Diabetes Mellitus, Type 1
Conditions
Keywords
Diabetes, Diabetes Mellitus, 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.
Interventions
DRUGMethyldopa
6 weeks of Methyldopa administration; where the dose will be increased according to safety of efficacy.
Sponsors
Juvenile Diabetes Research Foundation
University of Colorado, Denver
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 46 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| The Change in Insulin Use From Baseline to Study Completion. | 12 weeks (Baseline and week 12) | Exogenous insulin use per kg of body weight. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Study Group 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. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Study Group |
|---|---|
| Abnormal Hemoglobin Levels | 0 Participants |
| Age, Continuous Mean Age | 24.75 years |
| C-Peptide AUC following a 2 Hour Mixed Meal Tolerance Test | 0.64 nmol/L/Min |
| Diastolic Blood Pressure | 69.65 mmHg STANDARD_DEVIATION 8.16 |
| Duration of Type 1 Diabetes | 133 Days |
| Elevated ALT Values | 0 Participants |
| Elevated AST Values | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Hemoglobin A1c | 7.4 Percentage |
| Positive GAD Autoantibodies | 15 Participants |
| Positive IA-2 Autoantibodies | 14 Participants |
| Positive Insulin Autoantibodies (Index) | 1 Participants |
| Positive ZnT8 Autoantibodies | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Region of Enrollment United States | 20 Participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 13 Participants |
| Systolic Blood Pressure | 113.2 mmHg STANDARD_DEVIATION 10.03 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 25 |
| other Total, other adverse events | 5 / 25 |
| serious Total, serious adverse events | 0 / 25 |
Outcome results
Primary
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.
Time frame: 6 Weeks (Baseline and week 6)
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Study Group | The Change From Baseline of DQ8 Antigen Presentation by Peripheral Blood Mononuclear Cells After 6 Weeks of Methyldopa Treatment. | 6 weeks of treatment, insulin/DQ8 | 17.9 pg/mL | Standard Error 3.3 |
| Study Group | The Change From Baseline of DQ8 Antigen Presentation by Peripheral Blood Mononuclear Cells After 6 Weeks of Methyldopa Treatment. | Baseline, α-gliadin/DQ8 | 642 pg/mL | Standard Error 104 |
| Study Group | The Change From Baseline of DQ8 Antigen Presentation by Peripheral Blood Mononuclear Cells After 6 Weeks of Methyldopa Treatment. | 6 weeks of treatment, α-gliadin/DQ8 | 430 pg/mL | Standard Error 70 |
| Study Group | The Change From Baseline of DQ8 Antigen Presentation by Peripheral Blood Mononuclear Cells After 6 Weeks of Methyldopa Treatment. | Baseline, insulin/DQ8 | 27.4 pg/mL | Standard Error 5.2 |
Secondary
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.
Time frame: 12 weeks (Baseline and week 12)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Study Group | The Change in C-Peptide AUC Following a MMTT From Baseline to Study Completion. | Baseline | 0.6 nmol/L/min | Standard Deviation 0.5 |
| Study Group | The Change in C-Peptide AUC Following a MMTT From Baseline to Study Completion. | Study Completion | 0.7 nmol/L/min | Standard Deviation 0.6 |
Secondary
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.
Time frame: 12 weeks (Baseline and week 12)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Study Group | The Change in Hemoglobin A1c From Baseline to Study Completion. | Baseline | 7.4 percentage | Standard Deviation 1.6 |
| Study Group | The Change in Hemoglobin A1c From Baseline to Study Completion. | Study Completion | 6.5 percentage | Standard Deviation 0.8 |
Secondary
The Change in Insulin Use From Baseline to Study Completion.
Exogenous insulin use per kg of body weight.
Time frame: 12 weeks (Baseline and week 12)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Study Group | The Change in Insulin Use From Baseline to Study Completion. | Baseline | 0.37 units/Kg body weight | Standard Deviation 0.2 |
| Study Group | The Change in Insulin Use From Baseline to Study Completion. | Study Completion | 0.36 units/Kg body weight | Standard Deviation 0.19 |