Adjunctive Metformin Therapy in Double Diabetes

Study Overview
=================
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.

Official Title
-----------------
Glycemic Control in Children and Adolescents With Double Diabetes: Trial of Optimized Insulin-Metformin Regimen

Conditions
-----------------
Diabetes Mellitus

Intervention / Treatment
-----------------
* Drug: Metformin
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A. General inclusion criteria Ten to 20 years of age. Pubertal (Tanner stages 2-5, by examination). Hemoglobin A1c level of > 8.0% in the 6 months prior to enrollment. All subjects must have access to a computer. B. Specific inclusion criteria: [Subjects could have either #1, or #2]. 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 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: Subjects on weight altering medications, such as orlistat. Subjects with eating disorder Subjects on medications other than insulin and or metformin that may affect blood glucose level. Subjects with abnormal hepatic function tests. Subjects with nephropathy, defined in this case as an overnight albumin excretion rate of >200 mcg/min using a first morning urine sample collection. 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). Pregnant, breast-feeding or the intention of becoming pregnant or not using adequate contraceptive measures. Known or suspected allergy to metformin. The receipt of any investigational drug within 6 months prior to this trial. Active malignant neoplasms. No access to a computer. Subjects currently taking metformin for clinical purposes are not eligible to be enrolled in this study.

Ages Eligible for Study
-----------------
Minimum Age: 10 Years
Maximum Age: 20 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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 1000 mg once daily by mouth for 9 months | Drug: Metformin<br>* Metformin 1000 mg once daily by mouth for 9 months<br>* Other names: Glucophage;|
| Placebo Comparator: Placebo<br>2 capsules once daily by mouth for 9 months | Drug: Placebo<br>* 2 capsules once daily by mouth for 9 months<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline, 3mo, 6mo, and 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Baseline, 3mo, 6mo, and 9 months | 
| 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). | Baseline, 3mo, 6 mo, and 9 months | 
| 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). | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Obesity, Double Diabetes, Type 1 diabetes, Type 2 diabetes, Acanthosis nigricans, Diabetes associated autoantibodies