NCT00064714

Brief 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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
47

participants targeted

Target at P25-P50 for phase_2 diabetes-mellitus

Timeline
Completed

Started Jul 2003

Longer than P75 for phase_2 diabetes-mellitus

Geographic Reach
1 country

1 active site

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

July 1, 2003

Completed
9 days until next milestone

First Submitted

Initial submission to the registry

July 10, 2003

Completed
1 day until next milestone

First Posted

Study publicly available on registry

July 11, 2003

Completed
4.6 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

March 1, 2008

Completed
Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

March 1, 2008

Completed
Last Updated

March 11, 2015

Status Verified

January 1, 2015

Enrollment Period

4.7 years

First QC Date

July 10, 2003

Last Update Submit

February 23, 2015

Conditions

Diabetes Mellitus

Keywords

Type 1 Diabetes Mellitus (T1DM)Beta-CellC-PeptideImmunosuppressionInsulinIsletFunctionAC2993 (Synthetic Exendin-4)Diabetes MellitusType I Diabetes MellitusT1DM

Outcome Measures

Primary Outcomes (1)

  • Change in basal C-peptide level

    Assess whether patients treated with AC2993 (with or without concomitant immunosuppression) will display at least a 50% improvement in their basal C-peptide level. C-peptide level is a surrogate measure for insulin production.

    baseline and 6 months

Study Arms (4)

Group 1

EXPERIMENTAL

Group 1 will receive immunosuppression and AC2993; then immunosuppression only

Drug: AC2993 (exenatide)Drug: daclizumab (immunosuppressive)

Group 2

EXPERIMENTAL

Group 2 will receive AC2993 only; then neither immunosuppression nor AC2993

Drug: AC2993 (exenatide)Drug: daclizumab (immunosuppressive)

Group 3

EXPERIMENTAL

Group 3 will receive immunosuppression and AC2993; then immunosuppression and AC2993

Drug: AC2993 (exenatide)Drug: daclizumab (immunosuppressive)

Group 4

EXPERIMENTAL

Group 4 will receive AC2993 only; then AC2993 only

Drug: AC2993 (exenatide)Drug: daclizumab (immunosuppressive)

Interventions

AC2993 (exenatide)DRUG

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.

Group 1Group 2Group 3Group 4
daclizumab (immunosuppressive)DRUG

2 mg/kg intravenously infused over 30 minutes every month for 12 months

Group 1Group 2Group 3Group 4

Eligibility Criteria

Age18 Years - 60 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64)

You may qualify if:

  • T1DM for at least 5 years as defined by the following:
  • Insulin dependence (with an insulin requirement less than 0.8 units/kg/day).
  • 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).
  • 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 0.3 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.

You may not qualify if:

  • 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.
  • 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:
  • Anemia (hematocrit less than 31.8% in women and less than 36.7% in men).
  • Leukopenia (WBC count less than 3.4 K/mm(3)).
  • 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.

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

  • Bach JF, Chatenoud L. Tolerance to islet autoantigens in type 1 diabetes. Annu Rev Immunol. 2001;19:131-61. doi: 10.1146/annurev.immunol.19.1.131.

    PMID: 11244033BACKGROUND

  • Lernmark A, Barmeier H, Dube S, Hagopian W, Karlsen A, Wassmuth R. Autoimmunity of diabetes. Endocrinol Metab Clin North Am. 1991 Sep;20(3):589-617.

    PMID: 1935920BACKGROUND

  • Mathis D, Vence L, Benoist C. beta-Cell death during progression to diabetes. Nature. 2001 Dec 13;414(6865):792-8. doi: 10.1038/414792a.

    PMID: 11742411BACKGROUND

  • Rother KI, Spain LM, Wesley RA, Digon BJ 3rd, Baron A, Chen K, Nelson P, Dosch HM, Palmer JP, Brooks-Worrell B, Ring M, Harlan DM. Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes. Diabetes Care. 2009 Dec;32(12):2251-7. doi: 10.2337/dc09-0773. Epub 2009 Oct 6.

    PMID: 19808924DERIVED

Related Links

MeSH Terms

Conditions

Diabetes MellitusDiabetes Mellitus, Type 1Insulin Resistance

Interventions

ExenatideDaclizumabImmunosuppressive Agents

Condition Hierarchy (Ancestors)

Glucose Metabolism DisordersMetabolic DiseasesNutritional and Metabolic DiseasesEndocrine System DiseasesAutoimmune DiseasesImmune System DiseasesHyperinsulinism

Intervention Hierarchy (Ancestors)

PeptidesAmino Acids, Peptides, and ProteinsVenomsComplex MixturesToxins, BiologicalBiological FactorsAntibodies, Monoclonal, HumanizedAntibodies, MonoclonalAntibodiesImmunoglobulinsImmunoproteinsBlood ProteinsProteinsSerum GlobulinsGlobulinsImmunologic FactorsPhysiological Effects of DrugsPharmacologic ActionsChemical Actions and Uses

Study Officials

  • Vice President, Research and Development, MD

    Amylin Pharmaceuticals, LLC.

    STUDY DIRECTOR

Study Design

Study Type
interventional
Phase
phase 2
Allocation
RANDOMIZED
Masking
NONE
Purpose
TREATMENT
Intervention Model
CROSSOVER
Sponsor Type
INDUSTRY
Responsible Party
SPONSOR

Study Record Dates

First Submitted

July 10, 2003

First Posted

July 11, 2003

Study Start

July 1, 2003

Primary Completion

March 1, 2008

Study Completion

March 1, 2008

Last Updated

March 11, 2015

Record last verified: 2015-01

Locations

US(1)