Novel Therapy Combining Regenerative Stimuli Immunomodulation to Preserve Beta Cell Function in New Onset Type 1 Diabetes - Full Text View

Sponsor:	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Information provided by:	National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:	NCT00837759

Purpose

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.

Eligibility:

Patients 16 to 30 years of age diagnosed (within the preceding 4 months) with laboratory-confirmed diabetes caused by an immune response directed against pancreatic beta cells.

Design:

The study, lasting approximately 25 months, will consist of four periods: screening period (laboratory and clinical testing), run-in period (close monitoring of blood glucose via Web-based program; 4-6 weeks), active treatment period (12 months), and follow-up period (12 months).
Study participants will be randomly assigned to two groups:
Group A (placebo): Participants will receive insulin therapy adjusted to keep the blood sugar as close to normal as possible, 2 sugar pills (in place of sitagliptin and lansoprazole), and salt water injections (in place of Diamyd).
Group B (treatment): Participants will receive insulin therapy as in Group A, sitagliptin (100 mg once daily for adults; 50 mg once daily for children) and lansoprazole (30 mg twice daily for adults; 30 mg once daily for children) in pill form, and Diamyd injections (at initial treatment, 4 weeks, and 12 weeks).
Evaluations during the active treatment period:
Mixed meal studies: Participants in Groups A and B will drink the milkshake-like Boost High Protein to stimulate insulin production; blood will be drawn immediately thereafter and every 30 minutes for 2 hours to measure hormones in the blood stream. This procedure will be done a total of 5 times during the 25-month period.
Frequently sampled intravenous glucose tolerance test: After a 12-hour overnight fast, participants will be given IV glucose for 1 to 2 minutes in addition to a small amount of insulin. Blood will be collected at specified frequencies for up to 3 hours to measure sensitivity to insulin. This procedure will be done a total of 3 times during the 25-month period.
Evaluations during the follow-up period:
Blood and urine laboratory tests in addition to mixed meal studies.

Condition	Intervention	Phase
Diabetes Mellitus Type 1 Autoimmune Diabetes Diabetes Mellitus, Autoimmune	Drug: Insulin Drug: Lansoprazole Drug: Sitagliptin Biological: Diamyd Drug: GAD65 (Diamyd)	Phase II

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study
Official Title:	Novel Therapy Combining Regenerative Stimuli Immunomodulation to Preserve Beta Cell Function in New Onset Type 1 Diabetes

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Diabetes Type 1

Drug Information available for: Insulin Lansoprazole Sitagliptin Sitagliptin phosphate

U.S. FDA Resources

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:

Changes in beta cell function (Mixed Meal, Tolerance Test, C-peptide, AUC mean) [ Time Frame: 12 months following the protocol subject's randomization/treatment initiation (a ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Glycemia control, insulin requirements, changes in immune function [ Time Frame: 12 months following the protocol subject's randomization/treatment initiation (a ] [ Designated as safety issue: No ]

Estimated Enrollment:	164
Study Start Date:	February 2009
Estimated Study Completion Date:	October 2012
Estimated Primary Completion Date:	October 2012 (Final data collection date for primary outcome measure)

Intervention Details:

N/A

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.

Eligibility

Ages Eligible for Study:	16 Years to 30 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

-

INCLUSION CRITERIA:

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

EXCLUSION CRITERIA:

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 at the end of the run-in period
Regular use of a proton pump inhibitor within 3 months of enrollment
Use of GLP-1R agonist or DPP-4 inhibitor within 6 months prior to enrollment
Use of immunosuppressive therapy in the preceding 12 months
Evidence of chronic infection, for example, known human immunodeficiency virus (HIV) or hepatitis
History of any malignancy other than a treated basal or squamous skin cancer
Any chronic medical condition to unduly increase risk for the potential enrollee as judged by study investigators
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
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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00837759

Contacts

Contact: Patient Recruitment and Public Liaison Office	(800) 411-1222	prpl@mail.cc.nih.gov
Contact: TTY	1-866-411-1010

Locations

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

Sponsors and Collaborators

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

More Information

Additional Information:

NIH Clinical Center Detailed Web Page This link exits the ClinicalTrials.gov site

Publications:

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

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. 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:	National Institutes of Health ( David M. Harlan, M.D./National Institute of Diabetes and Digestive and Kidney Diseases )
Study ID Numbers:	090056, 09-DK-0056
Study First Received:	February 4, 2009
Last Updated:	October 14, 2009
ClinicalTrials.gov Identifier:	NCT00837759 History of Changes
Health Authority:	United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):

Type I Diabetes
Preserve Beta Cell Function
Sitagliptin
Lansoprazole

GAD65 (Diamyd)
Diabetes
Type 1 Diabetes
T1DM

Additional relevant MeSH terms:

Anti-Infective Agents
Metabolic Diseases
Autoimmune Diseases
Molecular Mechanisms of Pharmacological Action
Immune System Diseases
Diabetes Mellitus
Gastrointestinal Agents
Endocrine System Diseases
Enzyme Inhibitors

Pharmacologic Actions
Protease Inhibitors
Sitagliptin
Dipeptidyl-Peptidase IV Inhibitors
Diabetes Mellitus, Type 1
Therapeutic Uses
Anti-Ulcer Agents
Lansoprazole
Glucose Metabolism Disorders

ClinicalTrials.gov processed this record on November 05, 2009