How are patients evaluated for eligibility? Patients are evaluated by the islet transplantation physicians. Eye examination, urine tests, and blood work, will be monitored on a regular basis. Before transplantation, all patients will be treated with the best medical treatments for diabetes that we currently have which includes controlling blood sugars well with insulin injections, and treating any other medical problems such as high blood pressure or high cholesterol.

What is optimal medical therapy? Glycemic Control (blood sugars)

• Target fasting or pre-meal blood sugars by glucometer 4-7 mmol/L
• Target HbA1c <0.70 to be followed every 3 months.

These targets are based on the Diabetes Control and Complication Trial (DCCT), which demonstrated an approximately 50 percent reduction in eye, nerve, and kidney complications with intensive treatment for hyperglycemia.

Blood Pressure Control. Hypertension (blood pressure >140/90 mmHg) should be treated to attain target blood pressure <125/70 mmHg to prevent progression of renal disease.Treatment for high blood pressure is important because elevated diastolic blood pressure is a risk factor for the development of macular edema, and elevated systolic blood pressure is a risk factor for loss of vision.

Lipid Control (Blood fats). All patients will be treated to target values for the following fasting lipid profile:

• LDL-C level <2.5 mmol/L
• Total Cholesterol:HDL-C ratio <4
• Triglyceride level <2.0 mmol/L

Based on 10 year risk of coronary artery disease >30%, or a history of cardiovascular disease, or diabetes from the Recommendations for the Management and Treatment of Dyslipidemia , CMAJ, May 16, 2000; 162(10) 1441-1447.

Renal Protection (Kidneys). All patients with >300 mg/day of albumin in their urine and microalbuminuria (30-299 mg/day albumin in their urine) will receive ACE inhibitor treatment even in the absence of hypertension. Based on Should All Patients with Type 1 Diabetes Mellitus and Microalbuminuria Receive Angiotensin-Converting Enzyme Inhibitors? A Meta-Analysis of Individual Patient Data. Annals of Internal Medicine. March 2001, volume 134, pages 370-379.

Patients will be randomly selected from the group to receive an islet transplant.Of the group of 50, there will be 10 people at a time who will carry pagers so that they can be contacted in the case a transplant becomes immediately available.

Study Flow Chart

1. Meet Inclusion Criteria
2. Retinopathy Assessment
3. Cardiovascular Assessment
4. Transplantation Team Assessment
5. Exclusion Criteria and Assessment
6. Trial of Optimal Medical Therapy (3 months)
7. Collect Data on End Points on Optimal Medical Therapy
8. Await random selection for islet cell transplantation.

The Islet Cell Transplant Study (Blood fats). Despite medical treatment, complications related to diabetes still occur. This study will determine the rate of progression of complications related to type 1 diabetes in subjects with microalbuminuria and retinopathy on optimal medical therapy. The subjects will receive optimal medical treatment which includes: glycemic control, blood pressure control, lipid profile control, and all patients will be treated with an ACE inhibitor.

Trial Schedule

• Planned inclusion of first subject: started March 11, 2002
• Planned inclusion of last subject: When 50 patients have been recruited.

The study has started enrolling patients at this time. We anticipate that the first transplant will take place near the end of 2002 or early 2003.

Rationale for the Trial. These subjects will ultimately await random selection for pancreatic islet cell transplantion. The data collected in the first part of the study will ultimately be used to compare against data after islet cell transplantation.

The primary endpoints (key data measurements collected) are glycemic control, glycemia frequency, and progression of complications:

• rate of progression from microalbuminuria to proteinuria (kidney damage)
• rate of progression of diabetic non-proliferative retinopathy to proliferative retinopathy (eye damage).

The secondary endpoints of the study are:

• renal failure (elevated creatinine)
• end stage renal disease
• myocardial infarction (heart attacks).

Subjects will be randomly selected into the treatment arm or control arm. All subjects will be treated to the targets for optimal medical therapy (see previous page). Subjects in the treatment arm will randomly receive a transplant when there is a pancreas available. Randomization is similar to flipping a coin, and not controlled by the investigators. Both cohorts will be followed for primary and secondary endpoints (described earlier).

All study participants will be closely followed before the transplant as well as afterwards to determine whether the transplant has improved their quality of life as well as prevented progression of diabetes related problems.

Summary

Pancreatic islet cell transplantation is a potential new promising treatment for patients with type 1 diabetes. Currently, there are no clinical studies to show that pancreatic islet transplantation is better than the current optimal medical treatment for type 1 diabetes. There is also no long-term data on the effects of islet transplantation in the progression of complications related to diabetes. These complications include decrease in kidney function, diabetes-related eye disease, cardiovascular disease, and death. Currently, there is also no data on long-term safety of pancreatic islet transplantation. Studies to answer these questions have not yet been performed.

The study we are now starting will try to answer these questions. We will be comparing patients who receive optimal medical treatment for type 1 diabetes to patients who receive pancreatic islet cell transplantation. We hope to determine what differences in outcome and complications are seen between these two treatments. Should pancreatic islet transplantation be shown to be a superior treatment for type 1 diabetes than our current optimal medical therapy, we hope to be able to provide this treatment in improving the health of patients with type 1 diabetes.

Michelle Fung is a clinical fellow specializing in endocrinology and metabollism.