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

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ClinicalTrials.gov Identifier: NCT01883804
Recruitment Status : Completed
First Posted : June 21, 2013
Results First Posted : March 29, 2018
Last Update Posted : May 4, 2018
Sponsor:
Collaborator:
Juvenile Diabetes Research Foundation
Information provided by (Responsible Party):
Aaron Michels, MD, University of Colorado Denver School of Medicine Barbara Davis Center

Tracking Information
First Submitted Date  ICMJE June 17, 2013
First Posted Date  ICMJE June 21, 2013
Results First Submitted Date  ICMJE March 1, 2018
Results First Posted Date  ICMJE March 29, 2018
Last Update Posted Date May 4, 2018
Study Start Date  ICMJE June 2013
Actual Primary Completion Date February 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 3, 2018)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 19, 2013)
Inhibition of DQ8 Antigen Presentation [ Time Frame: 12 weeks ]
Investigators aim to observe inhibition of DQ8 antigen presentation; along with the dose required to achieve this aim. The researchers have devolved an assay to monitor the effect of Methyldopa on the presentation of the DQ8 antigen through the isolation of specific cells found in the blood. Using this assay, the investigators will analyze the ability to block DQ8 antigen presentation as the dose of Methyldopa changes through the course of the study.
Change History Complete list of historical versions of study NCT01883804 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 3, 2018)
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 19, 2013)
  • Assessment of C-Peptide Changes [ Time Frame: 12 weeks ]
    Investigators aim to observe changes in C-peptide production through the use of Mixed Meal Tolerance Tests. C-peptide is a product of insulin secretion and can help investigators monitor changes in insulin amounts over time. Blood samples will be collected at various time points during the Mixed Meal Tolerance Test, each of which will be analyzed for the amount of c-peptide present.
  • Assessment of Insulin Dose and Hemoglobin A1c [ Time Frame: 12 weeks ]
    Investigators aim to observe changes in insulin requirements, along with Hemoglobin A1c values, of each participant. Insulin requirements will be reported by each participant during each visit, by way of insulin units being taken or by downloading of insulin pump data. Hemoglobin A1c values will be analyzed during Mixed Meal Tolerance Tests, with the blood already being collected for C-peptide analysis.
  • Tolerability of Methyldopa [ Time Frame: 6 weeks ]
    Investigators aim to assess the tolerability of Methyldopa doses required to achieve the primary outcome. This will be assessed through discussions with participants and careful monitoring of any adverse events. Participants will be asked to wear a continuous blood pressure monitor during the 3 days following any changes in the dose of Methyldopa, or any other time point deemed necessary by the study doctor.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Methyldopa on MHC Class II Antigen Presentation in Type 1 Diabetes
Official Title  ICMJE Open Label Pilot Study of the Effect of Methyldopa on MHC-II Antigen Presentation in Type 1 Diabetes
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Diabetes Mellitus, Type 1
Intervention  ICMJE Drug: Methyldopa
6 weeks of Methyldopa administration; where the dose will be increased according to safety of efficacy.
Other Name: Aldomet
Study Arms  ICMJE Experimental: Study group
All participants selected to continue with Methyldopa administration.
Intervention: Drug: Methyldopa
Publications * Ostrov DA, Alkanani A, McDaniel KA, Case S, Baschal EE, Pyle L, Ellis S, Pöllinger 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 5, 2016)
30
Original Estimated Enrollment  ICMJE
 (submitted: June 19, 2013)
50
Actual Study Completion Date  ICMJE February 2016
Actual Primary Completion Date February 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 46 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01883804
Other Study ID Numbers  ICMJE 13-1408
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Aaron Michels, MD, University of Colorado Denver School of Medicine Barbara Davis Center
Study Sponsor  ICMJE University of Colorado Denver School of Medicine Barbara Davis Center
Collaborators  ICMJE Juvenile Diabetes Research Foundation
Investigators  ICMJE
Principal Investigator: Aaron Michels, MD Barbara Davis Center for Diabetes, University of Colorado School of Medicine
PRS Account University of Colorado Denver School of Medicine Barbara Davis Center
Verification Date April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP