Clinical trial NCT01883804: Effect of Methyldopa on MHC Class II Antigen Presentation in Type 1 Diabetes
Official title: Open Label Pilot Study of the Effect of Methyldopa on MHC-II Antigen Presentation in Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetes Mellitus, Type 1
Keywords: Diabetes
Diabetes Mellitus
Type 1 Diabetes
Lead sponsor: University of Colorado, Denver
Sponsor class: OTHER
Collaborators: name: Juvenile Diabetes Research Foundation
First posted: 2013-06-21
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Maximum age (years): 46
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.


Eligibility 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

Primary outcomes:
measure: The Change From Baseline of DQ8 Antigen Presentation by Peripheral Blood Mononuclear Cells After 6 Weeks of Methyldopa Treatment.
timeFrame: 6 Weeks (Baseline and week 6)
Secondary outcomes:
measure: The Change in C-Peptide AUC Following a MMTT From Baseline to Study Completion.
timeFrame: 12 weeks (Baseline and week 12)
measure: The Change in Hemoglobin A1c From Baseline to Study Completion.
timeFrame: 12 weeks (Baseline and week 12)
measure: The Change in Insulin Use From Baseline to Study Completion.
timeFrame: 12 weeks (Baseline and week 12)
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Barbara Davis Center for Diabetes, University of Colorado School of Medicine
state: Colorado
Study officials:
affiliation: Barbara Davis Center for Diabetes, University of Colorado School of Medicine
name: Aaron Michels, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.