Allogeneic Islet Cells Transplanted Onto the Omentum
Phase: PHASE1
Conditions: Type 1 Diabetes Mellitus, Hypoglycemia, Hypoglycemia Unawareness
Sponsor: Rodolfo Alejandro

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ALLOGENEIC ISLET CELLS TRANSPLANTED ONTO THE OMENTUM 
University of Miami IRB Protocol #: 20140144 
University of Miami 
Jackson Medical Towers East 
1500 NW 12th Avenue, Ste. 1002 
Miami, FL 33136 
 
Study Sponsor  
Alejandro, Rodolfo, MD 
Diabetes Research Institute 
1450 NW 10th Ave, 
Miami, Florida 33136 
 
Principal Investigators: 
Alejandro, Rodolfo, MD 
Diabetes Research Institute 
1450 NW 10th Ave, 
Miami, Florida 33136 
 
Co- Investigator:                                       
 
 
David Baidal, MD 
Diabetes Research Institute 
1450 NW 10th Ave, 
Miami, Florida 33136 
                                           
 
Dora Berman-Weinberg, PhD 
Diabetes Research Institute  
1450 NW 10th AVE R-134  
 
Miami, Florida 33136  United States 
 
 
Camillo Ricordi, M.D. 
Diabetes Research Institute 
1450 Northwest 10th Avenue R-134 
Miami, Florida 33136 United States 
 
 
Jason Salsamendi, M.D. 
University of Miami, Vascular Interventional Radiology 
1611 NW 12 Avenue 
Miami, Florida 33136 
 

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George Burke, M.D. 
UMH Medical Specialty Care (Transplant) 
1321 NW 14th Street 
Miami Florida 33136 
 
Gaetano Ciancio, M.D. 
UMH Medical Specialty Care (Transplant) 
1321 NW 14th Street 
Miami Florida 33136 
 
Gennaro Selvaggi, M.D. 
UMH Medical Specialty Care (Transplant) 
1321 NW 14th Street 
Miami Florida 33136 
 
 
SITE(S): 
University of Miami 
Diabetes Research Institute 
1450 Northwest 10th Avenue 
Miami, Florida 33136 
United States 
 
Jackson Memorial Medical Center 
1611 Northwest 12th Avenue 
Miami, Florida 33136 
United States 
 
Clinical Research Center  
University of Miami | Miller Office of Research 
University of Miami Hospital 
1400 NW 12th Avenue, 7th Floor South 
Miami, FL 33136  
 
 
 
 
 

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TABLE OF CONTENTS 
1 
INTRODUCTION ....................................................................................................................................... 6 
1.1 
Background ...................................................................................................................................... 6 
1.2 
Study Rationale .............................................................................................................................. 10 
2 
STUDY OBJECTIVES AND ENDPOINTS ................................................................................................... 15 
2.1 
Primary Objectives ........................................................................................................................ 15 
2.3 
Primary endpoints .......................................................................................................................... 15 
2.4 
Secondary endpoints ...................................................................................................................... 15 
2.5 
Statistical considerations and analytical plan ................................................................................ 16 
3 
STUDY DESIGN...................................................................................................................................... 18 
3.1 
Patient Population .......................................................................................................................... 19 
3.1.1 
Placement of Islets into the Omentum .................................................................................... 19 
3.2 
Inclusion Criteria ........................................................................................................................... 19 
3.3 
Exclusion Criteria .......................................................................................................................... 20 
4 
TREATMENT OF PATIENTS .................................................................................................................... 22 
4.1 
Study Therapy and Dosages .......................................................................................................... 22 
4.1.1 
Study Investigational Therapy: Isolation of Allogeneic Islet Cells ........................................ 22 
4.1.2 
Study Investigational Therapy: Administration ...................................................................... 23 
4.1.3 
Dose Rationale ....................................................................................................................... 24 
4.1.4 
Dosage and Dosing ................................................................................................................ 25 
4.1.5 
Storage and Handling of Study Investigational Therapy ........................................................ 26 
4.1.6 
Study Investigational Therapy Accountability Procedures..................................................... 26 
5 
STUDY PROCEDURES ............................................................................................................................ 26 
5.1 
Study outline .................................................................................................................................. 26 
5.2 
Islet Transplant: Immunosuppression, Adjuvant Therapies and Concomitant Medications ......... 27 
5.3 
Second Islet Transplant (re-transplant, intra-hepatic administration): Immunosuppression ......... 31 
5.4 Known and Potential Risks and Benefits to Human Subjects ........................................................... 33 
5.5.4.1 Risks of Use of Investigational Agent: Transplant of Allogeneic Islets .................................. 33 
5.4.2 Transmission of Disease from Donor to Recipient .................................................................... 33 
5.4.3 Risk of Microbial Contamination of Islet Preparations ............................................................. 34 
5.4.4 Sensitization of the Recipient to Donor Antigens ....................................................................... 35 
5.4.5 Acceleration of Retinopathy with acute correction in glycemic control .................................... 35 

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5.4.6 Psychological Impact of Successful or Failed Islet Transplantation ......................................... 36 
5.4.7 Risk of Induction and Maintenance Immunosuppressive Therapies .......................................... 36 
5.4.8 Risks of Immunosuppressive / Anti-inflammatory Therapy 
 ............................................................................................................................................................ 40 
5.4.9 Risks from Adjuvant Interventions ............................................................................................. 40 
5.4.10 Risk of Study Procedures ......................................................................................................... 43 
5.4.11 Benefits ..................................................................................................................................... 46 
5.5 Assessment of Compliance with Study Treatment ........................................................................... 46 
5.6 Modification or Discontinuation of Study Treatment ....................................................................... 46 
5.6.1 Islets are Unsuitable .................................................................................................................. 46 
5.6.2 Graft Failure .............................................................................................................................. 46 
5.6.3 Allergic Reaction to ATG ........................................................................................................... 47 
5.6.4 Intolerance of Protocol Medications ......................................................................................... 47 
5.6.5 RABBIT ANTI-THYMOCYTE GLOBULIN-Induced Anaphylaxis ............................................. 47 
5.6.7 Neutropenia ................................................................................................................................ 47 
5.6.8 Thrombocytopenia ..................................................................................................................... 48 
5.6.9 Nephrotoxicity ............................................................................................................................ 49 
5.6.10 Premature Discontinuation of Study Treatment (Transition to “Off-Protocol” Treatment) ... 49 
5.7 
Risks of surgery and anesthesia ..................................................................................................... 49 
5.8 
Study Stopping Rules .................................................................................................................... 50 
6 
STUDY PROCEDURES ............................................................................................................................ 50 
6.1 
Enrollment and Screening.............................................................................................................. 50 
6.2 
Waiting List/Baseline .................................................................................................................... 50 
6.3 
Islet Transplant, and Study Treatment Visits ................................................................................ 51 
6.4 
Follow-up Visits ............................................................................................................................ 51 
6.5 
Imaging modalities to localize the transplanted islet allograft. ..................................................... 51 
6.6 
Mechanistic assays ........................................................................................................................ 52 
7 
ADVERSE EVENTS ................................................................................................................................. 52 
7.1 
Serious Adverse Events ................................................................................................................. 53 
7.2 
Unexpected Adverse Event............................................................................................................ 53 
7.3 
 Collecting Procedures ................................................................................................................... 53 
7.4 
Recording Procedures .................................................................................................................... 54 

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7.5 
Reporting Procedure ...................................................................................................................... 54 
7.5.3 
Notifying the Institutional Review Board (IRB) and Ethics Committee ................................. 54 
7.6 
Grading and Attribution ................................................................................................................. 55 
7.6.1 
Grading Criteria ..................................................................................................................... 55 
7.6.2  
Definition of Attribution ........................................................................................................ 55 
7.6.3 
Attribution of adverse events .................................................................................................. 56 
8 
REVIEW OF SAFETY INFORMATION....................................................................................................... 56 
8.1 
Data Safety Monitoring Board (DSMB) ........................................................................................ 56 
9 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................................. 56 
9.1 
Compliance, Access, Entry and Handling of Study Data .............................................................. 57 
9.2 
Ethical Considerations and Compliance with Good Clinical Practice........................................... 57 
9.2.1  
Statement of Compliance ....................................................................................................... 57 
9.2.2  
Informed Consent and Assent ................................................................................................ 57 
9.2.3  
Privacy and Confidentiality ................................................................................................... 58 
13 
REFERENCES ....................................................................................................................................... 59 
APPENDIX A: SCHEDULE OF EVENTS (SOE) ............................................................................................ 68 
 
 

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1 
INTRODUCTION 
1.1 
Background 
Transplantation of pancreatic islets represents a clinical therapeutic option to preserve 
and/or restore beta-cell function in patients with diabetes (1, 2). Since the 1970’s islets are 
embolized into the hepatic portal system by a minimally invasive technique consisting of 
trans-hepatic cannulation of the portal vein under ultrasound and fluoroscopy guidance 
followed by sealing of the tract with thrombostatic treatment. Alternatively, in patients at 
risk of bleeding, the transplant is performed by cannulation of a tributary of the portal vein 
using open surgery (mini-laparotomy) or laparoscopic approach (3).  
Several improvements in islet cell processing, immunotherapy and patient management 
have led to incremental advances in islet graft outcomes (4, 5).  Progressive loss of islet 
graft function has been recognized after implantation in the intrahepatic site used clinically 
for the last three decades (2). This phenomenon seems to be common to autologous and 
allogeneic islets, and was described also in pre-clinical animal models of autologous islet 
transplantation (6). 
An instant blood-mediated inflammatory reaction (IBMIR) occurring early after intra-
portal islet infusion activates the coagulation cascade and the endothelium of the hepatic 
sinusoids, triggering adhesion of platelets and leukocytes, generation of thrombi and 
ischemia contributing to the loss of a conspicuous mass of transplanted tissue (7, 8). 
Nonspecific inflammation (innate immunity) generated at the time of transplant may 
heighten the intensity of subsequent adaptive immune responses that in organ 
transplantation are responsible for higher incidence of acute and chronic rejection episodes, 
and in type 1 diabetes mellitus (T1DM) promote also recurrence of autoimmunity. 
Accumulation of peri-insular fat in the liver of intrahepatic islet recipients has been 
described (9-14). Other disadvantages of the hepatic site include the relatively 
hyperglycemic environment and the elevated concentration of immunosuppressant (first-
pass) that are toxic to islets.  
Identification of a clinically relevant new ‘home’ for islet grafts will likely contribute 
achieving reproducibly successful biological replacement of beta-cell function in insulin-
requiring diabetes. Definition of extra-hepatic transplantation sites has been recognized 
one of the current research priorities, and the focus of actively ongoing investigations 
(Table 1) aimed at identifying a microenvironment that could provide prompt engraftment, 
minimize early inflammation and islet cell death, while achieving sustained function.  
Engraftment of islet grafts in several extra-hepatic sites and with or without 
bioengineering strategies has been demonstrated in experimental models (2, 15-17), 
although clinical translation for some remains arguable (Table 1)(18). An ideal new 
‘home’ for islet grafts should accommodate relatively large volumes of tissue (e.g., low 
purity, or pooled donor islet preparations, and/or re-transplantation), rely on minimally-
invasive transplant procedures, allow for noninvasive longitudinal monitoring and easy 
access for biopsy. Portal blood drainage may be preferable to reproduce physiological 
metabolic responses. Confinement and irretrievability of the graft is desirable, particularly 
for bioengineering approaches to optimize the site.  
Extra-hepatic sites already tested in humans include muscle (17, 19-21), and peritoneal 
cavity (to accommodate large microencapsulated islets) (22, 23). Clinical feasibility and 

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safety of intra-bone marrow (BM) islet transplantation (24) has also been recently proposed 
in patients with contraindications for intrahepatic islet transplantation.

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Table 1. Islet transplantation sites 
 
 

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Implantation of islets into the omentum is appealing because the site offers a large, 
well-vascularized surface that could be used to distribute an islet graft (18). Furthermore, 
the omentum has portal blood drainage, which may allow for the achievement of more 
physiological, metabolic responses when compared to other extra-hepatic sites shown to 
associate with hyperinsulinemia, insulin resistance and impairment of insulin action, none 
of which observed with intra-omental islet grafts (25, 26). 
The omentum develops as a loose mesothelial sheet of tissue from the yolk sac. The 
greater omentum develops in the eighth week of gestation from the dorsal mesogastrium 
(27). It is composed of two mesothelial sheets enclosing predominantly adipocytes 
embedded in a loose connective tissue, and also aggregates of mononuclear phagocytic 
cells. The omentum has a rich vascular supply with numerous characteristic capillary 
convolutions (a.k.a., omental glomeruli due to their similarity to renal glomeruli). These 
capillary beds lie directly under the mesothelium (28). The size of the human omentum 
varies from 300 to 2000 grams with a surface area of 300 to 1500 cm2 (29). 
 
The omentum has been utilized in different experimental models of islet transplantation 
over the last 20 years. Yasunami et al. first reported the successful reversal of experimental 
diabetes in rats after implantation of islet isografts into a peritoneal omental pouch 
constructed by encasing the omentum in a pouch formed from a strip of parietal peritoneum 
obtained from the recipient; normoglycemia was maintained in the recipients until removal 
of the pouch that resulted in a rapid return to hyperglycemia (30). The suitability of the 
omentum for islet transplantation in large animal model was first reported by Simeonovic 
et al. in pigs (31) and then extended by Ao et al. to the canine model with titration of mass 
in an allogeneic combination, though suggesting the need for higher numbers when 
compared to intrasplenic implantation (32, 33). More recently, the omental site has been 
explored as a site for bioengineering approaches aimed at enhancing islet transplant 
engraftment and survival (34, 35). 
An interesting approach to intra-omental islet transplantation was presented by Hefty et al. 
in a canine model of total and partial pancreatectomy (36). The autologous grafts were 
prepared in a three-dimensional (3D) matrix consisting of autologous plasma supplemented 
with Vascular Endothelial Growth Factor (VEGF) that was placed in and rolled-up with 
the greater omentum to have omental layers on both sides of the matrix (36). Another recent 
study by Jacobs-Tulleneers-Thevissen et al. in immunodeficient rats (nude rats) showed 
that human islet cell implants survive better in the omentum than intra-hepatically, with 
positive influences of the number and purity of implanted beta cells (37). Similarly, 
Bartholomeus et al. demonstrated that perinatal porcine islet cell grafts display comparable 
growth of the β-cell volume over time when comparing the omentum and the kidney 
subcapsular space; but that the omentum leads to higher insulin reserves and an increased 
pool of proliferating cells, which might be related to a more extended vascular network 
(38). 
 
Topical use of thrombin has become part of current medical practice as a means to 
attain hemostasis and prevent bleeding during various surgical procedures (39-41). The 
development of recombinant human thrombin lead to standardization of this product, 
overcoming limitations imposed by previous formulations of this product such as highly 
purified bovine thrombin and human plasma-derived thrombin, both of which were costly 
to manufacture.  In addition, bovine thrombin carries the risk of immunogenicity, 

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potentially resulting in formation of cross-reactive antibodies to bovine thrombin, factor 
V, and other impurities that may be present in these formulations, and potential bleeding 
and thromboembolic events (40). 
 
 
In this study we propose to use RECOTHROM  (thrombin alfa, ZymoGenetics, Inc.), 
developed via recombinant DNA technology, identical in amino acid sequence and 
structurally similar to naturally occurring human thrombin. The cell line used to 
manufacture RECOTHROM® has been extensively tested and shown to be free of known 
infectious agents. It is not derived from animal or human blood, and contains no added 
human or animal components. Thus, RECOTHROM ® is inherently free from the risk of 
transmission of human- borne pathogens, such as HIV, hepatitis, parvovirus, and the 
infectious agents associated with Creutzfeldt-Jakob Disease (CJD) and variant CJD. 
RECOTHROM ® has low immunogenicity with a significantly lower rate of specific anti-
product antibody formation than treatment with bovine thrombin. After surgery, only 1.5 
per cent of RECOTHROM ® patients developed antibodies (42). It could be used safely in 
patients with pre-existing anti-thrombin antibodies to bovine thrombin preparations (43).  
RECOTHROM ® is easy to prepare and use. It is supplied as a lyophilized powder and sterile 
diluent for reconstitution in single use, preservative-free vials of 5,000 IU or 20,000 IU. It 
requires no refrigeration and can be stored in the operating room. When reconstituted, it 
can be kept up to 24 hours for lengthy surgical procedures. According to a recent clinical 
study, RECOTHROM ® was found to successfully stop 80 per cent of surgical bleeding within 
three minutes and 95 per cent of bleeding within 10 minutes (42). RECOTHROM ® is intended 
for topical use, and it is generally applied directly to the bleeding site, or used in 
conjunction with a compatible absorbable gelatin sponges to promote hemostasis, with clot 
formation occurring shortly after reconstituted RECOTHROM ® solution comes into contact 
with blood. 
 
For the purposes of this study we propose to use RECOTHROM to promote clot 
formation in autologous plasma used to re-suspend allogeneic islet cells for the 
implantation onto the omentum. Hence, we intend to use RECOTHROM as for the approved 
clinical use. The data from the experimental studies conducted in small and large animals 
models confirm that the additional of RECOTHROM to islet cells re--suspended in 
autologous plasma and placed in the omentum results in prompt gel (clot) formation and 
adherence of the islets to the surface of the omentum, desirable to promote engraftment. 
The latter is achieved through increased surface exposure and circumventing pelleting, 
which may result in reduced oxygen diffusion, and competition for nutrients and 
accumulation of metabolism bi-products.  
 
1.2 
Study Rationale 
Current islet transplantation into the portal vein of the liver has shown the unique ability 
of islets to stabilize blood glucose levels and prevent severe hypoglycemia in a selected 
group of subjects with Type 1 diabetes. The main limitations of islet transplantation are the 
need for systemic immunosuppression to maintain function and the loss of islet function 
over time. Additionally, many studies have demonstrated that the current site of 
transplantation in the liver is not an ideal site due to several factors.  These factors include 
(1) significant liver inflammation following islet infusion; (2) potential for life-threatening 
procedure-related complications such as bleeding and thrombosis; (3) high levels of 

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immunosuppressive drugs and GI toxins in the liver contributing to islet toxicity; (4) the 
inability to retrieve islets after infusion; and (5) development of graft dysfunction in a 
number of recipients of intrahepatic allogeneic and autologous islets.  
Based on these premises, development of a clinical protocol for the implantation of 
islets into the omentum is a desirable goal. As an attempt to maximize the engraftment of 
islet cell clusters onto the omentum, implantation site should promote islet adherence to 
the omental peritoneal layer and avoid cell pelleting. We have recently performed a series 
of experiments in animal models of diabetes to assess the feasibility of transplanting 
pancreatic islets in the omentum using a plasma-thrombin gel. With our approach, the islets 
are re-suspended in either donor or autologous plasma and distributed onto the omentum. 
Cell adherence is achieved by addition of clinical-grade recombinant human thrombin that 
reacts with plasma to create a biocompatible, degradable gel containing the islet graft. 
Preliminary data obtained as a result of these studies demonstrate the feasibility of our 
approach, and are described in Section 8 of this document. 
We have outlined our initial patient trial as 6 subjects, based on clinical judgment and 
extensive experience in clinical islet transplantation trials. If initial safety and efficacy is 
satisfactory (no adverse events related to the transplantation and efficacy in two of the three 
first transplanted subjects), we will transplant 3 additional subjects. 
 
Following evaluation of the one year post transplant data for the first transplanted 
subject we have observed a decline in beta cell function compared to the 6 months data 
and similar to findings reported in recipients of intrahepatic islet allografts (114). 
Possible factors responsible for this loss/decline in graft function include immunological 
activation (i.e., allo- and/or autoimmune rejection), non-specific inflammatory responses 
and islet graft exhaustion due to metabolic demand in the setting of a marginal mass. In 
addition, factors inherent to this novel transplantation site may have also contributed to 
the observed decrease in beta-cell function.  
 
In order to preserve long-term islet allograft function the introduction of adjuvant 
therapies starting in the peri-transplant period may be required to minimize islet graft loss, 
sustain beta-cell health and decrease burden of metabolic demand on islet allograft.  
 
We have shown that in the intrahepatic site the use of GLP-1 RA therapies improve 
and prolong islet allograft function (115-118) for over 10 years. We have also recently 
reported that combination of GLP-1 RA therapies and granulocyte colony stimulation 
factor (G-CSF) leads to prolonged islet allograft survival (119). These therapies are aimed 
at improving metabolic function and allowing for an immunoregulatory repertoire that may 
promote a tolerogenic environment.  
 
It is known that inflammatory responses account for substantial beta-cell loss early 
after transplantation. Notably, TNF-alpha has been associated with islet graft loss. Farney 
et al. described a beneficial role of etanercept, a TNF-alpha blocker, in promoting 
engraftment of marginal mass islet grafts in mice (91). Hering et al. used etanercept in a 
recent trial of 8 type 1 diabetic patients receiving single donor islet transplant, and all 8 
achieved insulin independence suggesting a beneficial role for anti-TNF therapy in 

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clinical islet transplantation (92). Although experience with anti-TNF alpha therapies in 
clinical and experimental islet transplantation has been limited, the introduction of TNF-
alpha blocking therapies has led to improved long term outcomes likely related to 
improvement in engraftment due to minimization of early graft loss.  
Traditionally we have used etanercept (Enbrel®) as a TNF-alpha blocker in islet 
transplantation (5). Recently, it has been shown that adalimumab (Humira®) in addition 
to blocking TNF-alpha promotes the development of T-regulatory cells (128, 129). 
Adalimumab has been shown to be clinically comparable and with a similar side effect 
profile to Enbrel as tumor necrosis factor blocker. Since adalimumab may also promote a 
tolerogenic environment we will use adalimumab instead of Enbrel as a TNF-alpha 
blocker.  
 However, currently there are no clinical trials that incorporate the use of anti-
inflammatory therapies chronically in islet transplantation.  
 
A safe, orally administered, anti-inflammatory intervention that has been extensively 
evaluated in the medical literature is the use of omega 3 fatty acids (120). The use of omega 
3 fatty acids has been shown to reduce pro-inflammatory metabolites and increase anti-
inflammatory cytokines. The omega 3 fatty acids derived bioactive mediators, resolvins 
and protectins, have been postulated as the molecular basis for the anti-inflammatory 
properties of omega 3 fatty acids (121).  
 
 Derivatives from omega 3 fatty acids [eicosapentaenoic acid (EPA) and 
docosahexaenoic acid (DHA)] have been associated with marked anti-inflammatory effects 
whereas arachidonic acid (AA), an omega 6 fatty acid, is the precursor of eicosanoids 
associated with pro-inflammatory properties. Thus, a high AA/EPA ratio would suggest 
that the balance is shifted towards a pro-inflammatory state. Treatment with omega-3 fatty 
acids aimed at lowering the AA/EPA ratio may then prove to be beneficial particularly in 
diseases associated with a high inflammatory state. 
 
Taking into account the first transplant experience under this protocol as well as 
additional pre-clinical data in small and large animal models, it is clear that adjuvant 
therapies are likely required to improve long-term islet allograft survival and thus we will 
incorporate the following interventions to be started in the peri-transplant period: 
 
a. Pegylated G-CSF (Neulasta®; Pegfilgrastim) 
b. Exenatide extended-release (Bydureon®) 
c. Ultra-refined omega-3 EPA/DHA concentrate (ZoneLabs® OmegaRx®2) 
d. Supplemental oxygen therapy via nasal cannula 
 
 
Pegylated G-CSF (Neulasta®; Pegfilgrastim) 
G-CSF, an agent well known to help mobilize hematopoietic precursors from the bone 
marrow, has been used clinically for nearly 20 years to help repopulate peripheral cell 

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counts in patients undergoing cancer therapy. However, a rapidly growing body of 
experimental and clinical evidence suggests that G-CSF has the potential to be used in the 
treatment of autoimmune diseases. G-CSF has been shown to favor the differentiation 
and mobilization of Treg cells, induce tolerogenic DC, and alter the balance between 
proinflammatory and anti-inflammatory soluble mediators both animals and in humans 
Specifically, G-CSF can mobilize functional bone marrow CD4+CD25+FoxP3+ Treg 
cells. Preclinical models of G-CSF-induced inhibition of autoimmune and allogeneic T 
cell responses have demonstrated the potential efficacy of G-CSF in treating Crohn’s 
disease, myasthenia gravis, and T1D (122). 
Pegylated G-CSF is a covalent conjugate of recombinant methionyl human granulocyte 
colony stimulating factor (filgrastim) and monomethoxypolyethylene glycol. Neulasta® 
is a Colony Stimulating Factor that acts on hematopoietic cells by binding to specific cell 
surface receptors, thereby stimulating proliferation, differentiation, commitment, and end 
cell functional activation. Neulasta® is supplied in 0.6 mL prefilled syringes for 
subcutaneous injection. Each syringe contains 6 mg pegfilgrastim (based on protein 
weight), in a sterile, clear, colorless, preservative-free solution (pH 4.0) containing 
acetate (0.35 mg), sorbitol (30.0 mg), polysorbate 20 (0.02 mg), and sodium (0.02 mg) in 
water for injection, USP. 
 
Exenatide extended-release (Bydureon®) 
The naturally occurring form of exenatide (exendin-4) was originally isolated from the 
salivary secretions of the lizard Heloderma Suspectum (Gila monster). Exendin-4 has a 
53% amino acid sequence overlap with mammalian glucagon-like peptide-1 (GLP-1). In 
mammals, GLP-1 is processed from the proglucagon gene in L-cells in the small 
intestine.  Exendin-4 is transcribed from a distinct gene, not from the Gila monster 
homologue of the mammalian proglucagon gene, from which GLP-1 is expressed. In 
mammals, exendin-4 is resistant to degradation by dipeptidyl peptidase-IV (DPP-IV) and 
has a much longer plasma half-life than GLP-1, which is degraded by DPP-IV with a 
half-life of less than 2 min. Exendin-4 is not an analogue of GLP-1. In other words, the 
structure of the synthetic exendin-4 peptide (exenatide) was not created by sequential 
modification of the structure of GLP-1. However, exendin-4 and GLP-1 share many 
glucoregulatory actions, which may be mediated by the known pancreatic GLP-1 
receptor; they enhance glucose-stimulated insulin secretion and inhibit glucagon 
secretion. (123-125).  
A summary of the effects of GLP-1 are: 
•  Insulinotropic effects, which are glucose dependent (potentiates glucose action with no 
effect on insulin secretion at glucose <4.5mM); this contrasts with the action of other 
insulin secretagogues agents, such as sulfonylureas, which increase insulin secretion 
regardless of glucose concentrations; GLP-1 is therefore unlikely to cause lasting and 
profound hypoglycemia. GLP-1 enhances insulin secretion through the regulation of ion 
channels (including ATP-sensitive K+ channels, voltage-dependent Ca²+ channels, 
voltage-dependent K+ channels, and nonselective cation channels), of intracellular 
energy homeostasis, and exocytosis Moreover, the expression of genes that are essential 
for beta cell function, such as glucokinase and GLUT 2, are up- regulated following 
GLP-1 treatment  

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•  Stimulation of all steps of insulin biosynthesis, as well as insulin gene transcription, 
thereby providing continued supplies of insulin for secretion. Effects on insulin gene 
transcription are proposed to occur via the up-regulation of the transcription factor 
pancreatic duodenal homeobox-1 (PDX-1)  
•  Improvement of insulin sensitivity and glucose uptake, which was reported in human 
and rat adipose tissue and skeletal muscle. Several studies suggest that GLP-1 may 
directly enhance glucose disposal in an insulin-independent fashion, although this may 
also result from the overall inhibition of glucagon secretion  
•  Stimulation of beta-cell proliferation, and enhancement of the differentiation of new 
beta cells from progenitor cells in the pancreatic duct epithelium. A proliferative action of 
GLP-1 on insulin secreting cells has been shown both in vitro and in vivo models. 
•  Inhibition of apoptosis induced by cytokines or free fatty acids.). Studies have shown 
that GLP-1 added to freshly isolated human islets preserves morphology, function and 
inhibits cell apoptosis. (126) Furthermore, the ability of GLP-1 to inhibit apoptosis is 
relevant to the islet transplantation procedure. Treatment of islets with GLP-1 or its 
analog could potentially enhance islet graft survival through inhibition of apoptosis and 
stimulation of proliferation, thus decreasing the requirements for a large islet cell mass  
•  Anti-inflammatory properties, which have been documented in several studies (). Our 
own studies showed that exenatide has anti- inflammatory properties that protect human 
islets in vitro (127). Exenatide treatment improved islet function, significantly reduced 
content of inflammation-related molecules (tissue factor, IFN-γ, IL-17, IL-1β, and IL-2) 
and caspase 3 activation, whereas increased phosphorylation of ERK1/2, STAT3, and 
Akt in vitro. Immunostaining showed expression of GLP-1R in β-cells but not in α-cells. 
IL-1β colocalized with GLP-1R in β-cells. Induction of serine proteinase inhibitor 9 (PI-
9) was detected after exposure of human islets to exenatide in vitro, and after 
transplantation into immunodeficient mice. These anti- inflammatory and cytoprotective 
properties of exenatide could be beneficial to protect the transplanted pancreatic human 
islets. 
 
Ultra-refined 
omega-3 
EPA/DHA 
concentrate 
(ZoneLabs® 
OmegaRx®2)  
A safe, orally administered, anti-inflammatory intervention that has been extensively 
evaluated in the medical literature is the use of omega 3 fatty acids (120). The use of omega 
3 fatty acids has been shown to reduce pro-inflammatory metabolites and increase anti-
inflammatory cytokines. The omega 3 fatty acids derived bioactive mediators, resolvins 
and protectins, have been postulated as the molecular basis for the anti-inflammatory 
properties of omega 3 fatty acids (121).  
 
Derivatives from omega 3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic 
acid (DHA)] have been associated with marked anti-inflammatory effects whereas 
arachidonic acid (AA), an omega 6 fatty acid, is the precursor of eicosanoids associated 
with pro-inflammatory properties. Thus, a high AA/EPA ratio would suggest that the 
balance is shifted towards a pro-inflammatory state. Treatment with omega-3 fatty acids 
aimed at lowering the AA/EPA ratio may then prove to be beneficial particularly in 
diseases associated with a high inflammatory state. 

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Some fish may contain potentially harmful contaminants, such as heavy metals (including 
mercury), dioxins, and polychlorinated biphenyls (PCBs). In order to minimize 
contaminats we will use ultra-refined Omega-3 (ZoneLabs® OmegaRx®2). 
 
Supplemental Oxygen Therapy.  
a. Adequate oxygenation at implantation of the islet allograft is critical for beta cell 
survival. We hypothesize that oxygen supplementation in the peri-transplant period may 
result in increased oxygen delivery at the transplant site allowing for improved 
engraftment and allograft survival. Subjects will be started after islet transplantation on 
supplemental oxygen by nasal cannula at 4L/min (to provide FiO2 of 36%) which will be 
continued throughout the hospitalization, and up to 7 days post hospital discharge.  
 
 
 
2 
Study Objectives and Endpoints 
2.1 
Primary Objectives 
Safety: To demonstrate the safety of islet transplantation onto the omentum for the 
treatment of subjects with Type 1 Diabetes (T1D).  
 
2.2 
Secondary Objectives Efficacy: To demonstrate the efficacy of islet 
transplantation onto the omentum for the treatment of T1D in subjects with hypoglycemia 
unawareness and a history of severe hypoglycemic episodes.  
 
2.3 
Primary endpoints 
The primary safety endpoint is to demonstrate patient safety throughout all stages of 
the trial.  
 
The primary efficacy endpoint is the proportion of subjects with HbA1c ≤6.5% at 1 
year AND free of severe hypoglycemic events from Day 28 to Day 365, inclusive, after 
the islet transplant. 
 
 
 
2.4 
Secondary endpoints 
Secondary Efficacy Endpoints 
 
 
At 75±7, 365 ± 14 ,and 730 ± 14 days following the islet transplant(s): the percent 
reduction in insulin requirements; HbA1c; LI; Ryan hypoglycemia severity (HYPO) score; 
Clarke score; number of severe hypoglycemic episodes; basal (fasting) and 90-min glucose 
and c-peptide derived from the mixed-meal tolerance test (MMTT); β-score; C-

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peptide/glucose creatinine ratio; glucose variability and hypoglycemia duration derived 
from the continuous glucose monitoring  (CGM); and Quality of life (QOL) measures (EQ-
5D, Hypoglycemia Fear Survey-HFS, SF-36v2, Diabetes Distress scale).) 
 
 
Secondary Safety Endpoints 
Safety, including incidence of post-transplant infections, malignancies, morbidity, and 
other AEs (e.g., increased body weight and hypertension) associated with conventional 
immunosuppression. Renal function as measured by serum creatinine, GFR and other 
relevant laboratory parameters. Lipid profiles (triglycerides, total cholesterol, LDL 
cholesterol, HDL cholesterol) over time. 
 
At 75 ± 7 and 365 ± 14 days following the islet transplant, and at two years following 
the final islet transplant: the incidence and severity of AEs related to the islet transplant 
procedure including: bleeding (>2 g/dL decrease in hemoglobin concentration); wound 
complication (infection or subsequent hernia); torsion of omentum; gastrointestinal 
obstruction; abscess; cysts; need for surgical intervention. The incidence and severity of 
AEs related to the immunosuppression including: allergy; reduction in GFR; addition or 
intensification of antihyperlipidemic therapy; gastrointestinal toxicity; neutropenia, 
anemia, or thrombocytopenia; viral, bacterial, or fungal infections; and benign or malignant 
neoplasms. The incidence of immune sensitization defined by presence of anti-HLA 
antibodies absent prior to transplantation. The incidence of discontinuation of 
immunosuppression. 
 
2.5 
Statistical considerations and analytical plan 
Insulin usage will be estimated from the one-week self-report values.  Estimates of 
population means and confidence intervals for those means will be reported for each 
follow-up visit.  Linear mixed models methods will be used to describe the profile of 
change with time. 
Numbers of severe hypoglycemic events will be estimated from the self-report values 
obtained at each follow-up visit.  Estimates of population means and confidence intervals 
for those means will be reported for each follow-up visit.  Linear mixed models methods 
with appropriate likelihood functions will be used to describe trends with time. 
HbA1c and serum creatinine levels will be measured at study entry and at each follow-up 
visit.  GFR will be estimated using the updated CKD-EPI method.  Estimates of 
population means and confidence intervals for those means will be reported for each 
follow-up visit.  Linear mixed models methods will be used to describe trends with time. 
Incidence of serious adverse experiences will be tabulated by body system and graded by 
Terminology Criteria for Adverse Events (TCAE).   
Life table methods will be used to estimate mortality rates. 

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2.5.1 Baseline Characteristics and Demographics 
Summary descriptive statistics for baseline and demographic characteristics will be 
provided for all subjects in the transplanted sample.  Demographic data will include age, 
race, sex, body weight, and height; these data will be presented in the following manner: 
• 
Continuous data (i.e., age, body weight, and height) will be summarized 
descriptively by mean, standard deviation, median, and range.   
• 
Categorical data (i.e., sex and race) will be presented as enumerations and 
percentages.   
Statistical presentation for baseline and demographic characteristics may be further 
summarized by values of important baseline predictors of outcome and will be further 
defined in the SAP. 
 
 

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3 
STUDY DESIGN 
 
Figure 1: Study Design Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
Identify and approach potential study subject 
If potential study subject agrees to participate in the study, obtain written Informed Consent 
Screening and Enrollment 
Enroll subject using Velos  and receive computer generated unique subject ID number 
Perform screening visit assessment & evaluate all Inclusion / Exclusion criteria to determine subject 
eligibility 
Place eligible subject on waiting list 
Waiting list / Baseline procedures 
Repeat screening assessments as indicated on the SOE to ensure subject remains eligible for 
transplant 
Compatible islet preparation available 
Evaluate all Inclusion / Exclusion criteria to 
reconfirm eligibility 
Termination 
Terminate subjects who are no longer 
eligible 
Obtain transplant consent before islet transplant 
Study Treatment and Islet Transplant 
Subjects receive allogeneic islets, implanted into 
omentum
Reduced Follow-up 
Subjects withdrawn from study treatment 
for any reason enter a post-graft failure 
follow-up (5.6.2) 
Follow-up 
Subjects are followed for 24 months after the transplant 

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3.1 
Patient Population 
This trial is an open label, single-arm, Phase I/II, single center trial.  
 
Potential participants will be initially identified using pre-screening tools as approved 
by the IRB. Candidates who meet the general inclusion/exclusion criteria will be 
consented, enrolled, and assigned a unique subject identification number. Subjects will 
then be more thoroughly evaluated for eligibility as part of the protocol-specific screening 
visit procedure. Recruitment at the University of Miami will continue until all subjects 
[N=6] needed for the trial are identified, appropriately consented, screened and 
transplanted. 
 
3.1.1 
Placement of Islets into the Omentum  
The central hypothesis of this proposal is that the transplantation of islets in a more 
favorable alternative site, i.e. omentum, will result in similar islet engraftment (and 
therefore similar or higher rates of insulin dose decrease and similar or better metabolic 
outcomes) than conventional islet transplants in the liver. In the last 7 intraportal islet 
infusions, there was an insulin reduction of 57 ± 16% reduction of insulin use (range 
32 to78%), basal c-peptide 0.85 ± 0.35 ng/ml (range 0.4 to 1.48 ng/ml), and 90 minute 
C-peptide 1.89 ±1.19 ng/ml (range 0.8 to 4.3 ng/ml) at 75 days after a single islet 
infusion. Immunosuppression regimen will be similar to that used in the CIT 
consortium trials (44). In order to avoid side effects related to Sirolimus (e.g. 
impairment of wound healing), we will use Tacrolimus and Mycophenolate Mofetil 
(MMF) as maintenance immunosuppression. This protocol has proven to be successful 
in recent islet clinical trials conducted by the Edmonton group (45, 46). 
 
3.2 
Inclusion Criteria 
Patients who meet all of the following criteria are eligible for participation in the study: 
 
1. Male and female patients age 18 to 65 years of age. 
2. Ability to provide written informed consent. 
3. Mentally stable and able to comply with the procedures of the study protocol. 
4. Clinical history compatible with T1D with onset of disease at <40 years of age, insulin-
dependence for > 5 years at the time of enrollment, and a sum of subject age and insulin-
dependent diabetes duration of ≥28. 
5. Absent stimulated c-peptide (<0.3ng/mL) in response to a MMTT (Boost® 6 mL/kg 
body weight to a maximum of 360 mL; another product with equivalent caloric and 
nutrient content may be substituted for Boost®) measured at 60 and 90 min after the 
start of consumption. 
6. Involvement in intensive diabetes management, defined as self-monitoring of glucose 
values no less than a mean of three times each day averaged over each week and by the 
administration of three or more insulin injections each day or insulin pump therapy. 
Such management must be under the direction of an endocrinologist, diabetologist, or 
diabetes specialist, with at least 3 clinical evaluations during the 12 months prior to 
study enrollment. 

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7. At least one episode of severe hypoglycemia in the 12 months prior to study enrollment. 
8. Reduced awareness of hypoglycemia as defined by a Clarke score of 4 or more  
OR  
A HYPO score greater than or equal to the 90th percentile (1047) during the screening 
period; 
 
OR 
Marked glycemic lability characterized by wide swings in BG despite optimal diabetes 
therapy and defined by a lability index (LI) score greater than or equal to the 90th percentile 
(433 mmol/L2/h·wk-1) during the screening period; 
 
OR 
A composite of a Clarke score of3 or less and a HYPO score greater than or equal to the 
75th percentile (423) and a LI greater than or equal to the 75th percentile (329) during the 
screening period. 
 
 
3.3 
Exclusion Criteria 
Patients who meet any of these criteria are not eligible for participation in the study: 
 
1. Body Mass Index (BMI) >30 kg/m2 or patient weight ≤50 kg. 
2. Insulin requirement of >1.0 IU/kg/day or <15 U/day. 
3. HbA1c >10%. 
4. Untreated proliferative diabetic retinopathy. 
5. Blood Pressure: SBP >160 mmHg or DBP >100 mmHg. 
6. Measured glomerular filtration rate <80 mL/min/1.73 m2 calculated using the subject's 
measured serum creatinine and Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) equation1 or Modification of Diet in Renal Disease [MDRD] study 
estimation formula). Strict vegetarians (vegans) with a calculated GFR <70 
mL/min/1.73m2 are excluded. The absolute (raw) GFR value will be used for subjects 
with body surface areas >1.73m2 
7. Presence or history of macroalbuminuria (>300mg/g creatinine). 
8. Presence or history of panel-reactive anti-HLA antibodies above background by flow 
cytometry. 
9. For female subjects: Serum or urine Positive pregnancy test, presently breast-feeding, 
or unwillingness to use effective contraceptive measures for the duration of the study 
and 4 months after discontinuation. For male subjects: intent to procreate during the 
duration of the study or within 4 months after discontinuation or unwillingness to use 
effective measures of contraception. If sexually active, subject must use at least two 
medically accepted methods of birth control from the following list: oral 
contraceptives, Norplant®, Depo-Provera®, intrauterine device (IUD), barrier devices 
with spermicide. Condoms used alone are not acceptable. Instead of the male condom, 
it is acceptable to use a female condom with one of the other methods for women listed 
above. 

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10. Presence or history of active infection including hepatitis B, hepatitis C, HIV, or 
tuberculosis (TB) Subjects with laboratory evidence of active infection are excluded 
even in the absence of clinical evidence of active infection. 
11. Negative screen for Epstein-Barr Virus (EBV) by IgG determination. 
12. Invasive aspergillus, histoplasmosis, and coccidioidomycosis infection within one year 
prior to study enrollment. 
13. Any history of malignancy except for completely resected squamous or basal cell 
carcinoma of the skin. 
14. Known active alcohol or substance abuse. 
15. Baseline Hb below the lower limits of normal at the local laboratory; lymphopenia 
(<1,000/µL), neutropenia (<1,500/µL), or thrombocytopenia (platelets <100,000/µL). 
Participants with lymphopenia are allowed if the investigator determines there is no 
additional risk and obtain clearance from a hematologist. 
16. A history of Factor V deficiency. 
17. Any coagulopathy or medical condition requiring long-term anticoagulant therapy 
(e.g., warfarin) after transplantation (low-dose aspirin treatment is allowed) or patients 
with an international normalized ratio (INR) >1.5. 
18. Severe co-existing cardiac disease, characterized by any one of these conditions: 
a.) recent myocardial infarction (within past 6 months). 
b.) evidence of ischemia on functional cardiac exam within the last year. 
c.) left ventricular ejection fraction <30%. 
19. Persistent elevation of liver function tests at the time of study entry. Persistent serum 
glutamic-oxaloacetic transaminase (SGOT [AST]), serum glutamate pyruvat 
transaminase (SGPT [ALT]), Alk Phos or total bilirubin, with values >1.5 times normal 
upper limits will exclude a patient. 
20. Symptomatic cholecystolithiasis. 
21. Acute or chronic pancreatitis. 
22. Symptomatic peptic ulcer disease. 
23. Severe unremitting diarrhea, vomiting, or other gastrointestinal disorders potentially 
interfering with the ability to absorb oral medications. 
24. Hyperlipidemia despite medical therapy (fasting low-density lipoprotein [LDL] 
cholesterol > 130 mg/dL, treated or untreated; and/or fasting triglycerides > 200 
mg/dL). 
25. Receiving treatment for a medical condition requiring chronic use of systemic steroids, 
except for the use of ≤5 mg prednisone daily, or an equivalent dose of hydrocortisone, 
for physiological replacement only. 
26. Treatment with any anti-diabetic medications other than insulin within 4 weeks of 
enrollment. 
23. Use of any investigational agents within 4 weeks of enrollment. 
24. Administration of live attenuated vaccine(s) within 2 months of enrollment. 
25. Any medical condition that, in the opinion of the investigator, will interfere with the 
safe participation in the trial. 
26. Treatment with any immunosuppressive regimen at the time of enrollment. 
27. A previous islet transplant. 

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28. A previous pancreas transplant, unless the graft failed within the first week due to 
thrombosis, followed by pancreatectomy and the transplant occurred more than 6 
months prior to enrollment. 
29. Inflammatory bowel disease. 
30. History of intestinal obstructions. 
31. Previous major abdominal surgery. 
32. History of peritonitis. 
4 
TREATMENT OF PATIENTS 
4.1 
Study Therapy and Dosages 
4.1.1 
Study Investigational Therapy: Isolation of Allogeneic Islet Cells 
 
Pancreas is removed from the shipping container with UW solution and placed in a 
tray with Trimming Solution with Cefazolin (a sample of UW is collected for 
microbiological analysis), placed in a larger tray with 1 L of cold sterile ice slush. The 
organ is trimmed of fat and non-pancreatic tissue, and weighed.   
 
Trimming Solution is poured off, the tray with pancreas is removed from ice, and 
the organ is rinsed with HBSS. The pancreatic duct is cannulated with a 16-18 gauge 
angiocatheter, and the pancreas is distended with cold collagenase solution (Liberase 
MTF and Thermolysin dissolved in water, supplemented with HEPES, Calcium 
Chloride, NaOH, DNAse). The distended organ is placed inside a digestion chamber 
(47-49); additional collagenase solution is added, re-circulated and brought to 37oC, 
while chamber is agitated (47-49).  During the digestion samples are collected at 
regular intervals to monitor the breakdown of the pancreas, via microscopy.  When 
sufficient number of free islets are detected by DTZ staining, digestion is stopped, the 
heat is switched off, and digest is collected (while collagenase is diluted) in cold RPMI-
1640 (with 5-1.5% HSA, DNAse, 25 mM HEPES, 10 U/ml Heparin, 0.2 U/ml insulin) 
to quickly cool the digest. The digest is centrifuged and washed in Wash Solution (Cold 
Storage / Purification Stock Solution, 10% PentaStarch, 0.625% HSA, 10 U/ml 
Heparin, 0.2 U/ml Insulin).  Digest volume is recorded, and re-suspended in the final 
volume of 200 ml of CIT Purification Solution (Cold Storage / Purification Stock 
Solution, 10% PentaStarch, 10 U/ml Heparin). Islets are separated from exocrine tissue 
using continuous and modified continuous density gradient centrifugation, in a COBE 
2991 blood cell processor (47-51).   
 
Continuous gradients are composed of Purification Solution mixed with OptiPrep, 
10% PentaStarch and gradient Stock Solution to achieve densities of 1.100 gm/ml and 
1.065gm/ml. 20-30 ml of pancreatic digest is re-suspended in 100 ml total volume of 
Purification Solution, and incubated in the cold, for 30-45 minutes. High density 
gradient is topped off with a continuous density gradient made from the 1.100 and 
1.077 or 1.6065 density gradients, loaded while the COBE 2991 is spinning at a speed 
of 2,000 rpm. At this point, the digest is loaded and centrifuged 3-5 minutes. Purified 
islets are collected in fractions, the purity of which is assessed with DTZ. Islet fractions 
with purities >30% are saved and washed with CMRL-1066. Similar purity fractions 
are then combined for culture.  

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Modified continuous purification is used as a rescue purification method. Light 
(1.062 gm/ml) and heavy (1.073 gm/ml) modified continuous density gradients are 
achieved by adding different volumes of 1.1gm/ml Biocoll to UW. Up to ~45 ml of 
digest is re-suspended in 150 ml of UW and incubated for ~30 minutes. Biocoll 1.1 
gm/ml is loaded first, followed by heavy, 1.073 gm/ml, and light, 1.062 gm/ml, density 
gradients, followed by the digest. Digest is centrifuged for 3 minutes at 3000 rpm, islets 
are collected in the CMRL-1066, and their purity is assessed. Fractions of similar purity 
are cultured together.   
 
Islets are cultured 36-72 hours, in 95% air, and 5% CO2, at 37°C, in CMRL 1066, 
Supplemented (0.5% HSA, 10 U/ml Heparin and IGF-1), at a concentration of ~20,000 
IEQ/30 ml media, in 175cm2 tissue culture flasks. Islets with purity ≥70% are cultured 
at 37°C for the first 12-24 hours, and at 22°C thereafter; islets with purity ≤70% are 
cultured at 22°C. In preparation for implantation onto the Omentum, islets are collected 
from the tissue culture flasks, re-suspended in Tx media (CMRL 1066, 2.5% HSA, 25 
mM Hepes), washed and settled by gravity to remove cellular debris. Final assessment 
samples are collected at this point. The final settled islet cell pellet is transferred to a 
10 or 20 ml luer-lock syringe, depending on the settled tissue volume. 
 
4.1.2 
Study Investigational Therapy: Administration 
 This is a single procedure protocol. Only a single islet transplant will be performed 
in the patient. Islets are isolated from a single pancreas donor. A minimum of 5000 
IEQ/KG will be transplanted. A single dose of at least 5000 IEQ/KG should be able to 
achieve a meaningful metabolic improvement and prevention of severe hypoglycemia, 
as previously seen in our experience with intraportal islet transplants. 
Allogeneic islet cells will be isolated as described in section 4.1.1of this document 
(see above) and cultured for 36-72 hours. At the time of transplant, islets will be 
collected in a sterile conical tube, and settled by gravity. The final settled islet cell 
pellet in Tx media (CMRL 1066, 2.5% HSA, 25 mM Hepes) will be transferred to a 
10 or 20 ml luer-lock syringe, depending on the settled tissue volume. The final 
settled islet cell pellet is transported to the Operating Room (OR) in the final 
container (10-20 ml luer-lock syringe), washed in autologous plasma, settled again, 
and re-suspended in 2:1 ratio of settled islet cell pellet to autologous plasma for 
implantation in the omentum. The final islet product is a sterile suspension of ≥70% 
viable, ≥30% pure, allogeneic islets. The final product contains a single dose of 5,000 
or more Islet Equivalents (IEQ)/kg recipient body weight (BW). 
At the time of transplant and under general anesthesia, through a laparoscopic 
approach and/or mini laparotomy the islets will be delivered and distributed on the 
surface of the omentum using a 12 Fr. Gastrostomy catheter (Cook Medical).  
RECOTHROM® will be added to promote formation of a gel clot (as needed to cover the 
graft surface, approximately in a volume equal to that of the graft implanted) to 
promote islet cells adhering to the surface of the omentum, and avoid cell pelleting.  
An omental pouch will be created by wrapping the islets with an omental flap. Each 
procedure is projected to take approximately 1-2 hours. Recombinant human thrombin 

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is added to the islets placed on the omentum to promote formation of a gel clot and 
facilitate adherence to the surface of the omentum. Only in the case of a surgical 
complication a secondary procedure will be performed if needed. We have included in 
the exclusion criteria possible scenarios that may require future surgeries or subjects 
with previous abdominal surgeries, inflammatory bowel disease, and history of bowel 
obstruction.  
 
4.1.3 
Dose Rationale 
This study is not a dose escalation study. A single dose of 5,000 or more IEQ/kg 
recipient body weight (BW) will be transplanted. 
There is no method to assess islet survival as a fraction of surviving cells/total islets 
transplanted.  Once the patient is stabilized (in 6 – 8 weeks), however, it is possible to 
monitor islet mass via FSIGT.  FSIGT allows for measurement of acute insulin release 
in response to the injected glucose (38, 48). 
Our extensive past experience with islet transplantation has proven that a dose of 
≥5,000 IEQ/kg recipient body weight (BW) has proven to be safe, and demonstrated to 
result in long term improvement of metabolic control, and reduction of hypoglycemic 
unawareness associated with intensive insulin therapy (52-63).  
 
Although this study is a single dose protocol, islet transplant recipients with partial 
islet graft function will be considered for a second islet transplant (intra-hepatic 
administration) if they: 
 
a. 
do not achieve primary efficacy endpoint criteria at 1 year, or  
b. 
have evidence of a progressive decline in stimulated C-peptide during a 
MMTT resulting in either reintroduction of insulin therapy or increase in insulin 
requirements, or  
c. 
experience severe hypoglycemia from Day 28 to Day 365. 
 
In order to be eligible for a second islet transplant, the following requirements must be met:  
 
1. Subject received ≥5,000 IE/kg with the first transplant, but failed to achieve 
primary efficacy endpoint. 
2. Subject has been compliant with study monitoring and prescribed 
immunosuppressive therapy.  
3. Subject has no unresolved SAEs.  
4. No evidence of progressive renal dysfunction, with blood creatinine rising above 
2.0 mg/dL (177 μmol/L).  
5. No evidence of hypersensitization, allergic responses, or other potentially serious 
drug reactions to medications required by the protocol.  
6. PRA <50% by flow cytometry (assessment performed locally) and the 
alloantibody specificity not cross-reactive with antigen(s) present in the subsequent 
islet preparation in order to avoid unacceptable antigen(s).  

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7. Absence of any medical condition that, in the opinion of the investigator, will 
interfere with a safe and successful second islet transplant.  
 
 
If a participant is deemed eligible for an intrahepatic islet infusion, the participant 
will continue to be followed according to the 2nd year schedule of events until 
intrahepatic islet transplantation is performed at which time follow up will reset 
and continue for 2 years as per protocol.  
 
D-dimer testing and samples for unmethylated insulin DNA (Benaroya 
collaboration) are not required to be obtained for intrahepatic islet transplants under 
this protocol.  
 
If graft failure occurs after the second islet transplant, these recipients will be 
considered treatment failures and immunosuppression will be withdrawn. 
Islet transplant recipients with partial islet graft function, i.e. subjects who do not 
achieve primary endpoint criteria at 1 year follow-up, will be eligible to receive a 
second islet transplant via intra-hepatic administration. With the exception of 
performing induction with basiliximab (Simulect®) instead of anti-thymocyte globulin 
(ATG, Thymoglobulin®), the regimen will be identical to the initial islet transplant.  
The transplant will be done by a radiologist in the Special Procedures section of the 
Radiology department, under local anesthesia and conscious sedation. Islets will be 
infused under sterile conditions over 20-30 min. by gravity drainage. Gel foam plugs 
and/or collagen/thrombin paste will be used to embolize the entire peripheral catheter 
tract immediately before the catheter is withdrawn, to reduce the chances of bleeding. 
A minimum of 5,000 IEQ/kg recipient body weight (BW) will be transplanted to 
maximize possibility of insulin independence.  
In case the PI decides it is not safe for the subject to have the second transplant 
through intrahepatic infusion (in radiology), he can offer a second infusion through a 
mini-laparotomy (in the operating room). 
The mini-laparotomy is done under general anesthesia. A small incision (about 2-3 
inches) is done on the abdominal wall.  The surgeon will do a catheterization of the 
mesenteric vein toward the portal vein.  The study team will then infuse the islets into 
the portal system. Islets will be delivered from the Ricordi bag through catheter into 
your liver over about 30±25 minutes. The portal vein blood pressure will be checked 
often to make sure it does not critically increase. After the islets are injected, the 
catheter will be removed and the vein it was in will be tied off so it does not bleed.  The 
incision will be closed with stitches, and a sterile dressing will be put over the incision. 
 
4.1.4 
Dosage and Dosing 
The study team will maintain detailed records as to the cell dose each patient 
enrolled in this study will receive. Allogeneic islet cells will be placed in the omentum, 
under general anesthesia, by a mini laparotomy and/or laparoscopic approach. During 
the procedure, patients will be monitored followed established standard of care. The 

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procedure will be terminated if the patient becomes unstable.  
 
4.1.5 
Storage and Handling of Study Investigational Therapy 
Study therapy (allogeneic islet cells) will be dispensed only after a patient has 
provided a written informed consent, met all eligibility criteria for entry into the study, 
and completed all the necessary evaluations. As the cells are intended for 
administration immediately following preparation, they will be destroyed should 
they’re not used right away.   
4.1.6 
Study Investigational Therapy Accountability Procedures 
The Principle Investigator (PI) is responsible for the study investigational therapy 
accountability, reconciliation, and record maintenance. In accordance with all 
applicable regulatory requirements, the PI or the cGMP Cell Processing Facility (CPF) 
responsible for cell manufacture will maintain accountability records throughout the 
length of the study.  
5 
STUDY PROCEDURES 
5.1 
Study outline 
• 
Prior to transplantation, the patient is screened, qualified, listed for transplanted, and 
signs the informed consent form. 
 
• Subjects screening data from 20053135 protocol will be accepted for subjects eligible 
for this study. If 20053135 visit was 12 months prior to enrollment, Visit 2 laboratory 
should be repeated.  
 
• At the time a suitable islet preparation becomes available, the patient will receive 
allogeneic islet cells transplanted onto the omentum.  Islet transplant will be 
performed under rabbit Anti-Thymocyte Globulin (ATG, Thymoglobulin®) induction 
immunosuppression (5 doses, day -2 prior to transplant to day 2 post-transplant).  
Maintenance mycophenolate mofetil (MMF) therapy (1-2 g/day as BID dosing) will 
be started on Day –1 pre-transplant. Tacrolimus will be administered orally twice 
daily starting on Day 1 post-transplant to target a trough level of 10-12 ng/mL for the 
first 3 months, and 6-10 ng/mL thereafter. However, target drug levels will ultimately 
depend on clinical status, tolerability, and biochemical/immunological profiles as 
determined by the principal investigator. 
  
 Adalimumab (Humira) will be given IV before the islet transplant (80 mg) and then 
40 mg subcutaneously every 2 weeks after islet transplant for 2 doses. 
 

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5.2 
Islet Transplant: Immunosuppression, Adjuvant Therapies and Concomitant 
Medications  
The immunosuppressive agents used in this study are being administered for an 
indication other than the one for which they are currently approved and for use in 
combinations, which have not been formally studied. These medications have only been 
used for a short period of time and in a small number of subjects. In the islet transplant 
setting, they have been used in several islet alone and islet after kidney transplant trials. A 
number of known side effects can be experienced when taking these drugs. The study 
medications will be provided by study team upon to 2 years after the last islet infusion.  
 
IMMUNOSUPPRESSION REGIMEN 
o Induction immunosuppression will consist of five doses IV infusion of rabbit Anti-
thymocyte Globulin (ATG, Thymoglobulin®), starting two days prior to the islet 
transplant. The doses will be administered as directed on the package insert.  
 
Considering that the presence of pre-formed rabbit antibodies may predict the 
occurrence of an immunologic response against Thymoglobulin®, participants 
will be tested during the screening visit for presence of antibodies to rabbit serum 
proteins and epithelium.  
 
Patients who have: a) a positive history of rabbit allergy/anaphylaxis, or b) 
positive IgE to rabbit serum proteins and/or epithelium, will not be eligible to 
undergo induction with Thymoglobulin® due to the increased risk for an 
anaphylactic reaction. These patients will be considered for induction with 
alemtuzumab (see below) once this drug becomes available for utilization under 
this protocol.  
 
o Maintenance mycophenolate mofetil (MMF) therapy (1-2 g/day as BID dosing) 
will be started on Day –1 pre-transplant. Tacrolimus will be administered orally 
twice daily starting on Day 1 post-transplant to target a trough level of 10-12 
ng/mL for the first 3 months, and 6-10 ng/mL thereafter. However, target drug 
levels will ultimately depend on clinical status, tolerability, and 
biochemical/immunological profiles as determined by the principal investigator. 
 
 
Rabbit Anti-Thymocyte Globulin (ATG, Thymoglobulin)  
A total of 6 mg/kg will be given as an IV infusion on days –2, -1, 0, +1, and +2. The dose 
will be 0.5 mg/kg on day –2, 1.0 mg/kg on day –1, and 1.5 mg/kg on days 0, +1, and +2. 
The doses will be administered as directed on the package insert. 
 Pre-medications will be used as follows: 
#1: Acetaminophen (Tylenol) 650 mg PO/PR ½ hr before and midway through ATG 
infusion 
#2: Diphenhydramine (Benadryl) 50 mg PO ½ hr before and midway through ATG 
infusion 
#3: Methylprednisolone (Solu-Medrol®) 1 mg/kg IV one hour prior to ATG infusion and 
as needed to prevent cytokine release syndrome.  

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#4: Pentoxifylline (Trental®) 400 mg PO TID to be initiated one hour prior to the first 
ATG infusion and to be continued through day +7 
 
If the subject is admitted when the vascular access team is not available or at a time when 
the placement of a Peripherally Inserted Central Catheter could delay the first 
Thymoglobulin® dose, it may be administered IV via a peripheral line as follows: 
• Dilute the Thymoglobulin® in 500 cc Normal Saline (not D5W) 
• Combine with Heparin 1000 units and Hydrocortisone 20 mg. 
 
If a significant adverse reaction to Thymoglobulin® occurs, the patient will be treated 
accordingly, the transplant will be cancelled and no further doses of Thymoglobulin® 
will be administered. The patient will undergo islet transplantation at a later time under 
induction with basiliximab which will be administered as described for participants who 
are eligible for a second islet transplant (see section 5.3).   
 
Alemtuzumab (Lemtrada®): 
Alemtuzumab induction, instead of Thymglobulin®, will be performed in the event of high 
risk for anaphylactic reaction to Thymoglobulin® (i.e. patients with history of rabbit 
allergy/anaphylaxis or having positive IgE to rabbit serum protein and/or epithelium). 
  
Induction with alemtuzumab will consist of an initial dose of 20mg IV over 3 hours given 
on Day –1 and a second dose of 20mg IV administered on the day of transplant.  
           Patients will pre-medicated 30 minutes before the first dose of alemtuzumab with Benadryl 
(50mg IV), acetaminophen (650mg PO), ibuprofen (400mg PO) and (Solumedrol 125mg 
iv). Pre-medication, WITHOUT Solumedrol, will also be given before the second dose of 
alemtuzumab. 
 
We will monitor and perform Risk Evaluation and Mitigation Strategy (REMS) for 
Alentuzumab (Lemtrada®) due to serious risks of autoimmune conditions, infusion 
reactions and malignancy. 
 
 
Mycophenolate mofetil (CELLCEPT)  
Maintenance mycophenolate mofetil (MMF) therapy (1-2 g/day as BID dosing) will be 
started on Day–1 pre-transplant. 
The MMF treatment regimen may be modified if clinically required, (e.g. in times of inter-
current illness, suspected graft dysfunction, or other clinical circumstances including 
intolerable or undesirable side effects) at the discretion of the Principal Investigator. 
Enteric-coated mycophenolate sodium (Myfortic®) may be substituted for MMF, at the 
discretion of the Principal Investigator and as clinically indicated. Standard mycophenolate 
sodium dosing is 720 mg PO BID (or as tolerated).  
Mycophenolate-containing medicines are associated with an increased risk of first 
trimester pregnancy loss (miscarriage) and congenital malformation (birth defects) if taken 
during pregnancy. Subjects will be informed on these risks and must practice two methods 
of contraception while taking MMF.  

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If a subject experiences severe neutropenia (absolute neutrophil count <1x109/L) while 
taking mycophenolate mofetil), mycophenolate mofetil exposure will be reviewed and 
mycophenolate mofetil administration will be adjusted as part of the study protocol’s 
neutropenia management plan. 
  
The protocol and informed consent will be consistent with MMF’s Risk Evaluation and 
Mitigation Strategy (REMS). “Mycophenolate can cause fetal harm when administered to 
a pregnant female. Exposure to mycophenolate during pregnancy is associated with 
increased risks of: First-trimester pregnancy loss, congenital malformations (especially 
external ear and abnormalities such as a cleft lip and palate), anomalies in babies of the 
distal limbs, heart, esophagus, and kidney”. We will follow the following steps to help 
ensure the successful implementation of Mycophenolate REMS with females with 
reproductive potential: 
1.Enroll in Mycophenolate REMS  
2.Check Pregnancy Status  
3.Educate Females of Reproductive Potential  
4.Obtain a Signed Patient-Prescriber Acknowledgment Form  
5.Report Any Mycophenolate-Exposed Pregnancies. 
 
Tacrolimus (PROGRAF)  
Tacrolimus will be administered orally twice daily starting on Day 1 post-transplant to 
target a trough level of 10-12 ng/mL for the first 3 months, and 6-10 ng/mL thereafter. 
However, target drug levels will ultimately depend on clinical status, tolerability, and 
biochemical/immunological profiles as determined by the principal investigator. 
Should subjects experience a sustained increase in serum creatinine ≥ 2 times pre-
transplant baseline or decrease in their eGFR of ≥33% compared with baseline, a 
nephrology consult will be obtained, and Tacrolimus target trough levels will be reduced 
by 25% should CNI toxicity be suspected as the primary cause for the decline in renal 
function. 
 
Sirolimus (RAPAMUNE®) 
Sirolimus will be used in case of Tacrolimus or/and mycophenolate mofetil intolerance.  
 
 
ADJUVANT INTERVENTIONS 
b. Pegylated GCSF (Neulasta®) will be administered at a dose of 6mg SC every two 
weeks for a total of 6 doses (post-operative day [POD] 2, 14, 28, 42, 56, and 70).  
c. Exenatide extend-release (Bydureon®) will be administered subcutaneously at a dose 
of 2 mg SC weekly for as long as there is islet allograft function (POD -2 and weekly 
thereafter). If not tolerated or at the discretion of the PI we may consider an alternative 
GLP-1 RA or a DPP-4 inhibitor.  
d. Ultra-refined omega-3 EPA/DHA concentrate (ZoneLabs® OmegaRx®2 Fish Oil - 
Liquid). Patients will be started at a dose of one teaspoon (i.e., 4500 mg fish oil 
concentrate containing 2250 mg EPA and 1125 mg DHA in 5 mL) of Omega 3 fish oil 

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for the first two days (starting on POD -2) and then increasing to one tablespoon (i.e., 
13500 mg fish oil concentrate [6750 mg EPA, 3375 mg DHA]) by the third day and 
continuing daily administration thereafter. If liquid form is not tolerated, subject will be 
started on OmegaRx®2 capsules (containing 500 mg EPA and 250 mg DHA per 
capsule). The starting dose will be 1 capsule twice a day and increased up to 4 capsules 
three times a day as tolerated. Dose will be adjusted to maintain a target AA/EPA ratio of 
1.0-2.0. AA/EPA ratios will be monitored monthly until achieving target levels and as 
clinically indicated thereafter. 
e. Supplemental oxygen therapy. Supplemental oxygen will be delivered to subjects via 
nasal cannula at 4L/min continuously starting after islet transplantation, throughout the 
hospitalization, and up to 7 days post hospital discharge.  
 
 
CONCOMITANT MEDICATIONS 
Concomitant medications may be administered, as per standard clinical practice. Listed 
below are the expected concomitant medications to be used after islet transplant. A detailed 
list will be kept of all medications a subject takes from the time of admission for 
transplantation. However, a number of drug interactions with the three immunosuppressive 
agents are known to exist. Concomitant administration of any drug known to interact with 
the study drugs should be carefully considered and monitored as appropriate. Please refer 
to package inserts and investigational brochures of these drugs. It will be suggested that 
the participant refrain from using any herbal remedies.   
 
• Immunosuppressive / Anti-Inflammatory Therapy: Adalimumab (Humira) will be 
given IV before the islet transplant (80 mg) and then 40 mg subcutaneously every 2 weeks 
after islet transplant for 2 doses. 
• Antibacterial, 
Antifungal, 
and 
Antiviral 
Prophylaxis: 
Broad-spectrum 
antimicrobial prophylaxis should be administered preoperatively according to site-
specific standards, or as the Transplant Infectious Disease consultant recommends. 
 
• Trimethoprim / sulfamethoxazole (Septra SS®/Bactrim®): Trimethoprim / 
sulfamethoxazole will be administered at a dose of 80 mg/400 mg PO QD starting on 
Day +1 for the duration of study follow-up. In the event that a subject is unable to take 
Trimethoprim/Sulfamethoxazole, he/she will be treated on a case-by-case basis as is 
medically indicated. 
 
• Clotrimazole (Mycelex Troche) Clotrimazole will be administered as 1 troche PO 
QID starting on day –2 relative to transplant, to be continued for 3 months after 
transplantation. Alternatively, antifungal prophylaxis per standard practice at each site 
may be administered instead of Clotrimazole. 
 
• Valganciclovir (Valcyte) Valganciclovir will be administered starting on day -2 at a 
dose of 450 mg PO QD, increasing to 900 mg QD by day 12 and continuing for 14 
weeks post-transplantation. If the CMV status of the donor and recipient are both 
negative, then Valganciclovir administration can be adjusted or eliminated. 
 

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INSULIN THERAPY 
Glucose levels will be targeted to 80-120 mg/dL. Insulin (e.g., Regular, Lispro, NPH, 
Glargine) will be administered, as needed, to maintain glucose levels in the target range. 
The subject will test BG five times per day (AM fasting, before lunch, 2 hours after lunch, 
before supper, and at bedtime). For subjects not on CGM, a CGM device will be placed on 
day of admission to facilitate adjustments to insulin therapy for as long as clinical indicated. 
The subject’s daily BG levels will be reviewed by a study nurse and/or one of the 
investigators three times per week during the first two weeks after discharge, and then 
weekly during the next month. Exogenous insulin will be withdrawn or adjusted as needed. 
Patients able to maintain fasting BG levels below 140 mg/dL and 2-hour postprandial levels 
below 180 mg/dL after insulin discontinuation will be considered insulin independent. 
 
 
OTHER STANDARD THERAPIES 
Anti-hypertensive, anti-hyperlipidemia and other approved therapies for pre-existing 
and new medical conditions will be provided per standard of care. Pre- and post-islet 
transplant procedure drug regimens (e.g., pre-transplant sedation and anesthetic) will be 
given per standard of care. 
 
 
RESCUE MEDICATIONS 
Rescue therapy will not be initiated in this protocol to treat suspected rejection, 
immunologic surveillance methods that would allow diagnosis of islet allograft rejection 
early enough for timely intervention have yet to be identified and validated. 
 
 
PROHIBITED MEDICATIONS 
Prohibited medications for this protocol, except as specifically indicated in this 
protocol include: 
• steroid medication (except topical and prednisone at a dose of ≤5 mg daily, or an 
equivalent dose of hydrocortisone, for physiological replacement) 
• any medications in the macrolide antibiotic class other than Zithromax. 
• other investigational products 
• other immunosuppressive therapies 
• immunomodulatory agents 
• other anti-diabetic agents  
• Dapsone 
 
5.3 
Second Islet Transplant (re-transplant, intra-hepatic administration): 
Immunosuppression 
 
INDUCTION IMMUNOSUPPRESSION FOR SECOND ISLET INFUSION 
The immunosuppressive regimen for subsequent islet transplants will be identical 
to the regimen for the initial islet transplant with the exception of Thymoglobulin.  

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Basiliximab will be used instead of Thymoglobulin for all subsequent islet transplants. The 
follow-up will be per SOE in appendix A. (Same as first infusion). 
 
Basiliximab (SIMULECT®) 
Two IV doses of Basiliximab, a monoclonal antibody IL-2 receptor blocker, will be given 
with the second islet transplant. The first dose will be 20 mg and will be given within two 
hours prior to islet transplant on the day of islet transplantation. The second dose will be 
given on Day 4 after the transplant.  
 
Formulation, Dosage, and Administration  
The final product is a 200 mL sterile suspension of ≥70% viable, ≥30% pure, allogeneic 
human purified islets in CMRL 1066 Transplant Media for administration by intraportal 
infusion. The final product is supplied in up to three 200 mL Ricordi® bags, containing a 
dose of ≥4,000 IEQ/kg recipient body weight (BW). 
 
Administration:  
The islet mixture is delivered slowly via gravity drainage from a bag attached to the 
catheter in the portal vein or portal vein tributary. Access to the portal vein is achieved by 
percutaneous transhepatic access under fluoroscopic, ultrasonographic, or real-time CT 
guidance. Alternatively, access to a mesenteric or omental venous tributary of the portal 
vein can be obtained by mini-laparotomy under general anesthesia (transplant site 
preference or in the rare circumstance that percutaneous access cannot be achieved).  
At a minimum, portal pressure will be monitored before and after infusion of each bag of 
the islet product, as well as after the final wash. Portal pressure measurements will be 
documented in the medical record.  
 
 
CONCOMITANT MEDICATIONS 
 
 Anticoagulation Prophylaxis / Hematological Agents 
 (HEPARIN): In case of re-transplant, Heparin will be administered at a dose of 70 U/kg 
body weight of recipient, divided equally among the islet bags, given with islet 
infusion, followed by 3U/kg/hr IV for the next 4 hrs. From the 5th through the 48th hr 
post-transplant, heparin will be titrated to achieve and maintain partial thromboplastin 
time (PTT) between 50-60 seconds. If a site does not use PTT to titrate heparin, a 
comparable site-specific method and value should be used.  
 
ENOXAPARIN (LOVENOX®)  
In case of re-transplant Enoxaparin will be administered at a dose of 30 mg SC BID 
through day 7 post-islet transplant, with the first dose given 48 hours after the transplant 
procedure (when heparin is discontinued). The dose can be modified or extended at the 
discretion of the investigator.  
 
OTHER STANDARD THERAPIES 

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ASPIRIN  
Enteric coated aspirin will be administered at a dose of 81 mg PO qPM starting 24 
hours post-transplant and continued as medically indicated. 
 
5.4 Known and Potential Risks and Benefits to Human Subjects  
5.5.4.1 Risks of Use of Investigational Agent: Transplant of Allogeneic Islets  
Transplantation of islets is associated with the several potential risks. These risks 
may be categorized in terms of: a) transmission of disease from donor to recipient, b) 
risk of microbial contamination of islet preparations, c) sensitization of the recipient to 
donor antigens, d) acceleration of retinopathy with acute correction in glycemic control, 
and e) psychological impact of successful or failed islet transplantation.  
5.4.2 Transmission of Disease from Donor to Recipient   
Selection of potential donors for islet isolation must follow stringent guidelines. 
The aim of this process is to avoid use of any potential donor that might harbor 
transmissible viral disease or malignancy.  
A potential donor must have a favorable medical, sexual and social history, and clear 
all standard laboratory tests for low-risk of transmission of donor disease. Donor 
families are therefore questioned about high risk lifestyle and detailed medical history. 
Donor blood samples are screened for conditions including (but not limited to) Human 
Immunodeficiency Virus (HIV) 1, HIV2, hepatitis B, hepatitis C, CMV, Epstein Barr 
Virus (EBV) disease, and syphilis.  
Donors are excluded if: a) there is known pre-existing metabolic disease including 
T1 or Type 2 diabetes, or if the HbA1c is elevated above 6.1% in the absence of 
transfusions in the week prior to death, b) if there is malignancy other than primary 
brain tumors, c) septicemia is present or suspected at the time of death, d) there is 
evidence of clinical or active viral hepatitis (A, B or C), acquired immunodeficiency 
syndrome (AIDS), syphilis, active viral encephalitis of unknown origin, Creutzfeldt-
Jacob disease, rabies, treated or active tuberculosis, septicemia, dementia, individuals 
that have received pituitary growth hormone (pit-hGH), or serious illness of unknown 
etiology.  
Therefore, islets will only be isolated from donors who have undergone the same 
screening process used by the UNOS or similar procedures as required by competent 
organ procurement organizations in the country performing solid organ transplants. 
With careful donor selection as summarized above, the risk of transmission of disease 
from donor to recipient is regarded as low.  
The administration of valganciclovir routinely post-transplant may minimize risk for 
certain viral pathogens. The risk of transmission of CMV disease from donor to 
recipient has been surprisingly low in recipients of islet allografts to date, particularly 
in the most recent era with routine use of purified islet preparations. For instance, there 
have been no episodes of CMV disease in 77 consecutive islet recipients transplanted 
at the University of Alberta. In the international Immune Tolerance Network 

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(ITN)/NIAID multi-center islet trial, there was no CMV disease in any of the 36 
patients transplanted at the nine different sites. Sixteen of 36 (44%) subjects were CMV 
positive initially. Two initially negative subjects became CMV IgG positive without 
any apparent clinical sequelae. The University of Miami recently presented data on 
three islet recipients that became CMV positive and one did develop CMV disease 
occurring late, after discontinuation of anti-viral prophylactic therapy.  
Therefore, while CMV transmission from donor to recipient may occur in islet 
transplantation, the fact that islet preparations are purified and are contaminated with 
only a low number of passenger lymphocytes may explain why the risk of CMV 
transmission from donor to recipient is much less in islet transplantation than in other 
solid organ transplant grafts.  
With respect to EBV transmission, only recipients who are EBV positive are 
acceptable for the current trial. EBV polymerase chain reactions (PCR) monitoring will 
be carried out routinely after transplantation at defined intervals throughout the trial. 
EBV disease and the risk of PTLD have not been reported in the recent era of clinical 
islet transplantation, suggesting that the risk of this complication may be less than 2%.  
5.4.3 Risk of Microbial Contamination of Islet Preparations  
As isolated islets have gone through an extensive processing technique, the 
potential risk of bacterial contamination of the cellular product exists. The processed 
islets must fulfill stringent in-process and lot release criteria before use in 
transplantation. A Gram stain is obtained (and must be negative), and an endotoxin 
determination is completed (less than 5 EU/kg based on the recipient weight), prior to 
product release for transplantation. A sample of the final islet product is obtained prior 
to the addition of antibiotics and the absence of adventitious microbial and fungal 
contaminants is confirmed. Broad-spectrum antibiotics are added to the released final 
product prior to transplant to further diminish the subjects’ risk of infection.  
In 152 islet preparations transplanted consecutively at the University of Alberta 
since 1999, there have been no cases of transmission of bacterial or fungal disease 
through islet transplantation, when islets are prepared under cGMP conditions. In 74 
islet preparations transplanted consecutively at the University of Miami since 1999, 
there have been no cases of transmission of bacterial or fungal disease through islet 
transplantation, when islets are prepared under cGMP conditions.  
There have been previous reports of two cases of islet transplantation-related 
septicemia (Enterobacter cloacae) due to transplantation of contaminated 
cryopreserved pancreatic islets (64). Additionally, the University of Minnesota 
investigators have previously reported on the incidence and significance of 
contaminated islet preparations in clinical islet auto- and allotransplantation (65). 
Positive cultures from islet tissue preparations were identified in 11 of 29 patients 
(38%) receiving autologous islets. The occurrence of serious infection morbidity (as 
defined as positive blood cultures, abscesses, or intra-abdominal infections) did not 
differ significantly between the positive and negative culture groups (p=0.99). In the 
allogeneic islet transplant group, 7 of 33 patients (21%) received tissue that 
retrospectively was determined to be contaminated. None of these patients developed 
serious infectious complications (despite broad-spectrum immunosuppression). 
Despite the occurrence of contaminated grafts, there was no serious increase in 

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infectious morbidity. Presumably the inocula were kept low by the multiple washing 
steps allowing the recipients to clear the organisms without serious sequelae.  
Of the islet allotransplants performed at the University of Minnesota between 1993 
and 1999, 3 of 20 patients (15%) received tissue that was retrospectively determined to 
be contaminated. The species isolated included Candida krusei, Enterococcus faecium, 
and two strains of coagulase-negative Staphylococcus. None of these patients have had 
SAEs related to the contamination of the transplanted islet tissue.  
Additional steps have been taken to decrease the incidence of contamination. First, 
since 2000, pancreatectomy specimens for clinical islet allotransplantation have 
exclusively been processed under current cGMP regulations. Overall, the risk of islet 
transplantation-related septicemia is considered very low in view of the precautions 
detailed in the islet manufacturing protocol.  
5.4.4 Sensitization of the Recipient to Donor Antigens  
As with any allogeneic transplant, islet transplant recipients may become sensitized 
to islet-donor histocompatibility antigens (HLA), leading to development of panel 
reactive alloantibodies (PRA). These alloantibodies may develop while the recipients 
demonstrate full or partial islet function on maintenance immunosuppression. 
Furthermore, donor specific alloantibodies may develop after loss of the islet transplant 
function and discontinuation of the immunosuppressant drug. Data on the development 
of cytotoxic antibodies against donor HLA in islet allotransplant recipients with failing 
grafts have been reported from several islet transplant centers (66-69). In the ITN-
sponsored trial of islet transplantation using the Edmonton protocol of steroid-free 
immunosuppression, 5 of 36 subjects had evidence of elevated PRA post-transplant 
when measured by flow cytometry. Two of these 5 subjects experienced primary islet 
non-function. Moreover, data from five participating centers in the current CIT 
consortium indicate that approximately 25% of the islet alone transplant recipients 
developed a PRA >20% while on maintenance immunosuppression. These results are 
comparable to those reported for recipients of kidney transplant with stable serum 
creatinine and on maintenance immunosuppression (70-72). Importantly, the incidence 
of elevated PRA (>20%) in recipients who had lost their islet transplant function and 
discontinued their immunosuppression rose to approximately 84%.  
The available information suggests that there is a strong correlation between islet 
allograft failure and a rise in anti-donor HLA sensitization as detected by PRA testing. 
A potential consequence of high PRA levels in type 1 diabetic recipients with failed 
islet transplants is that if these individuals develop diabetic nephropathy in the future, 
it may increase their time waiting on a transplant list to qualify for a suitable kidney 
(73).  
5.4.5 Acceleration of Retinopathy with acute correction in glycemic control  
In the DCCT study28, about 10% of patients with pre-existing retinopathy 
receiving intensive treatment experienced a transient worsening of their retinopathy 
during the first year, but nonetheless had a lower cumulative incidence of sustained 
progression when compared to the conventional group after the third year. A transient 
worsening of retinopathy has not been formally documented in islet transplantation 
trials, but it is assumed that a similar process might occur. Exclusion of patients with 

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unstable retinopathy and careful post-transplant follow-up will help to minimize the 
incidence of such occurrences and their morbidity should they occur.  
When type 1 diabetic recipients of successful and unsuccessful pancreas transplants 
were compared for the end point of an increase of two or more grades in the retinopathy 
score, they did not differ significantly in the rate of progression whether retinopathy 
was mild (Grade P0 to P5) or advanced (Grade P6 to P14) at baseline (74). Long-term 
follow-up of both groups suggested that successful pancreas transplantation may have 
a late beneficial effect that becomes evident only after 36 months.  
5.4.6 Psychological Impact of Successful or Failed Islet Transplantation  
Clinical islet transplantation, as a potential therapy for T1D, has been discussed in 
the media and diabetes lay publications with an excessive degree of optimism not 
justified on the basis of clinical results to date. Therefore, failure of the procedure to 
reverse hyperglycemia and maintain insulin independence could be associated with a 
level of psychological disappointment that might progress to clinical depression. The 
informed consent process has been carefully organized to minimize unrealistic 
expectations or legal ramifications. Patients who appear to be incapable of 
understanding and/or coping with the possibility of failure will not be transplanted.  
5.4.7 Risk of Induction and Maintenance Immunosuppressive Therapies  
Administration of all immunosuppressive and immunomodulatory therapies used 
presently to prevent rejection of transplanted tissues carry general risks of opportunistic 
infection and malignancy, including lymphoma (~1%), and skin cancers. These agents 
are not recommended for nursing mothers, and it is recommended (and mandated in 
the current protocol) that women and men of childbearing potential use effective 
contraception before, during and for at least 4 months following administration of these 
agents.  
 
 
 BASILIXIMAB (SIMULECT®)  
Basiliximab is a chimeric (murine/human) monoclonal antibody (IgG1k) approved 
by the Food and Drug Administration (FDA) for prophylaxis against acute organ 
rejection in adult recipients of renal allografts. It is usually given at a dose of 20 mg IV 
on Days 0 and 4. Basiliximab is associated with constipation, nausea, abdominal pain, 
vomiting, diarrhea, dyspepsia, peripheral edema, fever, viral infections, hyperkalemia, 
hypokalemia, 
hyperglycemia, 
hypercholesterolemia, 
hypophosphatemia, 
hyperuricemia, urinary tract infections, upper respiratory infections, surgical wound 
complications, acne, hypertension, headache, tremor, insomnia, and anemia. In the four 
placebo-controlled studies, the pattern of adverse events in 590 patients treated with 
the recommended dose of basiliximab was similar to that in 594 patients treated with 
placebo (see product monograph for details). Basiliximab did not increase the incidence 
of serious adverse events observed compared with placebo. As with any protein 
product, anaphylaxis can occur, particularly with repeated administration, but this has 
been reported only rarely.  
 
 Rabbit ANTITHYMOCYTE GLOBULIN (THYMOGLOBULIN®)  

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Rabbit Thymoglobulin® was approved by the FDA in 1999 for the treatment for 
acute renal graft rejection in conjunction with concomitant immunosuppression (see 
product monograph for details). It is a polyclonal IgG antibody obtained by 
immunization of rabbit with human thymocytes and contains cytotoxic antibodies 
directed against antigens expressed on human T lymphocytes. Thymoglobulin® has 
shown a consistent safety profile with most AEs being manageable and reversible; the 
most common events are fever, chills and leukopenia. While rare, the most severe 
events include allergic or anaphylactoid reactions and serum sickness. As with all 
immunosuppression, administration of Thymoglobulin® may be associated with an 
increased risk of infection and development of malignancy (especially of the skin and 
lymphoid system).  
In 82 kidney transplant recipients receiving 1.5 mg/kg/day for 7 – 14 days, the principal 
AEs were fever (52%) and chills (47%) associated with the infusions, leucopenia 
(47%), and thrombocytopenia (30%). CMV infection (13%) and PTLD (2%). 
Neutropenia has been described; anaphylaxis has been reported rarely.  
Published results of the use of Thymoglobulin® in clinical and experimental islet 
transplantation are limited to relative small cohorts. Hirshberg et al. described the 
successful role of rabbit ATG and sirolimus in reducing rejection of islet allografts in 
primates, with no evidence of direct islet toxicity from Thymoglobulin®. Hering et al. 
described a beneficial role of Thymoglobulin® induction (6mg/kg) in 8 patients with 
T1D receiving single donor islet grafts, all of whom achieved insulin independence and 
were protected against recurrence of hypoglycemia (75). Acute islet rejection was 
described in patients receiving calcineurin-free immunosuppression when sirolimus 
levels fell below 9ng/mL. The use of higher doses of sirolimus exacerbated the 
neutropenic side effects of Thymoglobulin®, but these could be managed safely 
without risk of opportunistic infections when appropriate dose reduction and/or 
administration of Granulocyte Colony Stimulating Factor (G-CSF; Neupogen®) if 
required.  
 
 Alemtuzumab (Lemtrada®) 
Alemtuzumab is directed against the CD52 antigen expressed on virtually all 
lymphocytes and monocytes. The antibody is a powerful depleting agent that causes 
lysis of all cells expressing this antigen and resulting in a dramatic reduction in the 
levels of lymphocytes and monocytes in the peripheral blood and in the bone marrow. 
Alemtuzumab has shown to be effective in promoting the engraftment of CD34+ 
enriched stem cell infusions given for the treatment of a variety of hematological 
disorders (106). In clinical trials it has also been used to treat kidney transplant 
rejection, to prevent graft versus host disease and to treat lymphoid malignancies 
(107-110). Alemtuzumab has also been used effectively in the treatment of various 
autoimmune diseases (autoimmune thrombocytopenic purpura (111), multiple 
sclerosis.  The effect of Alemtuzumab on multiple inflammatory cell types may also 
provide a benefit by preventing the production of proinflammatory mediators by 
intrahepatic macrophages and endothelial cells, thus preventing early islet loss due to 
the deleterious effects of cytokines on islets (112, 113). 
 
Alemtuzumab, the initial dose of 20mg IV over 3 hours will be given on Day –1 and a 

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second dose of 20mg IV will be administered on the day of transplant. Patients will 
pre-medicated 30 minutes before the first dose of alemtuzumab with Benadryl (50mg 
IV), acetaminophen (650mg PO), ibuprofen (400mg PO) and (Solumedrol 125mg iv). 
Pre-medication, WITHOUT Solu-Medrol, will also be given before the second dose of 
alemtuzumab. The most common side-effects of alemtuzumab include infusion-related 
reactions characterized by fever, chills, rigors, nausea, vomiting and hypotension. 
These usually occur with the initial dose of alemtuzumab. These events are prevented 
or improved with the premedication treatment administered prior to the infusion of 
alemtuzumab. An increased incidence in infectious complications (when compared to 
other immunosuppressive regimens) was not apparent in 31 renal transplant patients 
who received alemtuzumab as induction therapy (113). These patients also received 
prophylactic treatment against PCP and viral infections such as CMV as detailed below. 
Hematologic Toxicity: Serious and, in rare instances fatal, pancytopenia/marrow 
hypoplasia, autoimmune idiopathic thrombocytopenia, and autoimmune hemolytic 
anemia have occurred in patients receiving alemtuzumab therapy. Single doses of 
alemtuzumab greater than 30 mg or cumulative doses greater than 90 mg per week 
should not be administered because these doses are associated with a higher incidence 
of pancytopenia. A recent trial using alemtuzumabfor treatment of patients with 
multiple sclerosis revealed a high incidence of Grave’s disease. One third of patients 
developed Graves’ disease between 6 and 18 months after the alemtuzumab treatment 
(112). This complication has not been described in patients who received alemtuzumab 
for other indications than multiple sclerosis (lymphoid malignancies, renal transplant 
recipients). Thyroid function will be closely monitored in all patients. Another recent 
trial has demonstrated a small but significant incidence of immune thrombocytopenic 
purpura (ITP) 3 cases in 334 subjects, one resulting in death (this subject did not seek 
medical attention). alemtuzumabIn both trials patients were treated with very high 
doses of alemtuzumab (100mg given over 5 days). 
 
 
SIROLIMUS (RAPAMUNE®)  
The FDA approved sirolimus (rapamycin, Rapamune®) as an immunosuppressive 
agent in 1999 (see product monograph for details). In 208 kidney transplant recipients 
receiving 5 mg of sirolimus daily compared to 124 receiving placebo, there was an 
increased incidence of hypercholesterolemia (46 vs. 23%), hyperlipemia (57 vs. 23%), 
rash (20 vs. 6%), arthralgia (31 vs. 18%), diarrhea (35 vs. 27%), anemia (33 vs. 21%), 
leucopenia (13 vs. 8%), thrombocytopenia (30 vs. 9%), and hypokalemia (17 vs. 9%). 
Side effects are related to drug concentration and are improved with maintenance of 
the sirolimus 24-hour trough level between 10–20 ng/mL. Of infections, only mucosal 
herpes simplex virus (HSV) occurred at a greater rate with sirolimus. There was no 
increase in rate of malignancy (3.4 vs. 3.1%). While sirolimus was originally proposed 
as a non-nephrotoxic agent, it is becoming apparent that sirolimus-associated 
nephrotoxicity does occur in clinical practice. Crew et al. described two patients with 
thrombotic microangiopathy secondary to sirolimus exposure121. Sirolimus alters the 
pharmacokinetic profiles of other CNIs (e.g., tacrolimus) and may thereby potentiate 
nephrotoxicity (76). Fervenza et al. described nephrotoxicity from sirolimus in patients 
with chronic glomerulopathies that was non-reversible on cessation of therapy (77). 

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Nephrotoxicity from combined sirolimus and tacrolimus has been described in patients 
with T1D undergoing islet transplantation, particularly where there is underlying pre-
existing renal damage from diabetes (78, 79). 
The majority of islet transplant recipients receiving sirolimus in conjunction with 
tacrolimus have experienced transient mouth ulceration, lower extremity edema; 
perinephric edema and a high incidence of benign ovarian cysts have also been 
described in islet recipients in association with sirolimus. Pneumonitis and colitis have 
also occurred (80-82). The most common (> 30%) adverse reactions are: peripheral 
edema, 
hypertriglyceridemia, 
hypertension, 
hypercholesterolemia, 
creatinine 
increased, abdominal pain, diarrhea, headache, fever, urinary tract infection, anemia, 
nausea, arthralgia, pain, and thrombocytopenia.  
Concerns have been raised by the FDA regarding trials of combined 
sirolimus/tacrolimus in liver transplant recipients, where there has been a statistically 
increased risk of hepatic artery thrombosis and late death in sirolimus-treated 
recipients. A careful analysis of these events does not establish causative association 
between sirolimus/tacrolimus and thrombosis or death events. There was no increased 
association with portal venous thrombosis in the liver transplant trials. While sirolimus 
continues to be used off-label in islet recipients, there is not presently felt to be an 
association between portal thrombus formation in islet recipients and the use of 
sirolimus or tacrolimus.  
 
 
TACROLIMUS (PROGRAF®)  
Tacrolimus (Prograf®, FK506) has been in wide clinical use for the prevention of 
allograft rejection since 1994 when the FDA approved it after several years of testing. 
Tacrolimus is a macrolide antibiotic which inhibits calcineurin after binding 
intracellularly to FKBP12 within T cells, inhibiting IL-2 transcription. Tacrolimus is 
invariably administered with other immunosuppressive agents but is known to be 
associated with several side effects including hypertension, diabetes, nephrotoxicity, 
hyperkalemia, dyslipidemia, pruritis, neurotoxicity, neurologic sequelae (including 
tremor, ataxia, and extremely rarely central pontine myelinolysis), posterior reversible 
encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy 
(PML), interstitial lung disease, BK nephropathy, nausea, vomiting and diarrhea (see 
product monograph for details). In 205 kidney transplant recipients receiving 
tacrolimus, the principal AEs were neurologic (tremor [54%], headache [44%], 
insomnia [32%], paresthesia [23%]) and gastrointestinal (diarrhea [44%], nausea 
[38%], constipation [35%]) complaints, hypertension (50%), and kidney dysfunction 
(52%); hyperkalemia (31%) and hyperglycemia (22% in previous non-diabetics) also 
occurred. The severity of these events appears to be dose dependent, with very high 
plasma levels also producing delirium, seizures, and coma. Complications can be 
minimized with the relatively low dose long-term therapy typically used in islet 
transplant trials.  
 
 
MYCOPHENOLATE MOFETIL (CELLCEPT®) AND MYCOPHENOLATE SODIUM 
(MYFORTIC®)  
CellCept® and Myfortic® are associated with: diarrhea, leucopenia, vomiting, and 
evidence of higher frequency of certain types of infections. CellCept® and Myfortic® 

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may increase the risk of developing lymphoproliferative disease, lymphomas, and other 
malignancies, particularly of the skin, and have been known to cause fetal harm when 
administered 
to 
a 
pregnant 
woman. 
Cases 
of 
progressive 
multifocal 
leukoencephalopathy, sometimes fatal, and pure red cell aplasia have been reported in 
patients treated with CellCept® or Myfortic®.  
 
5.4.8 Risks of Immunosuppressive / Anti-inflammatory Therapy: Adalimumab 
(Humira®) 
Adalimumab is a recombinant human IgG1 monoclonal antibody specific for 
human tumor necrosis factor (TNF). It is FDA-approved for use in rheumatoid arthritis, 
juvenile arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn’s disease, ulcerative 
colitis and uveitis. Inhibitors of tumor necrosis factor (TNF)-alpha represent important 
treatment advances in a number of inflammatory conditions, including rheumatoid 
arthritis (RA), the seronegative spondyloarthropathies, and inflammatory bowel 
disease (IBD). TNF-alpha inhibitors offer a targeted strategy that contrasts with the 
nonspecific immunosuppressive agents traditionally used to treat most inflammatory 
diseases. However, multiple adverse effects of TNF-alpha inhibition have been 
identified through both clinical trials and post-marketing surveillance. These include: 
Injection site reactions, infusion reactions, neutropenia, infections, demyelinating 
disease, heart failure, cutaneous reactions, malignancy and induction of autoimmunity. 
 
5.4.9 Risks from Adjuvant Interventions 
a. Exenatide Extended-Release (Bydureon®).  
Nausea, vomiting, dyspepsia, constipation, diarrhea, headache and injection-site 
pruritus were the most common adverse effects reported with ER exenatide in clinical 
trials. Gastrointestinal effects occurred in about 35% of patients, but decreased over 
time. Acute renal failure and acute pancreatitis have been reported in patients with 
diabetes taking exenatide; whether they were caused by the drug or the disease is not 
clear. Injection-site nodules have been reported in about 77% of patients and 
injection-site reactions in about 17% of patients. Weight loss is reported with 
exenatide. In subjects with T2D who took exenatide for 4 weeks, the average weight 
loss was 1.3±0.3 kg. Weight loss was also seen in the DURATION-5 trial of 
Bydureon.. Impaired recovery from hypoglycemia is a potential adverse effect of 
GLP-1 receptor agonists. However, the risk of hypoglycemia in patients with T2D 
treated with combination of exenatide (Byetta) and exogenous insulin has been low. 
In the DURATION 4 study, a non-inferiority study comparing Bydureon to 
Metformin, Pioglitazone, and Sitagliptin, no major hypoglycemia was seen.  
 
Exenatide may affect absorption of other drugs such as oral contraceptives, 
antibiotics, digoxin, lovastatin and warfarin. Participants will be informed to take 
their routine medications at least 1 hour prior to taking exenatide. 
 

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Thyroid C-cell hyperplasia has been reported with use of exenatide in rats, and the 
FDA has required a boxed warning about the risk of thyroid C-cell tumors in the 
package insert. 
 
Contraindications for the use of Exenatide include: 
• 
Medullary Thyroid Carcinoma: Exenatide is contraindicated in patients with a 
personal or family history of medullary thyroid carcinoma (MTC) or in patients with 
Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).  
• 
Hypersensitivity: Exenatide is contraindicated in patients with a prior serious 
hypersensitivity reaction to exenatide or to any of the product components.  
 
Warning and precautions: 
• 
Risk of Thyroid C-cell Tumors:  In both genders of rats, exenatide extended-
release caused a dose-related and treatment-duration dependent increase in the 
incidence of thyroid C-cell tumors (adenomas and/or carcinomas) at clinically 
relevant exposures compared to controls. A statistically significant increase in 
malignant thyroid C-cell carcinomas was observed in female rats receiving exenatide 
extended-release at 25-times clinical exposure compared to controls and higher 
incidences were noted in males above controls in all treated groups at ≥2-times 
clinical exposure. The potential of exenatide extended-release to induce C-cell tumors 
in mice has not been evaluated. Other GLP-1 receptor agonists have also induced 
thyroid C-cell adenomas and carcinomas in male and female mice and rats at 
clinically relevant exposures. It is unknown whether Bydureon will cause thyroid C-
cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human 
relevance of exenatide extended-release-induced rodent thyroid C-cell tumors could 
not be determined by clinical or nonclinical studies. Serum calcitonin was not 
assessed in the clinical trials supporting the approval of Bydureon.   
Serum calcitonin is a biological marker of MTC. Patients with MTC usually have 
calcitonin values >50 ng/L. Patients with thyroid nodules noted on physical 
examination or neck imaging should be referred to an endocrinologist for further 
evaluation. Routine monitoring of serum calcitonin or using thyroid ultrasound is of 
uncertain value for early detection of MTC in patients treated with Bydureon. Such 
monitoring may increase the risk of unnecessary procedures, due to the low 
specificity of serum calcitonin testing for MTC and a high background incidence of 
thyroid disease.    
 
• 
Acute Pancreatitis:  Based on post marketing data, exenatide has been associated 
with acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing 
pancreatitis. 
 
• 
Hypoglycemia:  The risk of hypoglycemia is increased when exenatide is used in 
combination with a sulfonylurea. Therefore, patients receiving Bydureon and a 
sulfonylurea may require a lower dose of the sulfonylurea to minimize the risk of 
hypoglycemia. It is also possible that the use of Bydureon with other glucose-
independent insulin secretagogues (e.g. Meglitinides) could increase the risk of 
hypoglycemia.  

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• 
Renal Impairment: Bydureon should not be used in patients with severe renal 
impairment (creatinine clearance < 30 mL/min) or end-stage renal disease and should 
be used with caution in patients with renal transplantation. In patients with end-stage 
renal disease receiving dialysis, single doses of Byetta 5 mcg were not well tolerated 
due to gastrointestinal side effects. Because Bydureon may induce nausea and 
vomiting with transient hypovolemia, treatment may worsen renal function. Use 
Bydureon with caution in patients with moderate renal impairment (creatinine 
clearance 30 to 50 mL/min). Bydureon has not been studied in patients with end-stage 
renal disease or severe renal impairment.   
There have been post marketing reports of altered renal function with exenatide, 
including increased serum creatinine, renal impairment, worsened chronic renal 
failure and acute renal failure, sometimes requiring hemodialysis or kidney 
transplantation. Some of these events occurred in patients receiving one or more 
pharmacologic agents known to affect renal function or hydration status such as 
angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, or 
diuretics. Some events occurred in patients who had been experiencing nausea, 
vomiting, or diarrhea, with or without dehydration. Reversibility of altered renal 
function has been observed in many cases with supportive treatment and 
discontinuation of potentially causative agents, including exenatide. Exenatide has 
not been found to be directly nephrotoxic in preclinical or clinical studies.  
 
• 
Gastrointestinal Disease:  exenatide is commonly associated with gastrointestinal 
adverse reactions, including nausea, vomiting, and diarrhea.  
 
• 
Immunogenicity:  Patients may develop antibodies to exenatide following 
treatment with Bydureon. Antiexenatide antibodies were measured in all Bydureon -
treated patients in the five comparator-controlled 24-30 week studies of Bydureon. In 
6% of Bydureon -treated patients, antibody formation was associated with an 
attenuated glycemic response.  
 
• 
Hypersensitivity:  There have been post marketing reports of serious 
hypersensitivity reactions (e.g. anaphylaxis and angioedema) in patients treated with 
exenatide.  
 
• 
Macrovascular Outcomes: There have been no clinical studies establishing 
conclusive evidence of macrovascular risk reduction with Bydureon or any other 
antidiabetic drug.   
 
• 
Pancreatic Cancer: A recent meta-analysis suggested an increase rate of 
pancreatic cancer in patients with T2D who used GLP-1 receptor agonists or DPPIV 
inhibitors. More recently, an analysis of histologic sections from patients with T2D 
suggested expansion of exocrine and endocrine pancreas with incretin therapy and 
increased exocrine pancreas dysplasia and the potential for glucagon-producing 
neuroendocrine tumors . As a result of these reports, the FDA is initiating an 
investigation of the safety of DPPIV inhibitors and GLP-1 receptor agonists. In the 

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event that this and other studies show efficacy of this and other agents in T1D, further 
assessment of the risk/benefit ratio will be necessary in the context of the forthcoming 
investigations. The potential risks for pancreatic cancer or medullary carcinoma of the 
thyroid are believed to be minimal for participants in this study because of the very 
short exposure to study drug. 
  
b. Pegylated G-CSF (Neulasta®).  
There are some potential risks associated with pegylated G-CSF therapy. 
Although the risk is entirely theoretical at this time, there is a possibility that the G-
CSF injections could worsen and not improve the autoimmunity associated with T1D. 
The side effect profile of pegylated G-CSF injection will be monitored by close 
clinical observation of the subjects for 1 hour after the first G-CSF injection as well 
as with daily phone calls to the subjects during the first 5 days of G-CSF therapy and 
weekly thereafter. Pegylated G-CSF carries a risk (10-20% of patients) of bone pain 
and a risk (less than 10%) of fever, pain or redness at the site of injection, headache, 
and dizziness. There is also a risk that the subjects’ WBC could become elevated 
while taking G-CSF. There are also now a small number of reports in which 
recipients of GCSF have developed splenomegaly and/or splenic rupture. This risk 
will be explicitly discussed in the consent form and subjects will have close physical 
examination and phone follow-up to screen for any signs or symptoms. In addition, 
weekly phone calls for the month following therapy will be used to document any 
adverse reactions. The CBC and complete metabolic profile at each blood draw will 
be carefully reviewed for any clinically relevant abnormalities. There are no other 
known long-term risks from a 12 week course of G-CSF. 
 
c. Ultra-refined omega-3 EPA/DHA concentrate (ZoneLabs® OmegaRx®2) 
Omega-3 Fatty Acids may cause gastrointestinal side- effects including stomach pain 
or discomfort, burping, heartburn, vomiting, constipation, diarrhea, nausea, change in 
the sense of taste and prolongation of bleeding time. Joint pain may be a side effect as 
well. As with any drug, it is possible that subjects could experience an allergic 
reaction to OMEGA-3. Such allergic reactions include: itching, skin rash, sudden 
drop in blood pressure, loss of consciousness and/or associated with seizures, 
including the possibility of death. 
  
d. Supplemental oxygen.  
Low flow supplemental oxygen therapy via nasal cannula can lead to dryness of nares 
and bleeding after prolonged use. Oxygen toxicity has been associated with hyperoxia 
from high FiO2. However, as per protocol, subjects will receive supplemental oxygen 
at FiO2 36% and data in the literature suggest that by keeping FiO2 below 40 to 50%, 
oxygen toxicity can be minimized.  
 
 
5.4.10 Risk of Study Procedures  
 

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The procedures involved with the care of research subjects undergoing clinical islet 
transplantation include risks pertaining to: a) blood draw testing, b) metabolic 
stimulation testing, c) the procedural risks of islet implantation, and d) specific follow-
up testing.  
 
 BLOOD DRAW TESTING  
Peripheral blood draws performed during these research studies will not exceed 450 
mL per six-week period. The subject may experience some discomfort at the site of 
the needle entry, and there is risk of bruising at the site. There is a remote risk of 
fainting or local infection.  
 
 METABOLIC STIMULATION TESTING  
The risks associated with metabolic testing are generally regarded as minor. Placement 
of IV cannulae may be associated with pain and discomfort at the puncture site, 
bruising, bleeding, interstitial infusion of fluids, local vein thrombosis, infection or 
thrombophlebitis.  
The administration of bolus glucose or insulin by mouth or intravenously may lead to 
acute hypoglycemia or hyperglycemia, or rarely may induce ketoacidosis.  
 
 HYPOGLYCEMIA 
Severe hypoglycemia is a risk associated with the infusion of islets. Iatrogenic 
hypoglycemia in the immediate post-transplant period is a rare event. Frequent blood 
glucose monitoring immediately following islet transplantation is recommended to 
avoid severe unrecognized hypoglycemia in the early post-transplant period. In 
longer-term follow-up, life-threatening hypoglycemia (Grade 4) occurred in six of the 
236 SAEs reported to CITR (93) For these six occurrences, the events occurred at the 
following time intervals; 59 days post the third infusion, 230 days post the second 
infusion, 296 days post the second infusion, 360 days post the third infusion, 673 days 
post the third infusion, and 318 days post the second infusion. The local CITR 
investigators did not attribute any of the six events to the infusion procedure or to the 
immunosuppression medication.  
 
 CHEST X-RAY 
A chest x-ray exposes subject to a dose of radiation equal to approximately the amount 
one receives in 10 days of normal day-to-day activity.  This amount of radiation should 
not create additional risk to the subject, but this is not known for sure.  
 
 MAGNETIC RESONANCE IMAGING (MRI) 
The risk of MRI performed with intravenous gadolinium contrast is that of an allergic 
reaction which can be life threatening (anaphylaxis).  Some patients with impaired 
kidney function who have received gadolinium have experienced a worsening of their 
kidney function that in some cases has been severe and irreversible and has required 
dialysis. Some patients may also experience claustrophobia and if this should happen 
the test will be stopped.  The MRI center has a physician available in the building 
while patients are being injected with contrast.  A crash cart with medications, a 
defibrillator, an Automated External Defibrillator (AED), oxygen, intubation 

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equipment, and automatic blood pressure monitor are in place.  The technologists are 
all Basic Cardiac Life Support (BCLS) certified.  In the case of an emergency, 911 is 
called.  For non-emergent problems that require admission, ambulance transportation 
can be arranged. 
 
 FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY 
INTEGRATED WITH COMPUTED TOMOGRAPHY (18F-FDG PET/CT) 
The risk associated with this procedure is the exposure to radiation. To better 
understand the amount of radiation that people receive from various medical X-ray 
exams it is best to compare it to the radiation people are exposed to from natural 
sources in the environment. The unit of measurement for an effective radiation dose 
is called the millisievert (mSv). The average person in the United States receives a 
dose of about 3 mSv per year from naturally occurring radiation. As a comparison, 
the radiation exposure from one chest X-ray is the same as the amount of radiation a 
person is exposed to from their natural surroundings in 10 days (94). 
 
The radiation exposure from a PET-CT can range from 12 to 30 mSv, which is 
comparable to what a person would receive from natural background radiation over a 
period of 3 to 9 years (94-95). This degree of radiation exposure has been associated 
with a less than 1% increase in lifetime risk of cancer (95, 96, 97).  
 
 
 RISKS FROM ISLET TRANSPLANT PROCEDURE IN RADIOLOGY: 
Islets will be transplanted under fluoroscopic guidance (X-RAY imaging). The 
procedure will expose subject to a dose of radiation equal to approximately the amount 
one receives in 7 years of normal day-to-day activity.  This amount of radiation should 
not create an additional risk for the subject, but this is not known for sure.  
 
 CENTRAL LINE 
A Central line will be needed for induction. The risks related to a PICC line are 
bleeding at the site of the vein puncture, infection, and clotting of the veins. In case a 
PICC line is not possible, a central line in the neck might be placed. The risks related 
to central line in the neck are: bleeding (internal or external), lung collapse, vein 
thrombosis, damage of adjacent structures, irregular heart rhythm, infection, shortness 
of breath, and hypotension.  
 
 CONTINUOUS GLUCOSE MONITORING  
It may cause skin irritation at the site of implantation. It may be related to:  bruising, 
discomfort, pain, bleeding, redness, raised bumps, local infection, and appearance of 
a small “freckle-like” dot where the needle was inserted.  It may lead to an infection 
where the sensor was inserted.  If there is pain, redness, irritation, or rash at insertion 
site, the sensor will be removed and re-inserted in a different site.   
 
 

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5.4.11 Benefits  
Successful islet transplantation alleviates T1D patients from life-threatening 
hypoglycemia and psychosocially debilitating glycemic lability. While the long-term 
durability of these responses is at present uncertain, they persist for as long as some 
graft function is maintained, despite the eventual return to insulin therapy in the 
majority of recipients. This partial function, as indicated by continued c-peptide 
production, may be present in as many as 80% of recipients after 5 years (101). 
Furthermore, as long as graft function is maintained, fear of hypoglycemia and anxiety 
are significantly lower after islet transplantation (102). Indeed, T1D subjects in the 
DCCT who had persistent c-peptide production had a significantly reduced risk of 
severe hypoglycemia despite intensive insulin therapy (103). Additionally, while most 
transplant recipients experience only a temporary reprieve from exogenous insulin 
therapy, a few have maintained insulin-independent graft function for more than 3 
years. Novel strategies aimed at promoting the engraftment or survival of transplanted 
islets may lead to improved long-term graft function and further the duration of insulin-
independence after transplantation, and hopefully lead to reductions in the secondary 
complications of T1D. 
 
5.5 Assessment of Compliance with Study Treatment  
Assessment of subject compliance will be determined by the completion of 
scheduled study visits and required documentation that the specific subject is responsible 
for (e.g., Blood Glucose Logs, AE and Insulin Use recording) as well as their willingness 
to comply with the recommendations of the study investigators. Any aberration of trough 
levels of immunosuppressive agents that could indicate no adherence, lack of compliance 
that poses a significant clinical risk and or derangement of protocol data collection will be 
documented.  
 
5.6 Modification or Discontinuation of Study Treatment  
5.6.1 Islets are Unsuitable  
Should an islet product become unsuitable for transplantation subsequent to 
recipient 
treatment 
with 
induction 
immunosuppression, 
maintenance 
immunosuppression will be discontinued. An emergency request will be placed 
through UNOS that the next available pancreas for islet transplantation is directed to 
the selected manufacturing site. When an organ becomes available, investigators 
should refer to the MOP to determine the amount and type of induction 
immunosuppression that will be administered at the time of the islet transplant.  
5.6.2 Graft Failure  
Immunosuppression will be stopped in subjects who experience graft failure and 
the subject will continue follow up as per SOE on appendix A. Post graft failure follow 
up will exclude graft function measurements: 90min MMTT, BSR, CGM, LI, HYPO, 
Beta Score, C-peptide ratio. Physical exam after graft failure will only be done at study 
visit 19 (M12) and Visit 23 (M24) or as medically indicated.  

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5.6.3 Allergic Reaction to ATG  
If a subject demonstrates an allergic reaction to thymoglobulin that results in 
cancellation of the initial transplant and the investigators feel that future use of the drug 
in that subject is contraindicated, the steps outlined in section 5.6.10 should be 
followed. Once another organ becomes available, the subject will receive an alternate 
induction immunosuppressive regimen with basiliximab (IL-2 receptor blocker). 
 5.6.4 Intolerance of Protocol Medications 
In the event that the immunosuppression regimen is not tolerated, the principal 
investigator (PI) may elect to prescribe an alternative immunosuppression regimen. 
The intent would be for the alternative regimen to be temporary in nature where 
possible. Any non-protocol directed study treatment modification that the site PI 
determines is necessary should be reported as a protocol deviation.  
5.6.5 RABBIT ANTI-THYMOCYTE GLOBULIN-Induced Anaphylaxis 
In rare instances, anaphylaxis has been reported with Thymoglobulin® use. In such 
cases, the infusion should be terminated immediately. Medical personnel should be 
available to treat subjects who experience anaphylaxis. Emergency treatment such as 
0.3 mL to 0.5 mL aqueous epinephrine (1:1000 dilution) subcutaneously and other 
resuscitative measures including oxygen, IV fluids, antihistamines, corticosteroids, 
pressor amines, and airway management, as clinically indicated, should be provided. 
Thymoglobulin® or other rabbit immunoglobulins should not be administered again 
for such subjects.  
 
5.6.6 RABBIT ANTI-THYMOCYTE GLOBULIN-Induced Cytokine Release  
Thymoglobulin® infusion may cause cytokine release-related fever and chills. To 
minimize these, the first dose should be infused over a minimum of 6 hours into a high-
flow vein. Also, premedication with corticosteroids, pentoxifylline, acetaminophen, 
and/or an antihistamine will be provided in order to minimize the reaction incidence 
and/or intensity. At any sign of the above reaction, slowing the infusion rate by 50% 
will also occur.  
5.6.7 Neutropenia 
Neutropenia is an expected consequence of the administration of several 
medications in this protocol. Subject safety is of utmost importance. Clinical treatment 
decisions take precedence over recommended guidelines.  
 
If a subject’s absolute neutrophil count is less than 1000 cells/μL and the subject 
is afebrile, then the following will be done:  
• Reduce rabbit ATG by 50%.  
• Reduce the prophylactic use of valganciclovir from 900 mg per day to 450 mg per 
day or hold valganciclovir.  
• Reduce trimethoprim/sulfamethoxazole to 80/400 mg on Monday, Wednesday, and 
Friday or hold trimethoprim/sulfamethoxazole.  
• If subject is using mycophenolate mofetil or mycophenolate sodium, consider dose 
reduction.  

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• Consider administration of G-CSF.  
• Monitor temperature BID.  
• Follow up within 48-72 hours to obtain: repeat complete blood count (CBC) with 
differential, subject symptoms, and measured temperatures.  
 
If a subject’s absolute neutrophil count is less than 1000 cells/μL and the subject 
is febrile, then the following will be done:  
• Obtain Infectious Disease Consult.  
• Hold rabbit ATG.  
• Hold valganciclovir and trimethoprim/sulfamethoxazole.  
• If subject is using mycophenolate mofetil or mycophenolate sodium, consider dose 
reduction.  
• Administer G-CSF.  
• Monitor temperature BID.  
• Follow up within 48-72 hours to obtain: repeat CBC with differential, subject 
symptoms, and measured temperatures.  
 
If a subject’s absolute neutrophil count is measured as less than 500 cells/μL and 
the subject is afebrile, then the following will be done:  
 • Hold rabbit ATG.  
• Hold administration of trimethoprim/sulfamethoxazole and/or valganciclovir.  
• If subject is using mycophenolate mofetil or mycophenolate sodium, consider holding 
dose.  
• Obtain CMV antigenemia or PCR for CMV.  
• Consider fluoroquinolones in afebrile subjects.  
• Consider clotrimazole.  
• Administer G-CSF.  
• Monitor temperature BID.  
• Follow up within 24 hours to obtain repeat CBC, subject symptoms, and measured 
temperatures. 
 
If a subject’s absolute neutrophil count is measured as less than 500 cells/μL and 
the subject is febrile, then the following will be done:  
 
• The subject will be hospitalized under neutropenic precautions and Infectious 
Disease/Hematology consult will be obtained.  
• Hold rabbit ATG.  
• Hold administration of trimethoprim/sulfamethoxazole and/or valganciclovir.  
• If subject is using mycophenolate mofetil or mycophenolate sodium, consider holding 
dose.  
• Obtain CMV antigenemia or PCR for CMV.  
• Administer G-CSF.  
5.6.8 Thrombocytopenia  
If the subject is found to have a platelet count (PLT) of <50 x 109/L, ATG will be 
withheld until PLT >50 x 109/L, then resume at a 50% reduced dose. If the PLT is <50 

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x 109/L, sirolimus will be withheld for 24 hours, then resumed at a 50% reduced dose. 
If PLT fails to return to >50 x 109/L within one week, sirolimus is to be withheld until 
PLT >50 x 109/L, after which sirolimus is resumed at 50% of the dose that preceded 
the drop in PLT to <50 x 109/L. If the PLT is between 50 and 75 x 109/L, reduce anti-
thymoglobulin dose by 50% until PLT is >75 x 109/L. 
5.6.9 Nephrotoxicity  
A sustained  increase in serum creatinine ≥ 2 times pre-transplant baseline or  
decrease in their GFR of ≥ 33% compared to baseline warrants a prompt referral to a 
nephrologist for evaluation. If it is determined that the decrease in renal function is 
attributable to CNI immunosuppressive therapy, the treating physician should choose 
a therapeutic alternative. A repeat assessment of creatinine should be performed 3 
months after the change in immunosuppression.  
Anti-hypertensives, anti-hyperlipidemics and other approved therapies for pre-existing 
and new medical conditions will be provided per standard of care.  
5.6.10 Premature Discontinuation of Study Treatment (Transition to “Off-Protocol” 
Treatment)  
Study treatment may be prematurely discontinued for any subject for any of the 
following reasons:  
1. The subject is unwilling or unable to comply with the protocol.  
2. The investigator believes that the study treatment is no longer in the best interest of 
the subject.  
3. Graft Failure.  
4. An unexpected related SAE. The agent(s) to which the event is attributed will be 
discontinued.  
Subjects who prematurely discontinue study treatment will remain in the study until 
normal termination, for the purpose of monitoring safety and efficacy parameters and 
will enter the post graft failure follow-up (section 5.6.2). Data from these subjects will 
be used in the intent-to-treat analysis. These subjects are permitted to simultaneously 
enroll in a specific graft failure follow-up protocol, if available. 
 
5.7 
Risks of surgery and anesthesia  
Islet cells will be placed in the omentum by an open surgical approach under general 
anesthesia. The general risks of surgery include bleeding, wound infection, wound hernia, 
bowel obstruction (adhesions), deep vein thrombosis and pulmonary embolism. Risks 
associated with anesthesia include difficulties with airway management, cardiac 
arrhythmias and drug-related anaphylactic reactions. Pain and discomfort at the surgical 
site is expected in the early period following surgery, and may be reduced by administration 
of opiate, opioid or non-steroidal analgesic medications. If an ileus develops, a prolonged 
hospital stay may be anticipated. The risks related to the intrahepatic islet transplantation 
are listed below: 
 
• moderate pain or discomfort; 

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• bleeding from the liver puncture, which may require a blood transfusion; 
• damage to liver or blood vessels, which may require surgery; 
• damage to gallbladder, which may lead to the removal of gallbladder; 
• bleeding as a result of the blood thinners used to prepare the islets; 
• portal vein thrombosis, which may heal itself or may lead to the need for a liver 
transplant; 
• shortness of breath or apnea as a result of the sedation used for the procedure; 
• pulmonary edema or/and pleura effusion; 
• death from complications (this risk is rare but possible); 
• liver or kidney injury that may or may not resolve; and severe hypoglycemia during the 
procedure, or in the hours afterwards. 
 
 
5.8 
Study Stopping Rules  
 
Study enrollment will be suspended if any one of the following occurs: 
1.  Any unexpected fatal or life-threatening AE possibly related to the use of the test 
therapy. 
2.  Primary non-function (PNF) occurs in 2 consecutive subjects. PNF is defined as no 
c-peptide detection up to 75 days post-transplant. 
3   C-peptide less than 0.3 ng/mL (on random testing, at baseline and 1-3 hours post 
MMTT) at 75-180 days post-transplant in 2 consecutive study subjects. 
4.  Torsion of omentum, GI obstruction, or abscess in 2 consecutive subjects. 
6 
STUDY PROCEDURES 
6.1 
Enrollment and Screening  
Patients who meet the general inclusion criteria for this study will be approached 
regarding their participation. The study procedures, risks, and potential benefits will be 
discussed with the potential study subject in lay language. The potential study subject will 
have an opportunity to review the informed consent and ask questions.  
 
Once informed consent has been obtained, the subject will be enrolled and assigned a 
unique subject identification number. Subject eligibility will be confirmed through the 
performance of the screening visit procedures detailed in the Schedule of Events (SOE). 
More than one visit may be necessary to complete all of the screening procedures.  
6.2 
Waiting List/Baseline  
After completion of the screening assessments required to confirm eligibility for the 
study, he/she will be listed for an islet transplant. Waitlist assessments will be repeated at 
pre-defined intervals as detailed in SOE. Results from assessments done closest to the start 
of immunosuppression will be used as the subject’s baseline values. All one-time 
waitlist/baseline assessments should be completed on Day -2, whenever possible, but 
always prior to the start of immunosuppression. As in any other transplant situation, 
medical conditions that arise (e.g., new serious infection, malignancy, compliance issues, 

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etc.) will automatically trigger a re-evaluation to determine if the subject remains qualified 
for the protocol. Only qualified subjects may proceed to donor organ matching and 
transplant.  
 
6.3 
Islet Transplant, and Study Treatment Visits  
Once compatible islet prep becomes available, subject eligibility will be re-confirmed. 
Subjects will receive the initial islet transplant on Day 0 and will continue the 
immunosuppression regimen as per protocol.  
 
6.4 
Follow-up Visits  
Subject will undergo a 24-month follow-up period following their islet transplant. 
Please refer to the Schedule of Events, for the clinical time points of specific follow-up 
study procedures.  
Subjects will be followed for adverse events only until 24 months after their islet 
transplant. 
 
6.5 
Imaging modalities to localize the transplanted islet allograft.  
A major challenge in islet transplantation has been the identification of imaging studies 
that may allow for in-vivo visualization of the transplanted islet allograft. Ideally, such 
imaging techniques should allow to adequately correlate the visualized islet mass with islet 
graft metabolic function and also permit quantification of the islet mass.   
 
The use of MRI in the assessment of the peritoneum, particularly for peritoneal 
malignancies, is well established in clinical practice.  In addition, MRI is the imaging 
modality of choice for primary pelvic/gynecologic malignancies due to its superior contrast 
resolution. Considering that in this protocol islets are transplanted onto the omentum and 
that it is possible that some of the islets may have not adhered onto the omentum but 
travelled down and engrafted in the pelvis, we have opted for the utilization of MRI with 
intravenous contrast as the imaging modality for localization of the islet graft in the 
abdomen and pelvis. 
 
Positron Emission Tomography integrated with Computed Tomography (PET/CT) has 
been used as a functional imaging modality for identification and visualization of islet 
allografts. Several tracers have been evaluated including 18F-FDG, GLP-1, Exendin-4 and 
most recently [11C]5-HTP (98-102). We will perform an 18F-FDG PET/CT study for 
localization of the islets. PET/CT is a functional imaging technique mostly used in the field 
of oncology. It comprises the use of a radiopharmaceutical which is administered 
intravenously to the patient. The uptake of the tracer by tissues is then evaluated by a PET 
scanner and CT providing two and three-dimensional images of the distribution of the 
tracer in the body. The most common tracer used is 2-deoxy-2-[fluorine-18]fluoro-D-
glucose (18F-FDG), also known as fluorodeoxyglucose, an analogue of glucose containing 
the positron-emitting radionucleide fluorine-18. 18F-FDG is taken up by cells that rely on 
glucose as an energy source and primarily by cells with high-metabolic activity such as 
cancer cells thus providing significant information regarding tumor identification and 

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response to treatment in the field of oncology. We expect that the uptake of 18F-FDG, a 
glucose analog, by the islets will be superior to the expected physiologic background 
uptake by the omentum thus allowing for functional visualization of the engrafted islet 
mass.  
 
Both studies will be performed at the 1-year post-islet transplant visit in patients with 
persistent graft function and fasting C-peptide ≥0.5 ng/mL.  
 
6.6 
Mechanistic assays 
 
Immunologic assays 
We will obtain islet transplant donor splenocytes and recipient lymphocytes to perform 
T-cell assays. A maximum of 50 ml of blood will be obtained from recipients to perform 
these tests in order to evaluate for anti-donor reactivity. Frequency of T-cell assays will 
be determined by the principal investigator but will occur no less than every 6 months. 
 
Cytokine/Chemokines 
We will perform a cytokine/chemokine panel to explore the inflammatory milieu during 
the peri-transplant period. In addition, we will also assess cytokine/chemokine profiles at 
6 and 12 months post-transplantation to evaluate the role of inflammation on islet 
allograft function.  
Unmethylated preproinsulin DNA 
It has been postulated that as β-cells die unmethylated preproinsulin DNA emanates from 
the β-cells and is detectable in the circulation. Thus, changes in circulating levels of 
unmethylated preproinsulin DNA during the peri-transplant period may correlate with 
beta cell loss.   
Investigators from the Human Islet Research Network (HIRN) have developed assays to 
detect circulating unmethylated preproinsulin DNA. We will collaborate with the HIRN 
for validation of these assays by providing samples.  Serum and plasma samples will be 
obtained pre-transplant, 1hr, 3hr and 3 days post-transplant. Urine samples will be 
obtained pre-transplant and 5hr post-transplant. Samples will be shipped to the Juvenile 
Diabetes Research Foundation (JDRF) Core for Assay Validation at the Benaroya 
Research Institute. Results from these assays will not be made available to our center.  
7 
ADVERSE EVENTS 
 
This section defines the types of AEs and outlines the procedures for appropriately collecting, 
grading, recording, and reporting them. Information in this section complies with International 
Conference on Harmonization (ICH) Guideline E2A: Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting and ICH E6: Guideline for Good Clinical 
Practice, and the CIT-TCAE V5.0 Date: 03Aug2011.  
 

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An AE is any occurrence or worsening of an undesirable or unintended sign, symptom 
(including an abnormal laboratory finding), or disease that is temporally associated with the use 
of a study-related treatment whether considered related to the treatment or not.  
 
7.1 
Serious Adverse Events 
An SAE is defined per 21CFR§312.32 as “an adverse event or suspected adverse 
reaction is considered "serious" if, in the view of either the investigator or sponsor, it results 
in any of the following outcomes.” This includes but is not limited to any of the following 
events: 
1. Results in death, 
2. Is life threatening, (Note: the term “life-threatening” refers to an event/reaction in 
which the patient was at risk of death at the time of the event/reaction; it does not refer 
to an event/ reaction which hypothetically might have caused death if it were more 
severe), 
3. Requires inpatient hospitalization or results in prolongation of existing 
hospitalization, 
4. Results in persistent or significant disability/incapacity, 
5. Is a congenital anomaly/birth defect, or 
6. Is a medically important event or reaction. Medical and scientific judgment should 
be exercised in deciding whether other situations should be considered serious, such 
as important medical events that might not be immediately life-threatening or result 
in death or hospitalization, but might jeopardize the patient or might require 
intervention to prevent one of the other outcomes listed in the definition above. 
7. Other conditions specified in the protocol. 
 
In addition, events that occur at a higher than expected frequency, as determined by 
appropriate medical judgment, may be consider SAE’s. Regardless of the relatedness of 
the AE to study drug, the event must be reported as an SAE if it meets any of the above 
definitions. 
 
7.2 
Unexpected Adverse Event 
An AE is considered “unexpected” when its nature (specificity) or severity is not 
consistent with available product information, such as safety information provided in the 
package insert, the protocol, or the investigator’s brochure. 
 
7.3 
 Collecting Procedures 
AEs that are associated with a protocol-mandated procedure, which is not part of the 
normal standard of care for the participant and hypoglycemic events, will be collected 
beginning immediately after enrollment consent has been obtained. All other AEs will be 
collected beginning immediately after transplant. All AEs will continue to be collected 
until study completion, or for 30 days after the subject prematurely withdraws from the 
study.  
 

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AEs will be followed until the time the event is resolved, stabilized, or the subject 
completes or withdraws form the study, whichever comes first. AEs may be discovered 
through any of these methods: 
 
1. Observing the subject. 
2. Questioning the subject, this should be done in an objective manner. 
3. Receiving an unsolicited complaint from the subject. 
4. An abnormal value or result from a clinical or laboratory evaluation (e.g., a 
radiograph, an ultrasound, or an electrocardiogram) can also indicate an AE. If this 
is the case, then the evaluation that produced the value or result should be repeated 
until the value or result returns to normal or can be explained and the subject’s 
safety is not at risk. If an abnormal value or result is determined by the investigator 
to be clinically significant, it must be reported as an AE. 
 
7.4 
Recording Procedures 
Throughout the study the investigator will record all AEs on the appropriate AE case 
report form (CRF) regardless of their severity or relation to study medication or study 
procedure. The investigator will treat subjects experiencing AEs appropriately and observe 
them at suitable intervals until their symptoms resolve or their status stabilizes. 
 
7.5 
Reporting Procedure 
The following process for reporting an SAE ensures compliance with the ICH 
guidelines and 21CFR §312.32. 
 
7.5.1 
Standard reporting. (i.e., should be included in the investigational new drug 
[IND] annual report to the health-authorities). This requirement applies if the AE is 
classified as any of the following: 
Serious, expected, and drug related. 
Serious, expected, and not drug related. 
Serious, unexpected, and not drug related. 
 
7.5.2 
Expedited reporting. This requirement applies if the AE is considered 
serious, unexpected, and drug related as defined in 21 CFR 312.32. This type of SAE 
must be reported by the sponsor to the appropriate health authorities within 15 days; 
fatal or life-threatening events must be reported within 7 days. 
7.5.3 
Notifying the Institutional Review Board (IRB) and Ethics Committee 
The investigator will ensure the timely dissemination of SAE information, 
including expedited reports, to the IRB and Ethics Committee (EC) in accordance with 
applicable regulations and guidelines. 
 
 PREGNANCY 
Sexually-active WOCBP must use an effective method of birth control during the 
course of the study, in a manner such that risk of failure is minimized. Prior to study 

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enrollment, WOCBP must be advised of the importance of avoiding pregnancy during 
trial participation and the potential risk factors for an unintentional pregnancy. The 
subject must sign an informed consent form documenting this discussion. In addition, 
all WOCBP should be instructed to contact the investigator immediately if they suspect 
that they might be pregnant (e.g., missed or late menstrual period) at any time during 
study participation. Male subjects should also notify study team in case their female 
partners become pregnant during the study participation. 
 
 REPORTING PREGNANCY AS A SERIOUS ADVERSE EVENT 
All pregnancies that are identified during the study must be followed to conclusion 
and the outcome of each must be reported. The investigator should report all 
pregnancies within 24 hours using the SAE report form. The investigator should 
counsel the subject and discuss the risks of continuing with the pregnancy and the 
possible effects on the fetus. A woman who becomes pregnant or wishes to while on 
the study will be counseled as to her choices and will be encouraged to discuss those 
choices with her obstetrician. Monitoring of the subject should continue until the 
conclusion of the pregnancy, and a follow-up SAE report form detailing the outcome 
of the pregnancy should be submitted. 
 
7.6 
Grading and Attribution 
7.6.1 
Grading Criteria 
The study site will grade the severity of AEs experienced by study subjects 
according to the criteria set forth in the CIT-TCAE V5.0 Date: 03Aug2011. This 
provides a common language to describe levels of severity, to analyze and interpret 
data, and to articulate the clinical significance of all AEs. 
AE severity will be graded on a scale from 1 to 5 according to the following 
standards in the CIT-TCAE manual: 
Grade 1 = Mild AE. 
Grade 2 = Moderate AE. 
Grade 3 = Severe and undesirable AE. 
Grade 4 = Life-threatening or disabling AE. 
Grade 5 = Death. 
AEs, not included in the CIT-TCAE listing, should be recorded and their severity 
graded from 1 to 5 according to the General Grade Definition provided below: 
All AEs will be reported and graded, by the PI or designee, whether they are or are 
not related to disease progression or treatment. 
7.6.2  
Definition of Attribution 
Attribution will only be determined and collected for all adverse events. 
The relatedness, or attribution, of an AE to islet transplantation, which includes the 
transplant procedure and/or the islet product, the secondary investigational agent, or to 
the immunosuppression and/or infection prophylaxis will be determined by the 
investigator. The investigator will also record the determination of attribution on the 

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appropriate eCRF and/or SAE report form. The relationship of an AE (attribution of 
AE) to islet transplantation (islets or transplant procedure),  
 
7.6.3 
Attribution of adverse events 
 
UNRELATED CATEGORY 
1 The AE is clearly not related to allogeneic islets; the islet transplant procedure; 
immunosuppression or infection prophylaxis. 
 
RELATED CATEGORIES 
2  Unlikely: The AE is doubtfully related to allogeneic islets; the islet transplant 
procedure; immunosuppression or infection prophylaxis. 
3  Possible: The AE may be related to allogeneic islets; the islet transplant procedure; 
immunosuppression or infection prophylaxis. 
4  Probable: The AE is likely related to allogeneic islets; the islet transplant procedure; 
immunosuppression or infection prophylaxis. 
5  Definite: The AE is clearly related to allogeneic islets; the islet transplant procedure; 
immunosuppression or infection prophylaxis. 
 
8 
REVIEW OF SAFETY INFORMATION 
This trial will be conducted following Good Clinical Practice (GCP) and International 
Committee on Harmonization Guidelines (ICH). All research project personnel who work with 
subjects or subject data, or subject research samples will be required to complete ethics and 
protection of human research participants training as per guidelines issued by the US Department 
of Health and Human Services, Office for Human Research Protection. This protocol will undergo 
review and approval by the University of Miami (UM) Miller School of Medicine IRB. UM Office 
of Clinical Research Operations and Regulatory Support (CRORS) will monitor this study and 
provide the investigator with the overall monitoring plan, visit follow up letters that will include 
the information regarding of what was monitored and any action items noted during the visit. 
CRORS will monitor according an executed monitoring plan. 
8.1 
Data Safety Monitoring Board (DSMB) 
Diabetes Research Institute (DRI) will appoint the DSMB to monitor the progress of 
the trial. DRI will provide DSMB with listings of all AE / SAEs on an ongoing basis, i.e. 
at least annually.  
9 
QUALITY CONTROL AND QUALITY ASSURANCE  
 
The investigator is required to keep accurate records to ensure that the conduct of the study is 
fully documented.  

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The investigator (sponsor investigator) is responsible for regularly reviewing the conduct of the 
trial, for verifying adherence to the protocol, and for confirming the completeness, consistency, 
and accuracy of all documented data.  
9.1 
Compliance, Access, Entry and Handling of Study Data 
The PI is required to keep accurate records to ensure that the conduct of the study is 
fully documented, and to ensure that CRFs are completed for all subjects according to study 
guidelines outlined in the study protocol. Access to the data entry screens will be user ID 
and password protected. Each user will be provided with a unique personal ID and 
password. The investigational site participating in this study will maintain the highest 
degree of confidentiality permitted for the clinical and research information obtained from 
the subjects in this clinical trial. Medical and research records should be maintained in the 
strictest confidence. However, as part of the quality assurance and legal responsibilities of 
an investigation, the investigational site must permit authorized representatives 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 of records, 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 of medical and research information 
that is linked to identify individuals. The investigational site will normally be notified 
before auditing visits occur.  
The results of all clinical and laboratory evaluations will be maintained in the subjects 
medical records and the data will be transferred from these source documents directly to 
the electronic study CRFs. 
9.2 
Ethical Considerations and Compliance with Good Clinical Practice 
9.2.1  
Statement of Compliance 
This clinical study will be conducted using cGCP, as delineated in Guidance for 
Industry: E6 Good Clinical Practice Consolidated Guidance 163, 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 UM IRB. Any 
amendments to the protocol or to the consent materials must also be approved by UM 
IRB and submitted to the applicable Health Authorities before they are implemented.  
9.2.2  
Informed Consent and Assent 
The informed consent form is a means of providing information about the trial to a 
prospective subject and allows for an informed decision about participation in the 
study. All subjects (or their legally acceptable representative) must read, sign, and date 
a consent form before entering the study, taking study drug, or undergoing any study-
specific procedures. Consent materials for subjects who do not speak or read English 
must be translated into the subjects’ appropriate language.  
The informed consent form 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.  

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A copy of the informed consent will be given to a prospective subject for review. The 
attending physician, in the presence of a witness if required by the IRB, will review the 
consent and answer questions. The prospective subject will be told that being in the 
trial is voluntary and that he or she may withdraw from the study at any time, for any 
reason.  
9.2.3  
Privacy and Confidentiality  
A subject’s privacy and confidentiality will be respected throughout the study. Each 
subject will be assigned a sequential identification number and these numbers rather 
than names will be used to collect, store, and report subject information. 
 
9. Archived Serum Samples 
 
In order to ensure that we will ultimately gain as much information as possible 
from these trials, Serum samples will be archived for future analyses. Details for 
subjects regarding the archiving of samples and use for future assays are 
contained in the study’s informed consent form. Subjects will have the option of 
whether or not they want to have samples archived and will indicate their choice 
on the informed consent form. A subject’s choice regarding archiving samples 
will not affect his/her participation in the study. Serum: Blood will be collected to 
obtain serum and archived.  
 
11. 
Financing section and Funding Agency:  
 
 
The study medications will be provided by study team upon to 2 years after the last 
islet infusion. Thereafter subject, or subject’s insurance will be responsible for the costs 
related to immunosuppression.  
 
Study team will be responsible for medical costs of AE related to study treatment upon 
to 2 years after last islet infusion. Thereafter subject or/and subject insurance carrier 
will be responsible for future medical events. 
 
 
Name:  JDRF Grant: 17-2012-361 
Address:  26 Broadway 14th floor NY, NY 10004 
 
Name: Diabetes Research Institute Foundation (DRIF) 
Address: 3440 Hollywood Blvd. Ste. 100 Hollywood, FL 
 
12. 
Publication Policy:  
 
University of Miami Publications policy will be used for results publication. 

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13 
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APPENDIX A: SCHEDULE OF EVENTS (SOE) 
Time points (specified in 
Days relative to 
transplant) 
SCR WL/BL1 
0 2 
3 3 
7 
14 
21 
28 
56 
75 
120 150 180 
210 
240 
270 
300 
330 
365 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
Visit Windows (specified 
in days) 
N/A 
N/A 
N/A N/A 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
Equivalent Week/Month 
N/A 
N/A 
N/A N/A W1 W2 W3 W4 M2 M2.5 
M4 
M5 
M6 
M7 
M8 
M9 
M10 
M11 
M12 
GENERAL ASSESSMENTS 
Informed Consent  
X 
X 
X22  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Med/Diabetes Hx & 
Demographics 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Evaluation of Inclusion / 
Exclusion 
X 
X 
 X22 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Physical Exam17 
X 
X-yrly 
X22 
  
X 
  
  
X 
  
X 
  
  
X 
  
  
 
  
  
X 
Telephone Consult 
  
  
  
  
  
X 
X 
  
X 
  
X 
X 
  
  
  
X  
  
  
  
QOL 
X 
X-Q6mo 
  
  
  
  
  
  
  
X  
  
  
 
 
 
 
 
 
X 
Chest X-Ray 
X 
X-yrly 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Abdominal US (total) 
X 
X-yrly 
  
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
MRI abdomen and pelvis 
with IV contrast30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
18F-FDG PET/CT30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
ECG 
X 
X-yrly 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Psychological Evaluation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiac Stress Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PPD 
X 
X-yrly 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
AE /Hypoglycemic 
Events/Toxicity Assess 
  
 
X22 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
X 
  
  
X 
LOCAL LABORATORY ASSESSMENTS 
CBC (WBC + Diff & Plat) 
X 
X-Q6mo 
X22  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry3 
X 
X-Q6mo 
X22 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipids 
X 
X-Q6mo 
X 
X 
X 
X 

 
 
 
 
 
Thyroid Function (TSH) 
X 
X-Q6mo 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Pregnancy test (females)  
X 
X4,22 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Serology5 
X 
X-yrly 
X22 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
 
Time points (specified in 
Days relative to 
transplant) 
SCR WL/BL1 
0 2 
3 3 
7 
14 
21 
28 
56 
75 
120 150 180 210 240 270 
300 
330 
365 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
Visit Windows (specified 
in days) 
N/A 
N/A 
N/A 
N/A 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±14 ±14 ±14 ±14 
±14 
±14 
±14 
Equivalent Week/Month 
N/A 
N/A 
N/A 
N/A W1 W2 W3 W4 M2 M2.5 
M4 
M5 
M6 
M7 
M8 
M9 
M10 M11 M12 
LOCAL LABORATORY ASSESSMENTS 
EBV IgG/IgM 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CMV IgG, CMV IgM 
 X 
X-yrly6 
X22  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
Coagulation (PT, PTT, INR) 
X 
X-yrly 
X22 
  
  
  
  
X  
  
X  
  
  
 X 
  
  
  
  
  
 X 
Blood Type 
X  
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
HLA  
X31 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Crossmatch 7 
  
X22 
 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Fasting & post-prandial  
glucose and C-peptide 
  
  
 
 X8 
X8 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
CMV by PCR 
  
 
X22  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
X 
EBV by PCR10 
  
 
 X22 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
AA/EPA ratio 
X 
X-yrly 
X22,28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DRI / UM LAB 
Urinalysis 
X 
X-yrly 
X22 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spot urine11 
X 
X-yrly 
 X22 
  
  
  
  
X 
  
X 
  
  
 X 
  
  
  
  
  
X 
Urine C-peptide/Creatinine 
ratio25 
X 
 
X 
X 
X 
X 
Calculated eGFR 
X 
X-yrly 
  
  
  
  
  
X 
  
X 
  
  
  
  
  
  
  
  
X 
HbA1c12 
X 
X-Q6mo   
  
  
  
  
  
  
X 
  
  
X 
  
  
  
  
  
X 
Fasting serum glucose and 
C-pep12 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
 
 
 
 
MMTT glucose C-peptide, 
and Acetaminophen 12,13 
X 
  
  
  
  
  
  
  
  
X 
  
  
X 
  
  
 
  
  
X 
 
 
Time points (specified in 
Days relative to 
transplant) 
SCR16 WL/BL1 
0 2 
3  
7 
14 
21 
28 
56 
75 
120 150 180 210 240 270 
300 
330 
365 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
Visit Windows (specified 
in days) 
N/A 
N/A 
N/A 
N/A 
±3 
±3 
±3 
±3 
±7 
±7 
±7 
±7 
±14 
±14 
±14 
±14 
±14 
±14 
±14 
Equivalent Week/Month 
N/A 
N/A 
N/A 
N/A 
W1 
W2 
W3 
W4 
M2 
M2.5 
M4 
M5 
M6 
M7 
M8 
M9 
M10 M11 M12 
IMMUNOSUPPRESSION LEVELS 
Tacrolimus 12-hour trough 
levels18 
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MECHANISTIC ASSAYS 
Alloantibody (PRA) 15 
X 
X-Q6mo   
  
  
  
  
  
  
X 
  
  
X 
  
  
X 
  
  
X 
Autoantibody (GAD, IA-2, 
IAA, Znt8) 
X 
X-
Q6mo 
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-rabbit antibodies27 
X 
X-yrly 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma D-dimer 
X 
X-yrly 
X21 
X21 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Pro-inflammatory 
cytokines/chemokines 19 
X 
X-yrly 
X20 
X 
X 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
Immunological assays26 
 
X22 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
Lymphocyte Subsets  
 
X22 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
X 
Unmethylated 
preproinsulin DNA assays 
 
 
X29 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LOCAL METABOLIC ASSESSMENTS 

 
 
 
 
 
Glycemic Stability (CGM) 12 
  
X-yrly 
X23 
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
  
X 
BSR 12,14 
X 
X-Q6mo   
  
  
  
  
  
  
X 
  
  
X 
  
  
 
  
  
X 
CALCULATED METABOLIC ASSESSMENTS 
LI 
X 
X-Q6mo   
  
  
  
  
  
  
X 
  
  
X 
  
  
 
  
  
X 
Clarke Score  
X 
X-Q6mo   
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
HYPO 
X 
X-Q6mo   
  
  
  
  
  
  
X 
  
  
X 
  
  
 
  
  
X 
Beta Score 
    X 
 
  
  
  
  
  
  
  
X 
  
  
X 
  
  
 
  
  
X 
 C-peptide/glucose 
creatinine ratio24 
X 
 
  
  
  
  
  
X 
X 
X 
X 
X 
X 
  
  
 
  
  
X 
ARCHIVED SAMPLES 
Serum 
 
X 
X22 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
IN CASE OF ALEMTUZUMAB INDUCTION 
Urinalysis 
 
 
X22 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/Diff and Plat 
 
 
X22 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Creatinine 
 
 
X22 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid function tests 
 
 
X22 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
1 WL = Waiting List. BL = Baseline. These samples can be obtained at any time before transplant. Repeat assessments as indicated while subject is on the waiting list every 6 
months or annually from screening. All one-time WL/BL assessments should be completed on Day -2 whenever possible, but always prior to start of immunosuppression. For 
repeat WL/BL assessments, results from test done closest to the start of immunosuppression will be used as the baseline value. 
2 Day 0 = the day of transplant.  
3 Chemistry includes: Sodium, albumin, magnesium, chloride, potassium, alk phosphatase, total bilirubin, CO2, creatinine, ALT (SGPT), BUN, gamma GT, 
glucose, AST (SGOT), calcium, phosphorus. 
4 Complete pregnancy test within 72 hours prior to the initiation of study medication. 
5 Serology includes: HBc Ab, HBs Ab, HBs Ag, HCV Ab, and HIV. Do not repeat Hepatitis B tests if HBs Ab was previously positive. 
6 Repeat only if previous test was negative. 
7 Sample used for crossmatch may be obtained up to 60 days prior to the start of immunosuppression, as long as there is no evidence of infections or transfusions 
since the time the sample was drawn.  
8 C-peptide should be done locally and drawn fasting, and twice between 1-3 hrs post-prandial on Day 3 and Day 7 post-transplant. 
9  Error.  
10 EBV by PCR should only be done post-transplant if reactivation is suspected. 
11 Spot urine testing includes: albumin, protein, and creatinine 
12 Do not collect for participants with graft failure. Results of tests performed at the time of graft failure will be used for day 75 endpoint calculations. 

 
 
 
 
 
13 MMTT with Acetaminophen (to measure gastric emptying) includes 0, 60 and 90 minute samples for glucose and islet hormones, and Acetaminophen. Following 
transplantation we will perform an extended 5 hr MMTT collecting samples at -10, 0,     
    15, 30, 60, 90, 120, 180, 240, and 300 minutes.   
14 Blood Sugar Record (BSR) is completed using information gathered from subject diary logs, glucometer download data, and insulin requirements. 
15 For transplant, complete alloantibody assessment every 6 months and again on Day -2, regardless of the most recent draw.  
16 Data from 20053135 protocol can be used for this visit. If data was collected more than 12 months prior to enrollment, screening labs from visit 2 should be repeated. 
17 All visits that include a physical exam are in person at Miami 
18 If Sirolimus is used, levels should be checked concomitant with Tacrolimus levels. 
19 Pro-inflammatory cytokines/chemokines  
20 Samples for pro-inflammatory cytokines/chemokines for day 0 will be collected at 12 and 24 hrs after transplant 
21 Daily while in the hospital. For D-dimer, a sample will be obtained prior to placement of peripherally inserted central catheter (PICC) for Thymoglobulin infusion.  
22 Day of admission 
23 Day of admission and will be continued as clinically indicated 
24 C-peptide/glucose creatinine ratio calculation is: [C-peptide (ng/mL) x100]/[glucose (mg/dL) x creatinine (mg/dL)] 
25 Urine C-peptide/Creatinine ratio is obtained from a spot urine. During protocol scheduled site visits coinciding with MMTT, spot urine for C-peptide/creatinine ratio will be 
obtained before and at completion of MMTT.  
26 A maximum of 50 ml of blood will be obtained to perform T-cell assays to evaluate for anti-donor reactivity. Frequency of T-cell assays will be determined by the principal 
investigator but will occur no less than every 6 months. 
27 IgG and IgE to rabbit serum proteins and epithelium will be obtained at screening. After transplantation, samples for these antibodies may be obtained as clinically indicated (e.g. 
in case of a patient developing an immunologic reaction against Thymoglobulin). 
28 AA/EPA ratio will be measured monthly starting at POD -2 until target levels are achieved and as clinically indicated thereafter. 
29 Samples for unmethylated preproinsulin DNA will be collected as follows:  
- 
Serum and plasma samples will be obtained pre-transplant, 1hr, 3hr and 3 days post-transplant.  
- 
Urine samples will be obtained pre-transplant and 5hr post-transplant. 
30  To be performed in patients with persistent graft function and fasting C-peptide ≥0.5 ng/mL. 
 31Test will be done prior to listing subject in UNOS waiting list. 
 
 
Time points (specified in Days relative to 
transplant) 
450 
540 
630 
730 
Time Point (months [M] relative to final 
islet transplant 
M15 
M18 
M21 
M24 
Visit Number 
20 
21 
22 
23 
Visit Windows (specified in days) 
±30 
±30 
±30 
±30 
GENERAL ASSESSMENTS 
Physical Exam 
  
X 
  
X 
Telephone Consult  
X 
  
X 
  
QOL 
  
  
  
X 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE /Hypoglycemic Events/Toxicity 
Assessment  
X 
X 
X 
X 
LOCAL LABORATORY ASSESSMENTS 
CBC (WBC + Diff & Plat)  
X 
X 
X 
X 
Chemistry  
X 
X 
X 
X 
Lipids 
  
X 
  
X 
DRI LABORATORY/METABOLIC ASSESSMENTS 
Spot urine 
  
X 
  
X 
Fasting glucose and C-peptide 
X 
X 
X 
X 
Urine C-peptide/creatinine ratio 
X 
X 
X 
X 
Calculated eGFR  
  
  
  
X 
HbA1c 
X 
X 
MMTT glucose  C-peptide, and 
Acetaminophen 12,13 
  
X 
  
X 
Glycemic Stability (CGM)  
  
  
  
X 
BSR eCRFs 
  
X 
  
X 
Lymphocyte Subsets 
 
      X 
 
X 
Immunological assays26 
 
      X 
 
X 
CALCULATED METABOLIC ASSESSMENTS 
LI, Clarke Score, HYPO, Beta SCORE,  
C-peptide/glucose ratio 
 
X 
 
X 
IMMUNOSUPPRESSION LEVELS 
Tacrolimus Levels 
X 
X 
X 
X 
MECHANISTIC ASSAYS 
Autoantibodies  
 X 
X 
 X 
X 
Alloantibodies 
 
X 
 
X