Protective Effects of Sitagliptin on β Cell Function in Patients With Adult-onset Latent Autoimmune Diabetes(LADA) (DPP-ⅣLADA)

This study is enrolling participants by invitation only.
Sponsor:
Collaborators:
Chinese Medical Association
Eli Lilly and Company
Information provided by:
European Foundation for the Study of Diabetes
ClinicalTrials.gov Identifier:
NCT01159847
First received: May 5, 2010
Last updated: July 9, 2010
Last verified: January 2010
  Purpose

The aim of this study is to investigate the protective effects of sitagliptin on β cell function in patients with adult-onset latent autoimmune diabetes (LADA) and its mechanisms.


Condition Intervention Phase
Type 1 Diabetes
Drug: sitagliptin
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Protective Effects of Sitagliptin on β Cell Function in Patients With Adult-onset Latent Autoimmune Diabetes(LADA)

Resource links provided by NLM:


Further study details as provided by European Foundation for the Study of Diabetes:

Primary Outcome Measures:
  • The effects of sitagliptin on β cell function and insulin sensitivity of LADA patients [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    1. The assessment of the change of β cell function in patients with LADA treated with sitagliptin or placebo plus insulin by the standardized mixed meal stimulation test and insulin sensitivity by HOMA-IR.
    2. The assessment of the change of insulin sensitivity in LADA patients by sequential insulin infusion with the euglycemic glucose clamp technique and β cell function (first-phase insulin release, FPIR) will be assessed using intravenous glucose tolerance test (IVGTT).


Secondary Outcome Measures:
  • The possible immunomodulatory effects of sitagliptin on LADA patients [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The change of the frequency of pathogenic Teff (CD4+Th1, Th2, Th17 and CD8+) cells and CD4+CD25+Foxp3+Tregs before and after sitagliptin treatment in LADA patients.

  • The possible immunomodulatory effects of sitagliptin on LADA patients [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Effect of sitagliptin on cytokine production of Teff and Tregs before and after sitagliptin treatment in LADA patients.

  • The possible immunomodulatory effects of sitagliptin on LADA patients [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    Effect of sitagliptin on Foxp3 mRNA expression of Tregs and RORγT mRNA expression of Th17 cells before and after sitagliptin treatment in LADA patients.

  • The possible immunomodulatory effects of sitagliptin on LADA patients [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The comparison of GAD65 reactive IFN-γ-Th1, IL-4-Th2, IL-17-Th17 and IL-10-Treg cells detected by ELISPOT before and after sitagliptin treatment in LADA patients.

  • The possible immunomodulatory effects of sitagliptin on LADA patients [ Time Frame: 2 years ] [ Designated as safety issue: No ]
    The change of the adiponectin, IL-6, IL-17 and CRP etc. before and after the sitagliptin treatment in LADA patients.


Estimated Enrollment: 60
Study Start Date: January 2010
Estimated Study Completion Date: December 2012
Estimated Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Sitagliptin
sitagliptin combined with insulin therapy
Drug: sitagliptin
sitagliptin tablet,100 mg p.o. qd,2 year
Other Name: Januvia
Active Comparator: insulin Drug: sitagliptin
sitagliptin tablet,100 mg p.o. qd,2 year
Other Name: Januvia

Detailed Description:

Adult-onset latent autoimmune diabetes (LADA), etiologically belongs to type 1 diabetes (T1D), is characterized by the presence of islet autoantibodies, such as islet cell antibody (ICA) and glutamic acid decarboxylase antibody (GADA), and prones to develop β-cell failure. The goals of treatment for LADA are suppression of autoimmune β cell destruction, preservation of islet function and prevention of diabetic complications. Recently two classes of compounds have been approved by the FDA as T2D therapeutics: the glucagon-like peptide-1 (GLP-1) receptor agonist (incretin mimetic) exenatide (Byetta) and the dipeptidyl peptidase IV (DPP-IV) inhibitor sitagliptin (Januvia) and vildagliptin (Galvus). They have been shown to reduce HbA1c, fasting glucose and to improve β cell function in T2D patients, as a mono-therapy or in combination with metformin or thizolidinediones. Besides, in vitro studies showed incretin-based therapy can stimulate β-cell proliferation and survival, increase β cell insulin content and inhibit apoptosis. Moreover, several short-term pilot studies suggest GLP-1 may also have the potential for treating T1D. Several findings suggest that Ex-4 may also act as a regulator of the immune response in addition to its potential effects on β cell proliferation. Therefore, we hypothesized DPP-IV inhibitors might provide therapeutic advantages in T1D though no study has been reported. Besides the β cell function, another important target is insulin sensitivity. As for DPP-IV inhibitor, clinical trials demonstrated their beneficial effects on insulin sensitivity in subjects with T2D and IFG and indiabetic rat model. We'd like to further explore the possible effect of sitagliptin on insulin sensitivity in LADA patients by HOMA-IR index and euglycemic clamp technique. In addition, the systemic inflammation associated with a wide array of plasma proteins and pro-inflammatory cytokines(i.e., CRP, TNF-α, IL-6) play an additional role in the pathogenesis of insulin resistance in diabetes. It will be of interest to investigate the adipokines and proinflammmatory cytokines after the sitagliptin therapy in the study. Hence, we aim to explore the effects of sitagliptin plus insulin on β cell function, insulin sensitivity, pro-inflammatory cytokines and immune regulation including Teff and Treg frequency, and function in patients with LADA.

  Eligibility

Ages Eligible for Study:   25 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Diabetes diagnosed according to the report of WHO in 1999.
  2. Age at onset between 25~70 years.
  3. Disease duration of less than 3 year.
  4. No ketoacidosis within the first 6 months after diagnosis of diabetes.
  5. GADA positive twice within one month.
  6. FCP level of 0.2 nmol/L or more.

Exclusion Criteria:

  1. Insulin requirements more than 0.8 units/kg/day.
  2. Evidence of chronic infection or acute infection affected blood glucose control within 4 weeks prior to visit 1.
  3. History of any malignancy.
  4. Pregnancy, breastfeeding or planned pregnancy within two years.
  5. Secondary diabetes.
  6. Congestive heart failure requiring pharmacologic treatment.
  7. Renal disease or renal dysfunction or diabetic nephropathy suggested by serum creatinine levels≥1.5 mg/dL (132μmol/L) for males and ≥1.4mg/dL (123μmol/L) for females or abnormal creatinine clearance at Visit 1.
  8. Concurrent medical condition that may interfere with the interpretation of efficacy and safety data during the study.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01159847

Locations
China, Hunan
Diabetes Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University
Changsha, Hunan, China, 410011
Sponsors and Collaborators
European Foundation for the Study of Diabetes
Chinese Medical Association
Eli Lilly and Company
Investigators
Principal Investigator: Zhiguang Zhou, M.D., Ph.D. Diabetes Center, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University, China
  More Information

Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Zhiguang Zhou/Director, Department of Endocrinology, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University; Head, Diabetes Center, Central South University, Department of Endocrinology, Institute of Metabolism and Endocrinology, Second Xiangya Hospital, Central South University; Diabetes Center, Central South University
ClinicalTrials.gov Identifier: NCT01159847     History of Changes
Other Study ID Numbers: EFSD DPP-Ⅳ LADA
Study First Received: May 5, 2010
Last Updated: July 9, 2010
Health Authority: China: Food and Drug Administration

Keywords provided by European Foundation for the Study of Diabetes:
sitagliptin
LADA
C-Peptide
Flow Cytometry
ELISPOT

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 1
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Autoimmune Diseases
Immune System Diseases
Sitagliptin
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Hypoglycemic Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 22, 2014