Islet Transplantation in Type 1 Diabetic Patients Using the Edmonton Protocol of Steroid Free Immunosuppression

Diabetes mellitus is becoming an unbearable burden for the health care system worldwide. The
incidence of disease has increased over the past 50 years, both for type I and type II
diabetes. In 2002, the expenditure for direct and indirect costs of diabetes reached the
astronomical amount of $132 billion for the USA alone. The burden suffered by patients is
also grave when we consider that diabetic neuropathy and retinopathy are now the leading
causes of renal failure and blindness in industrialized countries. Although major
improvements in insulin treatment and glycemic control have been achieved, the development of
hypoglycemic unawareness still represents a challenging clinical problem in the management of
diabetes. Severe hypoglycemic episodes are not only acutely life threatening but lead to
overall impairment of the quality of life of diabetic patients. Even under ideal study
conditions the pathophysiology of hypoglycemic unawareness is not fully understood. It seems
that each hypoglycemic episode reduces the counterregulatory hormone responses and the
subjective awareness of the following episode, generating a self-worsening mechanism. Islet
transplantation can effectively eliminate severe hypoglycemia and restore good glycemic
control. However, there are still several limitations to the widespread application of islet
transplantation. First, insulin independence is mostly achieved by transplanting a high
number of islets that are harvested from 2-4 donors. Second, post-transplant
insulin-independence is progressively lost over time despite continued endogenous insulin
secretion. Lastly, current immunosuppression carries potential risks and can only
incompletely prevent sensitization of the host and rejection.

At present, clinical trials in islet transplantation face stringent federal regulations,
which define islets as a biological drug and islet transplantation as an experimental
procedure. Limited resources impose small and uncontrolled trials investigating a limited
number of new interventions to improve outcomes.

This study is a Phase 1/2 single center, uncontrolled trial in which 1-3 allogeneic
pancreatic islet transplants are performed for each study subject. Post-transplant follow-up
continues for 64 weeks after the final islet transplantation. Thereafter, subjects are
enrolled for a 5-year follow-up study and a 5 to 10 year follow-up study.

The safety of islet transplantation depends primarily on the incidence of serious and
unexpected complications or adverse events and the ability of the cell isolation laboratory
to produce uncontaminated islet cell preparations with minimal endotoxin content. All study
subjects are followed for safety for one year. An independent Data Monitoring Committee
(DMC), composed of 3 members who have training in medicine and/or organ transplantation, will
review eligibility and safety data approximately 2 weeks after each islet transplantation and
every two months thereafter. An independent monitor knowledge on Good Clinical Practice(GCP)
guidelines and regulations monitors the study for compliance with 21 CFR and according to ICH
GCP Guidelines. Within the Clinical Research Center, the Scientific Advisory Committee and
the Research Subject Advocacy Program monitor safety. These entities report to the
Institutional Review Board, which also reviews safety data annually and on occurrence of
serious adverse events. The principal investigator also report serious adverse events to the
US Food and Drug Administration (FDA).

Success: Islet transplantation is considered a success when subjects do not use insulin and
they achieve a fasting glucose level not exceeding 140 mg/dL more than three times in a week,
and not exceeding two-hour post-prandial values of 180 mg/dL more than four times in a week.

Partial Success: Subjects who have a reduction in insulin requirements but who do not achieve
insulin independence and present with a reduction in HbA1c and number of hypoglycemic
episodes are considered to have partial success of islet transplantation. Reduction in
insulin-requirements are assessed by comparing the pre-transplant insulin requirement
recorded over two consecutive days (expressed as insulin units per kg) with the requirement
on the two consecutive days preceding the subsequent islet infusion, and the requirements on
two consecutive days at six months and again on two consecutive days at one year after the
final transplant.

Failure: Absence of measurable levels of C-peptide after transplantation is considered as
failure of islet cell transplantation.

Inclusion Criteria:

- Type 1 diabetes > 5 years complicated by at least one of the following situations
despite intensive insulin management:

- Reduced awareness of hypoglycemia at plasma glucose levels < 54 mg/dL

- Metabolic lability/instability characterized by two or more episodes of severe
hypoglycemia or hospital visits for diabetic ketoacidosis over the last year

- Progressive secondary complications of diabetes:

- Retinopathy—three step progression using the ETDRS grading system or
equivalent progression;

- Nephropathy— microalbuminuria rise of 50 µg/min (72 mg/24h) over three
months within the past two years despite using an ACE inhibitor;

- Neuropathy—persistent gastroparesis, postural hypotension, neuropathic bowel
or bladder, or severe peripheral neuropathy unresponsive to management

Exclusion Criteria:

- Co-existing cardiac disease:

- Myocardial infarction within past six months

- Angiographic evidence of non-correctable coronary artery disease

- Ischemia on functional cardiac exam d. Heart failure > NYHA II

- Active alcohol or substance abuse or cigarette smoking

- Psychiatric disorder: schizophrenia, bipolar disorder, or major depression that is
unstable on medication

- Non-adherence to prescribed regimens

- Active infection including hepatitis C, hepatitis B, HIV

- TB by history, current infection, or under treatment for suspected TB

- History of malignancies except squamous or basal skin cancer

- Stroke within the past 6 months

- BMI > 26 kg/m2 or body weight > 70 kg at screening visit

- C-peptide response to glucagon stimulation, any C-peptide ≥ 0.3 ng/mL

- Inability to provide informed consent

- Age less than 18 or greater than 65 years

- Creatinine clearance < 85 mL/min/1.73 m2 by 24-hour urine collection

- Serum creatinine > 1.5 mg/dL

- Macroalbuminuria > 300 mg/24h

- Baseline Hb < 12 gm/dL in women, < 13 gm/dL in men

- Baseline liver function tests outside normal range

- Untreated proliferative retinopathy

- Positive pregnancy test, intent for pregnancy, male's intent to procreate, unwilling
to use effective contraception, breast-feeding

- Previous transplant or PRA reactivity > 20%)

- Insulin requirement > 0.7 IU/kg/day

- HbA1C > 12%

- Hyperlipidemia

- Chronic use of steroids

- Use of coumadin or other anticoagulant (except aspirin) or PT INR > 1.5

- Addison's disease

- Allergy to radiographic contrast material