Bipolar Disorder
Conditions
Brief summary
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
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.
Interventions
DRUGMetformin
Metformin - to achieves maximum insulin-sensitizing effects
BEHAVIORALhealthy lifestyle intervention (LIFE)
Healthy Life style intervention
Sponsors
Patient-Centered Outcomes Research Institute
Melissa Delbello
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
8 Years to 19 Years
Healthy volunteers
No
Inclusion criteria
1. Inpatient or outpatient age 8-19 years inclusive; participants must live with a parent, guardian, or caregiver; 2. Fluent in English; 3. 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); 4. Body mass index \>85%ile for age and sex by standard growth charts; 5. 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
1. 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; 2. Patients will be excluded if they could not tolerate MET during the recommended titration schedule outlined in the protocol; 3. 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 \[steroids\]); 4. Fasting glucose ≥ 126 mg/dL on 2 occasions during screening indicating need for prompt treatment; 5. 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; 6. Pregnant or breast feeding; 7. Children and caregivers who are unable to complete assessments for any reason;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in BMI Z-score From Baseline to Month 6 in ITT Sample | Baseline to Month 6 | Raw body mass index (BMI) is calculated as (weight(kg)/ height(m)2). This raw BMI value is converted to a normalized BMI z-score, adjusted for age and sex using US Centers for Disease Control and Prevention growth charts. A z-score equal to 0 indicates the population mean and larger z-scores are heavier weights and worse outcomes. |
| Change in BMI Z-score From Baseline to Month 24 in ITT Sample | Baseline to Month 24 | Raw body mass index (BMI) is calculated as (weight(kg)/ height(m)2). This raw BMI value is converted to a normalized BMI z-score, adjusted for age and sex using US Centers for Disease Control and Prevention growth charts. A z-score equal to 0 indicates the population mean and larger z-scores are heavier weights and worse outcomes. |
| Change in BMI Z-score From Baseline to Month 6 in Per Protocol Sample | Baseline to Month 6 | Raw body mass index (BMI) is calculated as (weight(kg)/ height(m)2). This raw BMI value is converted to a normalized BMI z-score, adjusted for age and sex using US Centers for Disease Control and Prevention growth charts. A z-score equal to 0 indicates the population mean and larger z-scores are heavier weights and worse outcomes. |
| Change in BMI Z-score From Baseline to Month 24 in Per Protocol Sample | Baseline to Month 24 | Raw body mass index (BMI) is calculated as (weight(kg)/ height(m)2). This raw BMI value is converted to a normalized BMI z-score, adjusted for age and sex using US Centers for Disease Control and Prevention growth charts. A z-score equal to 0 indicates the population mean and larger z-scores are heavier weights and worse outcomes. |
Countries
United States
Participant flow
Pre-assignment details
1633 participants were screened. 68 did not meet criteria. Of the 1565 randomized patients, 228 patients did not have a visit after baseline and 38 patients, in the MET+LIFE group, did not start metformin per protocol by study day 137 post-randomization. These 266 patients were not included in the modified intent-to-treat (ITT) sample and results, giving an ITT sample size of 1299.
Participants by arm
| Arm | Count |
|---|---|
| MET and LIFE 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.
Metformin: Metformin - to achieves maximum insulin-sensitizing effects
healthy lifestyle intervention (LIFE): Healthy Life style intervention | 579 |
| Healthy Lifestyle Intervention (LIFE) 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).
healthy lifestyle intervention (LIFE): Healthy Life style intervention | 720 |
| Total | 1,299 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Censored (study ended before participant could complete) | 18 | 24 |
| Overall Study | Discharged from Clinic Services | 53 | 84 |
| Overall Study | Follow-up at non-study site | 8 | 16 |
| Overall Study | Lost to Follow-up | 119 | 126 |
| Overall Study | Moved from area | 9 | 14 |
| Overall Study | Withdrawal by Subject | 12 | 2 |
Baseline characteristics
| Characteristic | Total | Healthy Lifestyle Intervention (LIFE) | MET and LIFE |
|---|---|---|---|
| Age, Continuous | 13.9 Years STANDARD_DEVIATION 2.9 | 13.8 Years STANDARD_DEVIATION 2.9 | 14.0 Years STANDARD_DEVIATION 2.8 |
| BMI Z-Score | 1.87 Z-score STANDARD_DEVIATION 0.47 | 1.85 Z-score STANDARD_DEVIATION 0.46 | 1.90 Z-score STANDARD_DEVIATION 0.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 156 Participants | 96 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1141 Participants | 624 Participants | 517 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 2 Participants |
| Obesity | 859 Participants | 474 Participants | 385 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 6 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 24 Participants | 13 Participants | 11 Participants |
| Race (NIH/OMB) Black or African American | 222 Participants | 124 Participants | 98 Participants |
| Race (NIH/OMB) More than one race | 128 Participants | 78 Participants | 50 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 46 Participants | 29 Participants | 17 Participants |
| Race (NIH/OMB) White | 871 Participants | 472 Participants | 399 Participants |
| Sex: Female, Male Female | 614 Participants | 341 Participants | 273 Participants |
| Sex: Female, Male Male | 685 Participants | 379 Participants | 306 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 579 | 0 / 720 |
| other Total, other adverse events | 352 / 558 | 339 / 686 |
| serious Total, serious adverse events | 12 / 579 | 25 / 720 |
Outcome results
Primary
Change in BMI Z-score From Baseline to Month 24 in ITT Sample
Raw body mass index (BMI) is calculated as (weight(kg)/ height(m)2). This raw BMI value is converted to a normalized BMI z-score, adjusted for age and sex using US Centers for Disease Control and Prevention growth charts. A z-score equal to 0 indicates the population mean and larger z-scores are heavier weights and worse outcomes.
Time frame: Baseline to Month 24
Population: Modified intention-to-treat (ITT) sample consisting of patients who initiated randomized treatment and had at least one post-baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MET and LIFE | Change in BMI Z-score From Baseline to Month 24 in ITT Sample | -0.19 Z-score | Standard Deviation 1 |
| Healthy Lifestyle Intervention (LIFE) | Change in BMI Z-score From Baseline to Month 24 in ITT Sample | -0.11 Z-score | Standard Deviation 0.87 |
p-value: 0.044ANCOVA
Primary
Change in BMI Z-score From Baseline to Month 24 in Per Protocol Sample
Raw body mass index (BMI) is calculated as (weight(kg)/ height(m)2). This raw BMI value is converted to a normalized BMI z-score, adjusted for age and sex using US Centers for Disease Control and Prevention growth charts. A z-score equal to 0 indicates the population mean and larger z-scores are heavier weights and worse outcomes.
Time frame: Baseline to Month 24
Population: Per protocol sample consisting of patients who had continuously followed their randomized treatment through month 24
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MET and LIFE | Change in BMI Z-score From Baseline to Month 24 in Per Protocol Sample | -0.21 Z-score | Standard Deviation 1.11 |
| Healthy Lifestyle Intervention (LIFE) | Change in BMI Z-score From Baseline to Month 24 in Per Protocol Sample | -0.12 Z-score | Standard Deviation 1.01 |
p-value: 0.041ANCOVA
Primary
Change in BMI Z-score From Baseline to Month 6 in ITT Sample
Raw body mass index (BMI) is calculated as (weight(kg)/ height(m)2). This raw BMI value is converted to a normalized BMI z-score, adjusted for age and sex using US Centers for Disease Control and Prevention growth charts. A z-score equal to 0 indicates the population mean and larger z-scores are heavier weights and worse outcomes.
Time frame: Baseline to Month 6
Population: Modified intention-to-treat (ITT) sample consisting of patients who initiated randomized treatment and had at least one post-baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MET and LIFE | Change in BMI Z-score From Baseline to Month 6 in ITT Sample | -0.08 Z-score | Standard Deviation 0.29 |
| Healthy Lifestyle Intervention (LIFE) | Change in BMI Z-score From Baseline to Month 6 in ITT Sample | 0.00 Z-score | Standard Deviation 0.29 |
p-value: <0.001ANCOVA
Primary
Change in BMI Z-score From Baseline to Month 6 in Per Protocol Sample
Raw body mass index (BMI) is calculated as (weight(kg)/ height(m)2). This raw BMI value is converted to a normalized BMI z-score, adjusted for age and sex using US Centers for Disease Control and Prevention growth charts. A z-score equal to 0 indicates the population mean and larger z-scores are heavier weights and worse outcomes.
Time frame: Baseline to Month 6
Population: Per protocol sample consisting of patients who had continuously followed their randomized treatment through month 6
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MET and LIFE | Change in BMI Z-score From Baseline to Month 6 in Per Protocol Sample | -0.09 Z-score | Standard Deviation 0.46 |
| Healthy Lifestyle Intervention (LIFE) | Change in BMI Z-score From Baseline to Month 6 in Per Protocol Sample | 0.00 Z-score | Standard Deviation 0.42 |
p-value: <0.001ANCOVA