Evaluating the Effectiveness of Aripiprazole and D-Cycloserine to Treat Symptoms Associated With Autism

• ClinicalTrials.gov Identifier: NCT00198107
• Recruitment Status: Completed
• First Posted: September 20, 2005
• Results First Posted: March 29, 2019
• Last Update Posted: April 9, 2019
• Sponsor: Indiana University
• Collaborator: National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): Indiana University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Autistic Disorder
• Interventions: Drug: Aripiprazole; Drug: Placebo; Drug: D-cycloserine
• Enrollment: 81

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
Arm/Group Description	Participants will take placebo Placebo: Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.	Participants will take aripiprazole Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.	Participants first will take aripiprazole then will also take D-cycloserine Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg. D-cycloserine: D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.
Period Title: Double-Blind Period
Started	41	40	0
1 or More Follow-up Visits	40	38	0
Completed	35	37	0
Not Completed	6	3	0
Reason Not Completed
Adverse Event	1	1	0
Lack of Efficacy	2	0	0
Lost to Follow-up	2	1	0
Physician Decision	1	0	0
Withdrawal by Subject	0	1	0
Period Title: Pilot Add-On Aripiprazole +D-cycloserine
Started	0	0	10
Completed	0	0	8
Not Completed	0	0	2
Reason Not Completed
Withdrawal by Subject	0	0	2

Baseline Characteristics

Arm/Group Title		1 Placebo	2 Aripiprazole	Total
Arm/Group Description		Participants will take placebo Placebo: Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.	Participants will take aripiprazole Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.	Total of all reporting groups
Overall Number of Baseline Participants		41	40	81
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	41 participants	40 participants	81 participants
	<=18 years	41 100.0%	40 100.0%	81 100.0%
	Between 18 and 65 years	0 0.0%	0 0.0%	0 0.0%
	>=65 years	0 0.0%	0 0.0%	0 0.0%
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	41 participants	40 participants	81 participants
		9.4 (3.5)	9.0 (2.9)	9.2 (3.2)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	41 participants	40 participants	81 participants
	Female	7 17.1%	4 10.0%	11 13.6%
	Male	34 82.9%	36 90.0%	70 86.4%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	41 participants	40 participants	81 participants
		41 100.0%	40 100.0%	81 100.0%

Outcome Measures

1. Primary Outcome

Title	Mean Post-baseline Aberrant Behavior Checklist Irritability Score, Parent Report, Double-blind Phase
Description	The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscales is that higher scores, indicate greater severity. Fifteen item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total irritability scale store ranging from 0 to 45. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints. Confidence intervals reflect a Bonferroni multiple testing correction accounting
Time Frame	Weeks 1, 2, 3, 4, 6, and 8

Outcome Measure Data

Analysis Population Description

All randomized study participants with at least one post-baseline ABC score. One participant assigned to placebo and 2 participants assigned to aripiprazole had no post-baseline assessments.

Arm/Group Title	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
Arm/Group Description:	Participants will take placebo Placebo: Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.	Participants will take aripiprazole Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.	Participants first will take aripiprazole then will also take D-cycloserine Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg. D-cycloserine: D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.
Overall Number of Participants Analyzed	40	38	0
Mean (95% Confidence Interval); Unit of Measure: units on a scale
	25.5; (22.8 to 28.3)	18.6; (15.8 to 21.4)

2. Primary Outcome

Title	Odds of Improvement as Measured by the Clinical Global Impression-Global Improvement Scale (Improvement Defined as CGI-I=1 or CGI-I=2)
Description	Clinical Global Impressions (Guy, 1976) global improvement (CGI-I) is designed to take into account all factors to arrive at an assessment of response to treatment. The CGI-I scale ranges from 1 to 7, with lower scores indicating greater improvement (1=very much improved and 2=much improved). Participants with a CGI-I score of 1 or 2 were classified as improved. Odds were estimated using a repeated measures logistic regression model with treatment group, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average log odds across study timepoints. Confidence intervals reflect a Bonferroni multiple testing correction accounting for the selection of two primary outcomes.
Time Frame	Weeks 1, 2, 3, 4, 6 and 8

Outcome Measure Data

Analysis Population Description

All randomized study participants with at least one post-baseline CGI-I rating. One participant assigned to placebo and 2 participants assigned to aripiprazole had no post-baseline ratings.

Arm/Group Title	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
Arm/Group Description:	Participants will take placebo Placebo: Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.	Participants will take aripiprazole Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.	Participants first will take aripiprazole then will also take D-cycloserine Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg. D-cycloserine: D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.
Overall Number of Participants Analyzed	40	38	0
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: odds
	0.10; (0.05 to 0.23)	0.50; (0.31 to 0.79)

3. Secondary Outcome

Title	Mean Post-baseline Aberrant Behavior Checklist Hyperactivity Score, Parent Report, Double-blind Phase
Description	The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item Parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. The 16-item Hyperactivity subscale covers overactivity, impulsiveness, inattention and noncompliance. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscale is that higher scores, indicate greater severity. Sixteen item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total score ranging from 0 to 48. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints.
Time Frame	Weeks 1, 2, 3, 4, 6 and 8

Outcome Measure Data

Analysis Population Description

All randomized study participants with at least one post-baseline ABC score. One participant assigned to placebo and 2 participants assigned to aripiprazole had no post-baseline assessments.

Arm/Group Title	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
Arm/Group Description:	Participants will take placebo Placebo: Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.	Participants will take aripiprazole Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.	Participants first will take aripiprazole then will also take D-cycloserine Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg. D-cycloserine: D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.
Overall Number of Participants Analyzed	40	38	0
Mean (95% Confidence Interval); Unit of Measure: units on a scale
	29.7; (26.8 to 32.5)	22.5; (19.6 to 25.4)

4. Secondary Outcome

Title	Mean Post-baseline Aberrant Behavior Checklist Inappropriate Speech Score, Parent Report, Double-blind Phase
Description	The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item Parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscales is that higher scores, indicate greater severity. Four item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total inappropriate speech scale score ranging from 0 to 12. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints.
Time Frame	Weeks 1, 2, 3, 4, 6, and 8

Outcome Measure Data

Analysis Population Description

All randomized study participants with at least one post-baseline ABC score. One participant assigned to placebo and 2 participants assigned to aripiprazole had no post-baseline assessments.

Arm/Group Title	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
Arm/Group Description:	Participants will take placebo Placebo: Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.	Participants will take aripiprazole Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.	Participants first will take aripiprazole then will also take D-cycloserine Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg. D-cycloserine: D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.
Overall Number of Participants Analyzed	40	38	0
Mean (95% Confidence Interval); Unit of Measure: units on a scale
	7.4; (6.7 to 8.1)	5.0; (4.2 to 5.7)

5. Secondary Outcome

Title	Mean Post-baseline Aberrant Behavior Checklist Social Withdrawal Score, Parent Report, Double-blind Phase
Description	The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item Parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscales is that higher scores, indicates greater severity. Sixteen item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total social withdrawal scale score ranging from 0 to 48. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints.
Time Frame	Weeks 1, 2, 3, 4, 6, and 8

Outcome Measure Data

Analysis Population Description

All randomized study participants with at least one post-baseline ABC score. One participant assigned to placebo and 2 participants assigned to aripiprazole had no post-baseline assessments.

Arm/Group Title	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
Arm/Group Description:	Participants will take placebo Placebo: Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.	Participants will take aripiprazole Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.	Participants first will take aripiprazole then will also take D-cycloserine Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg. D-cycloserine: D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.
Overall Number of Participants Analyzed	40	38	0
Mean (95% Confidence Interval); Unit of Measure: units on a scale
	15.4; (13.4 to 17.5)	11.7; (9.6 to 13.7)

6. Secondary Outcome

Title	Mean Post-baseline Aberrant Behavior Checklist Stereotypy Score, Parent Report, Double-blind Phase
Description	The Aberrant Behavior Checklist (ABC) is a symptom checklist for assessing problem behaviors in individuals ages 6 to 54 with mental retardation. The full ABC is a 58-item Parent rating with five factors: Irritability, Social Withdrawal, Stereotypy, Hyperactivity and Inappropriate Speech. It has been used as a primary outcome measure in several trials of children with developmental disabilities. The interpretation of the tool and its subscales is that higher scores, indicates greater severity. Seven item scores with values ranging from 0 (not a problem) to 3 (problem is severe) are summed to arrive at the total stereotypy scale score ranging from 0 to 21. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints.
Time Frame	Weeks 1, 2, 3, 4, 6, and 8

Outcome Measure Data

Analysis Population Description

All randomized study participants with at least one post-baseline ABC score. One participant assigned to placebo and 2 participants assigned to aripiprazole had no post-baseline assessments.

Arm/Group Title	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
Arm/Group Description:	Participants will take placebo Placebo: Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.	Participants will take aripiprazole Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.	Participants first will take aripiprazole then will also take D-cycloserine Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg. D-cycloserine: D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.
Overall Number of Participants Analyzed	40	38	0
Mean (95% Confidence Interval); Unit of Measure: units on a scale
	10.0; (8.9 to 11.1)	7.2; (6.0 to 8.3)

7. Secondary Outcome

Title	Mean Post-baseline Score on a Modified Version of the Compulsion Subscale of the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS)
Description	The CYBOCS- PDD is a semi-structured clinician-rated scale designed to rate the current severity of repetitive behavior in children with idiopathic autism spectrum disorders. Once the current repetitive behaviors are identified, they are rated on: Time Spent, Interference, Distress, Resistance, and Control. Each of these items is scored from 0 (least symptomatic) to 4 (most symptomatic), yielding a Total score from 0 to 20. Higher scores indicate higher severity. Means were estimated using a repeated measures linear regression model with treatment group, baseline score, study week (in categories), and sex x Tanner stage stratum as covariates. A linear contrast estimated the average across study timepoints.
Time Frame	Weeks 2, 4, 6 and 8

Outcome Measure Data

Analysis Population Description

All randomized study participants with at least one post-baseline CY-BOCS score. Two participants assigned to placebo and 2 participants assigned to aripiprazole had no post-baseline assessments.

Arm/Group Title	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
Arm/Group Description:	Participants will take placebo Placebo: Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.	Participants will take aripiprazole Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.	Participants first will take aripiprazole then will also take D-cycloserine Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg. D-cycloserine: D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.
Overall Number of Participants Analyzed	39	38	0
Mean (95% Confidence Interval); Unit of Measure: units on a scale
	14.4; (13.4 to 15.5)	12.5; (11.5 to 13.5)

8. Secondary Outcome

Title	Mean Vineland Maladaptive Behavior Subscales Total Score, Week 8
Description	The Vineland Adaptive Behavior Scales, (Survey Interview Form) is a measure of adaptive behavior in children, adolescents and adults. It yields an overall standard score (Adaptive Behavior Composite, ABC) and age standard scores in four domains. ABC scores have a mean of 100 and a standard deviation of 15 (range = 20 to 160). Higher scores suggest a higher level of adaptive functioning. An increase in standard scores from Baseline to the Final Visit indicates improvement. Means were estimated using a repeated measures linear regression model with treatment group, study week (in categories, baseline or 8 weeks), and sex x Tanner stage stratum as covariates.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

All randomized study participants. For 7 participants who exited the double-blind phase prior to week 8 but completed an exit interview (all assigned to placebo), week 8 scores were imputed using a last observation carried forward approach.

Arm/Group Title	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
Arm/Group Description:	Participants will take placebo Placebo: Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.	Participants will take aripiprazole Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.	Participants first will take aripiprazole then will also take D-cycloserine Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg. D-cycloserine: D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.
Overall Number of Participants Analyzed	41	40	0
Mean (95% Confidence Interval); Unit of Measure: units on a scale
	33.1; (29.6 to 36.6)	23.1; (19.6 to 26.5)

9. Secondary Outcome

Title	Mean Autism Diagnostic Observation Schedule (ADOS) Social Affect and Restricted and Repetitive Behaviors Total Score, Week 8
Description	Autism Diagnostic Observation Scale (ADOS) (Lord), Modules 1-3 yields scores in 2 scales: Social Affect and Restricted and Repetitive Behavior. The ADOS has been repeatedly evaluated as a diagnostic measure, it has also been used as an outcome measure of autism severity (Aldred et al., 2004; Gutstein, 2007; Owly et al, 2001, Green et al, 2010). For modules 1-3, scores ranging from 0-2 on 14 items are summed to arrive at the Social Affect and Restricted and Repetitive Behavior Total Score, which ranges from 0 to 28. Higher scores indicate greater autism severity. Means were estimated using a repeated measures linear regression model with treatment group, study week (in categories, baseline or 8 weeks), and sex x Tanner stage stratum as covariates
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

All randomized study participants. For 9 participants who exited the double-blind phase prior to week 8 but completed an exit interview (8 assigned to placebo and 1 to aripiprazole), week 8 scores were imputed using a last observation carried forward approach.

Arm/Group Title	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
Arm/Group Description:	Participants will take placebo Placebo: Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.	Participants will take aripiprazole Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.	Participants first will take aripiprazole then will also take D-cycloserine Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg. D-cycloserine: D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.
Overall Number of Participants Analyzed	41	40	0
Mean (95% Confidence Interval); Unit of Measure: units on a scale
	19.0; (17.6 to 20.4)	18.3; (17.0 to 19.7)

10. Secondary Outcome

Title	Mean Social Reciprocity Scale (SRS) Total Score, Week 8
Description	The 65-item SRS is a standardized measure of the core symptoms of autism. Each item is scored on a 4-point Likert scale. The score of each individual item is summed to create a total raw score. A total score results are as follows: 0-62: Within normal limits 63-79: Mild range of impairment 80-108: Moderate range of impairment 109-149: Severe range of impairment. Means were estimated using a repeated measures linear regression model with treatment group, study week (in categories, baseline or 8 weeks), and sex x Tanner stage stratum as covariates.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

All randomized study participants. For 9 participants who exited the double-blind phase prior to week 8 but completed an exit interview (8 assigned to placebo and 1 to aripiprazole), week 8 scores were imputed using a last observation carried forward approach.

Arm/Group Title	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
Arm/Group Description:	Participants will take placebo Placebo: Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.	Participants will take aripiprazole Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.	Participants first will take aripiprazole then will also take D-cycloserine Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg. D-cycloserine: D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.
Overall Number of Participants Analyzed	41	40	0
Mean (95% Confidence Interval); Unit of Measure: units on a scale
	127.6; (119.8 to 135.3)	112.6; (104.8 to 120.3)

Adverse Events

Time Frame	Eight weeks or at the time of latest data collection.
Adverse Event Reporting Description	Adverse event information was collected via a structured side effect rating scale completed with the participant and their primary caregiver. This included a list of side-effects that have been reported with aripiprazole at a rate greater than 1%. The physician also asked about any visits to the doctor, new medication use, or any other complaints. Events that were not present at baseline and occurred or worsened after the date of randomization are reported.
Arm/Group Title	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
Arm/Group Description	Participants will take placebo Placebo: Participants assigned to placebo will take a placebo pill for the initial 8 weeks of treatment.	Participants will take aripiprazole Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg.	Participants first will take aripiprazole then will also take D-cycloserine Aripiprazole: Participants will receive 8 weeks of initial treatment with aripiprazole. If responsive to treatment, participants may be assigned to an additional 16 weeks of aripiprazole and then an additional 8 more weeks of aripiprazole with D-cycloserine. Dosing schedule for participants less than 50 mg maximum dose will be 10 mg per day. Dosing schedule for participants greater than 50 kg maximum dose will be 15 mg. D-cycloserine: D-cycloserine will be dosed in the range of 25 to 200 mg daily for the final 8 weeks of treatment.
All-Cause Mortality
	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/40 (0.00%)	0/40 (0.00%)	0/10 (0.00%)
Serious Adverse Events
	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/40 (0.00%)	0/40 (0.00%)	0/10 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	4%
	1 Placebo	2 Aripiprazole	3 Aripiprazole + D-cycloserine
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	35/40 (87.50%)	40/40 (100.00%)	10/10 (100.00%)
Gastrointestinal disorders
Change in Stool †	2/40 (5.00%)	2/40 (5.00%)	0/10 (0.00%)
Constipation †	4/40 (10.00%)	8/40 (20.00%)	0/10 (0.00%)
Diarrhea †	3/40 (7.50%)	7/40 (17.50%)	5/10 (50.00%)
Nausea †	0/40 (0.00%)	2/40 (5.00%)	0/10 (0.00%)
Stomach or abdominal discomfort †	4/40 (10.00%)	7/40 (17.50%)	2/10 (20.00%)
Vomiting †	8/40 (20.00%)	15/40 (37.50%)	3/10 (30.00%)
General disorders
Dry mouth †	2/40 (5.00%)	2/40 (5.00%)	0/10 (0.00%)
Hypersalivation †	3/40 (7.50%)	3/40 (7.50%)	1/10 (10.00%)
Appetite decrease †	6/40 (15.00%)	12/40 (30.00%)	1/10 (10.00%)
Appetite increase †	11/40 (27.50%)	16/40 (40.00%)	3/10 (30.00%)
Sedation/Drowsiness †	3/40 (7.50%)	5/40 (12.50%)	0/10 (0.00%)
Tiredness/fatigue †	10/40 (25.00%)	21/40 (52.50%)	2/10 (20.00%)
Fever †	2/40 (5.00%)	3/40 (7.50%)	0/10 (0.00%)
Infections and infestations
Flu or upper respiratory problems †	3/40 (7.50%)	3/40 (7.50%)	1/10 (10.00%)
Nasal congestion or Cold †	16/40 (40.00%)	16/40 (40.00%)	1/10 (10.00%)
Metabolism and nutrition disorders
Weight gain †	5/40 (12.50%)	8/40 (20.00%)	0/10 (0.00%)
Weight loss †	5/40 (12.50%)	4/40 (10.00%)	1/10 (10.00%)
Nervous system disorders
Headache †	8/40 (20.00%)	3/40 (7.50%)	1/10 (10.00%)
Muscle rigidity †	0/40 (0.00%)	3/40 (7.50%)	0/10 (0.00%)
Tremor †	0/40 (0.00%)	3/40 (7.50%)	0/10 (0.00%)
Psychiatric disorders
Anxiety/Nervousness/Worry †	0/40 (0.00%)	3/40 (7.50%)	1/10 (10.00%)
Change in speech †	7/40 (17.50%)	3/40 (7.50%)	2/10 (20.00%)
Difficulty falling asleep †	6/40 (15.00%)	3/40 (7.50%)	0/10 (0.00%)
Increased motor activity †	5/40 (12.50%)	3/40 (7.50%)	2/10 (20.00%)
Increased repetitive speech †	2/40 (5.00%)	3/40 (7.50%)	1/10 (10.00%)
Interrupted sleep/other sleep problems †	8/40 (20.00%)	4/40 (10.00%)	1/10 (10.00%)
Irritability †	7/40 (17.50%)	3/40 (7.50%)	2/10 (20.00%)
Restlessness/Agitation, including fidgety †	2/40 (5.00%)	3/40 (7.50%)	2/10 (20.00%)
Sadness †	0/40 (0.00%)	3/40 (7.50%)	0/10 (0.00%)
Self-Injurious Behavior †	1/40 (2.50%)	3/40 (7.50%)	0/10 (0.00%)
Stereotypy †	8/40 (20.00%)	3/40 (7.50%)	2/10 (20.00%)
Hypertalkativeness †	0/40 (0.00%)	0/40 (0.00%)	1/10 (10.00%)
Renal and urinary disorders
Enuresis †	2/40 (5.00%)	3/40 (7.50%)	0/10 (0.00%)
Respiratory, thoracic and mediastinal disorders
Cough †	4/40 (10.00%)	3/40 (7.50%)	2/10 (20.00%)
Skin and subcutaneous tissue disorders
Localized rash †	3/40 (7.50%)	3/40 (7.50%)	0/10 (0.00%)
Vascular disorders
Dizziness/faintness †	0/40 (0.00%)	4/40 (10.00%)	1/10 (10.00%)
Intermittent nosebleed †	0/40 (0.00%)	3/40 (7.50%)	0/10 (0.00%)
† Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

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.

Results Point of Contact

• Name/Title: Christopher J. McDougle, MD
• Organization: Indiana University
• Phone: 781-860-1783
• EMail: cmcdougle@partners.org

• Responsible Party: Indiana University
• ClinicalTrials.gov Identifier: NCT00198107
• Other Study ID Numbers: R01MH072961 ( U.S. NIH Grant/Contract ); R01MH072961 ( U.S. NIH Grant/Contract ); DSIR 82-SEDR
• First Submitted: September 12, 2005
• First Posted: September 20, 2005
• Results First Submitted: April 30, 2018
• Results First Posted: March 29, 2019
• Last Update Posted: April 9, 2019