Caspase Inhibition in Islet Transplantation

Inclusion criteria

To be eligible the participant must have had T1DM for more than 5 years, complicated by at least 1 of the following situations that persist despite intensive insulin management efforts:

• Reduced awareness of hypoglycemia, as defined by the absence of adequate autonomic symptoms at plasma glucose levels < 3.0 mmol/L, indicated by, 1 or more episodes of severe hypoglycemia requiring third party assistance within 12 months, a Clarke score ≥ 4, HYPO score ≥ 1,000, lability index (LI) ≥ 400 or combined Hypo/LI > 400/300
• Metabolic instability, characterized by erratic blood glucose levels that interfere with daily activities and or 1 or more hospital visits for diabetic ketoacidosis over the last 12 months.

Participants must be capable of understanding the purpose and risks of the study and must sign a statement of informed consent.

Exclusion criteria

• Severe co-existing cardiac disease, characterized by any one of these conditions: (a) recent myocardial infarction (within past 6 months); (b) left ventricular ejection fraction < 30%; or (c) evidence of ischemia on functional cardiac exam.
• Active alcohol or substance abuse, to include cigarette smoking (must be abstinent for 6 months prior to transplant).
• Psychiatric disorder making the subject not a suitable candidate for transplantation, (e.g., schizophrenia, bipolar disorder, or major depression that is unstable or uncontrolled on current medication).
• History of non-adherence to prescribed regimens.
• Active infection including Hepatitis C, Hepatitis B, HIV, TB (subjects with a positive PPD performed within one year of enrollment, and no history of adequate chemoprophylaxis).
• Any history of or current malignancies except squamous or basal skin cancer.
• BMI > 35 kg/m2 at screening visit.
• Age less than 18 or greater than 68 years.
• Measured glomerular filtration rate (GFR) < 60 mL/min/1.73 m2.
• Presence or history of macroalbuminuria (> 300 mg/g creatinine).
• Clinical suspicion of nephritic (hematuria, active urinary sediment) or rapidly progressing renal impairment (e.g. Increase in serum creatinine of 25% within the last 3-6 months).
• Baseline Hb < 105g/L (< 10.5 g/dL) in women, or < 120 g/L (< 12 g/dL) in men.
• Baseline screening liver function tests outside of normal range, with the exception of uncomplicated Gilbert's Syndrome. An initial LFT panel with any values > 1.5 times the upper limit of normal (ULN) will exclude a patient without a re-test; a re test for any values between ULN and 1.5 times ULN should be made, and if the values remain elevated above normal limits, the patient will be excluded.
• Untreated proliferative retinopathy.
• Positive pregnancy test, intent for future pregnancy or male subjects' intent to procreate, failure to follow effective contraceptive measures, or presently breast feeding.
• Previous transplant or evidence of significant sensitization on PRA (at the discretion of the investigator).
• Insulin requirement > 1.0 U/kg/day
• HbA1C > 12%.
• Uncontrolled hyperlipidemia [fasting LDL cholesterol > 3.4 mmol/L (133 mg/dL), treated or untreated; and/or fasting triglycerides > 2.3 mmol/L (90 mg/dL)].
• Under treatment for a medical condition requiring chronic use of steroids.
• Use of coumadin or other anticoagulant therapy (except aspirin) or subject with PT INR > 1.5.
• Untreated Celiac disease.
• Patients with Graves disease will be excluded unless previously adequately treated with radioiodine ablative therapy.