
SAER
serious adverse event report
SAF set
Safety Analysis set
SIC
subject identification code
ST2
suppression of tumorigenicity 2
Study treatment
GLASSIA or albumin (control)
SUSAR
Suspected Unexpected Serious Adverse Reaction
TNF
tumor necrosis factor
TNFR1
tumor necrosis factor receptor 1
Tregs
regulatory T cells
US
United States
US CFR
United States Code of Federal Regulations
VGPR
very good partial response


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 22 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
6. BACKGROUND INFORMATION
6.1 Description of Investigational Product
6.1.1 GLASSIA
GLASSIA (human alpha-1 proteinase inhibitor [A1PI]; also known as human alpha-1 
antitrypsin, Kamada-AAT or Kamada-API) is a stable, liquid, ready-to-use preparation of 
human A1PI. Alpha-1 proteinase inhibitor belongs to the family of serine protease 
inhibitors and is primarily produced in the liver and secreted into the circulation. In 
addition to its anti-protease activity, A1PI has anti-inflammatory, anti-apoptotic and 
immunomodulatory properties.1,2,3,4
GLASSIA is an injection solution prepared from human plasma collected from healthy 
volunteer blood donors in accordance with Food and Drug Administration (FDA) and 
European Medicines Agency (EMA) regulations. GLASSIA was approved in the United 
States (US) in 2010 JUL for chronic augmentation and maintenance therapy in 
individuals with emphysema due to congenital deficiency of A1PI.
In this 2-part study, GLASSIA will be administered intravenously (IV) in subjects with 
acute graft-versus-host disease (GvHD) with lower gastrointestinal (GI) involvement. 
GLASSIA will be administered at a dose of 90 mg/kg (Day 0) followed by 30 mg/kg 
every other day (Days 2 to 12), then followed by 120 mg/kg weekly (Days 14 to 49). 
Results from Part 1 will be used to determine whether continuation to Part 2 is warranted, 
if the criteria to initiate Part 2 are met.
Rationale for Dosing Regimen
The GLASSIA dosing regimen for this study was selected based on results from 
nonclinical mouse models of GvHD and the interim efficacy and pharmacokinetic (PK)
results from an ongoing Phase 1/2 study in subjects with steroid-refractory GI GvHD
(Study FHCRC 2571). In the interim analysis of Cohorts 1 and 2 in Study FHCRC 2571, 
efficacy was observed with doses of 30 or 60 mg/kg every other day (after induction with 
90 mg/kg on the first day of treatment), which resulted in plasma A1PI concentrations of 
2.5 to 3.5 mg/mL. The dose that Cohort 1 received (30 mg/kg every other day [after 
induction with 90 mg/kg]) led to a plasma level of A1PI in the high-normal range. 
Cohort 2 received 60 mg/kg every other day (after induction with 90 mg/kg) and had 
plasma A1PI levels that overlapped with Cohort 1 (especially the trough plasma 
concentration). In addition, the overall response in Cohort 1 was numerically greater than 
the overall response in Cohort 2. Recently published preliminary data with another A1PI 
product suggests that a dose similar to the Cohort 1 dose results in a similar outcome.5


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 23 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
As of 2016 JAN, 1 subject had been enrolled in Cohort 3; Cohort 3 receives 90 mg/kg 
every other day. The subject in Cohort 3 had a GI partial response (PR), a partial 
resolution of GI signs and symptoms. As the dose of A1PI was increased, there was not 
an increased rate of response, suggesting that the 30 mg/kg dose every other day (after 
induction with 90 mg/kg) may be sufficient to replace intestinal losses and to promote 
healing of the gut and resolution of GvHD.
In Study FHCRC 2571, 3 subjects who had responded at Day 28 subsequently relapsed 
2 or more weeks after the last dose of A1PI. This suggests that continued therapy beyond 
15 days may allow sustained response and reduce or prevent relapses of acute GvHD. 
Therefore, in the current protocol, subjects will receive weekly infusions (120 mg/kg) 
until Day 49 for maintenance. The dose and regimen will allow for the maintenance of 
plasma levels of A1PI in the high-normal range, despite ongoing losses of A1PI due to 
diarrhea. Less frequent doses can be justified by the data from Study FHCRC 2571
showing healing of the mucosal lesions and reduction of GI clearance of A1PI.
A loading dose of 90 mg/kg was used in Study FHCRC 2571 and is used in this study in 
order to reduce the time needed to achieve steady state plasma A1PI concentrations.
In the key nonclinical mouse models of GvHD, A1PI was dosed at 50 to 200 mg/kg every 
other day.6;7 Refer to Section 6.4 for a summary of the relevant nonclinical and clinical 
studies with GLASSIA and A1PI.
6.1.2 Control
In this protocol, study treatment is defined as GLASSIA or control. During Part 2 of the 
study, human albumin in normal saline solution will serve as the matching control (in 
volume, color and foaming characteristics) to GLASSIA. Albumin was chosen as the 
control because, as a protein, its physical properties will match those of GLASSIA, 
allowing the double-blind to be maintained. The placebo (albumin)-controlled, 
double-blind design used in Part 2 of this study is appropriate because there are currently
no FDA-approved treatments for acute GvHD. In this study, subjects will receive study 
treatment in addition to conventional steroid therapy, which is the current 
standard-of-care for acute GvHD; thus, the use of albumin as a control will allow the 
comparison of GLASSIA, in combination with the current standard-of-care, versus the 
current standard-of-care alone.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 24 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
6.2 Clinical Condition/Indication
Graft-versus-host disease is one of the most common complications of allogeneic 
hematopoietic stem cell transplantation (HSCT), a component of a treatment program for 
blood cancer and other blood disorders. Despite prophylactic treatment with 
immunosuppressive agents, acute GvHD occurs in 30% to 70% of patients undergoing 
HSCT and is associated with significant morbidity and mortality. Severe GI acute GvHD 
is estimated to have a mortality rate as high as 70% to 80%.8 Standard, frontline therapy 
for acute and chronic GvHD consists of glucocorticoids, but less than 40% of patients 
treated with steroids have durable complete responses (CRs) or PRs, a complete or partial 
resolution of all signs and symptoms of GvHD in all organs.9;10 The 1-year survival rate 
for subjects who do not respond to steroid therapy ranges from 5% to 30%.8;9;11;12,13,14
There is currently no FDA-approved treatment for acute GvHD. 
6.3 Population to be Studied
The population for this study will consist of male and female subjects ≥18 years of age 
who are recipients of an allogeneic HSCT and who have been newly diagnosed with 
acute GvHD with lower GI involvement (modified International Bone Marrow 
Transplant Registry [IBMTR] Severity Stage 1 to 4).15;16 Subjects with Stage 1 to 4 lower 
GI involvement have diarrhea >500 mL/day. Subjects must have evidence of myeloid 
engraftment. There are no restrictions on the prior conditioning treatments.
This population was selected because it has a high unmet medical need; as described in 
Section 6.2, severe acute GI GvHD is associated with high mortality. Furthermore, 
patients with acute GvHD with lower GI involvement with or without other organ 
involvement have a lower response rate to steroid treatment.13
In addition, nonclinical and clinical data support the hypothesis that administration of 
exogenous A1PI blocks pro-inflammatory cytokines and replaces intestinal losses 
(Section 6.4). This includes clinical data from Study FHCRC 2571 evaluating the 
treatment of subjects with GI GvHD with GLASSIA, in which endoscopic evaluation of 
patients with severe GI GvHD 1 week after completion of GLASSIA administration 
showed evidence of re-epithelialization of the bowel wall.17 Thus, it is expected that 
subjects with GI GvHD will benefit most from first-line treatment with GLASSIA, as the 
anticipated clinical benefit of healing of GvHD-related gut injury should be accompanied 
by a reduction in intestinal losses.
Refer to Section 6.4 for additional details of the nonclinical and clinical studies with A1PI 
and the rationale for GLASSIA in the treatment of acute GvHD with lower GI 
involvement.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 25 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
6.4 Findings from Nonclinical and Clinical Studies
6.4.1 Nonclinical Studies
Results from nonclinical studies demonstrated that administration of exogenous A1PI
significantly reduced the incidence and severity of GvHD in murine bone marrow 
transplant models.6;7 In addition, results from nonclinical studies showed that A1PI
administration interfered with the expression of pro-inflammatory cytokines such as 
interleukin (IL)-1, tumor necrosis factor (TNF) and IL-32, and was associated with
increased numbers of CD4+ CD25hi FoxP3+ regulatory T cells (Tregs) and CD8+/CD205+
dendritic cells in comparison with albumin-treated controls.18 Additionally, subjects with 
GI GvHD have been shown to lose endogenous A1PI in their stool. A correlation of stool 
content of A1PI (and A1PI clearance) with GvHD of the small bowel has been confirmed 
in pediatric 19 and in adult subjects.20 The loss of A1PI in stool is an expression of 
intestinal injury and presumably compromises the protective systemic and local effects of 
A1PI. On the basis of these results, the administration of exogenous A1PI may a) replace 
intestinal losses and b) block pro-inflammatory cytokines. The expected result would be 
healing of GvHD-related gut injury, which should also contribute to a reduction in 
intestinal losses. Furthermore, the resulting shifts in the cytokine milieu should lead to an 
environment that facilitates the establishment of T cell tolerance.3
Nonclinical PK studies in rabbits treated with a single bolus IV administration of 
GLASSIA showed that the half-life of GLASSIA during the Phase 1 elimination was 
16.3 hours; the maximum concentration, terminal half-life (Phase 2 half-life) and Phase 2 
elimination rate constants were 42 264 ± 3443 ng/mL, 68.13 ± 13.53 hours and 
-0.0046 ± 0.0014 hours-1, respectively. Nonclinical toxicology studies have evaluated 
acute and repeated dosing with GLASSIA in rats and rabbits; GLASSIA was well 
tolerated with no overt toxicities reported. Refer to the investigator’s brochure (IB) for 
further information on nonclinical studies with GLASSIA.
6.4.2 Clinical Studies
GLASSIA has been evaluated in 2 clinical studies in adult subjects with A1PI
deficiency, 1 clinical study in subjects aged 9 to 18 years with type 1 diabetes mellitus 
and 1 Phase 4 clinical study in healthy adult subjects. GLASSIA was generally safe 
and well tolerated in all studies; the majority of adverse events (AEs) reported were of 
mild or moderate severity. All serious adverse events (SAEs) reported in the clinical 
studies were assessed by the investigator as unrelated to GLASSIA. Three
treatment-emergent SAEs were reported in the studies: cholangitis, exacerbation of 
chronic obstructive pulmonary disease and pulmonary emboli. All 3 SAEs were 
reported in the Phase 2/3 study of adult subjects with A1PI deficiency.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 26 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
One subject in the Phase 2/3 study experienced a treatment-emergent serious adverse 
reaction (infective exacerbation of chronic obstructive pulmonary disease), considered 
possibly related to GLASSIA due to its temporal association.
One ongoing Phase 1/2 study is being conducted in subjects with steroid-refractory acute 
GvHD (Study FHCRC 2571). An interim analysis was conducted with the 12 subjects in 
Cohorts 1 and 2 in Study FHCRC 2571. Cohort 1 received a loading dose of GLASSIA 
of 90 mg/kg IV on Day 1, followed by 30 mg/kg every other day through Day 15. 
Cohort 2 received a loading dose of GLASSIA of 90 mg/kg IV on Day 1, followed by 
60 mg/kg every other day through Day 15. In the interim analysis, most AEs were of mild 
or moderate severity. Two subjects experienced bowel perforation 3 weeks and 2 months, 
respectively, after the last dose of GLASSIA. Neither AE resulted in death. Both AEs
were assessed by the investigator as possibly related to GLASSIA; the study’s Data 
Safety Monitoring Board reviewed the events and concluded that the 2 bowel perforation 
events were not related to GLASSIA, but instead were related to viral infections.
One fatal SAE in the study was assessed as possibly related to GLASSIA: liver failure, 
which occurred <30 days after the last dose of GLASSIA. Most AEs during the study 
were consistent with those expected in subjects undergoing HSCT or experiencing GvHD
and do not preclude further investigation of GLASSIA in GvHD.
The interim efficacy data from Study FHCRC 2571 showed that 8 of the 12 subjects had 
overall responses, 4 of which were CRs, and 4 of which were PRs. Six of the 12 subjects 
(50%) were alive at follow-up of up to 820 days at the time of the interim analysis. One 
of the 12 subjects died following the interim analysis. The subject in Cohort 3 died due to 
a fungal infection after the Day 28 assessments but was not included in the interim 
analysis.
6.5 Evaluation of Anticipated Risks and Benefits of the Investigational Product(s) to 
Human Subjects
GLASSIA was generally safe and well tolerated in the clinical studies of healthy adult 
subjects and subjects with A1PI deficiency and type 1 diabetes mellitus. In the 2 clinical 
studies in subjects with A1PI deficiency, the adverse reactions (ie, AEs assessed as 
related or possibly related to GLASSIA or temporally related to administration of 
GLASSIA) reported by >1 subject consisted of headache (6%) and dizziness (3%). In the 
ongoing clinical study in subjects with steroid-refractory acute GvHD, most AEs have 
been consistent with those expected in subjects undergoing HSCT or experiencing 
GvHD.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 27 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
GLASSIA may contain trace amounts of immunoglobulin A (IgA). Subjects with 
selective or severe IgA deficiency and with known antibodies to IgA have a greater risk 
of developing severe hypersensitivity and anaphylactic reactions. However, reactions due 
to IgA deficiency and anti-IgA antibodies are not expected in this study because of the 
immunosuppressive nature of the transplant procedure. 
Because the product is produced from human plasma, it may carry a risk of transmitting 
infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob disease agent. 
The risk of transmitting an infectious agent has been minimized by screening plasma 
donors for prior exposure to certain viruses, by testing for the presence of certain current 
virus infections and by inactivating and removing certain viruses during the 
manufacturing process. The risk of Creutzfeldt-Jakob disease transmission has been 
reduced by donor restriction and selection and the plasma derivative manufacturing 
process. In addition to the risks associated with GLASSIA, IV administration of 
GLASSIA could lead to inflammation or infection at the catheter contact area.
The preclinical literature for A1PI, in combination with the interim efficacy results from
Study FHCRC 2571, suggests that GLASSIA has the potential to provide significant 
clinical benefit as a first-line treatment in acute GvHD.
Refer to the IB for further guidance related to GLASSIA.
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, April 1996), 
Title 21 of the US Code of Federal Regulations (US CFR), the European Union
Directives 2001/20/EC and 2005/28/EC and applicable national and local regulatory 
requirements.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 28 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
7. STUDY PURPOSE AND OBJECTIVES
7.1 Study Purpose
The purpose of the study is to evaluate the safety and efficacy of GLASSIA as an add-on 
biopharmacotherapy to standard-of-care steroid treatment as the first-line treatment in 
subjects with acute GvHD with lower GI involvement.
7.2 Primary Objective
This study has 2 study parts:
The primary objective of Part 1 is to confirm the safety and efficacy of GLASSIA
administered at a dose of 90 mg/kg (Baseline/Day 0) followed by 30 mg/kg every other 
day (Days 2 to 12), then followed by 120 mg/kg weekly (Days 14 to 49), when added to 
conventional steroid therapy, in subjects with acute GvHD with Stage 1 to 4 lower GI 
involvement, as assessed by treatment response at Day 28, and to determine whether 
continuation to Part 2 is warranted.
The primary objective of Part 2 is to confirm the safety and efficacy of the GLASSIA 
dose regimen studied in Part 1 versus albumin (control), when added to conventional 
steroid therapy, in subjects with acute GvHD with Stage 1 to 4 lower GI involvement, as 
assessed by treatment response at Day 28.
7.3 Secondary Objectives
7.3.1 Efficacy
Part 1:
1.
To evaluate the treatment effects of GLASSIA, when added to conventional steroid 
therapy, on other clinical outcomes, such as rate, duration and magnitude of 
response; all-cause, transplant-related, infection-related and GvHD-related
mortality; overall survival; GvHD-free survival; treatment failure-free survival and 
incidence of chronic GvHD.
Part 2:
1.
To determine the efficacy of GLASSIA versus albumin (control), when added to 
conventional steroid therapy, on other clinical outcomes, such as rate, duration and 
magnitude of response; all-cause, transplant-related, infection-related and 
GvHD-related mortality; overall survival; GvHD-free survival; treatment 
failure-free survival and incidence of chronic GvHD. 


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 29 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
7.3.2 Safety (Parts 1 and 2)
1.
To evaluate the safety and tolerability of GLASSIA in addition to conventional 
steroid therapy (Part 1) and compared with conventional steroid treatment alone 
(Part 2)
2.
To assess the incidence of recurrence of primary malignancies
3.
To assess the incidence and type of infection
7.3.3 Pharmacokinetics (Part 1 Only)
1.
To characterize the PK profile of GLASSIA, when added to conventional steroid 
treatment, using noncompartmental analysis methodology
7.4 Exploratory Objectives (Parts 1 and 2)
1.
To assess A1PI plasma and stool concentrations and clearance in stool
2.
To characterize the PK profile of GLASSIA, when added to conventional steroid 
treatment, using a population PK approach
3.
To assess biomarkers in plasma (ie, inflammatory cytokines IL-2, IL-6, IL-8, and 
IL-10; IL-1 receptor antagonist [IL-1RA] and T cell subpopulations, including 
CD4+ CD25+ CD127+ FoxP3+ Tregs) and stool (ie, calprotectin concentrations)
4.
To assess quality-of-life (QoL), GvHD symptoms and healthcare resource 
utilization for GLASSIA treatment as a first-line add-on therapy
7.5 Exploratory Objectives (Part 2 Only)
1.
To assess the following additional biomarkers in plasma on Day 0 and Day 28: 
Reg3α, ST2, and TNFR1


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 30 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
8. STUDY DESIGN
8.1 Brief Summary
This is a 2-part Phase 2/3, prospective, controlled, randomized, multicenter study in 
subjects with acute GvHD with Stage 1 to 4 lower GI involvement. Part 1 will be a
nonrandomized, open-label, active treatment, multicenter study to evaluate the safety, 
efficacy and PK of GLASSIA in approximately 20 evaluable subjects. Part 2 will be a 
randomized, parallel-group, double-blind, multicenter study to compare the safety and 
efficacy of GLASSIA versus albumin (control) in a total of 148 randomized subjects 
(74 subjects/group).
Eligible subjects for Parts 1 and 2 must be recipients of an allogeneic HSCT and have 
been newly diagnosed with acute GvHD with Stage 1 to 4 lower GI involvement 
(modified IBMTR).15;16 Subjects must have evidence of myeloid engraftment. There are 
no restrictions on the prior conditioning treatments. Subjects may continue any prior 
therapy used for prophylaxis (eg, cyclosporine and/or mycophenolate mofetil) at a stable 
dose from baseline if the therapy agent was not discontinued and restarted after initiating 
first-line steroid treatment for acute GvHD. Subjects may have been treated with 
corticosteroids for acute GvHD with lower GI involvement for a maximum of 72 hours 
prior to initiation of GLASSIA administration.
All eligible subjects in Parts 1 and 2 will be given 2 mg/kg/day of methylprednisolone or 
equivalent steroid (either IV or oral per investigator discretion) and IV study treatment 
(defined as GLASSIA in Part 1; GLASSIA or control in Part 2). Steroids will be tapered 
as appropriate, according to institutional practice and guidance provided in Section 8.2.
Results from Part 1 will be used to determine whether continuation to Part 2 is warranted.
All efficacy data will be adjudicated by an Adjudication Committee (Section 11.13).
8.2 Overall Study Design 
The overall study design is illustrated in Figure 1 (Part 1) and Figure 2 (Part 2).
For Parts 1 and 2, screening for eligibility will occur from Days -2 to -1. After screening, 
subjects will undergo the baseline visit, which is also Day 0. 
Subjects will complete study visits either as inpatient or outpatient visits, in accordance 
with institutional practice. Following the first 2 weeks of every other day study treatment
(GLASSIA in Part 1; GLASSIA or control in Part 2), subjects will undergo visits on the 
following days to have study treatment administered (through Day 49) and to perform 
safety follow-up and study procedures: Days 14, 21, 28, 35, 42, 49 and 56.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 31 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
All subjects will be treated with study treatment in combination with conventional steroid 
treatment through Day 49, or until treatment failure, withdrawal from treatment or 
withdrawal from the study, whichever comes first. Thereafter, subjects will be treated 
with standard-of-care for the remainder of their participation in the study based on the 
investigator’s discretion. Subjects who are withdrawn from study treatment will continue 
to be followed through at least Day 28 (refer to Section 10.6), unless the subject 
withdraws consent.
Steroid treatment after Day 49 will be at the investigator’s discretion. Subjects will visit 
the site for follow-up visits on Days 56, 100, 180 and 365. In the event that it is not 
feasible for the subject to visit the site at Day 365, the visit may be conducted with a 
phone call.
Subjects will also receive standard antibiotic, antifungal and antiviral prophylactic 
treatment through Day 180 or per institutional guidelines.
Assessments of vital signs, clinical laboratory data (hematology and chemistry), local 
tolerability and AEs will be performed throughout the study.
Steroid Taper
Tapering of steroids may commence after a subject responds to therapy (overall response, 
also referred to as GvHD response, as defined in Section 8.4.1); however, the dose of 
steroid should not be tapered below 2 mg/kg/day (methylprednisolone or equivalent dose) 
before Day 2 or below 0.25 mg/kg/day (methylprednisolone or equivalent dose) before 
Day 28. 
Subjects who discontinue study treatment (GLASSIA or control) will be treated with 
standard-of-care for the remainder of their participation in the study.
Treatment Failures
Prior to Day 28 in Parts 1 and 2, subjects must be withdrawn from study treatment if a 
second-line treatment for acute GvHD is introduced. Second-line treatment may be 
introduced per investigator discretion prior to Day 28 if a subject experiences disease 
progression and/or new organ involvement or no change in acute GvHD status after at 
least 7 days of study treatment (Day 6). Subjects who experience recurrent malignancy 
will also be withdrawn from study treatment (Section 12.11).
An increase in steroid dose following steroid taper does not constitute second-line 
treatment; however, steroid treatment at methylprednisolone doses (or equivalent) of 
greater than 2 mg/kg/day for GvHD treatment will be considered a treatment failure.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 32 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Subjects classified as treatment failures will be included in the analysis, but will not be 
counted as either CR or PR for the primary (overall response) or key secondary (GI 
response) endpoints. Subjects classified as treatment failures will not be replaced.
All subjects will be followed up at Days 100, 180 and 365.
Data Monitoring Committee
A Data Monitoring Committee (DMC) will independently evaluate safety and efficacy 
data (Section 15.4). The recommendations of the DMC will be based on the analysis of 
safety in Parts 1 and 2 and the interim analysis of Part 2 (Section 8.2.2).
8.2.1 Part 1 Study Design
Part 1 of this study is a nonrandomized, open-label, multicenter, clinical study evaluating 
GLASSIA in combination with conventional steroid treatment.
The target population for Part 1 will include approximately 20 evaluable subjects
(Cohort 1).
All eligible subjects will be given GLASSIA with a loading dose of 90 mg/kg (Day 0) 
followed by GLASSIA 30 mg/kg every other day (Days 2 to 12), then followed by 
120 mg/kg weekly (Days 14 to 49) in combination with 2 mg/kg/day of 
methylprednisolone or equivalent steroid.
For Part 1, subjects who are treated but subsequently found to have a lower GI biopsy 
inconsistent with GvHD will be replaced to ensure a total of 20 evaluable subjects.
Interim Analyses
An analysis will take place when the last subject in Part 1 has completed the GvHD 
response assessment at Day 28, to determine whether continuation from Part 1 to Part 2 is 
warranted (Section 13.5).
8.2.2 Part 2 Study Design
Criteria for Initiation of Part 2
The following decision criteria will be followed for the initiation of Part 2 of the study:

The study may be terminated by the sponsor for toxicities or adverse safety findings 
observed in Part 1 of the study

The study may proceed to Part 2 if an overall response rate of ≥55% is observed at 
Day 28 in Part 1, as determined by the sponsor


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 33 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.

The study may be stopped for futility if the overall response rate is <55% at Day 28

The sponsor will be the final arbiter of the decision to move into Part 2. The 
decision will be based on the totality of cumulative data available (eg, rate of 
GvHD CR, PR and very good partial response [VGPR]; rate of GI CR and PR, 
including response at Days 28 and 56; duration of any overall and any GI response; 
and GvHD-free survival)
Study Design for Part 2
Part 2 of this study is a randomized, parallel-group, double-blind, placebo
(albumin)-controlled, clinical study comparing GLASSIA in combination with
conventional steroid treatment versus albumin (control) in combination with conventional 
steroid treatment. Part 2 of the study is planned to enroll approximately 148 randomized 
subjects (74 subjects/group) in order to obtain 134 evaluable subjects, provided that the 
study does not stop early for futility. 
On Day 0, eligible subjects will be randomized 1:1 in a double-blind fashion to the 
following groups:
Group 2a: GLASSIA with a loading dose of 90 mg/kg (Day 0) followed by 
GLASSIA 30 mg/kg every other day (Days 2 to 12), then followed by 120 mg/kg 
weekly (Days 14 to 49), in combination with 2 mg/kg/day methylprednisolone or 
equivalent steroid
Group 2b: Albumin (control) in combination with 2 mg/kg/day methylprednisolone 
or equivalent steroid
Randomization will be stratified, using a single stratification factor: lower GI 
involvement severity (2 strata), as described in Section 8.5.1. Subjects who are 
randomized to treatment in Part 2 and subsequently discontinue treatment or withdraw 
from the study will not be replaced. 
Interim Analyses
An interim analysis will take place when approximately 50% of the primary endpoint 
data in Part 2 has been collected (Section 13.5). An independent, unblinded biostatistics 
team will perform the interim analysis and present the results to the DMC. The study will 
be analyzed for futility based on the primary endpoint. The DMC will provide 
recommendations to the sponsor based on the interim analysis. However, the sponsor 
may decide to stop the trial even if statistical criteria for futility are not observed.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 34 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
8.3 Duration of Study Period(s) and Subject Participation
The overall duration of the study is approximately 3 years from study initiation (ie, first 
subject enrolled) to study completion (ie, last subject last visit). The recruitment period is 
expected to be approximately 2 years.
The subject participation period is approximately 52 weeks from enrollment to subject 
completion (ie, last study visit), unless prematurely discontinued.
8.4 Outcome Measures
8.4.1 Primary Outcome Measure (Parts 1 and 2)
The primary outcome measure for Parts 1 and 2 is the proportion of subjects achieving 
overall response at Day 28. The overall response is defined as GvHD CR + PR, as 
defined below:

GvHD CR is complete resolution of all signs and symptoms of acute GvHD in all 
organs without intervening salvage

GvHD PR is improvement of 1 stage in 1 or more organs involved in GvHD 
without progression in other organs
8.4.2 Secondary Outcome Measures
8.4.2.1 Efficacy (Parts 1 and 2)
Key Secondary Efficacy Outcome Measures
1.
Proportion of subjects achieving GI response at Day 28. Gastrointestinal response 
is defined as GI CR + PR, which are defined as follows:

GI CR is defined as
a) Able to eat; not requiring parenteral nutrition, and
b) Passing primarily formed stools

GI PR is defined as
a) Decrease in need for parenteral nutrition to ≤50% of required calories; and
b) Reduction of stool volume by ≥50%, without ileus 
Other Secondary Efficacy Outcome Measures
1.
Proportion of subjects achieving overall response at Day 56
2.
Change from baseline in acute GvHD grading at Days 28, 56 and 180
3.
Incidence of chronic GvHD at Days 100, 180 and 365


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 35 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
4.
Duration of any overall response
5.
Duration of any GI response
6.
Overall survival through Days 100, 180 and 365
7.
Transplant-related mortality at Days 28, 56, 100 and 180
8.
Failure-free survival at Days 100 and 180 
9.
GvHD-free survival at Days 28, 56, 100 and 180
10. Infection-related mortality at Days 28, 56, 100 and 180
11. GvHD-related mortality at Days 28, 56, 100 and 180
12. All-cause mortality at Days 28, 56, 100 and 180
8.4.2.2 Safety Outcome Measures (Parts 1 and 2)
1.
The incidence and severity of all AEs, related AEs, all SAEs, related SAEs and 
temporally-associated AEs
2.
Change from baseline in clinical laboratory safety parameters and vital signs
3.
Incidence of recurrence of primary malignancies through Days 180 and 365
4.
Incidence and type of infection (eg, bacterial, fungal, viral, etc) at Days 28, 56, 180 
and 365
8.4.2.3 Pharmacokinetic Outcome Measures (Part 1 Only)
The following noncompartmental analysis PK parameters by day and/or dosing 
frequency, as applicable, will be assessed:
1.
Area under the plasma concentration curve (AUC) from time zero to the last 
quantifiable activity
2.
AUC from time zero to time “t”
3.
Systemic clearance at steady state
4.
Maximum plasma concentration at steady state
5.
AUC from time zero to infinity 
6.
Apparent volume of distribution at steady state
7.
The terminal half-life
8.
Mean residence time
9.
Trough plasma A1PI levels at steady state


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 36 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
8.4.3 Exploratory Outcome Measures
Efficacy (Parts 1 and 2)
1.
Proportion of subjects achieving GvHD VGPR at Day 28. A GvHD VGPR is 
defined as follows:
Skin: no rash, or residual erythematous rash involving <25% of the body 
surface, without bullae (residual faint erythema and hyperpigmentation do not 
count) 
Liver: total serum bilirubin concentration <2 mg/dL or <25% of baseline at 
enrollment
Gut: tolerating food or enteral feeding, predominantly formed stools, no overt GI 
bleeding or abdominal cramping and no more than occasional nausea or 
vomiting
2.
Cumulative steroid dose at Days 28, 56, 100 and 180
3.
Steroid dose at Days 28, 56 and 100
4.
Proportion of subjects achieving GI CR and GI PR at Days 28, 56 and 180 at each 
baseline GvHD severity grade (B, C and D)
Pharmacokinetics (Parts 1 and 2)
An exploratory, mixed-effects population PK model will be developed from the Part 1 
and Part 2 data. Potential exploratory outcome measures include, but are not limited to, 
the following:
1.
Systemic clearance at steady state
2.
Maximum plasma concentration at steady state
3.
Apparent volume of distribution at steady state
4.
The terminal half-life
5.
Trough plasma A1PI levels at steady state 
Pharmacodynamics (Parts 1 and 2)
1.
Change from baseline in plasma and stool concentrations of A1PI
2.
A1PI clearance in stool
3.
Change from baseline in plasma biomarkers (eg, cytokines IL-2, IL-6, IL-8, and 
IL-10; and IL-1RA) and stool calprotectin concentrations
4.
T cell subpopulations including CD4+ CD25+ CD127+ FoxP3+ Tregs 


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 37 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Pharmacodynamics (Part 2 Only)
1.
Change from baseline in additional plasma biomarkers on Day 0 and Day 28
(Reg3α, ST2, and TNFR1)
Health Outcomes (Parts 1 and 2)
1.
Change from baseline in QoL as measured by the Functional Assessment of Cancer 
Therapy-Bone Marrow Transplant subscale version 4.0 instrument (FACT-BMT)
2.
Change from baseline in acute GvHD symptoms as measured by the Chronic 
GvHD Symptom Scale
3.
Change from baseline in health utility as measured by European Quality of Life-5 
Dimensions-5 Level (EQ-5D-5L)
4.
Healthcare resource utilization:
Type of admission (hospital, Intensive Care Unit and/or transplant unit)
Length of stay
Number of unscheduled physician office visits
Number of emergency room visits
5.
Medication:
Days on steroids
8.4.4 Rationale for Endpoints
The primary efficacy endpoint of overall response (GvHD response) was chosen because 
multiple studies have shown an association between overall response at fixed time points 
and an improvement in mortality up to 2 years post-transplant.21;22;23;24;25;26;27;28 Overall
response 28 days after initiating treatment was associated with lower non-relapse 
mortality at up to 2 years and has been supported as an endpoint in the guidelines issued 
by an expert panel of the American Society for Blood and Marrow Transplant and results 
from other studies.25;26;27;28
The key secondary endpoint of GI response was chosen because of the evidence of the 
role of A1PI in GvHD with lower GI involvement (Section 6).
The IBMTR Severity Index was chosen to allow comparison with other studies using the 
IBMTR criteria, including Study FHCRC 2571.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 38 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
The exploratory endpoint of GvHD VGPR was chosen on the basis of the 
recommendation of Martin et al.23 A VGPR approximates a GvHD CR and identifies 
subjects with excellent responses who may have outcomes similar to subjects with a 
GvHD CR.
8.5 Randomization and Blinding
8.5.1 Randomization
Part 1 is a nonrandomized, open-label, active treatment clinical study. In Part 1, if the 
subject has met all eligibility criteria, the Eligibility Criteria Form will be completed by 
the site, signed by the investigator and faxed to the Medical Monitor for review. The 
form must be signed by the Medical Monitor prior to proceeding with enrolling the 
subject in the Interactive Response Technology (IRT). 
Part 2 is a randomized, double-blind, concurrent, placebo (albumin)-controlled clinical 
study. In order to minimize/avoid bias, subjects will be randomly assigned to 1 of 
2 treatment regimens (investigational product [IP] or control) in equal numbers. 
Randomization codes will be maintained by the sponsor or the sponsor’s representative.
In Part 2, if the subject has met all eligibility criteria, the Eligibility Criteria Form will be 
completed by the site, signed by the investigator and faxed to the Medical Monitor for 
review. The form must be signed by the Medical Monitor prior to proceeding with 
randomizing the subject. The site will then request the study treatment assignment using 
the IRT system.
All randomized subjects will be managed by IRT. The IRT will assign subjects their 
6-digit subject number at the time of randomization and will provide the vial number of 
the blinded study treatments to be administered at each visit. Subjects will not be 
re-randomized.
Subjects will be randomized to treatment via stratified randomization, using a single 
stratification factor. Separate randomization schedules will be used within each strata of 
lower GI involvement severity, based on the modified IBMTR grading system 
(Section 11.4). The 2 strata will be as follows:

Lower GI Stage 4, or Stage 3 with other organ(s) involved

Lower GI Stage 1 to 2, or Stage 3 with no other organ involvement


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 39 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
8.5.2 Blinding
The solutions for GLASSIA and albumin (control) in Part 2 will be identical in volume, 
color and foaming characteristics. Blinding of the study treatment will be performed by 
an unblinded pharmacist at the study site, who will also prepare the study treatment for 
administration.
An independent, unblinded biostatistics team will perform the interim analysis of Part 2 
and will present the results to the DMC (Section 13.5).
The treatment each subject receives will not be disclosed to the investigator, study site 
staff, subject, sponsor or contract research organization, including at the interim analysis 
of Part 2, unless the subject meets criteria for unblinding (Section 8.5.3).
8.5.3 Unblinding
The process for breaking the blind in Part 2 will be handled through the IRT. 
Investigators are strongly discouraged from requesting the blind be broken for an 
individual subject, unless there is a subject safety issue that requires unblinding and 
would change subject management. Any site that breaks the blind under inappropriate 
circumstances may be asked to discontinue its participation in the study. If the blind is 
broken, it may be broken for only the subject in question.
The sponsor and the contract research organization must be notified immediately if a 
subject and/or investigator is unblinded during the course of the study. Pertinent 
information regarding the circumstances of unblinding of a subject’s treatment code must 
be documented in the subject’s source documents and electronic case report forms 
(eCRFs).
The study will be unblinded after all subjects complete Day 56 of Part 2 or discontinue 
study treatment and the Adjudication Committee adjudicates all efficacy data through 
Day 56 of Part 2 (Section 11.13).
8.6 Study Stopping Rules 
Stopping rules will not be established for Part 1 of this study. The study may be stopped 
at the sponsor’s discretion for any reason, including lack of efficacy, toxicities or adverse 
safety findings.
Part 2 of the study may be stopped based on the DMC’s nonbinding recommendation 
from the interim analysis (Section 13.5) if the statistical criteria for futility are met. The 
study may also be stopped at the sponsor’s discretion for any reason.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 40 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
8.7 Investigational Product(s)
8.7.1 Packaging, Labeling, and Storage
8.7.1.1 GLASSIA and Control
Dosage Form: Injection, solution
Packaging: GLASSIA and albumin (control) are supplied by the sponsor as 
ready-for-use, sterile, non-pyrogenic liquid preparations in single-dose containers of 
50 mL. GLASSIA containers contain approximately 1 g of functional A1PI in glass vials. 
The control vials contain human albumin 20% in 50 mL normal saline solution in glass 
vials (for EU/ROW), or Flexbumin 25% in 50 mL in normal saline solution in plastic IV 
bags (for US).
Labeling: The product is labeled according to the valid regulatory requirements for 
clinical studies. For Part 2, an unblinded pharmacist will prepare and blind the study 
treatment.
Storage: GLASSIA and control must be stored under refrigerated conditions (2°C to 8°C 
or 36°F to 46°F). Do not freeze the product. If removed from refrigeration, the product 
must be used in 1 month. Do not use if expiration date is exceeded or carton is damaged.
8.7.1.2 Conventional Steroid Treatment
The conventional steroid treatment (methylprednisolone or equivalent steroid) will be 
supplied by the investigators per their institutional practice. The conventional steroid 
treatment will be labeled by the manufacturer and will not be re-labeled by the sponsor; 
the product must be stored in accordance with the package label.
8.7.1.3 Anti-infective Prophylaxis
Subjects will receive standard antibacterial, antifungal and antiviral prophylactic 
treatment including that for herpes simplex virus, varicella-zoster virus and CMV (eg, 
acyclovir or valacyclovir), through Day 180 or per institutional guidelines.
8.7.2 Administration
For instructions for the preparation, blinding and administration of study treatment, 
please refer to the Pharmacy Manual. GLASSIA and control will be administered by IV 
infusion, through either a central indwelling catheter or peripheral line, per the 
investigator’s discretion.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 41 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
The dose (in mg) will be calculated based on the subject’s body weight at screening. The 
screening body weight will be used for the dose calculation throughout the study.
Study treatment will be prepared for administration and blinded by an unblinded 
pharmacist at the site. The volume of infusion solution (in mL) will be calculated based 
on the content of functional A1PI (potency) in the study treatment vials, as specified in 
the certificate of analysis to be provided with a particular GLASSIA lot and as printed on 
the vial. Note that the functional activity of A1PI is independent from the particle load of 
a GLASSIA manufacturing lot. Single-dose containers of albumin will have a 
corresponding label with a “hypothetical” functional A1PI potency.
The investigator will record in the eCRF whether study treatment was administered via a 
central indwelling catheter or peripherally and whether the line was flushed after 
administration.
The conventional steroid treatment (either IV or oral per investigator discretion) should 
be administered according to the package label.
8.7.3 Description of Treatment
In Part 1, Cohort 1 will receive a GLASSIA loading dose of 90 mg/kg (Baseline/Day 0) 
followed by GLASSIA 30 mg/kg every other day (Days 2 to 12), then followed by 
120 mg/kg weekly (Days 14 to 49). Refer to Section 6.1.1 for the rationale for the dose 
selection.
In Part 2, subjects will receive GLASSIA (Group 2a) or control (Group 2b). Group 2a 
will receive the same dose and regimen of GLASSIA that was used in Part 1.
In Parts 1 and 2, all subjects will receive 2 mg/kg/day of methylprednisolone or 
equivalent steroid (either oral or IV per investigator’s discretion). Steroids will be tapered 
as appropriate, according to institutional practice and the guidance provided in 
Section 8.2.
8.7.4 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 
includes the subject identification code (SIC), dispensation date and amount dispensed. 


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 42 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
All remaining partially used and/or unused IP(s) will be returned to the sponsor or 
sponsor’s representative after study completion/termination, or destroyed with the 
permission of the sponsor in accordance with applicable laws and study site procedures. 
If IP(s) is to be destroyed, the investigator will provide documentation in accordance with 
sponsor’s specifications.
8.8 Source Data
Per ICH GCP, source data are defined as all information in original records and certified 
copies of original records of clinical findings, observations or other activities in a clinical 
trial that are necessary for the reconstruction and evaluation of the trial. Source data are 
contained in source documents (original records or certified copies), which may be in 
paper and/or electronic format. Source data for this study comprise the following: 
hospital records, medical records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries, 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 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. The use 
of subject diaries is described in Section 10.5.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 43 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
9. SUBJECT SELECTION, WITHDRAWAL, AND DISCONTINUATION
9.1 Inclusion Criteria
Subjects who meet ALL of the following criteria are eligible for Parts 1 and 2 of this 
study:
1.
Male or female subjects aged ≥18 years at the time of screening
2.
Recipient of an HSCT
3.
The disease indication for which the subject required HSCT must be in remission
4.
Newly diagnosed acute GvHD, including lower GI involvement (modified 
International Bone Marrow Transplant Registry [IBMTR] Severity Stage 1 to 4 
[>500 mL diarrhea/day]), with or without other organ system involvement. 
5.
Willing to undergo or must have had a lower GI biopsy within 7 days of informed 
consent to confirm GI GvHD. Biopsy results are not needed to initiate treatment; 
however, if biopsy results are not consistent with aGvHD, treatment with 
GLASSIA will be discontinued.
6.
Subjects must be receiving systemic corticosteroids. Treatment with 
methylprednisolone/systemic steroids must have been initiated within 72 hours 
prior to the first dose of study treatment after enrollment.
7.
Evidence of myeloid engraftment (absolute neutrophil count ≥0.5 x 109/L)
8.
Lower GI GvHD manifested by diarrhea must have other causes of diarrhea ruled 
out (eg, negative for Clostridium difficile or cytomegalovirus [CMV] infection or
oral magnesium administration)
9.
Karnofsky Performance Score ≥50% 29
10. If female of childbearing potential, subject presents with a negative blood 
pregnancy test 
11. Females of childbearing potential with a fertile male sexual partner must agree to 
employ adequate contraception for the duration of the study. Adequate 
contraception is defined as using hormonal contraceptives or an intrauterine device 
combined with at least 1 of the following forms of contraception: a diaphragm,
cervical cap or a condom
12. Males must use adequate contraception and must not donate sperm for the duration 
of the study. Adequate contraception for the male subject and his female partner is 
defined as using hormonal contraceptives or an intrauterine device combined with 
at least 1 of the following forms of contraception: a diaphragm, cervical cap or a 
condom
13. Subject is willing and able to comply with the requirements of the protocol


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 44 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
9.2 Exclusion Criteria
Subjects who meet ANY of the following criteria are not eligible for this study:
1.
Subject with manifestations of chronic GvHD
2.
Subject with acute/chronic GvHD overlap syndrome
3.
Subject whose GvHD developed after donor lymphocyte infusion
4.
Subject with myocardial infarction within 6 months prior to enrollment or New 
York Heart Association Class III or IV heart failure, uncontrolled angina, severe 
uncontrolled ventricular arrhythmias or electrocardiographic evidence of acute 
ischemia or active conduction system abnormalities. Prior to the first dose of study 
treatment, any electrocardiogram (ECG) abnormality at screening must be 
documented by the investigator as not medically relevant
5.
Subject with evidence of recurrent malignancy
6.
Subject with veno-occlusive disease (ie, sinusoidal obstruction syndrome)
7.
Subject receiving GvHD treatment other than continued prophylaxis (eg, 
cyclosporine and/or mycophenolate mofetil, etc) or corticosteroid therapy. In 
addition, a subject who received the first dose of corticosteroid therapy for acute 
GvHD with lower GI involvement more than 72 hours before the first dose of study 
treatment is not eligible for the study
8.
Subject with severe sepsis involving at least 1 organ failure
9.
Subject who is seropositive or positive in the nucleic acid test for human 
immunodeficiency virus (HIV)
10. Subject with active hepatitis B or C
11. 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 investigational device during the course of this 
study
12. If female, subject is pregnant or lactating at the time of enrollment, or has plans to 
become pregnant during the study
13. Subject with a serious medical or psychiatric illness likely to interfere with 
participation in the study
14. Subject is a family member or employee of the investigator


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 45 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
9.3 Withdrawal from Study Participation and Discontinuation of Study Treatment
Any subject may voluntarily withdraw at any time consent for continued participation in 
the study and data collection. Every effort should be made prior to enrollment to ensure 
subjects are willing to comply with study procedures and assessments. The reason for 
withdrawal will be recorded on the End of Study CRF. 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.
Assessments to be performed at the termination visit (including in cases of withdraw or 
discontinuation) are described in Section 10.6 and Section 20.2.
Whenever possible, all subjects who prematurely withdraw from the study will be 
followed through Day 28 or 2 weeks after the last dose of study treatment, whichever 
comes later (refer to Section 10.6 for additional details), unless otherwise indicated 
below.
Subjects will be discontinued from study treatment for the following reasons:

The subject has a lower GI biopsy within 7 days of informed consent that in the 
opinion of a pathologist is inconsistent with acute GvHD (Section 11.3). If the 
results are obtained prior to the first dose of study treatment, the subject will be 
withdrawn from the study prior to study treatment for Part 1 and without being 
randomized for Part 2.

The subject becomes pregnant. 

The subject starts a second-line treatment for acute GvHD prior to Day 28
(Section 8.2). 

The subject experiences recurrent malignancy (Section 12.11). 

If the Sponsor medical monitor or the investigator deem it is in the best interest of 
the subject
Subjects who discontinue study treatment and/or the study will not be replaced.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 46 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
10. STUDY PROCEDURES
10.1 Informed Consent
Any patient who provides informed consent (ie, signs and dates the informed consent 
form and assent form, if applicable) is considered a subject in the study.
10.2 Subject Identification Code
The following series of numbers will comprise the SIC: protocol identifier (eg, 090701) 
to be provided by the sponsor, 2- or 3-digit number study site number (eg, 02) to be 
provided by the sponsor and 3- or 4-digit subject number (eg, 0003) reflecting the order 
of providing informed consent. For example, the third subject who signed an informed 
consent form at study site 02 will be identified as Subject 090701-020003. All study 
documents (eg, CRFs, clinical documentation, sample containers, drug accountability 
logs, etc.) will be identified with the SIC. Additionally, a uniquely coded SIC(s) is 
permitted as long as it does not contain a combination of information that allows 
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.
10.3 Screening and Study Visits
The study site is responsible for maintaining a 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 re-screened, the End of Study CRF should be 
completed, and a new ICF, new SIC and new CRF are required for that subject.
The overall study design is illustrated in Figure 1 (Part 1) and Figure 2 (Part 2). 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
Clinical Laboratory Assessments.
On visits at which study treatment is administered, all assessments and sample 
collections, except for PK and stool samples as indicated in Table 2, must be performed 
prior to the start of study treatment administration.
10.4 Medications and Non-Drug Therapies 
The following medications and non-drug therapies are not permitted within 30 days
before study entry and during the course of the study:

Medications:


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 47 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.

Any IP other than GLASSIA (GLASSIA is also not permitted prior to the 
first administration of study treatment)

Any GvHD treatment (eg, antithymocyte globulin, anti-TNF drugs) other 
than 1) prophylactic therapies started prior to study entry and 
2) corticosteroid therapy as described below

Prophylactic GvHD therapies started after study entry

Enteral corticosteroids

Non-drug therapies:

Any investigational device
A subject who has taken any of these medications or received any of these non-drug 
therapies will be discontinued from study treatment, and the medication/non-drug therapy
will be considered a protocol deviation.
Second-line GvHD treatment may be introduced per investigator discretion prior to 
Day 28 if a subject experiences disease progression and/or new organ involvement or no 
change in acute GvHD status after at least 7 days of study treatment (Day 6). Subjects 
receiving second-line treatment prior to Day 28 must be withdrawn from study treatment; 
if the subject meets the criteria for introducing second-line treatment prior to Day 28, the 
second-line treatment will not be considered a protocol deviation. Refer to Section 8.2 for 
additional details about second-line treatment.
The following medications and non-drug therapies are permitted before study entry and 
during the course of the study:

Medications:

Corticosteroid therapy for acute GvHD with lower GI involvement (treatment 
must have been initiated no more than 72 hours prior to the first 
administration of study treatment)

Prophylactic GvHD therapies started prior to study entry (eg, cyclosporine 
and/or mycophenolate mofetil, etc)

Topical corticosteroids including ophthalmic steroids

Any medications other than those listed as not permitted above

Non-drug therapies:

Any non-drug therapies other than those listed as not permitted above


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 48 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
10.5 Subject Diary
A paper subject diary will be provided to each subject at each visit as outlined in Table 1 
to record the following information:
Healthcare resource utilization
Unscheduled physician office visits
Emergency room visits
For any admissions after the initial hospitalization, the type of admission 
(hospital, Intensive Care Unit or transplant unit); the reason for admission and 
the length of stay
Subjects will be trained on use of the diary to record all healthcare utilization at baseline 
and following at their discharge for treatment of acute GvHD. The diary will be provided 
in paper format and remain with the subject for the duration of the study. The investigator 
will review the diary for completeness and request missing information periodically and 
in a timely manner. Untoward events recorded in the diary will be reported as AEs 
according to the investigator’s discretion and clinical judgment.
The subject diary will serve as a primary source record and remain at the study site. 
Entries in the subject diary will be transferred into the appropriate collection device. Any 
entry in the collection device that does not correspond with an entry in the subject diary 
will be explained by the investigator in source documentation.
10.6 Subject Completion/Discontinuation
A subject is considered to have completed the study when he/she ceases active 
participation in the study 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, 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 through the study follow-up period should be recorded on the 
appropriate CRF. 


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 49 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Every effort will be made to have discontinued subjects complete the study 
completion/termination visit. If the study completion/termination visit is done as an 
additional, unscheduled visit, the assessment results shall be recorded with the study 
completion/termination visit. If a subject terminates participation in the study and does 
not return for the study 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 study 
completion/termination visit (including in cases of withdraw or discontinuation) can be 
found in Supplement 20.2 Schedule of Study Procedures and Assessments.
Subjects who discontinue study treatment prior to Day 28 will complete the Day 28 visit 
on Day 28 (±1 day). If at least 2 weeks have passed since the last dose of study treatment, 
the Day 28 visit will serve as the study completion/termination visit. If Day 28 is less 
than 2 weeks following the last dose of study treatment, subjects will complete the 
Day 28 visit and then the study completion/termination visit 2 weeks (±1 day) after the 
last dose of study treatment. In this event, the study completion/termination visit will 
consist of an office visit with the same assessments as the Day 365 visit.
Subjects who discontinue study treatment after Day 28 will complete the study 
completion/termination visit as an office visit 2 weeks (±1 day) after the last dose of 
study treatment. Subjects who withdraw from the study after Day 56 will be encouraged 
to complete the study completion/termination visit at the time of discontinuation. In the 
event that it is not feasible for the subject to visit the site at the study 
completion/termination visit after Day 56, the visit may be conducted with a phone call.
Subjects who discontinue study treatment will not attend any other subsequent visits 
other than Day 28 and the study completion/termination visit (if applicable), except as 
needed for follow-up of recovering/resolving AEs (see Section 12.1.2).
In the event of subject discontinuation due to an 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. 


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 50 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
10.7 Procedures for Monitoring Subject Compliance
All study procedures are to be performed under the direct supervision of the 
investigator/a licensed healthcare professional at the study site, and thus, no separate 
procedures will be used to monitor subject compliance.
11. ASSESSMENT OF EFFICACY AND PHARMACOKINETICS
11.1 Demographics and Baseline Characteristics
At screening, the following subject demographics will be collected:

Gender

Date of birth

Race and ethnicity (where permitted by local regulations)

Smoking status
At screening, the following subject baseline characteristics will be collected: medical, 
surgical and transplant history, including the date and source of HSCT.
11.2 CMV and HIV Testing
At screening and at the visits indicated in Table 1, subjects will be tested for CMV, using 
antigenemia or polymerase chain reaction–based assays according to institutional 
guidelines. Subjects with evidence of CMV viremia (based on either assay) will receive 
antiviral therapy based on the investigator’s standard practice. Subjects may be tested for 
CMV at additional visits not indicated in Table 1, per institutional guidelines.
At screening, subjects will be tested for HIV using the antibody or nucleic acid test. If 
HIV testing was performed within the 3 months prior to screening, the results of the 
earlier tests may be used instead.
11.3 Lower GI Biopsy
Subjects will have a lower GI biopsy within 7 days of informed consent. If a biopsy was 
performed within 3 days prior to screening, results from that biopsy may be used instead. 
The type of lower GI biopsy is at the investigator’s discretion based on their standard 
institutional practice. If in the opinion of a pathologist, the results of the lower GI biopsy 
are inconsistent with acute GvHD, the subject will be withdrawn from the study. Results 
of the biopsy will not be required to assess eligibility prior to the first dose of study 
treatment, but are required for continuation in the study.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 51 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
11.4 GvHD Staging/Assessment
At screening and at the visits indicated in Table 1, GvHD will be assessed for severity. 
Grading of GvHD will be performed by the investigator according to the modified 
IBMTR grading system 15, which classifies the degree of involvement of each organ 
system by stage on a scale of 0 to 4 and the grade of severity of acute GvHD on a scale of 
A to D. The IBMTR grading system is modified on the basis of UpToDate 15 and is 
summarized below.
The degree of skin involvement is staged depending upon the degree and severity of the 
lesions as follows:

Stage 1: Maculopapular rash over <25% of body area

Stage 2: Maculopapular rash over 25 to 50% of body area

Stage 3: Generalized erythroderma

Stage 4: Generalized erythroderma with bullous formation, often with 
desquamation
The degree of GI involvement is staged based upon the severity of diarrhea as follows:

Stage 1: Diarrhea 500 to 1000 mL/day

Stage 2: Diarrhea 1000 to 1500 mL/day

Stage 3: Diarrhea 1500 to 2000 mL/day

Stage 4: Diarrhea >2000 mL/day OR pain OR ileus
The degree of liver involvement is staged based upon the serum total bilirubin level as 
follows:

Stage 1: Bilirubin 2 to 3 mg/dL

Stage 2: Bilirubin 3 to 6 mg/dL

Stage 3: Bilirubin 6 to 15 mg/dL

Stage 4: Bilirubin >15 mg/dL


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 52 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
The modified IBMTR grading system defines the severity of acute GVHD as follows:

Grade A: Stage 1 skin involvement alone (maculopapular rash over <25% of the 
body) with no liver or gastrointestinal involvement

Grade B: Stage 2 skin involvement and/or Stage 1 to 2 gut or liver involvement

Grade C: Stage 3 involvement of any organ system (generalized erythroderma; 
bilirubin 6.1 to 15.0 mg/dL; diarrhea 1500 to 2000 mL/day)

Grade D: Stage 4 involvement of any organ system (generalized erythroderma with 
bullous formation; bilirubin >15 mg/dL; diarrhea >2000 mL/day OR pain OR ileus)
The investigator will record the grade of GvHD (A through D) and the stage for each 
organ system (0 to 4) in the eCRF.
11.5 Overall Response, GI Response, and GvHD VGPR
At the visits indicated in Table 1, the investigator will assess the subject for overall and 
GI response, as well as GvHD VGPR, which are defined in the following sections:

Overall response: Section 8.4.1

GI response: Section 8.4.2.1

GvHD VGPR 23: Section 8.4.3
11.6 Chronic GvHD Assessment
At screening and Days 100, 180 and 365, the investigator will assess the subject for 
chronic GvHD and acute/chronic GvHD overlap syndrome, based on the investigator’s 
standard practice. The investigator will record the assessment in the eCRF.
11.7 Pharmacokinetic, Biomarker and Stool Sample Collection
Samples of whole blood will be obtained in a 10-mL Vacutainer® containing heparin 
anticoagulant for the determination of A1PI and selected metabolites, as well as 
biomarkers, in human plasma. Blood samples will be obtained prior to the first study 
treatment administration and at the visits and times indicated in Table 2. If study 
treatment is administered peripherally (Section 8.7.2), the PK samples should be taken 
from the opposite arm as the study treatment administration, if possible. If study 
treatment is administered via a central indwelling catheter, the PK samples may be taken 
from the same infusion line if the infusion line is flushed prior to collection of the sample
and the first 3 mL of blood is discarded. 


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 53 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Stool samples will be collected for assessment of A1PI levels and clearance and 
calprotectin concentrations. One sample will be collected prior to the first dose of study 
treatment (either during screening or on Day 0 prior to the start of study treatment 
administration). A stool sample will also be collected during the 24-hour period after 
initiation of study treatment on Days 0 and 12 and during the 24-hour period on Days 28 
and 56. The Day 28 stool sample must be collected prior to the start of study treatment 
administration. For inpatient visits, stool samples will be collected at the site. For 
outpatient visits, the sample can be collected at the site or can be collected at home and 
returned to the study site.
Refer to the Laboratory Manual for details of sample volumes and handling.
The following information will be captured for blood and stool sample collection in each 
subject’s eCRF:
1.
Subject’s SIC 
2.
Time and date of start of previous study treatment infusion
3.
Time and date of each blood and stool sample collected
4.
Time and date of subject’s most recent ingestion of food prior to sample collection
(blood sample only)
5.
Whether the blood sample was collected through a central or peripheral line
6.
If the blood sample was collected through a peripheral line, whether it was
collected through the same arm or the opposite arm, as the study treatment 
administration 
Biomarkers to be assessed in Parts 1 and 2 include cytokines IL-2, IL-6, IL-8, and IL-10;
IL-1RA; T cell subpopulations, including CD4+ CD25+ CD127+ FoxP3+ Tregs; and stool
calprotectin concentrations; in Part 2 only, the following biomarkers will also be 
assessed: Reg3α, ST2, and TNFR1. The cytokines will be measured by enzyme-linked 
immunosorbent assay. The T cells will be measured using epigenetic cell counting.
11.8 Functional Assessment of Cancer Therapy – Bone Marrow Transplant
Quality-of-life will be assessed with the FACT-BMT at the visits indicated in Table 1. 
The FACT-BMT is a 37-item scale comprised of a general core questionnaire, the 
FACT-G, which evaluates the health-related QoL of subjects receiving treatment for 
cancer, and a specific module, BMT Concerns, that addresses disease and treatment-
related questions specific to BMT. The FACT-G core questionnaire assesses 4 domains:


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 54 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Physical Well-being, Social/Family Well-being, Emotional Well-being and Functional 
Well-being. Each domain can be scored, with higher scores indicating better functioning.
The FACT-BMT, Chronic GvHD Symptom Scale and EQ-5D-5L should be collected 
before any other assessments are performed at the visit.
11.9 Chronic GvHD Symptom Scale
Symptoms of GvHD will be assessed with the Chronic GvHD Symptom Scale at the 
visits indicated in Table 1. The Chronic GvHD Symptom Scale is a 30-item validated 
scale that measures the extent to which the subject is bothered by chronic GVHD 
symptoms in the following domains: skin, energy, lung, nutrition, psychological, eye and 
mouth. Responses are captured on a 5-point Likert scale (“no symptoms, or not bothered 
at all,” “slightly bothered,” “moderately bothered,” “bothered quite a bit” or “extremely 
bothered”). Scores for each domain are converted to a 0 to 100 scale, with higher scores 
indicating a greater degree to which the subject is bothered by the symptoms.
Although the scale collects chronic GvHD symptoms, several of the domains are also 
applicable to acute GvHD. There is no validated symptom scale that is specific to acute 
GvHD.
The FACT-BMT, Chronic GvHD Symptom Scale and EQ-5D-5L should be collected 
before any other assessments are performed at the visit.
11.10 European Quality of Life – 5 Dimensions – 5 Level
Health utility will be assessed with the EQ-5D-5L 30 instrument at the visits indicated in 
Table 1. The EQ-5D-5L is a standardized subject-administered measure of health-related 
QoL states consisting of 5 dimensions (mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression) each of which can take 1 of 5 responses. The 
responses record 5 levels of severity (no problems/slight problems/moderate 
problems/severe problems/extreme problems) within a particular EQ-5D dimension.
The FACT-BMT, Chronic GvHD Symptom Scale and EQ-5D-5L should be collected 
before any other assessments are performed at the visit.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 55 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
11.11 Healthcare Resource Utilization
Healthcare resource utilization information will be recorded by the subject in the subject 
diary (Section 10.5) and by the investigator in the eCRF. The investigator will record the 
date of hospital discharge in the eCRF for the hospitalization that was ongoing at the time 
of the initiation of study treatment. In the subject diary, the subject will record the 
number and length of stay (in days) of: emergency room visits, hospital stays, intensive 
care admissions and urgent care center visits. After reviewing the subject diary with the 
subject, the investigator will enter the healthcare resource utilization data in the eCRF at 
the visits indicated in Table 1. These data will be collected to assess the economic impact 
of treatment with GLASSIA.
11.12 Mortality and Survival Assessments
All-cause, transplant-related, infection-related and GvHD-related mortality will 
be calculated as the time from HSCT to death; the cause of death will be based on 
the investigator’s assessment. The date and cause of death, if applicable, will be 
collected in the eCRF at the visits indicated in Table 1. The following definitions will be 
used by the investigator to assess the cause of death. These categories are not mutually 
exclusive, and the investigator will select all applicable categories:

Transplant-related mortality: death related to transplantation (including deaths 
related to GvHD)

Infection-related mortality: death related to infection (including infections related to 
HSCT)

GvHD-related mortality: death related to GvHD

Other cause: any death not related to transplant, infection or GvHD
Failure-free survival, GvHD-free survival and overall survival will be collected in the 
eCRF at the visits indicated in Table 1.
Failure-free survival is determined by the investigator and defined as the absence of all
3 of the following criteria:

Need for second-line treatment for acute GvHD
Second-line treatment is defined as any additional systemic treatment used for 
steroid nonresponsive treatment of acute GvHD. Methylprednisolone (or equivalent 
steroid) doses greater than 2 mg/kg/day required for the treatment of GvHD will 
also be considered second-line therapy


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 56 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.

Non-relapse mortality
Non-relapse mortality is defined as death during continuous complete remission

Recurrent malignancy
11.13 Adjudication Committee
An adjudication committee will review and adjudicate all efficacy data prior to statistical 
analysis. During Part 2 of the study, the committee will be blinded to study treatment 
assignment, until the committee has adjudicated all data through Day 56 and the study 
has been unblinded. The committee will be composed of experts in the fields of 
oncology, hematology or immunology who specialize in HSCT and are not participating 
as investigators in the study. The experts will adjudicate all efficacy data in both parts of 
the study. Adjudication of Part 1 efficacy data will not be required prior to initiating 
Part 2 of the study.
The adjudication committee’s responsibilities, definitions and operating procedures will 
be defined in a charter; the committee will maintain records of all its meetings.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 57 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
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 an 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 one or 
more of the following criteria:

Outcome is fatal/results in death (including fetal death)

Is life-threatening – defined as an event in which the subject was, in the judgment 
of the investigator, at risk of death at the time of the event; it does not refer to an 
event that hypothetically might have caused death had it been more severe.

Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization – inpatient hospitalization refers to any inpatient admission, 
regardless of length of stay.

Results in persistent or significant disability/incapacity (ie, a substantial disruption 
of a person’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect

Is a medically important event – a medical event that may not be immediately life-
threatening or result in death or require hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the definitions above. Examples of such events are: 
Intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependence or drug abuse
Reviewed and confirmed seroconversion for HIV, hepatitis A virus, 
hepatitis B virus, hepatitis C virus, hepatitis E virus or parvovirus B19


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 58 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Uncomplicated pregnancies, following maternal or paternal exposure to 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 Suspected Unexpected Serious Adverse Reaction (SUSAR)
Any suspected adverse reaction to study treatment (ie, including active comparators) that 
is both serious and unexpected. 
The event(s) must meet all of the following:

Suspected adverse reaction

Serious

Unexpected

Assessed as related to study treatment
Once determined to meet the criteria for a SUSAR, an SAE should be submitted to 
regulatory agencies expeditiously. 
12.1.1.3 Non-Serious Adverse Event
A non-serious AE is an AE that does not meet the criteria of an SAE.
12.1.1.4 Unexpected Adverse Events
An unexpected AE is an AE whose nature, severity, specificity or outcome is not 
consistent with the term, representation or description used in the Reference Safety 
Information. “Unexpected” also refers to the AEs that are mentioned in the IB or 
prescribing information as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the product, but are not specifically mentioned as 
occurring with the particular product under investigation. The expectedness of AEs will 
be determined by the sponsor using the IB and prescribing information as the Reference 
Safety Information. This determination will include considerations such as the number of 
AEs previously observed, but not on the basis of what might be anticipated from the 
pharmacological properties of a product.
12.1.1.5 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 after IP exposure, the event must 
be described on the AE CRF.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 59 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
For medical events occurring between study entry and IP exposure, see Section 12.3
Untoward Medical Occurrences.
12.1.2 Assessment of Adverse Events
For the purposes of this study, changes in the severity or duration of GvHD experienced 
after the first IP exposure are collected as an efficacy endpoint and thus are not reportable 
on the AE CRF, nor will they be included in the analysis of AEs.
Symptoms or diagnostic findings of GvHD, such as skin rashes, abnormal liver function 
tests, diarrhea, ileus and bowel perforation, should be collected on the AE CRF only if 
there is an increase in the severity, duration or frequency AND if they begin after first 
exposure to IP.
All other AEs from the first IP exposure until study completion 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 or 30 days after the 
study completion/termination visit, whichever comes first. The follow-up information 
will be documented in the AE CRF. 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 protocol-specified procedures of IMP use such as overdosing, 
underdosing, withdrawal, omission, incorrect route of administration, and use of a 
product other than the IMP, standard care of the underlying disease or treatment of a 
TEAE shall be recorded in the Protocol Deviation Form.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 60 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Any pregnancy that occurs after administration of IP will be reported on a Pregnancy 
Report Form.
12.1.2.1 Severity
The investigator will assess the severity of each AE using his/her clinical expertise and 
judgment based on the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) version 4.03. In the event an AE is not described in the 
NCI CTCAE version 4.03, the severity grades will be mapped to the terms listed in 
Table 3. For assessing the severity of AEs resulting from laboratory values, see 
section 12.7.3.2.
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


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 61 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.

Probably related (both circumstances must be met)

Follows a strong temporal relationship to the administration of IP, which may 
include but is not limited to the following: 
o
Reappearance of a similar reaction upon re-administration (positive 
rechallenge)
o
Positive results in a drug sensitivity test (skin test, etc.)
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 1 week of 
study treatment administration, the investigator shall provide the alternative etiology. 
These causality definitions will also be used to assess the relationship of an AE with a 
study-related procedure(s), if necessary.
12.2 Urgent Safety Measures
An urgent safety measure is an immediate action taken, which is not defined by the 
protocol, in order to protect subjects participating in a clinical trial from immediate harm. 
Urgent safety measures may be taken by the sponsor or clinical investigator and may 
include any of the following: 

Immediate change in study design or study procedures

Temporary or permanent halt of a given clinical trial or trials

Any other immediate action taken in order to protect clinical trial participants from 
immediate hazard to their health and safety
The investigator may take appropriate urgent safety measures in order to protect subjects 
against any immediate hazard to their health or safety. The measures should be taken 
immediately and may be taken without prior authorization from the sponsor. In the 
event(s) of an apparent immediate hazard to the subject, the investigator will notify the 
sponsor immediately by phone and confirm notification to the sponsor in writing as soon 
as possible, but within 1 calendar day after the change is implemented. The sponsor will 
also ensure the responsible ethics committee(s) (EC(s)) and relevant competent 
authority(s) are notified of the urgent safety measures taken in such cases according to 
local regulations.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 62 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
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 12.1.1). 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. These events will not be considered as 
SAEs and will not be included in the analysis of SAEs. 
For the purposes of this study, also each non-serious untoward medical occurrence 
experienced by a subject undergoing endoscopy or other procedure to obtain a biopsy for 
the diagnosis of GvHD before the first IP exposure will be recorded on the AE CRF; 
these events will not be considered as AEs and will not be included in the analysis of 
AEs. 
12.4 Non-Medical Complaints
A non-medical complaint (NMC) is any alleged product deficiency that relates to 
identity, quality, durability, reliability, safety and performance of the product but did not 
result in an AE. NMCs include but are not limited to the following:

A failure of a product to exhibit its expected pharmacological activity and/or design 
function, eg reconstitution difficulty

Missing components

Damage to the product or unit carton

A mislabeled product (eg, potential counterfeiting/tampering)

A bacteriological, chemical, or physical change or deterioration of the product 
causing it to malfunction or to present a hazard or fail to meet label claims
Any NMCs of the product will be documented on an NMC form and reported to the 
sponsor within 1 business day. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis according to procedures.
12.5 Medical, Medication and Non-Drug Therapy History
At screening, the subject’s medical history will be described for the following body 
systems including severity (defined in Section 12.1.2.1) or surgery and start and end 
dates, if known: eyes, ears, nose and throat; respiratory; cardiovascular; GI; 
musculoskeletal; neurological; endocrine; hematopoietic/lymphatic; dermatological; and 
genitourinary.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 63 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
All medications taken and non-drug therapies received from providing informed consent
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 1), a physical 
examination will be performed including 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 12.1.1.5), 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
12.7.1 Hematology and Clinical Chemistry
The hematology panel will consist of complete blood count (hemoglobin, hematocrit, 
erythrocytes [ie, red blood cell count] and leukocytes [ie, white blood cell count]) with 
differential (ie, basophils, eosinophils, lymphocytes, monocytes, neutrophils), mean 
corpuscular volume, mean corpuscular hemoglobin concentration and platelet counts. 
The clinical chemistry panel will consist of sodium, potassium, chloride, bicarbonate, 
total protein, albumin, alanine aminotransferase, aspartate aminotransferase, total 
bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine and glucose.
The coagulation panel will consist of prothrombin time (PT), partial thromboplastin time 
(PTT) and international normalized ratio (INR).
Blood will be obtained for assessment of hematology, clinical chemistry and coagulation 
panel parameters at screening and other study visits indicated in Table 2. Clinical 
laboratory assessments should also be performed whenever clinically indicated.
Hematology and clinical chemistry assessments will be performed on 
ethylenediaminetetraacetic acid (EDTA)–anticoagulated whole blood and serum, 
respectively, at the local laboratory. The coagulation panel assessment will also be 
performed at the local laboratory.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 64 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
12.7.2 Urinalysis
The urinalysis assessments will consist of color, specific gravity, pH, protein, glucose, 
ketones, bilirubin, urobilinogen, blood, nitrate, leukocyte esterase and microscopic 
examination (red and white blood cells, bacteria and casts). Urine samples will be 
obtained at screening and other study visits indicated in Table 2. Urinalysis will be 
performed at the local laboratory.
12.7.3 Assessment of Laboratory Values
12.7.3.1 Toxicity Grading Scale
Laboratory values will be evaluated according to the NCI CTCAE version 4.03 toxicity
grading scale by the investigator.
12.7.3.2 Assessment of Abnormal Laboratory Values 
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 a new AE (see definition in Section 12.1) or if the 
value is related to a previously recorded AE. Any clinically significant abnormal 
laboratory finding associated with a pre-existing condition (described in Section 12.1.1.5) 
or GvHD will not constitute an AE, unless judged by the investigator to be more severe 
than expected for the subject’s condition. The investigator will also record the severity 
grading (only if 3 or 4) within the respective laboratory page of the eCRF for a clinically 
significant laboratory value that constitutes an AE, and the severity grades for the sign, 
symptom or medical diagnosis in the AE page of the eCRF. Regarding clinically 
significant abnormal laboratory values that are adverse events, only the highest severity 
grading will be reported in the eCRF. Regardless of the severity grade, an AE will be 
followed until resolution or until no longer deemed necessary by the investigator.
If the abnormal value was not clinically significant, the investigator will indicate the 
reason, ie due to periodic variation, 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 abnormal value that persists should be followed at the 
discretion of the investigator.
Regarding laboratory abnormal values that are adverse events, only the highest grading 
will be reported in the eCRF. Regardless of the grade, the AE will be followed until 
resolution or until no longer deemed necessary by the investigator.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 65 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
12.7.4 Backup Samples and Biobanking
Backup samples taken and stored short-term may be used for example for re-testing, 
follow-up of an AE(s) or other test results and/or assay development for this study only. 
After study testing is completed, the remaining samples may be stored in a coded form 
for no more than 2 years after the final study report has been completed and then the 
samples will be destroyed.
Backup samples from a subject who has withdrawn consent will not be used for 
additional testing after the subject withdraws consent.
For this study, no samples will be taken or stored long-term in biobank(s) for future 
analyses.
12.8 Vital Signs
Vital signs will include body temperature (°C or °F), respiratory rate (breaths/min), pulse 
rate (beats/min) and systolic and diastolic blood pressure (mmHg). Height (in or cm) and 
weight (lb or kg) will also be collected. 
Vital signs will be measured at screening and within 30 minutes before and after 
administration of IP at the study visits indicated in Table 1. Height will be collected only 
at the screening visit. Blood pressure will be measured when subjects are in the sitting 
position; measurements in the supine position will also be acceptable if the subject is too 
ill to sit.
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 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.
12.9 Electrocardiogram
An ECG will be performed at screening to assess eligibility. Subjects should be in a 
supine or semi-supine position for at least 5 minutes prior to the assessment. 
All ECG printouts must be reviewed by the investigator or a medically qualified member 
of the site staff and annotated to indicate any clinical finding. Prior to the first dose of 
study treatment, any ECG abnormality must be documented by the investigator as not 
medically relevant


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 66 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
The ECG assessments (normal vs abnormal) are to be recorded on the CRF. For each 
assessment, the investigator will determine whether the assessment is considered an AE 
(see definition in Section 12.1 and record the sign, symptom, or medical diagnosis on the 
AE CRF). Additional tests and other evaluations required to establish the significance or 
etiology of an abnormal assessment, or to monitor the course of an AE should be 
obtained when clinically indicated. Any abnormal assessment that persists should be 
followed at the discretion of the investigator.
12.10 Pregnancy Test
A serum pregnancy test will be performed for females of childbearing potential only at 
screening and Day 56.
12.11 Recurrent Malignancy
At screening and all visits during the study, subjects will be assessed for recurrent 
malignancy. Recurrent malignancy must be confirmed by a biopsy, per standard 
institutional practice. The investigator will record the presence or absence of recurrent 
malignancy in the eCRF.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 67 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
13. STATISTICS
13.1 Sample Size and Power Calculations
Part 1: 
The sample size for Part 1 was determined from an operational perspective and was not 
based on statistical power considerations. With 20 evaluable subjects and an assumed 
true response rate of 65%, the probability of observing an overall response rate of at least 
55% is 87.8%. If the true response rate is 40%, the probability of observing an overall 
response rate of 55% or higher is less than 13%.
Part 2:
The primary endpoint for Part 2 is the overall response rate at Day 28.
The null hypothesis for Part 2 is that there is no difference in the overall response rate at 
Day 28 between the 2 treatment groups. The alternative hypothesis is that the overall 
response rate at Day 28 of the GLASSIA group is higher than that of the control group.
To determine the sample size for Part 2, the following assumptions were used: 
1.
Control group overall response rate of 40% across strata
2.
GLASSIA group overall response rate of 65% across strata
3.
Randomization ratio 1:1
4.
1-sided family wise Type I error rate of 0.025
5.
Type II error rate of 0.20 (ie, power=80%)
6.
A group sequential design with 1 interim look will be applied to the study. The 
gamma error spending function 31 with a parameter -2 will be used for beta 
spending (nonbinding). The interim analysis will take place when approximately 
50% of the primary endpoint data has been accumulated
SAS version 9.4, PROC SEQDESIGN with stop=both and nonbinding option for beta,
and a gamma parameter of -40 for alpha spending (and hence no alpha spent) and -2 for 
beta spending was used to calculate this design.
Based on the sample size calculations, using a Cochran-Mantel-Haenszel chi-squared
test, controlling the stratification factor, to detect the difference between the 2 groups, the 
primary analysis will require 67 evaluable subjects per group. Assuming a 10% early 
withdrawal rate, the target number of subjects will include 74 randomized subjects per 
group for a total of 148 randomized subjects.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 68 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
The early withdrawal rate will be monitored in a blinded manner, and if found to be 
greater or less than 10%, sample size assumptions may be revised.
13.2 Analysis Sets
Part 1
The Efficacy Analysis set will include all subjects who are evaluable for overall 
response at Day 28. Subjects who receive at least 1 dose of study treatment and who have 
a lower GI biopsy that is consistent with acute GvHD will be considered evaluable.
The Per-Protocol Analysis set will include all subjects who received at least 1 dose of 
study treatment, meet all key eligibility criteria, and have no major or clinically 
significant protocol deviations. Major protocol deviations that will lead to exclusion from 
this set will be determined prior to each database lock.
The Safety Analysis (SAF) set will consist of all subjects who receive at least 1 dose of 
study treatment.
The PK Analysis set will consist of all subjects in the SAF set who have at least 1 PK or 
stool sample collected.
Part 2
The Full Analysis (FA) set will include all subjects who are randomized at Day 0. 
Following the intent-to-treat principle, subjects will be analyzed according to the 
treatment they are assigned to at randomization. 
The Per-Protocol Analysis set will include all subjects who received at least 1 dose of 
study treatment, meet all key eligibility criteria, and have no major or clinically 
significant protocol deviations with a lower GI biopsy consistent with acute GvHD and 
without a major protocol deviation. Major protocol deviations that will lead to exclusion 
from this set will be prespecified prior to unblinding the treatment codes.
The SAF set will consist of all subjects who receive at least 1 dose of study treatment. 
Subjects will be analyzed according to the treatment received.
The PK Analysis set will consist of all subjects in the SAF set who have at least 1 PK or 
stool sample collected. 


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 69 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
13.3 Handling of Missing, Unused, and Spurious Data
Part 1
For the analysis of the primary and key secondary efficacy endpoints, subjects who do 
not have a response assessment at Day 28 will be classified as non-responders. This 
approach will also be applied to the analysis of other time point responses, including the 
overall response at Day 56. A sensitivity analysis will be performed for the primary and 
key secondary efficacy endpoints using the last-observation-carried-forward (LOCF) 
approach to impute the missing response assessment.
Part 2
For the primary analysis of the primary endpoint, subjects who do not have an overall
response evaluation at Day 28 will be classified as non-responders. If there are more than 
5% subjects missing for the primary endpoint in either treatment group, 2 sensitivity 
analyses will be carried out. In the first analysis, missing data will be imputed with a
missing-at-random assumption. This approach will assume that subjects who withdraw 
from a treatment group had missing values similar to subjects in that treatment group who 
completed the study. The second analysis will be a control-based imputation for the 
GLASSIA group (“jump to reference”). This approach will assume that subjects who 
withdraw had missing values similar to subjects in the control group who completed the 
study, regardless of the assigned treatment.
13.4 Methods of Analysis
Baseline characteristics of the subjects will be described using summary statistics overall
and by treatment group (Part 2 only).
All continuous variables will be reported with number of subjects, mean, median, SD,
minimum and maximum. All categorical variables will be summarized with number of 
subjects and frequency.
For Part 1, all endpoints will be summarized with descriptive statistics. Based on the 
characteristics of the study design and lack of a concurrent control arm, formal testing of 
treatment effects will not be performed. However, some measures will be summarized by 
both point estimates and the estimation of 95% confidence limits, where appropriate.
All statistical tests for Part 2 will be conducted at a 1-sided significance level of 2.5% 
unless otherwise specified.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 70 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
The primary analysis of Part 2 will occur after all subjects have completed Day 56 of 
Part 2 or discontinued from study treatment, the Adjudication Committee has adjudicated
all data through Day 56 of Part 2 and the study has been unblinded. The primary analysis 
will evaluate the primary outcome measure and all other outcome measures up to the data 
cutoff. A final analysis of the secondary and exploratory outcome measures will occur 
after all subjects have completed or discontinued from the study.
13.4.1 Primary Outcome Measure
Part 1
The overall response rate at Day 28 (see Section 8.4) will be summarized with descriptive 
statistics for Part 1 of the study. The primary analysis will use the Efficacy Analysis set, 
with sensitivity analyses carried out on the Per Protocol Analysis set and SAF set. A 
subgroup analysis of baseline lower GI involvement severity (stage 1 to 2 or stage 3 with 
no other organ involvement, stage 4 or stage 3 with other organ(s) involved) will be 
performed.
Part 2
The overall response rate at Day 28 (see Section 8.4) will be analyzed using the 
Cochran-Mantel-Haenszel chi-squared test, controlling the stratification factor (lower GI 
involvement severity), to test the null hypothesis that the odds ratio is equal to 1 for 
Part 2 of the study. To maintain the power of the study, the gamma error spending 
function 31 with a parameter -2 will be used for type II error.
An unstratified comparison of the overall response rate at Day 28 will be conducted as a 
sensitivity analysis.
13.4.2 Secondary Outcome Measures 
Part 1
The secondary efficacy outcome measures (see Section 8.4.2.1) and the secondary PK 
outcome measures (see Section 8.4.2.3) will be summarized with descriptive statistics.
PK parameters will be summarized with the mean, SD, median, minimum and maximum 
values, geometric mean and percentage of coefficient of variation.
Part 2
The key secondary endpoint of GI response rate at Day 28 (see Section 8.4.2.1) and all 
binary types of endpoints, including overall response at Day 56, will be analyzed 
similarly to the overall response rate at Day 28.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 71 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Other secondary endpoints that will be derived in the statistical analyses include, but are 
not limited to, the following:

All-cause, transplant-related, infection-related and GvHD-related mortality: defined 
as the time from HSCT to death due to any cause, transplantation, infection and 
GvHD, respectively

Duration of any overall and GI response
The secondary endpoints of overall survival and failure-free survival rate at different 
timepoints will be analyzed using the Cox proportional hazard model. The hazard ratio 
(and the corresponding 95% confidence interval) will be reported. A Kaplan-Meier plot 
will also be presented. All-cause, transplant-related, infection-related and GvHD-related
mortality will be analyzed using a similar method with competing-risk taken into 
consideration.
The other time-to-event types of secondary endpoints, including duration of any overall
response and any GI response, will also be analyzed using the Cox proportional hazard
model and summarized using Kaplan-Meier plots.
The change from baseline in acute GvHD grading will be analyzed with a shift table.
All other secondary efficacy endpoints will be summarized with descriptive statistics.
Safety Analyses (Parts 1 and 2)
Secondary safety outcome measures will be summarized with descriptive statistics and 
qualitative analysis (see Section 8.4.2.2). Adverse events will be listed for each subject 
and summarized by system organ class and preferred term by using the Medical 
Dictionary for Regulatory Activities. Safety laboratory data, vital signs measurements 
and biomarker data will be listed for each subject and summarized with descriptive 
statistics by treatment group (Part 2 only), visit and assessment time.
For the purpose of summaries and listings, the durations of AEs will be calculated as 
follows: (stop day – start day) + 1 day, which yields the number of days on which the AE 
was present. 
13.4.3 Exploratory Outcome Measures 
The exploratory outcome measures include GvHD VGPR, steroid use, GI CR and PR for 
each baseline GvHD severity grade, population PK, pharmacodynamics and health 
outcomes (see Section 8.4.3). Exploratory outcome measures will be summarized with
descriptive statistics.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 72 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
13.5 Planned Interim Analysis of the Study
Part 1
An analysis will be performed to determine whether continuation from Part 1 to Part 2 is 
warranted. It will be performed when the last subject in Part 1 has completed the GvHD 
response assessment at Day 28. The overall response rate at Day 28 will be analyzed, as 
well as the data collected at baseline, efficacy as measured by secondary efficacy 
outcome measures, and safety data. 
The analysis will be assessed by the Sponsor. The study may proceed to Part 2 if an 
overall response rate of ≥55% is observed at Day 28 in Part 1. The criteria for initiation 
of Part 2 are specified in Section 8.2.2. 
Part 2
A group sequential design with 1 interim look (Part 2) will be applied to the study. The 
gamma error spending function 31 with a parameter -2 will be used for beta spending 
(nonbinding). SAS version 9.4, PROC SEQDESIGN with stop=both and nonbinding 
option for beta, and a gamma parameter of -40 for alpha spending (and hence no alpha 
spent) and -2 for beta spending was used to calculate this design.
The interim analysis will take place when approximately 50% of the primary endpoint 
data for Part 2 has been accumulated (ie, approximately 67 evaluable subjects with 
Day 28 assessments).
An independent, unblinded biostatistics team will perform the interim analysis and 
present the results to the DMC. The study will be analyzed for futility based on the 
overall response at Day 28 in Part 2. The DMC will provide recommendations to the 
sponsor based on the interim analysis. However, the sponsor may decide to stop the trial 
even if statistical criteria for futility are not observed.
With the aforementioned spending functions, the DMC will recommend the study be 
stopped for futility if the nominal p-value is larger than 0.3430. The type II error spend at 
the interim analysis is 0.0538. As the interim analysis may not occur when exactly 50% 
of the primary endpoint data are accrued, the boundary may be adjusted at the analysis 
time using the specified gamma function (ie, a parameter of -2). A total of 134 evaluable 
subjects (67 per group) is planned.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 73 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
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 Trial Agreement (CTA). 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 CTA.
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 national and local regulatory requirements 
as described in the CTA. 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.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 74 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
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 national and local regulatory 
guidelines/requirements. The investigator will permit the study monitor to visit the study 
site at appropriate intervals, as described in the CTA. Monitoring processes specific to 
the study will be described in the clinical monitoring plan.
15.4 Safety Monitoring
The safety of the subjects in this study shall be monitored by an external 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 fields of oncology, hematology and immunology 
clinical care and research who are not actively recruiting subjects. The DMC may make a 
recommendation to continue the study as is, temporarily suspend the study, continue the 
study after proper amendment to the protocol or terminate the study based on predefined 
criteria such as unacceptable toxicities or lack of treatment benefits.
The DMC will meet to evaluate safety during Parts 1 and 2 and the interim analysis of 
overall response at Day 28 of Part 2 when approximately 50% of the primary efficacy 
data has been collected (Sections 8.2.2 and Section 13.5). The DMC may meet in ad hoc 
meetings at its discretion as needed in response to events occurring in the study. The 
DMC’s responsibilities, definitions and operating procedures will be defined in a charter; 
the committee will maintain records of all its meetings and of the interim analysis of 
Part 2.
15.5 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 national and local applicable regulatory 
guidelines/requirements. The investigator will permit auditors to visit the study site, as 
described in the CTA. Auditing processes specific to the study will be described in the 
audit plan.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 75 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
15.6 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 and relevant 
competent authority 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.
15.7 Laboratory and Reader Standardization
Local laboratories will be used for all clinical laboratory assessments (hematology, 
clinical chemistry, coagulation panel and urinalysis). No inter-laboratory standardization 
will be performed for these assessments.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 76 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
16. ETHICS
16.1 Subject Privacy
The investigator will comply with applicable subject privacy regulations/guidance as 
described in the CTA.
16.2 Ethics Committee and Regulatory Authorities
Before patients participate in this study, the protocol, informed consent form, any 
promotional material/advertisements and any other written information will be reviewed 
and approved/given favorable opinion by the EC and applicable regulatory authorities. 
The IB will be provided for review. 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(s) 
approval, as described in the CTA. 
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(s) approval.
16.3 Informed Consent
Investigators will choose patients for participation considering the study eligibility 
criteria. The investigator will exercise no selectivity so that no bias is introduced from 
this source. 
All patients must sign an informed consent form before entering into the study according 
to applicable national and local regulatory requirements and ICH GCP. Before use, the 
informed consent form will be reviewed by the sponsor and approved by the EC and 
regulatory authority(s), where applicable, (see Section 16.2). The informed consent form 
will include a comprehensive explanation of the proposed treatment without any 
exculpatory statements, in accordance with the elements required by ICH GCP and 
applicable national and local regulatory requirements. Patients will be allowed sufficient 
time to consider participation in the study. By signing the informed consent form, 
patients agree that they will complete all evaluations required by the study, unless they 
withdraw voluntarily or are terminated from the study for any reason.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 77 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
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 informed 
consent form 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.
17. DATA HANDLING AND RECORD KEEPING
17.1 Confidentiality Policy
The investigator will comply with the confidentiality policy as described in the CTA. 
17.2 Study Documentation 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 
informed consent forms, correspondence with the EC and the study monitor/sponsor, 
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).


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 78 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
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 CTA.
18. FINANCING AND INSURANCE
The investigator will comply with investigator financing, investigator/sponsor insurance
and subject compensation policies, if applicable, as described in the CTA.
19. PUBLICATION POLICY
The investigator will comply with the publication policy as described in the CTA. 


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 79 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
20. SUPPLEMENTS
20.1 Study Flow Chart
Figure 1
Study Design for Baxalta Clinical Study 471501 Part 1
Abbreviations: SOC=standard-of-care.
Note: Arrows indicate days of study treatment and the Day 28 primary endpoint assessment.
Day:  -2 to -1 
0  2 4 6 8 10 12 14      21       28       35      42       49        56                   100                 180           
365    
Part 1 
Screening
COHORT 1:  GLASSIA + Steroid; 8 week 
treatment period
No GLASSIA treatment – SOC only
Day 28 overall
response rate


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 80 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Figure 2
Study Design for Baxalta Clinical Study 471501 Part 2
Abbreviations: R=randomization; SOC=standard-of-care.
Note: Arrows indicate days of study treatment and the Day 28 primary endpoint assessment. The study will be unblinded after all subjects complete 
Day 56 of Part 2 or discontinue study treatment and the Adjudication Committee adjudicates all efficacy data through Day 56 of Part 2.
Day:  0 2  4  6 8 10 12 14      21      28      35      42       49        56                100               180                   
365
Part 2 
Screening
Group 2b: Placebo + Steroid; 8 week treatment 
period
No study treatment – SOC only
Group 2a: GLASSIA + Steroid; 8 week 
treatment period
No study treatment – SOC only
Day: 0  2 4 6 8 10 12 14      21       28      35      42       49        56              100                180                  
365  
R
1:1
Day 28 overall
response rate
Day: -2 to -1


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 81 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
20.2 Schedule of Study Procedures and Assessments
Table 1
Schedule of Study Procedures and Assessments (Parts 1 and 2)
Scr
Treatment Period
No Study Treatment 
Follow-Up
Study Day
-2 to 
-1
Baseline/
day 0
2
4
6
8
10
12
14
21
28a
35
42
49
56
100
180
365b
Visit window (± days)
1
1
1
1
1
1
1
1
1
1
1
1
1
1
5
5
5
Informed consentc
X
Inclusion/exclusion criteria
X
Demographics
X
Medical, surgical and transplant
history
X
Medication history
X
Randomization (Part 2 only)
X
Subject diary
X
X
X
X
X
X
X
FACT-BMT, Chronic GvHD 
Symptom Scale, EQ-5D-5Ld
X
X
X
X
X
X
Physical examination
X
X
X
X
X
Vital signse
X
X
X
X
X
12-lead ECG
X
CMV testing
X
X
X
X
X
X
X
X
X
X
X
HIV testingf,g
X
Clinical laboratory testsg
X
X
X
X
X
X
X
X
Serum pregnancy testh
X
X
Lower GI biopsyi
X
Biomarker sample collectiong
X
X
X
X
GvHD staging/assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 82 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Table 1
Schedule of Study Procedures and Assessments (Parts 1 and 2)
Scr
Treatment Period
No Study Treatment 
Follow-Up
Study Day
-2 to 
-1
Baseline/
day 0
2
4
6
8
10
12
14
21
28a
35
42
49
56
100
180
365b
Visit window (± days)
1
1
1
1
1
1
1
1
1
1
1
1
1
1
5
5
5
Overall response, GI response 
and GvHD VGPR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chronic GvHD assessment
X
X
X
X
Cumulative dose of steroids
X
X
X
X
PK sample collectiong
X  ---> X
X  ---> X
X
X
X ---> X
Assessment of recurrent 
malignancy
X  ------------------------------------------------------------------------------------------------------------------------------------------
>  X
Adverse events
X  ------------------------------------------------------------------------------------------------------------------------------------------
>  X
Medications and non-drug 
therapiesj
X
X  ---------------------------------------------------------------------------------------------------------------------------------
>  X
Mortality and survival 
assessmentsk
X
X
X
X
X
Study treatment administrationl
X
X
X
X
X
X
X
X
X
X
X
X
X
Administration of steroid 
treatmentl,m
X
X  ------------------------------------------------------------------------------------------------------------------>  
X
Viral prophylaxisn
X
X  ------------------------------------------------------------------------------------------------------------------>  
X
Stool sample collectiong
X
X
X
X
X
Abbreviations: CMV=cytomegalovirus; ECG=electrocardiogram; EQ-5D-5L=European Quality of Life-5 Dimensions-5 Level;
FACT-BMT=Functional Assessment of Cancer Therapy-Bone Marrow Transplant subscale version 4.0 instrument; Scr=screening; 
GI=gastrointestinal; GvHD=graft-versus-host disease; HIV=human immunodeficiency virus; HRU=healthcare resource utilization; 
PK=pharmacokinetic; VGPR=very good partial response.
Continued on next page


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 83 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Continued
a
Subjects who discontinue study treatment prior to Day 28 will complete the Day 28 visit on Day 28 (±1 day). If at least 2 weeks have passed 
since the last dose of study treatment, Day 28 will serve as the study completion/termination visit. If Day 28 is less than 2 weeks following the 
last dose of study treatment, subjects will complete the Day 28 visit and then the study completion/termination visit 2 weeks (±1 day) after the 
last dose of study treatment. In this event, the subject will have an office visit with the same assessments as the Day 365 visit. Subjects who 
discontinue study treatment will not attend any other subsequent visits other than Day 28 and the study completion/termination visit (if 
applicable), except as needed for follow-up of recovering/resolving AEs (see Section 12.1.2).
b
Study completion/termination visit after Day 28. Subjects who discontinue study treatment early but after Day 28 will complete a study 
completion/termination visit as an office visit 2 weeks (±1 day) after the last dose of study treatment. Subjects who withdraw from the study after 
Day 56 will be encouraged to complete the study completion/termination visit at the time of discontinuation. In the event that it is not feasible for 
the subject to visit the site at the study completion/termination visit after Day 56, the visit may be conducted with a phone call.
c
Occurs prior to any study-specific procedures including screening.
d
The FACT-BMT, Chronic GvHD Symptom Scale and EQ-5D-5L should be collected before any other assessments are performed at the visit.
e
Body height will be measured at screening visit only. At visits at which study treatment is administered, vital signs will be measured within 
30 minutes before and after administration of study treatment.
f
Antibody or nucleic acid test. The results of an HIV test performed within the 3 months prior to screening may be used instead.
g
See Table 2 for details.
h
Serum pregnancy test will be performed in females of childbearing potential only.
i
Results of a lower GI biopsy performed prior to screening may be used instead. The screening biopsy will be used to assess withdrawal criteria 
and will not be required to assess eligibility prior to the first dose of study treatment.
j
All medications taken and non-drug therapies received from providing informed consent until completion/termination will be recorded.
k
Investigator will assess the date and cause of death, if applicable. Cause of death will be assessed as related to transplant, infection and/or GvHD 
or any other cause. Failure-free, GvHD-free and overall survival will also be collected.
l
All assessments and sample collections, with the exception of PK and stool samples as described in Table 2, must be performed before 
administering study treatment and steroid treatment at each visit. 
m
Steroid treatment for acute GvHD with lower GI involvement must have been initiated within 72 hours prior to the first study treatment 
administration. Steroid tapering may commence after a subject responds to therapy as described in Section 8.2. Subjects who are withdrawn from 
study treatment will be treated with standard-of-care at the investigator’s discretion.
n
Subjects will receive standard prophylactic treatment for herpes simplex virus and varicella-zoster virus (eg, acyclovir or valacyclovir), through 
Day 180 or per institutional guidelines.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 84 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
20.3 Clinical Laboratory Assessments
Table 2
Clinical Laboratory Assessments
Assessments
Screening
Treatment Period
Days
-2 to -1
Baseline/day0
2
4
6
12
14
21
28a
49
56
Visit window (± days)
1
1
1
1
1
1
1
1
1
1
Hematologyb,c
X
X
X
X
X
X
Clinical chemistryb,d
X
X
X
X
X
X
Coagulation panelb,e
X
X
X
X
Urinalysisb,f
X
X
X
X
X
X
Stool assessmentsg
X
X
X
X
X
PK assessmenth
X------->X
X------->X
X
X
X------->X
Biomarker assessmenti
X
X
X
X
HIV testj
X
Abbreviations: A1PI=alpha-1 proteinase inhibitor; HIV=human immunodeficiency virus; IL=interleukin; IL-1RA=interleukin-1 receptor antagonist;
PK=pharmacokinetic; RBC=red blood cell; Reg3α=regenerating islet-derived protein 3α; ST2=suppression of tumorigenicity 2; 
TNFR1=tumor necrosis factor receptor 1; Tregs=regulatory T cells; WBC=white blood cell.
Note: All samples, except PK and stool samples as indicated below, must be collected prior to the start of study treatment at the visit.
a
Subjects who discontinue study treatment prior to Day 28 will complete the Day 28 visit on Day 28 (±1 day). If at least 2 weeks have passed 
since the last dose of study treatment, Day 28 will serve as the study completion/termination visit. If Day 28 is less than 2 weeks following the 
last dose of study treatment, subjects will complete the Day 28 visit and then the study completion/termination visit 2 weeks (±1 day) after the 
last dose of study treatment. In this event, the subject will have an office visit with the same assessments as the Day 365 visit (Table 1). Subjects 
who discontinue study treatment will not attend any other subsequent visits other than Day 28 and the study completion/termination visit (if 
applicable), except as needed for follow-up of recovering/resolving AEs (see Section 12.1.2).
b
In addition to the assessments shown, clinical laboratory assessments should be performed whenever clinically indicated.
c
Hematology assessments include hemoglobin, hematocrit, RBC count and WBC count with differential (ie, basophils, eosinophils, lymphocytes, 
monocytes and neutrophils), mean corpuscular volume, mean corpuscular hemoglobin concentration and platelet count.
d
Clinical chemistry assessments include: sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase, aspartate 
aminotransferase, total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine and glucose. 
Continued on next page


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 85 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
Continued
e
Coagulation panel includes PT, PTT and INR.
f
Urinalysis assessments include: color, specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrate, leukocyte esterase
and microscopic examination (RBC, WBC, bacteria and casts).
g
For the determination of stool A1PI level and clearance and calprotectin concentrations. One sample will be collected either during screening or 
prior to the first study treatment administration on Day 0. On Days 0 and 12, a sample will be collected during the 24 hours after the start of study 
treatment infusion. On Day 28, the sample will be collected prior to the start of study treatment infusion.
h
If study treatment is administered peripherally, the PK samples should be taken from the opposite arm as the study treatment administration, if 
possible. If study treatment is administered via a central indwelling catheter, the PK samples may be taken from the same infusion line, if the 
infusion line is flushed prior to collection of the PK sample and the first 3 mL of blood is discarded.
The PK samples for the measurement of plasma A1PI levels will be collected at the following timepoints:

Part 1, Cohort 1
-
Day 0: Prior to start of study treatment infusion, at 15 (±5) minutes, 2 hours (±12 minutes), 4 hours (±24 minutes), 8 hours 
(±48 minutes), 12 hours (±72 minutes) and 24 hours (±144 minutes) (ie, Day 1) following the end of study treatment infusion
-
Day 2: Within 2 hours prior to start of study treatment infusion, and at 15 (±5) minutes following the end of study treatment infusion
-
Day 12: Within 2 hours prior to start of study treatment infusion, at 15 (±5) minutes, 2 hours (±12 minutes), 4 hours (±24 minutes), 
8 hours (±48 minutes), 12 hours (±72 minutes) and 24 hours (±144 minutes) (ie, Day 13) following the end of study treatment infusion
-
Day 14: Within 2 hours prior to start of study treatment infusion, and at 15 (±5) minutes following the end of study treatment infusion
-
Day 21: Within 2 hours prior to start of study treatment infusion, and at 15 (±5) minutes following the end of study treatment infusion
-
Day 28: During the Day 28 clinic visit, but must be prior to the next study treatment
-
Day 49: Within 2 hours prior to start of study treatment, at 15 (±5) minutes, 2 hours (±12 minutes), 4 hours (±24 minutes), 24 hours 
(±144 minutes) (ie, Day 50), 72 (±7) hours (ie, Day 52) and 120 (±12) hours (ie, Day 54) following the end of study treatment infusion
-
Day 56: During the Day 56 clinic visit

Part 2
-
Day 0: Prior to start of study treatment infusion, and at 15 (±5) minutes following the end of study treatment infusion
-
Day 2: Within 2 hours prior to study treatment infusion
-
Day 12: Within 2 hours prior to start of study treatment infusion, and at 15 (±5) minutes following the end of study treatment infusion
-
Day 14: Within 2 hours prior to study treatment infusion
-
Day 21: Within 2 hours prior to start of study treatment infusion, and at 15 (±5) minutes following the end of study treatment infusion
-
Day 28: During the Day 28 clinic visit, but must be prior to the next study treatment infusion.
-
Day 49: Within 2 hours prior to start of study treatment infusion, and at 15 (±5) minutes following the end of study treatment infusion
-
Day 56: During the Day 56 clinic visit
i
Biomarkers to be assessed in Parts 1 and 2 will include cytokines IL-2, IL-6, IL-8, and IL-10; IL-1RA and T cell subpopulations, including CD4+
CD25+ CD127+ FoxP3+ Tregs; in Part 2 only, the following biomarkers will also be assessed: Reg3α, ST2, and TNFR1.
j
Antibody or nucleic acid test. The results of an HIV test performed within the 3 months prior to screening may be used instead.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 86 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
20.4 Toxicity Grading Scale for AEs 
Table 3
Mapping Conventions for AE Severity 
(For AEs Not Described Within NCI CTCAE version 4.03)
NCI CTCAE Grade
Corresponding AE Severity 
(if Not Provided in NCI CTCAE)
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated
Grade 2
Moderate; minimal, local, or noninvasive intervention indicated; 
limiting age-appropriate instrumental ADL
Grade 3
Severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization 
indicated; disabling; limiting self-care ADL
Grade 4 
Life-threatening consequences; urgent intervention indicated
Grade 5 
Death related to AE
Abbreviations: ADL=activities of daily living; AE=adverse event; 
NCI CTCAE=National Cancer Institute Common Terminology Criteria for Adverse Events.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 87 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
21. REFERENCES
1. Breit SN, Wakefield D, Robinson JP et al. The role of 1-antitrypsin deficiency in 
the pathogenesis of immune disorders. Clin.Immunol.Immunopathol. 1985;35:363-
380.
2. Toldo S, Seropian IM, Mezzaroma E et al. Alpha-1 antitrypsin inhibits caspase-1 
and protects from acute myocardial ischemia-reperfusion injury. J.Mol.Cell.Cardiol. 
2011;51:244-251.
3. Lewis EC, Mizrahi M, Toledano M et al. 1-Antitrypsin monotherapy induces 
immune tolerance during islet allograft transplantation in mice. 
Proc.Natl.Acad.Sci.U.S.A. 2008;105:16236-16241.
4. Churg A, Dai J, Zay K et al. Alpha-1-antitrypsin and a broad spectrum 
metalloprotease inhibitor, RS113456, have similar acute anti-inflammatory effects. 
Lab.Invest. 2001;81:1119-1131.
5. Goldstein SC, Koreth J, Magenau JM et al. Alpha 1 Anti-Trypsin (AAT): Novel 
strategy to treat steroid refractory acute graft versus host disease [abstract]. 
Biol.Blood Marrow Transplant. 2016;22:S57.
6. Marcondes AM, Li X, Tabellini L et al. Inhibition of IL-32 activation by -1 
antitrypsin suppresses alloreactivity and increases survival in an allogeneic murine 
marrow transplantation model. Blood. 2011;118:5031-5039.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 88 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
7. Tawara I, Sun Y, Lewis EC et al. Alpha-1-antitrypsin monotherapy reduces graft-
versus-host disease after experimental allogeneic bone marrow transplantation. 
Proc.Natl.Acad.Sci.U.S.A. 2012;109:564-569.
8. Martin PJ, Rizzo JD, Wingard JR et al. First- and second-line systemic treatment of 
acute graft-versus-host disease: Recommendations of the American Society of 
Blood and Marrow Transplantation. Biol.Blood Marrow Transplant. 2012;18:1150-
1163.
9. Weisdorf D, Haake R, Blazar B et al. Treatment of moderate/severe acute graft-
versus-host disease after allogeneic bone marrow transplantation: An analysis of 
clinical risk features and outcome. Blood. 1990;75:1024-1030.
10. Roy J, McGlave PB, Filipovich AH et al. Acute graft-versus-host disease following 
unrelated donor marrow transplantation: Failure of conventional therapy. Bone 
Marrow Transplant. 1992;10:77-82.
11. Deeg HJ. How I treat refractory acute GVHD. Blood. 2007;109:4119-4126.
12. Martin PJ, Schoch G, Fisher L et al. A retrospective analysis of therapy for acute 
graft-versus-host disease: Initial treatment. Blood. 1990;76:1464-1472.
13. MacMillan ML, Weisdorf DJ, Wagner JE et al. Response of 443 patients to steroids 
as primary therapy for acute graft-versus-host disease: Comparison of grading 
systems. Biol.Blood Marrow Transplant. 2002;8:387-394.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 89 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
14. Przepiorka D, Weisdorf D, Martin P et al. 1994 consensus conference on acute 
GVHD grading. Bone Marrow Transplant. 1995;15:825-828.
15. Rowlings PA, Przepiorka D, Klein JP et al. IBMTR severity index for grading acute 
graft-versus-host disease: Retrospective comparison with Glucksberg grade. 
Br.J.Haematol. 1997;97:855-864.
16. Chao, N. J. Clinical manifestations, diagnosis, and grading of acute graft-versus-
host disease.  2016.  Up To Date. 
Link to Publisher´s Site: http://www.uptodate.com/contents/clinical-manifestations-
diagnosis-and-grading-of-acute-graft-versus-host-
disease?source=search_result&search=clnical+manifestations+diagnosis+and+gradi
ng+of+acute+graft+versus+host+disease&selectedTitle=1%7E150
17. Marcondes AM, Hockenbery D, Lesnikova M et al. Response of steroid-refractory 
acute GVHD to 1-Antitrypsin. Biol.Blood Marrow Transplant. 2016;22:1596-
1601.
18. Marcondes AMQ, Lesnikova M, Georges G et al. 1 anti-trypsin (AAT-1), 
augments DCs and frequency of regulatory T cells (T reg), modulates GVHD, and 
increases survival after allogeneic transplantation [abstract]. Biol.Blood Marrow 
Transplant. 2012;18:S223.
19. Hagen LEM, Schechter T, Luk Y et al. High alpha-1 antitrypsin clearance predicts 
severity of gut graft-versus-host disease (GVHD) in children. Pediatr.Transplant. 
2011;15:659-663.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 90 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
20. Rodriguez-Otero P, Porcher R, Peffault de Latour R et al. Fecal calprotectin and 
alpha-1 antitrypsin predict severity and response to corticosteroids in 
gastrointestinal graft-versus-host disease. Blood. 2012;119:5909-5917.
21. Jacobsohn DA, Vogelsang GB. Acute graft versus host disease. Orphanet J.Rare 
Dis. 2007;2:35.
22. Pidala J. Graft-vs-host disease following allogeneic hematopoietic cell 
transplantation. Cancer Control. 2011;18:268-276.
23. Martin PJ, Bachier CR, Klingemann HG et al. Endpoints for clinical trials testing 
treatment of acute graft-versus-host disease: A joint statement. Biol.Blood Marrow 
Transplant. 2009;15:777-784.
24. Inamoto Y, Martin PJ, Storer BE et al. Response endpoints and failure-free survival 
after initial treatment for acute graft-versus-host disease. Haematologica. 
2014;99:385-391.
Link to Publisher´s Site: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3912972/pdf/0990385.pdf
25. Saliba RM, Couriel DR, Giralt S et al. Prognostic value of response after upfront 
therapy for acute GVHD. Bone Marrow Transplant. 2012;47:125-131.
26. Pavletic SZ. Response as an end point in treatment trials for acute GVHD. Bone 
Marrow Transplant. 2012;47:161-163.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 91 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
27. MacMillan ML, DeFor TE, Weisdorf DJ. The best endpoint for acute GVHD 
treatment trials. Blood. 2010;115:5412-5417.
28. Levine JE, Logan B, Wu J et al. Graft-versus-host disease treatment: Predictors of 
survival. Biol.Blood Marrow Transplant. 2010;16:1693-1699.
29. Altilio T, Otis-Green S. Oxford Textbook of Palliative Medicine.: Oxford 
University Press; 1993.
30. The EuroQol Group. EQ-5D.  2016.  The EuroQol Group. 
Link to Publisher´s Site: http://www.euroqol.org/
31. Hwang IK, Shih WJ, De Cani JS. Group sequential designs using a family of type I 
error probability spending functions. Stat.Med. 1990;9:1439-1445.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 92 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
22. SUMMARY OF CHANGES 
Protocol 471501: Amendment 1 2017 APR 19
Replaces: Original: 2016 APR 19
In this section, changes from the previous version of the Protocol, dated 2016 APR 19, 
are described and their rationale is given.
1.
Throughout the document
Description of Change: Minor grammatical and/or administrative changes have 
been made. 
Purpose for Change: To improve the readability and/or clarity of the protocol. 
2.
Throughout the document
Description of Change: NCT Number added. 
Purpose for Change: NCT Number provided has been obtained. 
3.
Throughout the document
Description of Change: IND Number added. 
Purpose for Change: IND Number provided has been obtained. 
4.
Section 1 Study Personnel; Investigator Acknowledgement Signature Pages
Description of Change: Name of Signatory has been changed. 
Purpose for Change: Sponsor Authorized Representative has changed. 
5.
Section 3 Synopsis and throughout document
Description of Change: Change Study Day 1 to Baseline/Day 0; all subsequent days 
for dosing/follow-up are in reference to the Baseline; changed Study Days 1, 3, 5, 
7, 9, 11, 13, 15, 22, 36, 43, and 50 to Baseline/Day 0 and Days 2, 4, 6, 8, 10, 12, 14,
21, 35, 42, and 49. 
Purpose for Change: To correct an error in calculating dosing schedule. 
6.
Section 3 Synopsis (Primary Objective); Section 7.2 Primary Objective
Description of Change: Change “treatment response at 28 days” to “treatment 
response at Day 28”. 
Purpose for Change: Day 28 is a planned study visit and it’s actually on the 29th day 
of treatment. 


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 93 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
7.
Section 3 Synopsis (Exploratory Objectives #3; Pharmacodynamics assessment 
#3); Section 7.4 Exploratory Objectives (Parts 1 and 2); Section 8.4.3 Exploratory 
Outcome Measures; Section 11.7 Pharmacokinetic, Biomarker and Stool Sample 
Collection; Section 20.3 Clinical Laboratory Assessments (Table 2 footnote i)
Description of Change: Deleted IL-32 and heparin sulfate.
Purpose for Change: There is no validated assay for these analyses. 
8.
Section 3 Synopsis (Exploratory Objectives #3; Pharmacodynamics assessment 
#3); Section 7.4 Exploratory Objectives (Parts 1 and 2); Section 8.4.3 Exploratory 
Outcome Measures; Section 11.7 Pharmacokinetic, Biomarker and Stool Sample 
Collection; Section 20.3 Clinical Laboratory Assessments (Table 2 footnote i)
Description of Change: Deleted Reg3α, ST2, and TNFR1 from Parts 1 and 2 and 
added these under new heading/text for Part 2 Only.
Purpose for Change: The rationale for this change is that this set of exploratory 
biomarkers will have limited clinical utility in the setting of Part 1 of this clinical 
study – given the small sample size (n=20) and the lack of an adequate controlled 
subject population for comparison; there might be more meaningful clinical utility 
of this exploratory data in Part 2 given the larger sample size, the presence of an 
adequately controlled population for comparison and also a disease severity 
stratification in this part of the clinical study.
9.
Section 3 Synopsis (Study Design/Part 1); Section 8.2.1 Study Design
Description of Change: Text added that subjects who are treated but found to have 
a baseline lower GI biopsy inconsistent with GvHD will be replaced to ensure 
20 evaluable subjects.
Purpose for Change: Conditions under which subjects are replaced clearly defined. 
10. Section 3 Synopsis (Study Design/Part 1); Section 8.2.1 Study Design; Section 13.5 
Planned Interim Analysis of the Study
Description of Change: Text added to describe an interim analysis that will be 
performed to determine continuation from Part 1 to Part 2.
Purpose for Change: Interim analysis added to determine if the study should 
continue from Part 1 to Part 2 based on overall response rate.
11. Section 3 Synopsis (Study Design/Part 2); Section 8.2.2 Part 2 Study Design
Description of Change: Text added that randomized subjects in Part 2 who 
discontinue will not be replaced. 
Purpose for Change: Conditions under which subjects are replaced clearly defined.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 94 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
12. Section 3 Synopsis (Study Design/Interim Analysis); Section 8.2.2 Part 2 Study 
Design; Section 13.5 Planned Interim Analysis of the Study
Description of Change: Text added to describe that sponsor may stop the trial 
following interim analysis even if futility criteria are not observed.
Purpose for Change: Text revised in response to scientific advisor’s question 
regarding nonbinding recommendations by DMC to sponsor based on interim 
analysis.
13. Section 3 Synopsis (Primary Outcome Measure, Secondary Outcome Measures, 
and Exploratory Outcome Measures); Section 8.4.1 Primary Outcome Measure 
(Parts 1 and 2); Section 8.4.2.1 Efficacy (Parts 1 and 2); Section 8.4.3 Exploratory 
Outcome Measures
Description of Change: Outcome measures assessed “by” Day 28 changed to “at” 
Day 28.
Purpose for Change: Analysis wording clarified to be consistent with analyses 
described in the Statistical Analysis Plan. 
14. Section 3 Synopsis (Health Outcomes #4); Section 8.4.3 Exploratory Outcome 
Measures (Health Outcomes Parts 1 and 2)
Description of Change: Text revised to “type of admission”.
Purpose for Change: Changed for consistency with Statistical Analysis Plan.
15. Section 3 Synopsis (Inclusion Criterion #4); Section 9.1 Inclusion Criteria 
(Criterion #4)
Description of Change: Moved text “newly diagnosed” from inclusion criterion 6 to 
criterion 4. 
Purpose for Change: Clarity of diagnosis for inclusion into the study.
16. Section 3 Synopsis (Inclusion Criterion #5); Section 8.1 Brief Summary; 
Section 9.1 Inclusion Criteria (Criterion #5); Section 11.3 Lower GI Biopsy
Description of Change: Inclusion criterion added for willingness to undergo lower 
GI biopsy within 7 days of informed consent; biopsy results not needed to start 
treatment; however, if biopsy results are not consistent with aGvHD, treatment will 
be discontinued. 
Purpose for Change: Clarity on pathological basis of disease diagnosis and 
temporal requirements.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 95 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
17. Section 3 Synopsis (Inclusion Criterion #6); Section 9.1 Inclusion Criteria 
(Criterion #6)
Description of Change: Moved text “newly diagnosed” from inclusion criterion 6 to 
criterion 4; added “subjects must be receiving systemic corticosteroids”. 
Purpose for Change: Clarity of diagnosis and requirement for systemic 
corticosteroids for inclusion into the study.
18. Section 8.2 Overall Study Design; Section 8.7.1.3 Anti-infective Prophylaxis
Description of Change: Section heading revised to “Anti-infective Prophylaxis”; 
antibiotic, antifungal and antiviral added to prophylactic treatment; CMV added. 
Purpose for Change: Prophylactic treatment clarified. 
19. Section 8.2 Overall Study Design
Description of Change: Text added that treatment failures will be included in the 
analysis. 
Purpose for Change: Analysis of treatment failures clarified.
20. Section 8.2 Overall Study Design
Description of Change: Retreatment allowance after Day 56 deleted. 
Purpose for Change: Removed option for retreatment after Day 56 in order to focus 
on the primary objective of the study, which is to confirm the safety and efficacy of 
GLASSIA in subjects with stage 1 to 4 lower GI aGVHD as assessed by treatment 
response at 28 days. Retreatment could be explored in a subsequent study.
21. Section 8.2 Overall Study Design
Description of Change: Steroid taper changed from not less than 0.5 mg/kg/day to 
0.25 mg/kg/day before Day 28. 
Purpose for Change: To align with broad clinical practice and provide greater 
flexibility of steroid tapering to investigators; with the potential to reduce patient 
exposure to steroids.
22. Section 8.5.1 Randomization
Description of Change: An Eligibility Criteria Form has been added. 
Purpose for Change: To ensure the appropriate population has been enrolled in the 
study.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 96 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
23. Section 8.7.2 Administration
Description of Change: Reference to Pharmacy Manual added for instructions to 
preparation, blinding and administration of study treatment. 
Purpose for Change: Specific instructions for study treatment added to Pharmacy 
Manual as no Study Procedures Manual will be prepared for this study. 
24. Section 9.7.3.2 Withdrawal from Study Participation and Discontinuation of Study 
Treatment 
Description of Change: Description of withdrawal and discontinuation clarified. 
Purpose for Change: The description of study withdrawal and treatment 
discontinuation was clarified. 
25. Section 10.4 Medications and Non-drug Therapies
Description of Change: Enteral corticosteroids included as medications not 
permitted during the study or within 30 days before study entry. Topical 
corticosteroids including ophthalmic steroids added to list of permitted 
medications. 
Purpose for Change: Permitted medications clarified. 
26. Section 10.5 Subject Diary; Section 20.2 Schedule of Study Procedures and 
Assessments
Description of Change: Subject diary will be provided to each subject once the 
subject is discharged; steroid dose, concomitant medications, non-drug therapies, 
and AEs will not be collected on the diary; text revised for clarity. 
Purpose for Change: Subjects will not need diaries when they are in the 
hospital/clinic; steroid doses, concomitant medications, and AEs will be collected 
on the CRF. 
27. Section 11.4 GvHD Staging/Assessment
Description of Change: GvHD grading and staging text revised. 
Purpose for Change: Grading and staging clarified for GvHD.
28. Section 11.8 Functional Assessment of Cancer Therapy – Bone Marrow Transplant; 
Section 11.10 European Quality of Life – 5 Dimensions – 5 Levels
Description of Change: Use of an electronic patient-reported outcome device has 
been deleted. 
Purpose for Change: No electronic device will be used.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 97 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
29. Section 11.11 Healthcare Resource Utilization
Description of Change: Description of information to be included in the diary was 
revised. 
Purpose for Change: Text revised for clarity and accuracy.
30. Section 12.1.1 Definitions
Description of Change: Definition of AEs revised by removing list of events that do 
not meet the definition of an AE; grading and follow-up of abnormal laboratory 
values reported as AEs has been added. 
Purpose for Change: Text revised for clarity.
31. Section 12.1.1.5 Preexisting Diseases
Description of Change: Text regarding the reporting of changes in severity, 
duration, or symptoms of GvHD deleted. 
Purpose for Change: The baseline state will not be captured because these signs and 
symptoms are part of the disease state. 
32. Section 12.1.2 Assessment of Adverse Events
Description of Change: Text added to clarify that changes in severity or duration of 
GvHD after first IP exposure are collected as efficacy data and not AE data; 
symptoms or diagnostic findings of GvHD will be collected as AE data; deviations 
from protocol-specified IMP use will be recorded in the Protocol Deviation Form. 
Purpose for Change: Clarification of language specifying collection of efficacy data 
vs safety data; also, text revised for clarity to indicate these above mentioned 
deviations from protocol-specified procedures will be recorded in the Protocol 
Deviation Form and not as AEs. 
33. Section 12.1.2 Assessment of Adverse Events
Description of Change: Text describing investigator responsibility for reporting an 
SAE that occurred after study completion has been deleted.
Purpose for Change: Text deleted for accuracy of reporting.
34. Section 12.7.1 Hematology and Clinical Chemistry; Section 15.7 Laboratory and 
Reader Standardization; Section 20.3 Clinical Laboratory Assessments (Table 2)
Description of Change: Lipid panel removed. 
Purpose for Change: Lipid panel will not be performed in this study.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 98 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
35. Section 12.7.1 Hematology and Clinical Chemistry; 
Section 20.3 Clinical Laboratory Assessments (Table 2 footnote f)
Description of Change: Fibrin, fibrin split products, fibrinogen and D dimer 
assessments replaced with PT, PTT, and INR assessments.
Purpose for Change: PT/PTT/INR are more relevant measures of coagulation 
function. FDP, D-Dimers and fibrinogen levels are part of a DIC panel that are not 
usually performed in the setting of GvHD, and the absence of these is not expected 
to impact clinical study safety measures.
36. Section 12.7.3.2 Assessment of Abnormal Laboratory Values
Description of Change: Abnormal laboratory values reportable as adverse events 
clarified. 
Purpose for Change: Clarification of language for accuracy. 
37. Section 12.7.4 Backup Samples and Biobanking
Description of Change: Backup samples to be used for analyses in this study only.
Purpose for Change: Use of backup samples clarified. 
38. Section 12.9 Electrocardiogram
Description of Change: ECG parameters/values changed to ECG assessments 
(normal vs abnormal). 
Purpose for Change: Revised to align with study eligibility criteria; ECG 
parameters will not be collected in this study. 
39. Section 13.2 Analysis Sets
Description of Change: Efficacy Analysis set clarified; Per-Protocol Analysis set 
added to Part 1; Per-Protocol Analysis set revised in Part 2. 
Purpose for Change: Analysis sets revised for accuracy and consistency.
40. Section 13.3 Handling of Missing, Unused, and Spurious Data
Description of Change: Text regarding missing efficacy response data in Part 1 
revised. 
Purpose for Change: Per SAP comments from Shire, there will be imputation for 
missing efficacy response data in Part 1 analysis.


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 99 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
41. Section 13.4.1 Primary Outcome Measure
Description of Change: Text regarding primary analysis in Part 1 revised. 
Purpose for Change: Per SAP comments from Shire, there will be planned 
sensitivity analysis and subgroup analysis for primary outcome measure for Part 1 
analysis.
42. Section 15.7 Laboratory Reader Standardization
Description of Change: Text regarding description of standardization methods for 
PK and biomarker analyses has been deleted. 
Purpose for Change: Text revised for accuracy.
43. Section 20.2 Schedule of Study Procedures and Assessments (Table 2, row for PK
sample collection); Section 20.3 Clinical Laboratory Assessments (PK row for PK 
assessment; footnote h)
Description of Change: PK samples after 15 minutes following the end of study 
treatment infusion on Day 21 have been deleted. 
Purpose for Change: The rationale behind the change has been driven by a 
combination of trying to reduce sampling points during the D21 to D28 time period 
to ease subject participation and improve compliance with the clinical study 
protocol, and the ability to compute required PK data without extensive PK 
sampling at this time point.
44. Throughout the document
Description of Change: Deletion of legally authorized representative(s). 
Purpose for Change: Patient’s consent is preferred given the clinical nature and 
prognosis of GI GvHD. Also to exclude patients with altered mentation, etc (not 
Alert And Oriented X3).


Alpha-1 Proteinase Inhibitor/GLASSIA
Page 100 of 101
Clinical Study Protocol Identifier: 471501
2017 APR 19
BAXALTA Confidential – Restricted: Do NOT distribute without prior approval.
INVESTIGATOR ACKNOWLEDGEMENT
PRODUCT: GLASSIA
STUDY TITLE: A Two-Part, Multi-Center, Prospective, Phase 2/3 Clinical Study to 
Evaluate the Safety and Efficacy of GLASSIA as an Add-On Biopharmacotherapy 
to Conventional Steroid Treatment in Subjects with Acute Graft-Versus-Host 
Disease with Lower Gastrointestinal Involvement
PROTOCOL IDENTIFIER: CT2/3-GVHD-IV-Multi-Center-KAM/BAX; 471501
CLINICAL TRIAL PHASE 2/3
AMENDMENT 1: 2017 APR 19
Replaces: ORIGINAL: 2016 APR 19
ALL VERSIONS:
AMENDMENT 1: 2017 APR 19
ORIGINAL: 2016 APR 19
OTHER ID(s) 
NCT Number: NCT02956122
EudraCT Number: To be determined
IND NUMBER: 017014
By signing below, the investigator acknowledges that he/she has read and understands 
this protocol, and will comply with the requirements for obtaining informed consent from 
all study subjects prior to initiating any protocol-specific procedures, obtaining written 
initial and ongoing EC(s) protocol review and approval, understands and abides by the 
requirements for maintenance of source documentation, and provides assurance that this 
study will be conducted according to all requirements as defined in this protocol, Clinical 
Trial Agreement, ICH GCP guidelines, and all applicable national and local regulatory 
requirements.
Signature of Principal Investigator
Date
Print Name of Principal Investigator


Al p ha- 1 Pr otei nase I n hi bit or/ G L A S SI A
Pa ge 1 0 1 of 1 0 1
Cli nical St u d y Pr ot oc ol I de ntifier: 4 7 1 5 0 1
2 0 1 7 A P R 1 9
B A X A L T A C o nfi de ntial – Restricte d: D o N O T distri b ute wit h o ut pri or a p pr o val.
I N V E S TI G A T O R A C K N O W LE D G E M E N T
P R O D U C T: G L A S SI A
S T U D Y TI T L E: A T w o -P a rt, M ulti- Ce nter, Pr os pecti ve, P h ase 2/ 3 Cli nic al St u d y t o 
E v al u ate t he S afet y a n d Effic ac y of G L A S SI A as a n A d d - On Bi o p h ar m ac ot her a p y 
t o C o n ve nti o n al Ster oi d Tre at me nt i n S u bjects wit h Ac ute Gr aft -Vers us - H ost 
Dise ase wit h L o wer G astr oi ntesti n al I n v ol ve me nt
P R O T O C O L I D E N TI F I E R: C T 2/ 3-G V H D -I V-M ulti -Ce nter -K A M/ B A X; 4 7 1 5 0 1
C LI NI C A L T RI A L P H A S E 2/ 3
A M E N D M E N T 1: 2 0 1 7 A P R 1 9
Re pl aces: O RI GI N A L: 2 0 1 6 A P R 1 9
A L L V E R SI O N S: 
A M E N D M E N T 1: 2 0 1 7 A P R 1 9
O RI GI N A L: 2 0 1 6 A P R 1 9
O T H E R I D(s ) 
N C T N u m ber: N C T 0 2 9 5 6 1 2 2
E u dr a C T N u m ber: T o be deter mi ne d
I N D N U M B E R: 0 1 7 0 1 4
B y  si g ni n g bel o w, t he i n vesti gat or ac k n o wle d ges t hat he/s he has rea d a n d u n dersta n ds 
t his pr ot oc ol, a n d pr o vi des ass ura nce t hat t his st u d y will be c o n d ucte d acc or di n g t o all 
re q uire me nts as defi ne d i n t his pr ot oc ol, Cli nical T rial A gree me nt , I C H G C P g ui deli nes, 
a n d all a p plica ble nati o nal a n d l ocal re g ulat or y re q uire me nts.
Si g nat ure of C o or di nati n g I n vesti gat or
Date
Pri nt Na me a n d Title of C o or di nati n g I n vesti gat or
Si g nat ure of S p o ns or Re prese ntati ve
Date
P P D
J u dit K ora n yi, M D
Gl o bal Cli nical De vel o p me nt O perati o ns
Ba xalta U S I nc. / Ba xalta I n n o vati o ns G m b H

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN
GLASSIA
PHASE 2/3
Two-Part, Multi-Center, Prospective, Phase 2/3 Clinical Study to
Evaluate the Safety and Efficacy of GLASSIA as an Add-On Biopharmacotherapy
to Conventional Steroid Treatment in Subjects with Acute Graft-Versus-Host
Disease with Lower Gastrointestinal Involvement (Part 1)
PROTOCOL IDENTIFIER: CT2/3-GVHD-IV-Multi-Center-KAM/BAX; 471501
Study Sponsor(s):
Baxalta US Inc.
One Baxter Way
Westlake Village, CA  91362
Baxter Innovations GmbH
Industriestrasse 67
A-1221 Vienna, AUSTRIA 
Author:
, 
, QuintilesIMS
                        
, 
, QuintilesIMS 
Protocol:
ORIGINAL: 2016 APR 19
SAP Version #:
1.0
SAP Date:
2017 SEP 13
Status:
Final
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
PPD
PPD
PPD
PPD


GLASSIA
  Page 2 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
TABLE OF CONTENTS
1.
INTRODUCTION AND OBJECTIVES .............................................................5
1.1
Study Objectives .................................................................................................6
1.1.1
Primary Objective........................................................................................6
1.1.2
Secondary Objective(s)................................................................................6
1.1.2.1 Efficacy ..............................................................................................6
1.1.2.2 Safety..................................................................................................6
1.1.2.3 Pharmacokinetics ...............................................................................6
1.1.2.4 Exploratory.........................................................................................6
2.
STUDY DESIGN....................................................................................................7
2.1
Study Population.................................................................................................8
2.2
Sample Size and Power Calculations..................................................................8
2.3
Randomization and Blinding ..............................................................................8
2.4
Study Stopping Rules..........................................................................................8
2.5
Study Assessments..............................................................................................8
2.6
Withdrawal and Discontinuation.........................................................................8
2.7
Data Monitoring Committee ...............................................................................9
3.
STUDY OUTCOME MEASURES.......................................................................9
3.1.1
Primary Outcome Measure ..........................................................................9
3.1.2
Secondary Outcome Measures...................................................................10
3.1.2.1 Efficacy ............................................................................................10
3.1.2.2 Safety................................................................................................10
3.1.3
Exploratory Outcomes Measure ................................................................10
3.1.3.1 Efficacy ............................................................................................10
3.1.3.2 Pharmacokinetics .............................................................................11
3.1.3.3 Pharmacodynamics...........................................................................11
3.1.3.4 Health Outcomes..............................................................................11
4.
ANALYSIS SETS.................................................................................................12
4.1
Efficacy Analysis Set........................................................................................12
4.2
Safety Analysis Set ...........................................................................................12
4.3
PK Analysis Set ................................................................................................12
4.4
Pharmacodynamic Analysis Set........................................................................12


GLASSIA
  Page 3 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
5.
STATISTICAL CONSIDERATIONS ...............................................................12
5.1
Handling of Missing, Unused, and Spurious Data............................................13
5.2
Definition of Baseline .......................................................................................13
5.3
Changes from the Planned Statistical Analysis in Protocol..............................14
6.
STUDY SUBJECTS.............................................................................................14
6.1
Disposition of Subjects .....................................................................................14
6.2
Demographic and Baseline Characteristics.......................................................14
6.3
Medical History.................................................................................................15
6.4
Concomitant Medications .................................................................................15
6.5
Protocol Deviations...........................................................................................16
7.
EFFICACY EVALUATION...............................................................................16
7.1
Analysis of Primary Efficacy Outcome Measure..............................................16
7.2
Analysis of Secondary Efficacy Outcome Measure..........................................17
7.2.1
Key Secondary Efficacy Outcome Measures ............................................17
7.2.2
Other Secondary Efficacy Outcome Measures..........................................18
8.
SAFETY EVALUATION....................................................................................21
8.1
Extent of Exposure............................................................................................21
8.2
Adverse Events..................................................................................................21
8.3
Clinical Laboratory Evaluations .......................................................................23
8.4
Vital Signs.........................................................................................................24
8.5
Recurrent Malignancies ....................................................................................24
8.6
Infection ............................................................................................................25
9.
EVALUATION OF PHARMACOKINETICS .................................................25
9.1
Concentration data ............................................................................................25
9.2
Pharmacokinetic parameters .............................................................................25
10.
EVALUATION OF QUALITY OF LIFE .........................................................28
10.1
Quality of Life Scoring .....................................................................................28
10.1.1 FACT-BMT ...............................................................................................28
10.1.2 Chronic GvHD Symptom Scale.................................................................29
10.1.3 EQ-5D-5L ..................................................................................................29
10.2
Analysis of QoL Data........................................................................................29


GLASSIA
  Page 4 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
11.
EVALUATION OF EXPLORATORY OUTCOME MEASURES ................30
11.1
Efficacy.............................................................................................................30
11.2
Pharmacodynamics ...........................................................................................31
11.3
Health Outcomes...............................................................................................32
12.
ANALYSIS SOFTWARE ...................................................................................33
13.
REVISION HISTORY ........................................................................................34
14.
APPENDICES......................................................................................................35
14.1
Study Flow Chart ..............................................................................................35
14.2
Schedule of Study Procedures and Assessments ..............................................36
14.3
Clinical Laboratory Assessments......................................................................39
14.4
Scoring guidance for FACT-BMT version 4.0 .................................................41


GLASSIA
  Page 5 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
1.
INTRODUCTION AND OBJECTIVES
The purpose of the study is to evaluate the safety and efficacy of GLASSIA as an add-on 
biopharmacotherapy to standard-of-care steroid treatment as the first-line treatment in 
subjects with acute graft-versus-host disease (GvHD) with lower gastrointestinal (GI) 
involvement. This is a 2-part study. Part 1 will evaluate the safety, efficacy and 
pharmacokinetic (PK) of GLASSIA in approximately 20 subjects. Start of any Part 2 
actvities was pending results from statistical analysis of Part 1 data. 
GLASSIA was approved in the United States for chronic augmentation and maintenance 
therapy in individuals with emphysema due to congenital deficiency of human alpha-1 
proteinase inhibitor (A1PI). The preclinical literature for A1PI, in combination with the 
interim efficacy results from a Phase 1/2 study, suggests that GLASSIA has the potential 
to provide significant clinical benefit as a first-line treatment in acute GvHD. There is 
currently no FDA-approved treatment for acute GvHD. The study population is selected 
because severe acute GI GvHD is associated with high mortality and patients with acute 
GvHD with lower GI involvement have a lower response rate to steroid treatment.
On 2 June 2017, Shire (sponsor) prematurely terminated the entire study (both Part 1 and 
Part 2) following an internal portfolio prioritization exercise which took into 
consideration difficulties in enrolling subjects and a reduced probability of success of the 
study. As of the decision date, only 1 subject had been enrolled in the study and no 
additional subject will be enrolled. That subject was treated with study drug under the 
original protocol because Protocol Amendment 1, while approved on 19 April 2017, prior 
to the study termination date, could not be implemented. 
This SAP is for Part 1 of the 2-part study and is based on the original protocol and thus 
documents all derivations of outcome variables, statistical analyses and summaries 
preplanned in the original protocol. Derivations of outcome variables, statistical analyses 
and summaries in this SAP are no longer applicable, as indicated by “Not Applicable” in 
the appropriate sections, but the analysis content is retained only for alignment with the 
original protocol. Only data listings will be produced for the single-enrolled subject, and
the listings will include raw (actual) values. In addition, since no adjudication of the 
response assessment data will be done, only the data based on the investigators’ 
assessments will be presented in the listings.
There will be no SAP for Part 2 since the entire study (Part 1 and Part 2) was terminated 
before start of Part 2. No subjects were enrolled in Part 2 at time of termination.


GLASSIA
  Page 6 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
1.1
Study Objectives
1.1.1
Primary Objective
To confirm the safety and efficacy of GLASSIA administered at a dose of 90 mg/kg 
(Day 1) followed by 30 mg/kg every other day (Days 3 to 13), then followed by 120 
mg/kg weekly (Days 15 to 50), when added to conventional steroid therapy, in subjects 
with acute GvHD with Stage 1 to 4 lower GI involvement, as assessed by treatment 
response at Day 28, and to determine whether continuation to Part 2 is warranted.
1.1.2
Secondary Objective(s)
1.1.2.1
Efficacy
To evaluate the treatment effects of GLASSIA, when added to conventional steroid 
therapy, on other clinical outcomes, such as rate, duration and magnitude of response; all-
cause, transplant-related, infection-related and GvHD-related mortality; overall survival; 
GvHD-free survival; treatment failure-free survival and incidence of chronic GvHD.
1.1.2.2
Safety
1. To evaluate the safety and tolerability of GLASSIA in addition to conventional 
steroid therapy (Part 1)
2. To assess the incidence of recurrence of primary malignancies
3. To assess the incidence and type of infection
1.1.2.3
Pharmacokinetics
To characterize the PK profile of GLASSIA, when added to conventional steroid 
treatment, using noncompartmental analysis methodology.
1.1.2.4
Exploratory
1. To assess A1PI plasma and stool concentrations and clearance in stool
2. To characterize the PK profile of GLASSIA, when added to conventional steroid 
treatment, using a population PK approach
3. To assess biomarkers in plasma (ie, inflammatory cytokines IL-2, IL-6, IL-8, 
IL-10 and IL-32; heparan sulfate; regenerating islet-derived protein 3α [Reg3α];
suppression of tumorigenicity 2 (ST2); tumor necrosis factor receptor 1 [TNFR1];
IL-1 receptor antagonist [IL-1RA] and T cell subpopulations, including CD4+
CD25+ CD127+ FoxP3+ Tregs) and stool (ie, calprotectin concentrations)


GLASSIA
  Page 7 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
4. To assess quality-of-life (QoL), GvHD symptoms and healthcare resource 
utilization for GLASSIA treatment as a first-line add-on therapy
2.
STUDY DESIGN
This is a 2-part Phase 2/3, prospective, controlled, randomized, multicenter study in
subjects with acute GvHD with Stage 1 to 4 lower GI involvement. Part 1 of this study is 
a nonrandomized, open-label, multicenter, clinical study evaluating GLASSIA in 
combination with conventional steroid treatment. The target population for Part 1 will 
include approximately 20 subjects (Cohort 1). The overall study design of Part 1 is 
illustrated in Figure 1 in Section 14.1. Part 2 of the study is not discussed in this SAP.
Screening for eligibility will occur from Days -2 to -1. After screening, all eligible 
subjects will be given GLASSIA with a loading dose of 90 mg/kg (Day 1) followed by 
GLASSIA 30 mg/kg every other day (Days 3 to 13), then followed by 120 mg/kg weekly 
(Days 15 to 50) in combination with 2 mg/kg/day of methylprednisolone or equivalent 
steroid. Tapering of steroids may commence after a subject responds to therapy. 
All subjects will be treated through Day 50, or until treatment failure, withdrawal from 
treatment or withdrawal from the study, whichever comes first. Thereafter, subjects will 
be treated with standard-of-care for the remainder of their participation in the study based 
on the investigator’s discretion. Prior to Day 28, subjects must be withdrawn from study 
treatment if a second-line treatment for acute GvHD is introduced. Subjects who 
experience recurrent malignancy will also be withdrawn from study treatment. Subjects 
who are withdrawn from study treatment will continue to be followed through at least 
Day 28, unless the subject withdraws consent.
Steroid treatment after Day 50 will be at the investigator’s discretion. Subjects will visit 
the site for follow-up visits on Days 56, 100, 180 and 365. In the event that it is not 
feasible for the subject to visit the site at Day 365, the visit may be conducted with a 
phone call.
Subjects requiring second-line treatment after Day 56 may be eligible to receive 1-time 
retreatment with GLASSIA with the same loading and maintenance dosing regimen (50 
days of treatment). Regardless of whether the subject receives retreatment, all subjects 
will be followed up at Days 100, 180 and 365.
Subjects classified as treatment failures will be included in the analysis but not be 
counted as either complete response (CR) or partial response (PR) for the primary 


GLASSIA
  Page 8 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
(overall response) or key secondary (GI response) endpoints. Subjects classified as 
treatment failures will not be replaced. Assessments of vital signs, clinical laboratory data 
(hematology and chemistry), local tolerability and adverse events (AEs) will be 
performed throughout the study.
2.1
Study Population 
The population for this study will consist of male and female subjects >=18 years of age 
who are recipients of an allogeneic hematopoietic stem cell transplantation (HSCT) and 
who have been newly diagnosed with acute GvHD with lower GI involvement (modified 
International Bone Marrow Transplant Registry [IBMTR] Severity Stage 1 to 4). Subjects 
with Stage 1 to 4 lower GI involvement have diarrhea >500 mL/day. Subjects must have 
evidence of myeloid engraftment. There are no restrictions on the prior conditioning 
treatments.
2.2
Sample Size and Power Calculations
The sample size for Part 1 was determined from an operational perspective and was not 
based on statistical power considerations. With 20 subjects and an assumed true response 
rate of 65%, the probability of observing an overall response rate of at least 55% is 
87.8%. If the true response rate is 40%, the probability of observing an overall response 
rate of 55% or higher is less than 13%.
2.3 Randomization and Blinding
Part 1 is a nonrandomized, open-label, active treatment clinical study.
2.4
Study Stopping Rules 
Stopping rules will not be established for Part 1 of this study. The study may be stopped 
at the sponsor’s discretion for any reason, including lack of efficacy, toxicities or adverse 
safety findings.
2.5
Study Assessments
A schedule of assessments for Part 1 is provided in Section 14.2. Details on clinical 
laboratory assessments can be found in Section 14.3.
2.6
Withdrawal and Discontinuation
Any subject may voluntarily withdraw (ie, reduce the degree of participation in the study)
consent for continued participation and data collection. 


GLASSIA
  Page 9 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
Discontinuation (ie, complete withdrawal from study participation) may be due to
dropout (ie, active discontinuation by subject) or loss to follow-up (ie, discontinuation by
subject without notice or action). Additionally, the investigator and sponsor have the
discretion to discontinue any subject from the study if, in their judgment, continued
participation would pose an unacceptable risk for the subject.
Subjects also will be withdrawn from treatment or discontinued from further study
participation for the following reasons:

The subject has a lower GI biopsy that in the opinion of a pathologist in
inconsistent with acute GvHD 

The subject becomes pregnant

The subject begins lactating

The subject starts a second-line treatment for acute GvHD prior to Day 28

The subject experiences recurrent malignancy 
2.7
Data Monitoring Committee
A Data Monitoring Committee (DMC) will independently evaluate safety and efficacy 
data. For this study, the DMC will be composed of recognized experts in the fields of 
oncology, hematology and immunology clinical care and research who are not actively 
recruiting subjects. The DMC may make a recommendation to continue the study as is, 
temporarily suspend the study, continue the study after proper amendment to the protocol 
or terminate the study based on predefined criteria such as unacceptable toxicities or lack 
of treatment benefits.
The DMC will meet periodically to evaluate safety during Part 1 and use the results from 
Part 1 to determine whether continuation to Part 2 is warranted. The DMC may meet in 
ad hoc meetings at its discretion as needed in response to events occurring in the study. 
The DMC’s responsibilities, definitions and operating procedures will be defined in a 
charter; the committee will maintain records of all its meetings.
3.
STUDY OUTCOME MEASURES 
3.1.1
Primary Outcome Measure
The primary outcome measure for Part 1 is the proportion of subjects achieving overall 
response (GvHD CR + PR) at Day 28. 


GLASSIA
  Page 10 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
3.1.2
Secondary Outcome Measures
3.1.2.1 Efficacy 
Key Secondary Efficacy Outcome Measures
1. Proportion of subjects achieving GI response (GI CR + PR) at Day 28
Other Secondary Efficacy Outcome Measures
1. Proportion of subjects achieving overall response at Day 56
2. Change from baseline in acute GvHD grading at Days 28, 56 and 180
3. Incidence of chronic GvHD at Days 100, 180 and 365
4. Duration of any overall response
5. Duration of any GI response
6. Overall survival through Days 100, 180 and 365
7. Transplant-related mortality at Days 28, 56, 100 and 180
8. Failure-free survival at Days 100 and 180
9. GvHD-free survival at Days 28, 56, 100 and 180
10. Infection-related mortality at Days 28, 56, 100 and 180
11. GvHD-related mortality at Days 28, 56, 100 and 180
12. All-cause mortality at Days 28, 56, 100 and 180
3.1.2.2 Safety
1. The incidence and severity of all AEs, related AEs, all SAEs, related SAEs and 
temporally-associated AEs
2. Change from baseline in clinical laboratory safety parameters and vital signs
3. Incidence of recurrence of primary malignancies through Days 180 and 365
4. Incidence and type of infection (eg, bacterial, fungal, viral, etc) at Days 28, 56,
180 and 365
3.1.3
Exploratory Outcomes Measure
3.1.3.1 Efficacy
1. Proportion of subjects achieving GvHD very good partial response (VGPR) at 
Day 28
2. Cumulative steroid dose at Days 28, 56, 100 and 180
3. Steroid dose at Days 28, 56 and 100
4. Proportion of subjects achieving GI CR and GI PR at Days 28, 56 and 180 at 
each baseline GvHD severity grade (B, C and D)


GLASSIA
  Page 11 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
3.1.3.2 Pharmacokinetics
The following noncompartmental analysis PK parameters by day and/or dosing 
frequency, as applicable, will be assessed:
1. Area under the plasma concentration curve (AUC) from time zero to the last 
quantifiable activity
2. AUC from time zero to time “t”
3. Systemic clearance at steady state
4. Maximum plasma concentration at steady state
5. AUC from time zero to infinity
6. Apparent volume of distribution at steady state
7. The terminal half-life
8. Mean residence time
9. Trough plasma A1PI levels at steady state
3.1.3.3 Pharmacodynamics
1. Change from baseline in plasma and stool concentrations of A1PI
2. A1PI clearance in stool
3. Change from baseline in plasma biomarkers (eg, cytokines IL-2, IL-6, IL-8, IL-10 
and IL-32; heparan sulfate; Reg3α; ST2; TNFR1 and IL-1RA) and 
stoolcalprotectin concentrations
4. T cell subpopulations from serum, including CD4+ CD25+ CD127+ FoxP3+
Tregs
3.1.3.4 Health Outcomes
1. Change from baseline in QoL as measured by the Functional Assessment of 
Cancer Therapy-Bone Marrow Transplant subscale version 4.0 instrument 
(FACT-BMT)
1. Change from baseline in acute GvHD symptoms as measured by the Chronic 
GvHD Symptom Scale
2. Change from baseline in health utility as measured by European Quality of Life-
5 Dimensions-5 Level (EQ-5D-5L)
3. Healthcare resource utilization:
•
type of admission (Hospital, Intensive Care Unit and/or transplant unit )
•
length of stay
•
Number of unscheduled physician office visits
•
Number of emergency room visits
4. Medication: 
•
Days on steroids


GLASSIA
  Page 12 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
4.
ANALYSIS SETS
4.1
Efficacy Analysis Set 
The Efficacy Analysis set will include all subjects who are evaluable for overall response 
at Day 28. Subjects who do not receive at least 1 dose or who are withdrawn due to a 
lower GI biopsy that is inconsistent with acute GvHD will not be considered evaluable.
The Efficacy Analysis set will be used for the primary analysis of the primary outcome 
measure and the analyses of selected secondary efficacy outcome measures and health 
outcomes.
4.2
  Safety Analysis Set
The Safety Analysis (SAF) set will consist of all subjects who receive at least 1 dose of 
study treatment and will be used in the analyses of safety variables, and the sensitivity 
analyses of the GvHD overall response rate at Day 28 and GI response rate at Day 28.   
4.3
PK Analysis Set
The PK Analysis set will consist of all subjects in the SAF set who have at least 1 PK or
stool sample collected.
4.4
Pharmacodynamic Analysis Set
The pharmacodynamic analysis set will consist of all subjects in the SAF set who have at 
least 1 postdose biomarker sample collected.
5.
STATISTICAL CONSIDERATIONS 
All derivations, analyses and summaries are not applicable (details in Section 1 and 
Section 5.3).
For Part 1, all the outcome variables will be summarized descriptively. Based on the 
characteristics of the study design and lack of a concurrent control arm, formal testing of 
treatment effects will not be performed.
Statistical summaries described will be provided for all subjects in the analysis set of 
interest unless otherwise stated.
For efficacy outcome measures, the point estimate and 95% confidence interval will be 
provided. For the other outcome measures, continuous variables will be summarized by 
the number of observations, mean, standard deviation, median, minimum, and maximum. 
Categorical variables will be summarized by frequency counts and percentages for each 


GLASSIA
  Page 13 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
category. Unless otherwise stated, percentages will be calculated out of the total in the 
analysis set. The number of missing values will be presented where necessary.
For continuous data the mean and median will be rounded to 1 additional decimal place 
compared to the original data. The standard deviation will be rounded to 2 additional 
decimal places compared to the original data. Minimum and maximum will be displayed 
with the same accuracy as the original data. For categorical data, percentages will be 
rounded to 1 decimal place.
For time-to-event outcome measures, Kaplan-Meier estimates will be provided, and the 
estimates will include 25th percentile, median and 75th percentile, if estimable, and the 
corresponding 95% confidence intervals.   
5.1
Handling of Missing, Unused, and Spurious Data
For Part 1, for the primary analysis of GvHD overall response, the non-responder 
imputation (NRI) approach will be used to impute the response status at Day 28 as no 
response for subjects without a response assessment at Day 28 due to any reason. The 
NRI approach will also be applied to GI response at Day 28 and other time point 
responses, including overall response at Day 56.
Regarding missing data in AE records:
o
Handling of unknown causality assessment:
•
If a subject experiences an AE with a missing causality assessment, the 
relationship of the AE will be counted as “related”.
o
Handling of unknown severity grades:
•
If a subject experiences more than one AE categorized under the same 
preferred term, the subject will be counted under the most severe toxicity 
grade reported for that AE. 
•
If a subject experiences an AE and the toxicity grade was not provided, the 
toxicity grade of this AE should be counted as “unknown”. A row or 
column labelled “Unknown” should be inserted for those AEs in tables
where AEs are summarized by toxicity grade.
5.2
Definition of Baseline
Baseline will be the last non-missing assessment of the variable under consideration prior 
to initial administration of study treatment (GLASSIA in Part 1). 


GLASSIA
  Page 14 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
Assessments on the day of first dose of study treatment where time is not captured will be 
considered as after the first dose unless a nominal pre-dose indicator is available or such 
procedures are required by the protocol to be conducted before the first dose of study 
treatment.  
5.3
Changes from the Planned Statistical Analysis in Protocol 
As indicated in Section 1, Shire (sponsor) prematurely terminated the entire study (both 
Part 1 and Part 2) on 2 June 2017 following an internal portfolio prioritization exercise 
which took into consideration difficulties in enrolling subjects and a reduced probability 
of success of the study. As of the decision date, only 1 subject had been enrolled in the 
study and no additional subject will be enrolled. That subject was treated with study drug 
under the original protocol because Protocol Amendment 1, while approved on 19 April 
2017, prior to the study termination date, could not be implemented. 
This SAP is for Part 1 of the 2-part study and is based on the original protocol and thus 
documents all derivations of outcome variables, statistical analyses and summaries 
preplanned in the original protocol. Unless otherwise specified in this SAP, only data 
listings will be produced for the single-enrolled subject, and the listings will include raw 
(actual) values. In addition, since no adjudication of the response assessment data will be 
done, only the data based on the investigators’ assessments will be presented in the 
listings. 
6.
STUDY SUBJECTS
All derivations, analyses and summaries are not applicable (details in Section 1 and 
Section 5.3).
6.1
Disposition of Subjects
Subject disposition will be summarized and presented with the number and percentage of 
subjects who were screened, screen-failed, treated, completed the study, and discontinued 
early (including reasons for discontinuations). The number and percentage of subjects in 
each analysis set (SAF, Efficacy, PK) will be displayed. A listing of subject disposition 
will be produced. Inclusion/exclusion criteria violations will be listed for screen-failed 
subjects. 
6.2
Demographic and Baseline Characteristics
Demographic and baseline characteristics, including age (years), sex, race (where 
applicable), ethnicity (where applicable), height (cm), weight (kg), BMI (kg/m2), 


GLASSIA
  Page 15 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
baseline GvHD stages as measured as the degree of skin, GI, liver involvement, severity 
grade of acute GvHD, stage of lower GI involvement, status of recurrent malignancy at 
baseline, and transplant history (source of HSCT, donor related or not, sex of donor, 
primary or repeated transplant) will be summarized using descriptive statistics. Age will 
be calculated as the integer of (Date of Informed Consent – Date of Birth)/365.25. 
Smoking history will be categorized (never, current, former) for each nicotine type and 
presented separately. Details of smoking history, including the age of starting and 
quitting smoking, daily amount, and pack years, will be listed only. 
Summaries will be provided for the SAF and Efficacy Analysis sets for all subjects in 
each analysis set. Demographics and baseline characteristics will also be presented in 
subject data listings.
6.3
Medical History 
The medical and surgical history of subjects will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA), version 19.1 or a later version and summarized 
separately for the SAF set, presenting the number and percentage of subjects with a 
history in each system organ class (SOC) and preferred term. For summary tables, a 
subject will be counted only once per body system and preferred term. Medical and 
surgical history will be included in data listings. Acute GvHD history will be listed only. 
6.4
Concomitant Medications 
Other than the study drug, any medications or therapies administered on or after the first 
dose of study treatment but not starting after the last dose of study treatment, or with a 
start date prior to and an end date on or after the date of the first dose of study treatment,
or marked as ongoing will be considered concomitant medications. Medications that 
ended prior to the date of the first dose of the study drug will be considered as prior 
medications. Concomitant and prior medications will be coded using the latest version of 
the WHO Drug dictionary and summarized separately. 
Concomitant anti-infective medications will be summarized by re-grouping antibiotics, 
antivirals, and antifungals agents, with the number and percentage of subjects using each 
concomitant medication according to the WHODRUG Anatomic Therapeutic Class 
(ATC) and preferred term for the SAF set. Subjects with multiple uses of a concomitant 
medication will be counted once by the drug class and preferred term. 
Prior and concomitant medications will be presented in the subject data listings.


GLASSIA
  Page 16 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
6.5
Protocol Deviations
Protocol deviations will be classified as Minor, Important/Major or Critical/Priority. For 
analysis and reporting purposes, deviations leading to exclusion from the Efficacy
Analysis set will include, but are not limited to: deviation from eligibility criteria, 
administration of prohibited medications and erroneous administration of study treatment. 
The criteria for grading protocol deviations will be proposed according to Quintiles SOP 
by the Quintiles Therapeutic Medical Advisor and aligned with the Baxalta Physician. 
All protocol deviations leading to exclusion from the Efficacy Analysis set are 
determined together with the Baxalta Physician on a case-by-case basis by the medical 
reviewer prior to each database lock of Part 1. 
The number and percentage of subjects for each type of protocol deviation will be 
tabulated for the SAF set and a listing will be produced showing individual subjects for 
all protocol deviations.
7.
EFFICACY EVALUATION  
7.1
Analysis of Primary Efficacy Outcome Measure
All derivations, analyses and summaries are not applicable (details in Section 1 and 
Section 5.3).
The primary outcome measure is the GvHD overall resonse rate, the proportion of 
subjects achieving overall response at Day 28. The overall response is defined as GvHD 
CR + PR, which are defined as follows:
•
GvHD CR is complete resolution of all signs and symptoms of acute GvHD in all 
organs without intervening salvage
•
GvHD PR is improvement of 1 stage in 1 or more organs involved in GvHD 
without progression in other organs 
Overall response at Day 28 will be based on the response assessments at Day 28 with a
+1- day window for this assessment. For the primary analysis in the efficacy analysis set, 
the NRI approach will be used to impute the missing response assessment at Day 28. For 
the GvHD overall response rate at Day 28 95% exact confidence intervals of the 
proportion will be calculated with Clopper-Pearson method.
The primary analysis of the GvHD overall resonse rate in the efficacy analysis set will 
use the investigators’ response assessment collected on the CRF Investigator Response 
Assessment [INVRES] module and use NRI approach for missing response assessment. 


GLASSIA
  Page 17 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
A sensitivity analysis in the efficacy analysis set will use the adjudicated response 
assessments by an adjudication committee and use NRI approach for missing response 
assessment. 
All the planned analyses of the GvHD overall response rate at Day 28 are listed in the 
table below.
Analysis
Analysis set
Response 
assessment data
Approach for missing 
response assessment 
imputation
Primary analysis
Efficacy analysis set
Investigators’ 
assessment
NRI
Sensitivity analysis 
Efficacy analysis set
Adjudicated data
NRI
Response assessments for each subject will be listed by visit.  
7.2
Analysis of Secondary Efficacy Outcome Measure
All derivations, analyses and summaries are not applicable (details in Section 1 and 
Section 5.3).
7.2.1
Key Secondary Efficacy Outcome Measures
The key secondary efficacy outcome is the GI response rate, the proportion of subjects 
achieving GI response at Day 28. GI response is defined as GI CR + PR, which are 
defined as follows:
•
GI CR is defined as
a) Able to eat; not requiring parenteral nutrition, and
b) Passing primarily formed stools
•
GI PR is defined as
a) Decrease in need for parenteral nutrition to ≤50% of required calories; and
b) Reduction of stool volume by ≥50%, without ileus
GI response at Day 28 based on investigator assessments (CRF INVRES module) and 
adjudicated data will be analyzed using the same approach as described for the primary 
outcome in Section 7.1.


GLASSIA
  Page 18 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
7.2.2
Other Secondary Efficacy Outcome Measures
Proportion of subjects achieving GvHD overall response at Day 56
GvHD overall response at Day 56 will be based on all the investigators’ assessments or 
the adjudicated data of GvHD response obtained at Day 56 (with a +1 day window) in the 
efficacy analysis set and using the NRI approach as for the primary outcome measure in 
Section 7.1.
Change from baseline in acute GvHD grading at Days 28, 56 and 180
Staging of GvHD will be performed by the investigator according to the modified 
IBMTR grading system, and recorded on CRF STAGE module. The degree of 
involvement of skin, GI and liver is classified by stage on a scale of 0 to 4 and the grade 
of acute GvHD is classified on a scale of A to D. 
Shift tables from baseline to Days 28, 56 and 180 visits will be provided for acute GvHD 
grading and organ system (involvement of skin, GI and liver) staging separately in the 
efficacy analysis set.
Incidence of chronic GvHD at Days 100, 180 and 365
At baseline and Days 100, 180 and 365, the investigator will assess the subject for 
chronic GvHD and acute/chronic GvHD overlap syndrome. The number and percentage
of subjects who have clinical evidence of chronic GvHD will be summarized at baseline 
and Days 100, 180 and 365 by organ systems (skin involvement, dry mouth/mouth 
sores/ulcers, dry eyes, joint involvement, liver involvement with cholestasis, esophageal 
involvement, obstructive lung disease) in the SAF. 
Duration of any overall response
Duration of overall response is defined as the time from the date of first overall response
(GvHD CR or PR) until the first date of progression (GvHD progressive disease [PD] on 
CRF INVRES module) or death in the absence of progression. Subjects without 
progression or death will be censored at the date of last GvHD response assessment.
Only subjects with an overall response will be summarized for duration of overall 
response. Descriptive data, including 25th percentile, median and 75th percentile will be 
estimated using Kaplan-Meier method. The summaries will be produced separately for 
investigator assessment and adjudicated data. Duration of overall response will also be 
presented using corresponding Kaplan-Meier plots.


GLASSIA
  Page 19 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
Duration of any GI response
Duration of GI response will be derived and summarized for subjects who achieved a GI 
response using the same approach as described for the duration of overall response above, 
based on GI response assessments.   
Overall survival through Days 100, 180 and 365
Overall survival is defined as the time from the date of first dose of study treatment until 
death (CRF DEATH module) due to any cause in the SAF. Any subject not known to 
have died in Part 1 will be censored at the date of study completion/early termination (or 
the last recorded date during the study). 
Number and percentage of subjects who have died will be provided along with median 
overall survival time. Overall survival through Days 100, 180 and 365 will be presented 
as the Kaplan-Meier estimates of the probability of subjects’ being alive at Days 100, 180 
and 365. The probability of overall survival will be presented in a Kaplan-Meier plot. 
All-cause, transplant-related, infection-related and GvHD-related mortality at Days 28, 
56, 100 and 180
All-cause, transplant-related, infection-related and GvHD-related mortality will be 
collected with the cause of death based on the investigator’s assessment. These categories 
are not mutually exclusive and they are defined as:
•
Transplant-related mortality: death related to transplantation (including deaths 
related to GvHD)
•
Infection-related mortality: death related to infection (including infections related 
to HSCT)
•
GvHD-related mortality: death related to GvHD
•
Other cause: any death not related to transplant, infection or GvHD
The proportion of subjects with all-cause mortality is a reverse of the proportion of 
subjects alive (overall survival). The mortalities at Days 28, 56, 100 and 180 and 95% 
confidence intervalswill be estimated using the uncorrected Kaplan-Meier method. The
cumulative mortality rate will be presented in a Kaplan-Meier plot.
Time to transplant-related, infection-related and GvHD related mortality are potientally 
dependent and competing mortality causes for a subject, and will be analyzed using the 
competing risk approach. These outcomes will be defined as the time from the date of 


GLASSIA
  Page 20 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
first dose of study treatment until death due to the corresponding cause, in the presence of 
other mortality causes. Any subject not having death will be censored at the date of study 
completion/early termination (or the last recorded date during the study). For time to 
transplant-related mortality, subjects having death due to a reason other than transplant-
related will be censored at the date of death, and handled differently in the estimation 
from the censoring not due to a competing cause. Time to infection-related mortality and 
time to GvHD-related mortity will be censored for subjects without an event in a similar 
fashion. The probability of transplant-related, infection-related and GvHD-related 
mortality at Days 28, 56, 100 and 180 will be estimated using the competing risk estimate 
of cumulative incidence function. GvHD-related mortality will also be presented using a 
cumulative incidence rate plot. 
Failure-free survival at Days 100 and 180
Failure-free survival is defined as the time from the first dose date of study treatment 
until death or the first date of failure-free survival not achieved (CRF Mortality and 
Survival Assessments [MORTAL] module), whichever comes earlier. The failure-free 
survival are determined by investigator with the absence of all 3 of the following criteria:
•
Need for second-line treatment for acute GvHD. Second-line treatment is defined 
as any additional systemic treatment used for steroid nonresponsive treatment of 
acute GvHD. Methylprednisolone (or equivalent steroid) doses greater than 2 
mg/kg required for the treatment of GvHD will also be considered second-line 
therapy
•
Non-relapse mortality. Non-relapse mortality is defined as death during 
continuous complete remission
•
Recurrent malignancy
Subjects without recorded death and failure-free survival not achieved at any survival and 
mortality assessment will be censored at the date of last mortality and survival 
assessment.  
Failure-free survival will be summarized at Days 100 and 180 using the same approach 
(Kaplan-Meier) as described for overall survival.
GvHD-free survival at Days 28, 56, 100 and 180
GvHD-free survival is defined as the time from the first dose date of study treatment until 
death or the first date of GvHD-free survival not achieved (CRF MORTAL module), 
whichever comes earlier. Subjects without recorded death and GvHD-free survival not 


GLASSIA
  Page 21 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
achieved will be censored at the date of last mortality and survival assessment. GvHD-
free survival will be summarized at Days 28, 56, 100 and 180 using the same approach
(Kaplan-Meier) as described for overall survival. 
8.
SAFETY EVALUATION 
8.1
Extent of Exposure
All derivations, analyses and summaries are not applicable (details in Section 1 and 
Section 5.3).
The below summaries related to study treatment will be produced for the SAF set:
•
Duration of exposure of study treatment (days): date of last dose – date of first 
dose + 1
•
Number of infusions received 
•
Number of subjects and reason for infusion rate change 
•
Number of subjects and reason for infusion interruption
8.2
Adverse Events
All derivations, analyses and summaries are not applicable (details in Section 1 and 
Section 5.3).
Adverse events (AEs) will be collected throughout the study, from the time the informed 
consent is signed until study completion. All AEs will be coded using MedDRA, version 
19.1 or a later version, and graded according to National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Grade (version 4.03).
A treatment-emergent AE (TEAE) is defined as an AE that occurred during or after study 
treatment application and until 30 days following the last dose of the study treatment. If the 
start date and time of the AE is provided, then the AE start date and time will be used to 
classify the AE as TEAE or not. If the start date and time or start time of an AE is 
unavailable, the CRF AE module asks the subject/investigator to identify whether it 
occurred before the first treatment, during treatment, within 24 hours after the last 
treatment, between 24 and 72 hours after last treatment, or more than 72 hours after the 
last treatment. This information will used to determine if the AE will be considered as 
TEAE, when necessary.    


GLASSIA
  Page 22 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
The number and percentage of subjects reporting the following TEAEs will be tabulated 
by SOC, PT and severity CTCAE grade, for the SAF set:
•
All TEAEs 
•
TEAEs related to study treatment 
•
TEAEs with CTCAE grade 3 or 4
•
TEAEs with CTCAE grade 3 or 4, related to study treatment
•
Serious TEAEs 
•
Serious TEAEs related to study treatment 
•
TEAEs leading to discontinuation of study treatment 
•
Temporally-associated TEAEs (occurring within 72 hours of termination of 
infusion)
An overall summary of the number and percentage of subjects in each category will be 
presented. Overview summaries of TEAEs by seriousness, severity CTCAE grade and 
relationship to study treatment (categories as collected and dichotomized) will be 
provided, separately as the subject-level and event-level summaries. Additionally, 
subjects with non-serious TEAEs will be presented by SOC, PT, severity CTCAE grade 
and dichotomized relationship to study treatment. 
The following conventions will be followed in summarizing TEAEs:
•
For subject incidence summaries, each subject will be counted only once within 
each system organ class and within each preferred term.
•
If a subject reports more than one TEAE within a preferred term and/or a body 
system, the TEAE with the highest known CTCAE grade within each body 
system and within each preferred term will be included in the summaries by 
CTCAE grade.
•
For summaries related to study treatment, AEs whose relationship to treatment are 
assessed as “possibly related”, “probably related” or missing will be included.
Listings of AEs that occurred before treatment application, non-serious AEs that occurred 
during or after treatment application, serious AEs that occurred during or after treatment 
application, all deaths, and AEs leading to study treatment discontinuation will be 
produced, including all data collected in the CRF, along with derived duration of AEs, 


GLASSIA
  Page 23 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
calculated as (end date – start date +1). If an event is ongoing at the end of the study then 
the duration of the event will not be calculated.
8.3
Clinical Laboratory Evaluations 
All derivations, analyses and summaries are not applicable (details in Section 1 and 
Section 5.3).
Laboratory evaluations will be conducted at screening and during treatment period, as 
described in protocol and Section 14.3. For hematology and clinical chemistry variables, 
change from baseline will be calculated for each post-baseline visit, and the laboratory 
values will be evaluated according to the NCI CTCAE version 4.03 toxicity grading scale 
by the investigator. All the laboratory data will be analyzed for the SAF set.
Observed laboratory values will be compared to the reference range and classified as low 
(below range), normal (within range or on limits of range) and high (above range). 
The maximum (or minimum) value during treatment will be defined for each laboratory 
parameter as the maximum (or minimum) post-baseline value at any time.
Summaries of laboratory results will be provided in standard international units. 
For continuous laboratory assessments observed values and changes from baseline will 
be summarized using descriptive statistics at each visit.  
Shift tables relative to the CTC grade will be produced to summarize the change from 
baseline to the worst CTC grade during treatment period. For specific parameters 
separate shift tables indicating hyper- and hypo- directionality of change will be 
produced. The following laboratory parameters will be included in the shift tables:
•
Haematology: hemoglobin, lymphocyte absolute counts, neutrophil absolute 
counts, platelet counts, leukocytes
•
Clinical chemistry: albumin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), total bilirubin, creatinine, 
corrected calcium (increased and decreased), glucose (increased and decreased), 
potassium (increased and decreased), magnesium (increased and decreased), 
sodium (increased and decreased)  


GLASSIA
  Page 24 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
For the laboratory parameters with no CTCAE grading, shifts tables from baseline to 
minimum and maximum value during treatment will be created. 
For urinalysis variables, a table will summarize the shift in the absence/presence of 
protein, glucose, blood, ketones, billirubin, urobilinogen, nitrate, leukocyte esterase, red 
blood cells, white blood cells, bacteria, and casts from baseline to each scheduled visit 
during treatment.
All laboratory test results (including urinalysis) will be presented in subject data listings.
8.4
Vital Signs 
All derivations, analyses and summaries are not applicable (details in Section 1 and
Section 5.3).
For vital signs, systolic and diastolic blood pressure (supine and standing), heart rate 
(supine and standing), weight, and respiratory rate and changes in these parameters from 
baseline will be summarized at each scheduled measurement using descriptive statistics. 
The summary table will be produced for the SAF set. All vital sign data will be included 
in a subject data listing.  
8.5
Recurrent Malignancies
All derivations, analyses and summaries are not applicable (details in Section 1 and 
Section 5.3).
Recurrent malignancy will be assessed at screening and all visits during the study. The
time to recurrent malignancies will be defined as the time interval from the first dose date 
of study treatment to the first onset date of recurrent malignancies. Subject without any 
recurrent malignancies will be censored on the last follow-up date. Subject who have died 
without recurrent malignancies will be censored on the date of death, and this censoring 
will be handled separately in the estimation. The competing risk method will be used to 
estimate the cumulative incidence of recurrent malignancies at Days 180 and 365. 
The incidence of recurrent malignancies will also be summarized by the number and 
percentage of subjects who had at least one presence of recurrent malignancy by Days 
180 and 365 for the SAF set. 


GLASSIA
  Page 25 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
8.6
Infection
All derivations, analyses and summaries are not applicable (details in Section 1 and 
Section 5.3).
The infections and the type of infections will be identified using preferred terms of AEs 
by the medical team. The incidence of infection will be analyzed as a time to event 
outcome measure. The time to infection will be defined as the time interval from the first 
dose date of study treatment to the first onset date of infection. Subject without any 
infection or the infection of interest or death will be censored on the last follow-up date. 
Subject who have died without any infection will be censored on the date of death, and 
this censoring will be handled separately in the estimation. The competing risk method 
will be used to estimate the cumulative incidence function of infection at Days 28, 
56,180, and 365 for any infection and by the type of infections, including viral infection, 
bacterial infection, and fungal infection. 
The number and percentage of subjects with infection for at least once by Days 28, 56, 
180 and 365 will be summarized for any infection and by the type of infections. 
9.
EVALUATION OF PHARMACOKINETICS 
9.1
Concentration data
Subjects with partial data will be evaluated on a case-by-case basis to determine if 
sufficient data are available for reliable estimation of PK parameters.
A listing of PK blood sample collection times as well as derived sampling time deviations 
and PK concentration data will be provided. A listing of PK stool sample collection 
times, sample weights and concentration and amount data will be provided where 
available.
Due to study discontinuation no population PK analysis is planned to be conducted based 
on the concentration data collected in this study.
9.2
Pharmacokinetic parameters
A listing of PK parameters by Day (Days 1, 13, and 22) will be provided.
For PK parameter calculations, predose samples that are BLQ or missing will be assigned 
a numerical value of zero.  Any other BLQ concentrations will be assigned a value of 
zero if they precede quantifiable samples in the initial portion of the profile.  A BLQ 


GLASSIA
  Page 26 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
value that occurs between quantifiable data points, especially prior to Cmax, will be 
evaluated to determine if an assigned concentration of zero makes sense, or if exclusion 
of the data is warranted.  Following Cmax, BLQ values embedded between 2 quantifiable 
data points will be treated as missing when calculating PK parameters.  If a BLQ value 
occurs at the end of the collection interval (after the last quantifiable concentration), it 
will be set to zero.  If consecutive BLQ concentrations are followed by quantifiable 
concentrations in the terminal portion of the concentration curve, these quantified values 
will be excluded from the PK analysis by setting them to missing, unless otherwise 
warranted by the concentration-time profile.  
Blood samples for PK collected after the infusion on Day 1, Day 13 or Day 22 prior to 
the next infusion will be used to estimate the following PK parameters if possible. A 
minimum of 3 quantifiable concentration-time data points will be required for calculation 
of PK parameters. The following PK parameters will be estimated for GLASSIA in 
plasma by non-compartmental methods using actual elapsed time from dosing, with 
additional parameters determined as appropriate.


GLASSIA
  Page 27 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
AUC(0-inf)
Area under the concentration-time curve in the sampled matrix from zero 
(predose) extrapolated to infinite time, calculated by linear up/log down 
trapezoidal summation and extrapolated to infinity by addition of the last 
quantifiable concentration divided by the elimination rate constant:  AUC(0-last) + 
Clast/z.  
AUC(0-t)
Area under the concentration-time curve in the sampled matrix from zero 
(predose) until time “t”, calculated by linear up/log down trapezoidal summation.
Cmax
Maximum concentration in plama, obtained directly from the observed 
concentration versus time data.
tmax
Time of maximum concentration (h), obtained directly from the observed 
concentration versus time data.
z
Apparent terminal rate constant (1/h), determined by linear regression of the 
terminal points of the log-linear concentration-time curve.  Visual assessment will 
be used to identify the terminal linear phase of the concentration-time profile.  A 
minimum of 3 data points will be used for determination.
t1/2
Apparent terminal half-life (h), determined as ln2/z.
CL
Systemic clearance after intravenous dosing (L/h), calculated as dose divided by 
AUC(0-inf).
Vss
Volume of distribution at steady state following intravenous dosing (L), calculated 
as mean residence time (MRT) extrapolated to infinity multiplied by clearance 
(MRTinf*CL)
MRT
Mean residence time
The following PK parameters will be calculated for diagnostic purposes and listed, but 
will not be summarized.
t1/2, Interval
The time interval (h) of the log-linear regression to determine z.
t1/2, N
Number of data points included in the log-linear regression analysis to determine 
z.  A minimum of 3 data points will be used for determination.
Rsq
Goodness of fit statistic for calculation of z (Regression coefficient/coefficient of 
determination).
%AUCex
Percentage of AUC(0-inf) obtained by extrapolation, calculated as [(Clast/z)/AUC(0-
inf)100.


GLASSIA
  Page 28 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
10.
EVALUATION OF QUALITY OF LIFE
10.1
Quality of Life Scoring
All derivations, analyses and summaries are not applicable (details in Section 1 and 
Section 5.3).
10.1.1
FACT-BMT
The Functional Assessment of Cancer Therapy-Bone Marrow Transplant subscale 
version 4.0 instrument (FACT-BMT) is a 37-item scale comprised of a general core 
questionnaire, the FACT-G, which evaluates the health-related QoL of subjects receiving 
treatment for cancer, and a specific module, BMT Concerns, which addresses disease and 
treatment-related questions specific to BMT. The FACT-G core questionnaire assesses 4 
subscales: physical well-being, social/family well-being, emotional well-being and 
functional well-being. Each subscale can be scored, the higher the score the better the 
QoL.
The FACT-G scoring guide on FACIT.org identifies items that must be reversed before 
being added to obtain subscale totals, which are listed in Section 14.4. Negatively stated 
items are reversed by subtracting the response from “4”. After reversing proper items, all 
subscale items are summed to a total, which is the subscale score.  
If there are missing items, subscale scores can be prorated. This is done by multiplying 
the sum of the subscale by the number of items in the subscale, then dividing by the 
number of items actually answered, using the formula below: 
Prorated subscale score = (Sum of item scores) x (N of items in subscale) / (N of items 
answered)
When there are missing data, prorating by subscale in this way is acceptable as long as 
more than 50% of the items were answered (e.g., a minimum of 4 of 7 items, 4 of 6 items, 
etc).    
For the “BMT Concerns” module, the procedure for scoring is the same as described 
above for the FACT-G. Again, over 50% of the items must be completed in order to 
consider the subscale score valid. The negatively stated items that must be reversed are 
listed in Section 14.4.


GLASSIA
  Page 29 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
10.1.2
Chronic GvHD Symptom Scale
The Chronic GvHD Symptom Scale is a 30-item validated scale that measures the extent 
to which the subject is bothered by chronic GvHD symptoms in the following domains: 
skin, eyes and mouth, breathing, eating and digestion, muscles and joints, energy, and 
mental and emotional. Responses are captured on a 5-point Likert scale (“no symptoms, 
or not bothered at all,” “slightly bothered,” “moderately bothered,” “bothered quite a bit” 
or “extremely bothered”). 
Scores for each symptom domain are converted to a 0 to 100 scale, by calculating the 
mean of the set of items from the domain and multiplying the result by 25. Higher scores 
indicate a greater degree to which the subject is bothered by the symptoms.
For each domain, if <50% of the items are missing, then the score will be divided by the 
number of non-missing items and multiplied by the total number of items on the domain. 
If at least 50% of the items are missing, then the score of that domain will be treated as 
missing.
10.1.3
EQ-5D-5L
The EQ-5D-5L is a standardized subject-administered measure of health related QoL 
states consisting of 5 dimensions (mobility, self-care, usual activities, pain/discomfort 
and anxiety/depression) each of which can take 1 of 5 responses. The responses record 5 
levels of severity (no problems/slight problems/moderate problems/severe 
problems/extreme problems) within a particular EQ-5D dimension. A unique EQ-5D 
health state is defined by combining 1 level from each of the 5 dimensions allowing for a 
total of 3125 health states. These data will be converted into a weighted health state 
utility by applying scores from EQ-5D-5L crosswalk value sets on EuroQol.org.
In addition, the EQ-VAS score record the respondent’s self-rated health on a 20 cm 
vertical visual analogue scale, ranging from 0 (worst imaginable health) to 100 (best 
imaginable health).
10.2
Analysis of QoL Data
All derivations, analyses and summaries are not applicable (details in Section 1 and 
Section 5.3).
For FACT-BMT, descriptive summaries of absolute value and change from baseline will 
be provided for FACT-G subscale scores (physical well-being, social/family well-being, 
emotional well-being, functional well-being), and “BMT concerns” subscale score.


GLASSIA
  Page 30 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
For Chronic GvHD Symptom Scale, descriptive summaries of absolute value and change 
from baseline will be provided for scores of each symptom domain (skin, eyes and 
mouth, breathing, eating and digestion, muscles and joints, energy, mental and 
emotional).   
For EQ-5D-5L, a shift table will be provided to summarize the number and percentage of 
subjects in each dimension with no, slight, moderate, severe and extreme problems or 
unable to perform the dimension from baseline to each scheduled post-baseline visit.
Additionally, summary statistics and change from baseline will be provided for the utility
score and EQ-VAS scores.
For each instrument, the questionnaire completion rate will by summarized by study visit, 
and defined as the proportion of patients who completed the questionnaire (at least one 
individual question within the questionnaire completed) at a certain time-point (e.g. 
Baseline, Day 28, Day 56, etc) using the number of patients in the study at the respective 
time-point as the denominator.
Efficacy Analysis set will be used for summary tables. QoL Data will also be included in 
listings.
11.
EVALUATION OF EXPLORATORY OUTCOME MEASURES
11.1
Efficacy 
All derivations, analyses and summaries are not applicable (details in Section 1 and 
Section 5.3).
Proportion of subjects achieving GvHD VGPR at Day 28
A GvHD VGPR is defined as follows:
•
Skin: no rash, or residual erythematous rash involving <25% of the body surface, 
without bullae (residual faint erythema and hyperpigmentation do not count) 
•
Liver: total serum bilirubin concentration <2 mg/dL or <25% of baseline at 
enrollment
•
Gut: tolerating food or enteral feeding, predominantly formed stools, no overt GI 
bleeding or abdominal cramping and no more than occasional nausea or vomiting
The investigator assessments of whether GvHD VGPR is achieved are recorded on CRF 
INVRES module (response = yes). The adjudication of VGPR will be performed. The 


GLASSIA
  Page 31 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
proportion of subjects with GvHD VGPR at Day 28 based on investigator assessments 
and adjudicated data will be derived and summarized for the Efficacy Analysis set using 
the NRI approach as described for primary efficacy outcome in Section 7.1.
Cumulative steroid dose at Days 28, 56, 100 and 180
The cumulative dose of steroid will be collected at Days 28, 56, 100 and 180 and 
summarized at each of these visits using descriptive statistics for the Efficacy Analysis
set. 
Average steroid dose by Days 28, 56, 100 and 180
The average doses of steroid from Day 1 to Days 28, 56, 100 and 180 will be summarized 
using descriptive statistics for the Efficacy Analysis set. 
Steroid dose at Days 28, 56 and 100
The daily steroid dose administered at Day 28, 56 and 100 will be summarized 
descriptively for the Efficacy Analysis set. 
Administration of steroid treatment will be listed for the SAF set.
Proportion of subjects achieving GI CR and GI PR at Days 28, 56 and 180 at each 
baseline GvHD severity grade (B, C and D)
The number and percentage of subjects achieving GI CR and GI PR will be summarized 
separately at Days 28, 56 and 180 by baseline GvHD severity grade for the Efficacy 
Analysis set, with subjects having GI CR and GI PR derived based on investigator 
assessments and adjudicated data of GI response at these visits using the NRI approach. 
11.2
Pharmacodynamics 
A listing of pharmacodynamic sample collection times will be provided.  Both the
absolute value and change from treatment naïve predose baseline will be presented for 
plasma biomarkers, serum T cell subpopulations, and A1PI and calprotectin
concentrations/amounts in stool samples will be provided where available.
The A1PI clearance in stool may be derived if unavailable from the laboratory reported 
data.


GLASSIA
  Page 32 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
11.3
Health Outcomes 
All derivations, analyses and summaries are not applicable (details in Section 1 and 
Section 5.3).
Change from baseline in QoL outcomes
• in QoL as measured by FACT-BMT
• in acute GvHD symptoms as measured by the Chronic GvHD Symptom Scale
• in health utility as measured by EQ-5D-5L
Analyses of FACT-BMT and Chronic GvHD Symptom Scales as wells EQ-5D-5L 
dimensions are described in Sections 10.1 and 10.2.
Healthcare resource utilization (HRU):
•
type of admission (Hospital, Intensive Care Unit and/or transplant unit)
•
length of stay
•
Number of unscheduled physician office visits
•
Number of emergency room visits
These information will be collected using a paper subject diary provided to each subject 
at screening for all health-care professional visits that the patient made, excluding 
scheduled study visits. 
Number of visits will be summarized descriptively as a continuous variable, for 
unscheduled physician office visits and emergency room visits separately. Length of stay 
will be summarized as the total length of stay (in days) across all the visits using 
descriptive statistics by the type of admission (hospital, intensive care unit, transplant 
unit). 
Summary tables will be provided for the Efficacy Analysis set. The HRU data will be 
included in subject listings. 
Medication:
Days on steroids is defined as (end date of last administration or Day 180 if end date 
missing due to steroid ongoing – start date of first administration + 1). Descriptive 
summaries will be provided for the Efficacy Analysis set. 


GLASSIA
  Page 33 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
12.
ANALYSIS SOFTWARE
All data processing, summarization, and analyses will utilize SAS® software package, 
Version 9.2 or higher.  If the use of other software is warranted the final statistical report 
will detail what software was used.


GLASSIA
  Page 34 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
13.
REVISION HISTORY
Version 
Issue Date
Summary of Changes
1.0
2017 SEP 13
New Document


GLASSIA
  Page 35 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
14.
APPENDICES
14.1 Study Flow Chart
Figure 1
Study Design for Baxalta Clinical Study 471501 Part 1
Abbreviations:  SOC=standard-of-care.
Note:  Arrows indicate days of study treatment and the Day 28 primary endpoint assessment.
Day:  -2 to 1 
1  3 5 7 9 11 13 15      22       28       36      43       50        56                   100                 180           
365    
Part 1 
Screening
COHORT 1:  GLASSIA + Steroid; 8 week 
treatment period
No GLASSIA treatment – SOC only
Day 28 overall
response rate


GLASSIA
  Page 36 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
14.2 Schedule of Study Procedures and Assessments
Schedule of Study Procedures and Assessments (Parts 1)
Scr
Treatment Period
No Study Treatment 
Follow-Up
Study Day
-2 to 
-1
1
3
5
7
9
11
13
15
22
28a
36
43
50
56
100
180
365b
Visit window (± days)
1
1
1
1
1
1
1
1
1
1
1
1
1
1
5
5
5
Informed consentc
X
Inclusion/exclusion criteria
X
Demographics
X
Medical, surgical and 
transplant history
X
Medication history
X
Review subject diary
X  ----------------------------------------------------------------------------------------------------------------------------- >  X
FACT-BMT, Chronic GvHD 
Symptom Scale, EQ-5D-5L
and HRUd
X
X
X
X
X
X
Physical examination
X
X
X
X
X
Vital signse
X
X
X
X
X
12-lead ECG
X
CMV testing
X
X
X
X
X
X
X
X
X
X
X
HIV testingf,g
X
Clinical laboratory testsg
X
X
X
X
X
X
X
X
Serum pregnancy testh
X
X
Lower GI biopsyi
X
Biomarker sample 
collectiong
X
X
X
X
GvHD staging/assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


GLASSIA
  Page 37 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
Schedule of Study Procedures and Assessments (Parts 1)
Scr
Treatment Period
No Study Treatment 
Follow-Up
Study Day
-2 to 
-1
1
3
5
7
9
11
13
15
22
28a
36
43
50
56
100
180
365b
Visit window (± days)
1
1
1
1
1
1
1
1
1
1
1
1
1
1
5
5
5
Overall response, GI 
response and GvHD VGPR
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chronic GvHD assessment
X
X
X
X
Cumulative dose of steroids
X
X
X
X
PK sample collectiong
X  ---> X
X  ---> X
X  ---> X
X  ---> X
Assessment of recurrent 
malignancy
X  ------------------------------------------------------------------------------------------------------------------------------------------ >  X
Adverse events
X  ------------------------------------------------------------------------------------------------------------------------------------------ >  X
Medications and non-drug 
therapiesj
X
X  --------------------------------------------------------------------------------------------------------------------------------- >  X
Mortality and survival 
assessmentsk
X
X
X
X
X
Study treatment 
administrationl
X
X
X
X
X
X
X
X
X
X
X
X
X
Administration of steroid 
treatmentl,m
X
X  ------------------------------------------------------------------------------------------------------------------>  X
Viral prophylaxisn
X
X  ------------------------------------------------------------------------------------------------------------------>  X
Stool sample collectiong
X
X
X
X
X
Abbreviations:  CMV=cytomegalovirus; ECG=electrocardiogram; EQ-5D-5L=European Quality of Life-5 Dimensions-5 Level; FACT-BMT=Functional 
Assessment of Cancer Therapy-Bone Marrow Transplant subscale version 4.0 instrument; Scr=screening; GI=gastrointestinal; GvHD=graft-versus-host 
disease; HIV=human immunodeficiency virus; HRU=healthcare resource utilization; PK=pharmacokinetic; VGPR=very good partial response.
Continued on Next Page


GLASSIA
  Page 38 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
Continued
a Subjects who discontinue study treatment prior to Day 28 will complete the Day 28 visit on Day 28 (±1 day). If at least 2 weeks have passed since the 
last dose of study treatment, Day 28 will serve as the study completion/termination visit. If Day 28 is less than 2 weeks following the last dose of study 
treatment, subjects will complete the Day 28 visit and then the study completion/termination visit 2 weeks (±1 day) after the last dose of study 
treatment. In this event, the subject will have an office visit with the same assessments as the Day 365 visit. Subjects who discontinue study treatment 
will not attend any other subsequent visits other than Day 28 and the study completion/termination visit (if applicable), except as needed for follow-up 
of recovering/resolving AEs.
b Study completion/termination visit after Day 28. Subjects who discontinue study treatment early but after Day 28 will complete a study 
completion/termination visit as an office visit 2 weeks (±1 day) after the last dose of study treatment. Subjects who withdraw from the study after 
Day 56 will be encouraged to complete the study completion/termination visit at the time of discontinuation. In the event that it is not feasible for the 
subject to visit the site at the study completion/termination visit after Day 56, the visit may be conducted with a phone call.
c Occurs prior to any study-specific procedures including screening.
d The FACT-BMT, Chronic GvHD Symptom Scale and EQ-5D-5L should be collected before any other assessments are performed at the visit.
e Body height will be measured at screening visit only. At visits at which study treatment is administered, vital signs will be measured within 30 minutes 
before and after administration of study treatment.
f Antibody or nucleic acid test. The results of an HIV test performed within the 3 months prior to screening may be used instead.
g See Section 14.3 for details.
h Serum pregnancy test will be performed in females of childbearing potential only.
i
Results of a lower GI biopsy performed prior to screening may be used instead. The screening biopsy will be used to assess withdrawal criteria and will 
not be required to assess eligibility prior to the first dose of study treatment.
j
All medications taken and non-drug therapies received from providing informed consent until completion/termination will be recorded. After screening, 
the source for concomitant medications, including steroid use, and non-drug therapies will be the subject diary, after the investigator reviews the diary 
with the subject.
k Investigator will assess the date and cause of death, if applicable. Cause of death will be assessed as related to transplant, infection and/or GvHD or any 
other cause. Failure-free, GvHD-free and overall survival will also be collected.
l
All assessments and sample collections, with the exception of PK and stool samples as described in Section 14.3, must be performed before 
administering study treatment and steroid treatment at each visit. 
m Steroid treatment for acute GvHD with lower GI involvement must have been initiated within 72 hours prior to the first study treatment administration. 
Steroid tapering may commence after a subject responds to therapy as described in protocol Section 8.2. Subjects who are withdrawn from study 
treatment will be treated with standard-of-care at the investigator’s discretion.
n Subjects will receive standard prophylactic treatment for herpes simplex virus and varicella-zoster virus (eg, acyclovir or valacyclovir), through Day 180 
or per institutional guidelines.


GLASSIA
  Page 39 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
14.3 Clinical Laboratory Assessments
Clinical Laboratory Assessments
Assessments
Screening
Treatment Period
Days
-2 to -1
1
3
5
7
13
15
22
28a
50
56
Visit window (± days)
1
1
1
1
1
1
1
1
1
1
Hematologyb,c
X
X
X
X
X
X
Clinical chemistryb,d
X
X
X
X
X
X
Lipid panelb,e
X
X
X
X
X
X
Coagulation panelb,f
X
X
X
X
Urinalysisb,g
X
X
X
X
X
X
Stool assessmentsh
X
X
X
X
X
PK assessmenti
X------->X
X------->X
X------->X
X------->X
Biomarker assessmentj
X
X
X
X
HIV testk
X
Abbreviations: A1PI=alpha-1 proteinase inhibitor; HIV=human immunodeficiency virus; IL=interleukin; IL-1RA=interleukin-1 receptor antagonist;
PK=pharmacokinetic; RBC=red blood cell; Reg3α=regenerating islet-derived protein 3α; ST2=suppression of tumorigenicity 2; TNFR1=tumor necrosis 
factor receptor 1; Tregs=regulatory T cells; WBC=white blood cell.
Note:  All samples, except PK and stool samples as indicated below, must be collected prior to the start of study treatment at the visit.
a Subjects who discontinue study treatment prior to Day 28 will complete the Day 28 visit on Day 28 (±1 day). If at least 2 weeks have passed since the 
last dose of study treatment, Day 28 will serve as the study completion/termination visit. If Day 28 is less than 2 weeks following the last dose of study 
treatment, subjects will complete the Day 28 visit and then the study completion/termination visit 2 weeks (±1 day) after the last dose of study 
treatment. In this event, the subject will have an office visit with the same assessments as the Day 365 visit (study procedures in Section 14.2). Subjects 
who discontinue study treatment will not attend any other subsequent visits other than Day 28 and the study completion/termination visit (if applicable), 
except as needed for follow-up of recovering/resolving AEs.
b In addition to the assessments shown, clinical laboratory assessments should be performed whenever clinically indicated.
Continued on Next Page


GLASSIA
  Page 40 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
Continued
c Hematology assessments include hemoglobin, hematocrit, RBC count and WBC count with differential (ie, basophils, eosinophils, lymphocytes, 
monocytes and neutrophils), mean corpuscular volume, mean corpuscular hemoglobin concentration and platelet count.
d Clinical chemistry assessments include: sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase, aspartate 
aminotransferase, total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine and glucose. 
e Lipid panel includes total cholesterol, very low density lipoprotein, low density lipoprotein, high density lipoprotein and triglycerides.
f Coagulation panel includes fibrin, fibrin split products, fibrinogen and D-dimer.
g Urinalysis assessments include: color, specific gravity, pH, protein, glucose, ketones, bilirubin, urobilinogen, blood, nitrate, leukocyte esterase and 
microscopic examination (RBC, WBC, bacteria and casts).
h For the determination of stool A1PI level and clearance and calprotectin concentrations. One sample will be collected either during screening or prior to 
the first study treatment administration on Day 1. On Days 1 and 13, a sample will be collected during the 24 hours after the start of study treatment 
infusion. On Day 28, the sample will be collected prior to the start of study treatment infusion.
i
If study treatment is administered peripherally, the PK samples should be taken from the opposite arm as the study treatment administration, if possible. 
If study treatment is administered via a central indwelling catheter, the PK samples may be taken from the same infusion line, if the infusion line is 
flushed prior to collection of the PK sample and the first 3 mL of blood is discarded.
The PK samples for the measurement of plasma A1PI levels will be collected at the following timepoints:
Part 1, Cohort 1
-
Day 1: Prior to start of study treatment infusion, at 15 (±5) minutes, 2 hours (±12 minutes), 4 hours (±24 minutes), 8 hours (±48 minutes), 
12 hours (±72 minutes) and 24 hours (±144 minutes) (ie, Day 2) following the end of study treatment infusion
-
Day 3: Within 2 hours prior to start of study treatment infusion, and at 15 (±5) minutes following the end of study treatment infusion
-
Day 13: Within 2 hours prior to start of study treatment infusion, at 15 (±5) minutes, 2 hours (±12 minutes), 4 hours (±24 minutes), 8 hours 
(±48 minutes), 12 hours (±72 minutes) and 24 hours (±144 minutes) (ie, Day 14) following the end of study treatment infusion
-
Day 15: Within 2 hours prior to start of study treatment infusion, and at 15 (±5) minutes following the end of study treatment infusion
-
Day 22: Within 2 hours prior to start of study treatment infusion, at 15 (±5) minutes, 2 hours (±12 minutes), 4 hours (±24 minutes), 24 hours 
(±144 minutes) (ie, Day 23), 72 (±7) hours (ie, Day 25) and 120 (±12) hours (ie, Day 27) following the end of study treatment infusion
-
Day 28: During the Day 28 clinic visit, but must be prior to the next study treatment
-
Day 50: Within 2 hours prior to start of study treatment, at 15 (±5) minutes, 2 hours (±12 minutes), 4 hours (±24 minutes), 24 hours 
(±144 minutes) (ie, Day 51), 72 (±7) hours (ie, Day 53) and 120 (±12) hours (ie, Day 55) following the end of study treatment infusion
-
Day 56: During the Day 56 clinic visit
j
Biomarkers will include cytokines IL-2, IL-6, IL-8, IL-10 and IL-32; heparan sulfate; Reg3α; ST2; TNFR1; IL-1RA and T cell subpopulations, including 
CD4+ CD25+ CD127+ FoxP3+ Tregs.
k Antibody or nucleic acid test. The results of an HIV test performed within the 3 months prior to screening may be used instead.


GLASSIA
  Page 41 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
14.4
Scoring guidance for FACT-BMT version 4.0
Item
Reverse?
FACT-G physical well being (PWB)
GP1: I have a lack of energy
4  -
GP2: I have nausea
4  -
GP3: Because of my physical condition, I have trouble meeting the needs of my family
4  -
GP4: I have pain
4  -
GP5: I am bothered by side effects of treatment
4  -
GP6: I feel ill
4  -
GP7: I am forced to spend time in bed
4  -
FACT-G social/family well-being (SWB)
GS1: I feel close to my friends
0  +
GS2: I get emotional support from my family
0  +
GS3: I get support from my friends
0  +
GS4: My family has accepted my illness
0  +
GS5: I am satisfied with family communication about my illness
0  +
GS6: I feel close to my partner (or the person who is my main support)
0  +
GS7: I am satisfied with my sex life
0  +
FACT-G emotional well-being (EWB)
GE1: I feel sad
4  -
GE2: I am satisfied with how I am coping with my illness
0  +
GE3: I am losing hope in the fight against my illness
4  -
GE4: I feel nervous
4  -
GE5: I worry about dying
4  -
GE6: I worry that my condition will get worse
4  -
FACT-G functional well-being (FWB)
GF1: I am able to work (include work at home)
0  +
GF2: My work (include work at home) is fulfilling
0  +
GF3: I am able to enjoy life
0  +
GF4: I have accepted my illness
0  +
GF5: I am sleeping well
0  +
GF6: I am enjoying the things I usually do for fun
0  +
GF7: I am content with the quality of my life right now
0  +
BMT concerns
Q1: I am concerned about keeping my job (include work at home)
4  -
Q2: I feel distant from other people
4  -
Q3: I worry that the transplant will not work
4  -
Q4: The side effects of treatment are worse than I had imagined
4  -
Q5: I have a good appetite
0  +
Q6: I like the appearance of my body
0  +


GLASSIA
  Page 42 of 42
Statistical Analysis Plan for Protocol Identifier: 471501
2017 SEP 13
Baxalta Confidential – Restricted: Do NOT distribute without prior approval
Item
Reverse?
Q7: I am able to get around by myself
0  +
Q8: I get tired easily
4  -
Q9: I am interested in sex
0  +
Q10: I have concerns about my ability to have children
4  -
Q11: I have confidence in my nurse(s)
0  +
Q12: I regret having the bone marrow transplant
4  -
Q13: I can remember things
0  +
Q14: I am able to concentrate
0  +
Q15: I have frequent colds/infections
4  -
Q16: My eyesight is blurry
4  -
Q17: I am bothered by a change in the way food tastes
4  -
Q18: I have tremors
4  -
Q19: I have been short of breath
4  -
Q20: I am bothered by skin problems (e.g., rash, itching)
4  -
Q21: I have trouble with my bowels
4 -
Q22: My illness is a personal hardship for my close family members
4  -
Q23: The cost of my treatment is a burden on me or my family
4  -