Type 1 Diabetes
Conditions
Brief summary
The objective of the proposed research is to evaluate the efficacy and safety of the use of metformin in addition to standard insulin therapy in overweight and obese children and adolescents, age 12-\<20 years, with type 1 diabetes for at least 1 year. Secondary objectives are to assess the effect of metformin on C-peptide levels, a measure of how much insulin is still being produced by the beta cells of the pancreas, and on vascular dysfunction. In addition, an ancillary study is planned to assess if metformin will improve tissue-specific insulin resistance in type 1 diabetes using a hyperinsulinemic euglycemic clamp.
Interventions
The strength of each tablet will be 500 mg. Participants will build up to a daily dose over four weeks by taking one tablet per day for 7 days, one tablet twice daily for 7 days, one tablet in morning and 2 tablets at night for 7 days, and then 2 tablets in the morning and 2 tablets at night, daily throughout the remainder of the study treatment period.
OTHERoral placebo
Sponsors
Juvenile Diabetes Research Foundation
Jaeb Center for Health Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to 19 Years
Healthy volunteers
No
Inclusion criteria
1. Clinical diagnosis of presumed autoimmune type 1 diabetes (T1D) as indicated by age of diagnosis \<10 years or documented positive diabetes-related autoantibodies. a. Note: For randomization, presence of at least one of the diabetes-related autoantibodies \[Insulin autoantibodies (IAA) at diagnosis prior to initiation of insulin, Islet cell antibodies (ICA), Anti-GAD (GAD65), Anti-IA2 (IA2), Zinc Transporter 8 (ZnT8)\] must be documented either from medical records or new laboratory measurement (IAA and ICA not measured by central lab) sent to central lab for participants who were ≥10 years old at diagnosis. 2. Age: 12 to \<20 years. 3. Duration of type 1 diabetes: ≥1 years. 4. Current insulin regimen involves either use of an insulin pump or multiple daily injections of insulin (at least 3 shots per day) for the last three months, with no plans to switch the modality of insulin administration during the next 6 months (e.g., injection user switching to a pump, pump user switching to injections). 5. Hemoglobin A1c: 7.5% - \<10.0% from point of care measurement or local lab on day of screening visit or within 1 month prior. 6. BMI: ≥85th percentile adjusted for age and sex . 7. Total daily dose of insulin: ≥0.8 units per kg per day. 8. Average of ≥3 Self-Monitoring Blood Glucose (SMBG) tests per day prior to initiating study and from download of study-provided blood glucose meter following screening visit. 9. Available for at least 6 months of follow-up, has home phone (or access to phone), and willing to be contacted by clinical site staff. 10. Expected to comply with protocol in investigator's judgment.
Exclusion criteria
1. Use of non-insulin medications for blood glucose control within prior 6 months or planning to use within next 6 months (other than study drug). 2. Use of medications for weight reduction (such as: Belviq (lorcaserin), Qsymia (Phentermine + topiramate), Orlistat (xenical)) within the prior 6 months or planning to use within next 6 months. 3. Use of a medication such as stimulants, psychotropic agents and oral/inhaled glucocorticoids that could affect weight gain or glycemic control of T1D or planning to use within the next 6 months. 4. Any condition that in the judgment of the investigator will adversely affect the completion of the protocol. 5. Females: pregnant, lactating, or intending to become pregnant within the next 34 weeks * A negative urine pregnancy test will be required for all females An effective contraceptive method or abstinence will be required for all females who have experienced menarche * Requirements regarding pregnancy testing prior to enrollment and monitoring for pregnancy over the course of the study may be further defined by each individual Institutional Review Board (IRB) 6. Clinical diagnosis of celiac disease that is in poor control as defined by most recent tissue transglutaminase (tTG) that is in the abnormal range. 7. History of ≥1 diabetic ketoacidosis events in the past 3 months. 8. History of ≥1 severe hypoglycemic events (cognitive impairment that required assistance to treat) in the past 3 months. 9. History of anemia or vitamin B12 deficiency in the past 2 years. 10. Participation in an intervention study in the past 3 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hemoglobin A1c From Baseline to 26 Weeks, Adjusted for Baseline Hemoglobin A1c. | 0-26 weeks | Hemoglobin A1c is a measure of glycemic control over approximately the past 3 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Body Mass Index (BMI) | 0-26 weeks | — |
| Change in Waist Circumference | 0-26 weeks | — |
| Change in Total Daily Dose of Insulin (TDI) Per kg | 0-26 weeks | — |
| Change in Serum Lipids | 0-26 weeks | — |
| Change in Blood Pressure | 0-26 weeks | — |
| Change in Body Composition | 0-26 weeks | Change in percent body fat |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in C-peptide | 0-26-weeks | Measured with mixed meal tolerance test among participants with evidence of residual C-peptide on a non-fasting C-peptide at screening |
| Change in Liver Enzymes and Serum Creatinine | 0-26 weeks | — |
| Change in Vascular Dysfunction | 0-26 weeks | — |
| Frequency of Severe Hypoglycemia | 26 weeks | — |
| Frequency of Diabetic Ketoacidosis | 26 weeks | — |
| Frequency of Gastrointestinal Side-effects Including Stomach Discomfort, Diarrhea, Nausea/Vomiting, Indigestion, Flatulence. | 26 weeks | — |
| Frequency of Lactic Acidosis | 26 weeks | — |
| Change in Adipocytokines | 0-26 weeks | — |
| Change in Androgen Levels in Females | 0-26 weeks | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Metformin Metformin 2000 mg per day
Metformin (glucophage): The strength of each tablet will be 500 mg. Participants will build up to a daily dose over four weeks by taking one tablet per day for 7 days, one tablet twice daily for 7 days, one tablet in morning and 2 tablets at night for 7 days, and then 2 tablets in the morning and 2 tablets at night, daily throughout the remainder of the study treatment period. | 71 |
| Oral Placebo A central pharmacy will compound a placebo to match the metformin tablets.
The placebo product will contain the following components:
* Micosolle™, silica based excipient
* Silicified Micro Crystalline Cellulose, National Formulary
* Safflower Oil, United States Pharmacopeia
* K-30 Povidone Powder
* Magnesium Stearate, National Formulary (Vegetable source)
* Fumed Silica, National Formulary
oral placebo | 69 |
| Total | 140 |
Baseline characteristics
| Characteristic | Metformin | Total | Oral Placebo |
|---|---|---|---|
| Age, Continuous | 15.4 years STANDARD_DEVIATION 1.7 | 15.3 years STANDARD_DEVIATION 1.7 | 15.1 years STANDARD_DEVIATION 1.8 |
| Age, Customized 12-15 years | 43 years | 90 years | 47 years |
| Age, Customized 16-19 years | 28 years | 50 years | 22 years |
| Body Mass Index (BMI) Percentile | 93.7 percentile STANDARD_DEVIATION 4.1 | 94 percentile STANDARD_DEVIATION 3.9 | 94.3 percentile STANDARD_DEVIATION 3.8 |
| Body Mass Index (BMI) Percentile Group Obese: ≥ 95th % | 33 participants | 74 participants | 41 participants |
| Body Mass Index (BMI) Percentile Group Overweight: 85th-<95th% | 36 participants | 62 participants | 26 participants |
| Body Mass Index (BMI) Z Score | 1.6 Z score STANDARD_DEVIATION 0.4 | 1.6 Z score STANDARD_DEVIATION 0.3 | 1.7 Z score STANDARD_DEVIATION 0.3 |
| Continuous Glucose Monitor Use | 2 participants | 4 participants | 2 participants |
| Diabetic Ketoacidosis Events Since T1D Diagnosis 1-2 episodes | 15 episodes | 28 episodes | 13 episodes |
| Diabetic Ketoacidosis Events Since T1D Diagnosis 3-4 episodes | 2 episodes | 8 episodes | 6 episodes |
| Diabetic Ketoacidosis Events Since T1D Diagnosis ≥ 5 episodes | 1 episodes | 3 episodes | 2 episodes |
| Diabetic Ketoacidosis Events Since T1D Diagnosis None | 53 episodes | 101 episodes | 48 episodes |
| Duration of Diabetes | 7.5 years STANDARD_DEVIATION 3.6 | 7.0 years STANDARD_DEVIATION 3.6 | 6.4 years STANDARD_DEVIATION 3 |
| Duration of Diabetes (group) 1-2 Years | 5 years | 14 years | 9 years |
| Duration of Diabetes (group) 3-5 Years | 23 years | 48 years | 25 years |
| Duration of Diabetes (group) 6-8 Years | 19 years | 41 years | 22 years |
| Duration of Diabetes (group) ≥ 9 years | 24 years | 37 years | 13 years |
| HbA1c Group < 8.5% | 25 participants | 49 participants | 24 participants |
| HbA1c Group 8.5%-9.4% | 32 participants | 58 participants | 26 participants |
| HbA1c Group ≥ 9.5% | 14 participants | 33 participants | 19 participants |
| HbA1c Lab | 8.8 percentage STANDARD_DEVIATION 0.8 | 8.8 percentage STANDARD_DEVIATION 0.7 | 8.8 percentage STANDARD_DEVIATION 0.7 |
| Highest Parent Educaiton Level Associate | 10 participants | 22 participants | 12 participants |
| Highest Parent Educaiton Level Bachelor | 18 participants | 33 participants | 15 participants |
| Highest Parent Educaiton Level High school diploma, GED, or less | 22 participants | 42 participants | 20 participants |
| Highest Parent Educaiton Level Master | 12 participants | 25 participants | 13 participants |
| Highest Parent Educaiton Level Professional | 5 participants | 12 participants | 7 participants |
| Highest Parent Educaiton Level Unknown / Do not want to answer | 4 participants | 6 participants | 2 participants |
| Income Category $100,000 to less than $200,000 | 5 participants | 11 participants | 6 participants |
| Income Category $35,000 to less than $50,000 | 3 participants | 10 participants | 7 participants |
| Income Category $50,000 to less than $75,000 | 10 participants | 23 participants | 13 participants |
| Income Category $75,000 to less than $100,000 | 14 participants | 26 participants | 12 participants |
| Income Category Less than $35,000 | 5 participants | 12 participants | 7 participants |
| Income Category Unknown / Do not want to answer | 23 participants | 41 participants | 18 participants |
| Insulin Pump Use | 50 participants | 99 participants | 49 participants |
| Insurance None | 0 participants | 2 participants | 2 participants |
| Insurance Other Insurance | 14 participants | 29 participants | 15 participants |
| Insurance Private Insurance | 53 participants | 101 participants | 48 participants |
| Insurance Unknown / Do not want to answer | 4 participants | 8 participants | 4 participants |
| Mean Sensor Glucose | 206 mg/dL STANDARD_DEVIATION 35 | 207 mg/dL STANDARD_DEVIATION 34.6 | 208 mg/dL STANDARD_DEVIATION 34 |
| Race/Ethnicity, Customized Asian | 2 participants | 2 participants | 0 participants |
| Race/Ethnicity, Customized Black | 4 participants | 9 participants | 5 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 13 participants | 24 participants | 11 participants |
| Race/Ethnicity, Customized More than one race | 1 participants | 2 participants | 1 participants |
| Race/Ethnicity, Customized White | 51 participants | 103 participants | 52 participants |
| Self-Monitoring of Blood Glucose group 3 | 13 participants | 27 participants | 14 participants |
| Self-Monitoring of Blood Glucose group 4-5 | 44 participants | 87 participants | 43 participants |
| Self-Monitoring of Blood Glucose group ≥ 6 | 14 participants | 26 participants | 12 participants |
| Self-Monitoring of Blood Glucose per day | 4.5 number of checks per day STANDARD_DEVIATION 1.2 | 4.5 number of checks per day STANDARD_DEVIATION 1.4 | 4.6 number of checks per day STANDARD_DEVIATION 1.6 |
| Severe Hypoglycemia Events Since T1D Diagnosis 1-2 episodes | 14 episodes | 24 episodes | 10 episodes |
| Severe Hypoglycemia Events Since T1D Diagnosis 3-4 episodes | 3 episodes | 5 episodes | 2 episodes |
| Severe Hypoglycemia Events Since T1D Diagnosis ≥ 5 episodes | 2 episodes | 7 episodes | 5 episodes |
| Severe Hypoglycemia Events Since T1D Diagnosis None | 52 episodes | 104 episodes | 52 episodes |
| Sex: Female, Male Female | 44 Participants | 92 Participants | 48 Participants |
| Sex: Female, Male Male | 27 Participants | 48 Participants | 21 Participants |
| Tanner Staging (Breasts/Genitals) Stage 1 | 1 participants | 2 participants | 1 participants |
| Tanner Staging (Breasts/Genitals) Stage 2 | 0 participants | 2 participants | 2 participants |
| Tanner Staging (Breasts/Genitals) Stage 3 | 5 participants | 11 participants | 6 participants |
| Tanner Staging (Breasts/Genitals) Stage 4 | 12 participants | 21 participants | 9 participants |
| Tanner Staging (Breasts/Genitals) Stage 5 | 53 participants | 104 participants | 51 participants |
| Tanner Staging (Pubic Hair) Stage 1 | 1 participants | 2 participants | 1 participants |
| Tanner Staging (Pubic Hair) Stage 2 | 1 participants | 4 participants | 3 participants |
| Tanner Staging (Pubic Hair) Stage 3 | 5 participants | 12 participants | 7 participants |
| Tanner Staging (Pubic Hair) Stage 4 | 16 participants | 25 participants | 9 participants |
| Tanner Staging (Pubic Hair) Stage 5 | 48 participants | 97 participants | 49 participants |
| Total Basal/Long Acting Insulin | 0.5 unit/kg/day STANDARD_DEVIATION 0.1 | 0.5 unit/kg/day STANDARD_DEVIATION 0.1 | 0.5 unit/kg/day STANDARD_DEVIATION 0.1 |
| Total Daily Insulin | 1.1 unit/kg/day STANDARD_DEVIATION 0.2 | 1.1 unit/kg/day STANDARD_DEVIATION 0.2 | 1.1 unit/kg/day STANDARD_DEVIATION 0.2 |
| Total Daily Insulin Group <1.0 | 33 participants | 59 participants | 26 participants |
| Total Daily Insulin Group 1.0-1.4 | 33 participants | 72 participants | 39 participants |
| Total Daily Insulin Group ≥ 1.5 | 5 participants | 9 participants | 4 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 71 | 0 / 69 |
| serious Total, serious adverse events | 3 / 71 | 3 / 69 |
Outcome results
Primary
Change in Hemoglobin A1c From Baseline to 26 Weeks, Adjusted for Baseline Hemoglobin A1c.
Hemoglobin A1c is a measure of glycemic control over approximately the past 3 months
Time frame: 0-26 weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Metformin | Change in Hemoglobin A1c From Baseline to 26 Weeks, Adjusted for Baseline Hemoglobin A1c. | HbA1c | 9.0 percentage |
| Metformin | Change in Hemoglobin A1c From Baseline to 26 Weeks, Adjusted for Baseline Hemoglobin A1c. | Change from Baseline to 26 Weeks | 0.2 percentage |
| Oral Placebo | Change in Hemoglobin A1c From Baseline to 26 Weeks, Adjusted for Baseline Hemoglobin A1c. | HbA1c | 8.9 percentage |
| Oral Placebo | Change in Hemoglobin A1c From Baseline to 26 Weeks, Adjusted for Baseline Hemoglobin A1c. | Change from Baseline to 26 Weeks | 0.2 percentage |
Primary
Change in Hemoglobin A1c From Baseline to 26 Weeks, Adjusted for Baseline Hemoglobin A1c.
Hemoglobin A1c is a measure of glycemic control over approximately the past 3 months
Time frame: 0-26 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Metformin | Change in Hemoglobin A1c From Baseline to 26 Weeks, Adjusted for Baseline Hemoglobin A1c. | HbA1c <7.5% | 3 percentage of participants |
| Metformin | Change in Hemoglobin A1c From Baseline to 26 Weeks, Adjusted for Baseline Hemoglobin A1c. | HbA1c Decrease ≥0.5% | 19 percentage of participants |
| Metformin | Change in Hemoglobin A1c From Baseline to 26 Weeks, Adjusted for Baseline Hemoglobin A1c. | HbA1c Increase ≥0.5% | 44 percentage of participants |
| Oral Placebo | Change in Hemoglobin A1c From Baseline to 26 Weeks, Adjusted for Baseline Hemoglobin A1c. | HbA1c Increase ≥0.5% | 35 percentage of participants |
| Oral Placebo | Change in Hemoglobin A1c From Baseline to 26 Weeks, Adjusted for Baseline Hemoglobin A1c. | HbA1c <7.5% | 4 percentage of participants |
| Oral Placebo | Change in Hemoglobin A1c From Baseline to 26 Weeks, Adjusted for Baseline Hemoglobin A1c. | HbA1c Decrease ≥0.5% | 18 percentage of participants |
Secondary
Change in Blood Pressure
Time frame: 0-26 weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Metformin | Change in Blood Pressure | Change in Systolic | 0 mm Hg |
| Metformin | Change in Blood Pressure | Change in Diastolic | 0 mm Hg |
| Oral Placebo | Change in Blood Pressure | Change in Systolic | -0 mm Hg |
| Oral Placebo | Change in Blood Pressure | Change in Diastolic | 0 mm Hg |
Secondary
Change in Body Composition
Change in percent body fat
Time frame: 0-26 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Change in Body Composition | -0 percentage of change |
| Oral Placebo | Change in Body Composition | 1 percentage of change |
Secondary
Change in Body Mass Index (BMI)
Time frame: 0-26 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Change in Body Mass Index (BMI) | -1 percentile |
| Oral Placebo | Change in Body Mass Index (BMI) | 1 percentile |
Secondary
Change in Serum Lipids
Time frame: 0-26 weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Metformin | Change in Serum Lipids | Change in VLDL | -0 mg/dL |
| Metformin | Change in Serum Lipids | Change in Triglycerides | 4 mg/dL |
| Metformin | Change in Serum Lipids | Change in LDL | -6 mg/dL |
| Metformin | Change in Serum Lipids | Change in Total Cholesterol | -5 mg/dL |
| Metformin | Change in Serum Lipids | Change in HDL | -0 mg/dL |
| Oral Placebo | Change in Serum Lipids | Change in Total Cholesterol | 3 mg/dL |
| Oral Placebo | Change in Serum Lipids | Change in VLDL | 1 mg/dL |
| Oral Placebo | Change in Serum Lipids | Change in HDL | -1 mg/dL |
| Oral Placebo | Change in Serum Lipids | Change in Triglycerides | 6 mg/dL |
| Oral Placebo | Change in Serum Lipids | Change in LDL | 2 mg/dL |
Secondary
Change in Total Daily Dose of Insulin (TDI) Per kg
Time frame: 0-26 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Change in Total Daily Dose of Insulin (TDI) Per kg | -0.1 insulin per kg |
| Oral Placebo | Change in Total Daily Dose of Insulin (TDI) Per kg | -0.0 insulin per kg |
Secondary
Change in Waist Circumference
Time frame: 0-26 weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Change in Waist Circumference | -0 centimeters |
| Oral Placebo | Change in Waist Circumference | 1 centimeters |
Other Pre-specified
Change in Adipocytokines
Time frame: 0-26 weeks
Other Pre-specified
Change in Androgen Levels in Females
Time frame: 0-26 weeks
Other Pre-specified
Change in C-peptide
Measured with mixed meal tolerance test among participants with evidence of residual C-peptide on a non-fasting C-peptide at screening
Time frame: 0-26-weeks
Other Pre-specified
Change in Liver Enzymes and Serum Creatinine
Time frame: 0-26 weeks
Other Pre-specified
Change in Vascular Dysfunction
Time frame: 0-26 weeks
Other Pre-specified
Frequency of Diabetic Ketoacidosis
Time frame: 26 weeks
Other Pre-specified
Frequency of Gastrointestinal Side-effects Including Stomach Discomfort, Diarrhea, Nausea/Vomiting, Indigestion, Flatulence.
Time frame: 26 weeks
Other Pre-specified
Frequency of Lactic Acidosis
Time frame: 26 weeks
Other Pre-specified
Frequency of Severe Hypoglycemia
Time frame: 26 weeks