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

• Sponsor: University of Colorado, Denver (Other)
• Overall Status: Completed
• CT.gov ID: NCT01883804
• Collaborator: Juvenile Diabetes Research Foundation (Other)
• Enrollment: 30
• Location: 1
• Arm: 1
• Duration (Months): 32
• Patients Per Site Per Month: 0.9

Study Details

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	N/A

Study Design

• Study Type: Interventional
• 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: Jun 1, 2013
• Actual Primary Completion Date: Feb 1, 2016
• Actual Study Completion Date: Feb 1, 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 Names: 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. [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. [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. [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. [12 weeks (Baseline and week 12)]

   Exogenous insulin use per kg of body weight.

Eligibility Criteria

Criteria

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

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

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Barbara Davis Center Website

Publications

None provided.

• Responsible Party: University of Colorado, Denver
• ClinicalTrials.gov Identifier: NCT01883804
• Other Study ID Numbers: 13-1408
• First Posted: Jun 21, 2013
• Last Update Posted: Jan 18, 2022
• Last Verified: Jan 1, 2022

• Keywords provided by University of Colorado, Denver: Diabetes; Diabetes Mellitus; Type 1 Diabetes
• Additional relevant MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1; Methyldopa

Study Results

Participant Flow

Recruitment Details	Participants were recruited through the adult clinic of the Barbara Davis Center, University of Colorado School of Medicine. Recruitment began in July of 2013 and concluded in November of 2015.
Pre-assignment Detail	A total of 30 participants joined the study. Five participants withdrew prior to the first visit or any study procedures. The remaining 25 participants started the study and 20 completed all study visits and procedures.

Arm/Group Title	Methyldopa Group
Arm/Group Description	All participants selected to continue with Methyldopa administration. Methyldopa: 6 weeks of Methyldopa administration; where the dose will be increased according to safety of efficacy.
Period Title: Overall Study
STARTED	25
COMPLETED	20
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Study Group
Arm/Group Description	All participants selected to continue with Methyldopa administration. Methyldopa: 6 weeks of Methyldopa administration; where the dose will be increased according to safety of efficacy.
Overall Participants	20
Age (years) [Mean (Full Range) ]
Mean Age	24.75
Sex: Female, Male (Count of Participants)
Female	7 35%
Male	13 65%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 5%
Not Hispanic or Latino	19 95%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 10%
White	18 90%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	20 100%
Duration of Type 1 Diabetes (Days) [Mean (Full Range) ]
Mean (Full Range) [Days]	133
Hemoglobin A1c (Percentage) [Mean (Full Range) ]
Mean (Full Range) [Percentage]	7.4
C-Peptide AUC following a 2 Hour Mixed Meal Tolerance Test (nmol/L/Min) [Mean (Full Range) ]
Mean (Full Range) [nmol/L/Min]	0.64
Positive Insulin Autoantibodies (Index) (Count of Participants)
Count of Participants [Participants]	1 5%
Positive GAD Autoantibodies (Count of Participants)
Count of Participants [Participants]	15 75%
Positive IA-2 Autoantibodies (Count of Participants)
Count of Participants [Participants]	14 70%
Positive ZnT8 Autoantibodies (Count of Participants)
Count of Participants [Participants]	11 55%
Systolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	113.2 (10.03)
Diastolic Blood Pressure (mmHg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmHg]	69.65 (8.16)
Elevated AST Values (Count of Participants)
Count of Participants [Participants]	0 0%
Elevated ALT Values (Count of Participants)
Count of Participants [Participants]	0 0%
Abnormal Hemoglobin Levels (Count of Participants)
Count of Participants [Participants]	0 0%

Outcome Measures

1. Primary Outcome

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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Group
Arm/Group Description	open label treatment; dose escalation of methyldopa
Measure Participants	20
Baseline, α-gliadin/DQ8	642 (104)
6 weeks of treatment, α-gliadin/DQ8	430 (70)
Baseline, insulin/DQ8	27.4 (5.2)
6 weeks of treatment, insulin/DQ8	17.9 (3.3)

2. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Group
Arm/Group Description	open label treatment; dose escalation of methyldopa
Measure Participants	20
Baseline	0.6 (0.5)
Study Completion	0.7 (0.6)

3. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Group
Arm/Group Description	open label treatment; dose escalation of methyldopa
Measure Participants	20
Baseline	7.4 (1.6)
Study Completion	6.5 (0.8)

4. Secondary Outcome

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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Study Group
Arm/Group Description	open label treatment; dose escalation of methyldopa
Measure Participants	20
Baseline	0.37 (0.20)
Study Completion	0.36 (0.19)

Adverse Events

Time Frame	Over the course of the 12 week study.
Adverse Event Reporting Description	Adverse event collection occurred at each visit through standard questions asked by the research coordinator and discussions with the investigator.
Arm/Group Title	Study Group
Arm/Group Description	All participants selected to continue with Methyldopa administration. Methyldopa: 6 weeks of Methyldopa administration; where the dose will be increased according to safety of efficacy.
All Cause Mortality
	Study Group
	Affected / at Risk (%)	# Events
Total	0/25 (0%)
Serious Adverse Events
	Study Group
	Affected / at Risk (%)	# Events
Total	0/25 (0%)
Other (Not Including Serious) Adverse Events
	Study Group
	Affected / at Risk (%)	# Events
Total	5/25 (20%)
General disorders
Fatigue	5/25 (20%)	5

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.