Alemtuzumab Induction in Islet Transplantation

Our experience suggests that further research with alemtuzumab is attractive in islet transplantation. Therefore, in this study we propose to combine alemtuzumab induction pre-transplant, with tacrolimus and mycophenolate mofetil maintenance immunosuppression post-transplant. In the critical early phase post transplant, we anticipate that this regimen will prove to be more effective in control of autoimmunity or rejection events, and have a more desirable side-effect profile, than previously tested combinations of induction and immunosuppressive agents.

This trial is a single-center, prospective, open-label study in 12 Type 1 diabetic participants receiving an islet-alone transplant along with alemtuzumab induction therapy followed by combination tacrolimus and MMF maintenance immunosuppression. Participants will receive 1 to 3 infusions of pancreatic islets of sufficient quantity to attain insulin independence.

The primary objective of this protocol is to assess the safety of a treatment regimen utilizing alemtuzumab induction and a combination of tacrolimus and MMF maintenance immunosuppression in adult Type 1 diabetic participants receiving their first islet transplant.

Eligibility Criteria:
Inclusion Criteria:

* open to Canadians only
* participant must have had Type 1 diabetes mellitus for more than 5 years
* diabetes must be complicated by at least 1 of the following situations that persist despite intensive insulin management efforts: (1) Reduced awareness of hypoglycemia, as defined by the absence of adequate autonomic symptoms at plasma glucose levels \< 3.0 mmol/L, indicated by, 2 or more episodes of severe hypoglycemia requiring third party assistance within 12 months; or (2) Metabolic instability, characterized by erratic blood glucose levels that interfere with daily activities and or 2 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
* Active alcohol or substance abuse, to include cigarette smoking
* Psychiatric disorder making the subject not a suitable candidate for transplantation
* History of non-adherence to prescribed regimens
* Active infection including Hepatitis C, Hepatitis B, HIV, TB
* Any history of or current malignancies except squamous or basal skin cancer
* BMI \> 28 kg/m2 at screening visit
* Creatinine clearance \< 65 mL/min/1.73 m2
* Blood creatinine \> 150 µmol/L (1.7 mg/dL)
* Macroalbuminuria (urinary albumin excretion rate \> 300 mg/24h)
* Baseline Hb \< 105g/L (\<10.5 g/dL) in women, or \< 130 g/L (\<13 g/dL) in men
* Baseline screening liver function tests outside of normal range
* 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
* Insulin requirement \>1.0 U/kg/day
* HbA1C \>12%
* Uncontrolled hyperlipidemia
* 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