Clinical Trial: Effect of AC2993 with or without Immunosuppression on Beta Cell Function in Patients with Type I Diabetes


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Sponsored by:	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by:	Warren G Magnuson Clinical Center (CC)

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:

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.

Official Title: Effect of AC2993 (Synthetic Exendin-4) - Administered Alone or in Combination with Rapamycin and FK506 - On Islet Function in Patients with Type I Diabetes

Condition	Treatment or Intervention	Phase
Diabetes Mellitus	Drug: AC2993	Phase II

Type I diabetes mellitus (T1DM) typically results from immune mediated destruction of pancreatic beta cells. Previous studies indicate that some patients retain the capacity for limited endogenous insulin production. AC2993 (synthetic exendin-4) has been shown in preclinical and in preliminary human studies to have several potentially beneficial antidiabetic actions, including recovery and neogenesis of pancreatic islets. Thus, we plan to enroll adults with long-standing T1DM who have some C-peptide secretion indicating residual beta cell mass. The latter will be targeted by AC2993. Due to the possibility of stimulating the underlying autoimmune process of T1DM, especially if islet regeneration occurs, we will subject half of the enrollees to immunosuppression. We plan to study the effects of AC2993 alone, immunosuppressive drugs (rapamycin and FK506) alone, as well as the combination of AC2993 and immunosuppressive drugs on insulin secretion and glycemia control.

Aim: To test:

1. Whether AC2993 administered with or without immunosuppressive therapy is safe and whether it can improve pancreatic beta cell function and therefore glycemia control in patients with long-standing T1DM.

2. Whether immunosuppression alone can lead to improved beta-cell function.

3. What effects the immunosuppressive drugs have on insulin secretion and insulin sensitivity.

Methods: We will enroll 16 patients between the age of 18 and 60 years, inclusive, with T1DM for at least 5 years who have measurable circulating C-peptide. Half of the enrollees will receive immunosuppressive agents (rapamycin and FK506) and all enrollees will receive AC2993 in an open label, cross-over design. Thus, the 16 participants will be divided into 4 groups: group 1 will receive immunosuppressive agents and AC2993; group 2 will receive AC2993 only; group 3 will receive immunosuppressive agents only; and group 4 will receive neither immunosuppressive agents nor AC2993. We will include only patients with clear T1DM as assessed by laboratory evidence of anti-islet cell antibodies, normal insulin sensitivity, and by insulinopenia. We plan to assess endogenous islet function by performing frequent arginine-stimulated C-peptide tests, and will monitor anti-islet immunity by periodically monitoring anti-islet autoantibody levels and by freezing lymphocytes for subsequent T-cell assays currently being developed.

INCLUSION CRITERIA:
T1DM for at least 5 years as defined by the following:
a. Insulin dependence (with an insulin requirement less than 0.8 units/kg/day).
b. Current or past anti-islet antibodies (anti-insulin before initiation of insulin therapy, anti-islet cell (ICA), anti-tyrosine phosphatase IA-2, and/or anti-glutamic acid decarboxylase (GAD65) antibodies).
c. BMI greater than or equal to 20 kg/m(2) and less than or equal to 30 kg/m(2).
C-peptide greater than or equal to 0.5 and less than or equal to 1.2 ng/mL at baseline or during an arginine-stimulated C-peptide test.
Age 18 to 60 years, inclusive.
EXCLUSION CRITERIA:
Symptomatic gastroparesis.
Diabetic nephropathy with a creatinine clearance less than 60 cc/min or 24-hour urine albumin greater than 300 mg.
Insulin requirements greater than 0.8 units/kg/day.
Hypoglycemia unawareness: Unless easily corrected via simple modifications in the patient's diabetes regimen, the potential enrollee will be excluded if he/she has suffered greater than or equal to 2 episodes of severe hypoglycemia during the most recent 12 months, defined as requiring assistance from a third party, receiving assistance from medics, visiting an ER or being hospitalized due to the hypoglycemia.
Hyperlipidemia, whether untreated or resistant to medical treatment, with LDL cholesterol greater than 110 mg/dL or TG greater than 300 mg/dL.
Evidence of chronic infection.
History of any malignancy.
Any chronic medical condition that unduly increase risk for the potential enrollee as judged by study investigators.
Hematologic abnormalities:
a. Anemia (hematocrit less than 31.8% in women and less than 36.7% in men).
b. Leukopenia (WBC count less than 3.4 K/mm(3)).
c. Thrombocytopenia (platelet count less than 162 K/mm(3)).
Hypertension, whether untreated or resistant to medical treatment, with blood pressure greater than 140/85 mm Hg.
Pregnancy, breastfeeding or planned pregnancy within two years. Unable to identify primary care provider willing to partner with study investigators.