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

Tracking Information

• First Submitted Date: August 4, 2017
• First Posted Date: August 8, 2017
• Results First Submitted Date: December 20, 2021
• Results First Posted Date: March 9, 2022
• Last Update Posted Date: March 22, 2022
• Actual Study Start Date: December 14, 2018
• Actual Primary Completion Date: December 28, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 20, 2021)

Change in Amount and Quality of Joint Engagement Between the Child and Parent During a Semi-structured 6 Minute Parent Child Interaction Task [ Time Frame: Baseline (Week -1), Endpoint (Week 10) ]

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.

Original Primary Outcome Measures (submitted: August 7, 2017)

Change in frequency of joint attention initiations [ Time Frame: Weeks 0, 6, 12, 18, 24, and 30 ]

Primary outcome will be measured using the Joint Attention Measure (JAMES) from the EScs (Early Social Communication Scales), a semi-structured, play-based assessment measures social communication behaviors that distinguish ASD from other developmental disorders. It yields measures of several specific behaviors noted to be impaired frequently in ASD, including frequency of joint attention initiations.

Current Secondary Outcome Measures (submitted: December 20, 2021)

• Change in Mean Composite Score (Socialization and Communication Subscales Standard Scores) of the Vineland Adaptive Behavior Scale - 3rd Edition, Interview Version (VABS-3) [ Time Frame: Baseline (Week -1), Endpoint (Week 10) ]
  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.
• Change in ADHD Symptoms Using Preschool or School Age ADHD Rating Scale (ADHD-RS) Total Score [ Time Frame: Baseline (Week 0), Week 10 ]
  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.
• Changes in Objective Measures of Social Attention and Social Engagement Using Eye Gaze Tracking [ Time Frame: Baseline (Week -1), Week 10 ]
  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.

Original Secondary Outcome Measures (submitted: August 7, 2017)

• Change in social communication functioning [ Time Frame: Weeks 0, 6, 18, 30 (week 0 = baseline) ]
  Measured using Vineland Scales of Adaptive Behavior (VABS) socialization and communication subscale standard scores.
• Change in ADHD symptoms [ Time Frame: Weeks 0, 6, 12,18, 24, 30 (week 0 = baseline) ]
  Symptoms assessed using clinician-completed ADHD Rating Scale (ADHD-RS).

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Impact of Combined Medication and Behavioral Treatment for ASD & ADHD
• Official Title: Impact of Combined Medication and Behavioral Treatment in Young Children With Comorbid ASD and ADHD
• Brief Summary: Children with comorbid autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) have significantly worse outcomes than those with either ASD alone or ADHD alone. Effective early treatments that account for ADHD symptoms have not been developed for young children with ASD+ADHD. The overarching goals of this randomized, placebo-controlled, phase 2, pilot study are to (1) evaluate a novel early intervention that pharmacologically addresses ADHD symptoms while providing an ASD-targeted behavioral intervention, and (2) identify changes in behavioral and neurophysiological activity that may underlie improved outcomes in children with comorbid ASD and ADHD ages 3-10 years. The primary aim of this study is to evaluate whether a stimulant treatment augments efficacy of an ASD specific form of parent child therapy based on the Early Start Denver Model called ESDM influenced Parent Coaching. Secondary aims are to determine the efficacy of combined intervention in improving ADHD symptoms and the efficacy, safety, and tolerability of Adzenys-XR-ODT in young children with ASD+ADHD. The study will also examine correlations between behavioral changes and state-of-the-art eye-gaze tracking (EGT) and electroencephalographic (EEG) biomarkers to elucidate key ways in which ADHD impacts attentional and neural functioning in ASD+ADHD, and to potentially identify new targets for intervention in children with ASD+ADHD. The study is about 8 months long and will involve screening, baseline assessment followed by 10- 11 weeks of study drug treatment (active or placebo) and 8 sessions of ESDM informed parent coaching beginning after 2 weeks of study drug treatment, primary endpoint assessments at ~11 weeks, AE follow-up by phone at ~week 13 and remote FU 24 weeks after baseline. Eligible participants will be randomly assigned to the active medication or placebo, Between weeks 11 to 24, it is expected that the parent will use the behavioral strategies they were coached in even though they will not receive parent coaching. Participants will be given the option to pursue ADHD medication outside of the research study after week 11 assessments.

Detailed Description

This randomized, placebo-controlled, Phase 2, single site, pilot study will evaluate the developmental impact of combined medication and behavioral treatment (COMB) versus placebo and behavioral treatment (BEH) in children with comorbid ASD +ADHD, who are between 36 and < 132 months of age. The active medication treatment will be an orally dissolvable, extended release amphetamine preparation (Adzenys-XR-ODT) administered from weeks 0-~11 and carefully titrated to the optimal dose using an algorithm that considers adverse events and improvement in attention symptoms with a flexible dose range of 1.55mg - 18.6mg/day. The target dose is 12.4mg/day. A placebo, matched to the active medication, will be titrated and adjusted using the same algorithm in the BEH arm. The provided behavioral treatment will be eight ~ hour long parent child therapy sessions of ESDM influenced parent coaching.

Approximately 48 participants will be randomly assigned to either the COMB or BEH treatment arms. To account for possible differences in attrition due to potential poor tolerability of Adzenys-XR-ODT, participants will be randomized in a 7 COMB to 6 BEH ratio. Treatment assignment will be provided by the Data Management and Analysis Core (DMAC)using computer generated algorithms.

The primary analyses will compare changes in outcomes between weeks 0 and 11 weeks. Exploratory analyses will explore changes between weeks 0 and 24.

The primary outcome measure is change in amount and quality of joint engagement between the child and the parent during a semi-structured, 6 minute parent child interaction task (PCIT), which reflects the core symptom domain targeted by P-ESDM: social communication.

Our key secondary outcomes will be changes in 1) the mean of the interview version of the VABS-3 socialization subscale and communication subscale standard scores and 2) clinician ratings of ADHD symptoms using the preschool ADHD-RS.

We will also assess the safety and tolerability of Adzenys-XR-ODT compared to placebo.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Autism Spectrum Disorder
• Attention Deficit Hyperactivity Disorder

Intervention

• Drug: 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.
  Other Name: Adzenys XR-ODT
• Behavioral: 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).
• Drug: 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.

Study Arms

• Active Comparator: ESDM informed parent coaching + Amphetamine
  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.
  Interventions:

  • Drug: Amphetamine
  • Behavioral: ESDM informed parent coaching
• Placebo Comparator: ESDM informed parent coaching + Placebo Oral Tablet
  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).
  Interventions:

  • Behavioral: ESDM informed parent coaching
  • Drug: Placebo Oral Tablet

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: August 17, 2021): 18
• Original Estimated Enrollment (submitted: August 7, 2017): 78
• Actual Study Completion Date: April 19, 2021
• Actual Primary Completion Date: December 28, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Provision of a parent signed and dated informed consent form.
2. Stated willingness to comply with all study procedures and availability for the duration of the study.
3. Aged 36 months to less than 132 months.
4. Diagnosed with both ASD and ADHD based consensus diagnosis informed by results of the Autism Diagnostic Observation Schedule 2nd edition (ADOS-2), Autism Diagnostic Interview - Revised (ADI-R), and a Standardized ADHD Diagnostic Interview and the MINI psychiatric diagnostic interview.
5. In good general health as evidenced by medical history and physical exam and review of safety labs and electrocardiogram.

Exclusion Criteria:

1. Recent use of prohibited psychoactive medication in close proximity of baseline assessments. See MOP for specific medications that are prohibited and washout procedures. Use of a monoamine oxidase inhibitor is prohibited within 14 days of baseline.
2. Known allergic reactions to amphetamines or components of Adzenys-XR-ODT.
3. Known history of sudden non-ischemic cardiac death in a first or second degree family member (sibling, parent, aunt, uncle, cousin or grandparent).
4. Personal history of significant cardiac abnormalities or disease, particularly rhythm abnormalities.
5. Significant visual, auditory or motor impairments that would preclude participation in ESDM-informed parent coaching or completion of key assessments.
6. Inability of the caregiver participating in P-ESDM and responding to questionnaires to fluently speak English.
7. Parent's participation in another parent coaching intervention on more than a monthly basis that may affect study provided therapy as determined by the PI or clinician.
8. Presence of any psychiatric conditions or psychiatric symptoms in addition to ASD and ADHD that would confound assessments and/or affect participation in the study as deemed by the PI or clinician.
9. Known genetic (e.g. Fragile X) or neurological syndrome or condition with established link to autism, but not events in which the link to ASD is less well known/established (e.g., 16p11.2 CNVs, CHD8 mutations, Trisomy 21, 22q deletion syndrome)
10. History of epilepsy or seizure disorder (except for history of simple febrile seizures or if the child is seizure free (regardless of seizure type) for the past year).
11. History of neonatal brain damage. (eg., with diagnoses hypoxic or ischemic event)
12. Any known environmental circumstances that is likely to account for the picture of autism in the proband (severe nutritional or psychological deprivation etc.)
13. Study clinician judgment that it is not in the best interests of the participant and/or the study for the child to participate.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 36 Months to 131 Months (Child)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03242772
• Other Study ID Numbers: Pro00085179; 1P50HD093074-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Through NDAR, core assessment and diagnostic data that is de-identified, including measures such as ADOS and Vineland.
• Supporting Materials: Study Protocol
• Time Frame: 1 year after publication of the results for each of the specific aims or 3 years after the statistical analyses are completed
• Access Criteria: determined by committee of researchers/administrator at NDAR
• URL: https://nda.nih.gov

• Current Responsible Party: Duke University
• Original Responsible Party: Same as current
• Current Study Sponsor: Duke University
• Original Study Sponsor: Same as current
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Geraldine Dawson, PhD; Duke
• Principal Investigator: Linmarie Sikich, MD; Duke
• Principal Investigator: Scott Kollins, PhD; Duke

• PRS Account: Duke University
• Verification Date: March 2022