Conditions: Chronic Pancreatitis
Keywords: Islet autotransplantation Alpha1 anti trypsin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 48
Healthy volunteers: no

Brief summary:
Primary objective: To describe and compare the safety and efficacy of treatment with AAT in chronic pancreatitis patients who undergo total pancreatectomy and islet autotransplantation (TP-IAT).

Detailed description:
The goal of this study is to assess whether infusion of Prolastin-C during peri-transplant period can enhance islet autograft survival and function in chronic pancreatitis patients who have total pancreatectomy and islet autotransplantation. This is a prospective, controlled, double-blind study. The primary endpoint will be area under the curve for the serum C-peptide level during the first 4 hours of an mixed meal tolerance test (MMTT), normalized by the number of islet equivalents (IEQ)/kg at day 365±14 after the transplant.

Arms:
arm 1: Subjects will be given Prolastin-C intravenously at 60mg/kg weekly for 4 weeks. arm 2: Subjects will be given Saline weekly for 4 weeks.

Interventions: intervention 1: Prolastin-C intervention 2: Placebo
Intervention descriptions: intervention 1: Patients will receive Prolastin-C at 60mg/kg on day 0, 7, 14, and 21 days of transplantation intervention 2: Patients will receive saline on day 0, 7, 14, and 21 days of transplantation

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 1 of 
38 
 
 
 
AAT in islet autotransplantation 
 
 
 
Alpha-1 Antitrypsin (AAT) Enhances Islet Autograft Survival 
 
Clinical Study protocol 
 
 
Grant #:  
 
 
R01DK105183  
 
Study sponsor:  
 
NIH/NIDDK 
 
IND Number:  
 
Waiver given by FDA 
 
MUSC IRB Number: 
Pro00053906 (version 3) 
 
Activation Date: 
 
12/01/2015 
Last Protocol Update  
05/14/2020 
Accrual Objective:  
48 
Investigational Product: 
Prolastin C (Alpha-1 antitrypsin, AAT) 
 
Objectives/endpoints: To describe and compare the safety and efficacy of treatment with AAT 
in chronic pancreatitis patients who undergo total pancreatectomy and islet autotransplantation 
(TP-IAT).  
 
Study Design: Prospective, randomized, double-blind single-center trial to assess the effects of 
AAT or placebo in 48 adult chronic pancreatitis patients who undergo total pancreatectomy and 
islet autotransplantation.  
 
Treatment Description: Randomly selected chronic pancreatitis patients with TP-IAT will 
receive intravenous infusion of AAT at 60mg/kg/week or placebo weekly for 4 weeks during the 
peri-transplant period.  
Table of Contents 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 2 of 
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AAT in islet autotransplantation 
 
 
1. 
Protocol Synopsis  
 
 
 
 
 
 
        
    5-6 
1.1. Abbreviations   
 
 
 
 
 
 
          
      7 
1.2. Study Definitions 
 
 
 
 
 
 
 
 
      8 
2. 
Background and Rationale 
 
 
 
 
 
 
 
   9-12 
2.1. Background 
 
 
 
 
                                       9-10 
2.1.1. TP-IAT                                                                       9-10 
2.1.2. Alpha-1 antitrypsin                                                              9 
2.1.3. Clinical trials use of AAT for Diseases                                             10 
2.2. Rationale:  
 
 
 
 
 
 
 
 
 
 10-12 
2.2.1. Rationale for selection of patient population                                        10 
2.2.2. Rationale for the selection of dosing regimen                                       10 
2.2.3. Rationale for the selection of administration and infusion rate                         11 
2.2.4. Known and potential risks and benefits to human participants                         11 
2.2.5. General risks 
 
 
 
 
 
 
 
 
    11 
2.2.6. Risks of use of Investigation product 
 
  
 
 
 
    11 
2.2.7. Risks of blood sampling 
 
 
 
 
 
 
 
    12 
2.2.8. Other study-related procedures 
 
 
 
 
 
 
    12 
2.3. Potential benefits 
 
 
 
 
 
 
 
 
    12 
2.3.1. Benefits to TP-IAT patients 
 
 
 
 
 
 
    12 
2.3.2. Benefits to society  
 
 
 
 
 
 
 
    12 
3. Overall study design and plan description 
 
 
 
 
 
 
 13-15  
3.1. Study design  
 
 
 
 
 
 
 
 
    13 
3.2. Study time table  
 
 
 
 
 
 
 
 
    13 
3.3. End of study 
 
 
 
 
 
 
 
 
 
    13 
3.4. Study objective  
 
 
 
 
 
 
 
 
    13 
3.5. Study endpoints 
 
 
 
 
 
 
 
 
    13 
3.5.1. Primary endpoints 
 
 
 
 
 
 
 
    13 
3.5.2. Secondary endpoints 
 
 
 
 
 
 
 
    14 
3.5.3. Exploratory endpoints 
 
 
 
 
 
 
 
    14 
3.5.4. Safety endpoints  
 
 
 
 
 
 
 
    14 
3.5.5. Pharmacokinetics endpoints 
 
 
 
 
 
 
    15 
4. Study population 
 
 
 
 
 
 
 
 
 
    16 
4.1. Inclusion criteria 
 
 
 
 
 
 
 
 
    16 
4.2. Exclusion criteria  
 
 
 
 
 
 
 
    16 
4.3. Assignment of patient number 
 
 
 
 
                  16 
5. Investigational product  
 
                                        
 
17-19 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 3 of 
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AAT in islet autotransplantation 
 
 
5.1. Investigational Product  
 
 
 
 
 
 
 
17-19 
5.1.1. Prolastin-C 
 
 
 
 
 
 
 
 
17 
5.1.2. Placebo  
 
 
 
 
 
 
 
 
17 
5.2. Formulation, dosing, administration and emergency precautions  
 
 
17 
5.3. Drug accountability 
 
 
 
 
 
 
 
 
18 
5.4. Criteria for schedule adjustment, dose modification, discontinuation 
 
 
18 
5.4.1. Dose adjustment, and modification 
 
 
 
 
 
18 
5.4.2. Criteria for discontinuation of investigational product  
 
 
 
18 
5.5. Study stopping rules 
 
 
 
 
 
 
 
 
18-19 
6. Study procedure and assessments  
 
 
 
 
 
 
20-23 
6.1. Hospital stay 
 
 
 
 
 
 
 
 
 
20 
6.1.1. Patient recruitment, blinding and randomization  
 
 
 
 
20 
6.1.2. Infusion of the investigational product 
 
 
 
 
 
20 
6.2. Drug administration post hospital stay  
 
 
 
 
 
21 
6.3. Post-operative assessments 
 
 
 
 
 
 
 
21 
6.3.1. IBMIR  
 
 
 
 
 
 
 
 
 
21 
6.3.2. Chemokines/cytokines 
 
 
 
 
 
 
 
21 
6.3.3. Plasma levels of AAT 
 
 
 
 
 
 
 
21 
6.3.4. Safety laboratory tests 
 
 
 
 
 
 
 
22 
6.3.5. Vital signs  
 
 
 
 
 
 
 
 
22 
6.4. Follow-up visits 
 
 
 
 
 
 
 
 
22-22 
6.4.1. Mixed meal tolerance test  
 
 
 
 
 
 
22-23 
7. Safety monitoring 
 
 
 
 
 
 
 
 
 
24-26  
7.1. Definitions 
 
 
 
 
 
 
 
 
 
24 
 
7.1.1. Definition of adverse events  
 
 
 
 
 
 
24 
7.1.2. Definition of serious adverse events 
 
 
 
 
 
24  
7.1.3. Evaluation of adverse events     
 
 
 
 
 
25 
7.2. Procedures for Recording and Reporting Adverse Events 
 
 
 
25  
7.2.1. Procedures for Recording and Reporting Adverse Events  
 
 
26 
7.2.2. Special Reporting Situations                  
 
 
 
 
26 
7.3 Data safety monitoring board   
 
 
 
 
 
 
26 
8. Statistical analysis 
 
 
 
 
 
 
 
 
 
27-31 
8.1. Statistical analysis and statistical reports  
 
 
 
 
 
27 
8.2. Analysis population 
 
 
 
 
 
 
 
 
27 
8.2.1. 
Modified intent-to-treat population  
 
 
 
 
 
27 
8.2.2. 
Per-protocol population  
 
 
 
 
 
 
27 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 4 of 
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AAT in islet autotransplantation 
 
 
8.2.3. 
Safety population  
 
 
 
 
 
 
 
27 
8.3. Sample size justification  
 
 
 
 
 
 
 
27 
8.4. Randomization  
 
 
 
 
 
 
 
 
28 
8.5. Blinding  
 
 
 
 
 
 
 
 
 
28 
8.6. Missing data    
 
 
 
 
 
 
 
 
29 
8.7. Assessment time window   
 
 
 
 
 
 
 
29 
8.8. Descriptive analyses    
 
 
 
 
 
 
 
29 
8.9. Efficacy analyses  
 
 
 
 
 
 
 
 
30 
8.10. Safety analyses   
 
 
 
 
 
 
 
 
30 
8.11. Secondary efficacy analyses   
 
 
 
 
 
 
30  
8.12. Mechanistic analysis  
 
 
 
 
 
 
 
31  
9. Quality control and quality assurance 
 
 
 
 
 
 
32 
10. Protocol deviations/amendments 
 
 
 
 
 
 
 
33 
11. Direct access to source data/documents 
 
 
 
 
 
 
34 
12. Ethical consideration and compliance with good clinical practice 
 
 
 
35 
12.1. Statement of compliance   
 
 
 
 
 
 
 
35 
12.2. Informed consent   
 
 
 
 
 
 
 
 
35 
12.3. Privacy and confidentially  
 
 
 
 
 
 
 
35 
13. Publication Policy    
 
 
 
 
 
 
 
 
36 
14. References   
 
 
 
 
 
 
 
 
 
37 
15. Appendix 1: Study timeline                                                           38 
16. Appendix 2: Study contacts                                                           39 
 
 
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 5 of 
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AAT in islet autotransplantation 
 
 
1.1. 
PROTOCOL SYNOPOSIS  
Study Sponsor 
NIH/NIDDK 
 
Investigational 
Product 
Alpha-1 antitryspin (AAT) 
Indication 
Patients with chronic pancreatitis  
Title of Study 
AAT Enhances Islet Autograft Survival 
 
Protocol Date 
12/01/15 
 
 
OBJECTIVES 
Primary objective: To describe and compare the safety and efficacy of treatment with AAT in 
chronic pancreatitis patients who undergo total pancreatectomy and islet autotransplantation 
(TP-IAT). 
 
METHODOLOGY 
Study Design 
Prospective, controlled, double-blind 
Treatments 
Recipients will receive AAT before and post islet transplantation  
Treatment 
Duration 
Recipients will receive a total of 4 weekly infusions of AAT or placebo. 
Study 
Drug 
and 
Formulation 
Prolastin-C (Grifols) 
Dose and Route of 
Administration 
• 
AAT         60 mg/kg (IV) 
• 
Placebo-      0.9 % sodium chloride (IV). 
 
The first dose will be given on the day of islet transplantation before 
total pancreatectomy (D0), and then on days 7, 14, and 21 days of islet 
transplantation. 
Number Planned 
48 
Major Inclusion 
Criteria 
• 
Patients 
scheduled 
for 
total 
pancreactectomy 
and 
islet 
autotransplantation 
• 
Age > 18 years 
• 
Diabetes free before surgery 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 6 of 
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AAT in islet autotransplantation 
 
 
Exclusion Criteria 
• 
Patients who are under immunosuppression 
• 
Patients who have had puestow or frey pancreatic surgery 
• 
Patients who have Immunoglobulin A (IgA) deficiency, known 
antibodies against IgA, or individuals with a history of severe 
immediate hypersensitivity reactions, including anaphylaxis to 
Alpha1-proteinase inhibitor products (allergic to AAT) 
 
Safety  
 
• 
Physical examination, hematology, serum chemistry, urinalysis, 
vital signs, adverse event (AE) monitoring, and concomitant 
medications. 
Efficacy 
Efficacy of AAT therapy during peri-transplant period in chronic 
pancreatitis patients who undergo TP-IAT as assessed through islet 
function, onset of diabetes, glycemic control, pain relief and quality of 
life measurements. 
 
ENDPOINTS 
Primary Endpoint 
Area under the curve for the serum C-peptide level during the first 4 
hours of an mixed meal tolerance test (MMTT), normalized by the 
number of islet equivalents (IEQ)/kg at day 365±14 after the transplant. 
Secondary 
Endpoints 
• 
Proportion of insulin-independent patients following IAT 
• 
Average daily insulin requirement. 
• 
β cell function as assessed by β-score. 
• 
Quality of life as measured by SF-12 questionnaire. 
 
Measurements will be performed at 365±14 days post-transplantation. 
 
Exploratory 
Endpoints 
• 
Measurements of primary and secondary endpoints at 75±14 day 
• 
Immediate blood mediated inflammatory response 
• 
Expression of chemokines/cytokines expression in serum  
• 
Genomic DNA analysis  
• 
RNAseq analysis of gene expression profiles in peripheral blood 
mononuclear cells post transplantation 
 
STATISTICAL METHODS AND ANALYSIS 
 
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 7 of 
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AAT in islet autotransplantation 
 
 
1.2. 
Abbreviations: 
 
AAT:   
Alpha-1 antitrypsin 
AE 
 
Adverse Event 
CP:  
 
Chronic pancreatitis 
CRF:  
Case report form 
CP:  
 
Chronic pancreatitis 
CFR:  
Code of Federal Regulations 
cGMP:  
Current good manufacture practices 
CRF 
 
Case Report Form 
CTCAE 
Common Terminology Criteria for Advance Event 
DSMB  
Data and Safety Monitoring Board 
GLMM 
Generalized Linear Mixed Model 
HbA1c: 
Glycosylated hemoglobin 
HR-QOL 
Health-Related Quality of Life 
LOCF  
Last Observation Carried Forward 
IEQ: 
 
Islet equivalent number 
IBMIR: 
Immediate blood mediated inflammatory response 
IV: 
 
intravenously 
Kg: 
 
Kilogram  
MMTT: 
Mixed meal tolerance test 
mITT  
Modified Intention-to-Treat 
MSM  
Medical Safety Monitor 
PAG  
Physician’s Global Assessment 
PBMCs:  
Peripheral blood mononuclear cells 
PP 
 
Per-Protocol 
QOL:  
Quality of Life 
SAE:  
Serious Adverse Event 
SOC  
Standard of Care 
SP 
 
Safety Population 
T1D:  
Type 1 diabetes 
TP-IAT 
Total Pancreatectomy and Islet Autotransplantation 
 
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 8 of 
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AAT in islet autotransplantation 
 
 
1.3. Study Definitions: 
 
Insulin-independence: is defined as free of exogenous insulin for 14 or more consecutive days, 
with adequate glycemic control as defined by: (1) A glycated hemoglobin (HbA1c) level < 6.5%, 
(2) Fasting blood glucose < 126 mg/dl more than 3 times in the past week based on a minimum 
of once daily measurement. (3) 2-hour post-prandial blood glucose does not exceed 180mg/dl 
more than 4 times in the past week,  (4) A laboratory fasting glucose in the non-diabetic range 
(< 126 mg/dl), and at least one MMTT fasting or stimulated c-peptide ≥ 0.5ng/ml 
 
Insulin dependent: Subjects who do not meet the criteria for insulin independent. 
 
Adverse events (AE): According to the International Conference on Harmonization (ICH) 
Guidelines (Federal Register.19995;60 (40):11285), an AE is defined as follows: An AE is any 
untoward medical occurrence in a subject administered an investigational drug that does not 
necessarily have a causal relationship with the treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of the investigational product whether or not related to 
the investigational product. An AE is any sign, symptom, or diagnosis that appears or changes in 
intensity during the course of the study. An AE may be an intercurrent illness or an injury that 
impairs the well-being of the subject. 
 
Severe hypoglycemia: Severe hypoglycemia is an event with one of the following symptoms: 
memory loss; confusion; uncontrollable behavior; irrational behavior; unusual difficulty in 
awakening; suspected seizure; seizure; loss of consciousness; or visual symptoms, in which the 
subject was unable to treat him/herself and which was associated with either a blood glucose 
level < 54 mg/dL or prompt recovery after oral carbohydrate, IV glucose, or glucagon 
administration. 
 
 
 
 
 
 
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 9 of 
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AAT in islet autotransplantation 
 
 
2. 
BACKGROUND AND RATIONALE: 
 
2.1. BACKGROUND: 
 
2.1.1. Total Pancreatectomy and islet autotransplantation (TP-IAT):  
Chronic pancreatitis (CP) is a disease in which long-standing inflammation of the pancreas alters 
the normal structure and function (1). Approximately 15,000 Americans are diagnosed with CP 
each year. Recurrent bouts of pancreatitis result in inflammation, scarring, and blockage of the 
pancreatic ducts. These effects produce chronic pain that is difficult to control with medications. 
TP-IAT is currently being performed in around 20 centers worldwide and can effectively 
increase patients’ quality of life and ameliorate post-operative diabetes in well-selected CP 
patients. A major hurdle in this procedure is that less than 30% of patients return to an insulin-
independent state after TP-IAT, compared to a >85% diabetes-free rate before surgery. 
Compromised islet function is caused by pre-operative loss of beta cell mass from long-term 
inflammation within the diseased pancreas, but also by dramatic stress-induced islet cell death 
during harvest and post transplantation. Currently, no interventional protocols are in place to 
improve islet autograft survival and function in TP-IAT patients. Our long-term clinical research 
goal is to apply effective therapies that can facilitate islet cell survival and function to benefit 
patient care. These therapies are not only urgently needed for the prevention of post-surgical 
diabetes in CP patients, but can potentially serve as a powerful platform on which to investigate 
strategies for allogeneic islet cell transplantation for patients with T1D.  
 
2.1.2. Alpha-1 antitrypsin (AAT)  
AAT is a serine protease inhibitor that belongs to the serpin family. It has a high concentration in 
serum, and is available for clinical use as an affinity-purified human product (2). AAT inhibits 
various enzymes including neutrophil elastase, cathepsin G, proteinase-3, thrombin, trypsin, and 
chymotrypsin (3). Patients with a genetic deficiency in AAT exhibit 15-60% lower circulating 
AAT levels than normal and are prone to develop pulmonary emphysema (4). Besides inhibition 
of neutrophil elastase, AAT exerts anti-inflammatory effects via suppressing cytokine 
production, complement activation, and immune cell infiltration. AAT also functions as an anti-
apoptotic factor for endothelial cells and vascular smooth muscle cells (5,6). AAT induces 
vascular endothelial growth factor (VEGF) expression and release, protects VEGF from 
proteolytic cleavage by elastase, promotes viability of endothelial cells, and enhances migration 
of myocytes. Recent studies indicated that AAT had profound beneficial effects in the treatment 
of diabetes. AAT protects β cells from apoptosis induced by pro-inflammatory cytokines and 
streptozotocin (7). A single injection of AAT to NOD mice reduced the intensity of insulitis, 
increased β cell mass, promoted β cell regeneration, and prevented the onset of diabetes via 
modulating T regulatory cells (8,9). AAT has been shown to protect islets from graft failure and 
immune rejection in mouse transplantation models with readily vascularized islet grafts (10,11). 
Adding AAT into ductal injection solution and collagenase solution improved porcine islet 
isolation by inhibiting trypsin activity during pancreas digestion (12). AAT monotherapy 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 10 of 
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AAT in islet autotransplantation 
 
 
elevates VEGF expression levels in islet allograft and prolongs islet allograft survival in mice via 
enhancement of intraislet VEGF expression and promotion of islet revascularization (11).  
 
A recent study published by Koulmanda and colleagues demonstrated that AAT treatment 
improved survival of islets after partial pancreatectomy and intrahepatic autologous islet 
transplantation in non-human primates (13). Thus, the beneficial effects of AAT in the islet 
transplantation setting may be mediated by its anti-apoptotic and anti-inflammatory properties 
and promotion of islet revascularization.  
 
2.1.3. Clinical trials use of AAT for diseases: 
 
Several clinical trials have been performed evaluating the effects of AAT in new onset diabetes. 
One trial entitled “A research trial of Aralast in new onset diabetes (RETAIN)”, gave patients 
with new onset T1D AAT (Aralast NP) at 45mg/kg by intravenous infusion once a week for 6 
weeks, and then a 3 week wash out, followed by a high dose of AAT at 90mg/kg for the next 6 
weeks, with a total of 12 infusions. Data from this trial has yet to be published.  
 
In another phase 1 open label trial in 12 new onset T1D patients treated with 80mg/kg of AAT 
weekly for 8 weeks, AAT led to increased, unchanged, or moderately reduced levels of C-
peptide responses compared with baseline in 5 patients. No control group is available for 
comparison. In addition, mechanistic analyses revealed reduced levels of toll-like receptor-
induced interlukin-1β expression in monocytes and dendritic cells at 12 months post AAT 
treatment (14).  
Most importantly, AAT has been used for the treatment of emphysema for more than 25 years 
with a remarkable record of safety (15), therefore it is an ideal candidate to be used in the islet 
transplantation setting to improve the efficacy of clinical islet transplantation. 
 
2.2. RATIONALE: 
 
2.2.1. Rationale for Selection of patient population: 
Although the beneficial effects of AAT have been demonstrated in rodents and non-human 
primate islet transplantation models, its potential therapeutic effect has not been evaluated in 
patients with islet transplantation. We designed this randomized, double-blind, placebo control 
study to assess the safety and efficacy of 60 mg/kg of weekly IV injection of AAT in subjects 
with autologous islet transplantation. Unlike patients with type 1 diabetes, there is no recurrence 
of autoimmunity and immune rejection response in patients receiving autologous islets. 
Therefore, it is a suitable disease model to evaluate the protective effect of AAT to transplanted 
islets. 
 
2.2.2. Rationale for the Selection of Dosing Regimen 
AAT (Prolastin-C, Grifols) used in the current trial has been given a waiver for IND by the FDA. 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 11 of 
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AAT in islet autotransplantation 
 
 
Prolastin-C is indicated for chronic augmentation and maintenance therapy in adults with 
clinically evident emphysema due to severe congenital deficiency of AAT. The dosing regimen 
of Prolastin-C chosen for this study, 60 mg/kg given intravenously once per week, is the standard 
FDA-approved dosing regimen for emphysema, and is identical to other plasma-derived AAT 
products in the same class. At this dosage, Prolastin-C has been demonstrated to be safe and well 
tolerated in subjects with congenital AAT-deficiency, and was shown to increase and maintain 
circulating trough antigenic and functional AAT levels to 14.7 μM (median; range: 11.6-18.5 
μM) and 11.9 μM (median; range: 8.2-16.9 μM), respectively (see Prolastin-c package insert).  
 
2.2.3. Rationale for the Selection of Route of Administration and Infusion Rate 
The route of administration (intravenous infusion), as well as the infusion rate (0.08ml/kg/min), 
selected for this study are in accordance with the FDA-approved package insert. 
 
2.3. KNOWN AND POTENTIAL RISKS AND BENEFITS TO HUMAN PARTICIPANTS 
 
2.3.1. General risks 
Transplantation of islets is associated with several potential risks. These are intrinsic to the 
procedure and may result from the intrahepatic islet infusion as well as testing involved in the 
care and evaluation of transplanted subjects. All patients receiving TP-IAT are at risk of 
complication regardless of study participation.  
 
2.3.2. Risks of use of Investigation product: Prolastin-C 
Because clinical studies for Prolastin-C are conducted under widely varying conditions, adverse 
reaction rates observed cannot be directly compared to rates in other clinical trials and may not 
reflect the rates observed in practice. According to the Prolastin-C package insert, the most 
serious adverse reaction observed during clinical studies with Prolastin-C was an abdominal and 
extremity rash in one subject. The rash resolved subsequent to outpatient treatment with 
antihistamines and steroids. Two instances of a less severe, pruritic abdominal rash were 
observed upon re-challenge despite continued antihistamine and steroid treatment, which led to 
withdrawal of the subject from the trial.  
 
The most common drug-related adverse reactions observed at a rate of > 1% in subjects 
receiving Prolastin-C were chills, malaise, headache, rash, hot flush and pruritus. Adverse 
reactions considered drug related by the investigators occurring in 1.6% of subjects (one subject 
each) treated with Prolastin-C were malaise, headache, rash, hot flush, and pruritus. Drug related 
chills occurred in 3.2% (2 subjects) of Prolastin-C subjects.  
 
Products made from human plasma may carry a risk of transmitting infectious agents, e.g., 
viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. In each of 2 randomized, 
double-blind studies in which the predecessor product, PROLASTIN® (Alpha1-Proteinase 
Inhibitor [Human]), was compared to other AAT products, there was a single case of parvovirus 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 12 of 
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AAT in islet autotransplantation 
 
 
B19 seroconversion in the Prolastin-C arms of each trial. In each case, it could not be determined 
whether parvovirus had been acquired from Prolastin-C or from the community. However, 
during clinical studies with Prolastin-C, there were no reported treatment emergent cases of 
hepatitis B, hepatitis C, HIV or parvovirus B19 viral infections. Furthermore, the Prolastin-C 
process incorporates additional plasma safety and virus reduction measures that minimize the 
residual risk of virus transmission. Risk for placebo: patient may not be receiving a therapy as 
good as the alternative arm of the study. There is no other risk to placebo infusion at the dose 
provided. 
2.3.3 Risks of blood sampling 
In addition to the routine blood sampling, participation in the study will require an amount of 
blood higher than routine sampling at some time points, so that biomarkers of inflammation, 
chemokine/cytokines, and RNA expression can be measured. The risks of drawing blood include 
temporary discomfort from the needle stick, bruising and infection. Fainting could occur. 
 
2.3.4. Other study related procedures 
All other procedures including islet transplantation, c-peptide, and glucose testing are part of 
standard patient care and would be performed regardless of study participation.  
 
2.4. POTENTIAL BENEFIT 
 
2.4.1. Benefits to TP-IAT patients 
There is no proven benefit to participants by entering this clinical trial. It is hoped that AAT 
treatment participants will have improved graft survival; however, this remains to be shown.   
 
2.4.2. Benefits to society 
This study may identify a useful medication that will benefit patients with islet transplantation. 
 
 
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 13 of 
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AAT in islet autotransplantation 
 
 
3. 
OVERALL STUDY DESIGN AND PLAN DESCRIPTION: 
 
3.1. 
STUDY DESIGN: 
 
Experimental design: We propose to enroll a total of 48 CP patients who are scheduled for TP-
IAT. This will be a 2:1 randomized, double blind, controlled study in which 32 patients receive 
islet cell transplantation together with intravenous AAT 60 mg/kg/week for 4 weeks, and 16 
patients receive islets with intravenous 0.9% saline control in equivalent volume.  
 
CP patients planning TP-IAT will receive an IRB approved consent form that describes the 
research study. Following signed consent, they will be enrolled and receive a baseline study visit. 
On the day of TP-IAT, an intravenous injection of AAT at the FDA approved dose of 60mg/kg 
or 0.9% normal saline will be infused before surgery. The autologous islet transplantation 
procedures will remain as routinely performed at MUSC. On the day of transplantation, the 
pancreas will be harvested and transferred to the Center for Cellular Therapy (CCT). Islets will 
be isolated and transplanted back to the patient via portal vein infusion. AAT or placebo will be 
given on day 0, 7, 14 and 21 days of islet transplantation. 
 
3.2. 
STUDY TIME TABLE 
 
Planned patients are expected to be recruited in a 36-month period. A follow-up of 12 months is 
planned for each patient. The overall timelines are as below: 
 
• 
Projected starting data (first-patient-in):  
 
 
 
June 1, 2016 
• 
Projected completion of patient accrual (last-patient-in):   
May 31, 2019 
• 
Projected study end date: 
 
 
 
 
 
May 31, 2020 
 
3.3. 
END OF STUDY 
 
For this trial, end of the study is defined as the date of the last visit of the last patient. 
 
3.4. 
STUDY OBJECTIVE 
 
The objective of this clinical trial is to describe and compare the safety and efficacy of treatment 
with AAT in chronic pancreatitis patients who undergo TP-IAT.  
 
3.5. 
STUDY ENDPOINTS: 
 
3.5.1. Primary endpoint: 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 14 of 
38 
 
 
 
AAT in islet autotransplantation 
 
 
The primary endpoint will be Area under the curve for the serum C-peptide level during the first 
4 hours of an mixed meal tolerance test (MMTT), normalized by the number of islet equivalents 
(IEQ)/kg at day 365±14 after islet transplant. 
3.5.2. Secondary endpoints (measurements will done at 365±14 days post-transplantation): 
• 
Proportion of insulin-independent patients following IAT. 
• 
Average daily insulin requirement. 
• 
β cell function as assessed by β-score. 
 
3.5.3. Exploratory endpoints 
 
• 
Measurements of primary and secondary endpoints at day 75±14. 
• 
Time course of instant blood mediated inflammatory reaction as measured by 
thrombin-anti-thrombin (TAT), C5a and c-peptide levels before, in the middle and 
after initiation of islet infusion, and 3h post islet infusion.   
• 
Time course of inflammatory chemokines/cytokines as assessed by serum level of 
CXCL8, CCL2 (MCP-1), CCL3, CCL4, CXCL10 (IP-10), CXCL9 (MIG), IL-6, 
IL-10, INF-γ, TNF-α, and IL-1β [pre-infusion, and 24, 72 and 168hrs, and day 14, 
and 21 after the end of islet infusion]. 
• 
Basal to 240 min time course of glucose, and C-peptide derived from the MMTT 
(day 75±14 to day 365±14). 
• 
The proportion of patients with an HbA1c ≤6.5% (day 365±14 days post-
transplant only) 
• 
Cumulative number of severe hypoglycemia events.  
• 
The proportion of patients with an HbA1c ≤6.5% at day 365±14 AND are free of 
severe hypoglycemic events from day 75±14 to day 365±14 inclusive. 
• 
Daily oral Morphine Equivalents on day prior to visit (day 75±14 to day 365±14). 
• 
Proportion of patients remaining on narcotics (day 75±14 to day 365±14). 
• 
RNA expression profile in peripheral blood mononuclear cells (PBMCs) at 168 h 
post transplantation. RNA analysis will be done in at least 10 patients to guarantee 
post-treatment sampling in at least 3-4 patients randomized to AAT and 3-4 to 
control. 
• 
SF-12 Quality of Life score 
 
3.5.4. Safety endpoints: 
• 
Incidence and severity of Adverse Events and Serious Adverse Events 
• 
Standard laboratory tests including hematology (hematocrit, hemoglobin, red 
blood cells, platelets, white blood cells, differential white blood cell count), 
clinical chemistry (sodium, potassium, serum creatinine, blood urea nitrogen, total 
bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and 
coagulation (International Normalized Ratio (INR), partial thromboplastin time 
(PTT)), at pre-transplant hospital admission and post-transplant hospital 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 15 of 
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discharge]. 
• 
Vital signs, i.e. blood pressure (BP) and heart rate (HR) at pre-transplant hospital 
admission and post-transplant hospital discharge. ALT/AST, INR/PTT  
• 
Weight loss from pre-transplant value [time frame: day 75+14 and 365±14 after 
the transplant] 
• 
Serum level of albumin and pre-albumin (absolute and change from pre-transplant 
value) [time frame: day 75±14 and 365±14 after the transplant]. 
• 
Proportion of patients falling into one of the following levels of steatorrhea 
severity [time frame: day 75±14 and 365±14 after the transplant];  
 
1. No steatorrhea;  
 
2. Steatorrhea few times per week;  
 
3. Steatorrhea daily;  
 
4. Stool incontinence. 
• 
Proportion of patients falling into one of the following malnutrition risk levels 
(poor prognosis, significant risk, increased risk, normal) according to pre-albumin 
level [time frame: day 75±14 and 365±14 after the transplant]. 
• 
Cumulative number of episodes of documented hypoglycemia (documented 
symptomatic; asymptomatic) [time frame: from day 75±14 to day 365±14 after 
the transplant]. 
• 
Cumulative number of diabetic ketoacidosis-related events [time frame: from day 
75±14 to day 365±14 after the transplant]. 
 
 
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 16 of 
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4. 
STUDY POPULATION 
 
CP patients scheduled for TP-IAT will be enrolled in this study. Our recruitment goal is to reach 
a total of 48 patients, each randomized to receive either standard of care (SOC) plus placebo or 
SOC with AAT after consent.  
 
4.1. Inclusion criteria 
 
• 
Patients scheduled for total pancreactectomy and islet autotransplantation 
• 
Age ≥ 18 years 
• 
Diabetes free before surgery 
 
4.2. 
Exclusion criteria 
 
• 
Patients who are under immunosuppression (eg. more than 5 mg prednisone use of 
another immunosupressive drug including but not limited to methotrexate, cyclosporine, 
tacrolimus, azathoprine, sirolimus, or rituxan). 
• 
Patients who have had puestow or frey pancreatic surgery 
• 
Patients who have Immunoglobulin A (IgA) deficiency, known antibodies against IgA, or 
individuals with a history of severe immediate hypersensitivity reactions, including 
anaphylaxis to Alpha1-proteinase inhibitor products (allergic to AAT) 
 
4.3. 
Assignment of patient number 
 
Once patient is determined eligible for the study, and randomized into a group, they will be 
assigned a unique number for the study. This patient is then evaluable under intention to treat 
analysis as defined in the statistical plan.  
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 17 of 
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5. INVESTIGATIONAL PRODUCT  
 
5.1. Investigational product:  
 
5.1.1. Prolastin-C (Grifols) is human alpha-1 proteinase inhibitor (AAT) that is indicated for 
chronic augmentation and maintenance therapy in adults with emphysema due to deficiency of 
alpha1-proteinase inhibitor. Prolastin-C is approved in the US, Canada, Columbia, and Argentina 
for 60 mg/kg weekly IV administration for augmentation therapy in patients with severe AATD 
and clinically evident emphysema. It is a sterile, stable, lyophilized preparation of purified 
human protein inhibitor. Prolastin-C is prepared from pooled human plasma from healthy donors 
by modification and refinements of the Cohn cold ethanol plasma fractionation technique 
followed by a purification process. Prolastin-C contains small amounts of other plasma proteins, 
which may include IgA, haptoglobin, alpha1-acid glycoprotein, lipoprotein A-1, and albumin. 
Reconstituted Prolastin-C contains no preservatives, has a pH of 6.6 to 7.4, and is to be 
administered by the IV route. 
 
5.1.2 Placebo 
Placebo used in this study will be 0.9% Sodium Chloride for Injection, USP. 
 
5.2. 
FORMULATION, 
DOSING, 
ADMINISTRATION 
AND 
EMERGENCY 
PRECAUTIONS 
 
Prolastin-C is commercially available, and packed as a lyophilized powder and is ready to use 
after reconstitution with dilute (sterile water) that comes with the drug. Each pack contains 
1000mg of AAT, and 20ml of dilutant. Both Prolastin-C and the dilutant should be stored at 
temperature not to exceed 25 (77 ° F). Reconstituted product from several vials may be pooled 
into an empty, sterile IV solution container by using aseptic technique. All the materials will 
have trial specific labels. The reconstitution should be used within 3 hours. The dosing will be 
administered at a rate of approximately 0.08ml/kg/min. The 60mg/kg dose takes approximately 
15-30 minutes to infuse. If assigned to the placebo group, saline will be infused at the same 
volume and speed. 
 
Each patient will receive 60mg/kg body weight if assigned in the AAT group. The first dose will 
be calculated based on the recipient’s body weight during admission for transplant. The 
subsequent doses will be calculated based on the body weight recorded at study entry. The final 
dose for infusion will be rounded to the nearest whole vial dose, but must be within 10% of 
calculated dose.   
 
The first infusion of the Investigational Product will start on the day of islet transplantation. 
Patient will receive 4 weekly doses of AAT or saline 7 ± 3 days apart.  
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 18 of 
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The Investigational Product will be dispensed only by a qualified individual. Vital signs will be 
recorded within 30 minutes before the infusion, during infusion and 15 minutes after infusion. 
With each infusion, medical personnel will be available to treat subjects who experience 
difficulties. Emergency treatment such as 0.3ml to 0.5ml aqueous epinephrine (1:1000 dilution) 
subcutaneously and other resuscitative measure including oxygen, IV fluids, antihistamines, 
corticosteroids, vasopressors, and airway management, will be available in the infusion suite. 
 
5.3. DRUG ACCOUNTABILITY  
 
Under Title 21 of the Code of Federal Regulation (21CFR{312.62 Investigator recordkeeping 
and record retention.), an investigator is required to maintain adequate records of the drug 
preparation and disposition, and maintain adequate and accurate case histories that record all 
observations and other data pertinent to the investigation.  
 
Records for receipt, storage, use and disposition will be maintained by the unblinded study 
coordinator. A drug dispersement log including the identification of each subject, date and 
quantity of drug used will be kept current for each subject. Any drug accidentally or deliberately 
destroyed will be recorded as well.  
 
5.4. 
CRITERIA 
FOR 
SCHEDULE 
ADJUSTMENT, 
DOSE–MODIFICATION, 
DISCONTINUATION OF INVESTIGATIONAL DRUG.  
 
5.4.1. No schedule adjustment and/or dose modification is foreseen, except for discontinuation of 
drug as detailed below: 
 
5.4.2. Criteria for discontinuation of Investigational Product 
 
Any subject may voluntarily withdraw (ie, reduce the degree of participation in the study) 
consent for continued participation and data collection. The reason for withdrawal will be 
recorded on the appropriate CRF. Patients who discontinue the treatment with the investigational 
drug will not be withdraw from the study by default, but will complete observations as per the 
protocol, unless otherwise they withdraw their consent.  
 
Discontinuation (ie, complete withdrawal from study participation) may be due to dropout (ie, 
active discontinuation by subject) or loss to follow-up (ie, discontinuation by subject without 
notice or action), or death. Additionally, the investigator and sponsor have the discretion to 
discontinue any subject from the study if, in their judgment, continued participation would pose 
an unacceptable risk for the subject. Subjects meeting the definition for intent-to-treat who are 
prematurely terminated from study treatment will not be replaced.  
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 19 of 
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5.5. STUDY STOPPING RULES 
 
Study enrollment will be suspended pending review of all pertinent data by the institutional 
review board (IRB), and the Data Safety Monitoring Board (DSMB), if any of the following 
occurs: 
• 
Any unexpected fatal or life-threatening AE possibly related to the use of the 
Investigational drug. 
• 
Any event(s) the protocol chair determines will require full DSMB review. 
• 
The DSMB recommends termination of protocol enrollment based on review of the data 
and evidence that such action is necessary.  
 
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 20 of 
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6. 
STUDY PROCEDURE AND ASSESSMENTS: 
 
6.1. 
HOSPITAL STAY 
 
6.1.1. Patient recruitment, blinding and randomization 
Subjects will be recruited from the clinical offices of Drs. David B Adams and Katherine A 
Morgan during their routine preoperative evaluation for pancreas resection and islet 
transplantation. During their preoperative evaluation, the purpose of the study and the associated 
consent form will be explained in detail and the participant will be given time to ask questions. If 
the subject wishes to participate, the proper consent and HIPAA forms will be signed and dated. 
The consent form may be signed in person in a clinic or via telehealth using an 
eConsent/doxy.me. On the doxy.me platform the study participant has the ability to download a 
copy of the signed consent for their record. They will be informed of this and encouraged to 
download their copy by the study team member who is obtaining consent. The virtual visit video 
chat feature of this platform allows for questions from the patient to be answered in real time by 
the study team. The study team member obtaining consent will also have the ability to review the 
HIPAA authorization form with the patient and obtain a signature through the doxy.me platform. 
A copy of the signed consent form will accompany the patient to the operating room for 
documentation of participation in the study. 
 
Consented patients will be screened based on inclusion and exclusion criteria. If patient meets 
the criteria, they will be randomized to either AAT or control group by block randomization. The 
PI (Wang) and the clinical PIs (Morgan, Adams, Strange, Luttrell) of this study will be blinded 
for the assignment of the study treatment. The Investigational Pharmacy at MUSC will prepare 
drug infusions using aseptic technique under a sterile hood. In the clinic, a trained RN will infuse 
the drug and monitor for side effects of AAT, These individuals will not be blinded.  
Diabetes care will be managed by the Endocrinology team at MUSC led by Dr. Louis Luttrell, 
co-investigator of our trial. The diabetes care is standardized while in the hospital with insulin 
drip for all patients post-operatively.  The drip is then weaned over the first few days with care 
individualized by the hospital diabetes management team. The discharge plan is then 
individualized in accordance with ADA standards. 
The required lab tests for the study include an IgA level and the MMTT at time 75 and 365 
days. There are no imaging screening tests required for this study. It is noted that many of the 
safety laboratories will be the same laboratory assesssments as are used for the usual surgical 
care.  
One basal serum sample will be collected prior the first infusion of study drug (AAT or normal 
saline) and be stored for pre-transplant chemokines/cytokines. The basal sample will be obtained 
before surgery. 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 21 of 
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6.1.2 Infusion of the Investigational Product 
Infusion of AAT will start on the day of islet transplantation before anesthesia and 
pancreatectomy, which is approximately 6-8 hours before islet infusion. The clinical PIs, Drs. 
Morgan and Strange, will identify the time to start the study drug infusion. Starting and ending 
time of drug administration, amount of drug infused, and infusion rate will be recorded for each 
subject. On Average, TP-IAT patients stay in the hospital for 7-28 days after islet 
transplantation. If they stay till 21 days post transplantation, they can have all four AAT 
injections in the hospital. If they are discharged earlier, patients will be requested to return to 
MUSC for additional drug infusion(s). A nurse will administer the AAT or placebo infusion to 
the patient while in the hospital. A nurse in the GI surgery clinic or SCTR outpatient clinic will 
administer AAT or placebo to patients discharged but returning for one of the weekly visits. The 
nurses infusing these drugs will be trained on the day of administration concerning the few 
known side effects of AAT and rate of infusion.  
 
6.2. 
DRUG ADMINISTRATION POST HOSPITAL STAY  
 
In the case when patient is discharged before completion of 4 doses of AAT, they will be asked 
to return to MUSC at the required times to get the investigational drug administered. Starting and 
ending time of drug administration and the infusion rate will be recorded for each drug 
administration. Serum AAT level will be measured before and 30 mins after the first drug 
administration. 
 
6.3. POST-OPERATIVE ASSESSMENTS 
 
All routine measurements for TP-IAT patients will be measured according to current protocols 
for this patient population. SF-12 Quality of life and reduction in narcotic dose of morphine or 
equivalent will be obtained fromthe Islet Longitudinal Outcome Database (ILOD) which has 
granted this project authorization to use their information. . The following will be assessed 
during hospital stay and each time or when patients return for drug injection:  
 
6.3.1. Instant blood mediated inflammatory reaction (IBMIR): 3ml of blood will be collected 
before AAT injection, before, in the middle, and after initiation of islet infusion and 3h post islet 
infusion. Serum will be collected and stored in -70 ° C for analysis of thrombin-anti-thrombin 
complex (TAT), C5a, and c-peptide level. 
 
6.3.2. Chemokines/cytokines: A blood sample will be obtained at 0, 24, 72, and 168 h (before 
AAT injection), and day 14 (before AAT injection), and 21 (before AAT injection) post 
transplantation to measure chemokine and cytokine expression in the serum using the Lumix 
machine. Each time 5 ml of blood will be collected and centrifuged; aliquots of serum will be 
stored in in -70 ° C for further analysis.  
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 22 of 
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6.3.3. DNA testing: A 10 ml whole blood sample will be collected during screening, and stored 
in -70 ° C for isolation of genomic DNA for further analysis. This future analysis may be 
conducted by the PI or by other researchers who obtain IRB approval for their research. This 
research may involve genetic studies. The specimens will be labeled with a code that only study 
personnel can link back to the patient. Researchers outside of this study will not be given a link 
between the code number and patient’s name or any other identifying information. We expect to 
store the specimens long-term for future studies on disease condition. Participant will not be 
contacted for additional consent. The investigators will not tell patient what they find out about 
the patient, nor will contact the patient if a test becomes available to diagnose a condition that a 
patient might have or later develop. Results will not be placed in the individual participant’s 
medical record.  
There is a risk of potential loss of patient’s privacy or confidentiality. Information about race, 
ethnicity, sex, medical history, and so forth might be available to investigators studying the 
specimen. Such information might be important for research or public health. It is possible that 
this information (including genetic information) might come to be associated with patient’s racial 
or ethnic group. The specimens obtained from patients in this research may help in the 
development of a future commercial product. There are no plans to provide financial 
compensation to patient should this occur. Whether patient will agree to have their blood stored 
will not impact their participation in the study.  
 
6.3.4. RNA and other analyses: PBMCs (10ml blood) and plasma (15ml of blood) will be 
collected at 168 h post transplantation and stored in -70 °C for RNA expression, proteonomics, 
metabolics and small RNA analysis. 
 
6.3.5. The total amount of blood drawn for research purposes will be 145 ml (10 tablespoons) 
over the course of the study.  
 
6.3.6.  Mixed meal tolerance test (MMTT) 
MMTT tests will be performed at 75±14 and 365±14 days post-surgery. During the MMTT, 
patients will be asked to drink a special drink called ‘BOOST’, which will be given at a dose of 6 
mL per kilogram body weight and contains a mixture of protein, fat and carbohydrates. Patient’s 
blood will be draw at 0, 15, 30, 60, 90, 120, 180 and 240 min after drinking the boost. In each 
time point, 4ml of blood will be collected, 2ml for measuring blood glucose, and 2ml to measure 
c-peptide levels. Samples will be sent to the blood lab for analysis.  
 
6.3.7. Safety laboratory tests:  
Laboratory tests will be performed before hospital discharge. These are standard of care tests 
done in all TP-IAT patients. 
 
6.3.6.Vital signs: Blood pressure and heart rate will be measured before hospital discharge. 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 23 of 
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6.4. FOLLOW-UP VISITS: 
Autologous islet transplant recipients will be followed up life-long in our center. For this study 
specifically, patients will be followed up till 12 months post-transplantation. They will have to 
attend 2 follow-up visits scheduled on day 75±14 and 365±14 days after the transplant, this can 
be combined with their routine returning visits.  
 
6.4.1. Mixed meal tolerance test (MMTT) 
MMTT tests will be performed at 75±14 and 365±14 days post-surgery.  
 
 
7. SATETY MONITORING 
 
7.1. DEFINITIONS:  
 
7.1.1. Definition of Adverse Events (AEs) 
According to the International Conference on Harmonization (ICH) Guidelines (Federal 
Register.19995;60(40):11285), an AE is defined as follows: An AE is any untoward medical 
occurrence in a subject administered an investigational drug that does not necessarily have a 
causal relationship with the treatment. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated with 
the use of the investigational product whether or not related to the investigational product. An 
AE is any sign, symptom, or diagnosis that appears or changes in intensity during the course of 
the study. An AE may be an intercurrent illness or an injury that impairs the well-being of the 
subject. 
 
Unchanged chronic conditions or those related to the underlying disease or medical conditions 
that are consistent with natural disease progression are not AEs and should not be recorded on 
the AE pages of the case report form. These medical conditions should be adequately 
documented on the appropriate page of the form (medical history or physical examination). 
However, medical conditions present on the first day of treatment that worsen in intensity or 
frequency during the treatment or post-treatment periods should be reported and recorded as 
AEs. The Investigator will actively solicit this information from the subject and assess the event 
in terms of severity and relationship to the study treatment regimen. 
 
7.1.2. Definition of Serious Adverse Events (SAEs) 
An AE occurring with any study treatment regimen should be classified as “Serious” if it meets 
one of the following criteria: 
• It results in death (i.e., the AE caused or led to death). 
• It is life threatening (i.e., the AE placed the subject at immediate risk of death). This 
classification does not apply to an AE that hypothetically might cause death if it is more 
severe. 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 24 of 
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• It requires or prolongs inpatient hospitalization (i.e., the AE requires at least a 24 hour 
inpatient hospitalization or prolongs a hospitalization beyond the expected length of 
stay). Hospitalizations for elective medical or surgical procedures, scheduled treatments, 
or routine checkups are not SAEs by this criterion. 
• It is disabling or incapacitating (i.e., the AE results in a substantial disruption of the 
subject’s ability to carry out normal life functions). 
• It is a congenital anomaly or birth defect (i.e., an adverse outcome in a child or fetus of a 
subject exposed the molecule or study treatment regimen before conception or during 
pregnancy). 
• It does meet any of the above criteria, but could jeopardize the subject and might require 
medical or surgical intervention to prevent one of the outcomes listed above. 
 
7.1.3. Evaluation of Adverse Events 
Serious AEs should be graded with respect to severity on the following 3 point scale and 
reported, in detail, on the appropriate CRF page: 
 
Grade 1: Mild AE. Discomfort noticed, but no disruption of normal daily activities; event 
usually requires no intervention. 
Grade 2: Moderate AE: Discomfort sufficient to reduce or affect normal daily activities; even 
may require intervention. 
Grade 3: Severe and undesirable AE: Incapacitating, with inability to perform normal daily 
activities; event usually requires treatment or other intervention. Subject may not be able to 
continue in the study. 
Grade 4: Life-threating or disabling AE 
Grade 5: Death 
 
The Investigator should evaluate the relationship of each SAE to the study treatment regimen, 
using the following criteria: 
• Unrelated: Another cause of the SAE is more plausible; a clinically plausible temporal 
sequence is inconsistent with the onset of the AE and administration of the study 
treatment regimen; or a causal relationship is considered biologically impossible. 
• Possibly related: There is a clinically plausible time sequence between onset of the SAE 
and administration of the study treatment regimen, but the SAE could also be attributed 
to concurrent or underlying disease, or the use of other drugs or procedures. “Possibly 
Related” should be used when the study treatment regimen is one of several biologically 
plausible SAE causes. 
• Definitely Related: The SAE is clearly related to use of the study treatment regimen. 
 
7.2. Procedures for Recording and Reporting Adverse Events 
 
Fatal or life-threatening events thought to be caused by Study Drug will be reported to the Chair 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 25 of 
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of the DSMB and the MUSC IRB. There are no events that are expected to occur as a result of 
AAT or placebo infusion.  
 
Serious AEs require expedited reporting to the DSMB Chair or designee, regardless of the 
relationship of the event to the study treatment regimen. Refer to the previous section for the 
definition of a serious adverse event. 
 
Investigators will report all SAEs to the DSMB Chair or designee within the timelines of 
NIDDK policy after observation or learning of the event. For initial SAE reports, the Investigator 
should record all case details that can be garnered on the SAE form and the AE CRF page. 
Relevant follow-up information is to be submitted to the Sponsor or its designee as soon as it 
becomes available. 
Adverse Events will be reported to the IRB and the NIDDK program officer. The DSMB will 
review all safety data and all adverse events that occur (see section 7.3). The MUSC Internal 
Review Board will also monitor this study.  
 
7.2.2. Special Reporting Situations 
• 
Death: Death is an outcome of an event. The event that resulted in death should be 
recorded and reported on the SAE form and the AE CRF page. 
• 
Hospitalization for Surgical or Diagnostic Procedures: The illness leading to the 
surgical or diagnostic procedure is to be recorded as the SAE, not the procedure itself. 
The procedure is to be captured in the case narrative as part of the action taken in 
response to the illness. 
 
7.3. Data Safety Monitoring Board (DSMB): 
 
DSMC recommended by the NIDDK will meet to approve the protocol and the statistical plan 
before patient recruitment. The DSMC meeting frequency will be determined by the NIDDK. 
We suggest that the committee meet after the 5th patient has been treated, so that safety issues 
can be discussed. We will send quarterly SAE/AE reports to the committee according to the 
safety procedures described above. Safety procedures have been in place for our current islet 
autotransplantation procedure at MUSC. Any Suspected Unexpected Serious Adverse Reaction 
will lead to interruption of study recruitment until the DSMC has reviewed and approved 
recommencing. An update of the progress of the study including an efficacy and safety report be 
submitted to the DSMB every 6 months during the conduction of the study and a report at the 
end of it.  
 
 
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 26 of 
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8.STATISTICAL ANALYSIS: 
 
8.1. STATISTICAL ANALYSIS PLAN AND STATISTICAL REPORTS 
The following section provides the details of statistical analyses planned, including safety and 
primary and secondary efficacy endpoints.  In addition, it discusses the statistical issues relevant 
to these analyses (e.g., sample data to be used, missing data). 
The Statistical and Data Management Center (SDMC) generates a closed statistical report to be 
distributed only to the DSMB. The timing of the report is determined in consultation with the 
DSMB. Reports will be sent from the SDMC to the NIDDK two weeks in advance of the 
scheduled meeting. 
Each report provides cumulative summary statistics on enrollment; subject status in the study; 
baseline characteristics; protocol violations; safety data, including AEs and SAEs, severity, 
expectedness and relatedness to the study treatment; and data management/quality information 
(e.g., timeliness and completeness of data entry; number of data clarification requests generated 
and resolved). The statistics are provided for the overall study in the open report. For the closed 
report only, the statistics are also provided by partially blinded treatment groups (A vs B). Due to 
the unequal allocation used in this study, partially blinded reports will not include the counts.  
8.2. ANALYSIS POPULATION: 
8.2.1. MODIFIED INTENT-TO-TREAT POPULATION 
The modified intent-to-treat (mITT) population includes all randomized subjects who meet study 
eligibility criteria and have received at least one injection (of AAT or placebo). The primary 
efficacy measures will be analyzed with the mITT population. 
8.2.2. PER-PROTOCOL POPULATION  
The per-protocol (PP) population includes all randomized subjects who meet the study eligibility 
criteria, completed the assigned treatment infusions, and have the primary efficacy endpoint 
assessed.  
8.2.3 SAFETY POPULATION 
The safety population (SP) includes all subjects for whom consent is obtained and surgery is 
performed.  
8.3. SAMPLE SIZE JUSTIFICATION  
We recognize that the number of participants is small given the heterogeneity of chronic 
pancreatitis but believe the numbers are appropriate for a proof-of-concept translational study. 
The goal of this aim would be to test whether IAT + AAT is feasible in this patient population 
and to obtain preliminary assessments of its success.  Having n=32 subjects treated with AAT 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 27 of 
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(and n=16 placebo controls) would allow us to make relatively precise estimates of feasibility 
measures and means of the study outcomes, with 95% confidence intervals that would extend 
approximately 0.3 standard deviation units in either direction.  While recognizing that the 
standard deviation will be slightly higher in the control population, we recognize that all 
hypothesis testing will be considered exploratory, enabling 80% power to detect moderately 
large differences (effect sizes of 0.9 standard deviation units) between the AAT and treated 
control groups with respect to the study outcomes, including the 4 hour C-peptide level AUC 
obtained at 12 months, assuming up to a 10% loss to follow-up over the 12 months. Having these 
numbers of subjects would also allow us to make preliminary comparisons between outcomes in 
the IAT + AAT group and outcomes observed in a group of 150 historical controls, each of 
whom received a total pancreatectomy with IAT at MUSC from 2009-2015. Most importantly, 
the data (e.g. means, standard deviations, and effect size estimates) from 32 subjects receiving 
AAT treatment, 16 control subjects receiving islets alone, and 150 historical controls will be vital 
for use in designing a larger more definitive randomized controlled trial in the future. Using 2:1 
randomization will help provide more precise estimates of outcomes in the IAT + ATT group 
and may also help with study recruitment, as subjects may tend to be more willing to consent if 
they have a stronger probability of receiving the active experimental treatment. 
 
8.4. RANDOMIZATION 
A randomization system will be developed by the biostatistician. The objective of randomization 
is to prevent possible selection bias by providing random treatment assignment to each subject; 
and to maintain treatment balance with respect to relevant prognostic variables. 
Each cohort will start from a permuted block randomization with a block size of 6, including 4 
assignments to the AAT arm and 2 assignments to the placebo arm. This initial block of 6 
patients will provide information for early safety assessment of AAT.  
Following the initial block, additional subjects will continued to be randomized between AAT 
and placebo in a 2:1 fashion, using random block sizes of 3 and 6.   
8.5. BLINDING 
The study will be conducted in a double blind manner. Identical study treatment infusion 
packages will be prepared by our clinical trial coordinator. Study subjects, treating investigators, 
and efficacy endpoint assessors will be blinded to treatment assignments.  
The clinical trial coordinator will produce identical sealed envelopes that contain identification 
of treatment codes.  Prior to initiation of the trial, these envelopes will be stored in a locked file 
cabinet at the coordinator’s office in its limited access central file room. 
The DSMB will be partially unblinded for the closed reports (data reported by treatment groups 
“A” and “B” only).  However, if it so wishes, it may be completely unblinded at any time during 
the trial.  If the DSMB wishes to be unblinded on a particular subject only, the NIDDK Liaison 
to the DSMB should email the request to the unblinded biostatistician. 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 28 of 
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8.6. MISSING DATA 
All efforts will be put forth to ensure near complete follow-up, in particular with the assessment 
of the primary outcome at 12 months and occurrence of death.  Nevertheless, minimal missing 
data may be inevitable.   
As the primary approach, for the primary efficacy analysis with the mITT population, data will 
be assumed to be missing at random, with no data imputation. Sensitivity analysis with multiple 
imputations for missing primary endpoints will be conducted to assess whether the findings are 
consistent across alternative analysis approaches. We plan to use PROC MI and PROC 
MIANALYZE in the SAS software. A distribution for the primary outcome is derived from a 
logistic regression model that accounts for covariates assessed at baseline and clinical visits prior 
to Day 75. A random sample from this distribution is used to impute values for missing primary 
outcomes.  Five sample data sets with complete efficacy endpoint are generated through PROC 
MI, and each of the data sets are analyzed according to the method described, and the results 
(regression parameter and covariance matrix estimates) for each sample are combined and 
analyzed with PROC MIANALYZE to derive a valid statistical inference about the treatment 
effect.  
Missing data in secondary endpoints will be assumed missing at random and no data imputation 
will be used in secondary endpoints analyses.   
8.7. ASSESSMENT TIME WINDOWS 
The Baseline visit should occur within 28 days of the screening visit. For all scheduled visits, 
allowable visit windows and study procedures are ± 14 days from the calculated target day. The 
target day is defined as (Baseline Visit + 75 days) for the Day 75 target day, and (Baseline Visit 
+ 365 days) for the Day 365 target day. If multiple measurements occur within the assessment 
time window, the measurement closest to the scheduled target day will be analyzed. Data 
collected outside of the specified time window will not be included in the primary analysis.  
8.8. DESCRIPTIVE ANALYSES 
Characteristics of studied patients (i.e., demographics, disease status, glucose & hba1c levels) 
and measures of study feasibility (i.e., enrollment refusal rate, proportion of enrolled subjects 
who are successfully transplanted) will be summarized using descriptive statistics (i.e., means, 
standard deviations, medians, percentages) and 2-sided 95% confidence intervals. 
8.9. EFFICACY ANALYSES 
The primary efficacy analyses will involve the use a general linear mixed model (GLMM) to test 
whether the primary endpoints differ over time between subjects assigned to the AAT arm when 
compared to subjects assigned to placebo.  The analysis will be performed on the mITT and PP 
populations, although the analyses within the mITT population will be considered primary. 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 29 of 
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Contrasts will be constructed to estimate the AAT treatment effect on outcomes at day 75 and at 
day 365.  To account for the fact that observations within the same subjects will be correlated, 
various error covariance structures will be considered, including unstructured, autoregressive, 
and compound symmetry.  If model assumptions are not met (e.g. normality) alternative 
strategies will be utilized, including transformations of dependent variables and non-parametric 
alternatives. Any pre-transplantation subject characteristics be found to be significantly different 
between the study subjects and historical controls will be included as covariates for all between-
group comparisons. Model fit will be assessed using criteria such as Akaike Information 
Criterion.  All primary and secondary outcomes will be reported in study communications. 
8.10. SAFETY ANALYSES 
Study subjects will be asked to report any and all AEs/new symptoms at any time from study 
enrollment until 52 weeks after study treatment, whether or not they attribute them to the study 
intervention or procedures. Subjects, who discontinue the study treatment regimen for any 
reason, including subjects who are treatment failures due to unable to return for some of the 
treatment injection(s) will be encouraged to attend the remaining visits for assessment of safety, 
secondary and pharmacokinetic endpoints.  
To assess safety in this population, vital signs will be performed at each of the study visits. 
Additionally, medical history will be collected at screening and baseline and adverse events 
occurring after start of study therapy will be recorded. 
Since the safety endpoints are primarily binary indicators for each subject (e.g. experiencing a 
particular AE during the 24-weeks post-treatment), their analyses will involve logistic regression 
models. For certain safety endpoints, it may be more appropriate for them to be analyzed using 
survival techniques, which are more suitable for time-to-event data than logistic regression.  In 
such circumstances, Cox proportional hazards models will be used to compare treatment arms; 
however, should the proportionality assumptions not hold, alternative strategies (e.g. stratified 
analyses) will be used. The safety analyses will be conducted in the Safety Population. 
8.11. SECONDARY EFFICACY ANALYSIS 
A series of secondary efficacy and exploratory endpoints will be evaluated, as listed in Section 
3.5.2 and 3.5.3. All secondary analyses will be conducted in an exploratory fashion with p-values 
and confidence intervals presented with no adjustments for multiple comparisons. Interval 
estimates will be generated at the 95% confidence level. Secondary analyses will be conducted 
on the mITT population and the per protocol population.  Since most secondary endpoints will 
be collected at multiple time points for each participant, generalized linear mixed models will be 
utilized, as they are appropriate for longitudinal data analyses and can be adapted for binary 
dependent variables. 
Secondary endpoints analyses are used to confirm or support the findings based on the primary 
outcome analysis. If most of the secondary endpoints show a change in the opposite direction 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 30 of 
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AAT in islet autotransplantation 
 
 
from the primary efficacy analysis or no direction, we might have less confidence in the primary 
endpoint.    
 
8.12. MECHANISTIC ANALYSIS 
Since many of the mechanistic endpoints will be collected at multiple time points for each 
participant, statistical models appropriate for longitudinal data analyses will be used. For 
example, serum samples for cytokines will be collected at Baseline, day 1, 3, and 7 days post 
transplantation.  The GLMM used to compare treatment groups will be of the form: 
𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝐾𝑖𝑖𝑖𝑖= 𝛼𝛼+ 𝛽𝛽1 ∙𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑖𝑖+ 𝛽𝛽2 ∙𝐾𝐾𝐾𝐾𝐾𝐾0 + 𝛽𝛽3𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑗𝑗+ 𝛾𝛾𝑖𝑖+ 𝛾𝛾𝑖𝑖𝑖𝑖∙𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑊𝑗𝑗+ 𝜖𝜖𝑖𝑖𝑖𝑖 
This GLMM example treats cytokine as the dependent variable, including fixed effects for 
treatment group, baseline cytokine, and week, along with random subject intercepts (γi) and 
random subject slopes (γij). Link functions appropriate for each dependent variable (i.e. each 
mechanistic outcome) will be selected, depending on its distributional form.  Similar models 
will be constructed for other mechanistic endpoints. 
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 31 of 
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9. QUALITY CONTROL AND QUALITY ASSURANCE 
 
The investigator is required to keep accurate records to ensure that the conduct of this study is 
fully documented, and to ensure that CRFs are completed for all subjects according to the study 
guidelines outlined in the study protocol and database training materials. As part of the quality 
assurance and legal responsibilities of an investigation, the study site permit authorized 
representatives of the sponsors and health authorities to examine (and when required by 
applicable law, to copy) clinical records for the purpose of quality assurance reviews, audits, and 
evaluations of the study safety and progress. Unless required by the laws that permit copying for 
recorders, only the coded identity associated with documents or with other subject data may be 
copied (and all personally identifying information must be obscured). Authorized representatives 
as noted above are bound to maintain the strict confidentiality or medical and research 
information that is linked to identified individuals.  
 
Results of all clinical and laboratory evaluations will be maintained in the subject’s medical 
records and the data will be transferred from these source documents directly to the study data 
base. All data will be entered/imported, stored, and managed in an encrypted database. Access to 
data entry screens will be user ID and password protected. Each user will be provided with a 
unique personal ID and password. The Data will be verified for missing data, inconsistencies, 
and for any necessary medical clarifications. All relevant data queries arising from these checks 
will be sent to the Investigator for response and signature. After all data is confirmed, it will be 
locked for further analysis. 
 
In addition, prior to study initiation, current, signed and dated curriculum vitae, CITI training 
certificates, and financial disclosure statement of PI and co-investigators will be gather in the 
regulatory binder, and information will be updated at least every two years. 
 
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 32 of 
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10. PROTOCOL DEVIATIONS/AMENDMENTS 
Any amendment will be sent to the appropriate IRB. No deviation from or changes to the 
protocol will be implemented without documented approval of an amendment from the IRB 
which granted the original approval, except where necessary to eliminate an immediate hazards 
to trial patient, or only when change(s) involves only logistical or administrative aspects of the 
trial. The deviation and the proposed amendment, if appropriate, should be submitted to the IRB 
for review and approval as soon as possible.  
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 33 of 
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11.  DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator will cooperate and provide direct access to study documents and data, including 
source documentation for monitoring by the study monitor, audits by the sponsor or sponsor’s 
representatives, review by the IRB, and inspections by applicable regulatory authorities. If 
contacted by an applicable regulatory authority, the investigator will notify the sponsor of 
contact, cooperate with the authority, provide the sponsor with copies of all documents received 
from the authority, and allow the sponsor to comment on any responses. 
 
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 34 of 
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12. ETHICAL CONSIDERATION AND COMPLIANCE WITH GOOD CLINICAL 
PRACTICE 
 
12.1. Statement of Compliance  
 
The clinical study will be conducted using cGCP, as stated in Guidance for Industry: E6 Good 
Clinical Practice Consolidated Guidance, and according to the criteria specified in this study 
protocol. Before study initiation, the protocol and the informed consent documents will be 
reviewed and approved by IRB, and submitted to the DSMB board through the NIH/NIDDK. 
Any amendments to the protocol or the consent materials must be approved by the IRB before 
implemented, and the amendments will be reported to the sponsor. 
 
12.2. Informed Consent 
 
The informed consent for research to be ethical, most agree that individuals should make their 
own decision about whether they want to participate or continue participating in research. This is 
done through a process of informed consent in which individuals (1) are accurately informed of 
the purpose, methods, risks, benefits, and alternatives to the research, (2) understand this 
information and how it relates to their own clinical situation or interests, and (3) make a 
voluntary decision about whether to participate. 
The informed consent must be revised whenever important new safety information is available, 
whenever the protocol is amended, and or whenever any new information becomes available that 
may affect participation in the trial.  
 
12.3. Privacy and Confidentiality 
Each patient will be assigned a unique identification number, and used for data collection, store 
and reporting subject information. Subjects’ privacy and confidentiality will be respected 
throughout the study.  
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 35 of 
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13. PUBLICATION POLICY 
Any publication of study results will adhere to the NIH Public Access Policy. 
 
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 36 of 
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References: 
1. 
Lankisch PG. Natural course of chronic pancreatitis. Pancreatology 2001; 1:3-14 
2. 
Brantly ML, Wittes JT, Vogelmeier CF, Hubbard RC, Fells GA, Crystal RG. Use of a highly 
purified alpha 1-antitrypsin standard to establish ranges for the common normal and deficient 
alpha 1-antitrypsin phenotypes. Chest 1991; 100:703-708 
3. 
Breit SN, Wakefield D, Robinson JP, Luckhurst E, Clark P, Penny R. The role of alpha 1-
antitrypsin deficiency in the pathogenesis of immune disorders. Clin Immunol Immunopathol 
1985; 35:363-380 
4. 
Mordwinkin NM, Louie SG. Aralast: an alpha 1-protease inhibitor for the treatment of alpha-
antitrypsin deficiency. Expert Opin Pharmacother 2007; 8:2609-2614 
5. 
Petrache I, Fijalkowska I, Medler TR, Skirball J, Cruz P, Zhen L, Petrache HI, Flotte TR, Tuder 
RM. alpha-1 antitrypsin inhibits caspase-3 activity, preventing lung endothelial cell apoptosis. Am 
J Pathol 2006; 169:1155-1166 
6. 
Tuder RM, Yoshida T, Fijalkowka I, Biswal S, Petrache I. Role of lung maintenance program in 
the heterogeneity of lung destruction in emphysema. Proc Am Thorac Soc 2006; 3:673-679 
7. 
Zhang B, Lu Y, Campbell-Thompson M, Spencer T, Wasserfall C, Atkinson M, Song S. Alpha1-
antitrypsin protects beta-cells from apoptosis. Diabetes 2007; 56:1316-1323 
8. 
Bruning JC, Winnay J, Bonner-Weir S, Taylor SI, Accili D, Kahn CR. Development of a novel 
polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 1997; 88:561-
572 
9. 
Koulmanda M, Bhasin M, Hoffman L, Fan Z, Qipo A, Shi H, Bonner-Weir S, Putheti P, Degauque 
N, Libermann TA, Auchincloss H, Jr., Flier JS, Strom TB. Curative and beta cell regenerative 
effects of alpha1-antitrypsin treatment in autoimmune diabetic NOD mice. Proc Natl Acad Sci U S 
A 2008; 105:16242-16247 
10. 
Lewis EC, Shapiro L, Bowers OJ, Dinarello CA. Alpha1-antitrypsin monotherapy prolongs islet 
allograft survival in mice. Proc Natl Acad Sci U S A 2005; 102:12153-12158 
11. 
Lewis EC, Mizrahi M, Toledano M, Defelice N, Wright JL, Churg A, Shapiro L, Dinarello CA. 
alpha1-Antitrypsin monotherapy induces immune tolerance during islet allograft transplantation in 
mice. Proc Natl Acad Sci U S A 2008; 105:16236-16241 
12. 
Shimoda M, Noguchi H, Fujita Y, Takita M, Ikemoto T, Chujo D, Naziruddin B, Levy MF, 
Kobayashi N, Grayburn PA, Matsumoto S. Improvement of porcine islet isolation by inhibition of 
trypsin activity during pancreas preservation and digestion using alpha1-antitrypsin. Cell 
Transplant 2012; 21:465-471 
13. 
Koulmanda M, Sampathkumar RS, Bhasin M, Qipo A, Fan Z, Singh G, Movahedi B, Duggan M, 
Chipashvili V, Strom TB. Prevention of nonimmunologic loss of transplanted islets in monkeys. 
Am J Transplant 2014; 14:1543-1551 
14. 
Gottlieb PA, Alkanani AK, Michels AW, Lewis EC, Shapiro L, Dinarello CA, Zipris D. alpha1-
Antitrypsin therapy downregulates toll-like receptor-induced IL-1beta responses in monocytes and 
myeloid dendritic cells and may improve islet function in recently diagnosed patients with type 1 
diabetes. The Journal of clinical endocrinology and metabolism 2014; 99:E1418-1426 
15. 
Crystal RG. Alpha 1-antitrypsin deficiency, emphysema, and liver disease. Genetic basis and 
strategies for therapy. J Clin Invest 1990; 85:1343-1352 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 37 of 
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APPENDIX 1: 
 
Study Phase 
Screening 
Treatment 
Premature 
Withdraw
al 
Time 
points 
(days 
relative 
to 
transplant) 
Screening 
Baseline 
Before 
Surgery 
Baseline 
After/ 
During 
Surgery 
Day 1 
Day 3 
D7 
D14 
D21 
D75 
D365 
 
Visit# 
1 
2 
3 
4 
5 
6 
7 
 
Visit Windows (days) 
 
 
 
 
 
±2 
±2 
±2 
±15 
±15 
 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
Medical and Diabetes 
History 
x 
 
 
 
 
x 
x 
x 
x 
x 
x 
Inclusion/Exclusion 
x 
 
 
 
 
 
 
 
 
 
 
Immunoglobulin 
A 
(IgA) 
x 
 
 
 
 
 
 
 
 
 
 
AAT infusion 
 
x 
 
 
 
x 
x 
x 
 
 
 
TP-IAT 
 
 
x 
 
 
 
 
 
 
 
 
Inflammatory 
Cytokine Levels 
 
x 
x3 
x 
x 
x 
x 
x 
 
 
 
TAT, C3a, c-pep 
 
x 
x1,    x2 
 
 
 
 
 
 
 
 
Serum AAT level 
 
X4 
 
 
 
 
 
 
 
 
 
Blood 
mononuclear 
RNA 
 
x 
 
 
 
x 
 
 
 
 
 
Blood DNA 
 
x 
 
 
 
 
 
 
 
 
 
Plasma for proteomics, 
siRNA, etc 
 
x 
 
 
 
x 
 
 
 
 
 
MMTT 
-240min 
c-
peptide and glucose 
 
 
 
 
 
 
 
 
x 
x 
 
Adverse 
Event 
Recording 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
1 Time 0 and 15 minutes after initiation of islet cell infusion in radiology suite. 
2 Time 3 hours after initiation of islet cell infusion when participant is back in ICU.  
3 Cytokine profile obtained 24 hours after initiation of islet cell infusion when participant 
is back in ICU. 
4 AAT levels will be measured prior and 30mins after the first AAT infusion.  
 
 
 
 


 
 
 
[Hongjun Wang, Ph.D]                                                                                      Page 38 of 
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APPENDIX 2:  
 
Study Contacts: 
Protocol Chair/Principal Investigator 
Hongjun Wang, Ph.D 
Associate Professor, 
Department of Surgery 
Medical University of South Carolina 
BSB 641, 17s Ashley Ave 
Charleston, SC 29425 
Phone: 843-792-1800 
Fax: 843-792-3315 
E-mail: wangho@musc.edu 
 
Clinical Investigator: 
Katherine A Morgan, M.D 
Professor of Surgery 
Chief, Division of Gastrointestinal and Laparoscopic Surgery 
Department of Surgery 
Medical University of South Carolina 
MUSC, Strom Thurmond Building 
114 Doughty Street 
Charleston, SC 29425 
Phone: (843)876-4268 
Email: morganka@musc.edu