Diabetes Mellitus
Conditions
Keywords
Double Diabetes, Type 1 diabetes, Type 2 diabetes, Obesity, Acanthosis nigricans, Diabetes associated autoantibodies
Brief summary
The significance of this project is to investigate the effects of adjunctive metformin therapy in children and adolescents with double diabetes. Double diabetes describes a clinical state where an individual possesses features of both type 1 and type 2 diabetes. There is a paucity of data on the role of adjunctive metformin therapy in children and adolescents with double diabetes. To help fill this knowledge gap, the investigators propose a randomized, double-blind, placebo-controlled trial of metformin in double diabetes. Specifically, the investigators will evaluate changes in hemoglobin A1c and anthropometry in patients with a diagnosis of type 1 diabetes who also have features of type 2 diabetes or metabolic syndrome as well as patients with type 2 diabetes who possess diabetes-associated autoantibodies. This will help determine the safety profile, and efficacy of adjunctive metformin therapy in these subjects.
Detailed description
In this 12-month clinical trial, a 3-month run-in period will precede the interventional phase of the study. All patients will be placed on treat-to-target insulin regimen alone during the run-in phase. At the end of the 3-month run-in period, all participants will continue on treat-to-target insulin regimen, and will then be randomized to either of the 2 arms of the study: an experimental arm, consisting of treat-to-target insulin regimen plus metformin, and a control arm consisting of treat-to-target insulin regimen plus placebo. Both the physicians and patients will be blinded to the oral agents being administered to patients.
Interventions
DRUGMetformin
Metformin 1000 mg once daily by mouth for 9 months
DRUGPlacebo
2 capsules once daily by mouth for 9 months
Sponsors
University of Massachusetts, Worcester
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
10 Years to 20 Years
Healthy volunteers
No
Inclusion criteria
A. General inclusion criteria 1. Ten to 20 years of age. 2. Pubertal (Tanner stages 2-5, by examination). 3. Hemoglobin A1c level of \> 8.0% in the 6 months prior to enrollment. 4. All subjects must have access to a computer. B. Specific inclusion criteria: \[Subjects could have either #1, or #2\]. 1. Subjects with clinical and biochemical features of T2DM of \> 6mo duration who also have positive T1DM antibodies * Clinical features: acanthosis nigricans, BMI \>85% * Biochemical: evidence of insulin resistance at diagnosis * fasting insulin \>27 uIU/mL(normal range 6-27) at a fasting blood glucose of ≥ 126 mg/dL, or * fasting c-peptide level of \> 7.1 ng/mL (normal range 0.9 - 7.1), or * Homeostasis model of insulin resistance of \>3.16 2. Patients with T1DM of \> one yr duration with BMI \>85% * Presentation with ketoacidosis at diagnosis * C-peptide \<0.9 ng/mL (normal range 0.9 - 7.1),or (insulin \< 6 uIU/mL) (NR 6-27) at diagnosis (when blood glucose is ≥ 126 mg/dL) * Can be antibody positive or negative * Increased insulin requirement (\>2 Units/kg/day)
Exclusion criteria
1. Subjects on weight altering medications, such as orlistat. 2. Subjects with eating disorder 3. Subjects on medications other than insulin and or metformin that may affect blood glucose level. 4. Subjects with abnormal hepatic function tests. 5. Subjects with nephropathy, defined in this case as an overnight albumin excretion rate of \>200 mcg/min using a first morning urine sample collection. 6. Subjects with recurrent diabetes ketoacidosis (more than 2 episodes in the past 12 months), or recurrent severe hypoglycemia (more than 2 episodes of hypoglycemia with altered level of consciousness, requiring assistance to treat in the past year). 7. Pregnant, breast-feeding or the intention of becoming pregnant or not using adequate contraceptive measures. 8. Known or suspected allergy to metformin. 9. The receipt of any investigational drug within 6 months prior to this trial. 10. Active malignant neoplasms. 11. No access to a computer. 12. Subjects currently taking metformin for clinical purposes are not eligible to be enrolled in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Adjusted Hemoglobin A1c Over Time | Baseline, 3mo, 6mo, and 9 months | Comparison of the baseline-adjusted differences in HbA1c between the metformin and placebo groups during the trial. Hemoglobin A1c is a marker of glycemic control. The reported values represented means adjusted for baseline values, age, gender, and BMI using repeated measures ANOVA (General Linear Model). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Adjusted Changes in Lipid Profile Over Time | Baseline, 3mo, 6mo, and 9 months | Comparison of the baseline-adjusted differences in total cholesterol/high density cholesterol index over time between the metformin and the placebo groups. The reported values represented means adjusted for baseline values, age, gender, and BMI using repeated measures ANOVA (General Linear Model). |
| Baseline Adjusted Changes in Adiponectin/Leptin Ratio Over Time | Baseline, 3mo, 6 mo, and 9 months | Comparison of the baseline-adjusted differences in adiponectin/leptin ratio over time between the metformin and the placebo groups. The reported values represented mean adjusted for baseline values, age, gender, and BMI using repeated measures ANOVA (General Linear Model). |
| Number of Participants With Minor, Major, and Nocturnal Hypoglycemia | 12 months | Comparison of the occurrence of hypoglycemic event requiring a third party assistance (major hypoglycemia) per subject during the study, and minor hypoglycemia (plasma glucose of \<60 mg/dL or no measurement), as well as nocturnal hypoglycemia (plasma glucose of ≤60 mg/dL between 11PM and 6AM). |
Countries
United States
Participant flow
Recruitment details
This study was conducted at a tertiary institution. The first patient was recruited on March 3rd 2011, and the last study patient was recruited on August 1, 2013. The study was closed on August 8, 2013.
Pre-assignment details
Following enrollment, all subjects entered a run-in phase of 3-month duration during which participants were placed on insulin aspart and insulin detemir, and the treat-to-target insulin regimen (TTIR) started.
Participants by arm
| Arm | Count |
|---|---|
| Metformin Metformin 1000 mg once daily by mouth for 9 months
Metformin: Metformin 1000 mg once daily by mouth for 9 months | 15 |
| Placebo 1 capsule once daily by mouth for 9 months
Placebo: 1 capsules once daily by mouth for 9 months | 13 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 3 | 3 |
Baseline characteristics
| Characteristic | Metformin | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 15 years STANDARD_DEVIATION 2.5 | 14.5 years STANDARD_DEVIATION 3.1 | 14.7 years STANDARD_DEVIATION 2.7 |
| Region of Enrollment United States | 15 participants | 13 participants | 28 participants |
| Sex: Female, Male Female | 7 Participants | 8 Participants | 15 Participants |
| Sex: Female, Male Male | 8 Participants | 5 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 15 | 3 / 13 |
| serious Total, serious adverse events | 4 / 15 | 1 / 13 |
Outcome results
Primary
Baseline Adjusted Hemoglobin A1c Over Time
Comparison of the baseline-adjusted differences in HbA1c between the metformin and placebo groups during the trial. Hemoglobin A1c is a marker of glycemic control. The reported values represented means adjusted for baseline values, age, gender, and BMI using repeated measures ANOVA (General Linear Model).
Time frame: Baseline, 3mo, 6mo, and 9 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Baseline Adjusted Hemoglobin A1c Over Time | 9.46 percentage of HbA1c |
| Placebo | Baseline Adjusted Hemoglobin A1c Over Time | 9.85 percentage of HbA1c |
Comparison: Analyses were based on the intent-to-treat principle and were performed using SPSS v.22 (IBM Corporation, Armonk, NY).p-value: 0.903ANOVA
Secondary
Baseline Adjusted Changes in Adiponectin/Leptin Ratio Over Time
Comparison of the baseline-adjusted differences in adiponectin/leptin ratio over time between the metformin and the placebo groups. The reported values represented mean adjusted for baseline values, age, gender, and BMI using repeated measures ANOVA (General Linear Model).
Time frame: Baseline, 3mo, 6 mo, and 9 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Baseline Adjusted Changes in Adiponectin/Leptin Ratio Over Time | 2.0 ratio |
| Placebo | Baseline Adjusted Changes in Adiponectin/Leptin Ratio Over Time | 1.2 ratio |
Comparison: Two way ANOVA comparison of the means of the adiponectin/leptin ratios between the metformin and placebo groupsp-value: 0.057ANOVA
Secondary
Baseline Adjusted Changes in Lipid Profile Over Time
Comparison of the baseline-adjusted differences in total cholesterol/high density cholesterol index over time between the metformin and the placebo groups. The reported values represented means adjusted for baseline values, age, gender, and BMI using repeated measures ANOVA (General Linear Model).
Time frame: Baseline, 3mo, 6mo, and 9 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Metformin | Baseline Adjusted Changes in Lipid Profile Over Time | 3.5 ratio |
| Placebo | Baseline Adjusted Changes in Lipid Profile Over Time | 4 ratio |
Comparison: Analyses were based on the intent-to-treat principle and were performed using SPSS v.22 (IBM Corporation, Armonk, NY).p-value: 0.578ANOVA
Secondary
Number of Participants With Minor, Major, and Nocturnal Hypoglycemia
Comparison of the occurrence of hypoglycemic event requiring a third party assistance (major hypoglycemia) per subject during the study, and minor hypoglycemia (plasma glucose of \<60 mg/dL or no measurement), as well as nocturnal hypoglycemia (plasma glucose of ≤60 mg/dL between 11PM and 6AM).
Time frame: 12 months
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Metformin | Number of Participants With Minor, Major, and Nocturnal Hypoglycemia | Major hypoglycemia | 1 participants |
| Metformin | Number of Participants With Minor, Major, and Nocturnal Hypoglycemia | Minor hypoglycemia | 3 participants |
| Metformin | Number of Participants With Minor, Major, and Nocturnal Hypoglycemia | Nocturnal hypoglycemia | 2 participants |
| Placebo | Number of Participants With Minor, Major, and Nocturnal Hypoglycemia | Major hypoglycemia | 0 participants |
| Placebo | Number of Participants With Minor, Major, and Nocturnal Hypoglycemia | Minor hypoglycemia | 2 participants |
| Placebo | Number of Participants With Minor, Major, and Nocturnal Hypoglycemia | Nocturnal hypoglycemia | 2 participants |
Comparison: p value represents the analysis for minor hypoglycemiap-value: 1t-test, 2 sided
Comparison: p value represents the analysis of the nocturnal hypoglycemiap-value: 1t-test, 2 sided