Effect of AC2993 With or Without Immunosuppression on Beta Cell Function in Patients With Type I Diabetes
Condition: Diabetes Mellitus
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will determine 1) the safety of AC2993 in patients with type I diabetes; 2) the
      ability of AC2993 to improve beta cell function; and 3) the effects of immunosuppression on
      beta cell function.

      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 level of insulin resistance by measuring
           the amount of glucose necessary to compensate for an increased insulin level while
           maintaining a prespecified blood glucose level.
    

Detailed description: 
      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 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,
      immunosuppression (daclizumab) alone, as well as the combination of AC2993 and
      immunosuppression on insulin secretion and glycemia control.
    

Intervention name(s): AC2993 (exenatide); daclizumab (immunosuppressive)
Intervention type(s): Drug; Drug
Intervention description(s): Dose-escalation beginning with 2.5 μg administered subcutaneously twice per day (BID); then to 2.5 μg four times a day (QID); then to 5 μg four times a day; then to 10 μg four times a day.; 2 mg/kg intravenously infused over 30 minutes every month for 12 months
Intervention MeSH terms: Exenatide; Daclizumab; Immunosuppressive Agents
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Type 1 Diabetes Mellitus (T1DM); Beta-Cell; C-Peptide; Immunosuppression; Insulin; Islet; Function; AC2993 (Synthetic Exendin-4); Diabetes Mellitus; Type I Diabetes Mellitus; T1DM