Autism Spectrum Disorder, Overweight
Conditions
Keywords
Metformin, Overweight, Atypical Antipsychotic, Medication, Randomized Clinical Trial, Children
Brief summary
The purpose of this study is to determine whether metformin is safe and effective in the treatment of weight or weight gain in young people with Autism Spectrum Disorders (ASD) who are currently taking atypical antipsychotic medication.
Detailed description
This is a double-blind, placebo-controlled, multi-site randomized trial to evaluate oral fixed dose metformin (Riomet®) in decreasing weight or weight gain in children ages 6-17 years, 4 months with ASD who are currently taking atypical antipsychotic medication. A 16-week, double-blind, placebo-controlled randomized trial of metformin with dose guided by age will be conducted. A secondary study aim will be to assess the long-term safety and efficacy of metformin by conducting a 16-week open label continuation.
Interventions
DRUGMetformin
Metformin will be dispensed in a liquid suspension of 100 mg/mL. For children 6-9 years of age, metformin will be started at 250 mg at their evening meal for 1 week, followed by the addition of a 250 mg dose at breakfast for 1 week. At the Week 2 visit, if metformin is well-tolerated, the dose will be increased to 500 mg twice daily. For children from 10-17 years of age, metformin will be started at 250 mg at their evening meal for 1 week, followed by the addition of a 250 mg dose at breakfast for 1 week. At the Week 2 visit, if metformin is well-tolerated, the dose will be increased to 500 mg twice daily. At the Week 4 visit, if metformin is well-tolerated, the dose will be increased to 850 mg twice daily.
DRUGPlacebo
The placebo hydrochloride oral solution will be prepared to match the appearance, smell and taste of the metformin as closely as possible. For children from 6-9 years of age, placebo will be started at 250 mg at their evening meal for 1 week, followed by the addition of a 250 mg dose at breakfast for 1 week. At the Week 2 visit, if placebo is well-tolerated, the dose will be increased to 500 mg twice daily. For children from 10-17 years of age, placebo will be started at 250 mg at their evening meal for 1 week, followed by the addition of a 250 mg dose at breakfast for 1 week. At the Week 2 visit, if placebo is well-tolerated, the dose will be increased to 500 mg twice daily. At the Week 4 visit, if placebo is well-tolerated, the dose will be increased to 850 mg twice daily.
Sponsors
Massachusetts General Hospital
Vanderbilt University
University of Pittsburgh Medical Center
Nationwide Children's Hospital
Ohio State University
Holland Bloorview Kids Rehabilitation Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of Autism Spectrum Disorder (autistic disorder, pervasive developmental disorder not otherwise specified), Asperger's disorder) based upon an Autism Diagnostic Observation Scale (ADOS) and Diagnostic and Statistical Manual (DSM-IV) interview. 2. Minimum of 1 month on a stable atypical antipsychotic dose with no plans to change the dose for the next 4 months. 3. A documented greater than/equal to 7% increase in BMI since starting atypical antipsychotic therapy(going back as far as prior 12 months); or, if BMI is greater or equal to 85th percentile corrected for age and sex, then a greater than 5% body weight increase per year (prorated at greater than 5% body weight increase if medicated for longer than a year). 4. Age 6 years to 17 years, 4 months. 5. Subjects and their parents (guardians) must be judged reliable for medication compliance and must agree to keep appointments for study visits and tests as outlined in the protocol. 6. Prior to the conduct of any study-specific procedures, the subject must provide assent to participate in the study (if developmentally appropriate), and their parents (guardians) must provide written informed consent.
Exclusion criteria
1. History of intolerable adverse effects with metformin. 2. Prior history of an exposure to metformin of sufficient dose or duration to determine response status. 3. History of liver disease, renal impairment, congestive heart failure, pernicious anemia, any other condition increasing the risk for lactic acidosis, or any serious medical illness requiring treatment. 4. Use of cationic drugs excreted by the kidneys. 5. Planned surgery or procedure requiring contrast. 6. Pregnant at screening contact. 7. On other psychotropic concomitant medications for less than 2 months. 8. Treatment or planned treatment with concomitant medications with unacceptable interactions with metformin, including topiramate, levetiracetam, beta blockers, angiotensin-converting-enzyme (ACE) inhibitors, diuretics, or histamine H2 receptor antagonists. 9. Unable to tolerate blood work. 10. Current use of medication for target symptoms of appetite or weight loss. 11. Planned change of medication, medication dose, or behavioral treatment targeting weight loss during the study period.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change in Body Mass Index Z-score | Baseline, 16 Weeks |
Secondary
| Measure | Time frame |
|---|---|
| Changes in Additional Body Composition Parameters (Relative Change in Weight) | Baseline, 16 Weeks |
| Changes in Additional Body Composition Parameters (Absolute BMI) | Baseline, 16 Weeks |
| Changes in Additional Body Composition Parameters (Abdominal Circumference) | Baseline, 16 Weeks |
| Changes in Additional Body Composition Parameters (Hip Circumference) | Baseline, 16 Weeks |
| Changes in Fasting Metabolic Parameters (Total Cholesterol) | Baseline, 16 Weeks |
| Changes in Additional Body Composition Parameters (Absolute Change in Weight) | Baseline, 16 Weeks |
| Changes in Fasting Metabolic Parameters (HDL) | Baseline, 16 Weeks |
| Changes in Fasting Metabolic Parameters (Triglycerides) | Baseline, 16 Weeks |
| Changes in Fasting Metabolic Parameters (Glucose) | Baseline, 16 Weeks |
| Changes in Fasting Metabolic Parameters (Insulin) | Baseline, 16 Weeks |
| Changes in Fasting Metabolic Parameters (LDL) | Baseline, 16 Weeks |
Countries
Canada, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Hydrochloride Oral Solution Placebo: The placebo hydrochloride oral solution will be prepared to match the appearance, smell and taste of the metformin as closely as possible. For children from 6-9 years of age, placebo will be started at 250 mg at their evening meal for 1 week, followed by the addition of a 250 mg dose at breakfast for 1 week. At the Week 2 visit, if placebo is well-tolerated, the dose will be increased to 500 mg twice daily. For children from 10-17 years of age, placebo will be started at 250 mg at their evening meal for 1 week, followed by the addition of a 250 mg dose at breakfast for 1 week. At the Week 2 visit, if placebo is well-tolerated, the dose will be increased to 500 mg twice daily. At the Week 4 visit, if placebo is well-tolerated, the dose will be increased to 850 mg twice daily. | 32 |
| Metformin Metformin: Metformin will be dispensed in a liquid suspension of 100 mg/mL. For children 6-9 years of age, metformin will be started at 250 mg at their evening meal for 1 week, followed by the addition of a 250 mg dose at breakfast for 1 week. At the Week 2 visit, if metformin is well-tolerated, the dose will be increased to 500 mg twice daily. For children from 10-17 years of age, metformin will be started at 250 mg at their evening meal for 1 week, followed by the addition of a 250 mg dose at breakfast for 1 week. At the Week 2 visit, if metformin is well-tolerated, the dose will be increased to 500 mg twice daily. At the Week 4 visit, if metformin is well-tolerated, the dose will be increased to 850 mg twice daily. | 28 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 5 |
| Overall Study | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo Hydrochloride Oral Solution | Metformin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 32 Participants | 28 Participants | 60 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 12.7 years STANDARD_DEVIATION 2.64 | 12.9 years STANDARD_DEVIATION 2.85 | 12.8 years STANDARD_DEVIATION 2.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 29 Participants | 28 Participants | 57 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 28 Participants | 22 Participants | 50 Participants |
| Region of Enrollment Canada | 8 participants | 8 participants | 16 participants |
| Region of Enrollment United States | 24 participants | 20 participants | 44 participants |
| Sex: Female, Male Female | 8 Participants | 7 Participants | 15 Participants |
| Sex: Female, Male Male | 24 Participants | 21 Participants | 45 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 32 / 32 | 28 / 28 |
| serious Total, serious adverse events | 1 / 32 | 0 / 28 |
Outcome results
Primary
Change in Body Mass Index Z-score
Time frame: Baseline, 16 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Hydrochloride Oral Solution | Change in Body Mass Index Z-score | 0.02 16-wk change in BMI z-score |
| Metformin | Change in Body Mass Index Z-score | -0.08 16-wk change in BMI z-score |
Secondary
Changes in Additional Body Composition Parameters (Abdominal Circumference)
Time frame: Baseline, 16 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Hydrochloride Oral Solution | Changes in Additional Body Composition Parameters (Abdominal Circumference) | 1.45 centimetres |
| Metformin | Changes in Additional Body Composition Parameters (Abdominal Circumference) | -0.21 centimetres |
Secondary
Changes in Additional Body Composition Parameters (Absolute BMI)
Time frame: Baseline, 16 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Hydrochloride Oral Solution | Changes in Additional Body Composition Parameters (Absolute BMI) | 0.52 16-wk change in BMI (kg/m2) |
| Metformin | Changes in Additional Body Composition Parameters (Absolute BMI) | -0.43 16-wk change in BMI (kg/m2) |
Secondary
Changes in Additional Body Composition Parameters (Absolute Change in Weight)
Time frame: Baseline, 16 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Hydrochloride Oral Solution | Changes in Additional Body Composition Parameters (Absolute Change in Weight) | 2.80 16-wk change in weight (kg) |
| Metformin | Changes in Additional Body Composition Parameters (Absolute Change in Weight) | 0.07 16-wk change in weight (kg) |
Secondary
Changes in Additional Body Composition Parameters (Hip Circumference)
Time frame: Baseline, 16 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Hydrochloride Oral Solution | Changes in Additional Body Composition Parameters (Hip Circumference) | 1.06 centimetres |
| Metformin | Changes in Additional Body Composition Parameters (Hip Circumference) | -0.63 centimetres |
Secondary
Changes in Additional Body Composition Parameters (Relative Change in Weight)
Time frame: Baseline, 16 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Hydrochloride Oral Solution | Changes in Additional Body Composition Parameters (Relative Change in Weight) | 0.04 16-wk change in weight (z-score) |
| Metformin | Changes in Additional Body Composition Parameters (Relative Change in Weight) | -0.10 16-wk change in weight (z-score) |
Secondary
Changes in Fasting Metabolic Parameters (Glucose)
Time frame: Baseline, 16 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Hydrochloride Oral Solution | Changes in Fasting Metabolic Parameters (Glucose) | -2.41 16-week change in gluclose (mg/dL) |
| Metformin | Changes in Fasting Metabolic Parameters (Glucose) | -3.06 16-week change in gluclose (mg/dL) |
Secondary
Changes in Fasting Metabolic Parameters (HDL)
Time frame: Baseline, 16 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Hydrochloride Oral Solution | Changes in Fasting Metabolic Parameters (HDL) | -0.98 16-week change in HDL (mg/dL) |
| Metformin | Changes in Fasting Metabolic Parameters (HDL) | 3.27 16-week change in HDL (mg/dL) |
Secondary
Changes in Fasting Metabolic Parameters (Insulin)
Time frame: Baseline, 16 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Hydrochloride Oral Solution | Changes in Fasting Metabolic Parameters (Insulin) | 2.95 16-week change insulin fasting (µIU/mL) |
| Metformin | Changes in Fasting Metabolic Parameters (Insulin) | 1.97 16-week change insulin fasting (µIU/mL) |
Secondary
Changes in Fasting Metabolic Parameters (LDL)
Time frame: Baseline, 16 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Hydrochloride Oral Solution | Changes in Fasting Metabolic Parameters (LDL) | -0.41 16-week change in LDL (mg/dL) |
| Metformin | Changes in Fasting Metabolic Parameters (LDL) | -4.41 16-week change in LDL (mg/dL) |
Secondary
Changes in Fasting Metabolic Parameters (Total Cholesterol)
Time frame: Baseline, 16 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Hydrochloride Oral Solution | Changes in Fasting Metabolic Parameters (Total Cholesterol) | -3.29 16-week change total cholesterol (mg/dL) |
| Metformin | Changes in Fasting Metabolic Parameters (Total Cholesterol) | -1.05 16-week change total cholesterol (mg/dL) |
Secondary
Changes in Fasting Metabolic Parameters (Triglycerides)
Time frame: Baseline, 16 Weeks
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo Hydrochloride Oral Solution | Changes in Fasting Metabolic Parameters (Triglycerides) | 6.18 16-week change in triglycerides (mg/dL) |
| Metformin | Changes in Fasting Metabolic Parameters (Triglycerides) | 5.74 16-week change in triglycerides (mg/dL) |