Metformin Therapy for Overweight Adolescents With Type 1 Diabetes

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized Trial of Metformin as Adjunct Therapy for Overweight Adolescents With Type 1 Diabetes

Conditions
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Type 1 Diabetes

Intervention / Treatment
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* Drug: Metformin (glucophage)
* Other: oral placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Age: 12 to <20 years. Duration of type 1 diabetes: ≥1 years. 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). Hemoglobin A1c: 7.5% - <10.0% from point of care measurement or local lab on day of screening visit or within 1 month prior. BMI: ≥85th percentile adjusted for age and sex . Total daily dose of insulin: ≥0.8 units per kg per day. 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. 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. Expected to comply with protocol in investigator's judgment. Exclusion Criteria: 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). 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. 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. Any condition that in the judgment of the investigator will adversely affect the completion of the protocol. 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) Clinical diagnosis of celiac disease that is in poor control as defined by most recent tissue transglutaminase (tTG) that is in the abnormal range. History of ≥1 diabetic ketoacidosis events in the past 3 months. History of ≥1 severe hypoglycemic events (cognitive impairment that required assistance to treat) in the past 3 months. History of anemia or vitamin B12 deficiency in the past 2 years. Participation in an intervention study in the past 3 months.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>Metformin 2000 mg per day | Drug: Metformin (glucophage)<br>* 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.<br>|
| Placebo Comparator: Oral Placebo<br>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 | Other: oral placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 0-26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Total Daily Dose of Insulin (TDI) Per kg |  | 0-26 weeks | 
| Change in Body Mass Index (BMI) |  | 0-26 weeks | 
| Change in Waist Circumference |  | 0-26 weeks | 
| Change in Body Composition | Change in percent body fat | 0-26 weeks | 
| Change in Serum Lipids |  | 0-26 weeks | 
| Change in Blood Pressure |  | 0-26 weeks |