Metformin for Overweight & OBese ChILdren and Adolescents With BDS Treated With SGAs

Study Overview
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Brief Summary
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A prospective, large, pragmatic, randomized trial to study the impact of METFORMIN and healthy lifestyle intervention (LIFE) vs. LIFE alone on patient-centered outcomes of body weight, SGA-adherence and satisfaction, psychiatric symptom burden (e.g. mood/anxiety), and Quality of Life.

Detailed Description
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The investigators propose to recruit 1800 overweight/obese youth with Bipolar Spectrum Disorder (BSD) who are prescribed second generation anti psychotics (SGAs) from at least 24 public and private mental health practices in the Greater Cincinnati and New York City regions, (approximately 900 each from  12 Cincinnati region and  12 Long Island/New York mental health treatment sites) to participate in the proposed patient-centered large pragmatic trial examining the effectiveness of MET and LIFE vs. LIFE alone. Patients will be eligible if they are ages 8-17 years old, inclusive, overweight or obese (BMI > 85%), continuing or starting treatment with at least one SGA (i.e., olanzapine, clozapine, risperidone, quetiapine, aripiprazole, ziprasidone, iloperidone, lurasidone, paliperidone, or asenapine) and have a clinical diagnosis of BSD (bipolar I or II disorder, cyclothymia, or bipolar or mood disorder not otherwise specified [or by Diagnostic and Statistical Manual of Mental Disorders V (DSM-5), other specified bipolar or mood disorder). The enrollment rate will be 2-3 patients/month/site for a recruitment time of 30 months.

Official Title
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MOBILITY- Metformin for Overweight & OBese ChILdren and Adolescents With BIpolar Spectrum Disorders Treated With Second-Generation AntipsYchotics

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Metformin
* Behavioral: healthy lifestyle intervention (LIFE)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Inpatient or outpatient age 8-19 years inclusive; participants must live with a parent, guardian, or caregiver; Fluent in English; Diagnosed or told by a clinician that they have any of the following bipolar spectrum disorders (BSD): bipolar I, bipolar II, unspecified bipolar and related disorders, Disruptive Mood Dysregulation Disorder (DMDD), cyclothymic disorder, other specified bipolar and related disorders, as well as mood disorder not otherwise specified (if diagnosed in the past as per DSM-IV); Body mass index >85%ile for age and sex by standard growth charts; Received a new or ongoing prescription for at least one SGA (i.e., olanzapine, clozapine, risperidone, quetiapine, aripiprazole, ziprasidone, iloperidone, lurasidone, paliperidone, brexpiprazole or cariprazine) that is not prescribed as a PRN medication; Exclusion Criteria: Patients will be excluded if they have had exposure to a total daily dose of MET 1000 mg bid for at least 2 weeks in the past 3 months; Patients will be excluded if they could not tolerate MET during the recommended titration schedule outlined in the protocol; Major neurological or medical illnesses that affect weight gain (e.g., unstable thyroid disease) or require a systemic medication that might impact weight or glucose regulation (e.g., diabetes mellitus [insulin], chronic renal failure [steroids]); Fasting glucose ≥ 126 mg/dL on 2 occasions during screening indicating need for prompt treatment; If lab results are available in the last 6 months, then a serum creatinine ≥1.3 mg/dL on 2 occasions during screening and/or follow-up, indicating potential impairment of renal functioning; Pregnant or breast feeding; Children and caregivers who are unable to complete assessments for any reason;

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 17 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MET and LIFE<br>Participants randomized to this group will receive both Metformin and lifestyle intervention.Participants randomized to treatment with MET will start at a dose of 500 mg orally at night and slowly titrated in 2-week intervals to ensure that each patient achieves maximum insulin-sensitizing effects of the drug while minimizing the chance of side effects. Investigators will also recommend that MET be taken with food to minimize side effects. If a participant's BMI percentile <5% (=underweight) his/her treatment with MET will be discontinued. Although the risk of low vitamin B12 while taking MET is associated with age > 50 years and having type II diabetes, Investigator will monitor B12 levels and a CBC throughout study participation. | Drug: Metformin<br>* Metformin - to achieves maximum insulin-sensitizing effects<br>* Other names: GLUCOPHAGE;Behavioral: healthy lifestyle intervention (LIFE)<br>* Healthy Life style intervention<br>* Other names: LIFE;|
| Experimental: Healthy lifestyle intervention (LIFE)<br>Participants randomized to this group will receive just lifestyle intervention alone.This healthy lifestyle intervention (LIFE) consists of counseling participants and families regarding a healthy eating plan, physical activity and sedentary activities. Prior to study initiation, clinical site staff will participate in a live (or taped) training session from a dietician to lean to administer LIFE. A trained site staff member (e.g. medical assistant or case manager) will meet with participants and their families for a 15-20 minute session at baseline that will focus on nutritional issues using the Traffic Light Plan (TLP). | Behavioral: healthy lifestyle intervention (LIFE)<br>* Healthy Life style intervention<br>* Other names: LIFE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| BMI z-score | BMI z-score will be computed from measurement of height and weight. Raw BMI is calculated as (weight(kg)/ height(m)2). Normalized BMI (z-score, adjusted for age and sex), will be calculated using the program provided by the USDA/ARS Children's Nutrition Research Center at Baylor College of Medicine (http://www.bcm.edu/cnrc/bodycomp/bmiz2.html). At each site weight will be measured with a Seca scale, model 882, calibrated to the nearest 0.2 kg per manufacturer instructions at intervals not to exceed 2 months using standard weights. | Screen/Baseline to Visit 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite Metabolic Health and Nutrition Measure | As per clinical standards, blood pressure will be measured after 5 minutes of sitting at each patient visit. A minimum of 8-hour fasting total cholesterol, low-density lipoprotein (LDL)-cholesterol, high density lipoprotein (HDL)-cholesterol, triglycerides, glucose, insulin, and glycosylated hemoglobin (HbA1c) will be collected. For HTE analyses the homeostatic model assessment for insulin-resistance (HOMA-IR) will be computed as: (Insulin [IU/mL] x Glucose [mg/dL] /405). Following the modified ATPIII guidelines,130-132 metabolic syndrome is defined when >3 of the following: 1) abdominal obesity (BMI >90%ile, as in NHANES study of metabolic syndrome in youth133; 2) blood pressure >90%ile for height, age, sex; 3) fasting triglycerides >150 mg/dL; 4) low HDL cholesterol (males <40 mg/dL and for females <50 mg/dL); 5) fasting glucose >100 mg/dL Fulfillment of individual criteria and metabolic syndrome will be outcome measures. | Screen/Baseline to Visit 24 |