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

Condition(s) targeted: Diabetes Mellitus Type 1; Autoimmune Diabetes; Diabetes Mellitus, Autoimmune

Intervention: Insulin (Drug); Lansoprazole (Drug); Sitagliptin (Drug); Diamyd (Biological); GAD65 (Diamyd) (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Overall contact:
Patient Recruitment and Public Liaison Office, Phone: (800) 411-1222, Email: prpl@mail.cc.nih.gov

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.

Official title: Novel Therapy Combining Regenerative Stimuli Immunomodulation to Preserve Beta Cell Function in New Onset Type 1 Diabetes

Study design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: Changes in beta cell function (Mixed Meal, Tolerance Test, C-peptide, AUC mean)

Secondary outcome: Glycemia control, insulin requirements, changes in immune function

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.

Minimum age: 16 Years. Maximum age: 30 Years. Gender(s): Both.

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).

Patient Recruitment and Public Liaison Office, Phone: (800) 411-1222, Email: prpl@mail.cc.nih.gov

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

NIH Clinical Center Detailed Web Page

Related 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.

Starting date: February 2009
Ending date: October 2012
Last updated: October 14, 2009