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

Primary Purpose

Diabetes Mellitus, Type 1

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Methyldopa
Sponsored by
University of Colorado, Denver
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Diabetes Mellitus, Type 1 focused on measuring Diabetes, Diabetes Mellitus, Type 1 Diabetes

Eligibility Criteria

18 Years - 46 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

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

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Study group

Arm Description

All participants selected to continue with Methyldopa administration.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
The Change in Insulin Use From Baseline to Study Completion.
Exogenous insulin use per kg of body weight.

Full Information

First Posted
June 17, 2013
Last Updated
January 6, 2022
Sponsor
University of Colorado, Denver
Collaborators
Juvenile Diabetes Research Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT01883804
Brief Title
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

2. Study Status

Record Verification Date
January 2022
Overall Recruitment Status
Completed
Study Start Date
June 2013 (undefined)
Primary Completion Date
February 2016 (Actual)
Study Completion Date
February 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Colorado, Denver
Collaborators
Juvenile Diabetes Research Foundation

4. Oversight

Data Monitoring Committee
No

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 1
Keywords
Diabetes, Diabetes Mellitus, Type 1 Diabetes

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Study group
Arm Type
Experimental
Arm Description
All participants selected to continue with Methyldopa administration.
Intervention Type
Drug
Intervention Name(s)
Methyldopa
Other Intervention Name(s)
Aldomet
Intervention Description
6 weeks of Methyldopa administration; where the dose will be increased according to safety of efficacy.
Primary Outcome Measure Information:
Title
The Change From Baseline of DQ8 Antigen Presentation by Peripheral Blood Mononuclear Cells After 6 Weeks of Methyldopa Treatment.
Description
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.
Time Frame
6 Weeks (Baseline and week 6)
Secondary Outcome Measure Information:
Title
The Change in C-Peptide AUC Following a MMTT From Baseline to Study Completion.
Description
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.
Time Frame
12 weeks (Baseline and week 12)
Title
The Change in Hemoglobin A1c From Baseline to Study Completion.
Description
Investigators aim to observe changes in hemoglobin A1c values, a measure of average blood glucose over the preceding 3 months.
Time Frame
12 weeks (Baseline and week 12)
Title
The Change in Insulin Use From Baseline to Study Completion.
Description
Exogenous insulin use per kg of body weight.
Time Frame
12 weeks (Baseline and week 12)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
46 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Aaron Michels, MD
Organizational Affiliation
Barbara Davis Center for Diabetes, University of Colorado School of Medicine
Official's Role
Principal Investigator
Facility Information:
Facility Name
Barbara Davis Center for Diabetes, University of Colorado School of Medicine
City
Aurora
State/Province
Colorado
ZIP/Postal Code
80045
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
29438107
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.
Results Reference
result
PubMed Identifier
30694829
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.
Results Reference
derived
Links:
URL
http://www.barbaradaviscenter.org/
Description
Barbara Davis Center Website

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

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