Novel Therapy to Preserve Beta Cell Function in New Onset Type 1 Diabetes

Study Description

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

Background:

• Type 1 diabetes (T1D) occurs when the immune system attacks insulin-producing cells (beta cells) in the pancreas, resulting in their death.
• Insulin injections currently are the best method for controlling blood sugar in individuals with T1D. However, animal studies have shown that the drugs sitagliptin and lansoprazole can help reverse beta cell damage or develop new beta cells. In addition, Diamyd has been shown to weaken the immune process that attacks pancreatic beta cells.

Objectives:

• To find out whether a combination treatment of sitagliptin, lansoprazole, and Diamyd will help maintain functioning beta cells and/or cause new beta cells to form.
• To determine how the drug combination affects insulin doses and blood sugar control.
• To determine whether the drug combination affects the immune response involved in T1D.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus Type 1; Autoimmune Diabetes	Drug: Insulin; Drug: Lansoprazole; Drug: Sitagliptin; Biological: Diamyd; Drug: GAD65 (Diamyd)	Phase 2

Detailed Description:

Type 1 diabetes (T1D) is the end result of immune mediated beta-cell destruction. It is generally accepted that at the time of T1D is diagnosed, an individual has lost most (60-80%) of his/her beta cell function. The loss of insulin-producing beta cells is believed to occur over a period of months to years and individuals can retain some endogenous insulin production even years after clinical diagnosis of diabetes. The presence of residual beta cell mass may signify a complex interplay between the auto-destructive immune response and the capacity for limited beta cell regeneration. When initiated at T1D onset, immunosuppression has been shown to preserve beta cell function, but with significant and limiting toxicities. Selectively targeting the pathogenic T-cells involved in T1D development and progression could achieve the same objective with less toxicity. Various studies of the non-obese diabetic (NOD) mouse model of spontaneous autoimmune diabetes have demonstrated that administering glutamic acid decarboxylase (GAD65), a beta cell autoantigen, can prevent the immune destruction and delay or prevent diabetes onset. Preclinical studies have also identified several growth factors, including epidermal growth factor (EGF), glucagon-like peptide 1 (GLP-1), and gastrin, that appear to promote beta cell proliferation. We seek to test the potential for preserving beta cell function early in the disease course of T1D by combining antigen-specific immunomodulation with regenerative stimuli.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	7 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	Novel Therapy Combining Regenerative Stimuli Immunomodulation to Preserve Beta Cell Function in New Onset Type 1 Diabetes
Study Start Date :	February 2009
Actual Primary Completion Date :	March 2011
Actual Study Completion Date :	March 2011

Arms and Interventions

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Arm	Intervention/treatment
T1D group; This study was terminated prior to full subject accrual because of changes to study personnel. The original study design was changed from a double-blind, placebo-controlled study to an open-label pilot study in order to collect safety data on enrolled subjects prior to study termination.	Drug: Insulin Drug: Lansoprazole Drug: Sitagliptin Biological: Diamyd Drug: GAD65 (Diamyd)

Outcome Measures

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Primary Outcome Measures :

1. Change in C-peptide [ Time Frame: 6 months following the protocol subject's randomization/treatment initiation ]

Secondary Outcome Measures :

1. Glycemia Control (Change in HbA1c Level) [ Time Frame: 6 months following the protocol subject's randomization/treatment initiation ]
2. Change in Insulin Dose [ Time Frame: 6 months following the protocol subject's randomization/treatment initiation ]
3. Change in Anti-GAD Autoantibody Titers [ Time Frame: 6 months following the protocol subject's randomization/treatment initiation ]
4. Change in Anti-IA2 Titer [ Time Frame: 6 months following the protocol subject's randomization/treatment initiation ]
5. Change in ZnT8 Autoantibody Titer [ Time Frame: 6 months following the protocol subject's randomization/treatment initiation ]

Eligibility Criteria

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Ages Eligible for Study:	16 Years to 30 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

• INCLUSION CRITERIA:

  1. Recently diagnosed (within the preceding 4 months of screening) diabetes clinically consistent with T1D:

     A. Positive for anti-GAD antibody.

     B. BMI between 19 and 28 kg/m2; for those between the ages of 16 to 18, the BMI must be within 10th to 90th percentile for the age.

  2. Ages between 16 and 30 years, inclusive
  3. Random plasma C-peptide level of equal to or greater than 0.20 nmol/L
  4. Willingness and ability to institute intensive insulin-based glucose management.

EXCLUSION CRITERIA:

1. Diabetic nephropathy with a creatinine clearance less than 60 cc/min or 24 hour urine albumin greater than 300 mg
2. Insulin requirements greater than 0.8 units/kg/day at the end of the run-in period
3. Regular use of a proton pump inhibitor within 3 months of enrollment
4. Use of GLP-1R agonist or DPP-4 inhibitor within 6 months prior to enrollment
5. Use of immunosuppressive therapy in the preceding 12 months
6. Evidence of chronic infection, for example, known human immunodeficiency virus (HIV) or hepatitis
7. History of any malignancy other than a treated basal or squamous skin cancer
8. Any chronic medical condition to unduly increase risk for the potential enrollee as judged by study investigators
9. Pregnancy, breastfeeding or planned pregnancy within two years, women of reproductive age not using an effective mode of contraception and unwilling to continue adequate contraception until 1 year after the last study drug administration
10. Any other co-existing condition/circumstances that would make patient unsuitable to participate in the study, as deemed by the investigators. For example, study investigators would exclude any potential candidate with any of the following (but the list is not inclusive):

A. Clinically significant past history of an acute reaction to vaccines or other drugs

B. Recent participation in other clinical trials with a new chemical entity

C. A history of alcohol or drug abuse

D. Significant neurological conditions like epilepsy, head trauma, or cerebrovascular accidents

E. Individuals with significant gastrointestinal disorders determined by the study investigators to influence either study safety or data interpretation. Such conditions include but are not limited to gastroparesis and gastric bypass surgery

F. Individuals with conditions prone to hypergastrinemia (Zollinger-Ellison syndrome, use of histamine-2 receptor blockers) or hypogastrinemia (gastric surgery).

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

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

Investigators

Study Director:	Balow James, MD	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications:

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

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

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

Responsible Party:	James Balow, Clinical Director Intramural NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
ClinicalTrials.gov Identifier:	NCT00837759 History of Changes
Other Study ID Numbers:	090056; 09-DK-0056 ( Other Identifier: National Institutes of Health Clinical Center ); 09-DK-0056 ( Other Identifier: NIHCC )
First Posted:	February 5, 2009
Results First Posted:	October 24, 2012
Last Update Posted:	January 3, 2013
Last Verified:	December 2012

Keywords provided by James Balow, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK):

Type I Diabetes; Preserve Beta Cell Function; Sitagliptin; Lansoprazole	GAD65 (Diamyd); Diabetes; Type 1 Diabetes; T1DM

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Sitagliptin Phosphate; Lansoprazole; Dexlansoprazole; Hypoglycemic Agents	Physiological Effects of Drugs; Incretins; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Dipeptidyl-Peptidase IV Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Ulcer Agents; Gastrointestinal Agents; Proton Pump Inhibitors