Conditions: Graft-versus-host-disease GVHD
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
Bone marrow transplant (BMT) patients can develop graft-versus-host disease (GVHD), a serious and potentially fatal complication. The researchers have developed a blood test to identify patients most at risk for developing severe GVHD. Patients who consent to this study will have their blood tested up to two times after BMT to determine if they are at high risk for severe GVHD. The tests will be performed one week and two weeks after BMT. Patients who are high risk will be treated with a drug called alpha-1-antitrypsin (AAT) to see if it prevents the development of severe GVHD. Patients will receive 16 doses of AAT through a catheter placed into a blood vessel over eight weeks. AAT will be given either in the hospital or the outpatient clinic two times per week. Patients will be followed for the development of severe GVHD for up to four months from the BMT and will continue to be followed at routine clinic visits for up to one year after BMT.

Detailed description:

Arms:
arm 1: 16 doses of AAT through a catheter placed into a blood vessel over eight weeks.

Interventions: intervention 1: Alpha 1-Antitrypsin
Intervention descriptions: intervention 1: AAT will be given either in the hospital or the outpatient clinic two times per week.

Protocol document:
Prot_SAP_000.pdf: 
A Proof of Concept Pilot Trial of Alpha-1-Antitrypsin for Pre-Emption Of 
Steroid-Refractory Acute GVHD  
PI: John Levine, MD
NCT03459040
Document date: 11-15-2019


A PROOF OF CONCEPT PILOT TRIAL OF ALPHA-1-ANTITRYPSIN FOR PRE-EMPTION OF 
STEROID-REFRACTORY ACUTE GVHD 
Principal Investigator: 
John E. Levine, MD, MS 
Bone Marrow Transplantation Program 
The Tisch Cancer Institute 
Division of Hematology/Medical Oncology 
Icahn School of Medicine at Mount Sinai 
1 Gustave L. Levy Pl, Box 1410,  
New York, New York 10029 
Phone: 212-241-6021 
Fax: 212-241-8618 
john.levine@mssm.edu 
Co-Investigators: 
James Ferrara, MD, DSc 
Icahn School of Medicine at Mount Sinai 
New York, New York 10029 
Phone: 212-824-9365 
Fax: 646-537-9576 
james.ferrara@mssm.edu 
Hannah Choe, MD 
The Ohio State University 
Columbus, Ohio 
Phone: 614-293-3271 
Fax: 614-293-7526 
hannah.choe@osumc.edu 
Karamjeet Sandhu, MD 
City of Hope National Medical Center 
Duarte, California 
Phone: 626-256-4673 
Fax: 626-218-6116 
ksandhu@coh.org    
Madan Jagasia, MBBS, MS 
Vanderbilt University 
Nashville, Tennessee 
Phone: 615-936-8422 
Fax : 615-936-1812 
madan.jagasia@vanderbilt.edu 
Zachariah DeFilipp, MD 
Massachusetts General Hospital  
Boston, Massachusetts 
Phone: 617-726-0187 
Fax: 617-643-5843 
zdefilipp@mgh.harvard.org   
Umut Özbek, PhD (Biostatistician) 
Icahn School of Medicine at Mount Sinai 
New York, New York  
Phone: 212-659-9633 
Fax: 212-241-2998 
umut.ozbek@mountsinai.org
Study Drug:
Alpha-1-antitrypsin (Glassia) 
US IND No.:
17878
Initial version:
12/05/2017 v2.0
Amended version:
12/04/2018 v3.0 
11/15/2019 v4.0


Page ii of iv 
TABLE OF CONTENTS 
ABBREVIATIONS................................................................................................. 1 
1.0 
BACKGROUND AND RATIONALE............................................................ 5 
1.1 
Acute GVHD .................................................................................................................... 5 
1.2 
GVHD Biomarker Algorithms Predict HCT Outcomes ..................................................... 5 
1.3 
Alpha-1-Antitrypsin .......................................................................................................... 7 
1.4 
Correlative Studies .......................................................................................................... 8 
1.5 
Summary of Study Rationale ........................................................................................... 9 
2.0 
STUDY OBJECTIVES ................................................................................. 9 
2.1 
Primary Objectives ........................................................................................................... 9 
2.2 
Secondary Objectives ...................................................................................................... 9 
2.3 
Primary Endpoint ............................................................................................................. 9 
3.0 
PATIENT ELIGIBILITY ............................................................................. 10 
3.1 
Inclusion Criteria ............................................................................................................ 10 
3.2 
Exclusion Criteria ........................................................................................................... 11 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES ............ 11 
5.0 
TREATMENT PLAN.................................................................................. 12 
5.1 
Treatment Dosage and Administration .......................................................................... 12 
5.2 
Toxicities and Dosing Delays/Dose Modifications ......................................................... 14 
5.3 
Concomitant Medications/Treatments ........................................................................... 14 
5.4 
Other Modalities or Procedures ..................................................................................... 14 
5.5 
Duration of Therapy ....................................................................................................... 14 
5.6 
Off Treatment Criteria .................................................................................................... 14 
5.7 
Duration of Follow-Up .................................................................................................... 15 
5.8 
Off Study Criteria ........................................................................................................... 15 


Page iii of iv 
5.9 
Patient Replacement ..................................................................................................... 15 
6.0 
STUDY PROCEDURES ............................................................................ 16 
6.1 
Screening/Baseline Procedures .................................................................................... 16 
6.2 
Follow-Up Procedures ................................................................................................... 16 
6.3 
Time and Events Table .................................................................................................. 17 
7.0 
GVHD CLINICAL STAGING ..................................................................... 18 
7.1 
ENDPOINT AND RESPONSE CRITERIA ..................................................................... 18 
7.2 
SAFETY/TOXICITY DEFINITIONS ............................................................................... 19 
7.3 
Safety/Tolerability .......................................................................................................... 20 
8.0 
ADVERSE EVENTS .................................................................................. 20 
8.1 
ALPHA-1-ANTITRYPSIN ............................................................................................... 20 
8.2 
Adverse Event Reporting Requirements ....................................................................... 21 
8.3 
Definitions ...................................................................................................................... 21 
8.4 
Adverse Event Characteristics ...................................................................................... 23 
8.5 
Serious Adverse Event Reporting Guidelines ............................................................... 24 
8.6 
Reporting of Unanticipated Problems ............................................................................ 25 
8.7 
Stopping Rules .............................................................................................................. 25 
9.0 
DRUG INFORMATION .............................................................................. 26 
9.1 
ALPHA-1-ANTITRYPSIN (AAT, AAT, A1PI) ................................................................. 26 
10.0 
CORRELATIVES/SPECIAL STUDIES .................................................. 28 
10.1 
Sample Collection Guidelines ........................................................................................ 28 
10.2 
Assay Methodology ....................................................................................................... 28 
10.3 
Specimen Banking ......................................................................................................... 28 
11.0 
STATISTICAL CONSIDERATIONS ...................................................... 29 
11.1 
Study Design/Study Endpoints ...................................................................................... 29 


Page iv of iv 
11.2 
Sample Size and Accrual .............................................................................................. 29 
11.3 
Data Analyses Plans ...................................................................................................... 29 
12.0 
DATA AND SAFETY MONITORING ..................................................... 30 
12.1 
Multisite Clinical Monitoring Procedures ........................................................................ 31 
13.0 
QUALITY ASSURANCE AND AUDITS ................................................. 31 
14.0 
REFERENCES ....................................................................................... 32 
15.0 
APPENDICES ........................................................................................ 33 
Appendix A: High Risk MAGIC Scoring Manual ......................................................................... 34 
Appendix B: BMT CTN Infection Severity Grading Table .......................................................... 34 
Appendix C: Suggested Steroid Taper for GVHD ...................................................................... 34 


1 
ABBREVIATIONS 
Examples Include [the list should be inclusive of the entire protocol]: 
6-MP
6-mercaptopurine
AAT
Alpha-1-antitrypsin
AE
Adverse Event
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BMT
Bone Marrow Transplant
BMT CTN
Blood and Marrow Transplant Clinical Trials Network
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CBC
Complete Blood Count
CD
Crohn’s Disease
CMP
Comprehensive Metabolic Panel
CMV
Cytomegalovirus
CNS
Central Nervous System
Co-PI
Co-Principal Investigator
CR
Complete Response
CRF
Case Report Form
CTCAE
Common Terminology Criteria for Adverse Events
CTEP
Cancer Therapy Evaluation Program
DCC
Data Coordinating Center
DSMB
Data and Safety Monitoring Board
DSMC
Data and Safety Monitoring Committee
DSMR
Data and Safety Monitoring Report
EBV
Epstein-Barr Virus
ELISA
Enzyme-Linked Immunosorbent Assay
FDA
Food and Drug Administration
GI
Gastrointestinal
GVHD
Graft-Versus-Host Disease
HCT
Hematopoietic Stem Cell Transplantation
HHV6
Human Herpes Virus 6
HSV
Herpes Simplex Virus
IND
Investigational New Drug
IL2Rα
Interleukin-2 receptor-alpha
IRB
Institutional Review Board
IV (or iv)
Intravenously
JC
John Cunningham (virus)
MAGIC
Mount Sinai Acute GVHD International Consortium
MS
Multiple Sclerosis
NCI
National Cancer Institute
NOS
Not Otherwise Specified


2 
NR
No Response
NRM
Non-Relapse Mortality
OS
Overall Survival
PE
Physical Exam
PI
Principal Investigator
PJP 
Pneumocystis Jiroveci Pneumonia 
PML
Progressive Multifocal Leukoencephalopathy
PR
Partial Response
PTLD 
Post-Transplant Lymphoproliferative Disorder 
REG3α 
Regenerating islet-derived 3 alpha 
SAE 
Serious Adverse Event 
SD
Stable Disease
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
ST2 
Suppressor of tumorigenicity-2 
TCI 
The Tisch Cancer Institute at the Mount Sinai Health System 
TNFR1 
Tumor necrosis factor receptor-1 
UGI
Upper Gastrointestinal
VZV
Varicella-Zoster Virus


3 
STUDY SYNOPSIS 
Title 
A Proof of Concept Pilot Trial of Alpha-1-Antitrypsin For Pre-Emption Of 
Steroid-Refractory Acute GVHD  
Phase 
Proof of Concept Pilot 
Methodology 
Open label single arm  
Study Duration 
2 years 
Study Center(s) 
Multicenter – Icahn School of Medicine at Mount Sinai, Mass General, 
Ohio State University, Vanderbilt University, City of Hope  
Objectives 
PRIMARY: To generate data for assessing the feasibility, safety and 
preliminary efficacy of alpha-1-antitrypsin (AAT) as pre-emptive therapy 
in patients at high risk for the development of steroid-refractory GVHD. 
SECONDARY: To generate a preliminary estimate of the 100 day 
incidence of clinically relevant GVHD states including steroid-refractory 
GVHD, grade II-IV GVHD, and grade III-IV in patients at high risk for the 
development of steroid-refractory GVHD treated with AAT. 
To generate a preliminary estimate of the non-relapse mortality, relapse, 
and survival rates in patients at high risk for the development of steroid-
refractory GVHD treated with AAT. 
To generate a preliminary estimate of the incidence of severe toxicities, 
serious infections, and viral reactivations in patients at high risk for the 
development of steroid-refractory GVHD treated with AAT. 
To assess the safety of AAT as pre-emptive therapy in patients at high 
risk for the development of steroid-refractory GVHD. 
EXPLORATORY: To correlate GVHD biomarkers with clinical endpoints 
Number of Subjects 
30 subjects 
Inclusion Criteria 
1.
High risk prediction score as determined by the MAGIC algorithm at
either day 7 or day 14 post HCT.
2.
Any donor type (e.g., related, unrelated) or stem cell source (bone
marrow, peripheral blood, cord blood).
3.
Related and unrelated donor and recipient match each other for at
least 7/8 HLA-loci (HLA-A, B, C, and DR)
4.
Cord blood donor(s) match recipient for at least 4/6 HLA-loci (HLA-A,
B, and DR)
5.
Subjects receiving either non-myeloablative or myeloablative or
reduced intensity conditioning regimen are eligible.
6.
Any GVHD prophylaxis is permitted.
7.
The use of serotherapy to prevent GVHD (e.g.,antithymocyte globulin)
prior to day 3 post-HCT is permitted.
8.
Age 18 years and older
9.
Direct bilirubin must be <2 mg/dL unless the elevation is known to be
due to Gilbert syndrome within 3 days of enrollment.
10. ALT/SGPT and AST/SGOT must be <5 x the upper limit of the normal
range within 3 days of enrollment.
11. Written informed consent from patient or legal representative.


4 
Exclusion Criteria 
1.
Patients who develop acute GVHD prior to start of study drug
2.
Patients at very high risk for primary disease relapse post HCT
defined as very high disease risk index (Armand et al. 2014)
3.
Patients participating in a clinical trial where prevention of GVHD is
the primary endpoint
4.
Uncontrolled active infection (i.e., progressive symptoms related to
infection despite treatment or persistently positive microbiological
cultures despite treatment or any other evidence of severe sepsis)
5.
Patients who are pregnant
6.
Patients on dialysis within 7 days of enrollment
7.
Patients requiring mechanical respiratory support or patients
requiring oxygen supplementation exceeding 40% FiO2 within 14
days of enrollment.
8.
Patients receiving investigational agent within 30 days of enrollment
However, the Principal Investigator (PI) may approve prior use of an
investigational agent if the agent is not expected to interfere with the
safety or the efficacy of alpha-1-antitrypsin
9.
History of allergic reaction to alpha-1-antitrypsin
Study Product(s), Dose, 
Route, Regimen 
Alpha-1-antitrypsin (Glassia) 90 mg/kg intravenous on day 0, then 45 
mg/kg twice weekly for 15 more doses 
Duration of 
Administration 
Eight weeks 
Statistical Methodology 
This is a proof of concept pilot study intended to determine if sufficient 
evidence can be developed to warrant further study of pre-emptive 
treatment with AAT. The expected incidence of steroid refractory (SR) 
GVHD by day 100 in patients who are high risk at either day 7 or 14 is 
28%. We assume that the incidence of steroid refractory GVHD by day 
100 among high risk patients treated pre-emptively will be 15% as a 
clinically meaningful incidence. Based on this assumption, a sample size 
of 30 achieves 85% power to detect a 13% improvement (28%-15%) in 
steroid refractory incidence rate using a one-sided exact test with a target 
significance level of 0.23. If we observe 6 or fewer cases of SR GVHD, we 
will consider this approach sufficiently promising to warrant further study. 


5 
1.0 
BACKGROUND AND RATIONALE 
1.1 
Acute GVHD 
Hematopoietic cellular transplantation (HCT or BMT) is an important treatment for high-risk 
hematologic malignancies whose curative potential depends on the graft-versus-leukemia (GVL) 
effect. Graft-versus-host disease (GVHD), the major cause of non-relapse mortality (NRM) after 
HCT, is closely associated with GVL 1-3. Pre-transplant clinical risk factors for GVHD include the 
degree of human leukocyte antigen (HLA) match between donor and recipient, recipient age, donor 
type, and conditioning regimen intensity 4,5. Some centers use one or more of these risk factors to 
guide GVHD prophylaxis, such as the use of anti-thymocyte globulin when the donor is not an HLA-
identical sibling 6, but such approaches are globally immunosuppressive and carry their own risks, 
in particular of opportunistic infections 7,8. 
Acute GVHD affects 40% to 60% of patients and targets the skin, liver, and gastrointestinal (GI) 
tract 5,9. The median onset of acute GVHD is approximately 1 month after transplant 10,11. The initial 
treatment for GVHD is typically high doses of systemic corticosteroids, but up to 50% of patients 
do not respond to this approach. Steroid refractory (SR) GVHD, which most often involves the GI 
tract, is the primary driver of lethal GVHD, and by extension, non-relapse mortality after HCT 10. 
However, until now there has been no reliable method to identify the patients at high risk for SR 
GVHD before GVHD develops.  
1.2 
GVHD Biomarker Algorithms Predict HCT Outcomes 
The concentrations of several protein biomarkers (e.g., ST2, REG3α, IL2Rα, TNFR1, hepatocyte 
growth factor, and elafin) in the serum are increased in patients with  GVHD 12-15. Combinations of 
ST2 and REG3α, with or without TNFR1, have been proven to be prognostic for GVHD outcomes 
when measured at the time GVHD is diagnosed 10,16. Recently, we used serum samples obtained 
from patients participating in the Mount Sinai Acute GVHD International Consortium (MAGIC) to 
develop and validate an algorithm that uses the combination of ST2 and REG3α concentrations, 
measured on Day 7 post-HCT, to predict the development of non-relapse mortality (NRM) 16. We 
used samples from Day 7 post-HCT to develop the algorithm because GVHD rarely develops in 
the first week after HCT, providing sufficient time to test pre-emptive treatment strategies. The 
MAGIC algorithm identified a high risk (HR) group in the training set whose NRM (28%) was 
significantly greater (p<0.001) than that of the low risk (LR) group (7%) (Figure 1A). Application of 
this algorithm to the test set produced similar, highly statistically significant differences between HR 
and LR groups (Figure 1B). We performed a second validation in the multicenter set and again 
observed large differences between groups, with an HR 6-month NRM of 26% versus 10% in the 
LR group (p<0.001) (Figure 1C). The proportion of patients in the HR group was similar in all 3 
patient sets (16% to 20%). Relapse rates were equivalent in both risk groups in all 3 sets (Figure 
1, D–F), with the result that HR patients experienced significantly worse overall survival (p<0.001) 
(Figure 1, G–I). Importantly, GVHD was the driver of NRM. HR patients were 3 times more likely to 
die from GVHD than LR patients (HR 19% vs. LR 6%, p<0.001), a finding explained by the much 
higher 6-month incidence of SR GVHD in high risk patients compared to LR patients (35% vs 15%, 
p<0.001). It is likely that the blood biomarker concentrations on Day 7 reflect subclinical GI 
pathology, a notion that is reinforced by the fact that ST2 and REG3α, the two biomarkers that 
performed the best in the models, are closely associated with GI GVHD12,17.  
Several pre-HCT clinical risk factors predict a higher risk of NRM, such as HLA mismatch, non-
family member donors, age of the recipient, and the intensity of the conditioning regimen5,18. 
Importantly, the MAGIC algorithm also stratified patients into distinct risk groups independently of 
patient age [≤21y: HR 27% vs LR 6%, p<0.001; >21y: HR 29% vs LR 8%, p<0.001], conditioning 
regimen [reduced intensity: HR 37% vs LR 8%, p<0.001; full intensity: HR 25% vs LR 8%, p<0.001] 
or the use of thymoglobulin in the conditioning regimen [ATG given: HR 31% vs LR 8%, p<0.001; 


6 
no ATG: HR 28% vs LR 8%, p<0.001]. Relapse rates were equivalent within all subgroups of clinical 
risk factors, resulting in a decrease of at least 20% in overall survival for HR patients  
We recently tested whether we could improve the sensitivity of the MAGIC algorithm by re-testing 
low risk patients one week later (Day 14), reasoning that the concentration of GVHD biomarkers 
would be higher one week closer to the onset of GVHD. Serum samples from both Day 7 and Day 
14 were available for 768 MAGIC patients (Figure 2) We measured ST2 and REG3α on Day 7 in 
all patients and identified 145 (19%) as high risk and 623 (81%) as low risk with distinctly different 
NRM (26% vs 8%, p<0.001). Twenty low risk patients (3%) developed GVHD between Day 7 and 
Day 14 and were excluded from further analysis. When we repeated the test on Day 14 in the 
remaining 603 LR patients, we identified 60 additional HR patients whose NRM risk was similar to 
the day 7 HR patients and significantly higher than the 543 patients who remained LR (24% vs 6%, 
p<0.001). Compared to the Day 7 test alone, repeat testing on Day 14 resulted in a large 
improvement in sensitivity for NRM (46% to 61%) with only a modest loss of specificity (80% to 
1 


7 
75%). Serial testing at both Days 7 and 14 significantly increases the proportion of patients 
potentially eligible to participate in a GVHD pre-emptive treatment trial from 19% (145/768) of the 
total population to 27% (205/768). 
For this proof of concept pilot trial we will use the incidence of SR GVHD by day 100 as the primary 
endpoint to determine whether pre-emption therapy with AAT warrants further study. The 
cumulative incidence of SR GVHD by day 100 in patients who are HR at either Day 7 or 14 is 
28%. 
1.3 
Alpha-1-Antitrypsin 
Few side effects and promising efficacy are desirable properties in an agent to be tested for GVHD 
preemption. Alpha-1-antitrypsin (AAT, A1PI, Glassia®) possesses these properties. Glassia is a 
stable, liquid, ready to use preparation of 2% human AAT that 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 
properties19-22. 
Glassia is an injection solution prepared from pooled human plasma collected from healthy 
volunteers in accordance with Food and Drug Administration (FDA) and European Medicines 
Agency (EMA) regulations. It was approved in the United States (US) in July 2010 for chronic 
augmentation and maintenance therapy in adults with clinically evident emphysema due to severe 
hereditary deficiency of AAT. 
The mechanism of action of AAT for GVHD is not fully understood. However, animal studies provide 
strong evidence to support AAT’s use in this setting. GVHD results when donor T cells are primed 
against host antigens in the context of a pro-inflammatory environment (e.g., high pro-inflammatory 
cytokines such as IL-1, TNF and IL-6, low anti-inflammatory cytokines such as IL-10, and 
decreased regulatory T cell numbers). First, the administration of exogenous AAT significantly 
reduced the incidence and severity of GvHD in murine bone marrow transplant models23,24. In one 
of these mouse GVHD models, Tawara et al showed that AAT administration before GVHD 
developed inhibited pro-inflammatory cytokine production, enhanced IL-10 production, and 
favorably altered regulatory T cell numbers23. These findings were confirmed in a separate murine 
study by Marcondes et al which developed evidence that AAT alters mitochondrial biogenesis in a 
cell-specific manner. Specifically, AAT exposed effector T cells (which cause GVHD related tissue 
damage) have significantly less respiratory reserve than T-regs and DCs. These cell specific 
differences favor survival of immune cells that promote tolerance25. Taken together, these data 
Figure 2: Serial monitoring of MAGIC biomarkers at Days 7 and 14 post‐BMT. Patients who are low 
risk at Day 7 but high risk at Day 14 are significantly more likely to die from non‐relapse causes 
than patients who are low risk at both Day 7 and Day 14.  


8 
show that AAT alters metabolism within immune system cells in an pro-tolerance, anti-inflammatory 
direction which supports its use in this trial of GVHD prevention. 
Nonclinical PK studies in rabbits treated with a single bolus IV administration of AAT showed that 
the half-life of A1AT 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 AAT in rats and rabbits; AAT was well 
tolerated with no overt toxicities reported.  
Glassia has been evaluated in two clinical studies in adult subjects with AAT deficiency, one clinical 
study in subjects aged 9 to 18 years with type 1 diabetes mellitus and one Phase 4 clinical study 
in adult healthy volunteers. Glassia was generally safe and well tolerated in all 4 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 
AAT.  
The relationship between alpha-1-antitrypsin and GVHD has been examined in human studies. A 
study of 12 children with GI GVHD found a significant positive correlation between more rapid GI 
clearance of AAT and severe symptoms26. Higher donor AAT levels correlated with significantly 
less GVHD in recipients25. 
One recent clinical trial tested the safety and efficacy of Glassia in 12 patients with SR- GVHD 27. 
Subjects received a loading dose of AAT of 90 mg/kg IV on Day 1, followed by either 30 or 60 
mg/kg every other day through Day 15. In the 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 AAT. Neither AE resulted in death and the study Data Safety Monitoring Board concluded 
that the 2 bowel perforation events were not related to AAT, but instead were related to viral 
infections. One fatal case of liver failure occurred <30 days after the last dose of AAT and was 
assessed by the investigator as possibly related to AAT. Further assessment by Kamada 
considered the case as unrelated. Other adverse events during the study were consistent with 
those expected in subjects undergoing HCT or experiencing GvHD. The efficacy data from this 
study 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.  
A second clinical trial tested the efficacy AAT in 26 patients with SR GVHD. Subjects received 
60mg/kg of AAT twice weekly for four weeks. A high overall response rate (CR+PR) of 62% at four 
weeks was reported28. Taken together, the preclinical and clinical data demonstrate that AAT has 
a favorable safety profile and is potentially beneficial as a treatment for GVHD. 
The AAT dosing for this study (90 mg/kg loading dose followed by 45 mg/kg twice weekly) is similar 
to the two dosing regimens used for SR-GVHD. Normal AAT levels in adults are 150-200 mg/dL, 
which is the equivalent of a total circulating amount of AAT of 7.5-10 gr based on typical adult blood 
volumes. Given the half-life of AAT (approximately five days) the dosing regimen in this study 
should increase plasma levels of AAT to 1.5 to 2 times normal for a 70 kg person. 
1.4 
Correlative Studies 
Serial serum biomarkers. GVHD biomarkers are prognostic early after HCT, at diagnosis, and 
during treatment10,13,16, but the relationship between changes in GVHD biomarker concentrations 
measured serially over time and outcomes is not yet well understood. We expect that larger 
increases in GVHD biomarker concentrations over time will correlate with worse outcomes. We will 
collect and store serum samples in subjects receiving AAT treatment for the purpose of exploratory 
analyses according to the study calendar in Section 6.3. 


9 
1.5 
Summary of Study Rationale 
The MAGIC algorithm identifies patients at high risk for developing steroid-refractory GVHD as 
early as seven days after HCT, which is days to weeks before GVHD symptoms develop. A second 
test at day 14, applied to subjects still at risk, and still two weeks before the median time of GVHD 
onset, dramatically improves the sensitivity of the test, which will facilitate rapid accrual.  Targeting 
HR patients allows experimental approaches to be tested in patients most likely to benefit, reducing 
exposure for low risk patients. A shift to objective laboratory measures from imprecise clinical 
symptoms has the potential to transform GVHD therapy and represents a key step towards a 
precision medicine approach for GVHD. Alpha-1-antitrypsin has an excellent safety profile as 
observed in other clinical settings, including as a treatment for SR GVHD, but it has not yet been 
tested in this context. Importantly, AAT has no effect on clinical chemistry or hematologic 
parameters in either animal or human studies. The absence of notable toxicities increases its 
attractiveness for use in HCT. This proof of concept pilot study will develop the safety and efficacy 
data needed for further clinical development.  
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
2.1.1 
To generate data for assessing the feasibility, safety and preliminary efficacy of 
alpha-1-antitrypsin (AAT) as pre-emptive therapy in patients at high risk for the 
development of steroid-refractory GVHD. 
2.2 
Secondary Objectives 
2.2.1 
To generate a preliminary estimate of the 100 days incidence of clinically relevant 
GVHD states including steroid-refractory GVHD, grade II-IV GVHD, and grade III-
IV in patients at high risk for the development of steroid-refractory GVHD treated 
with AAT. 
2.2.2 
To generate a preliminary estimate of the non-relapse mortality, relapse, and 
survival rates in patients at high risk for the development of steroid-refractory 
GVHD treated with AAT. 
2.2.3 
To generate a preliminary estimate of the incidence of severe toxicities, serious 
infections, and viral reactivations in patients at high risk for the development of 
steroid-refractory GVHD treated with AAT. 
2.3 
Primary Endpoint 
1.
Proportion of HR patients who develop steroid refractory GVHD by day 100 post HCT.
GVHD is defined as steroid refractory if CR or PR is not achieved by day 28 of systemic
steroid treatment OR if additional immunosuppression beyond steroids was given for
treatment of GVHD prior to 28 days of steroid treatment.
Secondary endpoints: 
1.
Overall survival at 6 months
2.
Cumulative incidence of NRM at 6 months and 1 year
3.
Relapse rate (see section 2.2.1)


10 
4.
100 days incidence of clinically relevant GVHD states including steroid-refractory
GVHD, grade II-IV GVHD, and grade III-IV GVHD (See section 2.2.1).
5.
For patients who develop GVHD prior to day 100 post-HCT, the overall response
rate (CR + PR) 28 days after initiation of systemic steroid treatment. PR is defined
as improvement in one or more organs involved with GVHD symptoms without
progression in others. For a response to be scored as PR on day 28, the patient
must be in PR on day 28 and have had no intervening systemic therapy for acute
GVHD other than steroids.
6.
Cumulative incidence of severe GI GVHD stage 3 or 4 by day 100 post-HCT
7.
Cumulative incidence of chronic GVHD requiring systemic steroid treatment by one
year
8.
Number of serious infections (defined as grade 3 by the Blood and Marrow
Transplant Clinical Trials Network)
Safety endpoints 
1.
Number and proportion of patients developing reportable AEs and SAEs according to
relatedness to study drug and stratified by severity
2.
Percentage of infusions for which the infusion rate was reduced and/or the infusion
interrupted or stopped for tolerability concerns or for adverse events (AEs)
Exploratory endpoints 
1.
Correlation of GVHD biomarkers with clinical endpoints
3.0 
PATIENT ELIGIBILITY 
Subjects must meet all of the inclusion and none of the exclusion criteria to be eligible to participate 
in the study. Study treatment may not begin until a subject is enrolled. 
3.1 
Inclusion Criteria 
3.1.1 
High risk prediction score as determined by the MAGIC algorithm at either day 7 
or day 14 post HCT. 
3.1.2 
Any donor type (e.g., related, unrelated) or stem cell source (bone marrow, 
peripheral blood, cord blood).  
3.1.3 
Related and unrelated donor and recipient match each other for at least 7/8 HLA-
loci (HLA-A, B, C, and DR) 
3.1.4 
Cord blood donor(s) match recipient for at least 4/6 HLA-loci (HLA A, B, and 
DR) 
3.1.5 
Any conditioning regimen (non-myeloablative, myeloablative, or reduced intensity) 
is acceptable. 
3.1.6 
Any GVHD prophylaxis is permitted. 
3.1.7 
The use of serotherapy to prevent GVHD (e.g., antithymocyte globulin) prior to day 
3 post-HCT is permitted.  


11 
3.1.8 
Age 18 years and older 
3.1.9 
Direct bilirubin must be <2 mg/dL unless the elevation is known to be due to Gilbert 
syndrome within 3 days prior to enrollment. 
3.1.10 ALT/SGPT and AST/SGOT must be <5 x the upper limit of the normal range within 
3 days prior to enrollment.  
3.1.11 Signed and dated written informed consent obtained from patient or legal 
representative.  
3.2 
Exclusion Criteria 
3.2.1 
Patients who develop acute GVHD prior to start of study drug 
3.2.2 
Patients at very high risk for relapse post HCT as defined by very high disease risk 
index29 
3.2.3 
Patients participating in a clinical trial where prevention of GVHD is the primary 
endpoint 
3.2.4 
Uncontrolled active infection (i.e., progressive symptoms related to infection 
despite treatment or persistently positive microbiological cultures despite 
treatment or any other evidence of severe sepsis) 
3.2.5 
Patients who are pregnant 
3.2.6 
Patients on dialysis within 7 days of enrollment 
3.2.7 
Patients requiring ventilator support or oxygen supplementation exceeding 40% 
FiO2 within 14 days of enrollment. 
3.2.8 
Patients receiving investigational agent within 30 days of enrollment. However, 
the Principal Investigator (PI) may approve prior use of an investigational agent if 
the agent is not expected to interfere with the safety or the efficacy of alpha-1-
antitrypsin  
3.2.9 
History of allergic reaction to alpha-1-antitrypsin 
4.0 
SUBJECT SCREENING AND REGISTRATION PROCEDURES 
Study Schema 
Figure 3: Study Schema 


12 
To be eligible for this study, patients must have a high MAGIC GVHD risk score on day 7 or 14 
post-HCT (see Appendix). Patients will be recruited from centers participating in the Mount Sinai 
Acute GVHD International Consortium (MAGIC) where the procedures for obtaining screening 
samples for biomarker scoring are already established.  
The pre-screening process is outlined in Figure 3 above. Consented patients will be registered into 
the remote data entry system using a unique study number assigned by the MAGIC DCC. Five mL 
of serum will be collected from patients on day 7 post-HCT (+/- 1 day) and shipped priority overnight 
to the Mount Sinai GVHD laboratory for early AM arrival (see MAGIC Sample Collection and 
Storage manual for shipping procedures). Samples can be received Tuesday through Saturday. 
Once received in the laboratory, the GVHD biomarkers used to assign the MAGIC GVHD risk score 
will be measured by ELISA using standard technical procedures. Processing, measuring, and 
confirming the ELISA assay results take 4.5 hours (range 4-6 hours). Once the MAGIC GVHD risk 
score is confirmed by Dr. Ferrara (or Dr. Levine in Dr. Ferrara’s absence), the investigator at the 
participating center will be notified of the MAGIC score by telephone and written confirmation by 
email. 
Patients who are low risk on day 7, who have not already developed GVHD requiring systemic 
treatment, and who meet the other eligibility criteria will be re-screened on day 14 (+/- 1 day). 
Patients who were low risk on day 7 but high risk on day 14 are also eligible for this study provided 
they have not already developed GVHD requiring systemic treatment. Only patients with confirmed 
high MAGIC GVHD risk scores will be eligible to enroll on the clinical trial.  
Patient registration for this trial will be centrally managed by the MAGIC Data Coordinating Center 
of the Icahn School of Medicine at Mount Sinai as described below: 
A potential study subject who has been screened for the trial and who has signed the Informed 
Consent document will be initially documented by the participating site on the Screening and 
Enrollment Log provided by the MAGIC Data Coordinating Center (DCC).  
It is the responsibility of the local site investigator to confirm patient eligibility for the clinical trial. 
Confirmation of a high MAGIC GVHD risk score will be provided directly to the identified Primary 
Site contact from the participating site by Dr. Ferrara, Dr. Levine or designee. All other eligibility 
criteria will be provided by the participating site. After patient eligibility has been determined, a copy 
of the completed Eligibility form will be submitted by the requesting site to the MAGIC Data 
Coordinating Center by email to magic@mssm.edu with local site investigator signature and 
supporting source documentation. 
The MAGIC Coordinator, who acts as the registrar, will review the submitted documents and 
process the registration.  
An email will be sent by the registrar to the requesting site registrar to confirm patient registration. 
Patients found to be ineligible for participation after being consented will be considered screen 
failures, and documented as such in the Screening and Enrollment Log. These patients will not 
receive study treatment. 
5.0 
TREATMENT PLAN 
5.1 
Treatment Dosage and Administration 
Protocol treatment must start within 2 days of confirmation of a high MAGIC GVHD risk 
score. For example, a patient whose Day 7 post-HCT falls on a Friday (day 7), who has a 
research sample shipped to the Ferrara Lab that day, will have their MAGIC GVHD risk 


13 
score assigned on Saturday (day 8). Such a patient must begin study treatment no later 
than Monday (day 10). There are no exceptions to this requirement. 
5.1.1 
Alpha-1-antitrypsin (Glassia) will be supplied by Kamada. Each participating site 
will have a sufficient supply of alpha-1-antitrypsin on hand to begin treatment, 
additional doses will be shipped to the participating site to complete treatment. 
See section 9.1 for preparation, dispensing, and administration information. 
5.1.2 
Study treatment will consist of alpha-1-anti-trypsin administered intravenously at a 
loading dose of 90 mg/kg (study day 0) followed by twice weekly doses of 45 mg/kg 
for 15 more doses (total of 16 doses over 8 weeks). 
5.1.3 
The planned schedule of subsequent doses (Mondays and Thursdays, Tuesdays 
and Fridays, Wednesdays and Saturdays) can be adjusted as necessary so long 
as the time between doses is not shorter than two days or longer than four days. 
5.1.4 
Missed doses will be made up as soon as possible and the schedule resumed until 
all sixteen doses have been administered or ten weeks from first dose, whichever 
comes first. 
5.1.5 
Subjects who miss more than two doses due to non-compliance will be analyzed 
for safety but considered inevaluable for efficacy assessment and replaced. 
5.1.6 
GVHD Prophylaxis Medications 
Medications given for GVHD prophylaxis such as cyclosporine, tacrolimus, 
sirolimus, methotrexate, mycophenolate should be continued at therapeutic doses 
(according to institutional standards) and adjusted as necessary for renal, central 
nervous system (CNS) or other toxicity using institutional guidelines.  This study 
allows for changes in GVHD prophylaxis medication (e.g., replacement of 
cyclosporine 
with 
sirolimus 
for 
management 
of 
posterior 
reversible 
encephalopathy syndrome [PRES]) as per institutional standards. The initiation of 
medications  other than AAT for the purpose of intensifying GVHD prophylaxis in 
high risk patients is prohibited. GVHD prophylaxis medications will be tapered 
according to local institutional tapering practices. 
5.1.7 
GVHD treatment 
The preliminary data for this study was generated from patients transplanted at 
multiple centers with heterogeneous GVHD treatment practices. In order to 
develop “real world” experience in this study, institutional GVHD treatment 
practices are permitted unless their use is explicitly prohibited.  
Patients who develop GVHD will be treated as per institutional standards with 
systemic and non-systemic treatments such as topical steroids or non-absorbable 
steroids for GI GVHD. If systemic steroid treatment is initiated the recommended 
starting dose is prednisone 2 mg/kg/day. Centers may use a starting dose of 2 
mg/kg of methylprednisolone if that is their institutional practice.  Additional agents 
for the purpose of treating GVHD (e.g., etanercept, extracorporeal photopheresis, 
ATG) are not allowed. The initiation of systemic GVHD treatment beyond 
continuation or adjustment of GVHD prophylaxis medications (see section 5.1.6) 
and corticosteroids will be considered the initiation of second line GVHD treatment 
and considered a treatment failure. Study treatment with alpha-1-antitrypsin 
continues during GVHD treatment until all 16 doses have been administered 
or ten weeks have elapsed from the start of AAT, whichever comes first. 


14 
GVHD treatment will be tapered according to local institutional tapering practices. 
A recommended taper is provided in the appendices. 
5.1.8 
Ancillary therapies 
Ancillary/supportive care measures for acute GVHD such as the use of anti-motility 
agents for diarrhea, including octreotide, is allowed at the discretion of the treating 
physician.  Use of ursodiol to prevent/reduce gall bladder sludging, or prevent 
hepatic transplant complications is allowed according to institutional guidelines 
5.1.9 
Supportive Care Guidelines 
All patients should receive the following: 

Transfusion support per institutional practice

Anti-infective prophylaxis against herpes virus is required but otherwise
institutional practice can be followed.

Anti-infective prophylaxis against Pneumocystis jiroveci, bacterial and
fungal infections according to standard institutional guidelines.

Pre-emptive monitoring and treatment for CMV infections is required but
otherwise institutional practice can be followed.
5.2 
Toxicities and Dosing Delays/Dose Modifications 
Any patient who receives treatment on this protocol will be evaluable for toxicity. Each 
patient will be assessed for the development of toxicity according to the Time and Events 
Table (Section 6.4). Toxicity will be assessed according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0.  
The dose of Glassia will not be modified. In the event of a SAE causally related to study 
drug, Glassia should be discontinued and the patient will be included in all analyses of 
safety and efficacy. 
5.3 
Concomitant Medications/Treatments 
Concomitant use of other investigational agents is not permitted during the treatment phase 
of the study without PI approval.   
5.4 
Other Modalities or Procedures 
Patients who have undergone allogeneic hematopoietic cell transplantation are often 
simultaneously being treated for other conditions and transplant-related complications. 
Such treatments will be considered distinct from the study drug treatment. 
5.5 
Duration of Therapy 
The duration of protocol therapy on this study is eight weeks (16 doses). Protocol therapy 
will end after the 16th dose of alpha-1-antitrypsin has been administered or if any of the 
following criteria apply: 

Patient voluntarily withdraws from  treatment OR

General or specific changes in the patient’s condition render the patient
unacceptable for further treatment in the judgment of the investigator OR

Ten weeks has elapsed since the first dose of AAT
5.6 
Off Treatment Criteria 
Patients will be removed from receiving the investigational drug when any of the criteria 
listed in Section 5.5 apply. The reason for ending investigational drug therapy and the date 


15 
the patient was removed from treatment will be documented in the study record. All patients 
who discontinue treatment should comply with protocol specific follow-up procedures as 
outlined in Section 5.7. The only exception to this requirement is when a subject withdraws 
consent for all study procedures. 
5.7 
Duration of Follow-Up 
Patients will be followed until 1 year post-HCT, withdrawal of consent or until death, 
whichever occurs first. HCT patients are followed closely and frequent clinical evaluations 
are the norm. The following outlines the minimum frequency of follow-up evaluations, it is 
anticipated that the majority of patients will be evaluated more frequently.  
During the first 8 weeks of participation (i.e., through the last dose of alpha-1-antitrypsin), 
patients will be seen twice weekly for study drug administration. GVHD staging should be 
performed approximately weekly through day 100 post-HCT as part of the standard of care 
for HCT recipients. Patients will be evaluated at least monthly until 6 months post-HCT 
than again at one year post-HCT. If GVHD develops during the first six months post-HCT, 
staging and treatment response should be evaluated at least weekly for four weeks as part 
of the standard of care for patients who develop GVHD. 
5.8 
Off Study Criteria 
Patients can be taken off study at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or 
administrative reasons. The reason(s) for discontinuation from study will be 
documented and may include: 
5.8.1 
Patient withdraws consent (termination of treatment and follow-up); 
5.8.2 
Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment;  
5.8.3 
Patient is unable to comply with protocol requirements; 
5.8.4 
The subject has any disorder or condition that in the investigator's judgment may 
impede the participant's participation in the study, pose increased risk to the 
participant, or confound the results of the study 
5.8.5 
Patient becomes pregnant (pregnancy to be reported along same timelines as a 
serious adverse event); 
5.8.6 
Termination of the study; 
5.8.7 
Patient completes protocol treatment and follow-up criteria. 
The informed consent documents will emphasize the importance of collecting outcome 
data from individuals who choose to discontinue treatment during the study, and 
participants will be encouraged to provide this information whether or not they complete 
the anticipated course of study treatment. 
5.9 
Patient Replacement 
Patients who enroll in the study but do not receive any study treatment will be replaced. 
Patients who initiate study treatment but miss more than two doses due to non-compliance 
will also be replaced. The number of patients and reason(s) for replacement will be 
recorded and will be used to assess the feasibility of the study design. 


16 
6.0 
STUDY PROCEDURES 
6.1 
Screening/Baseline Procedures 
Assessments performed exclusively to determine eligibility for this study will be done only after 
obtaining informed consent. Assessments performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values even if the studies were done before 
informed consent was obtained. Frequent monitoring of clinical chemistry and hematology is routine 
in HCT patients. This study does not require specific laboratory monitoring other than specified 
below. 
The screening procedures include: 
6.1.1 Informed Consent (informed consent can be obtained any time up to Day 7 post-
HCT). 
6.1.2 Demographics 
6.1.3 Review subject eligibility criteria (Eligibility criteria must be assessed between 
days 4-7 post-HCT. For patients who are screened again at day 14, eligibility criteria 
must be re-assessed between days 11-14 post-HCT). 
6.1.4 Review concomitant medications (immunosuppressants and GVHD prophylaxis 
medications only) 
6.1.5 Adverse event assessment 
Baseline adverse events will be assessed and preexisting conditions will be 
recorded. See Section 8.0 for Adverse Event monitoring and reporting. 
6.1.6 Serum chemistries (within 3 days prior to enrollment) 
ALT/SGPT, AST/SGOT, and total bilirubin are required for assessment of exclusion 
criteria within 3 days prior to enrollment. 
6.2 
Follow-Up Procedures 
The following outlines the minimum frequency of follow-up evaluations, it is anticipated that 
the majority of patients will be evaluated more frequently.  
During the first 8 weeks of participation (i.e., through the last dose of alpha-1-antitrypsin), 
patients will be seen twice weekly for study drug administration. GVHD staging should be 
performed weekly during the first eight weeks at intervals at the visit closest to 7 day interval 
from Study Day 0 (i.e., Study Day 7, 14, 21, etc). Between Study Day 56 and Study Day 
100, GVHD staging should be performed no less than every other week. Weekly staging 
is preferred and if performed should be reported on the case report forms. Patients will also 
be evaluated at six months and one year post-enrollment for survival, relapse, acute and 
chronic GVHD. If acute GVHD develops during the first 100 days post enrollment, the 
staging, immunosuppression medications and treatment response should be determined 
at least weekly for four weeks to assess the primary study endpoint. 
Follow-up studies are detailed in the Time and Events Table is section 6.3. 


17 
6.3 
Time and Events Table 
CALENDAR BASED ASSESSMENTS 
GVHD DRIVEN 
ASSESSMENTS 1 
Screening 
HCT Day 7 
HCT Day 14 2 
Study day 0 
Study 
day 7 
Study 
day 14 
Study 
day 21 
Study 
day 28 
Study 
day 35 
Study 
day 42 
Study 
day 49 
Study 
day 56  
Every other 
week to 
 HCT Day 
100 
HCT 
Day 
100 
HCT 
Day 
180 
1 Year 
Post 
HCT 
GVHD 
Diagnosis 
or Treatment 
Weekly x 4  
from start of 
GVHD Diagnosis 
or Treatment 
Windows 
+/- 1 day 
Within 2 
days of Risk 
Score 
Notification 
+/- 2 
days 
+/- 2 
days 
+/- 2 
days 
+/- 2 
days 
+/- 3 
days 
+/- 3 
days 
+/- 3 
days 
+/- 3 
days 
+/- 6 days 
+/- 3 
days 
+/- 14 
days 
+/- 14 
days 
+/-2 days 
+/-2 days 
Eligibility Review 
X 
Concomitant 
Medication 
Review 3 
X
X
X
X
X
X
X
X
X
X
X
X 
X
X
X
X
Adverse Event 
Evaluations 
X 
Adverse events will be reported from the time of the study day 0 through 30 days after the last dose of study drug.  
Report serious adverse events as they occur. 
Serum Chemistry 
X 
GVHD Staging 4 
X
X
X
X
X
X
X
X
X
X
X
X 
X
X
X
X
Alpha-1-
antitrypsin 
Administration 
90 mg/kg 
Once 
45 mg/kg  
Twice weekly for 15 more doses for a total of 16 doses. 
If GVHD occurs, continue AAT 
treatment. Complete 16 doses  
as per protocol. 
Survival, Relapse 
& Chronic GVHD 
Status 
X 
X 
X 
CORRELATIVES STUDIES 
Serum Sample  
(10 mL) 5 
X
X
X
X
X
X
  
X  (HCT day 56 +/-
3 days, not study 
day 56 ) 
X
X
1 When GVHD driven assessments and sample collections occur within 3 days of a calendar based assessment/collection, the calendar 
assessment/collection is not required. 
2 Screening occurs on day 7 post-HCT and, if still eligible for screening, again on day 14 post-HCT. Screening samples are sent via overnight shipping to 
the MAGIC laboratory in New York. Patients who do not meet eligibility by high risk biomarkers will be followed for minimum data collection: GVHD onset 
date, maximum GVHD severity, steroid refractory GVHD by day 100 (Y/N), chronic GVHD requiring treatment (Y/N), relapse and death with reporting 
once at one year post-BMT. 
3  Concomitant medication review will record only immunosuppressants and other drugs administered during the reporting period for GVHD prevention and 
treatment. 
4 GVHD staging will follow the detailed guidelines provided in the MAGIC Acute GVHD Staging Guidance. 
5 Serum samples will be banked for correlative studies. To avoid unnecessary sample collection, when GVHD driven samples are collected within 3 days 
of a scheduled calendar based sample, the calendar based sample should not be collected.


18 
7.0 
GVHD CLINICAL STAGING 
GVHD clinical staging will be according to the established criteria used for Blood and Marrow 
Transplant Clinical Trials Network GVHD staging (modified Glucksberg criteria).  
Stage 0 
Stage 1
Stage 2
Stage 3 
Stage 4
Skin 
No rash 
Rash < 25% BSA 
25-50%
> 50% Generalized
erythroderma
Plus bullae and 
desquamation 
>5% BSA
Liver 
Bilirubin ≤  2 mg/dl 
2.1-3 mg/dl 
3.1-6mg/dl
6.1-15mg/dl
>15mg/dl
GI tract 
Adult: < 500 
ml/day 
Adult: 500–1000 
ml/day  
Adult: 1001-1500 
ml/day  
Adult: >1500 
ml/day  
Severe abdominal 
pain +/- ileus, flank 
blood or melena 
(regardless of stool 
volume) 
UGI 
Severe
nausea/vomiting 

For stage 4 GI GVHD, severe abdominal pain is defined as (1) pain that requires opioid use and (2) pain that
significantly impacts on performance status as determined by the treating physician

Comprehensive GVHD staging guidance is provided in the MAGIC GVHD Staging Guidance.
Overall Clinical Grade: 
Grade 0 
No stage 1-4 of any organ 
Grade I  
Stage 1-2 skin and no liver or GI involvement 
Grade II 
Stage 3 skin and/or Stage 1 liver and/or Stage 1 GI 
Grade III 
Stage 0-3 skin with Stage 2-3 liver and/or Stage 2-3 GI 
Grade IV 
Stage 4 in any target organ (skin, liver, GI) 
7.1 
ENDPOINT AND RESPONSE CRITERIA 
7.1.1 
Definitions 
Evaluable for response: Safety, tolerability, and efficacy of AAT will be assessed 
from the initiation of the first AAT treatment 
Complete Response (CR): All evaluable organs (skin, liver, GI tract) stage 0. For 
a response to be scored as CR on day 28, the patient must be in CR on that day 
and have had no intervening additional GVHD therapy. 
Partial Response (PR): An improvement in one or more organ involved with GVHD 
symptoms without worsening in others. For a response to be scored as PR on day 
28, the patient must be in PR on that day and have had no intervening additional 
GVHD therapy. 
No response (NR): All responses that are not CR or PR. Patients who receive any 
systemic GVHD therapy other than the continuation or modification of GVHD 
prophylaxis, systemic steroids, and topical/non-absorbable oral steroid therapy, 
will be scored as NR on day 28 regardless of organ staging.  
7.1.2 
Proportion of CR and CR+PR 
CR and PR on day 28 are scored in comparison to the patient’s acute GVHD 
staging on the day systemic steroid treatment began. 


19 
7.1.3 
Steroid refractory GVHD 
Patients who are scored as no response on day 28 of systemic steroid treatment 
for GVHD or who receive additional systemic immunosuppression prior to day 28 
(i.e., no response) will be considered steroid refractory. Escalation of steroid doses 
during treatment for GVHD are not considered in the definition of steroid refractory 
GVHD. 
7.1.4 
Steroid discontinuation 
The date of discontinuation of steroid therapy will be recorded. 
7.1.5 
Lines of GVHD therapy 
Systemic steroids are the first line of GVHD treatment. Any additional systemic 
immunosuppression treatment to steroid therapy for acute GVHD will be 
considered 2nd line therapy and considered a failure to respond to steroid 
treatment. Resumption or changes in GVHD prophylaxis (e.g., substitution of 
mycophenolate for tacrolimus due to PRES) are not considered new lines of 
therapy. Topical steroids and non-absorbable oral steroids are not considered new 
lines of therapy. 
7.1.6 
Non-Relapse Mortality (NRM) 
Any death that occurs after HCT not attributable to relapse of the underlying 
disease will be considered a non-relapse death. 
7.1.7 
Chronic GVHD 
The occurrence of chronic GVHD as defined by NIH consensus criteria requiring 
systemic treatment, including date of diagnosis, will be recorded.  
7.1.8 
Relapse 
Relapse, including date of relapse, of the underlying malignancy will be recorded. 
7.2 
SAFETY/TOXICITY DEFINITIONS 
7.2.1 
Glassia was generally safe and well tolerated in clinical studies of healthy adult 
subjects, subjects with AAT deficiency, and type 1 diabetes mellitus. Headache 
(6%) and dizziness (3%) were reported by >1 subject in two clinical studies in 
patients with AAT deficiency. There were no toxicities observed in a study of AAT 
Glassia therapy in patients with steroid-refractory acute GVHD that were felt to be 
related to AAT administration. Although not previously reported, AAT has potential 
immunomodulatory activity that theoretically could increase the risk for infection. 
Known or plausible toxicities that may be related to alpha-1-antitrypsin will be 
reported.  
7.2.2 
Systemic Infections 
Infections are common in patients who undergo HCT and generally respond to 
treatment. Any grade 3 infection as defined by the Blood and Marrow Transplant 
Clinical Trials Network will be reported. The full table can be referenced in 
Appendix B.  
Grade 3 Bacterial Infections: 
a.
Bacteremia with deep organ involvement
b.
Severe sepsis with bacteremia
c.
Fasciitis requiring debridement
d.
Pneumonia requiring intubation
e.
Brain abscess or meningitis without bacteremia


20 
f.
Clostridium difficile toxin positive stool with toxic dilatation or renal
insufficiency with/without diarrhea.
Grade 3 Fungal Infections: 
a.
Fungemia, including candidemia
b.
Proven or probable invasive fungal infections (e.g. Aspergillus, Mucor,
Fusarium, Scedosporium)
c.
Disseminated fungal infections (e.g. multifocal pneumonia, presence of
urinary/blood antigen, CNS involvement) with Histoplasmosis,
Blastomycosis, Coccidiomycosis or Cryptomycosis
d.
Pneumocystis jiroveci pneumonia
Grade 3 Viral Infections: 
a.
Severe VZV infection with either associated coagulopathy or organ
involvement
b.
CMV end organ involvement (e.g. pneumonitis, enteritis, retinitis)
c.
EBV Post-transplant lymphoproliferative disorder (PTLD)
d.
Adenovirus with end organ involvement (except adenoviral conjunctivitis
or upper respiratory tract disease)
e.
All lower respiratory tract viruses
f.
Viral encephalitis or meningitis
Grade 3 parasitic infections: 
a.
Toxoplasmosis involving the CNS
b.
Strongyloides hyperinfection
Non-microbiologically documented infections: 
a.
Any acute pneumonia requiring mechanical ventilation
b.
Severe sepsis without an identified organism
7.2.3 
Viral Reactivations 
Because viral reactivations often require treatment in the HCT population, even in 
the absence of end organ disease, the following viral infections/reactivations will 
be reported: 
The date, anatomical site or body fluid (e.g., blood, nasopharyngeal swab, stool, 
etc.), and method of detection for CMV, EBV, HHV6, VZV, HSV and adenovirus 
will be reported. 
7.3 
Safety/Tolerability 
 
 Analyses will be performed for all patients having received at least one dose of study drug. 
The study will use the CTCAE version 4.0 for reporting of adverse events 
(http://ctep.cancer.gov/reporting/ctc.html). 
8.0 
ADVERSE EVENTS 
8.1 
ALPHA-1-ANTITRYPSIN 
For the most recent safety update, please refer to the current Investigator’s Brochure or 
Study Agent Prescribing Information. 


21 
8.1.1 
Contraindications 
Patients who have had an allergic reaction to alpha-1-antitrypsin 
8.1.2 
Special Warnings and Precautions for Use 
Severe hypersensitivity and anaphylactic reactions may occur in IgA deficient patients with 
antibodies against IgA and in patients with a history of hypersensitivity to other Alpha1-AT 
products. These reactions are not expected in this study because of the 
immunosuppressive nature of the transplant procedure.  
May carry a risk of transmitting infectious agents such as viruses, the variant Creutzfeldt-
Jakob disease (vCJD) and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. 
8.2 
Adverse Event Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial and is 
done to ensure the safety of subjects enrolled in the studies as well as those who will enroll 
in future studies using similar agents. Data on adverse events will be collected from the 
time of the initial study treatment (day 0) through 30 days after the last dose of alpha-1-
antitrypsin. Any serious adverse event that occurs more than 30 days after the last alpha-
1-antitrypsin dose and is considered related to the study treatment must also be reported.
Serious Adverse Events (SAEs) will continue to be followed until:

Resolution or the symptoms or signs that constitute the serious adverse event
return to baseline;

There is satisfactory explanation other than the study treatment for the changes
observed; or

Death.
The investigator is responsible for the detection, documentation, grading and assignment 
of attribution of events meeting the criteria and definition of an AE or SAE. The definitions 
of AEs and SAEs are given below. It is the responsibility of the principal investigator to 
ensure that all staff involved in the trial is familiar with the content of this section. 
Any medical condition or laboratory abnormality with an onset date before initial study 
treatment administration is considered to be pre-existing in nature. Any known pre-existing 
conditions that are ongoing at time of study entry should be considered medical history. 
All events meeting the criteria and definition of an AE (CTCAE grade 3 or higher) or SAE, 
as defined in Section 8.3, occurring from the initial study treatment administration through 
30 days following the last dose of the study treatment or study intervention must be 
recorded as an adverse event in the patient’s source documents and on the CRF.  
8.3 
Definitions 
8.3.1 Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient receiving 
study treatment and which does not necessarily have a causal relationship with 
this treatment. An AE can be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental intervention, whether or not related to the intervention.  

Diagnostic and therapeutic non-invasive and invasive (i.e., surgical)
procedures will not be reported as adverse events. However, the medical
condition for which the procedure was performed must be reported if it meets


22 
the definition of an adverse event unless it is a pre-existing (prior to protocol 
treatment) condition. 

Event reporting for GVHD treatment protocols can be complicated and
confusing for investigators, data managers, and regulatory oversight bodies
because patients typically develop numerous complications as part of the
typical treatment course not related to study therapy. Furthermore, transplant-
related complications often occur both simultaneously and in series, as one
complication leads to a series of downstream events. Therefore, a well-
conceived event reporting plan separates background transplant and GVHD
noise as might be seen with any transplant where GVHD develops from study
related events that are relevant to patient safety. On this study, we will not
report CTCAE grade 1 and 2 adverse events (which make up the majority of
events) unless the investigator determines the event should be reported to
protect subject safety.

It is common for HCT recipients to experience multiple complications as part
of the transplant itself that are unrelated to exposure to investigational agents.
Symptoms of the original or targeted disease are not to be considered adverse
events for this study except that all BMT CTN grade 3 infections will be
reported (see Appendix B). Symptoms related to the conditioning regimen or
GVHD will not be reported unless the event is serious (see section 8.3.2) and
considered by the investigator to be possibly, probably, or definitely related to
AAT. Events that are unlikely or unrelated to AAT are not required to be
reported. Reporting of such events should include the investigator’s
assessment as to whether the event should be attributed to any of the HCT
procedure itself, GVHD, exposure to immunosuppressive agents other than
AAT, and AAT. An event may be attributable to all, some, or one of these
categories.

Abnormal laboratory values or test results constitute adverse events only if
they induce clinical signs or symptoms or require therapy and otherwise meet
the criteria for a reportable adverse event as defined above. They are to be
captured under the signs, symptoms or diagnoses associated with them.
8.3.2 Serious Adverse Event 
An adverse event is considered “serious” if, in the view of the investigator, it results 
in any of the following outcomes: 
o
Death
If death results from (progression of) the disease, the disease should be
reported as event (SAE) itself.
o
A life-threatening adverse event
An adverse event is considered ‘life-threatening’ if, in the view of either the
investigator, its occurrence places the patient or subject at immediate risk of
death. It does not include an adverse event that, had it occurred in a more
severe form, might have caused death.
o
Inpatient hospitalization or prolongation of existing hospitalization for ≥24
hours.
o
A persistent or significant incapacity or substantial disruption of the ability to
conduct normal life functions


23 
o
A congenital anomaly/birth defect
o
Important medical event
Any event that may not result in death, be life-threatening, or require
hospitalization may be considered serious when, based upon appropriate
medical judgment, they may jeopardize the patient and may require medical
or surgical intervention to prevent one of the outcomes listed in this definition
of “Serious Adverse Event”. Examples of such medical events include allergic
bronchospasm requiring intensive treatment in an emergency room or at
home; convulsions that do not result in inpatient hospitalization or the
development of drug dependency or drug abuse.
Previously planned (prior to signing the informed consent form) surgeries should 
not be reported as SAEs unless the underlying medical condition has worsened 
during the course of the study. Preplanned hospitalizations or procedures for 
preexisting conditions that are already recorded in the patient’s medical history at 
the time of study enrollment should not be considered SAEs. Hospitalization or 
prolongation of hospitalization without a precipitating clinical AE (for example, for 
the administration of study therapy or other protocol-required procedure) should 
not be considered SAEs. However, if the preexisting condition worsened during 
the course of the study, it should be reported as an SAE. 
8.3.3 Expected Adverse Events 
An adverse event (AE) is considered “expected” if: 

For approved and marketed drugs or devices, those adverse events are
described in the approved Package Insert (Label).

For investigational new drugs or devices, those adverse events are
described in the FDA Investigator’s Brochure.

In clinical research studies, information on expected adverse events is
also summarized in the protocol and in the consent document.  See
section 9.1 for the list of expected adverse events related to the drug under
study.
8.3.4 Unexpected Adverse Event 
An adverse event (AE) is considered “unexpected” if it is not described in the 
Package Insert, Investigator’s Brochure, in published medical literature, in the 
protocol, or in the informed consent document.  
8.4 
Adverse Event Characteristics 
8.4.1 CTCAE Term 
(AE description) and grade: The descriptions and grading scales found in the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be 
utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 4.0. A copy of the CTCAE version 4.0 can be down 
loaded from the CTEP web site. (http://ctep.cancer.gov) 
8.4.2 Attribution of the AE 
The investigator or co-investigator is responsible for assignment of attribution. 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 


24 
Unrelated – The AE is clearly NOT related to the study treatment. 
8.5 
Serious Adverse Event Reporting Guidelines 
The Sponsor Investigator will report SAEs to regulatory bodies and to the participating 
sites in the following manner: 
Sponsor SAE Reporting  
Event occurring 
from Day 0 to 30 
Days post last 
AAT infusion 
Report to: 
Event occurring 
after 30 Days 
post last AAT 
infusion 
Report to: 
FDA / IRB 
Consortium
FDA / IRB 
Consortium
All SAEs; 

Expected or
Unexpected

Possible,
Probable, or
Definite
3 Days 
from 
knowledge 
Monthly 
SAEs –  

Expected

Probable or
Definite
OR

Unexpected

Possible,
Probable or 
Definite 
3 Days 
from 
knowledge 
Monthly 
SAEs –  

Expected

Possible
Annually 
Monthly 
8.5.2 
The Principal Investigator must be notified within 3 business day of study team’s 
knowledge of any event meeting the criteria and definition of a serious adverse 
event, regardless of attribution, occurring during the study or within 30 days of the 
last administration of the AAT.  Kamada should be notified within 3 days to enable 
reporting to regulatory authorities as required. 
8.5.3 
The investigator must report all events meeting the criteria and definition of a 
serious adverse event that are unexpected and possibly related (definite, probable 
or possible to study treatment administration) to the local IRB as per local IRB 
policy.  
8.5.4 
All Serious Adverse Events whether expected or unexpected and possibly related 
(definite, probable or possible) to study treatment administration will be reported 
using the Serious Adverse Event form within 3 days of first awareness of the event 
to the MAGIC Data Coordinating Center. A copy of the form should be sent to the 
MAGIC Coordinator via email to magic@mssm.edu. 
The MAGIC Data Coordinating Center will disseminate information regarding 
serious adverse events to the participating sites within 3 days of review of the 
information by Dr. Levine only in the case that the event(s) is believed to be related 
(i.e. probably or definitely) to the study medication. All other Serious Adverse 
Events will be discussed on monthly webinars held with all participating centers 
(see section 12). 


25 
The Principal Investigator will be responsible for reporting of events to the FDA 
and supporters, as appropriate and defined in the regulations under 21 CFR 
312.32.  
8.6 
Reporting of Unanticipated Problems 
Upon becoming aware of any incident, experience, or outcome (not related to an adverse 
event) that may represent an unanticipated problem involving risks to subjects or others, 
the investigator should assess whether the incident, experience, or outcome represents an 
unanticipated problem. The incident, experience or outcomes are considered unanticipated 
if it meets all of the following criteria: 
1.
Unexpected (not previously documented in terms of nature, severity, or frequency);
2.
Causally related or possibly related to participation in the study; and
3.
Suggests that the research places subjects or others at a greater risk of harm than
was previously known or recognized.
If the investigator determines that the incident, experience, or outcome represents an 
unanticipated problem, the investigator must report it to the MAGIC Data Coordinating 
Center within 3 days of first awareness of the events, and to the local IRB as per local IRB 
policy. 
8.7 
Stopping Rules  
Although alpha-1-antitrypsin is generally safe, its use as a pre-emptive therapy for acute 
GVHD has not been previously studied. We will continuously monitor the incidence of BMT 
CTN grade 3 infections occurring within 8 weeks of study administration and accrual will 
be halted if there is sufficient evidence that the infection rate exceeds the acceptable target 
rate of 24% (the incidence in patients with high risk GVHD) by more than 30%. If the 
incidence of BMT CTN grade 3 infections occurring within 8 weeks of study administration 
is greater than the associated boundary value bk listed in the table below, among the k 
patients enrolled in the trial, then accrual will be halted for safety considerations. 
Maximum 
# 
of 
Patients, k 
6 
7-12
13-18
19-24 25-30
Boundary, bk 
3 
5 
7 
9 
11 
Specifically, if more than 3 out of the first 6 patients, 5 out of the first 12 patients, 7 out of 
the first 18 patients, 9 out of the first 24 patients, or 11 out of the first 30 patients, experience 
grade 3 infections occurring within 8 weeks of study administration, the trial will be halted 
for safety considerations. 
The operating characteristics of this stopping rule are as follows: 
True Toxicity Rate 
24% 
30% 
40% 
50% 54% 
Probability 
of 
Early 
Stopping 
0.09 
0.25 
0.61 
0.89 0.94 
Using these boundaries, if the true toxicity rate is 24%, 30%, 40%, 50% or 54%, the 
probability of stopping the trial early is 0.09, 0.25, 0.61, 0.89, and 0.94 respectively. This 
stopping rule was computed using the toxbdry function in R and calculations of this function 
are based on methods described in Chapter 12 of Jennison and Turnbull (2000)30 and in 
the illustrative paper by Ivanova, Qaquish and Schell31. 


26 
An enrollment rule to prevent an excessive number of toxicities as described in Song and 
Ivanova32 will be used to inform us of the number of additional patients we can recruit when 
the current patient has not yet completed cycle 1. Formally, the trial can enroll m new 
patients such that r + x + m ≤bn+m, r + x + m– 1 < bn+m−1, and n + m ≤ K where r is defined 
as the number of patients that have not completed follow-up and are still being followed for 
toxicity; x is the number of patients that have experienced toxicity and n is the total number 
of patients enrolled to date. This enrollment rule is conservative in that it assumes the worst 
case scenario, that every patient in the follow-up will experience a dose-limiting toxicity. 
The study may also be stopped based on the recommendation of the investigators, the TCI 
DSMC, or at Kamada’s discretion for any reason.   
9.0 
DRUG INFORMATION 
9.1 
ALPHA-1-ANTITRYPSIN (AAT, AAT, A1PI) 

Commercial names for the drug: GLASSIA®

Classification - type of agent: Human Alpha-1 Proteinase Inhibitor

Description: AAT (Glassia) is supplied as contains a single use vial containing
approximately
1 gram of functional Alpha1-PI in 50 mL of solution and a sterile filter needle

Mode of action: The mode of action of AAT in graft-versus-host disease is not well
understood, but appears to be related to its anti-inflammatory, anti-apoptotic and
immunomodulatory properties19-22.

Pharmacokinetics: 
A 
prospective, 
open-label, 
uncontrolled 
multicenter
pharmacokinetic trial was conducted in 7 females and 11 males with congenital Alpha-
1 antitrypsin deficiency, ranging in age from 40 to 69 years. Subjects received a single
dose of GLASSIA either 30 mg/kg, 60 mg/kg or 120 mg/kg. Blood samples for
pharmacokinetic study were taken prior to and within 5 minutes of completion of the
infusion, and then at 1 hour, 6 hours, 12 hours, 24 hours, 3 days  and 7 days. The
mean results for  pharmacokinetic parameters in the 60 mg/kg dosage group are
shown in the Table. The  pharmacokinetics of  GLASSIA were linear over the dose
range of 30-120 mg/kg.
Pharmacokinetic Parameter 
60 mg/kg Dose Group
Terminal Half-Life (h) * 
111 ± 33 
Area under the curve 0-168 hrs (mg·hmL) 
89 ± 10 
Clearance (mL/h/kg) 
0.68 ± 0.1 
Volume of Distribution (L) 
3.2 ± 0.3 

Adverse reactions: The most common adverse reactions (>0.5% of infusions) in clinical
trials were headache and upper respiratory infection.
GLASSIA may contain trace amounts of IgA. Patients with known antibodies to IgA,
which can be present in patients with selective or severe IgA deficiency, have a greater
risk of developing severe hypersensitivity and anaphylactic reactions.
Because this product is made from human plasma, it may carry a risk of transmitting


27 
infectious agents, such as viruses, the variant Creutzfeldt-Jakob disease (vCJD) and 
theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown 
or emerging viruses and other pathogens. 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. Despite these measures, 
such products may still potentially transmit human pathogenic agents. 

Drug Interactions: Alpha-1-antitrypsin may interact with immunosuppressant agents
and increase the risk of infection.

Storage and stability: GLASSIA must be refrigerated between 2°C to 8°C (36°F to
46°F). Do not freeze. Product may be stored at room temperatures not exceeding 25°C
(77°F) for up to one month. Once removed from refrigeration use within one month.

Preparation:
1.
Use aseptic technique.
2.
Allow the product to reach room temperature prior to infusing and administer
within three hours of entering the vials.
3.
Inspect the vial of GLASSIA. The solution should be clear and colorless to
yellow-green and may contain a few protein particles. Do not use if the product is
cloudy.
4.
The product is suitable for infusion directly from the vial or pooled into a sterile
container for intravenous infusion.
5.
For pooling the product, use a vented spike (not supplied) to withdraw the
solution from the vial and then use the supplied 5 micron filter needle to transfer
the solution into the intravenous infusion container. NOTE: Do not use the 5
micron filter needle to withdraw GLASSIA from the vial.

Administration:
For intravenous infusion only.
GLASSIA should be administered by a healthcare professional or self-administered
by the patient/caregiver after appropriate training. For self-administration, provide the
patient/caregiver with detailed instructions and adequate training for infusion in the
home or other appropriate setting.
1.
Use aseptic technique.
2.
Inspect parenteral products visually for particulate matter and discoloration prior
to administration whenever solution and container permit.
3.
Administer GLASSIA alone. Do not mix with other agents or diluting solutions.
4.
When infusing directly from the vials, use a vented spike (not supplied). If the
contents of vials have been pooled to a sterile intravenous container, use an
appropriate intravenous administration set.
5.
Always use a 5 micron in-line filter (not supplied) during infusion.
6.
Administer GLASSIA within three hours of entering the vials to avoid the
potential ill effect of any inadvertent microbial contamination.
7.
Administer GLASSIA at room temperature through an appropriate intravenous
administration set at a rate not to exceed 0.2 mL/kg body weight per minute,
and as determined by the response and comfort of the patient.
8.
The recommended dosage of 90 mg/kg at a rate of 0.2 mL/kg/min will take
approximately 22 minutes to infuse and dosage of 45 mg/kg will take 11 minutes
to infuse.


28 
9.
Monitor the infusion rate closely during administration and observe the patient
for signs of infusion related reactions. If infusion related adverse reactions
occur, reduce the rate or interrupt the infusion as appropriate until the symptoms
subside. Resume the infusion at a rate tolerated by the patient, except in the
case of severe reaction
10. Monitor the patient for 30 minutes after completion of infusion for any adverse
reactions.
11. Following administration, discard all open vials, unused solution and
administration equipment.

Availability: Provided by Kamada, Ltd.

Return and Retention of Study Drug:
Any remaining/expired/used is to be destroyed on site according to the institution
standard operating procedure for drug destruction and documented on the drug
accountability logs.

Drug Accountability:
The principal investigator, or a responsible party designated by the investigator, must
maintain a careful record of the inventory and disposition of the investigational drug,
alpha-1-antitrypsin. The drug accountability records will capture drug receipt, drug
dispensing, drug return, and final disposition.
10.0 
CORRELATIVES/SPECIAL STUDIES 
The goal of the planned laboratory correlative studies is to improve our understanding of the 
biological processes that drive GVHD and its clinical outcomes. 
10.1 
Sample Collection Guidelines 
The correlative sample collection schedule is detailed in section 6.3 above. Serum will be 
collected in no additive, silicone coated glass or plastic tubes containing no anticoagulant 
(red or gold top tube). Samples will be processed at the participating center and batch 
shipped to Ferrara Laboratory quarterly for storage. Sample processing details are found 
in Appendix A. Instructions for quarterly batch shipping are found in the MAGIC Sample 
Collection and Storage Manual. 
10.2 
Assay Methodology 
See Appendix A. 
10.3 
Specimen Banking 
Patient samples collected for this study will be stored indefinitely or until they are used up. 
If future use is denied or withdrawn by the patient, best efforts will be made to stop any 
additional studies and to destroy the specimens. In addition to the biomarker studies 
planned as part of this study, additional studies may be performed on the banked research 
samples as part of collaborations with other institutions and entities.   
The specimens, DNA, and their derivatives may have significant therapeutic or commercial 
value. The Informed Consent form contains this information and informs the subject that 
there is the potential for financial gain by the Icahn School of Medicine at Mount Sinai, the 
investigator or a collaborating researcher or entity.  
The following information obtained from the subject's medical record may be provided to 
research collaborators when specimens are made available:  


29 

Diagnosis

Collection time in relation to study treatment

Clinical outcome – if available

Demographic data
11.0 
STATISTICAL CONSIDERATIONS 
11.1 
Study Design/Study Endpoints 
This is a proof of concept pilot single arm, open label multicenter clinical trial. The primary 
study measure of efficacy is the incidence of steroid-refractory GVHD by Day 100 after 
HCT. GVHD is defined as steroid refractory if CR or PR is not achieved by day 28 of 
systemic steroid treatment OR if additional immunosuppression beyond steroids was given 
for treatment of GVHD prior to 28 days of steroid treatment.  Subjects who start treatment 
for GVHD within 28 days of Day 100 (i.e., on or after Day 72 post-HCT) must be followed 
for a full 28 days of systemic steroid treatment for the purposes of assessing the primary 
study measure of efficacy.  
Because we expect improvements in the incidence of steroid refractory GVHD to translate 
into better long-term outcomes, secondary endpoints include 6 month NRM and 6 months 
overall survival.  Additional secondary endpoints related to efficacy will include, in subjects 
who develop GVHD, time to discontinuation of steroid therapy, number of lines of GVHD 
therapy, and cumulative incidence of chronic GVHD. Secondary endpoints related to safety 
include 6 month and 1 year relapse rates and incidence of serious (BMT CTN grade 3) 
infections by day 100.  
The historical control population for this study consists of patients who met the criteria for 
a high MAGIC GVHD risk score at either day 7 and 14 (see Background). 
11.2 
Sample Size and Accrual 
This is a proof of concept pilot study intended to determine if sufficient evidence can be 
developed to warrant further study of pre-emptive treatment with AAT. The expected 
incidence of steroid refractory GVHD by day 100 in patients who are high risk at either day 
7 or 14 is 28%. We assume that the incidence of steroid refractory GVHD by day 100 
among high risk patients treated pre-emptively will be 15% as a clinically meaningful 
incidence. Based on this assumption, a sample size of 30 achieves 85% power to detect a 
13% improvement (28%-15%) in steroid refractory incidence rate using a one-sided exact 
test with a target significance level of 0.23. It is suggested in the literature that in pilot 
studies, false positive rates up to 0.25 could be used as those studies are not designed to 
provide definite evidence but are designed to provide guidance to whether a larger study 
should be conducted33. If we observe 6 or fewer cases of SR GVHD, we will consider this 
approach sufficiently promising to warrant further study. 
Sample size calculations were computed using the binomial enumeration of all possible 
outcomes method in PASS 14 Power Analysis and Sample Size Software (2015) NCSS, 
LLC. Kaysville, Utah, USA, ncss.com/software/pass. 
The five centers participating in this clinical trial collectively perform >600 allogeneic HCT 
per year, of whom >90% should meet the eligibility criteria for this trial. We will need to 
screen approximately 120 eligible patients in order to enroll 30 high risk patients onto this 
clinical trial. We expect to be able to meet our accrual goals within one year. 
11.3 
Data Analyses Plans 
The primary endpoint is incidence of steroid-refractory GVHD by day 100. Death, lack of 
GVHD response to systemic steroids by day 28 of treatment, or initiation of additional 
systemic immunosuppressive therapy for GVHD will be considered failures for this 


30 
endpoint. The incidence of steroid-refractory GVHD by day 100 in the study patients will 
be compared to the historical control rate of 28%. 
Secondary outcomes such as the overall response rate (CR+PR), the incidence of severe 
GI GVHD (stage 3 or 4), non-relapse mortality, relapse rates, overall survival, will be 
estimated and compared to historical controls. 
Continuous variables will be summarized using standard summary statistics such as 
number of observations (n), mean, standard deviation (SD), minimum and maximum 
values, median, and 1st and 3rd quartiles. Categorical variables will be summarized in 
frequency tables as counts and percentages. 
Cumulative incidence of non-relapse mortality will be estimated by Gray’s method and 
relapse will be considered as a competing risk34. Disease free and overall survival, 
defined as the time from the transplantation to death or to last follow-up if alive, will be 
estimated by the method of Kaplan-Meier and the probability curves and 95% confidence 
intervals will be provided based on the method of Brookmeyer and Crowley35. 
12.0 
DATA AND SAFETY MONITORING 
The safety of subjects is paramount and supersedes all other concerns. This study employs several 
layers of oversight to ensure that patient safety is protected.  
1.
The local Data and Safety Monitoring Committee (DSMC) at each site which will be responsible
for monthly reviews of patient data at each site
2.
The Protocol Data and Safety Monitoring Committee (DSMC), composed of the individual site
PI’s which will review all facets of study conduct at all sites on monthly webinars
3.
The Tisch Cancer Institute Data and Safety Monitoring Committee (TCI DSMC) of the Mount
Sinai Health System is the DSMB of record for this study. The DSMB will be compliant with the
NIH approved DSMP Charter. This committee will be responsible for monitoring the safety and
data integrity of the trial. It is a DSMB entirely composed of members with no connection to this
clinical trial.
4.
Annual reviews and safety reporting will be provided to the IRBs at each participating site,  the
Mount Sinai Health System, and the FDA as required by IND regulations (21 CFR 312.3).
Protocol DSMC: The centers participating in this study are collaborating centers in MAGIC (Mount 
Sinai Acute GVHD International Consortium). The local site principal investigator, data manager, 
and study coordinator participates in monthly webinars where all facets of study conduct are 
discussed, thereby providing an additional layer of safety oversight. 
The MAGIC Data Coordinating Center is responsible for collating all data and safety reports from 
all the participating sites, and providing the information to the TCI Data Safety Monitoring 
Committee. 
TCI DSMC: The TCI DSMC serves as the data and safety monitoring board (DSMB) for investigator 
initiated studies conducted under the auspices of the Tisch Cancer Institute (TCI) at the Mount 
Sinai Health System. It is compliant with the National Institutes of Health and National Cancer 
Institute charter for DSMBs. This board will be responsible for monitoring the safety and data 
integrity of the trial. It is a DSMB entirely composed of members with no connection to this clinical 
trial. 


31 
12.1 
Multisite Clinical Monitoring Procedures 
This clinical study will be coordinated by the MAGIC Data Coordinating Center (DCC) of 
the Icahn School of Medicine at Mount Sinai. As such it will be conducted in accordance 
with the ethical principles that are consistent with Good Clinical Practices (GCP) and in 
compliance with other applicable regulatory requirements. 
Prior to subject recruitment, a participating site will undergo a site initiation meeting to be 
conducted by the DCC. This will be done as an actual site visit, teleconference, 
videoconference, or web-based meeting after the site has been given access to the study 
database and assembled a study reference binder.  The site’s principal investigator and 
his/her study staff should make every effort in attending the site initiation meeting. Study-
related questions or issues identified during the site initiation meeting will be followed-up 
by the appropriate DCC personnel until they have been answered and resolved. 
This study will be monitored by a representative of the MAGIC Data Coordinating Center. 
Monitoring visits, whether remote or in person, will be made during the conduct of the study 
and at study close-out. The following issues will be monitored. 

Signed and dated ICF

Adherence to the protocol

Completeness and accuracy of study data and laboratory samples collection

Proper storage, dispensing and inventory control of investigational drug

Compliance with state and local regulations
Any issues identified during these visits will be communicated to the site and are expected 
to be corrected by the site in a timely manner.  For review of study-related documents at 
the DCC, the site will be required to ship, fax, or email documents to be reviewed, ensuring 
compliance with HIPAA and other privacy regulations.  
Participating sites will also undergo a site close-out upon completion, termination or 
cancellation of a study to ensure fulfillment of study obligations during the conduct of the 
study, and that the site Investigator is aware of his/her ongoing responsibilities. In general, 
a site close-out is conducted during a site visit; however, site close-out can occur without 
a site visit if all of the following apply: 

No patient has signed the Informed Consent Form and has enrolled into the study

Investigational agent has not been dispensed

All investigational agent and materials have been returned as defined for the study
or destroyed and accounted for properly.
13.0 
QUALITY ASSURANCE AND AUDITS 
The Data Safety Monitoring Board can request a ‘for cause’ audit of the trial if the board identifies 
a need for a more rigorous evaluation of study-related issues. A “for cause” audit would be 
conducted by the Project Manager of the MAGIC Data Coordinating Center. 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during its 
conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the MAGIC Data Coordinating Center that 
such a request has been made. 


32 
14.0 
REFERENCES 
1.
Anasetti C, Logan BR, Lee SJ, et al. Peripheral-blood stem cells versus bone marrow from
unrelated donors. N Engl J Med 2012;367:1487-96.
2.
Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet 2009;373:1550-61.
3.
Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic hematopoietic-cell
transplantation. N Engl J Med 2010;363:2091-101.
4.
Harris AC, Ferrara JL, Levine JE. Advances in predicting acute GVHD. British journal of
haematology 2013;160:288-302.
5.
Jagasia M, Arora M, Flowers ME, et al. Risk factors for acute GVHD and survival after
hematopoietic cell transplantation. Blood 2012;119:296-307.
6.
Finke J, Bethge WA, Schmoor C, et al. Standard graft-versus-host disease prophylaxis with or
without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a
randomised, open-label, multicentre phase 3 trial. The Lancet Oncology 2009;10:855-64.
7.
Nucci M, Andrade F, Vigorito A, et al. Infectious complications in patients randomized to receive
allogeneic bone marrow or peripheral blood transplantation. Transplant infectious disease : an official
journal of the Transplantation Society 2003;5:167-73.
8.
Tomblyn M, Chiller T, Einsele H, et al. Guidelines for preventing infectious complications among
hematopoietic cell transplantation recipients: a global perspective. Biol Blood Marrow Transplant
2009;15:1143-238.
9.
Majhail NS, Chitphakdithai P, Logan B, et al. Significant improvement in survival after unrelated
donor hematopoietic cell transplantation in the recent era. Biol Blood Marrow Transplant 2015;21:142-50.
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15.0 
APPENDICES 


34 
Appendix A: High Risk MAGIC Scoring Manual 
Appendix B: BMT CTN Infection Severity Grading Table 
Appendix C: Suggested Steroid Taper for GVHD