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

Study Overview
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Brief Summary
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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.

Official Title
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Open Label Pilot Study of the Effect of Methyldopa on MHC-II Antigen Presentation in Type 1 Diabetes

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Methyldopa


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 46 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study group<br>All participants selected to continue with Methyldopa administration. | Drug: Methyldopa<br>* 6 weeks of Methyldopa administration; where the dose will be increased according to safety of efficacy.<br>* Other names: Aldomet;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Change From Baseline of DQ8 Antigen Presentation by Peripheral Blood Mononuclear Cells After 6 Weeks of Methyldopa Treatment. | 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. | 6 Weeks (Baseline and week 6) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Change in C-Peptide AUC Following a MMTT From Baseline to Study Completion. | 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. | 12 weeks (Baseline and week 12) | 
| The Change in Hemoglobin A1c From Baseline to Study Completion. | Investigators aim to observe changes in hemoglobin A1c values, a measure of average blood glucose over the preceding 3 months. | 12 weeks (Baseline and week 12) | 
| The Change in Insulin Use From Baseline to Study Completion. | Exogenous insulin use per kg of body weight. | 12 weeks (Baseline and week 12) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Diabetes Mellitus, Type 1 Diabetes