Protocol Number: 03-DK-0245

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

Number:

03-DK-0245

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 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.

Sponsoring Institute:

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

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.

Special Instructions: Currently Not Provided

Keywords:

Type 1 Diabetes Mellitus (T1DM)

Beta-Cell

C-Peptide

Immunosuppression

Insulin

Islet

Function

AC2993 (Synthetic Exendin-4)

Recruitment Keywords:

Diabetes Mellitus

Type I Diabetes Mellitus

T1DM

Conditions:

Diabetes Mellitus

Investigational Drug(s):

AC2993

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Bach JF, Chatenoud L. Tolerance to islet autoantigens in type 1 diabetes. Annu Rev Immunol. 2001;19:131-61.

Lernmark A, et al., Autoimmunity of diabetes. Endocrinol Metab Clin North Am. 1991 Sep;20(3):589-617.

Mathis D, Vence L, Benoist C., Beta-Cell death during progression to diabetes. Nature. 2001 Dec 13;414(6865):792-8.

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
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