IMPACT: Reducing Weight Gain and Improving Metabolic Function in Children Being Treated With Antipsychotics

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00806234
• Collaborator: National Institute of Mental Health (NIMH) (NIH), University of Maryland (Other), University of North Carolina, Chapel Hill (Other), The Zucker Hillside Hospital (Other)
• Enrollment: 127
• Locations: 4
• Arms: 3
• Duration (Months): 61.9
• Patients Per Site: 31.8
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This study will test the effectiveness of two different treatments for children and adolescents who have gained weight on their antipsychotic medications.

Condition or Disease	Intervention/Treatment	Phase
Psychotic Disorders	Drug: Aripiprazole or Perphenazine; Drug: Metformin; Drug: Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine	Phase 4

Detailed Description

Disorders that involve severe dysregulation of mood or thoughts in children -- such as early onset bipolar spectrum (BPS) and schizophrenia spectrum (SS) disorders -- are commonly treated with antipsychotic medications. However, many of the newest and most commonly prescribed antipsychotic medications can cause weight gain and metabolic dysfunctions. Use of these newer antipsychotics, called second generation antipsychotics (SGAs), is increasing rapidly in children, and the risk of weight gain from SGAs is higher among children than adults. Excessive weight gain can lead to obesity, which, in turn, can lead to increased health care costs, increased risk of sickness, and lower life expectancy. These factors are enhanced in children and adolescents who grow up obese.

Two different strategies to reduce weight gain and metabolic side effects from SGAs will be tested in this study. The first strategy involves switching from the current SGA to a lower risk agent (aripiprazole or perphenazine) hypothesized to result in weight loss and improved metabolic functioning. The second strategy involves taking the medication metformin in addition to the current SGA. Metformin is approved by the Food and Drug Administration (FDA) to promote weight loss in youth with diabetes and has been effective in reducing weight in youth taking SGAs.

Participation in this study will last between 26 and 27 weeks and will be divided into two parts. The first part will last 2 to 3 weeks and include three study visits. During this part, participants will undergo a physical exam, an electrocardiogram (EKG), a dual energy X-ray absorptiometry (DXA) test, and blood tests. The DXA measures body fat.

The second part will last 24 weeks and include nine study visits. During this part, participants will be randomly assigned to one of three conditions: gradual switch of current SGA medication to either aripiprazole or perphenazine, addition of metformin to current SGA medication, or no change to treatment with current SGA medication. Visits will take place on Weeks 1, 2, 4, 6, 8, 12, 16, 20, and 24. At each visit, participants will meet with a study doctor who will assess symptoms and side effects, and participants and their guardians will receive information and recommendations about childhood obesity and weight loss. There will also be monthly urine pregnancy tests, and two blood tests.

Study Design

• Study Type: Interventional
• Actual Enrollment: 127 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Improving Metabolic Parameters of Antipsychotic Child Treatment (IMPACT)
• Study Start Date: Jan 1, 2009
• Actual Primary Completion Date: Mar 1, 2014
• Actual Study Completion Date: Mar 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 Participants will continue on current antipsychotic medication.	Drug: Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine; Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated; Other Names: Zyprexa, Seroquel, Risperdal, Geodon, Abilify, Saphris, Sycrest, Fanapt, Fanapta, Zomaril, Latuda, Invega, Symbyax
Experimental: 2 Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine.	Drug: Aripiprazole or Perphenazine; Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.; Other Names: Abilify, Trilafon
Experimental: 3 Participants will add metformin to current antipsychotic medication treatment.	Drug: Metformin; Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.; Other Names: Glucophage

Outcome Measures

Primary Outcome Measures

1. Body Mass Index (BMI) Z-score Change [Change from baseline to 24 weeks]

Secondary Outcome Measures

1. Change in Whole Body Insulin Sensitivity Index [Change from baseline to 24 weeks]

2. Triglyceride Levels [Change from baseline to 24 weeks]

3. Change in Low Density Lipoprotein (LDL) Cholesterol Level [From Baseline to Week 24]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 8 Years to 19 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• DSM diagnoses that have an FDA indication for atypical antipsychotic use for at least one agent in the respective pediatric or adult age group. Specifically, primary DSM-IV diagnosis of Early Onset Schizophrenia Spectrum (EOSS; schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder NOS); Bipolar Spectrum (bipolar I, II and NOS); Major depressive disorder with psychosis; Mood disorder NOS corresponding to Leibenluft and colleagues severely mood dysregulated (SMD) broad spectrum bipolar disorder; Mood disorder NOS corresponding to irritability associated with autism spectrum disorders; or - for adult teen participants aged 18-19 years - Major depressive disorder. Diagnoses will be determined by clinical interview, Leibenluft's modification of the K-SADS-PL, and the "Aberrant Behavior Checklist" (cutoff score of 18, as used by FDA for approval of risperidone and aripiprazole in minors).

• Clinically stable on current treatment regimen for at least 30 days, as assessed in a three-step process

• Current SGA treatment with olanzapine, quetiapine, risperidone, ziprasidone aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine for ≥ 8 weeks

• Stable dose of current SGA and psychotropic co-medications for at least 30 days

• Body mass index (BMI) at least in the 85th percentile for age and gender

• Substantial weight gain over the previous 3 years while taking a SGA, as reflected by family and referring physician's judgment. The weight gain did not have to occur on the child's current SGA. Weight needs to have remained stable or increased over past year.

• Agrees to use two effective forms of birth control or to remain abstinent

• Has a primary caretaker who has known the child well for at least 6 months before study entry

• Primary caretaker is able to participate in study appointments as clinically indicated

Exclusion Criteria:

• Treatment with any medication (other than the currently prescribed psychotropic medications) that would significantly alter glucose, insulin, or lipid levels. Exception: orlistat and amantadine are permitted if the individual has taken the drug for at least one year without weight loss.

• Major neurological or medical illness that affects weight gain or that would prevent participation in physical activities

• Fasting glucose levels indicating need for prompt treatment

• Pediatrician or pediatric gastroenterologist recommendation to address abnormal fasting labs by pursuing more active treatment than those in the 2007 American Medical Association guidelines

• Diagnosis of anorexia nervosa or bulimia nervosa, as based on current or lifetime DSM-IV criteria

• Diagnosis of substance dependence disorder (other than tobacco dependence) within the past month, as based on DSM-IV criteria

• Positive urine toxicology indicating ongoing use of illicit substance

• Current treatment with more than one antipsychotic medication

• Current treatment with more than 3 total psychotropic medications (i.e., 2 psychotropics plus SGA), with the exception of subjects taking 2 medications for ADHD in which a total of 4 psychotropic medications are allowed.

• Known hypersensitivity to metformin

• Prior treatment with aripiprazole and perphenazine for more than 2 weeks that was stopped for inefficacy or intolerability

• Pregnant, breastfeeding, or unwilling to comply with contraceptive requirements of study

• IQ score less than 55

• Significant risk of dangerousness to self or to others that would make study participation inadvisable

• Language issues that prevent child and/or parent from completing assessments or treatment

• Ongoing or previously undisclosed child abuse requiring new department of social service intervention

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Maryland	Baltimore	Maryland	United States	21201
2	Johns Hopkins Hospital	Baltimore	Maryland	United States	21205
3	The Zucker Hillside Hospital	Glen Oaks	New York	United States	11004
4	University of North Carolina, Division of Child and Adolescent Psychiatry	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

• Johns Hopkins University
• National Institute of Mental Health (NIMH)
• University of Maryland
• University of North Carolina, Chapel Hill
• The Zucker Hillside Hospital

Investigators

• Principal Investigator: Gloria Reeves, MD, University of Maryland
• Principal Investigator: Linmarie Sikich, MD, University of North Carolina, Division of Child and Adolescent Psychiatry
• Principal Investigator: Christoph Correll, MD, The Zucker Hillside Hospital
• Principal Investigator: Mark A. Riddle, MD, Johns Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Reeves GM, Keeton C, Correll CU, Johnson JL, Hamer RM, Sikich L, Hazzard L, Alderman C, Scheer A, Mabe M, Kapoor S, Sheridan E, Borner I, Bussell K, Pirmohamed S, Bethea TC, Chekuri R, Gottfried R, Reinblatt SP, Santana E, Riddle MA. Improving metabolic parameters of antipsychotic child treatment (IMPACT) study: rationale, design, and methods. Child Adolesc Psychiatry Ment Health. 2013 Aug 15;7(1):31. doi: 10.1186/1753-2000-7-31.

• Responsible Party: Mark Riddle, MD, Principal Investigator, Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT00806234
• Other Study ID Numbers: R01MH080270; R01MH080270; DSIR 84-CTS
• First Posted: Dec 10, 2008
• Last Update Posted: Apr 25, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by Mark Riddle, MD, Principal Investigator, Johns Hopkins University: Weight Gain; Obesity; IMPACT; Antipsychotic Treatment; Excessive Weight Gain Associated With Antipsychotic Treatment; Hybrid Efficacy/Effectiveness Design; Reducing Weight Gain; Improving Metabolic Parameters; Aripiprazole; Metformin; Risperdal; Seroquel; Quetiapine; Olanzapine; Zyprexa; Geodon; Risperidone; Abilify; Trilafon; Perphenazine; Glucophage; Paliperidone; Olanzapine/fluoxetine
• Additional relevant MeSH terms: Weight Gain; Mental Disorders; Psychotic Disorders; Metformin; Olanzapine; Risperidone; Aripiprazole; Quetiapine Fumarate; Paliperidone Palmitate; Ziprasidone; Lurasidone Hydrochloride; Asenapine; Iloperidone; Perphenazine; Fluoxetine

Study Results

Participant Flow

Arm/Group Title	Healthy Lifestyle Information	Switch Treatment + Healthy Lifestyle Instruction	Metformin Treatment + Healthy Lifestyle Instruction
Arm/Group Description	Participants will continue on current antipsychotic medication. Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine: Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated	Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine. Aripiprazole or Perphenazine: Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.	Participants will add metformin to current antipsychotic medication treatment. Metformin: Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.
Period Title: Overall Study
STARTED	47	31	49
COMPLETED	34	19	37
NOT COMPLETED	13	12	12

Baseline Characteristics

Arm/Group Title	Healthy Lifestyle Information	Switch Treatment + Healthy Lifestyle Instruction	Metformin Treatment + Healthy Lifestyle Instruction	Total
Arm/Group Description	Participants will continue on current antipsychotic medication. Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine: Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated	Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine. Aripiprazole or Perphenazine: Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.	Participants will add metformin to current antipsychotic medication treatment. Metformin: Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.	Total of all reporting groups
Overall Participants	47	31	49	127
Age (Count of Participants)
<=18 years	41 87.2%	26 83.9%	45 91.8%	112 88.2%
Between 18 and 65 years	6 12.8%	5 16.1%	4 8.2%	15 11.8%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	17 36.2%	10 32.3%	18 36.7%	45 35.4%
Male	30 63.8%	21 67.7%	31 63.3%	82 64.6%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 10.6%	4 12.9%	7 14.3%	16 12.6%
Not Hispanic or Latino	42 89.4%	27 87.1%	42 85.7%	111 87.4%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	13 27.7%	9 29%	14 28.6%	36 28.3%
White	25 53.2%	16 51.6%	26 53.1%	67 52.8%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	9 19.1%	6 19.4%	9 18.4%	24 18.9%

Outcome Measures

1. Primary Outcome

Title	Body Mass Index (BMI) Z-score Change
Time Frame	Change from baseline to 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Lifestyle Information	Switch Treatment + Healthy Lifestyle Instruction	Metformin Treatment + Healthy Lifestyle Instruction
Arm/Group Description	Participants will continue on current antipsychotic medication. Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine: Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated	Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine. Aripiprazole or Perphenazine: Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.	Participants will add metformin to current antipsychotic medication treatment. Metformin: Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.
Measure Participants	44	30	47
Least Squares Mean (Standard Error) [Z Score]	0.040 (0.029)	-0.112 (0.037)	-0.088 (0.028)

2. Secondary Outcome

Title	Change in Whole Body Insulin Sensitivity Index
Time Frame	Change from baseline to 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Lifestyle Information	Switch Treatment + Healthy Lifestyle Instruction	Metformin Treatment + Healthy Lifestyle Instruction
Arm/Group Description	Participants will continue on current antipsychotic medication. Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine: Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated	Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine. Aripiprazole or Perphenazine: Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.	Participants will add metformin to current antipsychotic medication treatment. Metformin: Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.
Measure Participants	44	30	47
Least Squares Mean (Standard Error) [mU/L]	0.74 (0.82)	0.42 (0.91)	-0.34 (0.65)

3. Secondary Outcome

Title	Triglyceride Levels
Time Frame	Change from baseline to 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Lifestyle Information	Switch Treatment + Healthy Lifestyle Instruction	Metformin Treatment + Healthy Lifestyle Instruction
Arm/Group Description	Participants will continue on current antipsychotic medication. Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine: Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated	Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine. Aripiprazole or Perphenazine: Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.	Participants will add metformin to current antipsychotic medication treatment. Metformin: Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.
Measure Participants	44	30	47
Least Squares Mean (Standard Error) [mg/dL]	0.2 (9.1)	16.6 (12.0)	14.7 (8.7)

4. Secondary Outcome

Title	Change in Low Density Lipoprotein (LDL) Cholesterol Level
Time Frame	From Baseline to Week 24

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Healthy Lifestyle Information	Switch Treatment + Healthy Lifestyle Instruction	Metformin Treatment + Healthy Lifestyle Instruction
Arm/Group Description	Participants will continue on current antipsychotic medication. Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine: Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated	Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine. Aripiprazole or Perphenazine: Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.	Participants will add metformin to current antipsychotic medication treatment. Metformin: Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.
Measure Participants	44	30	47
Least Squares Mean (Standard Error) [mg/dL]	3.6 (4.2)	-8.1 (5.4)	-4.1 (3.9)

Adverse Events

Adverse Event Reporting Description	See the correct numbers for the 3 populations below. We had to exclude 5 participants (CONTROL = 2, METFORMIN = 2, SWITCH = 1). Randomized population: Control - 47 Metformin - 49 Switch - 31 Aripiprazole - 13 Molindone - 1 Perphenazine - 17 Safety population: Control - 45 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17 Efficacy population : Control - 44 Metformin - 47 Switch - 30 Aripiprazole - 12 Molindone - 1 Perphenazine - 17
Arm/Group Title	Healthy Lifestyle Information		Switch Treatment + Healthy Lifestyle Instruction		Metformin Treatment + Healthy Lifestyle Instruction
Arm/Group Description	Participants will continue on current antipsychotic medication. Olanzapine, quetiapine, risperidone, ziprasidone, aripiprazole, asenapine, iloperidone, lurasidone, paliperidone, or olanzapine/fluoxetine: Current antipsychotic medication will be continued throughout the treatment period, with changes in dose only made as clinically indicated		Participants will undergo a staggered switch from current antipsychotic medication to aripiprazole or perphenazine. Aripiprazole or Perphenazine: Baseline second generation antipsychotic (SGA) treatment will be gradually decreased and discontinued over 8 weeks while treatment with aripiprazole or perphenazine will be increased to effective levels.		Participants will add metformin to current antipsychotic medication treatment. Metformin: Metformin treatment will be added to current SGA treatment, with dosing based on participant weight and increased according to a preset titration schedule unless side effects interfere.
All Cause Mortality
	Healthy Lifestyle Information		Switch Treatment + Healthy Lifestyle Instruction		Metformin Treatment + Healthy Lifestyle Instruction
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Healthy Lifestyle Information		Switch Treatment + Healthy Lifestyle Instruction		Metformin Treatment + Healthy Lifestyle Instruction
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/45 (2.2%)		5/30 (16.7%)		3/47 (6.4%)
Gastrointestinal disorders
Appendicitis	0/45 (0%)	0	0/30 (0%)	0	1/47 (2.1%)	1
Psychiatric disorders
Aggression	0/45 (0%)	0	1/30 (3.3%)	1	0/47 (0%)	0
Hallucinations	0/45 (0%)	0	1/30 (3.3%)	1	0/47 (0%)	0
Suicidal ideation	0/45 (0%)	0	2/30 (6.7%)	2	0/47 (0%)	0
Hospitalization	0/45 (0%)	0	1/30 (3.3%)	1	1/47 (2.1%)	1
Respiratory, thoracic and mediastinal disorders
Asthma attack	0/45 (0%)	0	0/30 (0%)	0	1/47 (2.1%)	1
Surgical and medical procedures
Femur Fracture	1/45 (2.2%)	1	0/30 (0%)	0	0/47 (0%)	0
Other (Not Including Serious) Adverse Events
	Healthy Lifestyle Information		Switch Treatment + Healthy Lifestyle Instruction		Metformin Treatment + Healthy Lifestyle Instruction
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/45 (100%)		30/30 (100%)		47/47 (100%)
Gastrointestinal disorders
Abdominal pain or discomfort	0/45 (0%)	0	0/30 (0%)	0	5/47 (10.6%)	5
Vomiting or nausea	0/45 (0%)	0	0/30 (0%)	0	4/47 (8.5%)	4
General disorders
Infection	4/45 (8.9%)	4	3/30 (10%)	3	8/47 (17%)	8
Acne	1/45 (2.2%)	1	2/30 (6.7%)	2	0/47 (0%)	0
Energy increased	0/45 (0%)	0	2/30 (6.7%)	2	0/47 (0%)	0
Injury	3/45 (6.7%)	3	1/30 (3.3%)	1	1/47 (2.1%)	1
Nervous system disorders
Agitation	8/45 (17.8%)	8	6/30 (20%)	6	5/47 (10.6%)	5
Hypersomnia	1/45 (2.2%)	1	2/30 (6.7%)	2	1/47 (2.1%)	1
Restlessness	3/45 (6.7%)	3	0/30 (0%)	0	0/47 (0%)	0
Sedation	2/45 (4.4%)	2	2/30 (6.7%)	2	2/47 (4.3%)	2
Initial Insomnia	1/45 (2.2%)	1	1/30 (3.3%)	1	3/47 (6.4%)	3
Psychiatric disorders
Aggression or hostility	10/45 (22.2%)	10	6/30 (20%)	6	3/47 (6.4%)	3
Anger or irritability	9/45 (20%)	9	6/30 (20%)	6	5/47 (10.6%)	5
Impulse-control disorder	4/45 (8.9%)	4	4/30 (13.3%)	4	1/47 (2.1%)	1
Negativism	4/45 (8.9%)	4	5/30 (16.7%)	5	6/47 (12.8%)	6
Frustration	4/45 (8.9%)	4	4/30 (13.3%)	4	4/47 (8.5%)	4
Anxiety	3/45 (6.7%)	3	2/30 (6.7%)	2	6/47 (12.8%)	6
Mood swings	2/45 (4.4%)	2	2/30 (6.7%)	2	4/47 (8.5%)	4
Obsessive rumination	0/45 (0%)	0	2/30 (6.7%)	2	0/47 (0%)	0
Depressed Mood	4/45 (8.9%)	4	2/30 (6.7%)	2	1/47 (2.1%)	1
Hallucination	4/45 (8.9%)	4	1/30 (3.3%)	1	2/47 (4.3%)	2
Disturbance in attention	3/45 (6.7%)	3	0/30 (0%)	0	4/47 (8.5%)	4
Suicidal ideation	1/45 (2.2%)	1	2/30 (6.7%)	2	2/47 (4.3%)	2
Psychomotor hyperactivity	2/45 (4.4%)	2	1/30 (3.3%)	1	3/47 (6.4%)	3
Skin and subcutaneous tissue disorders
Rash	1/45 (2.2%)	1	2/30 (6.7%)	2	2/47 (4.3%)	2

Limitations/Caveats

27 subjects were randomized between 10/2009-10/2013 into three groups (CONTROL=47; MET=49; SWITCH=31). Safety analyses excluded 4 participants (CONTROL=1, MET=2, SWITCH=1) who discontinued at baseline.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.