A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder

• Sponsor: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00576732
• Collaborator: (none)
• Enrollment: 96
• Locations: 20
• Arms: 3
• Duration (Months): 27
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effectiveness (change in level of irritability and related behaviors) and safety and tolerability of the administration of 2 different fixed dose levels of risperidone (an atypical antipsychotic drug) compared with placebo in children or adolescents who have autism, and to evaluate the safety and tolerability of the drug for additional 26 weeks after the initial 6-week study period.

Condition or Disease	Intervention/Treatment	Phase
Autistic Disorder; Autism	Drug: Placebo; Drug: Risperidone high dose; Drug: Risperidone low dose	Phase 4

Detailed Description

Autistic Disorder is a condition that develops early in childhood and persists throughout life. Seventy-five percent of children and adolescents with autistic disorder have irritability symptoms such as aggression towards others, deliberate self-injurious behavior, temper tantrums, and quickly changing moods. These symptoms affect their daily functioning such as school performance, interactions with family members and compliance to treatment. Risperidone is an atypical antipsychotic agent that has been recently approved for the treatment of irritability associated with Autistic Disorder in children and adolescents aged 5 to 16 years. The approved dose range is 0.5-3 mg per day. The aim of this study is to evaluate the effectiveness (change in level of irritability and related behaviors) of a lower dose (0.125 mg or 0.175 mg risperidone per day depending on body weight). The study will include three treatment groups. A placebo group, a low dose risperidone group and a higher dose risperidone group (1.25 mg or 1.75mg per day depending on body weight). This phase of the study will be 6 weeks. During the study, neither investigators nor the patients will be told which treatment the patient received. This is called "double blind". The placebo treatment is not expected to be effective. The higher dose group is expected to be effective. At the end of the study, data from the lower dose group will be compared to the placebo group to see if it is effective. Another aim of this study is to evaluate the safety and tolerability of risperidone. At the end of the 6-week double-blind period, patients may enter a 6-month open-label period during which all patients will receive risperidone. During this phase of the study, the doses can be adjusted to a maximum of 1.25 mg or 1.75mg per day depending on body weight. Both investigator and the patient will know what dose the patient is taking. About 93 patients will be randomized. The study will be conducted by investigators from about 15 clinics. Assessments of effectiveness include the Aberrant Behavior Checklist (ABC) subscales including the irritability subscale (ABC-I), the Clinical Global Impression of Change (CGI C); the Clinical Global Impression of Severity (CGI-S); the response rate, and the Compulsions Subscale of the Children's Yale-Brown Obsessive Compulsive Scale (CY BOCS). Safety evaluations include monitoring of adverse events, physical examinations, clinical laboratory tests, nighttime sleep quality and daytime drowsiness, and extrapyramidal symptoms (EPS) as assessed using the Abnormal Involuntary Movement Scale (AIMS), the Barnes Akathisia Rating Scale (BARS) and the Simpson-Angus Scale (SAS). Venous blood samples will be collected for the determination of plasma concentrations of risperidone and 9-hydroxyrisperidone. The study hypotheses are that the higher dose level of risperidone is significantly superior to placebo as measured by change from baseline on the ABC-I Subscale score at end point (Week 6 or early withdrawal) and that the lower dose level of risperidone is significantly superior to placebo as measured by change from baseline on the ABC-I Subscale score at end point (Week 6 or early withdrawal). Double-blind phase: Risperidone oral solutions taken once daily. Depending on body weight patients take 1.25 mL or 1.75 mL of either a 0.1 mg/mL or a 1.0 mg/mL risperidone solution or matching placebo, for 6 weeks. Open-label phase: Medication can be taken once or twice a day. Starting from 0.125mg or 0.175mg per day, drug levels are titrated over 2 weeks to a maximum dose level of 1.25 mg risperidone/day or 1.75 mg /day depending on body weight, for 26 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 96 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Risperidone in the Treatment of Children and Adolescents With Autistic Disorder: A Double-Blind, Placebo-Controlled Study of Efficacy and Safety, Followed by an Open-Label Extension Study of Safety
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Sep 1, 2009
• Actual Study Completion Date: Mar 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 001 Risperidone low dose Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) qd or bid for 6 weeks	Drug: Risperidone low dose; Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) qd or bid for 6 weeks
Experimental: 002 Risperidone high dose Risperidone oral solution 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg) qd or bid for 6 weeks	Drug: Risperidone high dose; Risperidone oral solution 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg) qd or bid for 6 weeks
Placebo Comparator: 003 Placebo Oral solution qd or bid for 6 weeks	Drug: Placebo; Oral solution qd or bid for 6 weeks

Outcome Measures

Primary Outcome Measures

1. Change in Aberrant Behavior Checklist Irritability (ABC-I) Subscale [Baseline and 6 weeks]

   Measure of irritability symptoms of autism. Score range 0 to 45 (lower score = lesser severity).

Secondary Outcome Measures

1. Number of Participants Who Had at Least 25% Improvement in ABC-I [6 weeks]

   ABC-I is a measure of irritability symptoms of autism with score range 0 to 45 (lower score = lesser severity).

2. Change in Clinical Global Impression Severity (CGI-S) [Baseline and 6 weeks]

   Investigator evaluation of severity of illness and functional impairment on a 7-point scale (1="not ill", 2="very mild", 3="mild", 4="moderate", 5="marked", 6="severe", 7="extremely severe").

3. Number of Participants Who Had Clinical Global Impression Change Ratings of Much or Very Much Improved. [6 weeks]

   Investigator impression of change over time from double-blind baseline on a 7-point scale (1="very much improved", 2="much improved", 3="minimally improved", 4="no change", 5="minimally worse", 6="much worse", 7="very much worse").

4. Change in Fasting Glucose (mg/dL) at 6 Weeks [Baseline and 6 weeks]

5. Change in Insulin Resistance (IR) at 6 Weeks [Baseline and 6 weeks]

   Insulin resistance calculated using the homeostatic model assessment 1 (HOMA1)formula: fasting glucose (mmol/L) times fasting insulin (uU/L) divided by 22.5. HOMA-IR is a widely used clinical tool for estimating insulin resistance based upon the balance between glucose output and insulin secretion. Normal values should be close to 1, while an increase indicates a decrease in insulin sensitivity (or increase in insulin resistance), a potential predictor for the development of Type 2 Diabetes Mellitus.

6. Change in Fasting Glucose (mg/dL) at 6 Months [Baseline and 6 months]

7. Change in Insulin Resistance (IR) at 6 Months [Baseline and 6 months]

   Insulin resistance calculated using the homeostatic model assessment 1 (HOMA1) formula: fasting glucose (mmol/L) times fasting insulin (uU/L) divided by 22.5. HOMA-IR is a widely used clinical tool for estimating insulin resistance based upon the balance between glucose output and insulin secretion. Normal values should be close to 1, while an increase indicates a decrease in insulin sensitivity (or increase in insulin resistance), a potential predictor for the development of Type 2 Diabetes Mellitus.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 5 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• DSM-IV diagnosis of Autistic Disorder (299.00)

• ABC-I Subscale score of greater than or equal to 18

• CGI-S of greater than or equal to 4

• mental age >18 months, body weight of at least 20 kg, seizure-free for at least 6 consecutive months and if on anticonvulsants must be on a dosage that has been stable for at least 4 weeks

• Medication free for 1 week before the start of the study for all psychotropic drugs, except 4 weeks for fluoxetine and at least 8 weeks for injectable medications

• Female patients must be premenarchal or sexually abstinent or, if heterosexually active, must practice an effective method of birth control.

Exclusion Criteria:

• History of prior or current DSM-IV psychotic disorder (e.g., schizophrenia, bipolar disorder, other psychosis), Pervasive Developmental Disorder not otherwise specified (PDD NOS), Asperger's, or Rett's

• Any history of hypersensitivity to risperidone, or its excipients in formulation, or other known drug allergy

• Patients who received risperidone within 3 months before screening (except p.r.n. use)

• Patients who did not demonstrate sufficient clinical response to an adequate trial of risperidone treatment in the past (an adequate trial is defined as a period of at least 4 weeks at an adequate dose)

• Neurologic disorder (e.g., Neuroleptic Malignant Syndrome, seizure disorders that are unstable, seizure activity within the past 6 months)

• History of alcohol or substance dependence within 3 months of screening

• Female subject who is pregnant (positive beta-HCG) or breast feeding

• Patients with existing moderate or severe EPS or history of tardive dyskinesia

• Patients who have received an experimental drug or used an experimental medical device within 3 months before the planned start of treatment.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Dothan	Alabama	United States
2		Phoenix	Arizona	United States
3		Sacramento	California	United States
4		Santa Ana	California	United States
5		Boca Raton	Florida	United States
6		Miami	Florida	United States
7		Smyrna	Georgia	United States
8		Hoffman Estates	Illinois	United States
9		Naperville	Illinois	United States
10		Lake Charles	Louisiana	United States
11		Bronx	New York	United States
12		Manhasset	New York	United States
13		New York	New York	United States
14		Staten Island	New York	United States
15		Columbus	Ohio	United States
16		Oklahoma City	Oklahoma	United States
17		Philadelphia	Pennsylvania	United States
18		Houston	Texas	United States
19		Fairfax	Virginia	United States
20		Portsmouth	Virginia	United States

Sponsors and Collaborators

• Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Investigators

• Study Director: Johnson & Johnson Pharmaceutical Research & Development, L.L. C. Clinical Trial, Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder

Publications

None provided.

• Responsible Party: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
• ClinicalTrials.gov Identifier: NCT00576732
• Other Study ID Numbers: CR014740; RISAUT4002
• First Posted: Dec 19, 2007
• Last Update Posted: May 9, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.: Irritability; Risperidone; Antipsychotic agent; Autism; Adolescents; Children
• Additional relevant MeSH terms: Autistic Disorder; Risperidone

Study Results

Participant Flow

Arm/Group Title	Placebo	Risperidone Low Dose	Risperidone High Dose	Placebo/RIS	Ris Low Dose/RIS	Ris High Dose/RIS
Arm/Group Description	Double-blind Period. Oral solution for 6 weeks.	Double-blind Period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 6 weeks.	Double-blind Period. Risperidone oral solution 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg) for 6 weeks.	Open-label Period. Subjects in the double-blind placebo group who continued into open-label risperidone period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 3 days, 0.25 mg tablet on Day 4, flexible dose in 0.25 mg or 0.5 mg increments every 2 weeks, as clinically indicated, to a maximum dose of 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg).	Open-label Period. Subjects in the double-blind risperidone low dose group who continued into open-label risperidone period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 3 days, 0.25 mg tablet on Day 4, flexible dose in 0.25 mg or 0.5 mg increments every 2 weeks, as clinically indicated, to a maximum dose of 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg).	Open-label Period. Subjects in the double-blind risperidone high dose group who continued into open-label risperidone period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 3 days, 0.25 mg tablet on Day 4, flexible dose in 0.25 mg or 0.5 mg increments every 2 weeks, as clinically indicated, to a maximum dose of 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg).
Period Title: DOUBLE BLIND
STARTED	35	30	31	0	0	0
COMPLETED	27	25	25	0	0	0
NOT COMPLETED	8	5	6	0	0	0
Period Title: DOUBLE BLIND
STARTED	0	0	0	30	24	25
COMPLETED	0	0	0	19	20	17
NOT COMPLETED	0	0	0	11	4	8

Baseline Characteristics

Arm/Group Title	Placebo	Risperidone Low Dose	Risperidone High Dose	Total
Arm/Group Description	Double-blind Period. Oral solution for 6 weeks.	Double-blind Period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 6 weeks.	Double-blind Period. Risperidone oral solution 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg) for 6 weeks.	Total of all reporting groups
Overall Participants	35	30	31	96
Age (Count of Participants)
<=18 years	35 100%	30 100%	31 100%	96 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.6 (2.57)	10.2 (3.42)	9.3 (3.11)	9.3 (3.07)
Sex: Female, Male (Count of Participants)
Female	4 11.4%	5 16.7%	3 9.7%	12 12.5%
Male	31 88.6%	25 83.3%	28 90.3%	84 87.5%
Region of Enrollment (participants) [Number]
United States of America	35 100%	30 100%	31 100%	96 100%
Age (participants) [Number]
<12 years	30 85.7%	20 66.7%	24 77.4%	74 77.1%
>=12 years	5 14.3%	10 33.3%	7 22.6%	22 22.9%

Outcome Measures

1. Primary Outcome

Title	Change in Aberrant Behavior Checklist Irritability (ABC-I) Subscale
Description	Measure of irritability symptoms of autism. Score range 0 to 45 (lower score = lesser severity).
Time Frame	Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

All randomized subjects with at least one dose of study medication and both baseline and at least one postbaseline value. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward [LOCF]).

Arm/Group Title	Placebo	Risperidone Low Dose	Risperidone High Dose
Arm/Group Description	Double-blind Period. Oral solution for 6 weeks.	Double-blind Period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 6 weeks.	Double-blind Period. Risperidone oral solution 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg) for 6 weeks.
Measure Participants	34	29	29
Mean (Standard Deviation) [units on a scale]	-3.5 (10.67)	-7.4 (8.12)	-12.4 (6.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Risperidone High Dose
	Comments	A step-down testing procedure was employed with the risperidone high dose versus placebo comparison tested first. If this comparison was significant the risperidone low dose versus placebo comparison would be performed. A clinically relevant difference in the change from baseline on the ABC Irritability subscale was assumed to be 6 with a standard deviation of 8. To achieve 80% power with Type I error rate of 5%, 93 subjects were required.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Type I error is preserved by the step down procedure, no multiple comparison adjustment is needed. A priori threshold for statistical significance was 0.05.
	Method	ANCOVA
	Comments	ANCOVA model included factors for treatment group, center (after pooling of small centers), baseline weight stratification, and baseline ABC-I value
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.9
	Confidence Interval	(2-Sided) 95%; -12.19 to -3.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.18
	Estimation Comments	Mean difference is change in Risperidone high dose arm minus change in placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Risperidone Low Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.164
	Comments	Type I error is preserved by the step down procedure, no multiple comparison adjustment is needed. A priori threshold for statistical significance was 0.05.
	Method	ANCOVA
	Comments	ANCOVA model included factors for treatment group, center (after pooling of small centers), baseline weight stratification, and baseline ABC-I value
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.0
	Confidence Interval	(2-Sided) 95%; -7.36 to 1.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.17
	Estimation Comments	Mean difference is change in Risperidone low dose arm minus change in placebo arm.

2. Secondary Outcome

Title	Number of Participants Who Had at Least 25% Improvement in ABC-I
Description	ABC-I is a measure of irritability symptoms of autism with score range 0 to 45 (lower score = lesser severity).
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

All randomized subjects with at least one dose of study medication and both baseline and at least one postbaseline value. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward [LOCF]).

Arm/Group Title	Placebo	Risperidone Low Dose	Risperidone High Dose
Arm/Group Description	Double-blind Period. Oral solution for 6 weeks.	Double-blind Period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 6 weeks.	Double-blind Period. Risperidone oral solution 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg) for 6 weeks.
Measure Participants	34	29	29
Number [participants]	14 40%	15 50%	24 77.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Risperidone High Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	P-value is not adjusted for multiple comparisons.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test controlling for center (after pooling small centers) and baseline weight stratification.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Risperidone Low Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.817
	Comments	P-value is not adjusted for multiple comparisons.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test controlling for center (after pooling small centers) and baseline weight stratification.

3. Secondary Outcome

Title	Change in Clinical Global Impression Severity (CGI-S)
Description	Investigator evaluation of severity of illness and functional impairment on a 7-point scale (1="not ill", 2="very mild", 3="mild", 4="moderate", 5="marked", 6="severe", 7="extremely severe").
Time Frame	Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

All randomized subjects with at least one dose of study medication and both baseline and at least one postbaseline value. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward [LOCF]).

Arm/Group Title	Placebo	Risperidone Low Dose	Risperidone High Dose
Arm/Group Description	Double-blind Period. Oral solution for 6 weeks.	Double-blind Period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 6 weeks.	Double-blind Period. Risperidone oral solution 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg) for 6 weeks.
Measure Participants	34	29	29
Mean (Standard Deviation) [units on a scale]	-0.3 (0.79)	-0.4 (0.73)	-1.0 (0.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Risperidone High Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value is not adjusted for multiple comparisons.
	Method	ANCOVA
	Comments	ANCOVA model included factors for treatment group, center (after pooling of small centers), baseline weight stratification, and baseline CGI-S value.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 95%; -1.02 to -0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.17
	Estimation Comments	Mean difference is change in Risperidone high dose arm minus change in placebo arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Risperidone Low Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.769
	Comments	P-value is not adjusted for multiple comparisons.
	Method	ANCOVA
	Comments	ANCOVA model included factors for treatment group, center (after pooling of small centers), baseline weight stratification, and baseline CGI-S value
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.1
	Confidence Interval	(2-Sided) 95%; -0.39 to 0.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.17
	Estimation Comments	Mean difference is change in Risperidone low dose arm minus change in placebo arm.

4. Secondary Outcome

Title	Number of Participants Who Had Clinical Global Impression Change Ratings of Much or Very Much Improved.
Description	Investigator impression of change over time from double-blind baseline on a 7-point scale (1="very much improved", 2="much improved", 3="minimally improved", 4="no change", 5="minimally worse", 6="much worse", 7="very much worse").
Time Frame	6 weeks

Outcome Measure Data

Analysis Population Description

All randomized subjects with at least one dose of study medication and at least one postbaseline value. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward [LOCF]).

Arm/Group Title	Placebo	Risperidone Low Dose	Risperidone High Dose
Arm/Group Description	Double-blind Period. Oral solution for 6 weeks.	Double-blind Period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 6 weeks.	Double-blind Period. Risperidone oral solution 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg) for 6 weeks.
Measure Participants	34	30	30
Number [participants]	5 14.3%	5 16.7%	19 61.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Risperidone High Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value is not adjusted for multiple comparisons.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test controlling for center (after pooling small centers) and baseline weight stratification.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, Risperidone Low Dose
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.985
	Comments	P-value is not adjusted for multiple comparisons.
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test controlling for center (after pooling small centers) and baseline weight stratification.

5. Secondary Outcome

Title	Change in Fasting Glucose (mg/dL) at 6 Weeks
Time Frame	Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

All randomized subjects with at least one dose of study medication and both baseline and at least one postbaseline fasting laboratory samples. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period (Last Observation Carried Forward [LOCF]).

Arm/Group Title	Placebo	Risperidone Low Dose	Risperidone High Dose
Arm/Group Description	Double-blind Period. Oral solution for 6 weeks.	Double-blind Period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 6 weeks.	Double-blind Period. Risperidone oral solution 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg) for 6 weeks.
Measure Participants	22	23	23
Mean (Standard Deviation) [mg/dL]	-0.4 (8.20)	-0.1 (8.81)	-0.3 (9.74)

6. Secondary Outcome

Title	Change in Insulin Resistance (IR) at 6 Weeks
Description	Insulin resistance calculated using the homeostatic model assessment 1 (HOMA1)formula: fasting glucose (mmol/L) times fasting insulin (uU/L) divided by 22.5. HOMA-IR is a widely used clinical tool for estimating insulin resistance based upon the balance between glucose output and insulin secretion. Normal values should be close to 1, while an increase indicates a decrease in insulin sensitivity (or increase in insulin resistance), a potential predictor for the development of Type 2 Diabetes Mellitus.
Time Frame	Baseline and 6 weeks

Outcome Measure Data

Analysis Population Description

All randomized subjects with >=1 dose of study medication and fasting glucose and insulin at baseline and at >=1 postbaseline time point. For subjects who discontinued, Week 6 data is imputed using the subject's last nonmissing, postbaseline value in the double-blind period. Means are adjusted for baseline weight (<45 kg, >=45 kg) and baseline IR.

Arm/Group Title	Placebo	Risperidone Low Dose	Risperidone High Dose
Arm/Group Description	Double-blind Period. Oral solution for 6 weeks.	Double-blind Period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 6 weeks.	Double-blind Period. Risperidone oral solution 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg) for 6 weeks.
Measure Participants	22	21	22
Least Squares Mean (95% Confidence Interval) [units on a scale]	0.36	-0.10	0.45

7. Secondary Outcome

Title	Change in Fasting Glucose (mg/dL) at 6 Months
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

All subjects with at least one dose of study medication in the open label phase and both double-blind baseline and at least one open-label period fasting laboratory samples. For subjects who discontinued, Month 6 data is imputed using the subject's last nonmissing, postbaseline value in the open-label period.

Arm/Group Title	Placebo/RIS	Ris Low Dose/RIS	Ris High Dose/RIS
Arm/Group Description	Open-label Period. Subjects in the double-blind placebo group who continued into open-label risperidone period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 3 days, 0.25 mg tablet on Day 4, flexible dose in 0.25 mg or 0.5 mg increments every 2 weeks, as clinically indicated, to a maximum dose of 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg).	Open-label Period. Subjects in the double-blind risperidone low dose group who continued into open-label risperidone period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 3 days, 0.25 mg tablet on Day 4, flexible dose in 0.25 mg or 0.5 mg increments every 2 weeks, as clinically indicated, to a maximum dose of 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg).	Open-label Period. Subjects in the double-blind risperidone high dose group who continued into open-label risperidone period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 3 days, 0.25 mg tablet on Day 4, flexible dose in 0.25 mg or 0.5 mg increments every 2 weeks, as clinically indicated, to a maximum dose of 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg).
Measure Participants	19	16	16
Mean (Standard Deviation) [mg/dL]	4.0 (12.27)	3.5 (12.26)	2.3 (8.70)

8. Secondary Outcome

Title	Change in Insulin Resistance (IR) at 6 Months
Description	Insulin resistance calculated using the homeostatic model assessment 1 (HOMA1) formula: fasting glucose (mmol/L) times fasting insulin (uU/L) divided by 22.5. HOMA-IR is a widely used clinical tool for estimating insulin resistance based upon the balance between glucose output and insulin secretion. Normal values should be close to 1, while an increase indicates a decrease in insulin sensitivity (or increase in insulin resistance), a potential predictor for the development of Type 2 Diabetes Mellitus.
Time Frame	Baseline and 6 months

Outcome Measure Data

Analysis Population Description

All subjects with at least one dose of study medication in the open label phase and both double-blind baseline and at least one open-label period fasting laboratory samples. For subjects who discontinued, Month 6 data is imputed using the subject's last nonmissing, postbaseline value in the open-label period.

Arm/Group Title	Placebo/RIS	Ris Low Dose/RIS	Ris High Dose/RIS
Arm/Group Description	Open-label Period. Subjects in the double-blind placebo group who continued into open-label risperidone period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 3 days, 0.25 mg tablet on Day 4, flexible dose in 0.25 mg or 0.5 mg increments every 2 weeks, as clinically indicated, to a maximum dose of 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg).	Open-label Period. Subjects in the double-blind risperidone low dose group who continued into open-label risperidone period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 3 days, 0.25 mg tablet on Day 4, flexible dose in 0.25 mg or 0.5 mg increments every 2 weeks, as clinically indicated, to a maximum dose of 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg).	Open-label Period. Subjects in the double-blind risperidone high dose group who continued into open-label risperidone period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 3 days, 0.25 mg tablet on Day 4, flexible dose in 0.25 mg or 0.5 mg increments every 2 weeks, as clinically indicated, to a maximum dose of 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg).
Measure Participants	19	16	16
Mean (Standard Deviation) [units on a scale]	0.09 (2.67)	0.36 (0.89)	0.75 (0.91)

Adverse Events

Time Frame	Double-blind period: 6 weeks. Open-label period: 6 months.
Arm/Group Title	Placebo		Risperidone Low Dose		Risperidone High Dose		Open-label Risperidone
Arm/Group Description	Double-blind Period. Oral solution for 6 weeks.		Double-blind Period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 6 weeks.		Double-blind Period. Risperidone oral solution 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg) for 6 weeks.		Subjects who continued into open-label risperidone period. Risperidone oral solution 0.125 mg (if <45 kg) or 0.175 mg (if >=45 kg) for 3 days, 0.25 mg tablet on Day 4, flexible dose in 0.25 mg or 0.5 mg increments every 2 weeks, as clinically indicated, to a maximum dose of 1.25 mg (if <45 kg) or 1.75 mg (if >=45 kg).
All Cause Mortality
	Placebo		Risperidone Low Dose		Risperidone High Dose		Open-label Risperidone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Risperidone Low Dose		Risperidone High Dose		Open-label Risperidone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/35 (2.9%)		0/30 (0%)		0/31 (0%)		1/79 (1.3%)
Congenital, familial and genetic disorders
Hydrocele	0/35 (0%)		0/30 (0%)		0/31 (0%)		1/79 (1.3%)
Psychiatric disorders
Aggression	1/35 (2.9%)		0/30 (0%)		0/31 (0%)		0/79 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Risperidone Low Dose		Risperidone High Dose		Open-label Risperidone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/35 (57.1%)		12/30 (40%)		27/31 (87.1%)		39/79 (49.4%)
Gastrointestinal disorders
Abdominal discomfort	3/35 (8.6%)		0/30 (0%)		0/31 (0%)		2/79 (2.5%)
Abdominal pain upper	0/35 (0%)		1/30 (3.3%)		2/31 (6.5%)		1/79 (1.3%)
Constipation	1/35 (2.9%)		0/30 (0%)		2/31 (6.5%)		3/79 (3.8%)
Nausea	1/35 (2.9%)		1/30 (3.3%)		2/31 (6.5%)		0/79 (0%)
Vomiting	2/35 (5.7%)		2/30 (6.7%)		2/31 (6.5%)		7/79 (8.9%)
Diarrhea	1/35 (2.9%)		1/30 (3.3%)		0/31 (0%)		4/79 (5.1%)
General disorders
Pyrexia	0/35 (0%)		0/30 (0%)		2/31 (6.5%)		6/79 (7.6%)
Thirst	0/35 (0%)		0/30 (0%)		2/31 (6.5%)		0/79 (0%)
Fatigue	0/35 (0%)		0/30 (0%)		1/31 (3.2%)		4/79 (5.1%)
Infections and infestations
Ear infection	0/35 (0%)		0/30 (0%)		2/31 (6.5%)		1/79 (1.3%)
Nasopharyngitis	2/35 (5.7%)		2/30 (6.7%)		4/31 (12.9%)		5/79 (6.3%)
Upper respiratory tract infection	1/35 (2.9%)		1/30 (3.3%)		3/31 (9.7%)		6/79 (7.6%)
Investigations
Weight increased	2/35 (5.7%)		3/30 (10%)		4/31 (12.9%)		7/79 (8.9%)
Metabolism and nutrition disorders
Increased appetite	2/35 (5.7%)		5/30 (16.7%)		11/31 (35.5%)		9/79 (11.4%)
Nervous system disorders
Akathisia	1/35 (2.9%)		0/30 (0%)		2/31 (6.5%)		0/79 (0%)
Headache	4/35 (11.4%)		2/30 (6.7%)		2/31 (6.5%)		4/79 (5.1%)
Hypersomnia	1/35 (2.9%)		0/30 (0%)		2/31 (6.5%)		0/79 (0%)
Psychomotor hyperactivity	2/35 (5.7%)		1/30 (3.3%)		1/31 (3.2%)		1/79 (1.3%)
Sedation	0/35 (0%)		1/30 (3.3%)		8/31 (25.8%)		6/79 (7.6%)
Somnolence	1/35 (2.9%)		0/30 (0%)		7/31 (22.6%)		4/79 (5.1%)
Psychiatric disorders
Aggression	2/35 (5.7%)		0/30 (0%)		0/31 (0%)		2/79 (2.5%)
Agitation	2/35 (5.7%)		0/30 (0%)		1/31 (3.2%)		3/79 (3.8%)
Depression	0/35 (0%)		0/30 (0%)		2/31 (6.5%)		0/79 (0%)
Insomnia	2/35 (5.7%)		0/30 (0%)		0/31 (0%)		3/79 (3.8%)
Renal and urinary disorders
Enuresis	0/35 (0%)		2/30 (6.7%)		2/31 (6.5%)		4/79 (5.1%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	0/35 (0%)		0/30 (0%)		2/31 (6.5%)		0/79 (0%)
Cough	0/35 (0%)		0/30 (0%)		0/31 (0%)		4/79 (5.1%)
Skin and subcutaneous tissue disorders
Rash	0/35 (0%)		2/30 (6.7%)		0/31 (0%)		3/79 (3.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The sponsor can embargo results from a PI's center until the combined results from the completed study have been published in full or the sponsor confirms there will be no multicenter study publication. Results communications must be provided to the sponsor for review at least 60 days before submission for publication. By written request, the sponsor can extend the embargo up to an additional 60 days. The sponsor cannot require changes to scientific content and cannot further extend the embargo.