A Phase 3 Single Center Study of Islet Transplantation in Non-uremic Diabetic Patients

(T1D) Type 1 diabetes afflicts nearly 2 million people in the United States, most of them
children or young adults. Untreated, it is a fatal disease. Exogenous insulin, administered
by multiple injections or by a continuous subcutaneous (SC) infusion from a wearable pump,
allow long term survival in those who develop the disease, and most who are treated in this
way will have a very good health-related quality of life. However, insulin therapy does not
provide normal glycemic control, and long term survivors commonly develop vascular
complications such as diabetic retinopathy (the most common cause of adult blindness) and
diabetic nephropathy (the most common indication for adult kidney transplantation). The
Diabetes Control and Complications Trial (DCCT) established that these microvascular
complications of diabetes can be prevented by maintaining near-normal glucose control in
patients with T1D. However, this degree of control is not always achievable despite modern
insulin analogs and delivery systems, and when achieved, it is invariably associated with
episodes of insulin-induced hypoglycemia that can be life-threatening. A small minority of
individuals with T1D develop hypoglycemia unawareness, a condition that is life-threatening,
is associated with severe deterioration in quality of life and activity restriction, and is
not amenable to medical therapy.

The hope of achieving near-normal glucose control without hypoglycemia in T1D has provided
the impetus for developing effective strategies for β-cell replacement via pancreas or
isolated islet transplantation. When successful, pancreas transplantation can normalize blood
glucose(BG) in diabetic recipients, with associated stabilization and even reversal of
microvascular complications. However, the risks of the procedure (an almost 10% early failure
rate due to technical complications, anastomotic leak, bleeding, and infection) and the need
for lifelong immunosuppression have in most centers limited the target population of this
therapy to diabetics <50 years of age with minimal or no coronary artery disease, and at some
centers pancreas transplant is offered only with concomitant kidney transplant. As a result,
T1D patients in need of β-cell replacement are often excluded from whole pancreas
transplantation. Islet transplantation, in contrast, is accomplished by a much simpler
procedure in which the islets are infused into the portal vein. While this procedure is not
without risk, the procedural morbidity is much less than that of whole pancreas
transplantation.

On the other hand, whereas about 80% of whole pancreas transplant recipients will be insulin
independent at one year after their transplant, <10% of 447 islet recipients transplanted
between 1990 and 1999 achieved one year insulin independence. This was attributed to low
engrafted islet mass combined with high metabolic demand imposed by glucocorticoids used to
prevent rejection. In the year 2000, the group from Edmonton reported a series of 7
consecutive islet transplant recipients treated with islets from multiple donors and a
glucocorticoid-free immunosuppressive regimen. These islet recipients were insulin free at
follow-up ranging from 4.5 to 15 months. All of the recipients had experienced severe
hypoglycemic episodes prior to transplant, and afterwards, none did. The efficacy of the
Edmonton approach has now been confirmed by several other centers, and represents a major
breakthrough in the field. However, it has also become clear that, in most islet recipients,
there is loss of graft function over time; in Edmonton, insulin-independence rates have
declined from 72% at one year to 28% by three years. A multicenter trial using the Edmonton
protocol has both confirmed the results of the initial experience and raised questions
relating to the expansion of the procedure to multiple centers, the toxicities of the
immunosuppressive regimen, and the evaluation of the islet product.

In 2006, the NIH initiated several multi-center (Clinical Islet Transplantation Consortium)
clinical trials of islet transplantation with the primary goal of establishing islet
transplantation as a therapeutic treatment option for patients with type 1 diabetes either
already have had a successful kidney transplant or with severe hypoglycemic events and good
native renal function. The clinical protocol utilized for these trials improved from the
Edmonton protocol in that it incorporates (1) T cell depletion anti-thymocyte antibody(16,
17); (2) peri-transplant anti-inflammatory therapy using Tumor Necrosis Factor (TNF)-a
blockade; (3) aggressive control of glucose homeostasis after transplant with continuing,
albeit reduced, insulin therapy; (4) short-term anticoagulation therapy peri-intraportal
islet infusion. Northwestern is one of the clinical centers of the Consortium and has
successfully transplanted a total of eighteen patients with twenty-six islet preparations
using this protocol in the past two and half years.

The current study protocol modifies the protocol of the (CIT) Clinical Islet Transplantation
consortium and substituted anti-thymocyte polyclonal antibody with alemtuzumab which has been
shown to have efficacy in both pre-clinical model as well as clinical trials of allogeneic
islet transplantation.

Inclusion Criteria

1. Male and female patients age 18-65 years of age at consent

2. Ability to provide written informed consent

3. Mentally stable and able to comply with the procedures of the study protocol

4. Patients with T1D and insulin-dependent for at least 5 years fulfilling the following
criteria:

1. Absent stimulated c-peptide (<0.3 ng/mL) in response to a mixed meal tolerance
test (MMTT; ensure 6 mL/kg body weight to a maximum of 360mL) measured at 60 and
90 min after the start of consumption

2. Patients who have been followed by a qualified physician for diabetes management
for a minimum of 12 months

3. At least one episode of severe hypoglycemia in the past 12 months

4. A Clarke score of 4 or more defining reduced awareness of hypoglycemia

5. Or, previous islet cell transplant recipients who have returned to partial or full
insulin usage and are taking maintenance immunosuppression medications.

Exclusion Criteria

1. Body mass index (BMI) > 30

2. Insulin requirement of > 1.0 IU/kg/day

3. HbA1c > 10%

4. Calculated glomerular filtration rate (GFR) < 80mL/min for transplant-naïve patients
(using subjects serum creatinine and the Chronic Kidney Disease Epidemiology
Collaboration equation CKD-EPI) or 50mL/min for previously transplanted patients
currently on immunosuppression

5. Macroalbuminuria >300 mg/g creatinine

6. Panel reactive anti-HLA antibodies> 50% by flow cytometry

7. For female subjects: positive pregnancy test, breast feeding or unwillingness to use
effective contraceptive measures for the duration of the study.

8. Active infection including hepatitis B, hepatitis C, HIV, or tuberculosis (TB)

9. Negative Epstein-Barr Virus (EBV) by IgG

10. Any history of malignancy except resected squamous or basal cell carcinoma

11. Alcohol or substance abuse

12. Baseline Hb below the lower limit of normal

13. International normalized ratio >1.5 and long term anticoagulant therapy

14. Clinically significant coronary artery disease

15. Elevated liver function tests >1.5 times upper limit of normal

16. Symptomatic cholecystolithiasis

17. Gastrointestinal disorders interfering with ability to absorb oral medications

18. Uncontrolled hyperlipidemia (LDL cholesterol >130 mg/dL and/or triglycerides >200
mg/dL)

19. Chronic corticosteroid use