Treatment of Type I Diabetes by Islet Transplantation Into the Gastric Submucosa Study Protocol

Pancreatic islet transplantation offers a minimally invasive approach to restore
normoglycemia in type 1 diabetics while avoiding the hypoglycemic complications observed with
intensive insulin therapy and the surgical complications associated with pancreas
transplantation. Although significant progress has been made in clinical islet
transplantation, overall outcomes remain suboptimal since many patients lose insulin
independence a few years after transplantation and multiple donors are usually needed to
achieve independence. The cause of this progressive loss of function is multifactorial, but
mounting evidence suggests that much of the islet loss after transplant is directly related
to the intraportal transplant site that is used in clinical islet transplantation.
Intravascular infusion of the islets triggers a severe,non-specific inflammatory response
(immediate blood-mediated inflammatory reaction, IBMIR) which destroys at least 50% of the
islet mass. The engraftment of the surviving islets is further compromised by the relatively
hypoxic portal venous environment, and the infused islets are exposed to potentially toxic
levels of immunosuppressive agents being absorbed from the gut into the portal circulation.
Together, these characteristics contribute to early as well as late loss of islet function
after transplantation. The gastrointestinal submucosa is a newly described transplant site
that can support islet engraftment while avoiding many of the drawbacks associated with
intraportal infusion. In addition, this site is easily accessible via upper endoscopy and the
submucosal injection procedure is safe and technically straightforward.

The aim of this prospective, single-center trial is to provide initial clinical experience
regarding the safety and efficacy of endoscopic gastric and duodenal submucosal islet
transplantation in type I diabetic patients with kidney allografts. A total of 6 patients
will be recruited into the trial. The investigators will follow the standardized islet
manufacturing protocols and the thymoglobulin-based induction immunosuppressive regimen
developed by the Clinical Islet Transplant consortium (CIT). Outcomes will include safety
measures, glycemic control and insulin use, metabolic assessments of graft function,
allo/auto-immune responses, and protocol biopsies to assess graft rejection/inflammation. The
investigators believe that this novel approach to islet transplantation has the potential to
significantly improve current islet transplantation outcomes by enhancing islet engraftment
and long-term function.

Inclusion Criteria:

1. Male and female subjects age 18 to 70 years of age.

2. Subjects who are able to provide written informed consent and to comply with study
procedures.

3. Clinical history compatible with T1D (onset < 40 yrs old and insulin dependent for > 5
yrs at enrollment.

4. Absent stimulated c-peptide (< 0.3 ng/mL) in response to a (Boost® 6 mL/kg BW to a
maximum of 360 mL; another equivalent product), measured at 60 and 90 min after start
of consumption.

5. Subjects who are > 3 months post-renal transplant who are taking appropriate
calcineurin inhibitor (CNI) based maintenance immunosuppression ([tacrolimus alone or
in conjunction with sirolimus, mycophenolate mofetil, myfortic, or azathioprine; or
cyclosporine in conjunction with sirolimus, mycophenolate mofetil, or myfortic ±
Prednisone ≤ 10 mg/day).

6. Stable renal function as defined by a creatinine of no more than one third greater
than the average creatinine determination performed in the 3 previous months prior to
islet transplant, until rejection, obstruction or infection is ruled out.

7. Reduced awareness of hypoglycemia manifested a Clarke score >4 and at least 1 episode
of severe hypoglycemia in the past 12 months prior to study enrollment. This criterion
requires that there has been involvement in intensive diabetes management under the
direction of an endocrinologist, diabetologist, or diabetes specialist prior to study
enrollment. Intensive diabetes management is defined as self-monitoring of glucose
values no less than 3 times each day averaged over each week and by the administration
of three or more insulin injections each day or insulin pump therapy. Severe
hypoglycemia is defined as an event with one of the following symptoms: memory loss;
confusion; uncontrollable behavior; irrational behavior; unusual difficulty in
awakening; suspected seizure; seizure; loss of consciousness; or visual symptoms, and
which was associated with either a BG level < 54 mg/dl [3.0 mmol/L] or prompt recovery
after oral carbohydrate, IV glucose, or glucagon administration.

Exclusion Criteria:

1. Weight more than 100 kg or body mass index (BMI) > 30 kg/m2.

2. Insulin requirement of >1.0 IU/kg/day or <15 U/day.

3. Other (non-kidney) organ transplants except prior failed pancreatic graft where graft
failure is attributed to thrombosis within the first 4 weeks or to other technical
reasons that require graft pancreatectomy; with the graft pancreatectomy occurring
more than 6 months prior to enrollment.

4. Untreated or unstable proliferative diabetic retinopathy.

5. Blood Pressure: SBP > 160 mmHg or DBP >100 mmHg despite treatment with
antihypertensive agents.

6. Calculated GFR of ≤ 40 mL/min/1.73 m2 using the subject's measured serum creatinine
and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. (59)

7. Proteinuria (albumin/creatinine ratio or ACr > 300mg/g) of new onset since kidney
transplantation.

8. Calculated panel-reactive anti-HLA antibodies > 50%. Subjects with calculated panel
reactive anti-HLA antibodies ≤ 50% will be excluded if any of the following are
detected:

- Positive cross-match

- Islet donor-directed anti-HLA antibodies detected by Luminex® Single
Antigen/specificity bead assay including weakly reactive antibodies that would
not be detected by a flow cross-match

9. For female subjects: 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. Oral contraceptives, Norplant®, Depo-Provera®,
and barrier devices with spermicide are acceptable contraceptive methods; condoms used
alone are not acceptable.

10. Active infection including hepatitis B, hepatitis C, HIV, or TB. A positive skin test
(PPD) in itself is not an exclusion, and will be followed up by a QuantiFERON® gold
assay.

11. Negative screen for EBV IgG.

12. Invasive Aspergillus, Histoplasmosis, and Coccidioidomycosis infection within 1 year
prior to study entry.

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. Severe co-existing cardiac disease, characterized by any one of these conditions:

- Recent MI (within past 6 months),

- Evidence of ischemia on functional cardiac exam within the last year,

- Left ventricular ejection fraction < 30%,

- Valvular disease requiring replacement with prosthetic valve.

16. Persistent elevation of liver function tests at time of study entry. Persistent SGOT
(AST), SGPT (ALT), alkaline phosphatase values > 1.5, or total bilirubin > 1 times
normal upper limits will exclude a subject.

17. Active infections (except mild skin and nail fungal infections).

18. Acute or chronic pancreatitis.

19. Active peptic ulcer disease or gastritis, symptomatic gallstones, or portal
hypertension.

20. Treatment with any anti-diabetic medication other than insulin within 4 weeks of
enrollment.

21. Use of any investigational agents within 4 weeks of enrollment.

22. Administration of live attenuated vaccine(s) within 2 months of enrollment.

23. Any medical condition that, in the opinion of the investigator, will interfere with
safe study completion.

24. Positive screen for BK viremia at time of screening.

25. Untreated hyperlipidemia - TC > 200 mg/dL, TGC > 200 mg/dL, LDL > 130 mg/dL

26. Use of glucocorticoids for non-transplant-related indications.