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Protocol Number: 03-DK-0245 
Type I diabetes is an autoimmune disease, in which the immune system attacks the beta cells of the pancreas. These cells produce insulin, which regulates blood sugar. AC2993 may improve the pancreas's ability to produce insulin and help control blood sugar, but it may also activate the original immune response that caused the diabetes. Thus, this study will examine the effects of AC2993 alone as well as in combination with immunosuppressive drugs. Patients between 18 and 60 years of age who have type I diabetes mellitus may be eligible for this 20-month study. They must have had diabetes for at least 5 years and require insulin treatment. Candidates will be screened with a questionnaire, followed by medical history and physical examination, blood and urine tests, a chest x-ray and skin test for tuberculosis, electrocardiogram (EKG), and arginine stimulated C-peptide test (see description below). Participants will undergo the following tests and procedures: Advanced screening phase: Participants undergo a diabetes education program, including instruction on frequent blood glucose monitoring, dietary education on counting carbohydrates, intensive insulin therapy, review of signs and symptoms of low blood sugar (hypoglycemia), and potential treatment with glucagon shots. Patients must administer insulin via an insulin pump or take at least four injections per day including glargine (Lantus) insulin. 4-month run-in phase - Arginine-stimulated C-peptide test: This test measures the body's insulin production. The patient is injected with a liquid containing arginine, a normal constituent of food that increases insulin release from beta cells into the blood stream. After the injection, seven blood samples are collected over 10 minutes. - Mixed meal stimulated C-peptide test with acetaminophen: This test assesses the response of the beta cells to an ordinary meal and the time it takes for food to pass through the stomach. The patient drinks a food supplement and takes acetaminophen (Tylenol). Blood samples are then drawn through a catheter (plastic tube placed in a vein) every 30 minutes for 4 hours to measure levels of various hormones and the concentration of acetaminophen. - Euglycemic clamp: This test measures the body's sensitivity to insulin. The patient is admitted to the NIH Clinical Center the evening before the study and receives an insulin drip through an intravenous (IV) line overnight to maintain normal blood sugar levels. The next morning, another IV line is placed, glucose and insulin are being infused and frequent blood samples are being collected to measure blood sugar andinsulin levels. Test period A: Patients are randomly assigned to receive 1) AC2993 alone or 2) AC2993 plus immunosuppressive drugs (sirolimus and tacrolimus), along with an antibiotic to reduce the risk of fungal infections, for 6 months. If the patient receives immunosuppressive agents, blood is drawn twice a week to measure drug levels, then once a week for 1 month, and then every 2 weeks for the rest of the study. AC2993 is injected under the skin twice a day at first and then 4 times a day in increasing doses. Test period B: Patients who took immunosuppressive drugs in test period A continue to take them for the 6 months of test period B. Patients who took AC2993 in test period A do not take it in test period B, and those who did not take AC2993 in test period A do take it in test period B. Patients have three arginine-stimulated C-peptide tests during the last 3 months of test periods A and B and a euglycemic clamp study and mixed meal study at the end of each test period. Drug side effects are monitored throughout the study. Treatment and evaluation may be extended beyond the 20-month study period for patients who benefit from the treatment.
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National Institutes of Health Clinical Center