Effect of Methyldopa on MHC Class II Antigen Presentation in Type 1 Diabetes

• ClinicalTrials.gov Identifier: NCT01883804
• Recruitment Status: Completed
• First Posted: June 21, 2013
• Results First Posted: March 29, 2018
• Last Update Posted: January 18, 2022
• Sponsor: University of Colorado, Denver
• Collaborator: Juvenile Diabetes Research Foundation
• Information provided by (Responsible Party): University of Colorado, Denver

Study Description

Brief Summary:

Type 1 Diabetes is an autoimmune condition in which segments of the immune system cause the destruction of insulin producing cells in the pancreas, leaving individuals with an impaired ability to control blood glucose levels. Currently there is no cure for Type 1 Diabetes and the treatments involve lifelong insulin administration and careful monitoring of blood glucose levels. Long-term complications like cardiovascular disease, nerve damage, and retina damage, may result. Previous studies have shown that improvement in the control of blood glucose can reduce the risks from these long-term complications. Residual insulin production, typically within the first few years following diagnosis, helps to reduce an individual's need to supplement insulin by injection or pump. This effect helps in maintaining the body's ability to regulate blood glucose levels and reducing the needs of external insulin.

Methyldopa, or Aldomet, has been approved by the Food and Drug Administration and is commonly used to treat high blood pressure. This drug has been approved for several decades and has been shown to be safe and effective. This drug has been identified by the researcher to be able to block the communication between two important types of immune cells; which play a critical role in the autoimmune processes of Type 1 Diabetes. The investigators hypothesize that Methyldopa, over a 6 week treatment period, will block this communication and possibly slow down the destruction of insulin producing cells. The investigators hope to assess the appropriate and safe dose to achieve this effect, along with the drug's ability to maintain insulin production and blood glucose control.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 1	Drug: Methyldopa	Not Applicable

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open Label Pilot Study of the Effect of Methyldopa on MHC-II Antigen Presentation in Type 1 Diabetes
• Study Start Date: June 2013
• Actual Primary Completion Date: February 2016
• Actual Study Completion Date: February 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Study group; All participants selected to continue with Methyldopa administration.	Drug: Methyldopa; 6 weeks of Methyldopa administration; where the dose will be increased according to safety of efficacy.; Other Name: Aldomet

Outcome Measures

Primary Outcome Measures :

1. The Change From Baseline of DQ8 Antigen Presentation by Peripheral Blood Mononuclear Cells After 6 Weeks of Methyldopa Treatment. [ Time Frame: 6 Weeks (Baseline and week 6) ]
   Cryopreserved primary peripheral blood mononuclear cells were used as antigen presenting cells to stimulate engineered T-cells (T-cell receptor transductant) responding to a specific peptide presented by HLA-DQ8. Secreted IL-2 from the engineered T-cell was measured by a highly sensitive ELISA. This was done for both an α-gliadin/DQ8 responding T-cell and a separate insulin/DQ8 responding T-cell.

Secondary Outcome Measures :

1. The Change in C-Peptide AUC Following a MMTT From Baseline to Study Completion. [ Time Frame: 12 weeks (Baseline and week 12) ]
   Investigators aim to observe changes in residual endogenous insulin production as measured by C-peptide 2 hour area under the curve following a Mixed Meal Tolerance Test (MMTT). C-peptide is a measure of endogenous insulin secretion as both are secreted in a 1:1 molar ratio. Individuals ingested a liquid meal (Boost) with a fixed amount of protein, fat and carbohydrate in the fasting state followed by the timed measurements of serum C-peptide at 0, 15, 30, 60, 90 and 120 minutes to compute the AUC.
2. The Change in Hemoglobin A1c From Baseline to Study Completion. [ Time Frame: 12 weeks (Baseline and week 12) ]
   Investigators aim to observe changes in hemoglobin A1c values, a measure of average blood glucose over the preceding 3 months.
3. The Change in Insulin Use From Baseline to Study Completion. [ Time Frame: 12 weeks (Baseline and week 12) ]
   Exogenous insulin use per kg of body weight.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 46 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Diagnosis of Type 1 Diabetes Mellitus
• 18-46 years of age
• Residual C-peptide production during screening
• Positive for at least one islet autoantibody: insulin (if only insulin autoantibody positive, determination must be within two weeks of insulin initiation), GAD-65, IA-2 or ZnT8
• Positive for at least one gene encoding HLA-DQ8 (DQB*0302)
• No history of difficult to control hypertension (defined as requiring > 2 anti-hypertensive medications)
• Agree to intensive management of diabetes with an HgbA1c goal of < 8.0%
• If female: (a) surgically sterile or (b) postmenopausal or (c) if of reproductive potential, willing to use medically acceptable birth control (e.g. female hormonal contraception, barrier methods or sterilization.) until study completion
• If male and of reproductive potential, willing to use medically acceptable birth control until study completion, unless the female partner is postmenopausal or surgically sterile

Exclusion Criteria:

• Unable or unwilling to comply with the requirements of the study protocol
• No HLA-DQ8 gene (DQB*0302)
• Difficult to control hypertension (defined as requiring > 2 anti-hypertensive medications)
• History of postural hypotension or Addison's disease
• Body Mass Index (BMI) > 30 kg/m2
• Unstable blood sugar control defined as one or more episodes of severe hypoglycemia (defined as hypoglycemia that required the assistance of another person) within the last 30 days
• Administration of an experimental agent for T1D at any time or use of an experimental device for T1D within 30 days of screening, unless approved by the study PI
• History of any organ transplant, including islet cell transplant
• Active autoimmune or immune deficiency disorder (e.g. sarcoidosis, rheumatoid arthritis)
• Anticipated pregnancy during the 12 week study period
• Any social or medical condition that would, in the opinion of the investigator, prevent complete participation in the study or that would pose a significant hazard to the subjects' participation
• History of active substance abuse within 12 months of screening
• A psychiatric or medical disorder that would prevent giving informed consent

Contacts and Locations

Locations

United States, Colorado

Barbara Davis Center for Diabetes, University of Colorado School of Medicine

Aurora, Colorado, United States, 80045

Sponsors and Collaborators

University of Colorado, Denver

Juvenile Diabetes Research Foundation

Investigators

• Principal Investigator: Aaron Michels, MD; Barbara Davis Center for Diabetes, University of Colorado School of Medicine

More Information

Additional Information:

Barbara Davis Center Website 

Publications of Results:

Ostrov DA, Alkanani A, McDaniel KA, Case S, Baschal EE, Pyle L, Ellis S, Pollinger B, Seidl KJ, Shah VN, Garg SK, Atkinson MA, Gottlieb PA, Michels AW. Methyldopa blocks MHC class II binding to disease-specific antigens in autoimmune diabetes. J Clin Invest. 2018 May 1;128(5):1888-1902. doi: 10.1172/JCI97739. Epub 2018 Apr 3.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Ostrov DA, Gottlieb PA, Michels AW. Rationally designed small molecules to prevent type 1 diabetes. Curr Opin Endocrinol Diabetes Obes. 2019 Apr;26(2):90-95. doi: 10.1097/MED.0000000000000470.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01883804
• Other Study ID Numbers: 13-1408
• First Posted: June 21, 2013
• Results First Posted: March 29, 2018
• Last Update Posted: January 18, 2022
• Last Verified: January 2022

Keywords provided by University of Colorado, Denver:

Diabetes; Diabetes Mellitus; Type 1 Diabetes

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases; Methyldopa; Antihypertensive Agents; Sympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action