Impact of Combined Medication and Behavioral Treatment for ASD & ADHD

• ClinicalTrials.gov Identifier: NCT03242772
• Recruitment Status: Terminated
• First Posted: August 8, 2017
• Results First Posted: March 9, 2022
• Last Update Posted: March 22, 2022
• Sponsor: Duke University
• Collaborator: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): Duke University

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Conditions: Autism Spectrum Disorder; Attention Deficit Hyperactivity Disorder
• Interventions: Drug: Amphetamine; Behavioral: ESDM informed parent coaching; Drug: Placebo Oral Tablet
• Enrollment: 18

Participant Flow

Recruitment Details	Recruitment occurred through our autism research registry, community events and Duke clinics
Pre-assignment Details	Confirmation of dual diagnosis was required prior to randomization

Arm/Group Title	ESDM Informed Parent Coaching + Amphetamine	ESDM Informed Parent Coaching + Placebo Oral Tablet
Arm/Group Description	Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine. Amphetamine: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time. ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).	Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug). ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts). Placebo Oral Tablet: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.
Period Title: Overall Study
Started	9	9
Completed	6	8
Not Completed	3	1
Reason Not Completed
Lost to Follow-up	2	0
Physician Decision	0	1
Withdrawal by Subject	1	0

Baseline Characteristics

Arm/Group Title		ESDM Informed Parent Coaching + Amphetamine	ESDM Informed Parent Coaching + Placebo Oral Tablet	Total
Arm/Group Description		Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine. Amphetamine: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time. ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).	Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug). ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts). Placebo Oral Tablet: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.	Total of all reporting groups
Overall Number of Baseline Participants		9	9	18
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Months
	Number Analyzed	9 participants	9 participants	18 participants
		86.83 (20.80)	103.00 (18.88)	94.92 (19.84)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	9 participants	9 participants	18 participants
	Female	1 11.1%	5 55.6%	6 33.3%
	Male	8 88.9%	4 44.4%	12 66.7%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	9 participants	9 participants	18 participants
	Hispanic or Latino	0 0.0%	2 22.2%	2 11.1%
	Not Hispanic or Latino	9 100.0%	7 77.8%	16 88.9%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	9 participants	9 participants	18 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	0 0.0%	0 0.0%	0 0.0%
	White	8 88.9%	5 55.6%	13 72.2%
	More than one race	1 11.1%	4 44.4%	5 27.8%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	9 participants	9 participants	18 participants
		9	9	18

Outcome Measures

1. Primary Outcome

Title	Change in Amount and Quality of Joint Engagement Between the Child and Parent During a Semi-structured 6 Minute Parent Child Interaction Task
Description	Child engagement states measured by the Joint Engagement Rating Inventory (JERI); our outcome contains four items (rated on a 7-point Likert scale) that characterize various aspects of engagement. Higher scores mean greater/higher quality engagement and lower scores represent less/poorer engagement. Total range of score is 4-28.
Time Frame	Baseline (Week -1), Endpoint (Week 10)

Outcome Measure Data

Analysis Population Description

This variable required behavioral coding of videotaped caregiver-child interactions collected at two time points. This coding were not conducted due to the fact that the study was terminated and time 2 data were not collected for participants due to safety concerns related to Covid-19.

Arm/Group Title	ESDM Informed Parent Coaching + Amphetamine	ESDM Informed Parent Coaching + Placebo Oral Tablet
Arm/Group Description:	Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine. Amphetamine: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time. ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).	Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug). ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts). Placebo Oral Tablet: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

2. Secondary Outcome

Title	Change in Mean Composite Score (Socialization and Communication Subscales Standard Scores) of the Vineland Adaptive Behavior Scale - 3rd Edition, Interview Version (VABS-3)
Description	Mean of standard scores for VABS-3 (socialization subscale and communication subscales) assess how the participant actually has been functioning over the preceding month with regard to communication and social behaviors. The VABS-3 comprehensive form will be administered as a semi-structured interview by a trained and research reliable staff member. The standard score is based on the participant's age and is normed from a large sample of typically developing children. The standard score has a mean of 100 and a standard deviation of 15. The composite score range is 20-140; higher scores represent more adaptive functioning and lower scores represent less adaptive functioning.
Time Frame	Baseline (Week -1), Endpoint (Week 10)

Outcome Measure Data

Analysis Population Description

Not all participants completed all surveys.

Arm/Group Title	ESDM Informed Parent Coaching + Amphetamine	ESDM Informed Parent Coaching + Placebo Oral Tablet
Arm/Group Description:	Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine. Amphetamine: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time. ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).	Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug). ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts). Placebo Oral Tablet: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.
Overall Number of Participants Analyzed	6	7
Mean (Standard Deviation); Unit of Measure: score on a scale
	5.92 (5.34)	1.86 (6.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ESDM Informed Parent Coaching + Amphetamine, ESDM Informed Parent Coaching + Placebo Oral Tablet
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2664
	Comments	Significance at <0.05
	Method	95% confidence interval
	Comments	confidence interval (CI) = -3.5729 - 11.6929
Other Statistical Analysis		Presentation of results will include p-values and 95% confidence intervals for the least mean square values at weeks 0, 10, 24 (week 24 is exploratory).

3. Secondary Outcome

Title	Change in ADHD Symptoms Using Preschool or School Age ADHD Rating Scale (ADHD-RS) Total Score
Description	ADHD Rating Scale (ADHD-RS) will assess symptom frequency using data from clinician completed ADHD-RS and parent completed ADHD-RS. The ADHD-RS includes 18 items, each rated on a 4 point scale (0-3);Total Score is the sum of all responses (0-54). An Inattention subscale and Hyperactivity/Impulsivity subscale (each range 0-27) are calculated based on individual items assessing those symptoms. Higher values represent worse outcomes for the subscales and the total scale. Clinically significant scores in boys are 14 for inattention and 17 for hyperactivity/impulsivity items; thresholds in girls are 12 and 14 respectively. If subscales are used, they would be summed to compute the total score. *Baseline measures occur on visits weeks -1 and week 0 in the study.
Time Frame	Baseline (Week 0), Week 10

Outcome Measure Data

Analysis Population Description

Not all participants completed all surveys.

Arm/Group Title	ESDM Informed Parent Coaching + Amphetamine	ESDM Informed Parent Coaching + Placebo Oral Tablet
Arm/Group Description:	Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine. Amphetamine: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time. ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).	Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug). ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts). Placebo Oral Tablet: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.
Overall Number of Participants Analyzed	4	8
Mean (Standard Deviation); Unit of Measure: score on a scale
	-10.00 (6.81)	-4.75 (10.02)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	ESDM Informed Parent Coaching + Amphetamine, ESDM Informed Parent Coaching + Placebo Oral Tablet
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3721
	Comments	Significance at <0.05
	Method	95% confidence interval
	Comments	confidence interval (CI) = -17.7698 - 7.2698
Other Statistical Analysis		Presentation of results will include p-values and 95% confidence intervals for the least mean square values at weeks 0, 10, 24 (week 24 is exploratory).

4. Secondary Outcome

Title	Changes in Objective Measures of Social Attention and Social Engagement Using Eye Gaze Tracking
Description	Eye Gaze Tracking (EGT) during presentation of social and nonsocial stimuli. Key measure used is Proportion Looking Time, which is a number between 0 and 1, with a higher number indicating improved attention.
Time Frame	Baseline (Week -1), Week 10

Outcome Measure Data

Analysis Population Description

This variable required processing of eye tracking data collected at two time points. We chose not to process the eye tracking data due to the fact that the study was terminated and time 2 data were not collected for participants because of safety concerns related to Covid-19.

Arm/Group Title	ESDM Informed Parent Coaching + Amphetamine	ESDM Informed Parent Coaching + Placebo Oral Tablet
Arm/Group Description:	Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine. Amphetamine: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time. ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).	Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug). ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts). Placebo Oral Tablet: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.
Overall Number of Participants Analyzed	0	0

No data displayed because Outcome Measure has zero total analyzed.

Adverse Events

Time Frame	First three participants had a time frame of 52-64 weeks, and the remaining 15 had a timeframe 24 weeks, per protocol.
Adverse Event Reporting Description	First three participants were systematic using the SLAES, next 15 subjects were spontaneous (non-systematic).
Arm/Group Title	ESDM Informed Parent Coaching + Amphetamine	ESDM Informed Parent Coaching + Placebo Oral Tablet
Arm/Group Description	Amphetamine regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The drug is an orally dissolvable, extended-release form of d- and l-amphetamine. Amphetamine: Study drug will be administered in the morning. Treatment will be initiated at 1 tablet = 3.1 mg or 0 mg of mixed amphetamine. Doses will be flexibly titrated upward and may be decreased or stopped at any time. ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts).	Placebo regimen (11 weeks total duration) will begin 2 weeks prior to initiation of ESDM informed parent coaching (8 weekly sessions) and continue through the week 11 endpoint assessment. The placebo contains no active drug and appears identical to the amphetamine (active drug). ESDM informed parent coaching: All participants will receive 8 weekly parent child therapy sessions will be delivered by a therapist trained in parent coaching and ESDM principles and strategies and utilizing a therapy manual,(includes coaching for behavior management and handouts). Placebo Oral Tablet: Matched placebo tablets will be administered in the morning and provided for 11 weeks . The tablets will be titrated in the same way as the active drug and may be stopped at any time.
All-Cause Mortality
	ESDM Informed Parent Coaching + Amphetamine	ESDM Informed Parent Coaching + Placebo Oral Tablet
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/9 (0.00%)	0/9 (0.00%)
Serious Adverse Events
	ESDM Informed Parent Coaching + Amphetamine	ESDM Informed Parent Coaching + Placebo Oral Tablet
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/9 (0.00%)	0/9 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	ESDM Informed Parent Coaching + Amphetamine	ESDM Informed Parent Coaching + Placebo Oral Tablet
	Affected / at Risk (%)	Affected / at Risk (%)
Total	9/9 (100.00%)	8/9 (88.89%)
Ear and labyrinth disorders
Motion Sickness * 1	0/9 (0.00%)	1/9 (11.11%)
Gastrointestinal disorders
Constipation, increased * 1	1/9 (11.11%)	1/9 (11.11%)
General disorders
Decreased Appetite * 1	2/9 (22.22%)	1/9 (11.11%)
Immune system disorders
Environmental Allergies, worsened * 1	3/9 (33.33%)	0/9 (0.00%)
Infections and infestations
Viral Infections * 1	4/9 (44.44%)	7/9 (77.78%)
Injury, poisoning and procedural complications
Accidental Injury * 1	1/9 (11.11%)	0/9 (0.00%)
Musculoskeletal and connective tissue disorders
Inflamed Toe * 1	1/9 (11.11%)	0/9 (0.00%)
Myalgia * 1	1/9 (11.11%)	0/9 (0.00%)
Nervous system disorders
Headache * 1	1/9 (11.11%)	0/9 (0.00%)
Subjective Temperature Dysregulation * 1	1/9 (11.11%)	0/9 (0.00%)
Psychiatric disorders
Mood Dysregulation * 1 [1]	5/9 (55.56%)	4/9 (44.44%)
Insomnia * 1	5/9 (55.56%)	1/9 (11.11%)
Aggression * 1	2/9 (22.22%)	1/9 (11.11%)
Compulsions * 1	2/9 (22.22%)	0/9 (0.00%)
Hyperfocused * 1	1/9 (11.11%)	0/9 (0.00%)
Stereotypies, worsened * 1	1/9 (11.11%)	0/9 (0.00%)
Hyperactivity, worsened * 1	1/9 (11.11%)	0/9 (0.00%)
Flat affect, worsened * 1	1/9 (11.11%)	0/9 (0.00%)
Oppositionality, worsened * 1	1/9 (11.11%)	0/9 (0.00%)
Respiratory, thoracic and mediastinal disorders
Epistaxis * 1	0/9 (0.00%)	1/9 (11.11%)
Skin and subcutaneous tissue disorders
Pruitis * 1	1/9 (11.11%)	0/9 (0.00%)
1 Term from vocabulary, MedDRA 19.0; * Indicates events were collected by non-systematic assessment; [1] Mood Dysregulation includes verbatim reports of mood changes, poor coping, and low frustration tolerance.

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: Dr. Geraldine Dawson, PhD, PI of Duke Autism Center of Excellence
• Organization: Duke Center for Autism and Brain Development
• Phone: 919-668-0070
• EMail: geraldine.dawson@duke.edu

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT03242772
• Other Study ID Numbers: Pro00085179; 1P50HD093074-01 ( U.S. NIH Grant/Contract )
• First Submitted: August 4, 2017
• First Posted: August 8, 2017
• Results First Submitted: December 20, 2021
• Results First Posted: March 9, 2022
• Last Update Posted: March 22, 2022